HEALTH AND "ENVIRONMENTAL
EFFECT PROF.ILES
. , '".'•S'*- :•£. APRIL 30, 1980 .
' ^ll.'sl. ENVIRONMENTAL PROTECTION AGENCY
"•iVv-:,... . V QFFICE OF SOLID WASTE
'• ••'•:- • '.;
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No. LSI
Quinones
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D=C, 20460
APRIL 30, 1980
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DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because .of. the limitations, of such sources, this short profile
may not reflect ail available information including all the
adverse health and .environmental impacts presented by the
subject chemical. This document has undergone, scrutiny to
ensure its technical.accuracy.
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QUINONE
Summa ry
Quinoae has been reported Co produce neoplasms, but insufficient
data are available to assess its carcenogenic potential. Quinone
was not tnutagenic to Orosophi la melanog'a's t er, huma-n' leukocytes ,
nor Neurospora. .'"'.'
Quinone is very toxic to fish and plants. Exposure to humans
causes conjunctival irritation and, in~sbine cases, corneal edema,
ulceration, and scarring; transient "eye Irritation' was noted
above 0.1 ppm. Quinone is highly toxic to mammals via the oral
and inhalation route.
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I. INTRODUCTION
Quinone (p-Benzoquinone; Gas No. 106-51-4) is a yellow,
crystalline solid with chlorine-like irritating odor. It has the
following physical properties:
Formula: 0511402
Physical State: large, yellow, monoclinic
prisms
Molecular Weight: 108.09
Specific Gravity: 1.318 (20°C)
Melting Point: 112.9°C
Boiling Point: sublimes
Vapor Pressure: considerable; sublimes readily
upon gentle heating (Patty,1967)
Quinone is soluble in alcohol, ether, and alkali; and slightly
soluble in/hot water. Quinone can be prepared by oxidation starting
with aniline or by the reduction of -hydro.quinone with bromic acid.
The compound has found wide application in the dye, textile, chemical,
tanning, photography, and cosmetic industries primarily because of
its ability to transform certin nitrogen-containing compounds into
a variety of colored substances (Patty, 1967).
II. EXPOSURE
A. Water
Pertinent data could not be located in the availabe
literature.
B. Food
Pertinent data could not be located in the available
»
1 i c e ra t ure.
-/fey-
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C . Inhala tion
Because of its ability to sublime, quinone becomes an air
contaminant problem at the production site.
D. Dermal
Pertinent data could not be located in the available literature.
III. PHARMACOKINETICS
A. Absorption
Quinone is readily absorbed from the gastroenteric tract
and subcutaneous tissues (Patty, 1967). Sax, 1979, reports quinine
as capable of causing death or permanent injury due to the exposures
of normal use via absorption through oral and inhalation routes.
Quinone affects the eyes (Procter, 1978).
B. Distribution
Pertinent data could not be located in the available literature.
C. Mebalolism and Excretion
Quinone is partially excreted unchanged; but the bulk is
eliminated in conjugation with hexuronic, sulfuric, and other acids
(Patty, 1967).
IV. EFFECTS
A. Careinogenicity
Quinone has been reported to produce neoplasms but upon
review by the International Agency for Research on Cancer, it was
determined that there was insufficient data to conclude that it was
a carcinogen (IARC, 1977)
B. Mutagenic i t y
9
Quinone did not produce mutagenic effects in studies with
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Orosophila melanogas cer and human leukocytes (Lueers and Obe, 1972).
Another study reported quinone as nonmutagenic to Neuro-spora
(Reissig, 1963).
C. Teratbgenicity
Pertinent data could not be located in the available
literature.
D. Other Reproductive Effects
Pertinent data could not be located in the available literature.
E. Chronic Toxicity
Quinone has been reported1 to oxidize with the lens protein
SH groups in rabbits (Ikemota and Augusteyn, 1976). Chronic exposure
causes the gradual development of changes characterized as follows:
brownish discoloration of the conjunctiva and cornea confined to
the intrapalpebral fissure;.small opacities of the cornea; and
structural corneal changes which result in loss of visual acuity
(Sterner, et al., 1947; Anderson and Oglesby, 1958).
F. Other Relevant Information
Acute exposure causes conjunctival irritation and, in
some cases, corneal edema, ulceration, and scarring; transient eye
irritation may be noted above 0.1 ppm and becomes marked at 1 to 2
ppm (AIHA, 1963). Ulceration of the cornea has resulted from one
brief exposure to a high concentration of the vapor of quinone, as
well as from repeated exposures to moderately high concentrations
(Patty, 1967). Absorption of large doses of quinone from the gas
troenteric tract or from subcutaneous tissues of animals induces
chronic convulsions, respiratory difficulties, drop in blood pres-
sure, and death by paralysis of the medullary centers (Patty, 1967).
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Oral rat LDSOs have been reported for quinone ranging from
130 to 296 tug per kg body weight (Ver schueren, 1977). Inhalation
of quinone at concentrations ranging from 230 to 270 ng per cu.m.
for 2 hrs was lethal to 100 percent of the test population of
rat s .
IV. AQUATIC TOXICITY
A. Acute Toxicity
Quinone has been reported to be toxic to invertebrate
Daphnia at 0.4 ppm (Verschueren, 1977). Also, quinone has an LD50
for perch ranging from 5 to 10 mg/1 (Verschueren, 1977).
B. Chronic Toxicity, Plant Effects, and Residues
Quinone inhibits photosynthesis in the fresh water algae
S. capricornutum (Gidding, 1979), decreases chlorophyll flourescence
and cyclosis (protoplasmic streaming) of Nitella cells (Apartsin,
et al, 1979; Stom, 1977; Stom and Kuzevania, 1976; Stora and Rogozina,
1976), and inhibits carbon metabolism in Ghlorella pyrenoidosa
(Printavu, 1975).
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The 8-hour, time-weighted average occupational exposure
limit for quinone has been set in the United States at a concentration
of 0.1 ppm and in the U..S.S.R. at a concentration of 0.01 ppm
(Verschueren, 1977).
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REFERENCES
Procter , N.H. , and Jamas Hughes. Chemical Hazards of the Workplace.
J.B. LippincotC Company. Philadelphia. 1978.
Reissig, J.L. 1963. Induction of Foward Mutants in the Pyr-3
Region of Neorospora. J. Gen. Microbial. 30:317-325.
Sterner, J.H., et al. 1947. Quinone Vapors and Their Harmful
Effects to Corneal and Conjunctival Injury. J. Ind. Hyg.
Toxicol. 29:60.
Stom, D.I. 1977. Influence of Polyphenols and Quinones on Aquatic
Plants and Their Blocking of Sulfhydryl Groups. Acta Hydrochim.
Hydrobiol. Vol.5, ISS. 3, 291-8.
Stom, D.I, and E.N. Kuzevanova. 1976. The Distribution of
Sulfhydryl Groups in Nitella Cells and the Effects on Them
of Polyphenols and: p-Benzoquinone. Tsitologiya. Vol. 18,
ISS. 2, 230-2.
Stom, D.I., and N.A. Rogozina. 1976. Possible Mechanism of
Action of Quinone Pesticides on the Photoplasmic Streaming in
Marine Plants. Eksp. Vodn. Toksikol. . Vol. 6, 111-118.
Verschueran, K. 1977. Handbook of Environmental Data on Organic
Chemicals. Van Nostrand Reinhold Co. New York.
AIHA. 1963 Hygenic Guide -Series: Quinone. Am. Ind. Hyg. Assoc. J.
24:194. 1963.
Anderson, B., and F. Oglesby. 1958. Corneal Changes from Quinone-
Hydroquinone Exposure. A.M.A. Arch. Opthalmol. 59:495.
Apartsin, M.S., et al. 1979. Mechamism of the Effect of
Pyrocatechol and p-Benzoquinone on Nitella cells. Dokl. Akad. Nauk.
S.S.S.R. Vol. 244, ISS. 2, 510-12.
Giddings, J. M. 1979. Acute Toxicity to Selenastrum capricornutum
of Aromatic Compounds from Coal Conversion. Bull. Environ. Contam.
Toxicol. Vol. 23, ISS. 3, 360-4.
IARC. 1977. Monographs, on the Evaluation of Carcinogenic Risk of
Chemicals to Man, Vol. 15. World Health Organization.
Ikemoto, F., and R.C. Augusteyn. 1976. The Reaction of Lens
Proteins and Amino Acids with 1,4-Benzoquinone. Jpn. J. Ophthalmol,
(Japan). Vol. 20, ISS. 4, 457-65.
Lueers, H., and G. Obe. 1972. On the Possible Mutagenic Activity
of p-Benzoquinone. Mutut. Res. 15:77-80.
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Patty, F.A. 1967. Industrial Hygiene and Toxicology. Inter-
science Publishers. New York.
Pristavu, N. 1975. Action of p-Benoquinone on the Radioactive
Carbon Metabolism in Chlorella pyrenoidosa. Proc. Int. Congr
Photosynth., 3rd. Vol. 2. 1541-6.
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No. 152
Resorcinol
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
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DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
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RESORCINOL
Summary
Resorcinol, 1,3-dihydroxybenzene, is a phenolic compound. Resorcinol
is weakly antiseptic and resorcinol compounds are used in Pharmaceuticals
and hair dyes for human use. Major industrial uses are as adhesives in rub-
ber products and tires, wood adhesive resins, and as ultraviolet absorbers
in polyolefin plastics. Resorcinol is also a byproduct of coal conversion
and is a component of cigarette smoke. Thus, substantial opportunity exists
for human exposure.
Many phenolic compounds, including resorcinol, are strong mitotic spin-
dle poisons in plants. This evidence of mutagenic activity and the strong
oncogenic activity in. plants have not been adequately tested in animals to
provide an understanding of the processes. In animals the only cocarcino-
genic activity (in cigarette smoke condensate) demonstrated has been- as a
protective agent against benzo(a)pyrene carcinogenicity.
Resorcinol has been demonstrated to result in chronic toxicity: reduc-
ing growth rate in an insect species and causing chronic health complaints
from workers in a tire manufacturing plant.
Acute toxicity through oral, eye, skin penetration, and skin irritation
has been demonstrated by all tests. Values vary in the literature and are
inadequate to draw a quantitative conclusion. Resorcinol has also been
shown to be acutely toxic to both freshwater and marine aquatic organisms in
96-hour LC5Q tests.
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No standards or guidelines exist for resorcinoi. ACGIH's Committee on
Threshold Limits has proposed a TLV of 5 ppm but has not finalized that
recommendation. Industry has suggested this value is lower than is required
for safety, citing existing workplace levels of 9.6 ppm without worker com-
plaint or evidence of acute or chronic toxicity.
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I. INTRODUCTION
Resorcinol is a phenolic compound (molecular weight, 110.1; boiling
point, 276°C; melting point, 110.0°C). Synonyms are m-dihydroxybenzene,
1,3-benzenediol, 3-hydroxyphenol, and resorcin. Resorcinol occurs as white
or nearly white needle-shaped crystals or powder. It has a faint, charac-
teristic odor and a sweetish taste with a bitter aftertaste. One gram is
soluble in 1 ml of water and in 0.1 ml of alcohol.
Resorcinol is a weak antiseptic and is used in antiseptics, keratolytic
disease treatments and fungicides (Wilson, et al. 1977). Major uses of re-
sorcinol are: in tires and other rubber products; wood adhesive resins; as
an ultraviolet absorber in polyolefin plastics; as an intermediate in dye
manufacture (especially hair dyes); and in the production of synthetic tan-
ning agents, explosives, and specialty adhesives. The tire and rubber in-
dustries accounted for 43 percent of the use of resorcinol in 1974, primar-
ily as aahesives in fabricating belting, rubberized hose,- and rubberized
textile sheets (Stanford Research Institute, 1975).
Resorcinol is expected to be a component of various waste streams from
coal conversion facilities. The potential for removal through existing
waste treatment processes is currently under assessment (Herbes and Beau-
champ, 1977). .
II. EXPOSURE
Resorcinoi is used in substantial quantities in industry and frequently
in small quantities in the home. Although the potential for human exposure
exists, very little exposure information is available. The Koppers Company,
Inc., Monroeville, Pennsylvania, is the major supplier of resorcinol in the
United States. They report substantial testing of the plant environmen't in-
dicating resorcinol concentration up to 9.6 ppm in ambient air (Flickinger,
1976).
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Resorcinol is currently sold and transported as a solid, although the
Koppers Company reports increasing inquiries regarding bulk shipments of
molten resorcinol. They indicate that this would increase the opportunity
for industrial and public exposure to the compound (Flickinger, 1976).
In an epidemiological study of rubber workers at a hexamethylenetetra-
mine-resorcinol (HR) resin system tire manufacturing plant, all environment-
al samples in the study were less than 1 mg/nv5 (Gamble, et al. 1976).
Resorcinol has been shown to be present in cigarette smoke and is a
component of the weakly acidic fraction of cigarette smoke condensate which
has been shown to have tumor-promoting capability (Schlotzhauer, et al.
1978).
III. PHARMACOKINETICS
^ Despite the presence of.resorcinol and resorcinol compounds in numerous
pharmaceutical preparations, no specific information on the metabolism, dis-
tribution, absorption, or excretion of resorcinol was found in the available
literature.
IV. EFFECTS
A. Carcinogenicity
The available data dealing with the potential Carcinogenicity of
resorcinol are at this time inadequate to formulate a clear understanding of
resorcinol's oncogenic potential. In a study of commonly used cutaneous
agents, Stenback (1977) showed no tumor induction in rabbits and mice from
topically applied resorcinol. Resorcinol was selected because of its pre-
sence in hair dyes.
Van Ouuren and Goldschmidt (1976), in a study of 21 tobacco smoke
components, found that resorcinol reduced the carcinogenic potential or ben-
zo(a)pyrene (3aP) in dermal application to mice. Thus, fewer tumors were
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induced by BaP in the presence of resorcinol, indicating possible inhibition
of carcinogenic activity.
Substantial evidence appears to exist for the oncogenic activity
of resorcinol in plants. Anderson (1973) reports that the "strong carcino-
geriicity" of resorcinol tested in Nicotiana hybrids suggests that "an onco-
genic reactivity of phenols is common to plant and animal tissues but with
differences in strength of reaction to a derivative in a given system".
9. Mutagenicity
Dean (1978) reports that most phenolic compounds including resor-
cinol are mitotic spindle poisons in plant tissues. He further reports that
considering the severity of effects on plant chromosomes that it is surpris-
ing that in_ vivo plant and animal tests have not been done to determine
their clastogenic properties.
By micronucleus test, Hossack and Richardson (1977) were unable to
find evidence of mutagenicity in resorcinol or a number of other hair dye
constituents tested.
The Ames assay for resorcinol was negative in a test of commonly
used cutaneous agents (Stenback, 1977). ~\'
C. Teratogenicity and Other Reproductive Effects
Pertinent data could not be located in the available literature.
0. Chronic Toxicity
In a study of chronic.toxicity effects on the black cutworm, Agro-
tis epsilon, Reese and Beck (1976) found no significant correlation between
resorcinol concentration and pupation or survival but found correlation with
body weight at various stages of development. They report that resorcinol
is the only compound among those tested which had "no 'adverse effect oh any
of the nutritional indices and yet reduced growth. It is also the only com-
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pound which inhibited growth but did not inhibit pupation." They hypothe-
sized that resorcinol may act through a temporary inhibition of ingestion
but that the insects continued to eat regularly, allowing pupation on a nor-
mal schedule (Reese and Beck, 1976).
In the epidemiological study of the HR resin system tire manufac-
turing plant, Gamble, et al. (1976) reported that HR exposed workers consis-
tently showed an excess of respiratory symptoms and that there was a consis-
tent association of alcohol consumption with increased incidence of symp-
toms. The reported symptoms included rash, itch, difficult breathing at
work, cough, chest tightness, burning eyes, running nose, and burning sensa-
tion in the heart region.
E. Acute Toxicity
With one exception, all acute toxicity data in the readily avail-
able literature are supplied by Flickinger (1976) for the Koppers Company,
the primary manufacturer and supplier of resorcinol in the United States.
Lloyd, et al. (1977) independently reported the LD5Q for acute oral toxi-
city to be 370 mg/kg for resorcinol.
In a review of the industrial toxicology of the benzenediols,
Flickinger (1976) reports various acute toxicity data for resorcinol. A
summary of relevant results follows:
An acute oral LD5Q for resorcinol was reported by Flickinger
(1976) as 0.98 gm/kg in the rat. Rats dying during the period showed hyper-
emia and distension of the stomach and intestines. Surviving rats showed
normal weight and no gross lesions at necropsy.
The LD5Q for dermal application in the rat was 3.36 gm/kg. At
higher levels, resorcinol produced skin necrosis. At 1.0 gm/kg levels,
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moderate to severe irritation was followed in 24 hours by slight hyperkera-
tosis. Surviving rats showed reduced weight but no internal gross lesions
upon necropsy.
Flickinger (1976) reported that resorcinol is a severe eye irri-
tant (0.1 gm in eye of male, albino rabbits). No recovery was seen in the
14-day follow-up period with all exposed individuals exhibiting keratoconus
and pannus formation. .
Resorcinol is a primary skin irritant. Contact with 0.5 gm of re-
sorcinol on intact and abraided skin produced moderate irritation on intact
skin and varying reactions including necrosis on abraided skin.
Inhalation of up to 2,800 mg/nv5 of resorcinol aerosol for . 8
hours resulted in no observable toxic effects to the rats (Flickinger, 1976).
V. AQUATIC TOXICITY
The possibility that resorcinol may be present in some quantity in coal
conversion process effluents requires'further investigation as to the feasi-
bility of control .technology. Heroes and Beauchamp (1977) compared toxic
interactions of two coal conversion effluents, resorcinol and 6-methylquina-
line. With Daphnia maqna as a test species, they found mixtures of the two
compounds to be less toxic than either pure compound tested alone. They re-
port a 48-hour LC5Q for resorcinol alone to be 1.28 mg/1.
Curtis, et al. (1979) reported the acute toxicity of resorcinol to
freshwater and saltwater organisms. In freshwater, the LC5Q values for
fathead minnow are as follows: 24 hours, 88.6 mg/1; 48 hours, 72.6 mg/1;
and 96 hours, 53.4 mg/1. In saltwater, the LC5Q values for Palaemonetes
gugio or Penaeus setiferus are: 24 hours, 169.5 mg/1; 48 hours, 78.0 mg/1;
and 96 hours, 42.4 mg/1. Thus, resorcinol was found to be toxic to aquatic
life in both freshwater and saltwater.
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VI. EXISTING GUIDELINES AND STANDARDS
There are no OSHA regulations, NIOSH recommendations, or other guide-
lines concerning resorcinol. In 1974, ACGIH's Committee on Threshold Limits
proposed a TLV for resorcinol of 5 ppm. Flickinger (1976) reports of cur-
rent industrial 8-hour workday exposures at 9.6 ppm "without signs of intox-
ication or skin or respiratory irritation" and recommends TLV industrial ex-
posures of "at least 10 ppm, perhaps even 20 ppm or higher". ACGIH has not
issued a formal TLV for resorcinol.
Information regarding existing guidelines and standards to protect
aquatic life from the effects of resorcinol was not found in the available
literature.
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REFERENCES
Anderson, R.A. 1973. Carcinogenicity of phenols, alkylating agents, ure-
than, and a cigarette-smoke fraction in Nicotiana seedlings. Career Re-
search 33: 2450.
Curtis, M.W., et al. 1979. Acute toxicity of 12 industrial chemicals to
freshwater and saltwater organisms. Water Research 13: 137.
Dean, B.J. 1978. Genetic toxicology of benzene, toluene, hylenes, and phe-
nols. Mutation Research 47: 75.
Flickinger, C.W.. 1976. The benzenediols: catechol, resorcinol and hydro-
quinone — a review of the industrial toxicology and current industrial ex-
posure limits. Am. Ind. Hyg. Assoc. Jour. 37: 596.
Gamble, J.F., et al. 1976. Respiratory function and symptoms: an environ-
mental - epidemiological study of rubber workers exposed to a phenol-formal-
dehyde type resin. Am. Ind. Hyg. Assoc. Jour. (September 1976): 499.
Herbes, S.E. and J.J. Beauchamp. 1977. Toxic interactions of mixtures of
two coal conversion effluent components (resorcinol and 6-methylquinoline)
to Daphnia magna. Bull. Env. Contam. Toxicol. 17: 25.
Hossack, D.J.N. and J.C. Richardson. 1977. Examination of the potential
mutagenicity of hair dye constituents using the micronucleus test. Exper-
mentia 33: 377.
Lloyd, G.K., et al. 1977.. Assessment of the acute toxicity of potential
irritancy of hair dye constituents. Food Cosmet. Toxicol. 15: 607.
Reese, J.C. and S.Q. Beck. 1976. Effects of allelochemics on the black
cutworm, Agrostis ipsilon: effects of resorcinol, phloroglucinoal, and Gal-
lic acid on larval growth, development, and utilization of food. Ann. Ento-
mol. Soc. Am. 69: 999.
Schlotzhauer, W.S., et al. 1978. Characterization of catechols, resorci-
nols, and hydroquinones in an acidic' fraction of cigarette smoke condensate.
Jour. Agric. Food Chem. 26: 1277.
Stanford Research Institute. 1975. Chemical Economics Handbook. Stanford
Research Institute, Menlo Park, California.
Stenback, F. 1977. Local and systemic effects of commonly used cutaneous
agents: lifetime studies of 16 compounds in mice and rabbits. Acta. Pharma-
col. et Toxicol. 41: 417.
van Ouuren, B.L. and B.M. Goldschmidt. 1976. Cocarcinogenic and tumor-pro-
moting aoents in tobacco carcinogenesis. Jour. Natl. Cancer Institute
56: 1237."
Wilson, C.O., et al. (eds.) 1977.' Textbook of Organic and Pharmaceutical
Chemistry. J.B. Lippincott Co., Philadelphia, Pennsylvania, pp. 72, 181,
194.
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No. 153
Selenium
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
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DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical acc-uracy.
-------
SELENIUM
SUMMARY
Human daily intake of selenium has been estimated at 50
to 150 jag/day. While selenium is an essential nutrient for humans
and other species, it is toxic in excessive amounts. Selenium
poisoning produces symptoms in man similar to those produced
by arsenic. Although it has been shown to produce tumors in
animals, the Food and Drug Administration, the International
Agency for Research on Cancer and the National Academy of Science
have concluded that the available animal data are insufficient
to allow an evaluation of the carcinogenicity ca . ,jlenium compounds.
The data base for selenium for aquatic life is quite limited.
No chronic data are available for marine fish. Selenium does
not oioconcentrate to a great extent in freshwater species, indi-
x
eating that tissue residues should not be a i.jzara to freshwater
organisms. This information is not available for-marine organisms.
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SELENIUM •
I. INTRODUCTION
This profile is-based on the Ambient Water Quality Criteria
Document for Selenium (U.S. EPA, 1979).
Selenium (Se; atomic weight 78.96) is a naturally occurring
element which reacts with metals to form ionic selenides with
a valence of minus 2, and with most other chemials to form cova-
lent compounds. It may .assume any of several valence states
ranging from minus 2 to plus 6. Selenium is used in photocopying,
the manufacture of glass, electronic devices, pigments, dyes
ana insecticides (Dept. Interior, 1974). it is also used in
veterinary medicine (U.S. EPA, 1979) and in antidandruff shampoos
(Cummings and Kimura, 1971). The major source of selenium in
the environment is the weathering of rocks and soils (Rosenfeld
•and Beath, 1964) but human activities contribute about 3,500
metric tons per year (U.S. EPA, 1975a). Selenium is an essential
nutrient for humans and other species (Schroeder, 1970).
II. EXPOSURE
Selenium is not present in measurable quantities in most
U.S. drinking .water supplies. Of 3,676 residences located in
35 geographically dispersed areas, only 9.96 percent of the sam-
ples had selenium levels above the detection limits of 1 pg/l
(Craun, et al. 1977). However, in seleniferous areas of South
Dakota, levels of 50 to 330 ug/1 were measured in drinking waters
(Smith and. Westfall, 1937). Sewage plant effluents may contribute
to tne selenium content of water; as much as 230 jjg/1 have been
reported'in raw sewage, 45 jag/1 in primary effluent, and 50 jag/1
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in secondary effluent (Baird, et al. 1972). Selenium concentra-
tions in plants depend largely on the concentration in the soil
where the plants are grown. High selenium concentration in vegeta-
tion is transmitted to other food sources, e.g., meats and eggs.
The EPA (1979) has estimated the weighted average bioconcentration
factor for selenium to be 18 for consumed fish and shellfish.
Zoller and Reamer (1976) reported that most urban regions have
concentrations of particulate selenium ranging from 0.1 to 10
ng/m .
III. PHARMACOKINETICS
A. Absorption
Selenium appears to be effectively absorbed by the
gastrointestinal tract. Thomson and Stewart (1974) reported
absorptions of 70, 64, and 44 percent for sodium selenite in
three young women. Data from rats are similar with absorptions
ranging from 81 to 97 percent for a number of organic selenium
compounds and sodium selenite (Thomson and Stewart, 1973; Thomson,
et al. 1975) . The literature contains no information on absorp-
tion by inhalation or dermal exposures (National Research Council,
1976) .
B. Distribution
The primary disposition sites for selenium in the body
are the liver, kidney, spleen, and middle and lower sections
of the small intestine (U.S. EPA, 1979) . Based on the work of
Kincaid, et al. (1977) it is apparent that tissue concentration
levels of selenium can be affected both by dose and normal die'tary
intake, although the primary deposition sites remain the same.
T
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C. Metabolism
Selenium is an essential element ana at nutritional
levels it is incorporated into specific functional proteins;
at higher concentrations, it is substituted for sulfur in sulfur-
containing compounds. Selenium analogs are often less stable
than sulfur compounds, ana this lability may be the basis of
toxicity (Stadtman, 1974). Selenite and selenate are methylated
by mammalian tissues in an apparent detoxification process.
Mouse liver, lung and kidney (Ganther, 1966)_are active in methyla-
tion, but muscle, spleen, and heart have little activity.
D. Excretion
Thomson ana Stewart (1974) studied selenium excretion
by •... .^ding three women selenite. It was apparent that the pri-
mary routes of excretion were in the feces and urine, with little
loss through the skin or lungs.
IV. EFFECTS
J A. Carcinogenicity
Only six studies have been performed to specifically
investigate whether selenium is carcinogenic. From these studies
there is no conclusive evidence that selenium has induced tumors
in the test animals. The Food and Drug Administration has de-
clarea that selenium poses no carcinogenic risk (Food and Drug
Administration, 1973).
B. Mutagenicity
Selenium, has been shown to afreet the genetic process
in barley (Walker and Ting, 1967) and in Drosophila melanog,aster
(Ting and Walker, i96it; Walker ana Braaley, Ia6'9). However, these
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ana other genotoxic effects are not true mutagenic effects.
There- is no study in which a true mutagenic activity for selenium
has been demonstrated.
C. Teratogenicity
The consumption ' of seleniferous diets interfered with
the normal development of the embryo in many mammalian species,
including rats, pigs, sheep and cattle (U.S. EPA, 1979). Robertson
(1970) suggested that selenium may be a teratogen in man from
the examination of the older literature which correlated malformed
babies and the consumption of toxic grains by people in Columbia.
D. Other Reproductive Effects
Vesce (1947) noted changes in endocrine glands, espe-
cially the ovaries, following oral administration of 5 to 12.5
mg sodium selenide to guinea pigs over two periods of 20 days.
E. Chronic Toxicity
Chronic effects from prolonged feeding of diets contain-
ing added selenium in amounts of 5 to 15 pg/g include liver damage
in the form of atrophy, necrosis, cirrhosis, and hemorrhage,
and marked and progressive anemia in some species (Fishbein,
1977). In man hepatic necrosis has not been observed following
chronic exposure; however, lassitude, loss of hair, discoloration
ana loss of fingernails were symptoms (Beath, 1962) .
F. Other Relevant Information
The essentiality of selenium for several animals has
been known since the 1950's (Ganther, 1970; Schwarz, 1961) with
selenium deficiency resulting in white muscle disease in ruminants,
hepatic degeneration and peridontal disease in other mammals.
-------
Synerg ism/antagonism exists between the actions of selenium and
other metals such as arsenic, mercury, cadmium, silver and thal-
lium (Dip-lock, 1976) .
V. AQUATIC TOXICITY
A. Acute Toxicity
Cardwell, et al. (1976) exposed 6 species of freshwater
fish to selenium dioxide and observed the 96-hour LCcn values
to range from 2,060 to 28,500 ug/1. The 96-hour LC.5Q values
for fathead minnow fry and juveniles are 2,060 and 5,200 pg/1,
respectively, indicating an apparent decrease in toxicity with
age. With the invertebrates Daphnia magna and scud, the LCcQ
values are 430 and 318 pg/1 respectively (U.S. EPA, 1978; Adams,
1976) .
The 96-hour kCcg values for marine species are 6,710
jug/1 for the sheephead minnow (U.S. EPA, 1978) and 600 jug/1, for
mysid shrimp (U.'S. EPA, 1978).
B. Chronic Toxicity
No pertinent data are available on the chronic toxicity
of selenium to freshwater organisms. (U.S. EPA, 1979). The only
data available in marine species is that of the mysid shrimp
(Mysidopsis oahia) . It has been exposed to selenium for its
life cycle and the chronic value is 135 ug/1.
C. Plant Effects
Selenium is toxic to two freshwater algal species,
Chlorella vulgaris and Haematoccus cupensis, with growth being
retarded at 50 jug/I (Hutchinson and- Stokes, 1975) . For the ^salt-
water alga, Skeltonema costatum, the 96-hour EC50 . values for
-/m-
-------
chlorophyll a and cell numbers are 7,930 and 8,240 pg/1, respec-
tively (U.S. EPA, 1978).
D. Residues
Bioconcentration factors have been determined for the
rainbow trout, fathead minnow and bluegill. These factors range
from 2 to 20 (Adams, 1976; U.S. EPA, 1978). The tissue half-
life for the bluegill is between 1 and 7 days (U.S. EPA, 1978).
These results show that tissue accumulation of selenium should
not present a hazard to freshwater aquatic organisms.
No residue data are available for marine species (U.S.
EPA, 1979). •
VI. EXISTING GUIDELINES
A. Human
The U.S. Environmental Protection Agency (1975b) has
established the maximum permissible level of selenium at 0.01
mg/1 for U.S. drinking waters. A time-weighted average concentra-
tion threshold limit value (TLV) of 0.2 mg/m has been established
by the American Conference of Government Industrial Hygienists
(ACGIH, 1977). The minimum toxic dose for selenium has been
calculated to be 16.1 mg/day. The U.S. EPA (1979) draft water
criterion for selenium is 10 pg/1. As a result of public comments
received, additional review and consideration of the recommended
criterion is required.
B. Aquatic
For selenium in freshwater, the draft criterion to
protect aquatic life is 9.7 pg/1 as a 24-hour average and ' the
concentration should not exceed 22 pg/1 at any time (U.S. EPA,
1979). In saltwater the criterion is 4.4 pg/1 as a 24-hour average
and the concentration should not exceed 10 pg/1 at any time.
-------
SELENIUM
REFERENCES
Adams, W.J. 1976. The toxicity and residue dynamics of selenium
in fish and aquatic invertebrates. Diss. Abstr. Int. p. 121.
American Conference of Industrial Hygienists. 1977. Threshold
limit values for chemical substances in workroom air adapted
by ACGIH for 1977.
Baird, R.B./ et al. 1972. Determination of trace amounts of
selenium in wastewaters by carbon rod atomization. Anal. Chem.
44: 1887.
Beath, O.A. 1962. The story of selenium in Wyoming. University
of Wyoming, Laramie.
Cardwell, R.D., et al. 1976. Acute toxicity of selenium dioxide
to freshwater fishes. Arch. Environ. Contain. Toxicol. 4: 129.
Craun, G.F., et al. 1977. Preliminary report of an epidemio-
logic investigation of the relationship(s) between tap water
constituents and cardiovascular, disease. Proc. Am. Water Works
Assoc. Meet.
Cummins, L.M. and E.T. Kimura. 1971. Safety evaluation of
selenium sulfide antidandruff shampoos. Toxicol. Appl. Pharmacol.
20: 89.
Department of Interior. 1974. Minerals. yearbook, 1972. Bureau
of Mines, Washington, D.C.
Diplock, A.T. 1976. Metabolic aspects of selenium action and
toxicity.. CRC Crit. Rev. Toxicol. 271.
Fishbein, L. 1977. Toxicology of selenium and tellurium. Adv.
Mod. Toxicol., Vol. 2, .1 ISS Trace Elem., 191.
Food and Drug Administration. 1973. Selenium in animal feed.
Federal Register, Vol. 33, No. 81.
Ganther, H.E. 1966. Enzymic synthesis of dimethyl selenide
from sodium selenite in mouse liver extracts. Biochemistry
5: 1089.
Ganther, H.E. 1970. In Trace element metabolism in animals,
ed. C.F. Mills, Edenburgh~:Livingstone, 212.
Hutchison, T.C. and P.M. Stokes. 1975. Heavy metal toxicity
and algal bioassays. Water quality parameters. ASTM: 320.
Kincaid, R.L., et al. 1977. Effect of added dietary selenium
on .metabolism and tissue distribution of radioactive and stable
selenium in calves. Jour. Anim. Sci. 44:1: 147.
-------
National Research Council. 1976. Selenium. Comin. Med. Biol.
Effects Environ. Pollut., Subcomm. Selenium. Natl. Acad. Sci.,
Washington, D.C.
Robertson, D.S.F. 1970. Selenium, a possible teratogen? Lancet
1: 518.
Rosenfeld, I. 1964. Excretion and retention of °Se in relation
to modes of administration, toxicity and pregnancy in rats.
Metabolic effects and metabolism of selenium in animals. Part
IV, Bull. 414. Agric. Exp. Sta., University of Wyoming.
Rosenfeld, I. ana O.A. Beath. 1964. Selenium; geobotany, bio-
chemistry, toxicology and nutrition. Academic Press, New York.
Schroeder, H.A. 1974. Selenium. Page 101 ir\ The poisons around
us. Indiana University Press, Blooming ton. ..
Schroeder, H.A., et al. 1970. Essential trace metals in man:
selenium. Jour. Chron. Dis. 23: 227.
Schwarz, K. 1961. Development and status of experimental work
of factor 3 selenium. Fed. Proc. 20: 666.
Smith, M.I. and B.B. Westfall. 1937. Further field studies
on the selenium problem in relation to public health. U.S. Pub.
Health Rep. 52: 1375.
Stadtman, T.C. 1974. Selenium biochemistry. Proteins containing
selenium are essential components of certain bacterial and mamma-
lian enzyme systems. Science 183: 915.
Thomson, C.D. and R.D.H. Stewart. 1973. Metabolic studies of
( DSe) selenomethionine and ( Se) selenite in the rat. Br.
Jour. Nutr. 30: 139.
