DATE:
SUBJECT:
FROM:
TO:
December 2, 1980
Background Document: Resource Conservation and Recovery Act
Subtitle C
VotAtt-t-, J/£lA-Vj.^/H X^-^
Angela'WTlkes, Publications Officer
Office of Solid Waste (WH-562)
EPA Regional and Headquarters Librarians
Background Documents 1941.28 "Listing of Hazardous Wastes
(Section 3001 Parts 261.31 and 261.32)" and 1941.29 "Appen-
dix A-Health and Environmental Effect Profiles" will be sent
in replacement of existing documents of the same title. Please
note this change. Thank you.
WH-562: AWIlkesrjll:12-2-80
FORM 1320-6 (REV. 3-76)
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Preface
These health and environmental effect profiles have
been compiled to support the listing of approxmately 170
of the hazardous constituents identified on Appendix VIII
in the regulations (40 CFR, Part 261). These profiles are
also being used to support the listing of hazardous wastes
in Subpart T) of Part 261, due to the presence in the
wastes, of these hazardous constituents. Many of these
profiles