Thomson, C.D. and R.D.H. Stewart. 1974. The metabolism of ( Se)
selenite in young women. Br. Jour. Nutr. 32: 47.
Thomson, C.D.75et al. 1975. Metabolic studies of ( bSe) seleno-
cystine and ( Se) selenomethionine in the rat. Br. Jour. Nutr.
34: 501.
Ting, K.P. and G.W.R. Walker. 1969. The distributive effect
of selenoamino acid treatment on crossing-over in Drosophila
melanogaster. Genetics 61: 141.
U.S. EPA. 1974. Safe drinking water act/' puolic law 93-523,
93rd Congress, S. 433.
U.S. EPA. 1975a. Preliminary investigation of effects on the
environment of boron, indium, nickel, selenium, tin, vanadium
and their compounds. Selenium. U.S. Environ. Prot. Agency,
Washington, D.C.
U.S. EPA. i975b. National interim primary drinking water regu-
lations. Fed. Reg. 40:248: 59566.
-------
U.S. EPA. 1978. In-depth studies on health and environment
impacts of selected water pollutants. U.S. Environ. Prot. Agency.
Contract No. 68-01-4646.
U.S. EPA. 1979. Selenium: Ambient Water Quality Criteria.
Environmental Protection Agency, Washington, D.C.
Vesce, C.A. 1947. Intossicazione spermentale da selenio. Intos-
sicazione Sperimentale da Selenio, Folia Med. (NAPOLI) 33:. 209.
Walker, G.W.R. and A.M. Bradley. 1969. Interacting effects
of sodium monohydrogen arsenate and selenocystine on crossing-
over in Drosophila Melanogaster. Can. Jour. Genet. Cytol. 11: 677.
Walker, G.W.R. and K.P. Ting. 1967. Effects of selenium in
recombination in barley. Can. Jour. Genet. Cytol. 9: 314.
Windholz, M. , ed. 1976. The Merck Index. 9th ed. Merck and
Co., Inc., Rahway, N.J.
Zoller, W.H. and D.C. Reamer. 1976. Selenium in the atmosphere.
Proc. Symposium Selenium and Tellurium in the Environ. Ind. Health
Found.
-------
No. 154
Silver
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
i-
-------
SILVER
SUMMARY
While metallic silver in the zero valence state is not
considered to be toxic, most of its salts are toxic to a
large number of organisms. Silver salts can combine with
certain biological molecules and subsequently alter their
properties. Upon ingestion, many silver salts are absorbed
in the human circulatory system and deposited in various body
tissues, resulting in generalized or sometimes localized gray
pigmentation of the skin and mucous membranes known as argy-
ria. Silver has not been shown to be a carcinogen (except by
the mechanism of solid state tumorigenisis); however, there
is some evidence that silver salts can effect the growth of
tumors. The acceptable daily intake for silver has been de-
termined to be 1.6 mg per day for a 70 kg man.
• Silver is acutely lethal to aquatic species in the u.g/1
range. In terms of acute lethality, Daphnia magna appears to
be the most sensitive species, with a 48-hour EC5Q of 1.5
ug/1. At levels as low as 0.17 \j.g/I, silver caused premature
egg hatching and reduced fry growth in fathead minnows.
-------
SILVER
I. INTRODUCTION
This profile is based on the Ambient Water Duality Cri-
teria Document for Silver (U.S. EPA, 1979).
Silver (Ag; atomic weight 107.87) is a white ductile
metal occurring naturally in the pure form and in ores.
Silver can exist in two valence states, Ag"1" and Ag"1"1".
The solubility of common silver salts varies greatly, with
silver nitrate having a solubility of 2.5--X 10^ \j.g/l and
silver iodide having a solubility of 30 ug/1 (Windholz,
1976). Many silver salts are light-sensitive. Water or
atmospheric oxygen have no effect on metallic silver; how-
ever, ozone, hydrogen sulfide, and sulfur react with it. The
principle uses of silver are in photographic materials, elec-
troplating, dental alloys, solder and brazing alloys, paints,
jewelry, silverware, coinage, mirror production.
II. EXPOSURE
Exposure to silver is mainly.through food and water
intake with only minimal contribution from ambient aerosols.
Concentrations of silver in surface waters have been shown to
vary from 0-38 ug/1 with a mean of 2.6 ug/1 in samples
containing silver. High silver concentrations are obtained
in high silver mineralized areas or in waters receiving
effluent from industries that use silver.
The average intake of silver from food has been calcu-
lated to be 40 ug/day (Tipton, et al. 1966) to 88 ug/day
(Kehoe, et al. 1940) in the U.S. Although silver is detected
in meats and vegetables, the concentrations in fish, shell-
-------
fish, .and Crustacea are greater. Marine animals accumulate
silver in concentrations which are higher than their environ-
ment. This is particularly significatnt in areas such as
sewaqe-sludqe dumping sites, which contain high concentra-
tions of silver in the sediment. The dead bodies of animals
in reducing environments will contribute their silver to sed-
iments, a major factor in the geochemical cycle of silver
(Boyle, 1968).
Exposure to high levels of silver has. also occurred by
inhalation in specific industries (e.g., silver smelting and
photography) and from mechanical uses of silver compounds.
Steel mills do not seem to contribute to ambient air concen-
trations of silver (Harrison, et al. 1971).
III. PHARMACOKINETICS
A. Absorption
Silver may enter the body via the respiratory
tract, the gastrointestinal tract, mucous membranes, or bro-
ken skin. The efficiency of absorption by any of these
routes is poor. Colloidal silver given orally to rats showed
two to five percent absorption by the gastrointestinal tract
(U.S. EPA, 1979). Dogs receiving orally a tracer quantity of
silver nitrate absorbed ten percent. It was shown in hu-
mans who accidently inhaled silver that the biological half-
life of silver was about one day, probably due to rapid muco-
ciliary clearance, swallowing, and fecal excretion (Newton
and Holmes, 1966). Some absorpotion did take place since •
there was localization of silver in the liver, but quantifi-
cation was impossible. In human burn patients treated with
-------
silver nitrate dressing, only 0.008 percent of the silver was
absorbed (U.S. EPA, 1979).
E. Distribution
The amount of silver, its chemical form, and the
route by which it is administered affects the tissue content
and distribution of silver within the body (Furchner, et al.
1968). Table 1 summarizes data on the distribution of silver
in rats.
Table 1: Distribution of Silver in the Rat and Day 6
Following Intramuscular Injections of Differ-
ent Doses of Silver (percent of dose per or-
gan) (Scott and Hamilton, 1950).
Dose
Carrier-Free
Percent of Dose
Absorbed
Absorbed
Heart and Lungs
Spleen
Blood
Liver
Kidney
G.I. tract
Muscle
Bone
Skin
Urine
Feces
Unabsorbed
92
0
0
'0
0
0
1
0
0
0
n
96
7
.1
.06
.01
.50
.36
.07
.12
.27
.18
.24
.64
.56
.9
0.1
53
0
0
0
2
0
4
0
0
0
0
88
36
ng
.7
.13
.13
.95
.24
.92
.22
.56
.35
.67
.88
.95
.3
1.0
53
0
2
3
33
0
8
2
2
7
1
37
46
ma
.5
.59
.69
.03
.73
.63
.21
.39
.20
.39
.82
.33
.5
Silver administered to other species appears to generally
follow this distribution pattern..
C. Metabolism
Inhaled silver particles that are not removed from the.
lungs by the mucociliary reflex and coughing are probably
-------
phagocytized and transported via the protein fractions of the
blood plasma to the liver, from which they are eventually ex-
creted in the bile. Formation of silver selinide deposits in
the liver, as well as the formation of metallic silver,
silver sulfide, or silver complexes with sulfur amino acids
may be a method of detoxifying silver. In the kidney, com-
plexation with metallothionein may be another detoxification
pathway (U.S. EPA, 1979).
D. Excretion
Regardless of route and chemical form of silver
administered, fecal excretion always predominates over uri-
nary excretion. Most absorbed silver is excreted into the
intestines by the liver via the bile. Phalen and Morrow
(1973) exposed beagle dogs to an atmosphere containing silver
aerosols and showed the biological half-life to be 8.4 to
12.9 days.
IV. EFFECTS
A. Carcinogenicity
Implanted foils and disks and injected colloidal
suspensions of metallic silver have been found to produce
tumors or hyperplasia in several studies. These tumors may
be due to the particular physical form of the metal or to its
being an exogenous irritant. There is no evidence that
silver or its salts produce tumors by any other mechanisms.
In one study, intratumoral injections of colloidal silver ap-
peared to stimulate cancer growth (Guyer and Mohs, 1933), and
»
in another study silver nitrate appeared to act as a promoter
with DMBA (7,12-dimethylbenz(a)anthracene) initiated mice
-------
(Saffrotti and Shubik, 1963). On the other hand, Taylor and
Carmichael (1953) showed a tumor growth inhibitor effect of
silver chloride. The evidence for any carcinogenic effect of
silver is very tenuous (U.S. EPA, 1979).
B. Mutagenicity
Silver nitrate (Demerec, et al. 1951), silver chlo-
ride (Nishioka, 1975), and silver sulfadiazine (Fox, et al.
1969) have been examined for mutagenicity in microorganisms
and shown to be nonmutagenic in these test systems.
C. - Teratogenicity
Few associations between silver and birth defects
have appeared in the literature and one is apparently erro-
neous. Kukizaki (1975). found only weak cytotoxic effects
when silver-tin alloy powder was incubated in seawater with
fertilized eggs or early embryos of the sea urchin Hem ice ni-
trons pulcherriraus. Silver salts were tested for toxicity
to 4- and 8-day-old chick embryos but did not produce abnor-
malities in development (Ridgway and Karnofsky, 1952).
D. Other Reproductive Effects
Pertinent information could not be located in the
available literature concerning any other reproductive ef-
fects due to exposure to silver.
E. Chronic Toxicity
In rats, chronic exposure to 0.4 mg/1 of silver in
drinking water causes hemorrhages in the kidney. Larger
doses cause changes in conditioned-reflex activity, lowering
of immunological resistance (0.5 mg/1), and growth depression
(20 mg/1). In humans, the most common noticeable effect of
-------
chronic exposure to silver or silver compounds is generalized
arqyria (generalized gray pigmentation).
F. Other Relevant Infornation
Silver exhibits antagonism to selenium, vitamin E,
and copper, inducing deficiency symptoms in animals fed ade-
quate diets or aggravating deficiency symptoms when the ani-
mal's diet lacks one or more of the nutrients. The effects
have been described in dogs, sheep, pigs, rats, chicks, tur-
key, poults, and ducklings (U.S. EPA, 1979).
V. AOUATIC TOXI.CITY
A. Acute Toxicity
Davies, et al. (1978) conducted 96-hour tests with
rainbow trout in both hard (350 mg/1 as CaCC>3) and soft
water (26 mg/1 as CaCO^) water. The LC^Q values were
6.5 and 13 ug/1 for soft and hard water, respectively. There
are too few data to assess the relative importance of hard-
ness and experimental variability on these nonreplicated re-
sults .
The 48-hour static ECgg for Daphnia roagna in
soft water (40 mg/1 as CaC03) is 1.3 ug/1 (U.S. EPA, 1978),
indicating that this species is the most sensitive freshwater
invertebrate species tested.
Acute toxicity data are available only, for four
saltwater invertebrate species and range from 5.8 to 262 ug/1
(Calabrese, et al. 1973; Calabrese and Nelson, 1974; tlelson,
et al. 1976; Sosnowski and Gentile in: U.S. EPA, 1979). Th.e
American oyster is the most sensitive saltwater species test-
ed, and the mysid shrimp is the most resistant.
-------
B. Acute Toxicity
Davies, et al. (1978) conducted an 18-month mortal-
ity test with rainbow trout and found the no-effect concen-
tration of silver to be 0.09 - 0.17 ug/1 (17.2% mortality at
0.17 ug/1 and no mortality at 0.09 ug/1). There was also
premature hatching of eggs and reduced growth of fry at 0.17
.ug/i.
The .chronic toxicity of silver to mysid shrimp has
been determined based on a flow-through, life-cycle exposure
(Sosnowski and Gentile in: U.S. EPA, 1979). No spawning
occurred at 103 ug/1. The time of spawning was delayed to
seven days at 33.3 ug/1. Brood size was statistically
smaller at 33.3 ug/1 when compared to the controls, although
larval survival was not affected. The highest concentration
of silver tested that had no effect on growth, reproduction,
or survival was 10.2 ug/1, which is approximately 0.04 times
the 96-hour LC^Q determined for adult shrimp.
C. Plant Effects
Hutchinson and Stokes (1975) observed growth retar-
dation in the freshwater alga, Chlorella vulgaris, at silver
concentrations between 10 and 60 ug/1. A concentration of
2,000 ug/1 was determined to be toxic to six additional algal
species (Gratteau, 1970).
The only marine algal species tested, Skeltonema
costatum, showed growth inhibition after a 96-hour exposure
to 130 ug/1 (U.S. EPA, 1978).
D. Residues
Bioconcentration factors of 17 to 368 were deter-
mined for three species of insects exposed to silver
-------
(Nehring, 1973). Bluegills showed no bioccncentration of
silver at a water concentration of 0.03 ug/1 after a 28-day
test (U.S. EPA, 1978). Pertinent information on residues in
saltwater species could not be located in the available
literature.
VI. EXISTING GUIDELINES AND STANDARDS
A. Humans
Both the U.S. standard for silver in drinking water
and in workplace air have been based on a '-presumed 1 g mini-
mum dose of silver that has caused agryia.
The.existing standards for silver are:
Existing Standards Regarding Silver
Med ium . Silver Concentration Authority
Drinking water 50 ug/1 U.S. EPA (1976),-Na-
tional Academy of
Sciences (1977)
Prinking water 0.5 ug/1 State of Illinois
(cited in National
Academy of Sci-
ences ,1977)
Drinking water '10 ug/1 State of California
(cited in National
Academy of Sciences,
1977)
Workplace air, thresh- 0.01 mg/m^ Occupational Safety
old limit value and Health Adminis-
time-weighted tration (1974)
(39 FR 23541)
Short-term exposure 0.03 mg/m^ American-Conference
limit (_> 15 minutes) . of Governmental I n-
- 4 times per day dustrial Hygiensts
(1977)
»
The acceptable daily intake (ADI) for silver is 1.6 mg/day. The
U.S. EPA draft water criterion for silver is 10 ug/1 for the
protection of human health. This criterion is presently
-------
undergoing further evaluation and review before final recom-
mendation.
B. Aquatic
For silver the draft criterion to protect fresh-
water aquatic life is 0.009 ug/1 as a 24-hour average; the
concentration should not exceed 1.9 ug/1 at any time (U.S.
EPA, 19.79).
To protect saltwater aquatic life, the draft cri-
terion is 0.26 ug/1 as a 24-hour average; the concentration
should not exceed 0.58 ug/1 at any time (U.S. EPA, 1979).
-------
SILVER
REFERENCES
American Conference of Governmental Industrial Hygienists, 1977
TLV Airborne Contaminants Committee. 1977. TLVs threshold
limit values for chemical substances and physical agents in the
workroom environment with intended changes for 1977. Am. Conf.
Govt. Ind. Hyg . , Cincinnati, Ohio.
Boyle, R.W. 1968. Geochemistry of silver and its deposits with
notes on geochemical prospecting for the element. Geol. Surv.
Can., Bull. No. 160. p. 1.
Calabrese, A. and D.A. Nelson.
development of the hard clam,
metals. .Bull. Environ. Contam. Toxicol.
1974. Inhibition of embryonic
Mercenar ia mercenar ia by heavy
Calabrese, A., et al. 1973. The toxicity of heavy metals to
the embryos of the American oyster (Crassostrea virginica).
Mar. Biol. 18: 162.
Davies. P.H., et al. 1978. Toxicity of silver to rainbow trout
(Salmo gairdneri). Water Res. 12: 113.
Demerec, M. , et al. 1951. A survey of chemicals for mutagenic
action on E. coli... Am. Nat. 35: 119.
Fox, C.L., et al. 1969. Control of Pseudomonas infection in
burns by silver sulfadiazine. Surg. GynecoT"!Obstet. 128: 1021.
Furchner, J.E., et al. 1968. Comparative metabolism of radio-
nuclides in mammals. IV. Retention of silver-HOm in the mouse,
rat, monkey and dog. Health Phys. 15: 505.
Gratteau, J.C. 1970. Potential algicides for the control of
algae. Ref. No. 1970. Water Sewage Works p. R-24.
Guyer, M.F. and F.E. Mohs. 1933. Rat carcinoma and injected
colloidal platinum. Arch. Pathol. 15: 796.
Harrison, P.R., et al. 1971. Areawide trace metal concentra-
tions measured by multielement neutron activation analysis:
A one day study in northwest Indiana. Jour. Air Pollut. Contro.
Assoc. 21: 563.
Hutchinson, T.C., and P.M. Stokes. 1975. Heavy metal toxicity
and algal bioassays. Water Quality Parameters. ASTM SPT 573: 320.
Kehoe, R.A., et al. 1940.
ranges of concentration of
materials. Jour. Nutr. 19:
A spectrochemical study of the normal
certain trace metals in biological
579.
-------
Kukizaki, S. 1975. Studies on the effects of dental amalgam
upon the fertilization and early development of sea urchin eggs
(Hemicentrotus pulcherr imus). Jour. Jap. Soc. Dent. Apuar. Mater.
16:
National Academy of Sciences. 1977. Drinking water and health.
U.S. Environ. Prot. Agency, Washington, D.C., PB-269 519. Natl.
Tech. Inf. Serv., Springfield, Va.
Nehring, R.V. 1973. Heavy metal toxicity in two species of
aquatic insects. Master's Thesis, Colorado State Univ., Fort
Collins, Colorado. 82 p.
Nelson, D.A. , et.-al. 1976. Biological effects of heavy metals
on juvenile bay scallops, Argopecten irradians, in short-term
exposures. Bull. Environ. Contain. ToxicoTT Is": '215.
Newton, D. and A. Holmes. 1966. A case of accidental inhalation
of zinc-65 and silver-HOm. Radiat. Res. 29: 403.
Nishioka, H. 1975. Mutagenic activities of metal compounds
in bacteria. Mutat. REs. 31: 185.
Phalen, R.F. and P.E. Morrow. 1973. Experimental inhalation
of metallic silver. Health Phys. 24: 509.
Ridgway, L.D., and D.A. Karnofsky. 1952. The effects of metals
on the chick embryo: Toxicity and production of abnormalities
in- development. Ann. N.Y. Acad. Sci. 55: 203.
Saffrotti, U. and P. Shubik. 1963. Studies on promoting action
in skin carcinogenesis. Natl. Cancer-Inst. Monogr. 10: 489.
Scott, K.G. and J.G. Hamilton. 1950. The metabolism of silver
in the rat with radiosilver used as an indicator. Univ. Calif.
(Berkeley) Publ. Pharmacol. 2: 241.
Sosnowski, S.L. and J.H. Gentile. Chronic toxicity of copper
and silver to the mysid shrimp Mysidopsis bahj.a. EPA-Environ-
mental Research Lab., Narragansett, R.I. Manuscript.
Taylor, A. and N. Carmichael. 1953. The effect of metallic
chlorides on the growth of tumor and non-tumor tissue. Univ.
Texas Publ. No. 5314, Biochem. Inst. Stud. 5, Cancer Stud. 2.
p. 36.
Tipton, I.H., et al. 1966. Trace elements in diets and excreta.
Health Phys. 12: 1683.
U.S. EPA. 1976. National interim primary drinking water regula-
tions. EPA-570/9-76-003. U.S. Environ. Prot. Agency, Off.' of
water Supply.
U.S. EPA. 1978. In-depth- studies on health and environmental
impacts of selected water pollutants. U.S. SPA Contract No.
68-01-4646. U.S. Environ. Prot. Agency, Washington, D.C.
-------
U.S. EPA. 1979. Silver: Ambient Water Quality Criteria. Envi-
ronmental Protection Agency, Washington, D.C.
Windholz, M. (ed.) 1976. The iMerck Index. 9th ed.- Merck
and Co., Inc., Rahway, N.J.
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No. 155
TCDD
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposura to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Becaus " >f the limitations of such sources, this short profile
may not -reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
2,3,7,3-TETRACHLORODIBENZO-P-DIOXIN (TCDD)
SUMMARY
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been
found to induce heptocellular carcinomas and tumors in two
rat feeding studies. TCDD has also produced fetotoxic and
teratogenic effects in laboratory animals. The positive
mutagenicity of TCDD has been demonstrated in three bacte-
rial bioassay systems. TCDD is also a potent inducer of
hepatic and renal microsomal- drug metabolizing enzymes.
No standard tests for acute or chronic toxicity in
aquatic life have been conducted with TCDD. Other studies,
however, have shown adverse effects over a period of 96
hours to concentrations as low as 0.000056 jug/1. The weighted
average bioconcentration factor for TCDD for edible portion
of all aquatic organisms consumed by Americans has been
calculated to be 5,300.
-------
2,3,7,8-TETRACHLORODISENZO-P-DIOXIN (TCDD)
I. INTRODUCTION
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a contami-
nant unintentionally formed during the production of 2,4,5-
trichlorophenol (TCP) from 1,2,4,5-tetrachlorobenzene.
TCDD is also found as a contaminant of 2,4,5-trichlorophenoxy-
acetic acid (2,4,5-T) (U.S. EPA, 1979).
Characteristically, TCDD (C^^C^^ is a white crystal-
line solid with the following physical properties: melting
point, 302-305°C; solubility in water, 0.2 to 0.6 ug/1;
lipiphilic, and non-volatile (U.S. EPA, 1979).
TCDD is considered a relatively stable compound which
can be degraded at temperatures in excess of 500°C, or by
irradiation with UV light or sunlight, under certain condi-
tions (U.S. EPA, 1979). It has been shown to disappear
slowly from soil with residues persisting for ten years
after application. TCDD bio-accumulates in aquatic organisms.
II. EXPOSURE
A. Water
The amount of human exposure that can be directly
attributed to drinking water alone is difficult to determine
(U.S. EPA, 1979). It has been stated that no TCDD has ever
been detected in drinking water, with limits of detection
in the parts per trillion range (National Research Council,
1977). Underground water supplies would probably not be
contaminated with TCDD under most conditions since vertical
movement of TCDD has not been demonstrated in soil (Kearney,
et al., 1972).
-------
B. Food
The occurence of TCDD in food could result from
(1) accidental spraying of plant crops; (2) contaminated
forage or (3) food chain magnification (U.S. EPA, 1979).
TCDD is neither absorbed by oat and soybean seeds
after spraying, nor taken up from the soil into the mature
plants (Isensee and Jones, 1971; Matsumura and Benezet,
1973). Aqueous solutions of pure TCDD exposed to either
artificial light or sun light, do not decompose, whereas
TCDD photodecomposes rapidly when applied to leaf surfaces
as a contaminant of the herbicides Agent Orange and Esteron
(Crosby, et al. , 1971; Crosby and Wong, 2 '"_)).
TCDD has been detected in the adipose tissue of
cattle feeding on contaminated forage (Kocher, et al. , 1978).
Studies conducted for the U.S. EPA also found TCDD in fat
of cattle previously exposed to 2,4,5-T ('''"<-S. EPA, 1979).
No TCDD, however, was detected in liver samples.
The U.S. EPA (1979) has estimated" the weighted
average bioconcentration factor of TCDD at 5,800. This
estimate is based on measured steady state bioconcentration
studies in channel catfish containing 3.2 percent lipids
(Isensee and Jones, 1975).
C. Inhalation
Pertinent information could.not be located in
the available literature.
-------
.III. PEARMACOKINETICS
A. Absorption
Approximately 83-86 percent of the TCDD administered
in a single oral dose, following activation with multiple
oral doses, is absorbed from the intestinal tract (Rose,
et al., 1976).
B. Distribution
The excretion of a single oral dose of TCDD in
rats occurred via the feces (53 percent), urine (13 percent),
and expired air (two percent) (Piper, et al. , 1973). An-
alysis after three days showed the highest percent of the
administered dose per gram in the liver (3.18 percent) and
adipose (2.60 percent).
Rose, et al. (1976) found that 22 days after a single
14
oral dose of C labeled TCDD, 1.26 and 1.25 percent of
14
the C was retained per gram of liver and adipose tissue,
respectively. After repeated oral doses, however, the liver
was found to have five times as much radioactivity as adi-
pose tissue. Single oral doses of TCDD were excreted through
the feces, whereas significant amounts of radioactivity
were found both in the urine and the feces after repeated
oral doses.
C. Metabolism
There is no complete agreement as- to whether or
not TCDD is actually metabolized (U.S. SPA, 1979). Rose,
et al. (1976) found unchanged 14C-labeled TCDD in the liver
after oral administration, but noted that most of the radio-
-------
activity in the feces came from compounds other than TCDD.
The slow elimination of TCDD from rats and monkeys suggests
that it is not readily metabolized (Van Miller, et al. ,
1976).
D. Excretion
See also section B., Distribution.
Differences in TCDD elimination have been observed
between .the sexes and between species. Rose, et al. (1976)
found male rats excreted 3.1 percent of the cumulative dose
in the urine while females excreted 12.5 percent in the
urine.
The half-life of radioactive TCDD following a
single oral dose to rats was 31— 6 days, while that follow-
ing repeated oral doses was 23.7 days (Rose, et al., 1976).
IV. EFFECTS
A. Carcinogenicity
Three studies have reported data concerning the
carcinogenicity of TCDD. Van Miller, et al. (1977) fed rats
dietary levels of TCDD ranging from 0.001 to 1000 jug/kg
of diet for up to 78 weeks. In 50 animals receiving diets
ranging from 0.005 jug/kg to 5 jug/kg 13 benign and 15 malig-
nant tumors were observed. No tumors were found in controls
or those fed a dietary level of 0.0001 fig/kg. Animals fed
diets of 50 jug/kg or more died between the second and fourth
week of treatment.
Toth, et al. (1977) administered TCDD to, mice
at levels of 0.007, 0.7, and 7 pg/kg per week for 12 months.
No tumors were noted at anv dose.
-------
Kociba, et al. (in press) administered 0.1, 0.01,
and 0.001 ;jg/kg ofTCDD per kg of body weight to male and
female rats. Males at the 0.1 jug/kg dose exhibited a statis-
tically significant increased incidence of squamous cell
carcinomas of the hard palate (4 out of 50) and of the tongue
(3 out of 50). No carcinomas were observed in the male
controls (0 out of 85). Females at the 0.1 ,ug/kg dose had
a statistically significant increase in incidence of car-
cinomas at three sites: squamous cell carcinoma of the
hard palate (4 out of 49), squamous cell carcinoma of the
lung (7 out of 40), and hepatocellular carcinoma of the
liver (11 out of 49). Only one carcinoma of these three
sites occurred in the female controls (1 out of 86), and
that was hepatocellular carcinoma of the liver. Five sites,
pancreas, adrenal gland, pituitary gland, uterus, and mam-
mary gland, had a statistically significant decrease in
their tumor incidence at certain dose levels (Kociba, et
al., in press).
B. Mutagenicity
Multiple oral doses of TCDD over 5 weeks resulted
in vacuolization of liver cell nuclei, increased mitotic
rate, and a polyploid chromosome number (Vos, et al., 1974).
TCDD administered by intubation intraperitonealy,
or orally did not cause chromosomal aberrations in bone
marrow cells (Green and Moreland 1975). However, repeated
dosing of TCDD over 13 weeks produced an increase in chro-'
rnosomal breaks in rat bone marrow (Green, et al. 1977).
-------
Some studies have been conducted showing that
TCDD might be a dominant lethal inducing agent, while others
have found no evidence of this effect (U.S. EPA, 1979).
Bacterial assays with E. coli, and S_. typhimur ium
have found TCDD to be mutagenic via intercalation with DNA
(Hussain, et al., 1972). Some strains of Salmonella, how-
ever, have yielded negative mutagenic results when tested
'(Seller, 1973) . . .
Tenchini, et al. (1977) found no significant differ-
ences in chromosome number or chromosomal abnormalities
in maternal or abortive fetal samples from pregnant women
exposed to TCDD during the explosion of a 2,4,5-T factory
in Italy.
C. Teratogenicity
Teratogenic effects from TCDD have been reported
in several studies. Both teratogenic and fetotoxic effects
were observed in mice and rats administered 2,4,5-T contain-
ing 30 ppm TCDD (Courtney, et al., 1970). Smith, et al.
(1976) found the incidence of cleft palate to be signifi-
cantly higher in mice receiving 1 jug/kg and 3 jug/kg per
day of TCDD for 10 days during gestation. At 3 jug/kg, the
incidence of bilateral dilated renal pelvis among fetuses
was also significantly greater. TCDD levels of 0.125 to
2.0 /jg/kg/day given orally to rats on days .6 to 15 of gesta-
tion produced dose-related increases in fetal mortality,
fetal intestinal hemorrhages, and early and late resorptio'ns
(Sparschu, et al., 1971).
-------
D. Other Reproductive Effects
Pertinent information could not be located in
the available literature.
E. Chronic Toxicity
Chronic studies involving administration of TCDD
to rats, guinea pigs and mice, have reported toxic effects
to the liver and thymus (U.S. EPA, 1979). Female rhesus
monkeys fed a diet containing 500 ppt TCDD for up to nine
months, exhibited symptoms of facial hair and eyelash loss,
edema, accentuated hair follicles, and dry scaly skin (Allen,
et al., 1977).
A large number of studies have reported the inci-
dence of chloracne among workers exposed to TCDD during
the production of 2,4,5-trichlorophenol (TCP, 2,4-D or 2,4,5-
T) (U.S. EPA, 1979). Other chemical manifestations among
exposed workers include muscular weakness, loss of appetite
and weight, sleep disturbances, orthostatic hypotension,
abdominal pain, liver impairment, hyperpigmentation of the
skin, hirsutism, and psychopathological changes (U.S. EPA,
1979) .
F. Other Relevant Information
No synergistic effect was detected when 2,4,5-
T and TCDD were administered to mice alone, or in combina-
tion with each other (U.S. EPA, 1979). Both compounds are
capable of producing cleft palates and kidney anomalies
in fetuses.
The International Agency for Research on Cancer
(1977) has reviewed the literature and concludes that TCDD
is a potent inducer of hepatic and renal microsomal drug
-------
. metabolizing enzymes. TCDD intoxication results in a marked
increase in the cellular smooth endoplasmic reticulum con-
tent of hepatic and renal cells. This compound is also
capable of simultaneously activating and suppressing certain
microsome associated foreign compound and steroid-hormone-
metabolizing enzyme systems. It has been found to increase
the activity of renal and hepatic glutathione-S-transferase,
and hepatic
-------
D. Residues
TCDD has a high affinity for the tissues of aquatic
species. Isensee and Jones (1975) conducted a model fresh-
water ecosystem study on TCDD and observed bioconcentration
factors between 3,500 and 26,000 over a 3 to 31 day period.
The highest bioconcentration factors were reported for Dyphnia
magna (26,000), the mosquito fish, Gambusia affinis (25,000),
and the snail, Physa sp. (20,000).
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The calculated acceptable daily intake (ADI) for
TCDD is 10 jug/kg/day. This ADI does not. •'-- psider TCDD
to be a known or suspected carcinogen (NRC, 1977).
The draft ambient water quality criterion has
been set by the U.S. EPA (1979) at levels intended to reduce
the human carcinogenic risk to rhe range of -.10~", 10~ ,
and 10~ . The corresponding draft criteria are 4.55 x 10~
7 jug/1, 4.55 x 10~8 ,ug/l, and 4.55 x 10~9 p^/l, respectively.
B. Aquatic
No drafted criterion is available to protect fresh
and saltwater species from TCDD toxicity.
-------
TCDD
REFERENCES
Allan, J.R., et al. 1977. Morphological changes in monkeys
consuming a diet containing low levels of TCDD. Pood Cosmet.
Toxicol. 15: 401.
Courtney, K. Diane,-et al. 1970. Teratogenic evaluation of
2,4,5-T. Science 168: 864-.
Crosby, D.G., and A.S. Wong. 1977. Environmental degrada-
tion of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Science 195:
1337.
Crosby, D.G., et al. 1971. Photodecomposition of chlori-
nated dibenzo-p-dioxin. Science 173: 748.
Green, S., and F.S. Moreland. 1975. Cytogenetic evaluation
of several dioxins in the rat. Toxicol. Appl. Pharmacol.
33: 161.
Green, S., et al. 1977.- Cytogenetic effect of
2 , 3 , 7, 8tetrachiorodibenzo-p-diox_in on rat bone marrow cells.
FDA By-lines 7:- 292. Food Drug Admin., Washington, D.C.
Hussain, S., et al. 1972. Mutagenic effects of TCDD on
bacterial systems. Ambico. 1:32.
International Agency for Research on Cancer, Chlorinated.
1977. Dibenzodioxins. IARC Monographs on The Evaluation of
Carcinogenic Chemicals 'to- Man. Vol. 15, Lyon, France.
Isensee, A.R., and G.E. Jones. 1971. Absorption and trans-
location of root and foliage applied 2,4-dichlorophenol, 2,7-
dichlorodibenzo-p-dioxin and TCDD. Jour. Agri. Food Chem.
19: 1210.
Isensee, A.R., and G.E. Jones. 1975. Distribution of
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in aquatic model
ecosystems. Environ. Sci. Technol. 9: 668.
Kearney, P.C.., et al. 1972. Persistence and metabolism of
chlorodioxins in soils. Environ. Sci. Tech. 5: 1017.
Kocher, et al. 1978, A search for the presence of
2,3,7,Stetrachlorodibenzo-p-dioxin in beef fat. Bull.
Environ. Cont. Toxicol. 19: 229.
Kociba, et al. Toxic, and App. Pharm. In press.
Matsumura, F., and H.J. Benezet. 1973. Studies on the bio-
accumulation and microbial degradation of TCDD. Environ.
Health Perspect. 5: 253.
-------
Miller, R.A. , et al. 1973. Toxicity of 2 ,3 , 7, 8-tetrachloro-
dibenzo-p-dioxin (TCDD) in aquatic organisms. Environ.
Health Perspect. 5: 177.
National Research Council, Safe Drinking Water Committee.
1977. Drinking water and health: Part II. Natl. Acad. Sci.,
Washington, D.C.
Piper, W.N., et al. 1973. Excretion and tissue distribution
of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat. Environ.
Health Perspect. 5: 241.
Rose, J.Q. , et al. 1976. The fate of 2,3,7,8-TCDD following
single and repeated oral doses to the rat. Toxicol. Appl.
Pharmacol. 36: 209.
Seiler, J.P. 1973. A survey on the mutagenicity of various
pesticides. Experientia 29: 622.
Smith, F.A., et al. 1976. Teratogenicity of TCDD in DF-1
mice. Toxicol. Appl. Pharmacol. 38: 519
Sparschu, G.L., et al. 1971. Study of the teratogenicity of
TCDD in the rat. Food Cosmet. Tech. 9: 405.
Tenchini, M.L. , et al. 1977. Approaches to examination of
genetic damage after a major hazard in the chemical industry:
Preliminary cytohenic findings on TCDD exposed subjects after
the Seveso accident. Presented at the Expert Conference on
Genetic Damage Caused by Environmental Factors, Oslo, Norway,
May 11-13, 1977.
Toth, K., et al. 1977. Carcinogenic bioassay of the herbi-
cide 2,4,5-TCPE with different TCDD content in Swiss mice.
In: International Conference on Ecological Perspectives on
Carcinogens and Cancer Control, Cremona, 1976, Basel, Karger,
A.G.
U.S. EPA. 1979. 2,3,7,8-Tetrachlorodibenzo-p-dioxin: Am-
bient Water Quality Criteria. (Draft).
Van Miller, J.P. , and J.-R.'Allen. 1977. Chronic toxicity of
2,3,7,8-tetrachlorodibenzo-p-dioxin in rats. Fed. Proc. 35:
396.
Van Miller, J.P. , et al. 1976. Tissue distribution and ex-
cretion of tritiated tetrachldrodibenzo-p-dioxin in nonhuman
primates and rats. Food Cosmet. Toxicol. 14: 31.
Vos, J.G., et al. 1974. Toxicity of 2,3,7,8-tetrachlorodi-
benzo-p-dioxin in C-573L-6 mice. Toxicol. Appl. Pharmacof.
29: 229.
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No. 156
1,1,1,2-Tetrachloroethane
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
SUMMARY
- 1,1,1,2-Tetrachloroethane is potentially formed during chlorinaticn of
drinking water and has been identified at a concentration of 0.11 jug/1.
Although inhalation is the major route of exposure to chlorinated ethanes,
specific information on 1,1,1,2-tetrachloroethane inhalation is .not .avail-
able.
Literature reporting adverse occupational exposures to this chloro-
ethane cannot be found. Animal experiments measuring the acute and subacute
effects indicate, however, that chronic exposure may produce liver damage.
1,1,1,2-Tetrachloroethane is currently being tested by the National Cancer
Institute • for possible carcinogenicity. The compound not mutagenic
according to one report. Data . could not be located in the available
literature showing it to be teratogenic.
Pertinent information could not be found in the available literature
regarding the adverse effects of this compound on aquatic animals or plants.
-------
1,1,1,2-TETRACHLOROETHANE
I. INTRODUCTION
This profile is based primarily on the Ambient Water Quality Criteria
Document for Chlorinated Ethanes (U.S. EPA, 1979a).
The chloroethanes are hydrocarbons in which one or more of the hydrogen
atoms of ethane are replaced by chlorine atoms. In general, water solu-
bility and vapor pressure decrease with increasing chlorination, while dens-
ity and melting point increase. 1,1,1,2-Tetrachloroethane (molecular weight-
167.9) is a liquid at room temperature with a bailing point of 129°C, a
melting point of -68°C, a specific gravity of 1.553, and a solubility in
water of 2.85 mg/1 (U.S. EPA, 1979a).
1,1,1,2-Tetrachloroethane is used as a solvent and in the manufacture
of a number of widely used products, as are the other chloroethanes (U.S.
EPA, 1975). In general, these compounds form azeotropes with water (Kirk
and Othmer, 1963) and are very soluble in organic solvents (Lange, 1956).
Pearson and McConnell (1975) were unable to demonstrate microbial degrada-
tion of these compounds, but did report chemical degradation. For a more
general treatment of the chlorinated ethanes as a class, the reader is
referred to the EPA/ECAO Hazard Profile on Chlorinated Ethanes (U.S. EPA,
1979b).
II. EXPOSURE
1,1,1,2-Tetrachloroethane is potentially formed during chlorination of
drinking water and has been identified at a concentration of 0.11 ^g/l (U.S.
EPA, 1974). Information on the levels of 1,1,1,2-tetrachloroethane in food
are not available although other chloroethanes have been detected (U.S. EPA,
*
1979a). Inhalation is the major route of exposure to chlorinated ethanes.
However, specific information on 1,1,1,2-tetrachloroethane exposure is not
-------
available (U.S. EPA, 1979a). As with most solvents, chloroethanes can be
absorbed through the skin. This is not, however, a major route of exposure
(U.S. EPA, 1979a).
The U.S. EPA (1979a) has estimated a weighted average bioconcsntration
factor of 18 for 1,1,1,2-tetrachloroethane for the edible portions of fish
and shellfish consumed by Americans. This value was based on an estimated
steady-state bioconcentration factor of 62, which was determined from an
octanol/water partition coefficient of 457.
III. PHARMACOKINETICS
A. Absorption
Specific information on the absorption of 1,1,1,2-tetrachloro-
ethane is not available. In general,, the chloroethanes are absorbed rapidly
following ingestion or inhalation (U.S. EPA, 1979a).
B. Distribution
Inhalation or ingestion of 1,1,1,2-tetrachloroethane results in
the presence of high levels of solvent in the fetuses of the exposed animals
(Truhaut, et al. 1974). Other studies indicate a widespread distribution of
chloroethanes throughout the body after administration (U.S. EPA, 1979a).
C. Metabolism
After oral administration to . rats, guinea pigs, and rabbits,
1,1,1,2-tetrachloroethane underwent hydrolytic dehalogenation resulting in
formation of trichloroethanol, which was eliminated primarily in the urine
in the form of a conjugated glucuronic derivative, urochloralic acid. Oxi-
dation to trichloroacetic acid was considerable only in rats (Nguyen, et al.
1971; Truhaut and Nguyen, 1973). In the latter study monochloroacetic acid
*
and mercaptan derivatives were not .found in the urine. The only halogenated
-------
compound found in the expired air was untransformed 1,1,1,2-tetrachloro-
ethane. Trichloroethanol and trichloroacetic acid have also been identified
in the urine of rats following interperitoneal (i.p.) injection or vapor
inhalation of 1,1,1,2-tetrachloroethane (Ikeda and Ohtsuji, 1972), and have
been identified in the urine of mice following i.p. injection of the parent
compound (Yllner, 1971).
In general, the metabolism of chloroethanes involves both enzy-
matic dechlorination and hydroxylation and non-enzymatic oxidation (U.S.
EPA, 1979a). Oxidation reactions may produce unsaturated metabolites which
are then transformed to the alcohol and ester (Yllner, 1971).
D. Excretion
Murine studies show that, after i.p. injection of 1,1,1,2-tetra-
chloroethane, approximately 78 percent of the dose is excreted in 72 hours;
from 21 to 62 percent of this dose is excreted in the breath and from 18 to
56 percent as metabolites in the urine (Yllner, 1971). Other studies also
indicate that 1,1,1,2-tetrachloroethane is excreted in the urine as
metabolites and in the expired breath as the parent compound (see above).
IV. EFFECTS
A. Carcinogenicity
1,1,1,2-Tetrachloroethane is currently being tested by NCI for
possible carcinogenicity; results are not available (NTCTP, 1980). Other
information relative to the potential carcinogenicity of
1,1,1,2-tetrachloroethane was not located in the available literature.
8. Mutagenicity
Simmon, et al. (1977) tested 71 chemicals identified in the U.S.
*
drinking water for mutagenesis with an Ames Salmonella/microsome assay.
1,1,1,2-Tetrachlorcethane was found not to be mutagenic in this study.
-------
C. Teratogenicity and Other Reproductive Effects
The isomer of 1,1,1,2-tetrachloroethane, syn-tetrachloroethane, is
a weak teratogen in two strains of mice .(Schmidt and Reiner, 1976). Both
tetrachloroethanes are embryotoxic (Schmidt and Reiner, 1976; Truhaut, et
al., 1974). Other pertinent data have not been found.
D. Chronic Toxicity
Adverse occupational exposure to 1,1,1,2-tetrachloroethane has not
been reported by NIOSH. (U.S. EPA, 1979a). Animal experiments measuring
acute and subacute effects indicate that chronic "inhalation exposure may
produce liver damage (see below).
E. Acute and Subacute Toxicities
At 24 hours after the oral administration of 0.5 g 1,1,1,2-tetra-
chloroethane/kg to rabbits, the blood cholesterol and total lipid levels
were increased and the glutamic-pyruvic transaminase, glutamic-oxalacetic
transaminase, creatine phosphokinase, lactate dehydrogenase, • and a-hydroxy-
butyrate dehydrogenase activities were enhanced. Except for creatine phos-
phokinase, these enzyme levels remain elevated at 72 hours after poisoning
(Truhaut, et al. 1973). Subsequent studies by this research group found
that in rabbits, 1,1,1,2-tetrachloroethane was only slightly irritating to
the skin .and ocular mucous membrane, and its cutaneous ID was 20 g/kg.
Its acute toxicity by inhalation, for an exposure of 4 hours, was similar in
rats and rabbits, with the LC5Q being 2500 mg/m3. The oral LD50
values in rats and mice were 800 and 1500 mg/kg, respectively. Histological
examination revealed hepatotoxic activity, including' formation of micro-
vacuolizations and centrolobular necrosis. 1,1,1,2-Tetrachloroethane was
from two to three times less toxic than 1,1,2,2-tetrachloroethane (Truhaut,
et al. 1974).
-------
Recent studies exploring subacute effects indicate that in female
Wistar rats, 1,1,1,2-tetrachloroethane (0.30 g/kg, 5 days/week, for 2 weeks,
orally) induced hepatic steatosis by accumulation of triglycerides, accom-
panied by a decrease in liver lactate dehydrogenase, malate dehydrogenase,
and glutamic pyruvic transaminase activities. The tetrachloroethane caused
no changes in the liver of male rats (Truhaut, et al. 1975). However,
another team of investigators found that 1,1,1,2-tetrachloroethane (from 1GO
to 800 /jmoles/kg/day for 7 days, i.p.) to male rats increased liver
succinate dehydrogenase, acid phosphatase and glucose 6-phosphatase
activities and decreased liver DNA content. In addition, the white cell
count was increased and the red cell count and blood cholesterol content
were decreased (Chieruttini, et al. 1976).
V. AQUATIC TOXICITY
Pertinent data could not be located in the available literature re-
garding either the acuta and chronic tcxicity to aquatic animals, or the
aquatic residues of 1,1,1,2-tetrachloroethane.
VI. EXISTING GUIDELINES AND STANDARDS
Guidelines for occupational exposure to 1,1,1,2-tetrachloroethane do
not exist (International Labor Office, No. 37, 1977; NIOSH, 1978); however,
1,1,2,2-tetrachloroethane exposure is limited in the workplace to 5 ppm (35
mg/cu m) as an 8-hour time-weighted average (TWA) concentration.
-------
1,1,1,2-TETRACHLOROETHANE
REFERENCES
Chieruttini, M.E., et al. 1976. The toxicology of the tetrachloroethanes.
Br. Jour. Pharmacol. 57: 421.
Ikeda, M. and H. Oht.suji. 1972. Comparative study of the excretion of
Fujiwara reaction-positive substances in urine of humans and rodents given
trichloro- or tetrachloro-derivatives of - ethane and ethylene. 8r. Jour.
Ind. Med. 29: 99.
International. Labor Office. 1977. Occupational exposure limits for airborn
toxic substances — A tabular compulation of values for selected countries.
Occupational Safety and Health Series, NO. 37. Geneva .
Kirk, R. and D. Othmer. 1963. Encyclopedia of chemical technology. 2nd
ed. John Wiley and Sons, Inc., New York.
Lange, N. (ed.) 1956. Handbook of chemistry. 9th ed. Handbook Pub-
lishers, Inc., Sandusky, Ohio.
National Toxicology Carcinogenesis Testing Program. 1980. Chemicals on
Standard Protocol.
National Institute for Occupational Safety and Health. 1973. Current in-
telligence bulletin, No. 27, OHEW Pub.. No. 78-181, p. 4.
Nguyen, P., et al. 1971. 1,1,1,2-Tetrachloroethane metabolism. C.R. Acad.
Sci., Ser. D. 272: 1173.
Pearson, C.R., and G. McConnell. 1975. Chlorinated hydrocarbons in the
marine environment. Proc. R. Soc. London. Ser. B. 189: 305.
Schmidt and Reiner. 1976. The embryotoxic and. teratogenic effect of tetra-
chloroethane - experimental studies. Biol. Rundsch. 14: 220.
Simmon, V., et al. 1977. Mutagenic activity of chemicals identified in
drinking water. .Dev. Toxicol. Environ. Sci. 2: 249.
Truhaut, R. and P. Nguyen. 1973. Metabolic transformations of
1,1,1,2-tetrachloroethane in.the rat, guinea pig, and rabbit. Jour. Eur.
Toxicol. 6: 211.
•Truhaut, R., et al. 1973. Serum enzyme activities and biochemical blood
components in subacute 1,1,1,2-tetrachloroethane pdisoning in the rabbit.
Jour. Eur. Toxicol. 6: 81.
Truhaut, R., et al. 1974. Toxicological study of 1,1,1,2-tetrachloro-
ethane. Arch. Mai. Prof. Med. Trav. Secur. Soc. 35: 593.
-------
Truhaut, R., et al. 1975. Preliminary biochemical study of the hepato-
toxicity of 1,1,1,2-tetrachloroethane in the Wistar rat. Effect of sex.
Eur. Jour. Toxicol. Environ. Hyg. 8: 175.
U.S. EPA. 1974. "Draft analytical report - New Orleans area water supply
study," EPA 906/10-74-002. Lower Mississippi River Facility, Slidell, La.,
Surveill. Anal. Oiv. Region VI, Dallas, Tex.
U.S. EPA. 1975. Identification of organic compounds in effluents from in-
dustrial sources. EPA 560/3-75-002.
U.S. EPA. 1979a. Chlorinated Ethanes: Ambient Water Quality Criteria.
(Draft)
U.S. EPA. 1979b. Hazard Profile: Chlroinated Ethanes (Draft).
Yllner, S. 1971. Metabolism of 1,1,1,2-tetrachloroethane in the mouse.
Acta Pharmacol. Toxicol. 29(5-6): 471-4SO, 1971.
-------
No. 157
1,1,2,2-Tetrachloroethane
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-/m-
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-1*73-
-------
SPECIAL NOTATION
U.S. EPA1s Carcinogen Assessment Group (CAG) has evaluated
1,1, 2 , 2 ,-tetrachloroethane and has found sufficient evi-
dence to indicate that this compound is carcinogenic.
-------
1,1,2,2-TETRACHLOROETHANE
SUMMARY
An increased incidence of hepatocellular carcinomas has
been shown in mice following oral administration of 1,1,2,2-
tetrachloroethane. Mutagenic effects have been reported in
the Ames Salmonella assay and in E. coli. There is no avail-
able evidence to indicate that 1,1,2,2-tetrachloroethane pro-
duces teratogenic effects. Occupational exposure to 1,1,2,2-
tetrachloroethane has produced several toxic effects includ-
ing neurological symptoms, liver and kidney damage, pulmonary
edema, and fatty degeneration of heart muscle.
The toxicity of 1,1,2,2-tetrachloroethane has been exam-
ined in one species each of freshwater and marine fish, in-
vertebrates, and plants. Freshwater invertebrates appear to
be the most sensitive species examined, with acute toxic con-
centrations of 9,320 ug/1 being reported.
-------
1,1,2,2-TETRACHLOROETHANE
I. INTRODUCTION
This profile is based on the Ambient Water Quality Cri-
teria Document for Chlorinated Ethanes (U.S. EPA, 1979a).
The chloroethanes are hydrocarbons in which one or more
of the hydrogen atoms of ethane are replaced by chlorine
atoms. In general, water solubility and vapor pressure
decrease with increasing chlorination, while density and
melting point increase. 1,1,2,2-Tetrachloroethane (molecular
weight 167.9) is a liquid at room temperature with a boiling
point of 146.3°C, a melting point of -36°C, a specific
gravity of 1.596, and a solubility in water of 2.9 gm/1 (U.S.
EPA, 1979a).
The chloroethanes are used as solvents, cleaning and de-
greasing agents, and in the chemical synthesis of a number of
compounds.
The chlorinated ethanes form azeotropes with water (Kirk
and Othmer, 1963). All are very soluble in organic solvents
(Lange, 1956). Microb-ial degradation of the chlorinated
ethanes has not been demonstrated (U.S. EPA, 1979a). For
additional information regarding the chlorinated ethanes in
general, the reader is referred to the Hazard Profile on
Chlorinated Ethanes•(U.S. EPA, 1979b).
II. EXPOSURE
The chloroethanes present in raw and finished waters are
due primarily to industrial discharges. Small amounts of '
chloroethanes .may be formed by chlorination of drinking water
or treatment of sewage. Atmospheric chloroethanes result
-------
from evaporation of volatile chloroethanes during use as
degreasing agents or in dry cleaning operations (U.S. EPA,
1979a).
Routes of human exposure to chloroethanes include water,
air, contaminated foods and fish, and dermal absorption.
Fish and shellfish have shown levels of chloroethanes in the
nanogram range (Dickson and Riley, 1976). Information on the
levels of 1,1,2,2-tetrachloroethane in foods is not avail-
able.
The EPA (1979a) has estimated a weighted average biocon-
centration factor for 1,1,2,2-tetrachloroethane to be 18 for
the edible portions of fish and shellfish consumed by Ameri-
cans. This estimate was based on steady-state bioconcentra-
tion studies in the bluegill.
III. PHARMACOKINETICS
A. Absorption
The chloroethanes are absorbed rapidly following
ingestion or inhalation (U.S. EPA, 1979a). Morgan, et al.
(1972) have determined that 1,1,2,2-tetrachloroethane has a
high octanol/water partition coefficient, high rate of pul-
monary absorption, and low rate of elimination by exhalation.
B. Distribution
Pertinent data could not be located in the avail-
able literature on 1,1,2,2-tetrachloroethane. The reader is
referred to a more general treatment of chlorinated ethanes
»
(U.S. EPA, 1979b), which indicates widespread distribution of
these compounds throughout the body.
-------
C. Metabolism
The metabolism of chloroethanes involves both enzy-
matic dechlorination and hydroxylation and non-enzymatic oxi-
dation (U.S. EPA, 1979a). Oxidation reactions may produce
unsaturated metabolites which are then transformed to the
alcohol and ester (Yllner, 1971). Trichloroethanol and tri-
chloro acetic acid have been identified in the urine of rats
following inhalation of 1,1,2,2-tetrachloroethane vapor
(Ikeda and Ohtsuji, 1972). Metabolism of.this compound ap-
pears to involve the activity of the mixed-function oxidase
system (Van Dyke and Wineman, 1971).
D. Excretion
The chloroethanes are excreted primarily in the
urine and expired air. Murine studies indicate that, after
intraperitoneal (i.p.) injection of 1,1,2,2-tetrachloro-
ethane, approximately 80 percent of the dose is excreted in
72 hours. Half of this dose is excreted as carbon dioxide in
the breath and one-fourth as metabolites in the urine (Yllner/
1971). Human studies (Morgan, et al. 1972) indicate that
after inhalation exposure of 1,1, 2,2-tetrachloroethane the
amount expired in the breath is less than that observed in
animal studies, although a different radioactive tracer was
used.
IV. EFFECTS
A. Carcinogenicity
Results of a National Cancer Institute (NCI) car-'
cinogenesis bioassay for 1,1,2,2-tetrachloroethane show that
oral administration produced an increased incidence of hepato-
-------
cellular carcinomas in exposed mice (NCI, 1978). No sta-
tistically significant tumor increase was seen in rats.
B. Mutagenicity
The mutagenic activity of 1,1,2,2-tetrachloroethane
has been shown in the Ames Salmonella assay and in a DNA
polymerase-deficient strain of E. coli (Brem, et al., 1974).
C. Teratogenicity and Other Reproductive Effects
Embryo toxicity and weak teratogenicity have been
reported in two strains of mice exposed with 1,1,2,2-tetra-
chloroethane (Schmidt and Reiner, 1976). Other pertinent in-
formation could not be located in the available literature.
D. Chronic Toxicity
Occupational .exposure to 1,1,2,2-tetrachloroethane
has produced toxic effects including neurological symptoms,
liver and kidney damage, pulmonary edema, and fatty degenera-
tion of heart muscle (U.S. EPA, 1979a).
Animal experiments have indicated that chronic in-
halation exposure may produce liver and kidney degeneration
(U.S. EPA, 1979a).
V. AQUATIC TOXICITY
A. Acute Toxicity
Toxicity studies on one species from each category
of freshwater and marine fish and invertebrates have been re-
ported (U.S. EPA, 1978). In freshwater fish, the study
yielded a 96-hour static LC$Q value of 21,300 ug/1 for
the bluegill ( Leponis macrocb. i rus ) . For freshwater inverte'-
brates, the study yielded a 48-hour static LC50 value of
-------
9,320 ug/1 for the caldoceran Daphnia- magna. In marine fish
and invertebrates, the studies yielded a 96-hour static LCcn
value of 12,300 ug/1 for the sheepshead minnow (Cyprinodon
varieoatus), and of 9,020 ug/1 for the mysid shrimp (Mys i-
dopsis bahia).
B. Chronic Toxicity
Pertinent information could not be located in the
available literature.
C. Plant Effects
When the freshwater algae Selenastrum capricornutum
was tested for adverse effects of 1,1,2,2-tetrachloroethane
on chlorophyll and cell numbers ECgg values of 136,000
and 146,000 ug/1 were obtained. When the marine algae Skele-
tonema costatum was tested for these adverse effects, 96-hour
EC^Q values were 6,440 and 6,230 ug/1, respectively.
D. Residues
A b.ioconcentration value of 8 was reported for the
bluegill (U.S. EPA, 1979a).
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human, health nor aquatic criteria derived by
U.S. EPA (1979a), which are summarized below, have gone
through the process of public review; therefore, there is a
possibility that these criteria will be changed.
A. Hunan
Based on the NCI carcinogenic data, and using a
*
linear, nonthreshold model, the U.S. EPA (1979a) has esti-
mated the level of 1,1, 2 , 2-tetrachloroethane in ambient water
-------
chat will result in an additional cancer risk of 10~5 to
be 1.8 ug/1.
The exposure standard determined by OSHA for 1,1,-
2,2-tetrachloroethane is 5 ppm as an eight-hour time-weighted
average concentration.
B. Aquatic
The draft criterion for protection of freshwater
aquatic life is 170 ug/1 as a 24-hour average, not to exceed
380 ug/1- The draft criterion to protect, marine life from
1,1,2,2-tetrachloroethane is 70 ug/1 as a 24-hour average,
not to exceed 160 ug/1 (U.S. EPA, 1979a).
-------
1,1,2,2-TETRACHLOROETHANE
REFERENCES
Brem, H., et al. 1974. The mutagenicity and ONA-modifying effect of halo-
alkanes. Cancer Res. 34: 2576.
Dickson, A.G. and J.P. Riley. 1976. The distribution of short-chain halo-
genated aliphatic hydrocarbons in some marine organisms. Mar. Pollut. Bull.
79: 167.
Ikeda, M. and H. Ohtsuji. 1972. Comparative study of the excretion of
Fujiwara reaction-positive substances in urine of humans and rodents given
trichloro- or tetrachloro-derivatives of ethane and ethylene. Br. Jour.
Ind. Med. 29: 99.
Kirk, R. and D. Othmer. 1963. Encyclopedia of chemical technology. 2nd
ed. John Wiley and Sons, Inc., New York.
Lange, N. (ed.) 1956. Handbook of chemistry. 9th ed. Handbook Publish-
ers, Inc., Sandusky, Ohio.
Morgan, A., et al. 1972. Absorption of halogenated hydrocarbons and their
excretion in breath using chlorine-38 tracer techniques. Ann. Occup. Hyg.
15: 273.
National Cancer Institute. 1978. Bioassay of 1,1,2,2-tetrachloroethane for
possible carcinogenicity. Natl. Inst. Health, Natl. Cancer Inst. DHEW Publ.
NO. (NIH) 78-827. Pub.; Health Serv., U.S. Dept. Health Edu. Welfare.
Schmidt and Reiner. 1976. The embryotoxic and teratogenic effect "of
tetrachloroethane - experimental studies. Biol. Rudsch 14: 220.
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. Contract No. 68-01-4646, U.S. Environ. Prot.
Agency.
U.S. EPA. 1979a. Chlorinated Ethanes: Ambient Water Quality Criteria.
(Draft)
U.S. EPA. 1979b. Environmental Criteria and Assessment Office. Chlori-
nated Ethanes: Hazard Profile. (Draft)
Van Dyke, R.A. and C.G. Wineman. 1971. Enzymatic dechlorination: Oechlor-
ination of chloroethanes and propanes in vitro. Biochem. Pharmacol.
20: 463. • -
Yllner, S. 1971. Metabolism of 1,1,2 ^-tetrachloroethane-1^ in the
mouse. Acta. Pharmacol. Toxicol. 29: 499.
-------
No. 158
Tetrachloroethylane
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
SPECIAL NOTATION
U.S. EPA's Carcinogen Assessment Group (GAG) has evaluated
tetrachloroethylene and has found sufficient evidence to
indicate that this compound is carcinogenic.
-------
TETRACELOROETHYLEN E
SUMMARY
Tetrachloroethylene is widespread in the environment,
and. is found in trace amounts in water, aquatic organisms,
air, foodstuffs, and human tissue. Tetrachloroethylene
causes mild intoxication and liver dysfunction following
chronic exposure to high levels associated with certain in-
dustries. Tetrachloroethylene has not been shown to be tera-
togenic, but it has been shown to be mutagenic in bacterial
assays and carcinogenic in mice.
The bluegill (Lepomis macrochirus) is the most sensitive
freshwater species to acute tetrachloroethylene toxicity
with a reported 96-hour LC50 of 12,900 ug/1. In the only
acute toxicity study for saltwater species the mysid shrimp
(Mysidopsis bahia) has an observed 96-hour LC^Q value of
10,200 ug/1. The chronic value for this shrimp is 448 ug/1.
A freshwater algae has a reported no-effect concentration of
tetrachloroethylene at 816,000 ug/1. A marine alga, however,
was adversely affected at the considerably lower level of
10,000 ug/1- Tetrachloroethylene is only slightly bioconcen-
trated by the bluegill (49 times) after 21 days of exposure,
and has an elimination half-life of less than one day.
-------
I. INTRODUCTION
This profile is based on the Ambient Water Quality Cri-
teria Document for Tetrachloroethylene (U.S. EPA, 1979).
Tetrachloroethylene (C2^^^r 1,1,2,2-tetrachloroethy-
lene, perchloroethylene, PCE; molecular weight 165.85) is a
colorless, nonflammable liquid. It has the following physi-
cal/chemical properties (Patty, 1963):
Melting Point: -23.25°C
Density: 1.623 g/ml
Vapor Pressure: 19 mm Hg
Water Solubility: 150 ug/ml
Octanol/Water
Partition Coefficient: 339
Tetrachloroethylene is primarily used as a solvent in
the dry cleaning industry and, to a lesser extent, as a de-
greasing solvent in metal industries (Windholz, 1976).
II. EXPOSURE
The National Organics Monitoring Survey (U.S. EPA, 1978)
. detected tetrachloroethylene in 9 out of 105 drinking water
samples between November 1976 and January 1977 (range, <0.2
to 3.1 ug/1; median <0.2 ug/D- No data exist for ingestion
of tetrachloroethylene from food for the United States. How-
ever, in England, tetrachloroethylene concentrations in foods
ranged from nondetectable amounts in orange juice to 13 ug/kg
in butter (McConnel," et al., 1975). The U.S. EPA (1979) has
estimated the weighted bioconcentration factor of tetrachlo-
roethylene to be 110 for the edible portion of consumed fish
and shellfish. This estimate is based on measured steady-.
state bioconcentration studies in bluegills. Generally,
-------
environmental tetrachloroethylene concentrations in air tend
to be low. A survey of eight locations in the U.S. indicated
concentrations up to 6.7 ug/m3 in urban areas and less than
0.013 ug/m3 in rural areas (Lillian, et al., 1975). By far
the most significant exposure to tetrachloroethylene is in
the industrial environment (Fishbein, 1976). Significant der-
mal exposure would be confined to occupational settings.
III. PHARMACOKINETICS
A. Absorption
Using inhalation exposure, Stewart, et al. (1961)
found that tetrachloroethylene reached near steady-state
levels in the blood of human volunteers with two hours of
continuous exposure. However, steady-state conditions in
this study were probably obtained by a redistribution phenom-
enon, since the biological half-life of tetrachloroethylene
metabolites in humans has been measured to be 144 hours
(Ikeda and Imamura, 1973).
B. Distribution
In humans (McConnell, et al., 1975) and rats (Savo-
lainen, et al., 1977), tetrachloroethylene tends to accumu-
late in the body fat, and to a lesser extent in the brain and
liver. Measurements in the rat suggests that the level of
PCS in the liver and blood remains constant after three hours
of exposure.
C. Metabolism
In a qualitative sense, metabolic products appear
to be similar in humans (Ikeda, et al., 1972; Ikeda, 1977)
and experimental animals (Yllner, 1961; Daniel, 1963; Ikeda
-------
and Ohtsuji, 1972). The metabolism of tetrachloroethylene
leads to the production of trichloroacetic acid, and is ap-
parently saturable (Ikeda, 1977). The enzyme systems respon-
sible for this metabolism are inducible with phenobarbital
(Ikeda and Imamura, 1973) and polychlorinated biphenyls
(Moslen, et al. , 1977).
D. Excretion
In humans tetrachloroethylene is primarily elimi-
nated from the body via the lungs with a half-life of elimi-
nation estimated to be 65 hours (Stewart, et al., 1961, 1970;
Ikeda and Imamura, 1973). Its metabolite, trichloroacetic
acid, is eliminated in the urine of humans with a half-life
estimated to be 144 hours (Ikeda and Imamura, 1973).
IV. EFFECTS
A. Carcinogenicity
Tetrachloroethylene caused hepatocellular carcino-
mas in B6C3-F1 mice of both sexes (NCI, 1977). An experiment
in Osborne-Mendel rats produced negative results, although
early mortality precluded the use of this data in evaluating
the carcinogenicity of PCE (NCI, 1977).
Greim, et al. (1975) could not demonstrate an in-
crease in the mutation rate of jE. coli K^ with tetra-
chloroethylene. However, Cerna and Kypenova (1977) tested
PCE and found elevated mutagenic activity in Salmonella
strains sensitive to both base pair substitution and frame-
shift mutations.
C. Teratogenicity
Only one report has appeared concerning possible
-------
tetrachloroethylene-induced teratogenesis (Schwetz, et al.
1975). Female rats and mice were exposed to 2000 mg/m^ 7
hours daily on days 6 to 15 of gestation. Significant de-
creases in fetal body weight and resorption, subcutaneous
edema and delayed ossification of skull bones and sternabone
in the pups were noted. These effects were mild, however,
and led the authors to conclude that PCE was not teratogenic.
Additional work is necessary to determine whether PCE is ter-
atogenic (U.S. EPA, 1979).
D. Other Reproductive Effects
No information available.
E. Chronic Toxicity
Repeated exposure to tetrachloroethylene has re-
sulted in damge to liver and kidney in dogs (Klaassen and
Plaa, 1967). Toxic nephropathy has also been observed in
mice and rats (NCI, 1977). In humans, chronic exposure to
. 1,890 to 2,600 mg PCE/m3 caused three of seven men to have
impaired liver function (Coler and Rossmiller, 1953). Occa-
sional reports have even associated tetrachloroethylene expo-
sure with the symptomatology of more serious chronic diseases
such as Raynaud's disease (Lob, 1957; Sparrow, 1977). Spar-
row (1977) reported a case which involved depressed immune
function, mildly depressed liver function, polymyopathy and
severe acrocyanosis. In a group of workers occupationally
exposed to lower concentrations of tetrachloroethylene at ap-
proximately 400 mg/m^ (one for 15 years), subjective com- •
plaints, such as headache, fatigue, somnolence, dizziness,
-------
and a sensation of intoxication were noted (Medek and
Kovarik, 1973).
F. Other Relevant'Information
Intolerance of alcohol has been reported with tet-
rachloroethylene exposure (Gold, 1969).
V. AQUATIC TOXICITY
A. Acute Toxicity
Ninety-six hour LCgg values for flow-through
and static tests are 18,400 and 21,400 ug/1, respectively,
with the fathead minnow, Pimephales promelas (Alexander, et
al. 1978). With the bluegill, Lepomis macrochirus, the 96-
hour LC50 value is 12,900 ug/1 (U.S. EPA, 1978). For
Daphnia magna, an observed 48-hour LCgg value of 17,700
ug/1 .has been recorded (U.S. EPA, 1978).
Mb acute data are available for saltwater fish.
The mysid shrimp (Mysidopsis bahia) has an observed 96-hour
LC5Q of 10,200 ug/1 (U.S. EPA, 1978).
B. Chronic Toxicity
Chronic test data are not available for freshwater
species. A chronic value for the saltwater mysid shrimp in a
life cycle test is 448 ug/1 (U.S. EPA, 1978).
C. Plant Effects
No adverse effects on chlorophyll a^ concentration
or cell numbers with the alga, Selenastrum capricornutum,
were observed at exposure concentrations as high as 816,000
ug/1 (U.S. EPA, 1978). Two 96-hour EC50 values were re- •
ported for the marine micro alga, Skeletonema costatura:
504,000 ug/1 based on cell numbers and 509,000 ug/1 based on
-------
chlorophyll a concentration (U.S. EPA, 1978). The macroalga,
Phaeodectylum tricornu'tum, was considerably more sensitive to
tetrachloroethylene toxicity with a reported EC50 of
10,500 ug/1 (Pearson and McConnell, 1975).
D. Residues
The bioconcentration factor for bluegills, Lepomis
macrochirus, has been reported to be 49 (U.S. SPA, 1978).
Equilibrium was reached within 21 days and the depuration
rate was rapid with a half-life of less than one day.
VI.G EXISTING GUIDLINES AND STANDARDS
A. Human
Based on the NCI mice data, and using the "one-hit"
model, the U.S. EPA (1979) has estimated levels of tetrachlo-
roethylene in ambient water which will result in specified
risk levels of human, cancer:
Risk Levels and
Exposure Assumptions Corresponding Draft Criteria
(per day) £ 10"7 10~6 10"5
2 liters of drinking
water and consumption
of 18.7 grams fish and
shellfish. 0 0.020 ug/1 0.20 ug/1 2.0 ug/1
Consumption of fish and
shellfish only. 0 0.040.ug/1 0.40 ug/1 4.0 ug/1
The present American Governmental Conference on Industrial
Hygiene (AGCIH, 1977) threshold limit value (TLV) is 670
-------
B. Aquatic
For tetrachloroethylene, the draft criterion to
protect saltwater aquatic life is 79 ug/1 as a 24-hour aver-
age; the concentration should never exceed 180 ug/1 at any
time (U.S. EPA, 1979).
For freshwater aquatic life, the draft criterion is
310 ug/1 as a 24-hour average; the concentration should never
exceed 700 ug/1 at any time (U.S. EPA, 1979).
This draft criteria to protect aquatic life is
presently being reviewed before final recommendation.
-------
TETRACHLOROETHYLEN E
REFERENCES
Alexander, H., et al. 1978. Toxicity of perchloroethylene,
trichloroethylene, 1,1,1-trichloroethane, and methylene chlo-
ride to fathead minnows. Bull. Environ. Contam. Toxicol.
20: 344.
American Conference of Governmental Industrial Hygienists.
1977. Documentation of the threshold limit value. 3rd ed.
Cerna, M., and H. Kypenova. 1977. Mutagenic activity of
chloroethylenes analyzed bv screening system tests. Mutat.
Res. 46: 214.
Coler, H.R., and H.R. Rossmiller. 1953. Tetrachloroethylene
.exposure in a small industry. Arch. Ind. Hyg. Occup. Med.
8: 227.
Daniel, J.W. 1963. The metabolism of 36cl-labelled tri-
chloroethylene and tetrachloroethylene in the rat. Biochem.
Pharmacol. 12: 795.
Fishbein, L. 1976. Industrial mutagens and potential muta-
gens I. Halogenated aliphatic hydrocarbons. Mutat. Res.
32: 267.
Gold, J.H. 1969. Chronic perchloroethylene poisoning. Can.
Psychiat. Assoc. Jour. 14: 627.
Greim, H., et al. 1975. Mutagenicity in vitro and potential
carcinogenicity of chlorinated ethylenes as a function of
metabolic oxirane formation. Biochem. Pharmacol. 24: 2013.
Ikeda, M. 1977. Metabolism of trichloroethylene and tetra-
chloroethylene in human subjects. Environ. Health Perspect.
21: 239.
Ikeda, M., and T. Imamura. 1973. , Biological half-life of
trichloroethylene and tetrachloroethylene in human subjects.
Int. Arch. Arbeitsmed. 31: 209.
Ikeda, M., and H. Ohtsuji. 1972. A comparative study of the
excretion of Fujiwara - reaction-positive substances in urine
of humans and rodents given trichloro- or tetrachloro- deriv-
atives of ethane and ethylene. Br. Jour. Ind. Med. 29: 99.
Ikeda, M., et al. 1972. Urinary excretion of total tri-
chloro-compounds, trichloroethanol and trichloracetic acid as
a measure of exposure to trichloroethylene and tetrachlorc--
ethylene. Br. Jour. Ind. Med. 29: 328.
-------
Klaassen, C.D., and G.L. Plaa. 1967. Relative effects of
chlorinated hydrocarbons on liver and kidney function in
dogs. Toxicol. Appl. Pharmacol. 10: 119.
Lillian, D., et al. 1975. Atmospheric fates of halogenated
compounds. Environ. Sci. Technol. 9: 1042.
Lob, M. 1957. The dangers of perchloroethylene. Int. Arch.
Gewerbe-patholog. und Gewerbhyg. 16: 45.
McConnell, G., et al. 1975. Chlorinated hydrocarbons and
the environment. Endeavour 34: 13.
Medek, V., and J. Kovarik. 1973. The effects of perchloro-
ethylene on the health of workers. Pracovni Lekarstvi 25:
339.
Moslen, M.T., et al. 1977. Enhancement of the metabolism
and hepatoxicity of trichloroethylene and perchloroethylene.
Biochem. Pharmacol. 26: 369.
National Cancer Institute. 1977. Bioassay of tetrachloro-
ethvlene for possible carcinogenicity. CAS No. 127-18-4 NCI-
CG-TR-13 DREW Publication No. (filH) 77-813.
Patty, F. 1963. Aliphatic halogenated hydrocarbons. Ind.
Hyg/Toxicol. 2: 1314.
Pearson, C.R., and G. McConnell. 1975. Chlorinated Cj_ and
C2 hydrocarbopns in the marine environment. Proc. R. Soc.
London B. 189: 305.
Savolainen, H., et al. 1977. Biochemical and behavioral
effects of inhalation exposure to tetrachloroethylene and
dichloromethane. Jour. Neuropathol. Exp. Neurol. 36: 941.
Schwetz, B.A., et al. 1975. The effect of maternally in-
haled trichloroethylene, perchloroethylene, methyl chloro-
form, and methylene chloride on embryonal and fetal develop-
ment in mice and rats. Toxicol. Appl. Pharmacol. 32: 84.
Sparrow, G.P. 1977. A connective tissue disorder similar to
vinyl chloride disease in a patient exposed to perchloroethy-
lene. Clin. Exp. Dermatol. 2: 17.
Stewart, R.D, et al. 1970. Experimental human exposure to
tetrachloroethylene. Arch. Environ. Health 20: 225.
-------
Stewart, R.D., et al. 1961. Human exposure to tetrachloro-
ethylene vapor. Arch. Environ. Health 2: 516.
U.S. EPA. 1978. In-depth studies on health and environmen-
tal impacts of selected water pollutants. Contract No. 68-
01-4646. U.S. Environ. Prot. Agency.
U.S. EPA. 1979. Tetrachloroethylene: Ambient Water Quality
Criteria (Draft).
Windholz, M. , ed. 1976. The Merck Index. 9th ed. Merck
and Co., Rahway, N.J.
Yllner, S. 1961. Urinary metabolites of ^-4c-tetrachloro-
ethylene in mice. Nature (Lond.) 191: 820.
itf
-------
No. 159
Thallium
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-/m-
-------
THALLIUM
Summary
Thallium is a highly toxic element to many organisms,
including humans. Symptoms of acute exposure to thallium
include alopecia, ataxia, and tremors, occasionally leading
to irreversible coma and death. There is no information
available on the mutagenic and carcinogenic properties of
thallium. Although thallium has been reported to be terato-
genic, the evidence is not convincing. The acceptable daily
intake (ADI) of thallium has been, determined to be 15.4 mg
per day. Thallium can be chronically toxic to fish at con-
centrations as l-w as 20 u.g/1- -Algae are also sensitive,
^
with effects produced at concentrations as low as 100 ug/1-
•if??-
-------
THALLIUM
I. INTRODUCTION
This profile is based on the Ambient Water Quality Docu-
ment for Thallium (U.S. EPA, 1979).
Thallium (Tl; atomic weight 204.37) is a soft, malle-
able, heavy metal with a silver-white luster (Lee, 1971).
Thallium exists in either the monovalent (thallous) or tri-
valent (thallic) form, the former being the more common and
stable and therefore forming more numerous and stable salts
(Hampel, 1968). Thallium reacts chemically with moisture in
air to form oxides. Thallous oxide is easily oxidized to
thallic oxide, a very hygroscopic compound, or reduced to
thallium. While thallium itself is relatively insoluble in
water (Windholz, 1976)., thallium compounds exhibit a wide
range of solubilities.
Current production and use of thallium and its compounds
approximated 680 kg in 1976 (U.S. Dept. Interior, 1977). In-
dustrial uses of thallium include the manufacture of alloys,
electronic devices, and special glass. Many thallium-con-
taining catalysts have been patented for industrial organic
reactions (Zitko, 1975).
II. EXPOSURE
There is little information on the extent of thallium
contamination of water. In a single study 'by Greathouse
(1978) evaluating drinking water from 3,834 households ran-
»
domly selected from 35 geographic areas, thallium was detect-
able in only 0.68 percent of the samples (detection limit was
0.3 ppb), with the average concentration at detection of 0.89
-------
ppb. Assuming a water consumption of 2 liters per day for
the average adult, over 99 percent of adults would consume <
1 ug per day. The only study pertaining to natural water
measured the thallium content of run-cffs from mining and
smelting operations involving copper, gold, zinc, and cadmium
with which thallium is associated in trace quantities (U.S.
EPA, 1978). The highest concentrations reported were 30 ppb
in slag run-off near Kellog, Idaho and 21 ppb in the Colorado
River below drainage from a copper mine.
Ingestion of thallium from food is mainly due to the
consumption of vegetables. Little data is available, al-
though Geilmann, et al. (1960) found an average of 68.2 ppb
dry weight thallium in four vegetables analyzed. This may be ^
high due to the small sample size. Breads contain 0.75 ppb
dry weight thallium, and the thallium content of meats has
not been adequately determined. The EPA (1979) estimated
the weighted average bioconcentration factor for thallium to
be 61 for the edible portions of fish and shellfish consumed
by Americans. This estimate is based on measured steady-state
bioconcentration studies in bluegill. A daily intake from
food has been calculated at 3.8 ug/day. However, due to the
sparse data, this is probably not an accurate estimate.
The contribution of thallium in air to exposure is, in
most instances, small. However, thallium is a contaminant in
flyash, and in a worst case situation in the vicinity of a
coal-fired plant, daily absorption could be as high as 4.9
ug (Carson and Smith, 1977). .Due to possible high concentra-
tions in vegetable matter, cigarette smoke may be a signifi-
-------
cant source of thallium, with urinary excretion of thallium
in smokers being twice that in non-smokers (Weinig and Zink,
1967).
III. P HARMACOKIN ETICS
A. Absorption
Gastrointestinal absorption of trace quantities of
thallium appears to be almost complete in both man (Barclay,
et al. 1953) and rats (Lie, et al. 1960). No information was
found in the available literature concerning the deposition
and clearance of inhaled thallium aerosols. The skin would
not be expected to be a significant route of absorption of
thallium; however, systemic pois_oning has resulted from oint-
ments containing 3-8 percent thallium acetate applied to the
skin (Munch, 1934).
B. Distribution
Thallium is widely distributed in the body in the
intracellular space. Active transport of thallium, mediated
by Na/K ATPase into erythrocytes has been demonstrated
(Gehring and Hammond, 1964; Cavieres and Ellroy, 1974).
Other factors besides active transport into cells must be
operating, since in both conditions of normal thallium expo-
sure and fatal exposure in man, there is a tendency for thal-
lium to concentrate in the kidneys, colon and hair (Weinig
and Zink, 1967; Cavanagh, et al. 1974).
Thallium crosses the placenta freely from the ma-
»
ternal circulation to the fetus. In studies using rats and
mice, steady state maternal/fetal ratios of 0.84 and 0.46,
-------
respectively, were obtained (Gibson, et al. 1967); and under
non-steady state conditions, wide variations in dosage (0.2-
6.4 mg/kg/min) did not alter the distribution from mother to
fetus (Gibson and Becker, 1970). Richeson (1958) cites one
report in which thallium was found in the tissue of a baby
whose mother had taken 1.2 g thallium at term.
C. Metabolism
Pertinent information could not be located in the
available literature.
D. Excretion
Human excretion of thallium has been estimated from
two studies, one involving a tracer dose of 204 Tl given to a
middle-age woman with osteogenic carcinoma metastatic to the
lungs (Barclay, et al. 1953) and the other involving a woman
suffering from thallium poisoning (Innis and Moses, 1978).
From these two less than ideal studies, total excretion of
thallium per day in adults not exposed to unusual sources of
thallium is probably as follows:
Excretory route ug Tl/day
CJrine 1.20
Feces 0.06
Hair 0.32
Skin and Sweat 0.06
Total 1/64
-------
IV. EFFECTS
A. Carcinogenicity and Mutagenicity
Information regarding the carcinogenic and muta-
genic potential of thallium could not be located in the
available literature.
B. Teratogenicity
There are two reports of the teratogenicity of
thallium, one involving chicken embryos .(Karnofsky, et al.
1950) and the other rats (Gibson and Becker, 1970). m both
cases, overt fetal toxicity due to thallium was noted, making
it impossible to distinguish teratogenicity from a more
general toxic effect.
C. Other Reproductive Effects
The only known reproductive effect is fetal tox ic-
ity in cases of acute poisoning of the mother.
D. Chronic Toxicity
There are few reports of chronic thallium poisoning
in man. In one brief report concerning 13 men exposed 3 to 4,
months, the signs and symptoms were pains in the legs, weari-
ness, loss.of hair, disturbance of sensation, psychic trouble
albuminuria and nephritis (Meyer, 1928).
Rats fed thallous acetate in their diet for 105 days ex-
perienced no reduction in weight gain at concentrations of 5
and 15 ppm; 30 ppm, however, proved fatal to approximately
half the animals (Downs, et al. 1960).
E. Other Relevant Information
Potass ium has been shown to markedly enhance the
rate of thallium excretion (primarily urinary) in both rats
-------
and dogs (Gehring and Hammond, 1967). Potassium also in-
creased somewhat the acute LDqQ of thallium. In humans,
potassium also increases urinary excretion with accompanying
temporary accentuation of the neurological signs and symptoms
(Innis and Moses, 1978; Papp, et al. 1969).
V. AQUATIC TOXICITY
A. Acute Toxicity
The bluegill appears to be extremely resistant to y
thallium under renewal and static test conditions with 96-
hour LC50 values of 132,000 and 121,000 v.q/1, respectivel
(U.S. EPA, 1979). The fathead minnow was tested under flow- ).
through conditions with measured concentrations, and the 96- 0
hour kC50 value was found to be 860 ug/1 (U.S. EPA, 1978 /
Atlantic salmon, when exposed to thallium for as long as 2,60
hours, experienced 40 and 70 percent mortality at approxi- zO
mately 20 and 45 ug/l» respectively, with mortality occuring
throughout the test (Zitko, et al. 1975). The 48-hour LC5
for Daphnia magna is 2,180 ug/1 (U.S. EPA, 1978).
3. Chronic Toxicity
An embryo-larval test with the fathead minnow indi-1-
cated adverse effects at the lowest thallium concentration
tested of 40 ug/1 (U.S. EPA, 1978). No chronic data are avai
able for freshwater invertebrate species, and no chronic ef-
fects of thallium on saltwater organisms have been reported
(U.S. EPA, 1979).
-------
C. Plant Effects
There is a 40 percent inhibition of oxygen evolu-
tion by the alga, Chlamydomonas reinhardi, exposed to a con-
centration of 40,800 ug/1 (Overnell, 1975). The 96-hour
ECgg values for chlorophyll £ inhibition and cell number
are 110 and 100 ug/1, respectively.
D. Residues
The bluegill bioconcentrated thallium 34 times
(whole body), and the Atlantic salmon bioconcentrated this
heavy metal 130 times above that of the ambient water (Zitko,
et al. 1975? U.S. EPA, 1978).
VI. EXISTING GUIDELINES
/ A. Human
The American Conference of Governmental Industrial
Hygienists (ACGIH, 1971) and the Occupational Safety and
Health Administration (OSHA) adopted a threshold limit value
of 0.1 mg/m3 for thallium. The acceptable daily intake
-.' (ADI) of thallium has been calculated to be 15.4 mg per day.
The U.S. EPA (1979) draft water criterion document for
thallium recommends a criterion of 4 ug/1 for the protection
of human health.
B. Aquatic
A criterion for the protection of aquatic species
from excess thallium exposure has not been -derived.
-------
THALLIUM
REFERENCES
American Conference of Governmental Industrial Hygienists.
1971. Documentation of threshold limit values for substances
in workroom air. 3rd ed.
Barclay, R.K., et al. 1953. Distribution and excretion of
radioactive thallium in the chick embryo, rat and man. Jour.
Pharmacol. Ex. Therap. 107: 178.
Carson, B.L., and I.C. Smith. 1977. Thallium. An appraisal
of environmental exposure. Tech. Rep. No. 5, Contract No.
N01-ES-2-2090. Natl. Inst. Environ. Health Sci.
Cavanagh, J.B., et al. 1974. The effects of thallium salts
with particular reference to the nervous system changes.
Jour. Med. 43: 293.
Cavieres, J.D., and J.C. Ellroy. 1974. Thallium and the
sodium pump in human red cells. Jour. Physiol. (London)
243: 243.
Downs, W.L., et al. 1960. Acute and subacute toxicity
studies of thallium compounds. Am. Ind. Hvg. Assoc. Jour.
21: 399.
Geilmann, W. , et al. 1960. Thallium ein regelmassig vor-
handenes spurenelement im tierschen und pflanzlichen or-
ganismus. Biochem. Zeit. 333: 62.
Gehring, P.J., and P.B. Hammond. 1964. The uptake of thal-
lium bv rabbit erythrocytes. Jour. Pharmacol. Exp. Therap.
145: 2l5.
Gehring, P.J., and P.B. Hammond. 1967. The interrelation-
ship between thallium and potassium in animals. Jour.
Pharraacol. Exp. Therap. 155: 137.
Gibson, J.E., et al. 1967. Placental transport and distri-
bution of thallium-204 sulfate in newborn rats and mice.
Toxicol. Appl. Pharmacol. 10: 408 (Abstract).
Gibson, J.E., and B.A. Becker. 1970. Placental transfer,
embryo toxicity and teratogenicity of thallium sulfate in
normal and postassium-deficient rats. Toxicol. Appl.
Pharmacol. 16: 120.
Greathouse, D.G. 1978. Personal communication.
Hampel, C.A., ed. 1968. The encyclopedia of chemical ele-
ments. Reinhold Pub., Mew York.
-------
Innis, R., and H. Moses. 1978. Thallium poisoning. Johns
Hopkins Med, Jour. 142: 27.
Karnofsky, D.A., et al. 1950. Production of achondroplasia
in the chick embryo with thallium. Proc. Soc. Exp. Biol.
Med. 73: 255.
Lee, A.G. 1971. The chemistry of thallium. Elsevier Pub-
lishing Co., Amsterdam.
Lie, R., et al. 1960. The distribution and excretion of
thallium-204 in the rat, with suggested MFC's and a bio-assay
procedure. Health Phys. 2: 334.
Meyer, S. 1928. Changes in the blood as reflecting
industrial damage. Jour. Ind. Hyg. 10: 29.
Munch, J.C. 1934. Human thallotoxicosis. Jour. Am. Med.
Assoc. 102: 1929.
Overnell, J. 1975. Effect of some heavy metal ions on
photosvnthesis in a freshwater alga. Pest. Biochem. Physiol.
5: 19.
Papp, J.P. , et al. 1969. Potassium chloride treatment in
thallotoxicosis. Ann. Intern. Med. 71: 119.
Richeson, E.M. 1958. Industrial thallium intoxication.
Ind. Med. Surg. 2: 607.
U.S. Department of the Interior. 1977. Commodity data sum-
maries. Bur. Mines.
U.S. EPA. 1978. In-depth studies on health and environmen-
tal impacts of selected water pollutants. Contract No. 68-
01-4646. U.S. Environ. Prot. Agency.
U.S. EPA. 1979. Thallium: Ambient Water Quality Criteria.
(Draft) EPA PB-292444. National Technical Information .Ser-
vice, Springfield, Va.
Weinig, E., and P. Zink. 1967.. Uber die quantitative mas-
senspektrometrische bestimmung .des normalen thallium-gehalts
im menschlichen organismus. Arch., f. Topxikol. 22: 255.
Windholz, M., ed. 1976. The Merck Index. 9th ed. Merck
and Co., Inc., Rahway, M.J.
Zitko, V. 1975. Toxicity and pollution potential of thallium
. Sci. Total Environ. 4: 185.
Zitko, V., et al. 1975. Thallium: Occurrence in the
environment and toxicity to fish. Bull. Environ. Contam.
Toxicol. 13: 23.
-------
No. 160
Toluene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, B.C. 20460
APRIL 30, 1980
-190?-
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
TOLUENE
Summary
Toluene has not been reported to be carcinogenic or teratogenic in
humans or animals. There is no conclusive evidence that toluene is
mutagenic. Some neuromuscular deficiencies have been reported in women
exposed chronically to toluene in the workplace. Subacute and chronic
studies on experimental animals have failed to show evidence of severe
cumulative toxicity. Acute exposure to high levels of toluene causes
CNS depression. The U.S. EPA (1979) has calculated an ADI of 29.5 mg
for toluene.
Toluene has been shown to be acutely toxic to freshwater fish at
concentrations of 6,940 to 32,400 ug/I and to marine fish at concentrations
from 4,470 to 12,000 pg/1. A single chronic value of 2,166 ;ug/l has
been reported for marine fish. Aquatic plants appear to be resistant
to the action of toluene with effective concentrations ranging from
8,000 to 433,000 ;ug/l.
-------
I. INTRODUCTION
This profile is based primarily on the Ambient Water Quality Criteria
Document for Toluene (U.S. EPA, 1979) and to a lesser extent on Criteria
For a Recommended Standard: Occupational Exposure to Toluene (NIOSH,
1973) and its update (NIOSH, 1977).
Toluene (CgHgCH^; molecular weight 92113) is a clear,.colorless,
non corrosive liquid with a sweet pungent odor. It has the following
physical and chemical properties (Kirk and Othmer, 1963; Sutton and
Calder, 1975; Shell and Ettre, 1971; Weast, et al. 1971):
Boiling Point 110.6°C
Freezing Point -94.9°C
Flash Point 6-10°C
Vapor Pressure 28 mm Hg at 25°C
Solubility Water: 534.3 + U.9 mg/1 in
freshwater and 379.3 + 2.8 mg/1
in seawater. Miscible with
alcohol, chloroform, ether,
acetone, glacial acetic acid,
carbon disulfate and other organic
solvents.
Production 7.3 x 103 tons/year (USITC, 1977)
Approximately 35 percent of the toluene produced is converted into
benzene and other chemicals. The remainder is used as a solvent and as
a gasoline additive (NIOSH, 1973).
Little is known about the transport and persistence of toluene in
the environment. Toluene is volatile and can evaporate into the atmosphere
from bodies of water (MacKay and Wolkoff, 1973). In the atmosphere,
toluene is photochemically degraded to benzaldehyde and traces of peroxybenzoyl
nitrate. Toluene can re-enter the hydrosphere in rain- (Walker, 1976).
-------
II. EXPOSURE
A. Water
No estimates of average daily uptake of toluene from water,
food, and air are available. In nationwide surveys of organic chemicals
in the drinking water of respresentative U.S. communities, toluene was
found to contaminate 1 raw and 11 finished water supplies out of the 133
water supplies, surveyed (U.S. EPA, 1975a; 1975b; 1977). Quantitative
analyses of five of the above finished waters revealed levels of toluene
ranging from 0.1 ug/1 to 19 pg/1. Benzaldehyde and benzoic acid, metabolites
of toluene, were also detected. Benzaldehyde was found in the water of
five cities, and in two of these cities was measured at levels of 0.1
and 0.5 ug/1. Benzoic acid at 15 ug/1 was found in the water of another
city. i
3. Food
Little data on levels of toluene in food are available. Toluene
was detected in sea water and fish obtained near petroleum and petrochemical
plants in Japan (Ogata and Miyake, 1973)- The muscle of one representative
fish contained five ug toluene/g of tissue. Benzaldehyde, a metabolite
of toluene, occurs naturally in some foods and is intentionally added
to others as a flavoring agent. Benzoic acid, another metablite of
toluene, is added to some foods as a preservative.
The U.S. EPA (1979) has estimated the weighted average bioconcentration
factor for toluene to be 20 for the edible portions of fish and shellfish
consumed by Americans. This estimate is based on 'the octanol/water
partition coefficient of toluene and estimates of fish and shellfish
»
consumption.
-------
C. Inhalation
Toluene has been detected in urban air at concentrations many
times lower than vapor levels considered to be potentially harmful in
occupational settings. An average level of 37 ppb and a maximum level
of 129 ppb were measured in the air of Los Angeles (Lonneman, at al.
1963). Comparable levels were found in the air of Toronto, Canada (Pilar
and Graydon, 1973) and the air of Zurich, Switzerland (Grob and Grob,
1971). In these latter studies, atmospheric toluene in urban areas
appeared to arise primarily from motor vehicle emissions.
III. PHARMACOKINETICS
A. Absorption
No reports are available on oral administration of toluene to ^
humans (U.S. EPA, 1979). Toluene concentrations in arterial blood of
persons continuously inhaling toluene vapors appeared to approach equilibrium
after 20 to 30 minutes, at which time blood levels were about 1 .ug/ml in
persons inhaling 100 ppm and 2 ug/ml in persons inhaling 200 ppm toluene
(Astrand, at al. 1972). Systemic uptake of toluene was doubled^by exercise,
due primarily to increased ventilation rate (Astrand, et al. 1972).
This increased uptake of toluene upon exercise was also noted by Carlsson
and Lindqvist (1977), who, in addition, noted that obese persons retained
more toluene than thin ones. In their study, the average uptake of toluene
vapor during exercise was approximately 49 percent for obese subjects
versus 37 percent for thin subjects. The rate of percutaneous toluene
absorption in humans was reported to be 1U to 23 mg/cm^/hour (Dutkiewicz
•
and Tyras, 1968).
-------
Rats absorbed toluene much acre rapidly and developed substantially
higher peak blood and tissue toluene concentrations when toluene was
administered to the lungs, rather than to the gastrointestinal tract
(Pyykko, et al. 1977). Toluene absorption through the skin of experimental
animals occurred to a considerably lesser degree than through the lungs
or gut (Wahlberg, 1976).
3. Distribution
Toluene is rapidly taken up from the blood into body tissues
according to their iipid content and blood perfusion (U.S. EPA, 1979).
Partition coefficients (tissue:blood) for toluene in homogenates of
rabbit tissues have been determined. The partition coefficient for
adipose tissue was 50 times greater, the coefficient for- bone marrow was
approximately 15 times greater, and those for brain and liver were roughly
2 times greater than the partition coefficients for lung, kidney, heart,
and muscle (Sato, et al. 1974). Saturation of liver and brain tissue of
mice was not reached even after 3 hours of inhalation of concentrations
as high as UOOO ppm toluene (Bruckner and Peterson, 1976).
C. Metabolism
In humans and experimental animals, toluene is thought to be
enzymatically converted by the mixed function oxidase (MFO) system to
benzyl alcohol, which is subsequently oxidized to benzaldehyde and benzoic
acid. Benzoic acid is then conjugated with glycine to form hippuric
acid (U.S. EPA, 1979). There has also been a report, however, of glucuromide
conjugation of benzoic acid in rabbits given large doses (Bray, et al.
1951). Toluene toxicity is diminished in rats by MFO inducers (Ikeda
»
and Ohtsuji, 1971) and enhanced by MFO inhibitors (Koga and Ohmiya,
1978), suggesting that meteabolism of toluene results in detoxication.
-------
D- Excretion
Toluene is rapidly excreted from the body following inhalaton
exposure. Most of the estimated absorbed dose of toluene can be accounted
for within the first 12 hours as the parent compound in expired air and
as hippuric acid in the urine (U.S. EPA, 1979). Elimination rates are
slower for women than for men, probably because of the larger proportion
of fatty tissue in women (U.S. EPA, 1979).
Excretion of toluene in experimental animals is similar to that
found in man. In the rat, for example, elimination of toluene occurs
more slowly from adipose tissue than from any other (Pyykko, et al.
1977; Carlsson and Lindqvist, 1977), including bone marrow from which
elimination is also relatively slow (U.S: EPA, 1979). Toluene is rapidly
lost from the brain, as reflected in rapid recovery from toluene-induced
CNS depression (Peterson and Bruckner, 1976; Savolainen, 1978).
IV. EFFECTS
A. Carcinogenicity
No accounts have been found in the literature in which cancer
in humans has been attributed specifically to toluene. It is difficult
to link cancer induction with any single solvent, as persons having occupational
exposure to solvents are characterized by considerable job mobility and
exposure to a variety of chemicals (U.S. EPA, 1979). Toluene has not
been demonstrated to be carcinogenic when applied to the skin of mice
for one year (Doak, et al. 1976) or throughout a lifetime (Poel, 1963)-
Toluene has not shown carcinogenicity when administered to rats by inhalation
at concentrations of up to 300 ppm, 6 hours/day1, 5 days/week for as long,
as 18 months (Gibson, 1979).
-------
B. Mutagenicity
There is no conclusive evidence that toluene is mutagenic.
For example, the incidence of chromosomal abnormalities in peripheral
blood lymphocytes of humans who had been exposed to an average of 200
ppm toluene for as long as 15 years was no greater than in controls
(Forni, et al. 1971). However, there have been two reports that toluene
induced chromosomal aberrations in the bone marrow cells of rats (Lyapkalo,
1973; Dobrokhotov and Enikeev, 1977). Toluene has not been tested in
bacterial screening systems (Dean, 1978).
C. Teratogenicity
Although toluene should readily pass the placenta, there are
no reports of teratogenic effects in humans or laboratory animals
linked to toluene exposure (U.S. EPA, 1979). For example, toluene is
not teratogenic in rats or chickens (Roche and Sine, 1968), or in rats
or mice (Hudak and (Jngvary, 1978).
D. Other Reproductive Effects
Women occupationally exposed to multiple solvents including
toluene through the use of varnishes had a relatively high incidence of
menstrual disorders. Their offspring were said to experience more fre-
quent fetal asphyxia, to be more underweight, and not to nurse as well
as "normal" infants (Syrovadko, 1977). Dysmenorrhea was a frequent
subjective complaint of female shoemakers chronically exposed to 60-100
ppm toluene (Matsushita, et al. 1975). In a single study, some retardation
of body weight and skeletal growth were seen in fetuses of rats exposed
continuously to 399 ppm toluene on days 1 to 8 of gestation; inhalation
of lower levels of toluene had no effect (Hudak and Ungvary, 1978).
-------
E. Chronic Toxicity
A study of 38 female shoemakers exposed chronically to solvents
including toluene at 60 to 100 ppm for about three years revealed abnormal
tendon reflexes, reduced grasping power, and decreased finger agility
when compared to controls (Matsushita, et al. 1975). Reports reviewed
by the National Institute for Occupational Safety and Health (1973) have
failed to demonstrate adverse effects on the hematopoietic, hepatic,
renal, or other physiologic systems of workers routinely inhaling approxi-
mately 100 ppm toluene. Numerous subacute and chronic studies on a
variety of experimental animals have failed to show evidence of severe
cumulative toxicity (U.S. EPA, 1979).
F. Other Relevent Information.
The primary hazard associated with acute exposure to high
levels of toluene is excessive CNS depression (U.S. EPA, 1979). Toluene
is capable of altering the metabolism and bioactivity of other chemicals
which are metabolized by the mixed function oxidase system. For example,
simultaneous administration of toluene and trichloroethylene or toluene
and benzene to experimental animals resulted in suppression of metabolism
of both compounds (Ikeda, 1974; Ikeda, et al. 1972). Another showed
marked reduction in the concentration of benzene metabolites in various
tissues, including bone marrow,after simultaneous administration of toluene,
and data that suggested that toluene might protect against benzene myelotoxicity
(Andrews, et al. 1977).
V. AQUATIC TOXICITY
A. Acute Toxicity
»
For freshwater fish, 96-hour static LC5Q values ranged from
12,700 ug/1 for the bluegill (Lepomis macrochirus) to 59,300 ug/1 for
'/ T'S-
-------
for the guppy (Poeeilia reticulatus) (U.S. EPA, 1978; Pickering and
Henderson, 1966). Only a single US-hour LC5Q value for Daphnia magna of
313,000 ug/1 has been obtained for toluene. In marine fish, two 96-hour
static LC5Q values of 6,300 and 10,000-50,000 jug/1 were obtained for
striped bass (Morone saxatilis) and coho salmon Oncorhynchus icisutch
(Benville, et al. 1977; Morrow, et al. 1975). Among four species of
marine invertebrates, the bay shrimp (Crago franciscorum) was most sensitive,
with a 96-hour static LC5Q value of 3,700 jug/1 (Benville, et al., 1977),
while the mysid shrimp Mysidopsis bahia was most resistant, with a 96-
hcur static LC50 value of 56,300 jug/1 (U.S. EPA, 1978).
B. Chronic Toxicity
No freshwater chronic data could be found in the available
literature. The only marine chronic value .reported was 2,166 ,ug/l for
the sheepshead minnow (Cyorinodan variegatus) (U.S. EPA, 1978).
C. Plant Effects
The freshwater algae Chlorella vulgaris and Selenastrum capricornutum
were fairly insensitive to the action of toluene EC5Q values for cell
numbers ranging from 245,000 ;ag/l for Chlorella (Kauss and Hutchinson,
1975) to U33.000 ug/1 for Selenastrum (U.S. EPA, 1978). Among five
marine algal species tested, Skeletonema costatum was the most sensitive
with an adverse effect on growth at 8,000 ug/1 (Dunstan, et al. 1975).
D. Residues
No bioconcentration factors are available for toluene in freshwater
or marine organisms.
-------
VI EXISTING GUIDELINES AND STANDARDS
Both the human health and aquatic criteria derived by U.S. EPA
(1979), which are summarized below, have not yet gone through the process
of public review; therefore, there is a possibility that these criteria
may be changed.
A. Human
The NIOSH (1973) recommended standard for exposure to toluene
is TOO ppm,determined as a time-weighted average for an 8-hour workday,
with a ceiling of 200 ppm.
The U.S. EPA (1979) draft criterion for toluene in ambient
water is 12.U ng/1, corresponding to a calculated acceptable daily intake
of 29-5 mg. This criterion is based on chronic toxicological test data.
for rats (maximum.no-effect" level-of 590 mg/kg,.5 days/wk) and the
application of an uncertainty factor of 1000.
3. Aquatic
The criterion for the protection of freshwater organisms is
2,300 _ug/l, as a 2^-hour average( not to exceed 5,200 .ug/1; and for marine
life the draft criterion is 100 _ug/l, as a 24-hour average, not to exceed
230 ug/1.
-------
• TOLUENE
REFERENCES
Andrews, L.S., et al. 1977. Effects of toluene on the
metabolism, disposition and heraopoietic toxicity of ( H]
benzene. Biochem. Pharmacol. 26: 293.
Astrand, I.., et al. 1972. Toluene exposure. I. Concentra-
tion in alveolar air and blood at rest and during exercise.
Work Environ. Health 9: 119.
Benville, P.E., Jr., et al. 1977. The acute toxicity of
six monocyclic aromatic crude oil components to striped
bass (Morone saxatilis) and bay shrimp (Crago franciscorum).
Calif. Fish game.£7: 204.
Bray, H.G., et al. 1951. Kinetic studies of the metabolism
of foreign organic compounds. I. The formation of benzoic
acid from benzamide, toluene, benzyl alcohol and benzalde-
hyde and its conjugation with glycine and glycuronic acid
in the rabbit. Biochem.. Jour. .48: 88.
Bruckner, J.V., and R.G. Peterson. 1976. Evaluation of ;
toluene toxicity utilizing the mouse as an animal model
of solvent abuse. Pharmacologist 18: 244.
Carlsson, A., and T. Lindqvist. 1977. Exposure of animals
and.man to toluene. Scand. Jour. Work Environ. Health
3: 135.
Dean, B.J. 1978. Genetic toxicology of benzene, toluene,
xylene, and phenols. Mutat. Res. 47: 75.
Doak, S.M.A., et al. 1976. The carcinogenic response in
mice to the topical application of propane sultone to the
skin. Toxicology 6: 139 .
Dobrokhotov, V.B., and M.I. Enikeev. 1977. Mutagenic effect
of benzene, toluene, and a mixture of these hydrocarbons
in a chronic experiment. Gig. Sanit. 1: 32.
Dunstan, W.M., et al. 1975. Stimulation and inhibition
of phytoplankton growth by low molecular weight hydrocar-
bons. Mar. Biol. 31: 305.
Dutkiewicz, T., and H. Tyras. 1968. The quantitative estima-
tion of toluene skin absorption in man. Int. Arch. Gewerbepath
Gewerbehyg. 24: 253.
-------
TOLUENE
REFERENCES
Andrews, L.S., et al. 1977. Effects of toluene on the
metabolism, disposition and hemopoietic toxicity of ( H)
benzene. Biochem. Pharmacol. 26: 293.
Astrand, I., et al. 1972. Toluene exposure. I. Concentra-
tion in alveolar air and blood at rest and during exercise.
Work Environ. Health 9: 119.
Benville, P.E., Jr., et al. 1977. The acute toxicity of
six raonocyclic aromatic crude oil components to striped
bass (Morone saxatilis) and bay shrimp (Crago franciscorum).
Calif. Fish game.5~J: 204.
Bray, H.G., et al. 1951. Kinetic studies of the metabolism
of foreign organic compounds. I. The formation of benzoic
acid from benzamide, toluene, benzyl alcohol and benzalde-
hyde and-its conjugation with glycine and glycuronic acid
in the rabbit. Biochem. Jour. .48: 88.
Bruckner, J.V., and R.G. Peterson. 1976. Evaluation of ;
toluene toxicity utilizing the mouse as an animal model
of solvent abuse. Pharmacologist 18: 244.
Carlsson, A., and T. Lindqvist. 1977. Exposure of animals
and man to toluene. Scand. Jour. Work Environ. Health
3: 135.
Dean, B.J. 1978. Genetic toxicology of benzene, toluene,
xylene, and phenols. Mutat. Res. 47: 75.
Doak, S.M.A., et al. 1976. The carcinogenic response in
mice to the topical application of propane sultone to the
skin. Toxicology 6: 139.
Dobrokhotov, V.B., and M.I. Enikeev. 1977. Mutagenic effect
of benzene, toluene, and a mixture of these hydrocarbons
in a chronic experiment. Gig. Sanit. 1: 32.
Dunstan, W.M., et al. 1975. Stimulation and inhibition
of phytoplankton growth by low molecular weight hydrocar-
bons. Mar. Biol. 31: 305.
Dutkiewicz, T., and H. Tyras. 1968. The quantitative estima-
tion of toluene skin absorption in man. Int. Arch. Gewerbepath.
Gewerbehyg. 24: 253.
-------
Forni, A., et al. 1971. Chromosome studies in workers
exposed to benzene or toluene or both. Arch. Environ. Health
22": 373.
Gibson, J.S. 1979. Chemical Industry Institute of Toxi-
cology - Two year vapor inhalation toxicity study with toluene
in Fischer-344 albino rats: 18-month status summary. (Personal
commun.)
Grob, K., and G. Grob. 1971. Gas-liquid chromatographic/mass
spectrometric investigation of C,--C20 organic compounds
in an urban atmosphere. Jour. Cnromatogr. 62: 1.
Hudak, A., and G. Ungvary. 1978. Embryotoxic effects of
benzene and its methyl derivatives: toluene and xylene.
Toxicology 1L: 55.
Ikeda, M. 1974. Reciprocal metabolic inhibition of toluene
and trichloroethylene _in vivo and _in vitro. Int. Arch.
Arbeitsmed. 33: 125.
Ikeda, M., and H. Ohtsuji. 1971. Phenobarbital-induced
protection against toxicity of toluene and benzene in the
rat.. Toxicol. Appl. Pharmacol. -20: 30.
Ikeda, M., et al. 1972. In vvyg suppression of benzene
and styrene oxidation by co-a5ministered toluene in rats
and effects of phenobarbital. Xenobiotica 2: 101.
Kauss, P.B., and T.C. Hutchinson. 1975. The effects of
water-soluble petroleum components on the growth of Chlorella
vulgar is Beijernck. Environ. Pollut. 9: 157.
Kirk, R.E. » and D. Othmer. 1963. Kirk-Othmer -Encyclopedia
of Chemical Technology. 2nd ed. John Wiley and Sons, Inc.,
New York.
Koga, K., and Y. Ohmiya. 1978. Potentiation of toluene
toxicity by hepatic enzyme inhibition in mice. Jour. Toxicol.
Sci. 3: 25.
Lonneman, W.A., et al. 1968. Aromatic hydrocarbons in
the atmosphere of the Los Angeles Basin. Environ. Sci. Technol.
2: 1017.
Lyapkalo, A.A. 1973. Genetic activity .of benzene and toluene.
Gig. Tr. Prof. Zabol. 17: 24.
Mackay, D., and A.W. Wolkoff. 1973. Rate of evaporation
of low-solubility contaminants from water bodies to atmos-
phere. Environ. Sci. Technol. 7: 611.
-------
Matsushita, T., et al. 1975. Hematological and neuro-muscular
response of workers exposed to low concentration of toluene
vapor. Ind. Health 13: 115.
Morrow, J.E., et al. 1975. Effects of some components
of crude oil on young coho salmon. Copeia 2: 326.
National Institute for Occupational Safety and Health.
1973. Criteria for a recommended standard...occupational
exposure to toluene. HEW Publ. No. HSM 73-11023. U.S.
Government Printing Office. Washington, D.C.
National Institute for Occupational Safety and Health.
1977. Review, summarization and evaluation of literature
to support the update and revision of criteria documents.
V. Toluene. U.S. EPA Contract No. 210-76-0167.
Ogata, M., and Y. Miyake. 1973. Identification of substances
in petroleum causing objectionable odor in fish. Water
Res. 7: 1493.
Peterson, R.G., and J.V. Bruckner. 1976. Measurement of
toluene levels in animal tissues. Proc. Int. Symp. Deliberate
Inhalation of Industrial Solvents, Mexico City.
Pickering, Q.H., and C. Henderson. 1966. Acute toxicity
of some important petrochemicals.to fish. Jour. Water Pollut.
Control Fed. 38: 1419.
Pilar, S., and W.F. Graydon. 1973* Benzene and toluene
distribution in Toronto atmosphere. Environ. Sci. Technol.
7:628.
Poel, W.E. 1963. Skin as a test site for the bioassay
of carcinogens and carcinogen precursors. Natl. Cancer
Ins't. Monogr. 10: 611.
Pyykko, K., et al. 1977. Toluene concentrations in various
tissues of rats after inhalation and oral administration.
Arch. Toxicol. 38: 169.
Roche, S.M., and C.H. Hine. 1968. The teratogenicity of
some industrial chemical. Toxicol. Appl. Pharmacol. 12:
327-.
Sato, A., et al. 1974. Pharmacokinetics of benzene and
toluene. Int. Arch. Arbeitsmed. 33: 169. ,
Savolainen, H. 1978. Distribution and nervous system bind-
ing of intraperitoneally injected toluene. Acta Pharmacol.
Toxicol. 43: 78.
Shell, F.D., and L.S. Ettre. eds. 1971. Encyclopedia of
Industrial Chemical Analysis. Interscience Publishers,
John Wiley and Sons. Inc., New York.
-------
Sutton, C., and J.A. Calder. 1975. Solubility of alkylben-
zenes in distilled water and seawater at 25 C. Jour. Chem.
Eng. Data 20: 320.
Syrovadko, O.N. 1977. Working conditions and health status
of women handling organosiliceous varnishes containing toluene,
Gig. Tr. Prof. Zabol. 12: 15.
U.S. SPA. 1975a. New Orleans area water supply study.
Analysis of. carbon and resin extracts. Prepared and submitted
to the lower Mississippi River Branch, Surveillance and
Analysis Division, Region VI, by the Analytical Branch,
Southeast Environ. Res. Lab. Athens, Ga.
U.S. EPA. 1975b. Preliminary assessment of suspected carcin-
ogens in drinking water. Rep. to Congress, Washington,
D.C.
U.S. EPA. 1977. National Organic Monitoring Survey, general
review of results and methodology: Phases I-III.
U.S. EPA. 1978. In-depth studies on health and environmental
impacts of selected water pollutants. Contract No. 68-01-
4646.
U.S. SPA. 1979. TolueneJambient water quality criteria.
(Draft).
U.S. ITC, Annual. 1977. Synthetic Organic Chemicals, U.S.
Production and Sales. U.S. International Trade Commission,
Washington, D.C.'
Wahlberg, J.E. 1976. Percutaneous toxicity of solvents.
A comparative investigation in the guinea pig with benzene,
toluene and 1,1,2-trichloroethane. Ann. Occup. Hyg. 19:
115.
Walker, P. 1976. Air pollution assessment of toluene.
MTR-7215. Mitre Corp., McLean, Va.
Weast, R.C., et al. 1971. Handbook of chemistry and phy-
sics. 52nd ed. CRC Press, Cleveland, Ohio.
-------
No. 161
2,4-Toluenediamine
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-1926-
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
2,4-TOLUENEDIAMINE
Summary
2,4-Toluenediamine produced carcinogenic effects in rats and mice in a
long-term National Cancer Institute (NCI) feeding study (50 ppm; 100 ppm).
2,4-Toluenediamine was found to be mutagenic, using mutants of Salmonella
typhimurium, hamster embryo cell systems, and Drosophila melanoqaster.
2,4-Toluenediamine was also found to be hepatotoxic to rats and mice in
the NCI study on carcinogenicity. The compound--also hastened the develo-
pment of chronic renal disease and accelerated animal morbidity. Data con-
cerning the teratogenicity of 2,4-toluenediamine was not found in the avail-
able literature. However, a closely related compound, the 2,5-diamino
analog, is teratogenic in mice.
-------
I. INTRODUCTION
2,4-Toluenediamine (molecular weight 122.17) is white solid that
melts at 99°C, has a boiling point of 292°C, a density of 1.047 g/cm at
100°C, heat of vaporization of 27.975 kJ/mol, heat of fusion of 19.874,
and a specific heat of 2.572 J/g at 150°C (Milligan and Gilbert, 1973).
This compound is very soluble in hot benzene, in hot water, and in both
alcohol and ether (Weast, 1971). The major use for 2,4-toluenediamine -is in
the manufacture of 2,4-toluenediisocyanate (TDI), the major raw material for
the producton of flexible polyurethane foams ana1 elastomers (Milligan and
Gilbert, 1978). The production of 2,4-toluenediamine has increased more
than 100 percent since 1966 and was reported in 1976 at 2.05 X 105 tons,
with a predicted growth rate of 8-12 percent per year (Milligan and Gilbert,
1973). 2,4-Toluenediamine can also be used in the manufacture of dyes and
was an important ingredient in human hair dyes of the permanent, oxidative
type until 1971, when its use was restricted after being implicated in the
induction of liver carcinomas in rats (Ito, et al. 1969). Using mutants of
Salmonella typhimurium, Ames, et al. (1975) found 2,4-toluenediamine to be
mutagenic.
II. EXPOSURE
Two potential sources of exposure to 2,4-toluenediamine are in its
manufacture and its use as an intermediate in the production of 2,4-toluene-
diisocyanate. 2,4-Toluenediamine is manufactured by seven U.S. companies at
nine U.S. locations (Muller, 1979; Gunn and Cooke, 1976), and most of the
corresponding diisocyanate is produced by the same companies at the same
locations. Capacity for the latter compound is 3.75 X 10 tons yearly
»
(Muller, 1979). Some additional amounts are consumed in the production of
dyes or are exported to manufacturers of 2,4-toluenediisocyanate outside the
United States. The amount consumed as a dye intermediate is believed to be
-------
quite small, and the magnitude of the exports of 2,4-toluenediamine is un-
known (Gunn and Cooke, 1976). Monitoring data are not available concerning
exposure to 2,4-toluenediamine dermally or by water, food, inhalation.
Dermal carcinogenicity in mice is discussed below under "Effects" ("Chronic
Toxicity").
III. PHARMACOKINETICS
Information on the absorption, distribution, metabolism, and ex-
cretion of 2,4-toluenediamine was not found in the available literature.
IV. EFFECTS
A. Carcinogenicity
Carcinoma of the liver with invasion and metastases was observed
in rats fed diets containing 0.1 or 0.06 percent 2,4-toluenediamine (Ito, et
al. 1969). When the compound was fed at levels of 50 and 100 ppm to inbred
barrier-raised F344 rats for 2 years, a statistically significant increase
was observed in the incidence of hepatic neoplasia in males, and it induced
a significant dose-related positive trend in the incidence of liver neo-
plasms in both sexes. Hepatocellular changes considered to be associated
with neoplasia were increased at a high level of statistical significance in
both sexes. The compound also caused statistically significant increases in
the incidence of mammary tumors in females, and an increase of mammary
tumors in males, although not significant statistically, was believed
related to the chemical (Cardy, 1979; Ulland, 1979). 2,4-Toluenediamine was
also carcinogenic for female B6C3F1 mice, inducing hepatocellular
carcinomas. The incidence of lymphomas in the female mice suggested that
these tumors may have been related to administration of the test chemical as
well (Ulland, 1979).
'/? 30-
-------
8. Mutagsnicity
Fahmy and Fahmy (1977) conducted a comparative assay in Drosophila
melanqaster for the assessment of the mutagenic efficiency of the hair dye
components 2,4-toluenediarnine and 4-nitro-o-phenylenediamine relative to
benzidine, a human carcinogen which, like 2,4-toluenediamine, is also an
aromatic amine. All compounds showed mutagenicity activity. Although act-
ivities of the chemicals on the different genetic sites varied between com-
pounds and as a function of cell stage, mutagenic activity did not vary in
response to changes in dose. The mutagenicities'- and selectivities of the
test compounds for ribosomal ONA gradually decreased in the order benzidine
greater than 2,4-toluenediamine greater than 4-nitro-o-phenylenediamine.
For 2,4-tcluenediamine a good correlation was found between mutagenicity in
the Salmonella/microsome test and morphological transformation in- a hamster
embryo cell system (Shah, et al. 1977). For mutagenesis, the compound re-
quired metabolic activation by a rat liver microscmal enzyme (S9) pre-
paration. In contrast, transformation of hamster cells was induced without
activation by external enzymes. In the Ames assay there was no mutagenic
activity in the strain TA100, indicating that the product is not a base pair
mutagen. The dose response curves -obtained with tester strain TA1538 and
TA53 show that 2,4-toiuenediamine is metabolized by the S9 to a frameshift
mutagen (Shah, et al. 1977). In a study of the mutagenic effect of 2,4-
toluenediamine in mice, Soares and Lock (1978) found no significant increase
in dominant lethal mutations (seven weeks post-treatment) on males.
C. Teratogenicity
Data concerning the teratogenic effects of 2,4-toluenediamine were
t
not found in the available literature. However, 2,5-toluenediamine, a
closely related compound which is a hair dye constituent, was found terato-
genic in mice (Inouye and Murakami, 1977).
-mi-
-------
0. Other Reproductive Effects
Information on other reproductive effects was not found in the
available literature.
E. Chronic Toxicity
Two reports primarily dealing with carcinogenicity provide infor-
mation on chronic toxicity. Cardy (1979) found that 2,4-toluenediamine was
hepatotoxic when fed at levels of 50 and 100 ppm to inbred, barrier-raised
F344 rats for 2 years. The compound also accelerated the development of
chronic renal disease in the strain, an effect that contributed to a marked
decrease in the survival rate. Giles and Chung (1976), in a chronic
toxicity study of 2,4-toluenediamine alone or in combination with selected
hair dye complexes, found the compound to be nontoxic and noncarcinogenic to
.•• " \
the skin of mice.
F. Acute Toxicity
Lewis and Tatken (1979) summarize the available information:
'•y
Oral-human ID.: 50 mg/kg ' jSubcutaneous-rat LD|_Q: 50 mg/kg
Oral-rat LD :. 500 mg/kg . Subcutaneous-dog TO : 200 mg/kg
Oral-rat TDLQ: 11 g/kg • .."Subcutaneous-dog LnLo: 400 mg/kg
where LDQ—lethal dose to all animals; TD|_Q—lowest -toxic dose (other
than inhalation); LDLQ—the lowest published lethal dose (other than
LD5Q) introduced by any other route than inhalation.
G. Other Relevant Information
Except as reported above, no additional information was found on
the effects of 2,4-toluenediamine.
-------
V. AQUATIC TOXICITY
A. Acute Toxicity, Chronic.Toxicity, Plant Effects, and Other
Relevant Information.
No information was found in the available literature on acute
toxicity, chronic toxicity, plant effects, and other relevant information.
B. Residues
Veith, et al. (1979), in a method of estimating the bioconcen-
tration factor of organic chemicals in fathead minnows (Pimephales
promelas), report a log biocentration factor of 1.96 and log n-octanol/water
partition coefficient of 3.16* for the fathead minnow in 32 days' exposure.
A structure-activity correlation between the bioconcentration .factor (8CF)
and the n-octanol/water partition coefficient (P) is expressed by the
equation—log BCF = 0.85 log P-70. According to the authors, this permits
the estimation of the bioconcentration factor of chemicals to within 60 per-
cent before laboratory testing.
VI.. EXISTING GUIDELINES AND STANDARDS
No existing guidelines or standards were found in the available
literature.
*Under the same conditions the log n-octanol/water partition coefficient for
heptachlor was 5.4A; for hexachlorobenzene, 5.23; for mirex, 6.89; and for
dipheylamine, 3.42.
-------
DEFERENCES
Ames, B.N., et al. 1975. Hair dyes are mutagenic: Identification of a
variety of mutagenic ingredients. Proc. Nat. Acad. Sci. U.S.A. 72: 2423.
Cardy, R.H. 1979. Carcinogenicity and chronic toxicity of 2,4-toluene-
diamine in F344 rats. Jour. Natl. Cancer Inst. 62: 1107.
Fahmy , M.J. and O.G. Fahmy. 1977. Mutagenicity of hair dye components
relative to the carcinogen benzidine in Drosghila melanoqaster. Mutat.
Res. 56: 31.
Giles, A.L. and C.W. Chung. 1976. Dermal Carcinogenicity study by mouse-
skin painting with 2,4-toluenediamine alone or in representative hair dye
formulations. Jour. Toxicol. Environ. Health. 1: 433.
Gunn, T.C. and s. Cooke. 1976. Toluene In: Chemical Economics Handbook.
Stan- ford Research Institute, p. 696.5033.
Inouye, M. and U. Murakami. 1977. Teratogenicity of 2,5-diaminotoluene, a
hair-dye constituent in mice. Fd. Cosmet. Toxicol. 15: 447.
Ito, N.,-et al. 1969. The development of carcinoma in liver of rats
treated with m-toluylenediamine and the synergistic effects with other chem-
icals. Cancer Res. 29: 1137.
Lewis, R.J. and R.L. Tatken. 1979. Registry of Toxic Effects of Chemical
Substances. National Institute for Occupational Safety and Health,
Cincinnati,.Ohio.
Milligan, B. and K.E. Gilbert. 1978. Amines, aromatic (diaminotoluenes).
Vol. 2., p. 321. In: M. Grayson (ed.), Encyclopedia of Chemical Tech-
nology. 3rd ed. John Wiley & Sons,-New York. '
Muller, R.G. 1979. Directory of Chemical Producers. Stanford Research In-
stitute.
Shah, M.J., et al. 1977. Comparative .studies of bacterial mutation and
hamster cell transformation induced by 2,4-toluenediamine. •• Am. Assoc.
Cancer Res. Proc. 18: 23.
Soares, E.R. and L.F. Lock. 1978. The mutagenic effect. of 2,4-dinitro-
toluene and 2,4-diaminotoluehe in mice. Pharmacologist. 20: 155.
Ulland, 8. 1979. Bioassay of 2,4-diaminotoluene for possible Carcino-
genicity. NCI-CG-TR-162. U. S. Department of Health, Education and Wel-
fare. .National Institute of Health. U.S..DHEW Pub. NO. (NIH) 79-1718.
Veith, G.D., et al. 1979. Measuring and estimating bioconcentration factor
of chemicals in fish. Jour. Fish. Res. Board Canada. 36: 1040.
Weast, R.C.. 1971. Handbook of Chemistry -and Physics. 51st ed. Chemical
Rubber Co., Cleveland, Ohio.
-------
No. 162
Toluene Diisocyanate
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
TOLUENE OIISOCYANATE
Summary
Toluene diisocyanate (TDI) is used in the manufacture of polyurethane
foam. TDI is formed through the reaction of 2,4-toluenediamine with phos-
gene. The TDI is then reacted with di- and poly-functional hydroxy com-
pounds to form polyurethane foam.
TDI is readily reactive in water, forming carbon dioxide and polyurea
derivatives. Environmental occurrence of TDI is unlikely due to its high
reactivity with hydroxy compounds and peroxy radicals.
Information on the carcinogenicity and teratogenicity of toluene diiso-
cyanate was not found in the available literature. As of September 1978,
TDI was being tested by the National Cancer Institute for carcinogenicity
using a standard bioassay protocol, but results have not been reported.
Toluene diisocyanate did not show mutagenic activity on testing of
Salmonella typhimurium strains with and without a mammalian liver microsome
activating system.
Extensive toxicologic data exists for TDI, primarily from occupational
exposure studies. TDI produces respiratory effects, including mucous mem-
brane irritation, bronchoconstriction, coughing, and wheezing. Exposure to
high concentrations can result in pulmonary edema or death.
The effects from chronic, low-level exposure to TDI vary. Decreased
lung function has been reported from inhalation of 0.003 ppm TDI, but other
investigators have not seen «these respiratory effects from inahlation of
0.02 ppm TDI. Hypersensitivity to TDI has also been observed from occupa-
*
tional respiratory exposure. Immunologic and pharmacologic reactions have
been proposed as the mechanism of action of TDI.
-/937-
-------
Other reported effects include memory loss, psychological disturbances,
and skin irritation. Uncertainty exists regarding the frequency of these
effects in those occupationally exposed. Maintaining exposure below 0.005
ppm has proven effective in protecting health of unsensitized workers.
Where an individual has previously been sensitized, a no-threshold effect is
indicated upon subsequent exposure to TDI.
-------
TOLUENE OIISOCYANTE
Environmental Fate
Toluene diisocyanate (TDI) readily reacts with hydroxy compounds. Its
atmospheric half-life is approximately three days (Brown, et al. 1975). TDI
readily hydrolyzes in neutral aqueous media, or more rapidly under acidic or
basic conditions, to give unstable carbonic acids (Tennant, 1979). The
acids tend to lose carbon dioxide, giving the corresponding amine which, in
turn, reacts with the starting isocyanate to produce a urea derivative.
This reaction produces a concurrent decrease in water pH (Curtis, et al.
1979). TDI readily hydrolyzes in water, with a half-life of 0.5 seconds
(Brown, et al. 1975). As temperature increases the reaction becomes more
vigorous (Tennant, 1979).
Toluene diisocyanate reactions with ozone progress more slowly than the
hydroxy reaction, with an atmospheric half-life of 3,981 days. The reaction
of TDI with R02 peroxyradical groups has an environmental half-life of
approximately 7.94 x 105 days in the water phase.
. Brown, et al. (1975) concluded that the short lifetime of toluene di-
isocyanate in various media makes environmental occurrence unlikely.
-/? 31-
-------
I. INTRODUCTION
This profile is based upon relevant literature identified through bib-
liographic searches in TOXLINE and Chemical Abstracts, and through manual
searches. The National Institute for Occupational Safety and Health (NIOSH)
has published a criteria document for diisocyanates (NIOSH, 1978). This re-
port represents a comprehensive review of the available toxicologic litera-
ture on toluene diisocyanate (TDI) and was the source for much of the ef-
fects data described below.
Toluene diisocyanate is also reported as 2,'4-diisocyanate-l-methyl-
benzene, tolylene diisocyanate, methylphenylene isocyanate, diisocyano-
toluene, and stilbene diisocyanate. The compound is a colorless-to-pale-
yellow liquid. The chemical formula is CgH^NoOo. Physical proper-
ties of TDI are as follows: molecular weight, 174.16; melting point, 20 to
22°C; boiling point, 251°C; vapor pressure, 0.05 mm Hg at 25°C; and
specific gravity, 1.22 at 25°C (NIOSH, 1978). TDI is soluble in aromatic
hydrocarbons, nitrobenzene, acetone, ethers, and esters.
The most common method of synthesizing toluene diisocyanate is through
the primary reaction of diaminotoluene with phosgene. Toluene diisocyanate
is then reacted with di- and poly-functional hydroxy compounds to form poly-
- .urethane foams, coatings, elastomers, and spandex fibers (NIOSH, 1978).
Toluene diisocyanate production in the U.S. was 605 million pounds
(Predicasts, Inc., 1980) in 1978, with an estimated 6.4 percent annual
growth in production./ Production capacity amounted to. 775 million pounds
per year -in 1978.
-------
II. EXPOSURE
Repiratory and dermal exposure to toluene diisocyanate has been well
documented in occupational environments (NIOSH, 1978). Sources of occupa-
tional exposures include production processes of basic TOI manufacture, pro-
duction of polyurethane foam, and accidental releases or spills in product
synthesis, transportation, use, or disposal.
Non-occupational exposure to TDI through ingestion of contaminated food
or water is unlikely since TDI released to the environment would readily re-
act with other compounds, farming stable polyurea "end products. For ex-
ample, Curtis, et al. (1979) conducted acute aquatic toxicity studies of TDI
and reported the immediate reaction of TDI with water resulting in the pro-
duction of carbon dioxide and a polyurethane foam-like solid. Human expo-
sures would most likely occur to these polyurea compounds and not TDI. Ac-
cidental releases and spills may result in respiratory TDI exposure of per-
sons in the immediate vicinity. . Dermal exposure may also occur in persons
ccming in direct contact with the compound.
III. PHARMACOKINETICS
Information on the absorption, distribution, metabolism, and excretion
of TDI was not identified in the available literature. NIOSH (1978), in de-
scribing the sensitization phenomenon of TDI exposure, hypothesized that
this response may be the result of TDI reacton with _in_ vivo hydroxyl, amino,
sulfhydryl, or similar compounds which form a hapten complex with TDI. This
complex is believed to be responsible for the sensitization of individuals
to TDI.
-------
IV. EFFECTS
A. Carcinogenicity
Information on the carcinogenic effects of toluene diisocyanate
was not found in the available literature. Lewis and Tatken (1979) reported
that TDI is currently being tested by NCI for carcinogenicity by standard
bioassay protocol as of September 1978.
B. Mutagenicity
Toluene diisocyanate did not show mutagenic activity on testing
Salmonella typhimurium strains with or without a mammalian liver microsome
activating system (NIOSH, 1978).
C. Teratogenicity and Other Reproductive Effects
Information on teratogenic or other reproductive effects of tol-
uene diisocyanate was not found in the available literature.
D. Chronic Effects
Inhalation of toluene diisocyanate represents the primary route of
exposure which has produced chronic effects, although the mechanism of the
chronic respiratory changes is uncertain.
Toluene diisocyanate induces a hypersensitive reaction in specific
individuals. Predisposing factors may include both environmental and endo-
genous host factors (Adkinson, 1977). Intensity and duration of exposure
are important in eliciting a hypersensitive reaction. Genetic factors con-
trolling immune responsiveness, metabolic processes, atopic diathesis, and
coexisting disease states and metabolic aberration were suggested as factors
influencing the allergic reaction (Adkinson, 1977). 'However, Butcher, et
al. (1976) found no pattern of prior hay fever or asthma, or of atopy (by
#
skin testing) in clinically sensitized individuals.
-------
Exposure to high concentrations has caused respiratory sensitiza-
tion in workers (Walworth and Virchow, 1959; Bruckner, et al. 1968). These
sensitization reactions were described earlier. The sensitization can pro-
gress to a condition resembling chronic bronchitis and pulmonary edema. In-
dividuals sensitized to TDI will present an asthmatic reaction upon reexpo-
sure to very low concentrations of TDI. Butcher, et al. (1979) described
four.specific types of responses in hypersensitive workers: (1) immediate;
(2) late; (3) dual; and (4) dose-related. The responses were measured as
percent change in one-second Forced Expiratory Volume (FEV^) over time.
Immediate response occurred within one hour of exposure, whereas late re-
sponse exhibited a gradual decline in FEV1 over five hours. The dual re-
sponse elicited an early response within one hour and a late response after
eight hours. The dose-related response was exhibited at 0.01 ppmr whereas
'exposure to 0.005 ppm did not show a significant decrease in FEV-^ The
author suggested a pharmacologic basis for the hypersensitivity, but noted
that an allergic mechanism could not be ruled out.
Porter, et al. (1975) reported sensitization correlated with the
frequency and severity of significant exposures greater than 0.05 ppm. Once
sensitized, an individual exposed to very low concentrations of TDI will
produce asthmatic reactions upon subsequent TDI exposure.
Wegman (1977) reported decrements in FEV-L in Doth sensitized and
unsensitized workers. However, Adams (1975) and Butcher, et al. (1977) did
not show decreased FEVl after occupational exposures of 11 and 2.5 years,
respectively. TDI concentrations were 0.02 ppm and below, with occasional
excursions above this level. Consequently, the National Institute for Occu-
•
pational Safety and Health (NIOSH) recommended an eight hour time-weighted
-------
average limit of 5 ppb, noting that the above studies and others had not re-
ported significant effects on lung function at concentrations of 14-50
/jg/m3 (2.0-7.0 ppb).
Some authors have reported skin sensitization in persons occupa-
tionally exposed to TDI (Nava, et al. 1975; Karol, et al. 1978), but other
investigators have not observed such skin sensitization reactions (Munn,
1960; Bruckner, et al. 1968).
Other chronic effects from TDI exposure include neurologic ef-
fects, eye irritation, and psychological symptoms. Le Quesne, et al. (1976)
reported memory loss .lasting 4 years in workers exposed to massive concen-
trations of TDI while fighting a fire at a polyurethane foam factory.
F. Acute Effects
Inhalation of TDI is the primary route of exposure which has de-
monstrated acute' effects. Several authors have reported daily and cumula-
tive decreases in lung function - following respiratory exposure to TDI. In-
vestigations of acute effects from TDI exposure have produced contradictory
results. Peters, et al. (1968) .reported significant decreases in lung func-
tion upon exposure to 0.1-3.0,ppb, whereas Adams (1975) noted no significant
decrease in lung function at 20 ppb.
Occupational exposure to high concentrations of TDI causes direct
irritation of the respiratory tract (Walworth and Virchow, 1959; Maxon,
1964; Axford, et al. 1976; Gandevia, 1963).
Eye, nose, and throat irritation was observed upon atmospheric ex-
posures to 500 ppb (Henschler, 1962). Nausea, vomiting, and abdominal pain
-------
may also occur (Key, et al. 1977). Dermal contact with liquid TDI may pro-
duce redness, swelling, and blistering. Contact with eyes may produce se-
vere irritation and permanent damage. Ingestion of TDI may cause burns of
the mouth and stomach (Key, et al. 1977).
Lewis and Tatken (1979) reported an inhalation LC5Q for rats Of
600 ppm following a 6-hour exposure; and an inhalation LCcg for mice of 10
.ppm following a 4-hour exposure.
V. AQUATIC TOXICITY
A. Acute Toxicity
Curtis, et al. (1979) reported a 96-hour LC5Q Of 154.5 mg/i j_n
the fathead minnow (Pimephales promelas). No significant mortality was
noted in grass shrimp (Palaemonetes pugio) exposed to 508.3 mp
-------
The American Conference of Governmental Industrial Hygienists
(1979) has published a threshold limit value-time weighted average for tol-
uene diisocyanate of 5 ppb (0.04 mg/nv3). NIOSH (1978) recommended a time-
weighted-average limit for airborne toluene diisocyanate of 5 ppb, with a
ceiling value of 20 ppb. NIOSH (1978) also reported occupational exposure
limits for TOI in numerous countries. These limits ranged from 0.07 to 0.5
-------
TOLUENE DII50CYANATE
References
Adams, W.G.F. 1975. Long-term effects on the health of men engaged in the
manufacture of tolylene di-isocyanate. 8r. Jour. Ind. Med. 32: 72.
Adkinson, N.F. 1977. Environmental influences on the immune system and al-
lergic responses. Environ. Health Perspect. 20: 97.
American Conference of Governmental Industrial Hygienists. 1979. Threshold
limit values for chemical substances and physical agents in the workroom en-
vironment with intended changes for 1979. American Conference of Govern-
mental Industrial Hygienists. Cincinnati, Ohio, p. 94.
Axford, A.T., et al. 1976. Accidental exposure to isocyanate fumes in a
group of firemen. Br. Jour. Ind. Med. 3: 65.
Brown, S.L., et al. 1975. Research program on hazard priority ranking of
manufactured chemicals. Phase II-Final Report. NTIS P8-263162.
Bruckner, H.C., et al. 1968. Clinical and immunologic appraisal of workers
exposed to diisocyanates. Arch. Environ. Health 16: 619.
Butcher, B.T., et al. 1976. Toluene diisocyanate (TDI) pulmonary disease—
immunologic and inhalation challenge studies. Jour. Allergy, din.
Immunol. 58: 89.
Butcher, B.T., et al. 1977. Longitudinal study of workers employed in the
manufacture of toluene-diisocyanate. Am. Rev. Resp. Dis. 116: 411.
Butcher, 8.T., et al. 1979. Inhalation challenge and pharmacologic studies
of toluene diisocyanate (TDI)—sensitive workers. Jour. Allergy. Clin.
Immunol. 64: 146.
Curtis, M.W., et al. 1979. Acute toxicity of 12 industrial chemicals to
freshwater and saltwater organisms. Water Res. 13: 137.
Gandevia, B. 1963. Studies of ventilatory capacity and histamine response
during exposure to isocyanate vapour in polyurethane foam manufacture. Br.
Jour. Ind. Med. 20: 204.
Henschler, D., et al. 1962. The toxicology of the toluene diisocyanates.
Arch. Toxikol. 19: 364.
Karol, M.H., et al. 1978. Tolyl-specific IgE antibodies in workers with
hypersensitivity to toluene diisocyanate. Am. Ind.' Hyg. Assoc. Jour.
39: 454.
Key, M.M., et al. 1977. Occupational diseases—a guide to their recogni-
tion. National Institute for Occupational Safety and Health. Cincinnati,
Ohio. p. 233.
-If-/7-
-------
LeQuesne, P.M., et al. 1976. Neurological complications after a single ex-
posure to toluene diisocyanate. Br. Jour. Ind. Med. 33: 72.
Lewis, R.J. and R.L. Tatken (ed.) 1979. Registry of toxic effects of chem-
ical substances. National Institute for Occupational Safety and Health.
Cincinnati, Ohio. U.S. Government Printing Office, Washington, D.C., p. 180.
Maxon, F.L. 1964. Respiratory irritation from toluene diisocyanate. Arch.
Environ. Health. 8: 755.
Munn, A. 1960. Experience with diisocyanates. Trans. Assoc. Ind. Med.
Off. 9: 134.
National Institute for Occupational Safety and Health. 1978. Criteria for
a recommended standard: Occupational exposure to diisocyanates. National
Institute for Occupational Safety and Health. Cincinnati, Ohio, p. 138.
Nava, C., et al. 1975. Pathology produced by isocyanates—methods of im-
munological investigation. Ric. Clin. Lab. 5: 135.
Peters, J.M., et al. 1968. Acute respiratory effects in workers exposed to
low levels of toluene diisocyanates (TDI). Arch. Environ. Health. 16: 642.
Porter, C.V., et al. 1975. A retrospective study of clinical, physiologic
and immunologic changes in workers exposed to toluene diisocyanate. Am.
Ind. Hyg. Assoc. Jour. 36: 159.
Predicasts, Inc. 1980. Predicast No. 78 (2nd Quarter) Jan 18, 1980. Pred-
icasts Inc., Cleveland, Ohio.
Tennant, G. 1979. Imines, nitrones, nitriles and isocyanates. In; 0.
Barton, W.D. Qllis.(eds.) Comprehensive Organic Chemistry, Vol. 2: Nitro-
gen compounds, carboxylic acids, phosphorous compounds. Pergamon Press.
New York, p. 521.
Walworth, H.T. and W.E. Virchow. 1959. Industrial hygiene experience with
toluene diisocyanate. Am. Ind. Hyg. Assoc. Jour. 20: 205.
Wegman, O.H., et al. 1977. Chronic pulmonary function loss from exposure
to toluene diisocyanate.. Br. Jour. Ind. Med. 34: 196.
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No. 163
Toxaphene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
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DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
SPECIAL NOTATION
U.S. EPA's Carcinogen Assessment Group (GAG) has evaluated
toxaphene and has found sufficient evidence to indicate
that this compound is carcinogenic.
-------
TOXAPHENE
SUMMARY
Toxaphene is a mixture of polychlorinated camphenes.
It is obtained from camphene by photochemical chlorination,
which produces a heterogeneous mixture of chemicals (177)
containing 67 to 69 percent chlorine. Toxaphene has not
produced teratogenic effects in laboratory animals, but
has been found to be mutagenic in two strains of Salmonella
typhimurium with metabolic activation. A National Cancer
Institute (NCI) 1979 study found that toxaphene signifi-
cantly increased the incidences of hepatocellular carcinomas
in mice.
The insecticide, toxaphene has been demonstrated to
be a potent toxin to a variety of aquatic life. For both
freshwater and marine fish species, acute toxicity values
of 0.8 to 28 ^ag/1 were reported. Marine invertebrate species
displayed considerable interspecies variation, with LCcn
values ranging from 0.08 to 2,700
-------
TOXAPHENE
I. INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria document for Toxaphene (U.S. EPA, 1979).
Toxaphene is a commercially produced, broad spectrum,
chlorinated hydrocarbon consisting primarily of chlorinated
camphene and related compounds and isomers. It is currently
the most heavily used insecticide in the U.S., with an annual
production rate exceeding 50 x 10 tons (-.U.S. EPA, 1979).
On May 25, 1977, because of its carcinogenic effects,
aquatic toxi.city, and high bioconcentration factor, the
U.S. EPA issued a notice of rebuttable presumption against
registration and continued registration of pesticide pro-
ducts containing toxaphene.
Toxaphene is an amber, waxy solid with a mild terpene
odor and an average molecular weight of 414. Its physical
properties include: melting point of 65-90°C; vapor pres-
sure, 0.17-0.40 mm Hg at 25°C; solubility in water, 0.4-
3.0 mg/1; and is soluble in relatively non-polar solvents,
with an octanol/water partition coefficient of 825 (U.S
EPA, 1979).
The commercial product is relatively stable but may
dehydrochlorinate upon prolonged exposure to sunlight, alkali,
or temperatures above 120°C (Metcalf, 1966; Brooks, 1974).
In natural water systems, toxaphene tends to be absorbed
by the particulates present or to be taken up by.living
organisms and bioconcentrated. Thus, it is seldom found
as a soluble component in receiving waters but can persist
y
iff3-
-------
in sediments or remain absorbed on suspended solids for
prolonged periods (U.S. EPA, 1979).
II. EXPOSURE
A. Water
Toxaphene has been monitored in the U.S. since
1959. Although it has been detected at several locations,
it is not found in all waters (U.S. EPA, 1979). Seven rou-
tine monitoring studies of U.S. surface water prior to 1975
did not detect toxaphene (U.S. EPA, 1979).'•
Nicholson, et al. (1964, 1966) detected toxaphene
in the drinking water obtained from Alabama at levels rang-
ing from 0.01-0.1 pg/1. A survey of commercial drinking
water samples by the U.S. EPA (1976a) during 1975 and 1976
found no detectable levels of toxaphene (limit of detection
0.05 pg/1).
Toxaphene has been detected in water around areas
where it is applied to crops as an insecticide. For example,
it has been detected in surface waters in California at
levels ranging from 0.02 to 7.9 jjg/1, and in drainage ef-
fluents at levels of 0.130 to 0.950 ^g/1 (Johnston, et al.
1967; Bailey and Hammon, 1967). Several studies of an agri-
cultural watershed in Alabama found that treatment of drink-
ing water did not reduce toxaphene concentrations (U.S.
EPA, 1979).
Toxaphene has been detected in the sediment samples
of various waters even when it is not found in samples of
the surface waters (Mattraw, 1975). Concentrations as high
as 2.46 p.q/1. have been found in sediments (U.S. EPA, 1979).
-------
Sediment samples at three locations downstream of a plant
producing toxaphene had a maximum residue level of 15 ^g/1
toxaphene before dredging (Reimold and Durant, 1972).
B. Food
The best available estimate of dietary intake
of toxaphene is 0.021 jag/kg/day, based on the U.S. Food
and Drug Administration basket survey between 1964 and 1970
(Duggan and Corneliussen, 1972). Based on recent market
basket surveys indicating a decrease in the incidence of
toxaphene contamination, a stable incidence of toxaphene
in raw meat since 1969, and a two-fold increase in the inci-
dence of toxaphene in unprocessed food samples between 1972
and 1976, the U.S. EPA (1979) estimates the current dietary
intake to be 0.042 pg/kg/day.
The U.S. EPA (1979) has estimated the weighted
average bioconcentration factor for toxaphene to be 18,000
for the edible portions of fish and shellfish consumed by
Americans. This estimate was based on the measured steady-
state bioconcentration studies in five species of fish and
shellfish.
C. Inhalation
The highest toxaphene residues in air have been
found in areas where toxaphene is applied for agricultural
purposes (especially cotton production in the Southern U.S.)
(U.S. EPA, 1979). Studies indicate that airborne residues
are highest during cotton growing season and decrease to
low levels after harvesting, but spring tilling releases
-------
soil residues to the air. Concentrations ranging from 0
to 2520 ng/m- have been measured in southern agricultural
areas (Arthur, et al. 1976; Stanley, et al. 1971.) Mean
monthly concentrations have been measured as high as 167
ng/m3 (Arthur, et al. 1976).
Toxaphene has also been monitored in the atmos-
phere over the east coast near Bermuda and the open ocean
(Bidleman and Olney, 1975). The mean concentrations were
0.79 and 0.53 ng/m , respectively. Using .the maximum mean
monthly concentration of 167 ng/m (Arthur, et al. 1976),
the average daily dose of toxaphene from air is approximately
0.057 jjg/kg (U.S. EPA,. 1979). This amount would reflect
intake at a high toxaphene use area, whereas a more conserva-
tive value using a concentration of 0.53 ng/m monitored
over open ocean (Bidleraan and Olney, 1975) would be an aver-
age daily intake of 0.13 ng/kg of toxaphene from air (U.S.
EPA, 1979) .
.D. Dermal
Toxicity studies with laboratory animals indicate
that toxaphene can be absorbed -across the skin in toxic
amounts by humans (U.S. EPA, 1979). Incidence of dermal
absorption of toxaphene by humans is restricted to occupa-
• tional or accidental exposure.
III. PHARMACOKINETICS
A. Absorption
The recently completed U.S. EPA (1978) study sug-'
gests that inhalation exposures to toxaphene do not result
in sufficient absorption by humans to cause quantifiable
levels in the blood.
^
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Animal studies show absorption of toxaphene across
the alimentary tract, skin, and respiratory tract, -as indi-
cated by adverse effects elicited by oral, dermal, and in-
halation exposures (U.S. EPA, 1979). The vehicle and mode
of administration, as well as individual differences, affect
the rate of absorption of toxaphene. The ratio of oral
LD50" to dermal LD5Q (in comparable lipophilic solvents) is
about 0.1 (Lackey, 1949a,b; Conley, 1952; U.S. EPA, 1979).
B. Distribution
Toxaphene is readily distributed throughout the
body, with highest residues found in fat tissue. Three
hours after single intubations of Cl-36 labelled toxaphene,
rats had detectable levels of Cl-36 activity in all tissues
examined (kidney, muscle, fat, testes, brain, blood, liver,
intestines, esophagus, spleen, and stomach), with the highest
levels being found in the stomach and blood (Crowder and
Dindal, 1974.) After 9 to 14 days, most of the activity
is found in the fat, blood, kidney, liver, and intestines
(Crowder and Dindal, 1974; Ohsawa, et al. 1975). The pre-
dominance of fat storage had been demonstrated in 12-week
feeding studies with rats, and 2-year feeding studies with
rats and dogs (Clapp, et al. 1971; Lehman, 1952; Hercules,
Inc., undated). In the above studies, toxaphene residues
were highest in fat tissues but always remained below the
levels administered in the diet, thus suggesting that toxa-
phene is not biomagnified in terrestrial organisms (U.S.
EPA, 1979).
-------
C. Metabolism
Toxaphene undergoes reductive dechlor ination,
dehydrochlor ination, and hydroxylation in mammalian systems
(U.S. EPA, 1979). Studies by Crowder and Dindal (1974),
Ohsawa, et al. (1975) and Khalifa, et al. (1976) have ob-
served 50 percent dechlor ination of toxaphene after adminis-
tration by intubation to rats, or in_ vitro with rat liver
microsomes and NADPH under anaerobic conditions. Toxaphene
has been suggested as a substrate for the hepatic microsomal
mixed-function oxidases because of type I binding spectra
with cytochrome P-450, and NADPH dependence (Kulkarni, et
al. 1975; Chandurkar, 1977).
Several investigators have noted that fat residues
of toxaphene resemble whole toxaphene, while residues in
both the liver and feces are consistently more polar (Pollock,
1978; Saleh, et al. 1977).
D. Excretion
The half-life of C-14 or Cl-36 labelled toxaphene
in rats after single oral doses appears to be from one to
three days, with most of the excretion occurring via the
urine and feces (Crowder and Dindal, 1974; Ohsawa, et al.
1975) . Only a small portion of the urine and fecal metabo-
lites is eliminated as glucuronide or sulfate conjugates
(Chandurkar , 1977) .
A study of the blood levels of toxaphene in an
individual consuming contaminated fish (52 ug toxaphene/g .
fish) revealed levels of 142 ppb , 47 ppb,
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IV. EFFECTS
A. Carcinogenicity
The National Cancer Institute (1979) has recently
completed a' carcinogenicity bioassay of toxaphene. The
80-week feeding study did not follow current NCI standards;
• only ten animals were used in each matched control group,
and matched-fed control groups were not utilized (NCI, 1977).
The feeding schedule was as follows: for rats - males, time
weighted average (TWA) doses at 556 mg/kg and 1,112 mg/kg,
and females, TWA doses at 540 mg/kg and 1,080 mg/kg; and for
mice, males and females, TWA doses at 99 mg/kg and 198 mg/kg.
In male rats in the high dose group, a significant
increase was noted in the incidence of follicular-cell car-
cinomas and adenomas of the thyroid. Of the nine thyroid
tumors which were found in this group, two were carcinomas.
A significant increase of follicular-cell adenomas of the
thyroid was also noted in the high-dose group of female
rats. No carcinomas of the thyroid were found in this group.
In both of these groups, the development of thyroid tumors
was dose-related.
In both male and female mice, significant increases
were noted in the incidence of hepatocellular carcinomas
and in the incidence of hepatocellular carcinomas combined
with neoplastic nodules of the liver.
Based on the results of this study, -the National
Cancer Institute has concluded that "Toxaphene was carcino-
genic in male and female B6C3F1 mice, causing increased
-------
incidences of hepatocellular carcinomas. The test results
also suggest carcinogenicity of toxaphene for the thyroid
of male and female Osborne-Mendel rats" (NCI, 1979).
Litton Bionetics, Inc. (1978) also reported a
significant excess of hepatocellular tumors (hepatocellular
adenoma plus hepatocellular carcinoma) in male mice fed
dietary levels of 50 ppm toxaphene.
B. Mutagenicity
The mutagenicity of toxaphene has been tested
in bacterial systems using Salmonella typhimurium strains
TA1535, TA1S37, TA1538, TA98, and TA100 (Hill, 1977). Posi-
tive test results were obtained for strains TA98 (frameshift
mutation) and TA100 (base pair substitution) only in tests
without metabolic activation. All other tests were nega-
tive. A "high temperature" toxaphene has elicited positive
dos.e response increases in strains TA98 and TA100 only with
metabolic activation. In other studies, toxaphene and toxa-
phene subfractions have been found to be mutagenic to strain
TA100 with or without metabolic activation (Hill, 1977).
A study conducted by the U.S. EPA (1978) found
no significant differences in the rates of chromosomal aber-
rations in leukocytes between groups of workers occupation-
ally exposed to toxaphene and those not exposed.
C. Teratogenicity
Toxaphene did not produce teratogenic effects
when administered in the diet of rats, mice, and guinea
pigs (U.S. EPA, 1979). Kennedy, et al. (1973) found no
indication of teratogenic effects in F3 weanlings of rats
-------
fed toxaphene at levels of 25 mg/kg diet and 100 mg/kg diet.
Pregnant rats and mice fed 15 to 35 mg/kg/day of toxaphene
produced young with no teratogenic effects as did pregnant
guinea pigs fed 15 mg/kg body weight (Chernoff and Carver,
1976; DiPasquale, 1977).
D. Other Reproductive Effects
Adverse effects on fertility, gestation, viability,
lactation, or survival indices were not observed in male
and female rats fed dietary levels of 25 mg/kg and 100 mg/kg
toxaphene (Kennedy, et al. 1973), or in mice fed dietary
levels of 25 mg/kg toxaphene (Keplinger, et al. 1970).
E. Chronic Toxicity
Long term exposures to low dietary levels of toxa-
phene have been investigated in several studies involving
rats, dogs, and monkeys (U.S. EPA, 1979). All studies noted
some form of liver pathology in rats at dietary levels of
100 mg/kg or above. At 100 mg/kg, cytoplasmic vacuolization
was noted by Kennedy, et al. (1973). Increased liver weight
with minimal liver cell enlargement was noted in rats at
dietary levels of 25 mg/kg (Fitzhugh and Nelson, 1951).
The lowest dietary level of toxaphene producing unequivocal
liver damage over a two-year feeding period was 20 mg/kg
(U.S. EPA, 1979). Only at high concentrations, i.e., 1,000
mg/kg diet, does toxaphene elicit central nervous system
effects (Hercules, Inc., undated).
F. Other Relevant Information
Induction of hepatic microsomal mixed-function
oxidase (MFO) appears to account for most of the interactions
-------
of toxaphene with other compounds (U.S. EPA, 1979). Pre-
treatment with known MFO inducers, such as DDT, aldrin,
-and dieldrin, increases oral LC^Q's two to three-fold (Deich-
man and Keplinger, 1970). Piperonyl butoxide, which inhibits
the metabolism of many toxicants by MFO, has been shown
to potentiate the toxicity of toxaphene in houseflies (Saleh,
et al. 1977).
Keplinger and Deichmann (1967) found that equitoxic
combinations of toxaphene with parathion, diazinon, or tri-
thion were less toxic than expected based on the assumption
of simple similar action.
Acute human intoxication by toxaphene-lindane
mixtures produces signs and symptoms that are not character-
istic of toxaphene or lindane poisoning (Pollock, 1958;
Masumura, 1975).
V. AQUATIC TOXICITY
A. Acute
Acute toxicity data of toxaphene to freshwater
fish are derived from 52 96-hour LC^Q values for 18 species
resulting from 48 static and 4 flow-through assays. Observed
LC^Q values for these species of fish range from 0.8 pg/1
for the channel catfish (Ictalurus punctatus) to-28 ug/1
for the goldfish, (Carassius auratus) (U.S. EPA, 1979).
No single family or species appeared to be dramatically
more resistant or sensitive to toxaphene. For freshwater
invertebrates, 17 static bioassays on 13 species resulted
in reported LC<-Q values of 1.3 ug/1 for the stonefly (Cla-
asenia sabulosa) to 178 pg/1 for the crayfish.(Procambarus
simulans) (U.S. EPA, 1978).
-------
For the marine fish, toxicity data were determined
from five flow-through and two static assay procedures repre-
senting six species. Observed LC5Q values ranged from 0.5
ug/1 for the pinfish (Lagodon rhomboides) to 4.7 ug/1 for
the threespine stickleback (Gasterosteus aculeatus) (U.S.
EPA, 1979). The toxicity of toxaphene to marine inverte-
brates shows considerable interspecific variation in 31
assays (10 flow-through and 21 static) with reported LC50
values ranging from 0.054 yag/1 for larval stages of the
driftline crab (Sesarma cineseum) to 2,700 pg/1 for the
blue crab (Callinecten sapilus).
B. Chronic
Chronic life cycle toxicity tests have produced
chronic values of 0.037 and 0.059 jug/1 for the fathead min-
now (Pimephales promelas) and channel catfish (Ictalurus
punctatus), respectively (Mayer, et al. 1977). Growth ef-
fects were noted in brooktrout chronically exposed to concen-
trations of 0.038 ug/1. Life cycle tests on freshwater
invertebrates have been performed on three species with
chronic values of 0.09, 0.18, and 1.8 jag/1 reported for
Daphnia magna; the scud (Gammarus pseudolimnaeus); and midge
larvae (Chironomus plumosus), respectively (Sanders, in
press). An embryo-larval test on the marine fish sheeps-
head minnow (Gyprinodon variegatus) produced a chronic value
of 0.83 /jg/1 (Goodman, et al. 1978). A chronic value of
0.097 ^g/1 was obtained for the marine mysid shrimp (Mysi- •
dopsis bahia) (Nimmo, 1977).
rf
-1963-
-------
C. Plant Effects
No data for the effects of toxaphene were found
for freshwater species. Effective concentrations for five
species of marine plants ranged from 0.15 ug/1 for reduced
growth in the dinoflagellate (Monochrysis lutheri) to 150
pg/1 for lethality in the dinof lagellate (panalj.ella euchlora)
and no growth of the algae (Protococcus) sp. (U.S. EPA,
1978) .
D. Residues
Bioconcentration factors for three species of
fish were reported (Mayer, et al. 1975; Mayer, et al. 1977).
Brooktrput fry (Salvelinus fontinalis) had the highest fac-
tor of 76,000 in 15 days, while yearling brooktrout had
the lowest factor of 16,000 in 161 days. In the marine
longnose killifisn (Fundulas similis), bioconcentrations
for a number of different life stages were reported as 29,450
for juveniles, 27,900 for fry, 5,400 for adults, and 1,270
to 3,700 for ova of exposed adults (Schimmel, et al. 1977).
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor aquatic criteria derived
by U.S. EPA (1979), which are summarized below, have gone
through the process of public review; therefore, there is
a possibility that these criteria will be changed.
A. Human
The standards for toxaphene in air, water, and
food which have been established or recommended by various
groups and agencies were set .before the results of the MCI
bioassay for carcinogenicity were available (U.S. EPA, 1979).
-------
The ACGIH (1977) recommends a time weighted average value
of 500 mg/m for the working environment and a tentative
short-term exposure limit: of 1 mg/m . The national interim
primary drinking water standard for toxaphene is 5 pg/1
(40 FR 11990; U.S. EPA, 1976b, 1976c). The National Academy
of Sciences (1977) estimated the acceptable daily intake
of toxaphene for man at 1.25 jag/kg and suggested no-adverse-
effect levels from water at 8.75 pg/1 (assigning 20 percent
of the total ADI to water) or 0.44 yjg/1 (assigning 1 percent
of the total ADI to water). Effluent standards for toxa-
phene manufacturers have been set at 1.5 jjg/1 for existing
facilities and 0.1 ug/1 for new facilities (U.S. EPA, 1976a),
Tolerances established by the U.S. Food and Drug Administra-
tion for toxaphene in various agricultural products range
from 0.1 mg/kg in sunflower seeds to 7 mg/kg in meat fat
(U.S. EPA, 1979).
The U.S. EPA (1979) draft water quality criterion
—4
for toxaphene is 0.467 ng/1 or 4.7 x 10 pg/1. This cri-
terion is based on the NCI (1979) study that reported hepato-
cellular carcinoma and neoplastic nodules in mice fed toxa-
phene; the criterion was calculated to keep the lifetime
cancer risk below 10 for humans.
B. Aquatic
A drafted criterion for the protection of fresh-
water aquatic organisms is 0.007 iag/1 for a 24-hour average
concentration, not to exceed 0.47 ug/1 at any time. For
marine aquatic life, the drafted criterion is 0.019 fig/1
for a 24-hour average concentration not to exceed 0.12 ug/1
at any time (U.S. EPA, 1979).
-------
TOXAPHENE
REFERENCES
American Conference of Governmental Industrial Hygien.ists.
1977. TLVs: Threshold limit values for chemical substances
and physical agents in the workroom environment with intended
changes for 1977. Cincinnati, Ohio.
Arthur, R.D., et al. 1976. Atmospheric levels of pesti-
cides in the Mississippi delta. Bull. Environ. Contam.
Toxicol. 15: 129.
Bailey, T.E., and J.R. Hannum. 1967. Distribution of pesti-
cides in California. Jour. San. Eng. Div. Proc. Am. Soc.
Civil Eng. 93: 27.
Bidleman, T.F., and C.E. Olney. 1975. Long range transport
of toxaphene insecticide in the atmosphere of the western
North Atlantic. Nature 257: 475.
Brooks, G.T. 1974. Chlorinated insecticides. CRC Press,
Cleveland, Ohio.
Chandurkar, P.S. 1977. Metabolism of toxaphene components
in rats. Microfilmed by Photogr. Media Center, University
of Wisconsin.
Chernoff, IJ., and 3.D. Carver. 1976. Fetal toxicity of
tcxachene in rats and mice. Bull. Environ. Contam. Toxicol.
15: 660.
Clapp, K.L., et al. 1971. Effect of toxaphene on the hepatic
ceils of rats. In: Proc. Ann. Meet. Western Section, Am.
Soc. Anim. Sci. Fresno State College, Fresno, Calif.
Conley, B.E. 1952. Pharmacological properties of toxaphene,
a chlorinated hydrocarbon insecticide. Jour. Am. Med. Assoc.
149: 1135.
Crowder, L.A., and E.F. Dindal. 1974. Fate of chlorine-
36-labeled toxaphene in rats. Bull. Environ. Contam. Toxicol.
12: 320.
Deichmann, W.B., and M.L. Keplinger. 1970. Protection
against the acute effects of certain pesticides by pretreat-
ment with aldrin, dieldrin, and DDT. Pestic. Symp. Collect.
Pap. Inter-Am. Conf. Toxicol. Occup. Med., 6'th, 7th, 1968-
1970.
DiPasquale, L.C. 1977. Interaction of toxaphene with ascor-
bic acid in the pregnant guinea pig. Master's Thesis.
Wright State University, 1976. EPA in-house rep. 1977.
Summarized by K. -Diane'Courtney, Environ. Toxicol. Div.,
Health Eff. Res. Lab., U.S. Environ. Prot. Agency, in a
Toxaphene review dated Nov. 16, 1977.
-------
Duggan, R.E., and P.E. Corneliussen. 1972. Dietary intake
of pesticide chemicals in the United States (III). June
1968-April 1970 (with summary of 1965-1970). Pestic. Monitor.
Jour. 5: 331.
Fitzhugh, O.G., and A.A. Nelson. 1951. Comparison of chronic
effects produced in. rats by several chlorinated hydrocarbon
insecticides. Fed. Proc. 10: 295.
Goodman, L.R., et al. 1978. Effects of heptachlor and
toxaphene on laboratory-reared embryos and fry of the sheeps-
head minnow. 30th Ann. Conf. Southeast Assoc. Game Fish
Comm.
Hercules Inc. Undated. Hercules toxaphene insecticide.
Bull. T-105c.
Hill, R.N. 1977. Mutagenicity testing of toxaphene. Memo
dated Dec. 15, 1977, to Fred Hageman. Off. Spec. Pestic.
Rev. U.S. Environ. Prot. Agency, Washington, D.C.
Johnston, W.R., et al. 1967. Insecticides in tile drainage
effluent. Water Resour. Res. 3: 525.
Kennedy, G.L., Jr., et al. 1973. Multigeneration reproduc-
tive effects of three pesticides in rats. Toxicol. Appl.
Pharmacol.- 25: 589.
Keplinger, M.L., et al. 1970. Effects of combinations
of pesticides on reproduction in mice. In_: Pestic. Symp.
Collect. Pap. Int. Am. Conf. Toxicol. Occuo. Med. 6th, 7th.
Khalifa, S., et al. 1976. Toxaphene degradation by iron
(II) protoporphyrin systems. Jour. Agric. Food Cham. 24:
277.
Kulkarni, A.?., et al. 1975. Cytochrorae P-450 optical
difference spectra of insecticides. Comparative study.
Jour. Agric. Food Chem. 23: 177.
Lackey, R.W. 1949a. Observations on the acute and chronic
toxicity of toxaphene in the dog. Jour. Ind. Hyg. Toxicol.
31: 155.
Lackey, R.W. 1949b. Observations on the percutaneous absorp-
tion of toxaphene in the rabbit and dog. Jour. Ind. Hyg.
Toxicol. 31: 155.
Lehman, A.J. 1952. Oral toxicity of toxaphene. U.S. Q.
Bull. Assoc. Food Drug Off. 16: 47.
Litton Bionetics, Inc. Carcinogenic evaluation in mice.
Toxaphene. Final Report. LBI Project No. 20602. Kensington,
MD. Submitted to Hercules, Inc., Wilmington,'Del. Nov.
1978.
-------
Matsumura, F. 1975. Toxicology of insecticides. Plenum
Press.
Mattraw, H.C. 1975. Occurrence of chlorinated hydrocarbon
insecticides - southern Florida - 196.8-1972. Pestic. Monitor.
Jour. 9: 106.
Mayer, F.L., Jr., et al. 1975. Toxaphene: Effects on
reproduction, growth, and. mortality of brook trout. EPA-
600/3-75-013. U.S. Environ. Prot. Agency.
Mayer, F.L., et al. 1977. Toxaphene: Chronic toxicity
to fathead minnows and channel catfish. EPA-600/3-77-069.
U.S. Environ. Prot. Agency.
Metcalf, R.L. 1966. Kirk-Othmer encyclopedia of chemical
technology. John Wiley and Sons, Inc., New York.
National Academy of Sciences. 1977. Drinking water and
health. A report of the Safe Drinking Water Committee Ad-
visory Center on Toxicology Assembly of Life Sciences, National
Research Council. Washington, D.C.
National Cancer Institute. 1977. Guidelines for carcino-
genesis bioassays in small rodents. Tec. Rep. No. 1. Publ.
No. 017-042-00118-8. U.S. Government Printing Office,
Washington, D.C.
National- Cancer Institute. 1979. Bioassay of toxaphene
for possible carcinogenicity. DHEW Publ. No. (NIH) 73-837.
Nicholson, H.P., et al. 1964. Water pollution .by insecti-
cides in an agricultural river basin. I. Occurrence of
insecticides in river and treated water. Limnol. Oceanog.
9: 310.
Nicholson, H.P., et al. 1966. Water pollution by insecti-
cides: A six and one-half year study of a watershed. Proc.
Symp. Agric. Waste Waters Rep. No. 10 of Water Resour.
Center. University of California.
Nimmo, D.W. 1977. Toxaphene: Its effects on mysids.
Memo to Fred Hagman, U.S. Environ. Prot. Agency, Washington,
D.C.
Ohsawa, T.,.et al. 1975. .Metabolic dechlorination of toxa-
phene in rats. Jour. Agric. Food Chem. 23: 98.
Pollock, G.A. 1978. The toxicity and metabolism of toxa-
phene. University.of California, Davis.
Reimold, R.J., and C.J. Durant. 1972. Monitoring toxaphene
contamination in a Georgia estuary. Natl. Tech. Inf. Serv.
COM 73-1072. Springfield, Va.
-------
Saleh, M.A., et al. 1977. Polychlorobornane components
of toxaphene: Structure-toxicity relations and metabolic
reductive dechlorination. Science 198: 1256.
Schimmel, S.C., et al. 1977. Uptake and toxicity of toxa-
phene in several estuarine organisms. Arch. Environ. Contain.
Toxicol. 5: 353.
U.S. EPA. 1976a. Laboratory examination of drinking water
pesticide.analysis. Unpublished. Summarized in U.S. EPA
1977.
U.S. EPA. 1975b. National interim primary drinking water
regulations. EPA-570/9-76-003. Off. of Water Supply.
U.S. EPA. 1976c. Quality criteria for water. Report No.
EPA-440/9-76-023.
U.S. EPA. 1973. Occupational exposure to toxaphene. Final
Rep. by the Epidemiol. Stud. Progr. Off. Tox. Subst. Wash-
ington, D.C. (Draft).
U.S. EPA. 1979. Toxaphene: Ambient Water Quality Criteria
(Draft).
-------
No. 164
1,1,1-Trichloroethane
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
1770-
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect' ~}1 available information including all the
adverse health and' environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-1971-
-------
1,1,1-TRICHLOROETHANE
SUMMARY
Results of an NCI carcinogenesis bioassay have indi-
cated that oral administration of 1,1,1-trichloroethane
produced a variety of neoplasms. Retesting of this compound
is underway since a high incidence of premature deaths in
this initial study was observed.
There is no evidence to indicate that 1,1,1-trichloro-
ethane has mutagenic or teratogenic activity.
Human. toxic effects seen after exposure to 1,1,1-tri-
chloroethane include central nervous system disorders.
Animal studies indicate that toxic effects may be produced
in the central nervous system, pulmonary system, heart,
kidney, and liver.
Relatively little aquatic toxicity data is available.
In acute studies both, freshwater and marine fish are com-
parably sensitive, with LC5Q values ranging from 69,700
to 105,000 jag/1.
7972--
-------
I . INTRODUCTION
This profile is based on the Ambient Watar Quality
Criteria Document for Chlorinated Ethanes (U.S. EPA, 1979a) .
The chlorinated ethanes are hydrocarbons in which one
or more of the hydrogen atoms of ethane are replaced by
chlorine atoms. Water solubility and vapor pressure decrease
with increasing chlor ination, while density and melting
point increase. At room temperature, 1, 1 , 1-tr ichloroethane
.(M.W. 133.4) is a liquid with a boiling point of 74.1°C,
a melting point of -33°C, a specific gravity of 1.3492,
and a low solubility in water (U.S. EPA, 1979a) .
The chloroethanes are used as solvents, cleaning and
degreasing agents, and in the chemical synthesis of a number
of compounds.
The 1976 production of 1,1, 1-tr ichloroethane was:
315 x 103 ton/year (U.S. SPA, 1979a) .
The chlorinated ethanes form azeotropes with water (Kirk
and Othmer, 1963). All are very soluble in organic solvents
(Lange, 1956). Microbial degradation of the chlorinated
ethanes has not been demonstrated (U.S. EPA, 1979a) .
The reader is referred to the Chlorinated Ethanes Hazard
Profile for a more general discussion of chlorinated ethanes
(U.S. EPA, 1979b) .
II. EXPOSURE
The chloroethanes present in raw and finished waters
are due primarily to industrial discharges. Small amounts
of the chloroethanes may be formed by chlor ination of drink-
ing water or treatment of sewage. Air levels of chloroethanes
~/973-
-------
are produced oy evaporation of these compounds, widely used
as degreasing agents and in dry cleaning operations (U.S.
EPA, 1979a). Occupational air monitoring studies have indi-
cated 1,1,1-trichloroethane levels ranging from 1.5 to 396
ppm (U.S. EPA, 1979a).
Sources of human exposure to chloroethanes include
water, air, contaminated foods and fish, and dermal absorp-
tion. An analysis of several foods indicated 1,1,1-trichloro-
ethane was present at levels of 1-10 ug/kg*- (Walter, et al. ,
1976). Fish and shellfish have shown levels of 1,1,1-tri-
chloroethane in the nanogram range (Dickson and Riley, 1976) .
The U.S. EPA (1979a) has estimated the weighted average
bioconcentration factor for 1,1,1-trichloroethane to be
21 for the edible portions of fish and shellfish consumed
by Americans. This estimate is based on the measured steady-
state bioconcentration studies in bluegills.
i"
III. PHARMACOKINETICS
A. Absorption )
The chloroethanes are absorbed rapidly following
oral or inhalation routes of exposure (U.S. EPA, 1979a).
Slow dermal absorption of 1,1,1-trichloroethane has been
demonstrated in humans (Stewart and Dodd, 1964).
B. Distribution
Stahl, et al. (1969) have noted the presence of
JL , 1,1-tr ichloroethane in the liver, brain, kidney, muscle,
lung, ana blooa in post-mortem tissue samples following
/
-------
high level exposures. Animal studies have indicated that
the compound accumulates in the liver, kidney, and brain
of the mouse following inhalation exposure. (Holmberg, et
al. , 1977) .
C. Metabolism
The metabolism of chloroethanes involves both
enzymatic dechlorination and hydroxylation to corresponding
alcohols (U.S. EPA, 1979a). Oxidation reactions may produce
unsaturated metabolites which are then transformed to the
alcohol and ester (Yllner, 1971a,b,c,d). Trichloroethanol
and trichloroacetic acid have been identified in the urine
of rats following inhalation exposure to 1,1,1-trichloro-
ethane (Ikeda and Ohtsuji, 1972). Metabolism appears to
involve the activity of the mixed-function oxidase system
(Van Dyke and Wineman, 1971).
D. Excretion
The chloroethanes are excreted primarily in the
urine and expired air (U.S. EPA, 1979a). Monster and co-
workers (1979) reported that 60-80 percent of i,1,1-trichloro-
ethane inhaled by volunteers was expired unchanged; two
urinary metabolites represented 3 percent of the uptake.
Excretion of the chloroethanes is generally rapid, the major-
ity of compound being eliminated within 24 hours (U.S. EPA,
1979a).
IV. EFFECTS
»
A. Carcinogencity
An NCI bioassay for carcinogenicity (1977) has
indicated that 1,1,1-trichloroethane induced a variety of
-------
neoplasms. A high incidence of deaths in test animals has
led to the retesting of this compound by NCI. Price, et
al. (1978). have demonstrated _in vitro transformation of
rat embryo cells with 1, 1 ,1- tr ichloroethane; injection of
these cells iri vivo produced undif f erentiatea f ibrosarcomas
in all tested animals.
B. ' Mutagenicity
Pertinent information could not be located in
the available literature on the mutagenicity of 1,1,1-tri-
cnloroethane .
C. Teratogenicity
Inhalation studies with 1, 1 , 1-tr ichloroethane
in mice and rats have shown the production of some soft
tissue and skeletal anomalies (Schwetz, et al . ly?4) .
These were not shown to be statistically significant by
the Fisher Exact probability test. >.
D. Other Reproductive Effects
Pertinent information could not be located in
the available literature on other reproductive effects of
1,1 , 1-tr ichloroethane .
E. Chronic Toxicity
Human toxic effects seen after exposure to 1,1,1-
tr ichloroethane include several central nervous system dis-
orders. These include changes in reaction time, perceptual
speed, manual dexterity, and equilibrium (U.S. EPA, 1979a) .
Animal studies have indicated that l, 1 , 1-tr ichloro-
ethane produces toxic effects in the central nervous system,
1 976-
-------
cardiovascular system, and pulmonary system, and induces
liver and kidney damage (U.S. EPA, 1979a).
V. AQUATIC TOXICITY
A. Acute Toxicity
For freshwater fish, 96-hour static LC^0 values
of 69,700 ug/1 for the bluegill Lepomis macrochirus and
150,000 ug/1 for the fathead minnow, Pimephales promelas,
while a single 96-hour flow-through LC5Q value of 52,800
ug/1 was obtained for the fathead minnow, Pimephales promelas,
(Alexander, et al. 1978). For marine organisms, 96-hour
static LC-Q values ranged from 31,200 ug/1 for the mysid
shrimp, Mysidopsis bahia, to 70,900 ug/1 for the sheepshead
minnow, Cyprinodoh var iegatus, (U.S. EPA, 1978).
B. Chronic Toxici'ty and Plant Effects
Pertinent information could not be . located in
the avaiiaole literature.
C. Residues
A bioconcentration factor of 9 was obtained for
the bluegill (U.S. EPA, 1979a).
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor aquatic criteria derived
by U.S. EPA (1979a) , which are summarized below, have gone
through the process of puolic review; therefore, there is
a possibility that these criteria will be changed.
A. Human
Based on mammalian toxicology data, the EPA (197Sa)
•
has prepared a draft ambient water quality criterion to
-------
protect human health at the level of 15.7 mg/1 for 1,1,1-
trichloroethane.
The 8-hour, TWA exposure standard established
by OSHA for 1,1,1-trichloroethane is 350 ppm.
B. Aquatic
The freshwater criterion has been drafted as 5,300
ug/1 as a 24-hour average, not to exceed 12,000. jjg/1; while
the criterion to protect marine life has been drafted as
a 24-hour average concentration of 240 jag/1, not to exceed
540 pg/1.-
itn
-------
1,1,1-TRICHLOROETHANE
REFERENCES
Alexander, H.C., et al. 1978. Toxicity of perchlorcethylene, trichloro-
ethylene, 1,1,1-trichloroethane and metnylene chloride to fathead minnows.
Bull. Environ. Contain. Toxicol. 20: 344.
Dickson, A.G. and J.P. Riley. 1976. The distribution of short-chain halo-
genated aliphatic hydrocarbons in some marine organisms. Mar. Pollut. Bull.
79: 167.
Holmberg, B., et al. 1977. A 'study of the distribution of methylchloroform
and n-octane in the mouse during and after inhalation. Scand. Jour. Work
Environ. Health 3: 43.
*.
Ikeda, M. and H. Ohtsuji. 1972. Comparative study of the excretion of
Fujiwara reaction-positive substances in urine of humans and rodents given
trichloro- or tetrachloro-derivatives of ethane and ethylene. Br. Jour.
Ind. Med. 29: 99.
Kirk, R. and 0. Othmer. 1963. Encyclopedia of chemical technology. 2nd
ed., John Wiley and Sons, Inc., New York.
Lange, N. (ed.) 1956. Handbook of chemistry. 9th ed., Handbook Publish-
ers, Inc., Sandusky, Ohio.
Monster, A.C., et al. 1979. Kinetics of 1,1,1-trichloroethane in volun-
teers; influence of exposure concentration and work load. Int. Arch. Occup.
Environ. Health 42: 293.
National Cancer Institute. 1977. Bioassay of 1,1,1-trichloroethane for
possible carcinogenicity. Carcinog. Tech. Rep. Ser. NCI-CG-TR-3.
Price, P.J., et al. 1978. Transforming activities of trichloroethylene and
proposed industrial alternatives. In vitro 14: 290.
Schwetz, B.A., et al. 1974. Embryo- and fetotoxicity of inhaled carbon
tetrachloride, 1,1-dichloroethane, and methyl ethyl ketone in rats. Toxi-
col. Appl. Pharmacol. 28: 452.
Stahl, C.J., et al. 1969. Trichloroethane poisoning: observations on the
pathology and toxicology in six fatal cases. Jour. Forensic Sci. 14: 393.
Stewart, R.D. and H.C. Dodd. 1964. Absorption of carbon tetrachloride,
trichloroethylene, tetrachloroethylene, methylene chloride, and 1,1,1-tri-
chloroethane through the human skin. Am. Ind. Hyg. Assoc. Jour. 25: 439.
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. Contract No. 68-01-4646, U.S. Environ.' Prot.
Agency.
•m-
-------
U.S. EPA. 1979a. Chlorinated Ethanes: Ambient Water Quality Criteria.
(Draft) "
U.S. EPA. 1979b. Environmental Criteria and Assessment Office. Chlorinat-
ed Ethanes: Hazard Profile. (Draft)
Van Dyke, R.A. and C.G. Wineman. 1971. Enzymatic dechlorination: De-
chlorination of chloroethanes and propanes in vitro. Biochem. Pharmacol.
20: 463.
Walter, P., et .al. 1976. Chlorinated hydrocarbon toxicity (1,1,1-tri-
chloroethane, trichloroethylene, and tetrachloroethylene): a monograph.
PB-257185. Natl. Tech. Inf. Serv., Springfield, Va.
Yllner, S. 1971a. Metabolism of l,2-dichloroethane-14c in the mouse.
Acta. Pharmacol. Toxicol. 30: 257.
Yllner, S. 1971b. Metabolism of 1,1,2-trichloroethane-l,2-1*C in the
mouse. Acta. Pharmacol. Toxicol. 30: 248.
Yllner, S. 1971c. Metabolism of 1,1,1,2-tetrachloroethane in the mouse.
Acta. Pharmacol. Toxicol. 29: 471.
Yllner, S. 1971d. Metabolism of l.,l,2,2-tetrachloroethane-14C in the
mouse. Acata. Pharmacol.'Toxicol. 29: 499.
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No. 165
1,1,2,-Trichloroe chane
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
•mi-
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
SPECIAL NOTATION
U.S. EPA's Carcinogen Assessment Group (GAG) has evaluated
1,1,2-trichloroethane and has found sufficient evidence to
indicate that this compound is carcinogenic.
-------
1.1.2-TRICHLaROETHANE
Summary
Results of a National Cancer Institute carcinogenesis bioassay indicate
that oral administration of 1,1,2-trichloroethane produces an increase of
several tumor types in rats and mice.
Information is not available to indicate if 1,1,2-trichloroethane has
any mutagenic effects, teratogenic effects, or adverse reproductive effects.
Animal studies have indicated that exposure to 1,1,2-trichloroethane
may produce liver and kidney toxicity.
Aquatic toxicity data for 1,1,2-trichloroethane is limited, with only
two acute studies in freshwater fish and invertebrates available. Toxic
doses ranged ' ji 18,000 to 40,200
-------
i,1,2-TRICHLOROETHANE
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Chlorinated Ethanes (U.S. EPA, 1979a).
The chloroethanes are hydrocarbons in which one or more of the hydrogen
atoms of ethane are replaced by chlorine atoms. Water solubility and vapor
pressure decrease with increasing chlorination, while both density and melt-
ing points increase. 1,1,2-Trichloroethane (molecular weight. 133.4) is a
liquid at room temperature with a boiling point of 113°C, a melting point
of -37.4°C, a specific gravity of 1.4405, and slightly soluble in water
(U.S. EPA, 1979a).
The chloroethanes are used as solvents, cleaning and degreasing agents,
and in the chemical synthesis of a number of compounds.
The chlorinated ethanes form azeotropes with water (Kirk and Othmer,
1963) and all are very soluble in organic solvents (Lange, 1956). Microbial
degradation of the chlorinated ethanes has not been demonstrated (U.S. EPA,
1979a).
The reader is referred to the Chlorinated Ethanes Hazard Profile for a
more general discussion of chlorinated ethanes (U.S. EPA, 1979b).
II. EXPOSURE
The chloroethanes are present in raw and finished waters primarily from
industrial discharges. Small amounts of chloroethanes may be formed by
chlorination of drinking water or treatment of sewage. A metropolitan water
monitoring study has shown finished water levels from 0.1 to 8.5 ug/1 for
1,1,2-trichloroethane (U.S. EPA, 1979a). Air levels of chloroethanes are
#
produced by evaporation of volatile chloroethanes widely used as degreasing
agents and in dry-cleaning operations (U.S. EPA, 1979a).
-------
Sources of human exposure to chloroethanes include water, air, contami-
nated foods and fish, and dermal absorption. Fish and shellfish have shown
levels of chloroethanes in the nanogram range (Dickson and Riley, 1976).
Pertinent information was not found in the available literature on
1,1,2-trichloroethane levels in food.
The U.S. EPA (1979b) has estimated the weighted bioconcentration factor
for 1,1,2-trichloroethane to be 6.3. This estimate was based on the octa-
nol/water partition coefficient for 1,1,2-trichloroethane.
III. PHARMACOKINETICS
A. Absorption
The chloroethanes are absorbed rapidly following oral or inhalation
routes of exposure (U.S. EPA, 1979a). .Dermal absorption of 1,1,2-trichloro-
ethane may be extensive as indicated by lethal toxicity in animals following
dermal exposure (Smyth, et al. 1969).
3. Distribution
Specific information on the distribution of 1,1,2-trichloroethane
has not been found in the available literature. The reader is referred to a
more general treatment of the chloroethanes (U.S. EPA, 1979b) which indi-
cates widespread distribution of these compounds throughout the body.
C. Metabolism
The metabolism of chloroethanes involves both enzymatic dechlorina-
tion and hydroxylation to corresponding alcohols (U.S. EPA, 1979a). Oxida-
tion reactions may produce unsaturated metabolites which are then transform-
ed to the alcohol and ester (Yllner, 1971). Trichloroethanol and trichloro-
acetic acid have been identified in the urine of rats following inhalation
exposure to 1,1,2-trichloroethanol (Ikeda and Ohtsuji, 1972). Metabolism
appears to involve the activity of the mixed function oxidase system (Van
Dyke and Wineman, 1971).
'/9 S 6-
-------
D. Excretion
The chloroethanes are excreted primarily in the urine and in ex-
pired air (U.S. EPA, 1979a) with excretion being generally rapid. Experi-
ments' conducted by Yllner (1971) indicate that following intraperatoneal in-
jection of 1,1,2-trichloroethane into mice, more than 90 percent of the ad-
ministered dose is excreted in 24 hours, with more than half found in the
urine. Ten to twenty percent of injected compound is found in expired air.
IV. EFFECTS
A. Carcinogenicity
Results of an NCI carcinogenesis bioassay for 1,1,2-trichloroethane
show that oral administration of compound produced an increase of several
tumor types (NCI, 1978). Rats showed adrenal carcinomas, kidney carcinomas,
and varied hemangiosarcomas, while mice showed an increase in hepatocellular
carcinomas.
3. Mutagenicity, Teratogenicity and Other Reproductive Effects
Available information on this compound is very limited in these
areas. A search of the literature did not reveal any pertinent data.
C. Chronic Toxicity
Animal studies have indicated that exposure to 1,1,2-trichloroeth-
ane .may produce liver and kidney toxicity (U.S. EPA, 1979a).
V. AQUATIC TOXICITY
A. Acute Toxicity
The only aquatic toxicity data for 1,1,2-trichloroethane are single
static bioassays on the bluegill (Lepomis macrochirus) and Oaphnia magna.
The acute 96-hour LC5Q value for the bluegill was 40,200 yg/1, while the
48-hour LC50 value for Daohnia maona .was 18,000 ug/1 (U.S. EPA, 1979).
Marine studies are presently not available.
-------
3. Chronic Toxicity, Plant Effects and Residues
Available information on this compound is very limited in these
areas. A search of the literature did not reveal any pertinent.data.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived by U.S. EPA
(1979), which are summarized below, have gone through the process of public
review; therefore, there is a possibility that these criteria will be
changed.
A. Human
Based on the NCI carcinogenesis data, and using a linear, non-
threshold model, the U.S. EPA (1979a) has estimated the level of 1,1,2-tri-
chloroethane in ambient water that will result in an additional cancer risk
of 10"5 to be 2.7pg/l. 4
The 8-hr, TWA exposure standard for 1,1,2-trichloroethane is 10 ppm.
8. Aquatic
The draft criterion for protection of freshwater aquatic life is
310 ug/1 as a 24-hour average; the concentration should not exceed 710 ug/1
at any time (U.S. EPA, 1979a). NO criterion for protection of saltwater
aquatic life has been found.
-/9rs-
-------
1,1,2-TRICHLOROETHANE
REFERENCES
Oickson, A.G., and J.P. Riley. 1976. The distribution of short-chain halo-
genated aliphatic hydrocarbons in some marine organisms. Mar. Pollut.
Bull. 79: 167.
Ikeda, M., and H. Ohtsuji. 1972. Comparative study of the excretion of
Fujiwara reaction-positive substances, in urine of humans and rodents given
trichloro- or tetrachloro-derivatives of. ethane and ethylene. 8r. Jour.
Ind. Med. 29: 99.
Kirk, R. and Othmer. D. 1963. Encyclopedia of Chemical Technology. 2nd
ed. John Wiley and Sons, Inc. New York.
Lange, N. (ed.) 1956. Handbook of Chemistry. 9th ed. Handbook
Publishers, Inc. Sandusky, Ohio.
National Cancer Institute. 1978. Bioassay of 1,1,2-trichloroethane for
possible carcinogenicity. Natl. Inst. Health, Natl. Cancer Inst. OHEW Publ.
No. (NIH) 78-1324.. Pub. Health Serv. U.S. Dep. Health Edu. Welfare.
Smyth, H.F., Jr., et al. 1969. Range-finding toxicity data: list VII.
Am. Ind. Hyg. Assoc. Jour. 30: 470.
U.S. EPA. 1979a. Chlorinated Ethanes: Ambient Water Quality Criteria.
(Draft).
U.S. EPA. 1979b. Environmental Criteria and Assessment Office.
Chlorinated Ethanes: Hazard Profile (Draft).
Van Dyke, R.A., and C.G. Wineman. 1971. Enzymatic dechlorination:
Oechlorination of chlorcethanes and propanes in vitro Biochem. Pharmacol.
20: 463.
Yllner, S. 1971. Metabolism of l,l,2-trichloroethane-l,2~L4c j.n the
mouse. Acta. Pharmacol. Toxicol. 30: 248.
-------
No. 166
Trichloroethylene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-1970 -
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical acc-uracy.
-------
SPECIAL NOTATION
U.S. EPA's Carcinogen Assessment Group (GAG) has evaluated
trichloroethylene and has found sufficient evidence to
indicate that this compound is carcinogenic.
-I??*-
-------
TRICHLOROETHYLENE
SUMMARY
Trichloroethylene is a colorless liquid used mainly as a degreasing
solvent. Both acute and chronic exposure to high levels of trichloro-
ethylene produce central nervous system depression and other neurological
.effects. Trichloroethylene also causes some kidney and liver damage. Tri-
chloroethylene has not been shown to be a teratogen, and the data suggesting
mutagenicity and carcinogenicity are weak. The studies of mutagenicity and
carcinogenic!ty have been complicated by the presence of contaminants with
known carcinogenic and mutagenic activity. However, the cancer assessment
group has determined that Trichloroethylene is carcinogen^ic.
Only a few studies have been reported on trichloroethylene toxicity to
•»
aquatic species. Fathead minnows, when exposed in flow through and static
tests, had 96 -hour LC_Q values of 40,700 and 66,300 ug/1, respectively.
The 96 hour LC--. for the bluegill was 44,700 ug/1 in static tests. The 48
hour LC_Q for the freshwater invertebrate, Daphnia magna, was 85,200
ug/1. In the only reported chronic test, no adverse effects were observed
in Daphnia. magna exposed to 10,000 >jg/l. Photosynthesis was reduced by 50
percent in the alga, Phaedactylan tricornutum, at a concentration of 8,000
ug/1. Trichloroethylene was bioconcentrated 17-fold by the bluegill after
14 days exposure. The half life of this compound in tissues was less than 1
day.
-------
TRICHLOROETHYLENE
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Trichloroethylene (U.S. EPA, 1979).
Trichloroethylene (C-HCl,, 1,1,2-trichloroethylene, TCE, molecular
weight 131.4) is a clear,, colorless liquid. Trichloroethylene has a water
solubility of 1,000 ug/ml; a vapor pressure of 77 mm Hg and a melting point
of 83°C (Patty, 1963). Trichloroethylene is mainly used as a degreasing
solvent, and. is used to lesser extents as a household and industrial dry-
cleaning solvent, an extractive solvent in foods, and as an inhalable
anesthetic during certain short-term sdrgical procedures (Huff, 1971).
Current Production: Annual production of trichloroethylene in the
United States approximates 234,000 metric tons (U.S. EPA, 1979). The vola-
tilization of trichloroethylene during production and use is the major
source of environmental levels of. this compound. Trichloroethylene is not
expected to persist in the environment because of its rapid photooxidation
in air, its low water solubility, and its volatility (Pearson and McConnell,
1975; Dillings, et al. 1976; Patty, 1963).
II. EXPOSURE
A. Water
The National Organics Monitoring Survey observed, trichloroethylene
in 28 of 113 drinking waters at a mean concentration of 21 ug/1 in May
through July, 1976 (U.S. EPA, 1979). Trichloroethylene may be formed during
the chlorination of water (National Academy of Science, 1977; Bellar,.et al.
1974).
-------
3. Food
There is little information concerning the occurencs of trichloro-
ethylene in U.S. foodstuffs. In England, trichloroethylene has been ob-
served at concentrations up to 10 ug/kg in meats, up to 5 jjg/kg in fruits,
vegetables, and beverages (McConnell, et al., 1975); packets of tea were
found to contain 60 >jgAg (Fishbein, 1976). Little trichloroethylene would
be expected in other foodstuffs, except in the case where it is used as a
solvent for food extractions. The U.S. EPA (1979) has estimated the
weighted bioconcentration factor of trichloroethylene to be 39. This esti-
mate is based on measured steady-state bioconcentration studies in bluegills
and estimates of fish and shellfish consumption.
C. Inhalation
The only significant exposure to trichloroethylene in air occurs to
a relatively small, industrially exposed population (Fishbein, 1976).
III. PHARMACQKINETICS
A. Absorption
trichloroethylene is readily absorbed by all routes of exposure.
In humans exposed to the compound by inhalation, steady state conditions are
approached within two hours. Absorption of trichloroethylene following in-
gestion has not been studied in humans. In rats, at least 80 percent of an
orally administered dose is systemically absorbed (U.S. EPA, 1979).
-------
8. Distribution
In humans, trichloroethylene is distributed mainly to body fat
(McConnell, et al. 1975). Laham (1970) demonstrated transplacental dif-
fusion of trichloroethylene in humans.
C. Metabolism
Qualitatively, the metabolism of trichloroethylene appears to be
similar across species (Kimmerle and Eben, 1973). The principal products of
trichloroethylene metabolism measured in urine are, trichloroethanol, tri-
chloroacetic acid, and conjugated derivatives (glucuronides) of trichloro-
ethanol. A reactive epoxide, trichloroethylene oxide, has been shown to be
formed during the metabolism of trichloroethylene; it can alkylate nucleic
acids and proteins (Van .Ouureen and Banerjee, 1976; Bolt and Filser, 1977).
Patterns of, metabolism of trichloroethylene in humans differ between mala
and female (Nomiyama and Nomiyama, 1971), and with age (U.S. EPA, 1979).
Increased microsomal enzyme activity enhances the conversion of trichloro-
ethylene to trichloroacetaldehyde (U.S. EPA, 1979). Ethanol interferes with
the metabolism of trichloroethylene, causing ethanol intolerance in exposed
workers (U.S. EPA, 1979).
0. Excretion
Trichloroethylene and its metabolites are excreted in exhaled air,
urine, sweat, feces, and saliva (Kimmerla and Eben 1973; U.S. EPA, 1979).
Trichloroethylene is lost from the body with a half-life of about 1.5 hours
*
(Stewart, et al. 1962); however, its metabolites have longer half-lives
ranging from 12 to 73 hours (Ikeda and Imamura, 1973; Ertle, et al. 1972).
-1116-
-------
IV. EFFECTS
A. Carcinogenicity
The National Cancer Institute (NCI, 1976) observed an increased
incidence of hepatocellular carcinoma in mice (strain B6C3-F1) treated with
trichloroethylene. Similar experiments in Osborne-Mendel rats failed to
increase the incidence of tumors in this species. It has been pointed out
that trichloroethylene used in the NCI bioassay (1976) contained traces of
monofunctional alkylating agents, epichlorohydrin and epoxibutane, as sta-
bilizers, and they might account for the observed carcinogenicity (U.S. EPA,
1979). No systematic study of humans exposed to trichloroethylene have
revealed a correlation with cancer (Axelson, et al. 1978).
8. Mutagenicity
Trichloroethylene has been reported to be mutagenic, in the pre-
sence of mammalian liver enzymes, to a number of bacterial strains. These
include E. coli K12, and S. typhimurium strain TA 100 (U.S. EPA, 1979:
Simmon, et al. 1977), in addition to ,-the yeast Saccharomyces cerevisiae
(Shahin and VonSarstel, 1977). However, there is some doubt as to the muta-
genicity of trichloroethylene due to epichlorohydrin and epoxibutane contam-
ination. Henscher, et al. (1977) observed that these contaminants were
potent mutagens in S. typhimurium strain TA100. Pure trichloroethylene was
weakly mutagenic.
C. Teratogenicity
Exposure of mice and rats to 1600 mg/m trichloroethylene for
seven hours a day on days 6 through 15 of gestation did not produce tera-
togenic effects (Schwetz, et al. 1975).
-------
0. Other Reproductive Effects
Pertinent data could not be located in the available literature.
E. Chronic Toxicity
Disturbances of the nervous system, which continue for at least a
year after final exposure, were observed following industrial exposure to
trichloroethylene (Nomiyama and Nomiyama, 1977; Bardodej and Vyskoch,
1956). Symptoms included headaches, insomnia, tremors, severe neuroasthemic
syndromes coupled with anxiety states, and bradycardia. Prolonged
occupational exposures to trichloroethylene have been also associated with
impairment of the peripheral nervous system. This can include persistent
neuritis (Sardodej and Vyskoch, 1956), temporary loss of tactile sense, and
paralysis of the fingers (McSirney, 1954). Rare cases of hepatic damage
have been observed following repeated abuse of trichloroethylene (Huff,
»
1971).
F. Other Relevant Information
Long-term toxicity of trichloroethylene appears to depend largely
on its metabolic products (U.S. EPA, 1979). Chemicals that enhance or
depress the mixed function oxidase system will have a synergistic or antago-
nistic effect, respectively, on the toxicity of trichloroethylene.
Trichloroethylene has been shown to induce transformation in a
highly sensitive in vitro Fischer rat embryo cell system (F1706) (U.S. EPA,
1979). Following exposure of cells to 1 M trichlbroethylene, the cells
formed progressively growing foci made up of cells lacking contact inhibi-
tion, and the cells gained the ability to grow in semi-solid agar.
-------
V. AQUATIC TOXICITY
A. Acute Toxicity
Alexander, et al. (1978) exposed fathead minnows (Pimeohales
promelas) to trichloroethylene in flow-through and static tests. The
observed 96-hour LC50 values were 40,700 and 66,800 ug/1, respectively.
...... .....The observed 96-hour LC5(, for the bluegill (Lepomis macrochirus) is 44,700
jjg/1 in static tests (U.S. EPA, 1978). The 48 hour LC5Q for Oaphnia maqna
and is 85,200 pg/1 (U.S. EPA, 1978). No saltwater fish or invertebrate
acute toxicity data were found in the available literature.
8. Chronic Toxicity
In the only reported chronic test, no adverse effects were observed
with Daohnia maqna at the highest test concentration of 10,000 /jg/1 (U.S.
EPA, 1978). -'
C. Plant Effects
14
There was a 50 percent decrease noted in C uptake by the salt-
water alga, Phaedectylum tricornutum, at a concentration of 8,000 pg/1
(Pearson and McConnell, 1975).
0. Residues
Bioconcentration by bluegills was studied (U.S. EPA, 1978) using
radiolabeled trichloroethylene. After 14 days the bioconcentration factor
was 17. The half-life of this compound in tissues was less than one day.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The Food and Drug Administration (1974)" has limited the concen-
tration of trichloroethylene in final food products to 10 mg/kg in instant
-------
coffee, 25 mg/kg in ground coffee and 30 mg/kg in spice extracts. The
American Conference of Governmental Industrial Hygienists (ACGIH) TLV is 535
mg/m .
The Cancer Assessment Group (CAG) has determined that, at the
present time, under existing.policy, TCE is a carcinogen. The NCI bioassay
(the results from which CAG has made their determination) is being repeated.
When the data is available, -it should be reviewed.
B. Aquatic
for trichloroethylene, the draft criterion to protect freshwater
aquatic life is 1,500 jjg/1 as a 24-hour average; the concentration should
not exceed 3,400 jug/1 at any time. 'Criterion for saltwater species has not
been developed because sufficient data could not be located in the available
literature. i
•&OOD
/
-------
TRI CHLOROETHYLEN E
REFERENCES
Alexander, H.C., et al. 1978. Toxicity of perchloroethy-
lene, trichloroethylene , 1 ,1 ,1-trichloroethane, and methylene
chloride to fathead minnows. Bull. Environ. Contain. Toxicol.
In press.
Axelson, 0., et al. 1978. A cohort study on trichloroethy-
lene exposure and cancer mortality. Jour. Occup. Med. 20:
19.4. . . " .
Bardodej, Z., and J. Vyskocil. 1956. The problem of
trichloroethylene in occupational medicine. AMA Arch. Ind.
Health 13: 581.
Bellar, T.A. , et al. 1974. The occurrence of organohalides
in chlorinated drinking waters. Jour. Am. Water Works Assoc.
66: 703.
Bolt, H.M., and J.G. Filser. 1977. Irreversible binding of -
chlorinated ethylenes to macromolecules . Environ. Health
Perspect. 21:
Dillings, et al. 1976. Simulated atmospheric photodecomposi
tion rates of methylene chloride, 1 ,1,1-trichloroethane, tri-
chloroethvlene, and other compounds. Environ. Sci. Technol.
10: 351.
Ertle, T., et al. 1972. Metabolism of trichloroethylene in
man. I. The significance of trichloroethanol in long-term
exposure conditions. Arch. Toxicol. 29: 171.
Fishbein, L. 1976. Industrial mutagens and potential muta-
gens. I. Halogenated aliphatic derivatives. Mut. Res. 32:
267.
Food and Drug Administration. 1974. Code of Federal Regula-
tions, Title 21, 121.1041. Trichloroethylene.
Henschler, D. , et al. 1977. Short communication: Carcino-
genicity of trichloroethylene: fact or artifact? Arch. Toxi-
col. 233.
Huff, J.E. 1971. New evidence, on the old problems of
trichloroethylene. Ind. Med. 40: 25.
Kimmerle, G. , and A. Eben. 1973. Metabolism, excretion and
tox icology of trichloroethylene after inhalation. 2. Exper-
imental human exposure. Arch. Toxicol. 30: 127.
Laham, S. 1970. Studies on placental transfer trichloro-
ethylene. Ind. Med. 39: 46.
-otOOl
-------
McBirney, 3.S. 1954. Trichloroethylene and dichloroethylene
poisoning. AMA Arch* Ind. Hyg. 10: 130.
McConnell, G., et al. 1975. Chlorinated hydrocarbons and
the environment. Endeavour. 34: 13.
National Academy of Science. 1977. Drinking water and
health. Safe Drinking Water Comm., Adv. Center on Toxicol.,
Assembly of Life Sci., Natl. Res. Council, Washington, D.C.
National Cancer Institute. 1976. Carcinogenesis bioassay of
trichloroethylene. CAS No. 79-01-6, NCI-CG-TR-2.
Nomiyama, K., and H. Nomiyama. 1971. Metabolism of tri-
chloroethylene in human sex differences in urinary excretion
of trichloroacetic acid and trichloroethanol. Int. Arch.
Arbeitsmed. 28: 37.
Patty, F.A. 1963. Aliphatic halogenated hydrocarbons. Ind.
Hyg. Tox. 2: 1307.
Pearson, C., and G. McConnell. 1975. Chlorinated Cj_ and
C2 hydrocarbons in the marine environment. Proc. R. Soc.
London B. 189: 302.
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.
Shahin, M., and R. von Barstal. 1977. Mutagenic and lethal
effects of benzene hexachloride, dibutyl, phatalage and
trichloroethylene in Saccharomyces cervisae. Mut. Res. 48:
173.
Simmon, V.F., et al. 1977. Mutagenic activity of chemicals
identified in drinking water. Paper presented at 2nd Int.
Conf. Environ. Mutagens, Edinburgh, Scotland, July 1977.
Stewart, R.D., et al. 1962. Observations on the concentra-
tions of trichloroethylene in blood and expired air following
exposure to humans. Am. Ind. Hyg. Assoc. Jour. 23: 167.
U.S. EPA. 1978. In-depth studies on health and environmen-
tal impacts of selected water pollutants. Contract' No. 68-
01-4646. U.S. Environ. Prot. Agency.
U.S. EPA. 1979. Trichloroethylene: Ambient Water Quality
Criteria. U.S; Environ. Prot. Agency.
Van Duuren, B.L., and S. Banerjee. 1976. Covalent intera*c-
tion of metabolites of the carcinogen trichloroethylene in
rat hepatic microsomes. Cancer Res. 36: 2419.
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No. 167
Trichlorofluoromethane and Dichlorofluororaethane
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-zoo*/-
-------
TRICHLOROFLUOROMETHANE
AND
DICHLORODIFLUOROMETHANE
SUMMARY
Trichlordfluoromethane (F-ll) and dichlorodifluoromethane
(F-12) are not easily degraded in the environment. After release
at the surface of the earth, F-ll and F-12 mix with the
atmosphere and rise slowly into the stratosphere where they are
decomposed by ultraviolet radiation to release chlorine atoms.
The chlorine atoms remove ozone catalytically, thereby reducing
the total amount of ozone in the stratosphere and permitting an
increased amount of biologically active ultraviolet radiation to
reach the earth's surface. The accumulation of F-ll and F-12 in
the atmosphere also increases the absorption and emission of
infrared radiation (the "greenhouse effect").
F-ll and F-12, while fairly lipophilic, are not expected to
bioaccumulate because of their high volatility. The compounds
are absorbed via the lungs, gastrointestinal tract, and skin,
however, most of that which is absorbed is eliminated unchanged
in expired air.
F-ll was not found carcinogenic in a long-term mouse study.
F-ll and F-12 were negative in the Ames Salmonella test; F-12 was
positive in a Neurospora crassa test system. '
At high concentrations in the air, F-ll and F-12 have been
*
shown to induce cardiovascular and pulmonary effects in animals.
In March 1979, fully halogenated chlorofluoroalkanes
(including F-ll and F-12) were banned as propellants in the
-------
United States except for essential uses. The action was taken
because the chlorofluoroalkanes may deplete the stratospheric
ozone, leading to various adverse effects.
I. INTRODUCTION
This paper is based on an EPA report entitled "Environmental
Hazard Assessment Report: Major One- and Two-Carbon Saturated
Fluorocarbons" .(U.S. EPA, 1976a).
Trichlorofluoromethane and dichlorofluoromethane are
commonly referred to by their fluorocarbon numbers, which are F-
11 and F-12, respectively. This convention will be followed in
this paper.
F-ll, a colorless volatile liquid, and F-12, a colorless
gas, have the following physical/chemical properties (U.S. EPA,
1976a):
F-ll . F-12
Molecular Formula CC^3F CC12F2
Molecular Weight 137.37 120.92
Boiling Point (°C) 23.82 -29.79
Freezing Point (°C) -111 -158
Solubility Both are soluble in water and
many organic solvents
A review of the production range (includes importation)'
statistics for trichlorofluoromethane (CAS No. 75-69-4) which is
listed in the initial TSCA Inventory (1979) has shown that
-3006-
-------
between 100 million and 200 million pounds of this chemical were
produced/imported in 1977._V
A review of the production range (includes importation)
statistics for dichlorodifluoromethane (CAS No. 75-71-8) which is
listed in the initial TSCA Inventory (1979) has shown that
between 200 million and 300 million pounds of this chemical were
produced/imported in 1977._V
The major uses of F-ll and F-12 are as aerosol propellants,
refrigerants, and foaming agents (U.S. EPA, 1976a).
II. EXPOSURE
< '• )
A. Enviroiimental Fate
Although F-ll and F-12 will volatilize quickly from water
and soils, they are considered persistant in the environment due
to their resistance to biodegradation, photodecomposition, and
V
V
chemical degradation (U.S. EPA, 1975a). After release at the
surface of the '--•rth, F-ll and F-12 (as well as other chloro-
fluoromethanes) mix with the atmosphere and rise slowly into the
stratosphere where they are decomposed by ultraviolet radiation
to release chlorine atoms. Chlorine atoms and a subsequent
reaction product, chlorine oxide, remove ozone catalytically,
thereby reducing the total amount of ozone in the stratosphere
This production range information does not include any
production/importation data claimed as confidential by the
person(s) reporting for the TSCA Inventory, nor does it
include any information which would compromise Confidential
Business Information. The data submitted for the TSCA
Inventory, including production range information, are
subject to the limitations contained in the Inventory
Reporting Regulations (40 CFR 710).
-------
and somewhat shifting the distribution of ozone toward lower
altitudes. As a consequence/ there is an increase in the amount
of biologically active ultraviolet radiation (below 295 nm)
reaching the earth's surface. In addition, the temperature
distribution in the stratosphere is somewhat altered.
The accumulation of chlorofluoromethanes in the atmosphere,
at all levels, also increases the absorption and emission of
infrared radiation (the "greenhouse effect"). This retards heat
loss from the earth and thus affects the.earth's temperature and
climate. The amount of change in infrared absorption and emis-
sion is well known, however, the amount and details of the
further effects on the earth's climate are uncertain. This
effect is inevitably combined with the effects due to increased
carbon dioxide in the atmosphere and works in the same direction
(NAS, 1976, 1979).
B. Bioconcentration
While F-ll and F-12 are quite,lipophilic and have the poten-
tial to bioaccumulate in organisms, their high volatility appears
to preclude significant bioaccumulation (U.S. EPA, 1975a).
C. Environmental Occurrence
Trichlorofluoromethane has been detected in finished drink-
ing water, effluents from raw sewage and sewage treatment plants,
and in rivers and lakes (U.S. EPA, 1976b). It is known that F-ll
will form in small quantities during chlorination and fluorida-
»
tion of drinking water (U.S. EPA, 1975b).
The major routes by which the fluorocarbons reach the envi-
ronment involve their commercial applications. Because of their
•f
-------
characteristic high vapor pressures and low boiling points, it is
expected that all losses of fluorocarbons would ultimately reach
the atmosphere (U.S. EPA, 1976a).
III. PHARMACOKINETICS
The available data on fluorocarbon absorption and elimina-
tion indicate that fluorocarbons are absorbed across the alveolar
membrane, gastrointestinal tract, and skin. Inhaled fluorocar-
bons are taken up readily by the blood. Fluorocarbons absorbed
by any route are eliminated through the expired air (U.S. EPA,
1976a).
Data from Allen and Hanburys, Ltd. (1971) show that subse-
quent to a five-minute exposure in ambient air to rats, F-ll and
F-12 are concentrated to the greatest extent in the adrenals, the
fat, and the heart.
Eddy and Griffith (1971) observed metabolism in rats follow-
ing oral administration of C-labelled F-12. About 2% of the
total dose was exhaled as CO2 and about 0.5% was excreted in the
urine; the balance was exhaled unchanged. Within thirty hours
after administration, the fluorocarbon and its metabolities were
no longer present in the body. Blake and Mergner (1974) have
indicated that the apparent resistance of F-ll and F-12 to bio-
transformation may be more a function of their rapid elimination
rather than their general stability.
-3.00?-
-------
IV. HEALTH EFFECTS
A. Carcinogenicity
A bioassay of F-ll for possible carcinogenicity was con-
ducted using rats and mice. Animals were subjected to F-ll by
gavage for 78 weeks. The results of the bioassay in rats were
not conclusive because an inadequate number of animals survived
to the end of the study. Under the conditions of the bioassay,
F-ll was not carcinogenic in mice (NCI, 1978)'.
B. Mutagenicity
Mutagenicity data on the fluorocarbons are scant. Neither
of the compounds was mutagenic in Salmonella tester - ,Drains
TA1535 or TA1538 with activation (Uehleke _el_ jal_. , 1977). Sherman
(1974) found no increase in mutation rates over controls in a rat
feeding study of F-12. Stephens _e_l_ _al_. (1970) reported signif-
icant mutagenic activity of F-12 in a Neurospora era, ia test
system.
C. Other Toxicity
Taylor (1974) noted that exposure to 7% oxygen-15% trichlo-
rofluoromethane (F-ll) caused cardiac arrhythmias in all rabbits
exposed. F-ll was subsequently shown to exert its toxicity at
air concentrations of 0.5-5% in the monkey and dog, and from
1-10% in the rat and mouse. In all these animals it induced
cardiac arrhythmias, sensitized the heart to epinephrine-induced
arrhythmias, and caused tachycardia (increased heart rate),
myocardial depression, and hypertension. The concentrations of
F-12 that sensitized the dog to epinephrine and that influenced
circulation in the monkey and dog were similar to those reported
-------
for F-ll, however, F-12 differed in its effects on the
respiratory parameters. It caused early respiratory depression
and bronchoconstriction which predominated over its
cardiovascular effects (Aviado, 1975a,b).
A possible increased sensitivity to the fluorocarbons in
humans with cardiac or respiratory illness may exist, but this is
difficult to determine definitively on the basis of animal
studies. Azar et al. (1972) noted that human inhalation of 1,000
ppm (4,949 mg/nr) F-12 did not reveal any adverse effect, while
exposure to 10,000 ppm resulted only in a 7% reduction in a
standardized psychomotor test score.
V. AQUATIC EFFECTS
No data were found.
VI. EXISTING GUIDELINES
As of March 17, 1979, fully halogenated chlorofluoroalkanes
were banned as propellants in the United States except for essen-
tial uses. The action was taken because the chlorofluoroalkanes
(including F-ll and F-12) may deplete the stratospheric ozone,
leading to an increase in skin cancer, climatic changes, and
other adverse effects (43CFR11301).
-------
REFERENCES
Allen and Hanburys, LTD. 1971. An Investigation of Possible
Cardio-Toxic Effects of the Aerosol Propellants, Arctons 11 and
12. Vol. 1, Unpublished Reported. (as cited in U.S. EPA,
1976a).
Aviado, D.M. 1975a. Toxicity of aerosol propellants on the
respiratory and circulatory systems. IX. Summary of the most
toxic: trichlorfluoromethane (FC-11). Toxicology _3_, 311-314.
(as cited in U.S. EPA, 1976a).
Aviado, D.M. 1975b. Toxicity of aerosol propellants on the
respiratory and circulatory systems. X. Proposed classifica-
tion. Toxicology _3_, 321-332. (as cited, in U.S. EPA, 1976a) .
Azar, A., C.F. Reinhardt, M.E. Maxfield, P.E. Smith, and L.S.
Mullin. 1972. Experimental human exposure to fluorocarbon 12
(dichlorofluoromethane). Amer. Indust. Hyg. Assoc. J. 33(4),
207-216. (as cited in U.S. EPA, 1976a).
Blake, D.A. and G.W. Mergner. 1974. Inhalation studies on the
biotransformation and elimination of [ C]-trichlorofluoromethane
and [ C]-dichlorodifluoromethane in beagles. Tox. Appl. Pharm.
30, 396-407. (as cited in U.S. EPA, 1976a).
Eddy, C.W. and F.D. Griffith. 1961. Metabolism of dichlorodi-
fluoromethane-C by rats. Presented at Amer. Indust. Hyg.
Assoc. Conf., Toronto, Canada, May 1971. (as cited in U.S. EPA,
1976a).
National Academy of Sciences, National Research Council. 1976.
Halocarbons: Environmental Effects of Chloromethane Release.
National Academy of Sciences, National Research Council. 1979.
Stratospheric Ozone Depletion by Halocarbons: Chemistry and
Transport.
National Cancer Institute. 1978. Bioassay of trichlorofluoro-
methane for possible carcinogenicity. PB-286-187.
Sherman, H. 1974. Long-term feeding studies in rats and dogs
with dichlorodifluoromethane (Freon 12 Food Freezant).
Unpublished Report, Haskell Laboratory, (as cited in U.S. EPA,
1976a).
Stephens, S. _et_ _al_. 1970. Phenotypic and genetic effects in
Neurospora crassa produced by selected gases and gases mixed*with
oxygen. Dev. Ind. Microbiol. 12, 346.
Taylor, O.C. 1974. Univ. of California, Riverside, Unpublished
Data. (as cited in U.S. EPA, 1976a).
-------
CJehleke, H. ^t_ _al_. 1977. Metabolic activation of haloalkanes
and tests in vitro for mutagenicity. Xenobiotica _7_, 393.
U.S. EPA. 1975a. Environmental Hazard Assessment of One- and
Two-Carbon Fluorocarbons. EPA-560/2-75-003.
U.S. EPA. 1975b. Identification of Organic Compounds in Efflu-
ents from Industrial Sources. EPA-560/3-75-002.
U.S. EPA. 1976a. Environmental Hazard Assessment Report: Major
One- and Two-Carbon Saturated Fluorocarbons, Review of Data.
EPA-560/8-76-003.
U.S. EPA. 1976b. Frequency of Organic Compounds Identified in
Water. PB-265-470.
U.S. EPA. 1979. Toxic Substances Control Act Chemical Sub-
stances Inventory, Production Statistics for Chemicals on the
Non-Confidential Initial TSCA Inventory.
-------
No. 168
2,4,6-Trichlorophenol
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical acc-uracy.
-------
' SPECIAL NOTATION
U.S. EPA1s. Carcinogen Assessment Group (GAG) has evaluated
2,4,6-trichlorophenol and has found sufficient evidence to
indicate that this compound is carcinogenic.
-------
SPECIAL NOTATION
The National Cancer Institute (1979) has recently published the results
of a bioassay indicating that 2,4,6-trichlorophenol induced cancer in rats
and mice. This study was not included in the Ambient Water Qualit "N Criteria
Document (U.S. EPA, 1979) and has not been reviewed for this hazard profile.
'
-------
. 2,4.6-TRICHLOROPHENOL
Summary
Little is known about the chronic effects of 2,4,6-trichlorophenol on
mammals. 2,4,6-Trichlorophenoi did not promote skin cancer in skin painting
studies with mice, but gave evidence of mutagenicity in two assay systems.
No information was available on teratogenicity or subacute or chronic toxi-
cities. 2,4,6-Trichlorophenol is a convulsant and an uncoupler of oxidative
phosphorylation.
2,4,6-Trichlorophenol is acutely toxic to freshwater fish with LC,.,-.
values ranging from 320 to 9,040 wg/1. No chronic or marine studies were
available. Tainting of fish flesh has been estimated at concentrations in
the water greater than • 52 jug/1. -
-------
2,4,6-TRICHLOROPHENOL
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Chlorinated Phenols (U.S. EPA,' 1979a).
2,4,6-Trichlorophenol (2,4,6-TCP) is a colorless, crystalline solid
with the empirical formula C^LCl^Q and a molecular weight of 197.5
(Weast, 1978). It has the following physical and chemical properties (Weast,
1978):
Melting Point: 69.5°C
Boiling Point: 246°C
Vapor Pressure: 1 mm Hg at 76°C
Solubility: slightly soluble in water; soluble in
alcohol and ether
Trichlorophenols are used as antiseptics and disinfectants, as well as
for intermediates in the synthesis of other chemical products (U.S. EPAr-i
1979).
It is generally accepted that chlorinated phenols will undergo photoly-
sis in aqueous solutions as a result of ultraviolet irradiation and that
photodegradation leads to the substitution of hydroxyl groups in place of
the chlorine atoms and subsequent polymerization (U.S. EPA, 1979a). For
additional information regarding the chlorinated phenols as a class, the
reader is referred to the Hazard Profile on Chlorinated Phenols (U.S. EPA,
1979b).
II. EXPOSURE
Unspecified isomers of trichlorophenols have been detected in surface
waters in Holland at concentrations of 0.003 to O.l.jjg/1 (Piet and DeGrunt,
1975). 2,4,6-Trichlorophenol can be formed from the chlorination of phenol
»
in water (Burttschell, et .al. 1959). Exposure to other chemicals such as
1,3,5-trichlorobenzene, lindane, the alpha- and delta-isomers of 1,2,3,-
-------
4,5,6-hexachlorocyclohexane, and hexachlorobenzene could result in exposure
to 2,4,6-trichlorophenol via metabolic degradation of the parent compound
(Kohli, at al. 1976; Foster and Saha, 1978; Tanaka, et al. 1977).
The U.S. EPA (1979a) has estimated the bioconcentration factor of 2,4,-
6-trichlorophenol to be 110 for the edible portion of aquatic organisms.
This estimate is based on the octanol/water partition coefficient for this
chemical.
Trichlorophenols are also found in flue gas condensates from municipal
incinerators (Olie, et al. 1977).
III. PHARMACOKINETICS
A. Absorption, Distribution and Metabolism
Informal ) regarding the absorption, distribution and metabolism
of 2,4,6-trichlorophenol could not be located in the available literature.
8. Excretion
In rats, 82 percent of an administered dose (1 ppm in the diet for
3 days) of 2,4,6-. "achlorophenol was eliminated in the urine and 22 percent
in the feces. Radiplabelled trichlorophenol was not detected in liver,
")
lung, or fat obtained five days after the last dose (Korte, et al. 1978).
IV. EFFECTS
A. Carcinogenicity
2,4,6-Trichlorophenol did not increase the incidence of papillomas
or carcinomas when applied repeatedly at a high concentration to the skin of
mice after initiation with dimethylbenzanthracene (Boutwell and Bosch, 1959).
Results from a study of mice receiving 2,4,6-trichlorophenol in the
diet throughout their lifespans (18 months) showed an increased incidence of
tumors. This increased incidence, however, was in an uncertain range such
that conclusive interpretation could not be made (Innes, et al. 1969).
-3.0*
°-
-------
3. Mutagenicity
However, Ames tests using Salmonella, with and without mammalian
microsomal activation, were negative for 2,4,6-trichlorophenol (Rasanen, et
al. 1977). 2,4,6-Trichlorophenol increased the rate of mutations, but not
the rate of intragenic recombination in a strain of Saccharomvces cerevisiae
(Fahrig, et al. 1978). In addition, two of the 340 offspring from female
mice injected with 50 mg/kg of 2,4,6-trichlorophenol during gestation were
reported to have changes in hair coat color (spots) of genetic significance.
At 100 mg/kg, 1 out of 175 offspring exhibited this response (U.S. EPA,
1979a).
C. Teratogenicity, Other Reproductive Effects and Chronic Toxicity
Information regarding teratogenicity, other reproductive effects
and chronic toxicity of 2,4,6-trichlorophenol could not be located in the
available literature.
0. Other Relevant Information
2,4,5-Trichlorcphenol is a convulsant (Farquharson, et al. 1958)
and an uncoupler of oxidative phosphorylation (Weinbach and Garbus, 1965;
Mitsuda, et al. 1963).
V. AQUATIC TOXICITY
A. Acute Toxicity
Three assays have been conducted with 2,4,6-trichlorophenol to de-
termine its acute toxicity to freshwater fish. A 96-hour static LCqo val-
ue of 600 ug/1 has been obtained for the fathead minnow (Pimephales prome-
las) -(U.S. EPA, 1972). In a flow-through assay, 'a 96-hour LC5Q value of
9,040 pg/1 was obtained for juvenile fathead minnows (Phipps, et al., manu-
»
script). The bluegill (Leoomis macrochirus) has been shown to be the most
sensitive species studied, with a 96-hour static LC_Q of 320 jug/1 (U.S.
•joa.1-
-------
EPA, 1978). Only one acute study has been performed on a freshwater inver-
tebrate species. The result of a 48-hour static assay produced an LC50
value of 6,040 pg/1 for DaPhnia magna (U.S. EPA, 1978). There were no acute
studies for any species of marine life.
B. Chronic Toxicity
There were no chronic data for any freshwater or marine organisms
for 2,4,6-trichlorophenol.
C. Plant Effects
Complete destruction of chlorophyll in the algae, Chlorella pyreno-
idosa, has been reported at concentrations of 10,000 ;jg/l (Huang and Gloyna,
1968). A chlorosis LC5Q value of 5,923 pg/1 was obtained for the duck-
weed, Lemna minor (Blackman, et al. 1955). Studies of the effects of 2,4,6-
trichlorophenol on marine plants have not been reported. ..
D. Residues
NO actual bioconcentration factors have been determined, but based
upon the octanol/water partition coefficient of 4,898, a bioconcentration
factor of 380 has been estimated for those aquatic organisms having an eight
percent lipid content. Thus, the weighted average bioconcentration factor
for the edible portions of all organisms consumed by Americans is estimated
to be 110 (U.S. EPA, 1979a).
E. Miscellaneous
The tainting of fish flesh by 2,4,6-trichlorophenol has been ob-
served in the rainbow trout.(Salmo qairdneri). The highest estimated con-
centration of 2,4,6-trichlorophenol that will not impair the flavor of trout
exposed for 48 hours to the chemical is 52 fjg/l (Shumway and Palensky, 1973).
-------
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived by U.S. EPA
(1979a), which are summarized below, have gone through the process of public
review; therefore, there is a possibility that these criteria will be
changed.
A. Human
The U.S. EPA (1979a) has recommended a draft criterion of 100 jug/1
for 2,4,6-trichlorophenol in ambient water for the prevention of adverse
organoleptic affects.
NO other existing guidelines or standards were found for exposure
to 2,4,6-trichlorophenol.
8. Aquatic
The draft criterion to protect freshwater organisms is a 24-hour
average concentration of 52 ug/1 not to exceed 150/jg/1. Data were insuffi-
cient to derive a criterion for marine organisms (U.S. EPA, 1979a).
~Q03L3-
-------
2,4,6-TRICHLOROPHENOL
REFERENCES
Slackman, G.E., et al. 1955. The physiological activity of substituted
phenols. I. Relationships between chemical structure and physiological
activity. Arch. Biochem. Biophys. 54: 45.
Soutwell, R.K. and O.K. Bosch. 1959. The tumor-promoting action of phenol
and related compounds for mouse skin. Cancer Res. 19: 413.
Burttschell, R.H., et al. 1959. Chlorine derivatives of phenol causing
taste and odor. Jour. Am. Water Works Assoc. 51: 205.
Fahrig, R., et al. 1978. Genetic activity of chlorophenols and chlorophe-
nol impurities. Pages 325-328. In: Pentachlorophenol: Chemistry,
pharmacolo- gy and environmental toxicology. K. Rango Rao, Plenum Press,
New York.
Farquharson, M.E., et al. 1958. The biological action of chlorophenols.
3r. Jour. Pharmacol. 13: 20.
Foster, T.S. and J.G. Sana. 1978. The _in_ vitro metabolism of lindane by an
enzyme preparation from chicken liver. Jour. Environ. Sci. Health 13: 25. *
Huang,. J and E.F. Gloyna. 1968. Effect of .organic compounds on photosyn-
thetic oxygenation. I. Chlorophyll, destruction ana suppression of photosyn-
t.-enie oxygen production. Water Res. 2: 347.
Ir.nss, J.R.M., et al. 1969. Sioassay of pesticides.and industrial chemi-
cals for tumorigenicity in mice: A preliminary note. Jour. Natl. Cancer
.Inst. 42: 11G1.
;
-------
Rasanen, L., at al. 1977, The tnutagenicity of MCPA and its soil metabo-
lites, chlorinated phenols, catechols and some widely used slimicides in
Finland. Bull. Environ. Contam. Toxicol. 18: 565.
Shumway, O.L. and J.R.- Palensky. 1973. Impairment of the flavor of fish by
water pollutants. EPA-R3-73-010. U.S. Environ. Prot. Agency, U.S. Govern-
ment Printing Office, Washington, O.C.
Tanaka, K., et al. 1977. Pathways of chlorophenol formation in oxidative
biodegradation of 3HC. Agric. Biol. Chem. 41: 723.
U.S. EPA. 1972. The effect of chlorination on selected organic chemicals.
Water Pollut. Control Res. Ser. 12020.
U.S. EPA. 1978. In-depth studies on health and environmental impacts on
selected water pollutants. Contract NO. 63-01-4646.
U.S. EPA. 1979. Chlorinated Phenols: Ambient Water Quality Criteria.
(Draft)
Weast, R.C. (ad.) 1978. Handbook of Chemistry and Physics. 59th ad. CRC
Press, Cleveland, Ohio.
Weinbach, E.C. and J. Garbus. 1965. "The interaction of uncoupling phenols
with mitochondria and with mitochondria! protein. Jour. Biol. Chem. 21Q:
1811.
-------
No. 169
1,2,3-Trichloropropane
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
1,2,3-TRICHLOROFROPANE.
Summary
Pertinent data are not available on the possible carcinogenicity, muta-
genicity, teratogenicity, or chronic toxicity of 1,2,3-trichloropropane.
Acute toxicity studies with animals suggest harmful effects to the liver.
1,2,3-Trichloropropane is reported to be irritating to the eyes and mucous
membranes of humans.
Pertinent data on the toxicity of trichloropropane to aquatic organisms
are not available.
-------
1,2.3-TRICHLOROPROPANE
I. INTRODUCTION
1,2,3-Trichloropropane (CAS registry 96-18-4) is a colorless,
clear liquid made from the chlorination of propylene. It has the following
chemical and physical properties (Windholz, 1976; Hawley, 1971; Verschueren,
1977):
Formula: C3H5C13
Molecular Weight: 147.43
Melting Point: -14.7°C
Boiling Point: 156.85°C
Density: 1.388920
Vapor Pressure: 2.0 torr @ 20°C
Solubility: Sparingly soluble in
water, soluble in alcohol
and ether.
1,2,3-Trichloropropane is used as a paint and varnish remover, solvent,
and degreasing agent (Hawley, 1971), in addition to its use as a cross-
linking agent in the elastomer Thickol ST (Johnson, 1971).
II. EXPOSURE
A. Water
1,2,3-Trichloropropane has been detected in drinking water (U.S.
EPA, 1975) and also in 6 of 204 surface water samples taken in various loca-
tions throughout the United States (U.S. EPA, 1977). No information con-
cerning concentration was available.
8. Food
Pertinent data were not found in the available literature.
-------
C. Inhalation
Pertinent data were not found in the available literature; how-
ever, fugitive emissions from manufacturing and production facilities pro-
bably would account for the major portion of 1,2,3-trichloropropane if found
in air.
D. Dermal
Pertinent data were not found in the available literature.
III. PHARMACOKINETICS
Pertinent data were not found in the available -literature.
IV. EFFECTS
A. Carcinogenicity, Mutagenicity, Teratogenicity,
Reproductive Effects, Chronic Toxicity.
Pertinent data were not found in the available literature.
B. Acute Toxicity
Exposure to trichloropropane at high concentrations is irritating
to the eyes and mucous membranes and causes narcosis.
McOmie and Barnes (1949) exposed 15 mice to 5000 ppm. trichloro-
propane for 20 minutes. Seven of the mice survived exposure; however, four
of these mice died from liver damage 7 to 10 days later. Seven of ten mice
exposed to 2500 ppm trichloropropane for 10 minutes per day for 10 days
died. McOmie and Barnes (1949) found that liquid trichloropropane applied
to the skin of rabbits produced irritation and erythema, followed by slough-
ing and cracking. Repeated application of 2 ml of. trichloropropane caused a
. painful • reaction,. including subdermal bleeding, and the death of one of
seven rabbits treated.
Silverman, et al. (1946) reported eye and throat irritation and an
objectional odor to human volunteers exposed to 100 ppm trichloropropane for
-------
15 minutes. McOtnie and Barnes (1949) found that ingestion of 3g of tri-
chloropropane by humans caused drowsiness, headache, unsteady gait, and lum-
bar pain.
V. AQUATIC TOXICITY
Pertinent data were not found in the available literature..
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The American Conference of Governmental Industrial Hygienists re-
commends a threshold limit value of 50 ppm for occupational exposure to
1,2,3-trichloropropane (ACGIH, 1977).
8. Aquatic
No guidelines on standards to protect aquatic organisms from
1,2,3-trichloropropane toxicity have been established because of the lack of
pertinent data.
-4.0 3h
-------
1,2,3-TRICHLOROPROPANE
References
American Conference of Governmental Industrial Hygienists. 1977. Documen-
tation of the Threshold Limit Values for Substances in Workroom Air, 3rd
ed. American Conference of Governmental Industrial Hygienists Cincinnati,
OH.
Hawley, G.G. (ed.) 1971. The Condensed Chemical Dictionary. 8th ed. Van
Nostrand Reinhold Co., New York.
Johnson, R.N. 1971. Polymers containing sulfur. In: Kirk-Othmer Encyclo-
pedia of Chemical Technology. John Wiley and Sons, New York, p. 253.
McOmie, W.A. and T.R. Barnes. 1949. Acute and subacute toxicity of
1,2,3-trichloropropane in mice and rabbits. Fed. Proc. 8: 319.
Silverman, L., at al. 1946. Further studies on sensory response to certain
industrial solvent vapors. Jour. Ind. Hyg. Toxicol. 28: 262.
U.S. EPA. 1975. New Orleans area water supply study, draft analytical
report. U.S. Environ. Prot. Agency. April update.
U.S. EPA. 1977. Monitoring to detect previously unrecognized pollutants in
surface waters. U.S. Environ. Prot. Agency. NTIS PB273-349.
Verschueren, K. 1977. Handbook of Environmental Data on' Organic Chem-
icals. Van Nostrand Reinholcl Co., New York.
Windholz, M. (ed.) 1976. The Merck Index, 9th ed. Merck and Co., Inc.,
Rahv/ay, NJ.
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No. 170
o,o,o-Triethyl Phosphorothioate
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
'£033-
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DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations.of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
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0,0,0-TRIETHYL PHOSPHOROTHIOATE
Summary
There is no information available on the possible carcinogenic, muta-
genic, teratogenic, or adverse reproductive effects of 0,0,0-triethyl phos-
phorothioate. Triethyl phosphate, a possible metabolite of the compound,
has shown weak mutagenic activity in Salmonella, Pseudomonas, and Drosophila.
Like other organophosphates, 0,0,0-triethyl phosphorothioate may be ex-
pected to produce cholinesterase inhibition in humans.
No pertinent data are available on the aquatic effects of the compound.
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0,0.0-TRIETHYL PHQSPHOROTHIOATE
I. INTRODUCTION
0,0,0-Triethyl phosphorothioate (CAS registry number 126-68-1), also
known as triethyl thiophosphate, is a colorless liquid with a characteristic
odor. It has the following physical and chemical properties (Hawley, 1971):
Formula: C^15QJPS
Molecular Weight: 198
Soiling Point: 93.5°C-94°C (10 torr)
Density: 1.074
0,0,0-Triethyl phosphorothioate is used as a plasticizer, lubricant ad-
ditive, antifoam agent, hydraulic fluid, and as a chemical intermediate
(Hawley, 1971).
II.- EXPOSURE
A. water and Food
Pertinent data were not found in the available literature.
8. Inhalation
Pertinent data were not found in the available literature; how-
ever, fugitive emissions from production and use would probably constitute
the major source of contamination (U.S. EPA, 1977).
D. Dermal
Pertinent data were not found in the available literature.
III. PHARMACOKINETICS
A. Absorption
Pertinent data were not found in the available literature. Acute
toxicity studies with a number of organophosphate insecticides indicate that
these compounds are absorbed following oral or dermal administration
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(Gaines, 1960). March, et al. (1955) have reported rapid absorption of the
structurally similar insecticide demeton from the gastrointestinal tract of
mice following oral administration.
B. Distribution
Pertinent data were not found in the available literature.
C. Metabolism
Pertinent data were not found in the available literature. The
thiono isomer of the insecticide demeton may be metabolized via oxidative
desulfuration by the liver at the P=S bond in mammals (March, et al. 1955)
to form the thiolo derivative. Thus, 0,0,0-triethyl phosphorothioate may be
converted to triethylphosphate in vivo (Matsumura, 1975).
0. Excretion
Pertinent data were not found in the available literature. .March,
et al. (1955) have reported that following oral administration of demeton,
the large majority of compound was eliminated as urinary metabolites, with
small quantities detected in the feces. Elimination was rapid following
oral administration.
IV. EFFECTS
A. Carcinogenicity
Pertinent data were not found in the available literature.
B. Mutagenicity
Pertinent data were not found in the available literature. The
insecticide oxydemeton methyl has been shown to produce mutations in
Drosophila, E_, coll and Saccharomyces (Fahrig, 1974). Triethyl phosphate, a
possible metabolite of 0,0,0-triethyl phosphorothioate, has produced^ weak
mutagenic effects in Salmonella and Pseudomonas (Dyer and Hanna, 1973) and
recessive lethals in Drosophila (Hanna and Dyer, 1975).
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C. Teratogenicity
Pertinent data were not found in the available literature. A
single intraperitdneal injection of demeton (7 to 10 mg/kg) between days
seven and twelve of gestation has been reported to produce mild teratogenic
effects in mice (Budreau and Singh, 1973).
D. Other Reproductive Effects ' '
Pertinent data were not found in the available literature. Em-
bryotoxic effects (decreased fetal weights, slightly increased fetal mor-
tality) have been reported following intraperitoneal administration of deme-
ton (7 to 10 mg/kg) to pregnant mice (Budreau and Singh, 1973).
E. Chronic Toxicity
Pertinent data were not found in the available literature.
0,0,0-triethyl phosphorothioate, like other organophosphates, may be ex-
pected to produce symptoms of cholinesterase inhibition in humans (NAS,
1977).
v. AQUATIC TOXICITY
Pertinent data were not found in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
Pertinent data were not found in the. available literature.
-303*-
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0,0,0-TRIETHYL PHOSPHOROTHIOATE
References
Budreau, C. and R. Singh. 1973. Teratogenicity and embryotoxicity of deme-
ton and fenthion in CF 1 mouse embryos. Toxicol. Appl. Pharmacol. 24: 324.
Dyer, K. and P. Hanna. 1973. Comparative mutagenic activity and toxicity
of triethyl phosphate and dichlorvos in bacteria and Orosophila. Mut. Res.
21: 175.
Fahrig, 0. 1974. Comparative mutagenicity studies with pesticides. Chem-
ical Carcinogenesis Assays, IARC Scientific Publication. 10: 161.
Hanna, P. and K. Dyer. 1975. Mutagenicity of organophosphorous compounds
in bacteria and Orosophila. Mut. Res. 28: 405.
Gaines, T. 1960. The acute toxicity of pesticides to rats. Toxicol. Appl.
Pharmacol. 2: 88.
Hawley, G.G. (sd.) 1971. The Condensed Chemical Dictionary. 8th ed. Van
Nostrand Reinhold Co., New York.
March, R., et al. 1955. Metabolism of syston in white mouse and American
cockroach. Jour. Econ. Entom. 48: 355.
Matsumura, F. 1975. Toxicology of Insecticides. Plenum Press, New York,
223.
National Academy of Sciences. 1977. Drinking Water and Health. National
Research Council, Washington, DC, p. 615.
U.S. EPA. 1977. Industrial process profiles for environmental use: Plas-
ticizer industry. U.S. Environ. Prot. Agency, NTIS PB-291-642.
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No. 171
Trinitrobenzene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
.WASHINGTON, D.C. 20460
APRIL 30, 1980
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DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
TRINITROBENZENE
Summary
Information on the carcinogenicity, mutagenicity, teratogenicity, or
adverse reproductive effects of trinitrobenzene was not found in the avail-
able literature.
Trinitrobenzene has been reported to produce liver damage, central ner-
vous system damage, and methemoglobin formation in animals.
Slight irritant effects have been reported for marine fish exposed to
trinitrobenzene at concentrations of 100 ug/1.
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TRINITROBENZENE
I. INTRODUCTION
This profile is based on the Investigation of Selected Potential
Environmental Contaminants: Nitroaromatics (U.S. EPA, 1976).
Trinitrobenzene (1,3,5-trinitrobenzene, molecular weight, 213.1) is a
crystalline solid with the following physical properties: melting point,
122.5°C; specific gravity, 1.76. The compound is explosive upon rapid
heating. Trinitrobenzene is insoluble in water, but soluble in alcohol or
ether (Windholz, 1976).
Trinitrobenzene is used as an explosive, and as a vulcanizing agent for
natural rubber (U.S. EPA, 1976).
Hydrolysis . ' trinitrobenzene under neutral pH conditions is not
expected to be rapid; as pH increases, hydrolysis would be favored (Murto,
1966). Photolytic degradation of trinitrobenzene has not been demonstrated
in aqueous solutions (Burlinson, et al. 1973).
A bioconcer. Cation factor is not available for trinitrobenzene; how-
ever, the work of ,Neely, et al. (1974) on several nitroaromatics would
".»
suggest a low theoretical bioconcentration of the compound.
Biodegradation of trinitrobenzene by acclimated microorganisms has been
reported by Chambers, et al. (1963).
II. EXPOSURE
Pertinent information on levels of exposure to trinitrobenzene from
occupational contact or from non-occupational sources of exposure (air,
water, food) was not found in the available literature.
III. PHARMACOKINETICS
Pertinent information on the absorption, distribution, metabolism, or
excretion of trinitrobenzene was not found in the available literature. The
-------
reader is referred to a discussion of the pharmacokinetics of dinitro-
benzenes, which may show pharmacokinetic similarities (U.S. EPA, 1979).
•••.. .Acute oral,-toxicity. studies conducted with dogs indicate that trinitro-
benzene' is'effectiveiy' absorbed" by this route (Fogleman, et al. 1955).
•iv.~ EFFECTS' -~::-';v' ''.. '.'••.'
,. ..... Pertinent, information on the carcinogenic, mutagenic, teratogenic, or
adverse reproductive effects of trinitrobenzene, was not found in the avail-
/
'able literature.' /
\
. .... A series of toxicity studies in rats, mice, and guinea Bigs have indi-
cated that orally administered trinitrobenzene causes liver damage and
central nervous system damage (Korolev, et al. 1977). The acute toxicity
stcidy of Fogleman, et al. (1955) has shown that trinitrobenzene, like dini-
trobenzenes, induces methemoglobin formation in vivo.
•V. AQUATIC -TOXICITY
The only study reporting the effects of trinitrobenzene to aquatic life
has been presented by Hiatt, et al. (1957). Slight irritant effects i.e.,
excitability, violent swimming, opercular movement increases suggesting res-
.piratory distress upon short term exposure to marine fish Kuhlia
sandvicensis were observed at exposure levels of 100 ug/1, while moderate
and violent reactions to the chemical were produced at exposures of 1,000
and 10,000 jug/1. No effects were noted on exposures to concentrations of 50
or 10 ug/1.
VI. EXISTING GUIDELINES
There is no available 8-hour, TWA exposure limit for trinitrobenzene.
The compound has been declared a hazardous chemical by the Department of
Transportation (Federal Register, January • 24, 1974).
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TRINITROBENZENE
References ._.. ".„....
Burlinson, N.E. et al. 1973. Photochemistry- of :TN-T:-"~Inve;sftigatlon of the
'pink water1 problem. U.S. Nat. Tech. Inform... .Sery.v ACC. Ng.,sAD. 769-67Q..
Chambers, C.W., et al. 1963. Degradation of aromatic compounds..by phenol-
adapted bacteria. Jour. Water Pollut. Contr. Fedr.. 35: 1517. '' ' " ' '
Fogleman, R.W., et al. 1955. Toxicity of trinitrobenzene-ahiiine complex,
a rodent repellent. Agric. Food Chem. 3(11):. .936..,„ .. •.., __ . .....
Hiatt, R.W., et al. 1957. Relationship of chemical structure ..to :irratient
response in marine fish. Nature. 179: 904. ' ''" '
v
Korolev, A., et al. 1977. Experimental- data for"hygienic standardization
of dinitrotoluene and trinitrobenzene in reservoir waters. Gig... Sanit.
'10: 17. ..-.....:-..-,. - --- - - •
Murto, J. 1966. Nucleophilic reactivity, vrr: kinetics of"the reactions
of hydroxide ion and water with picrylic compounds. Acta.-Che.rn. ..Scand.
20: 310. •• - • •"' "• --
Neely, W.B., et al. 1974. Partition coefficient to measure 'bioconcen-
tration potential of organic chemicals in fish. Environ. -Sci,. Technol.
8: 1113. ' . • - . ••
v , , . - . • - •
U.S. EPA. 1976. Investigation of- selected potential environmental contam-
inants: Nitroaromatics. . .., ... .__,...„.. .....
U.S. EPA. 1979. Environmental Criteria and. Assessment Office. Dinitro-
benzene: Hazard Profile.'(Draft).
Windholz, M. (ed.). 1976. The Merck Index, 9th ed. -.Merck and Co., Inc.
Rahway, N.J. p. 9392.
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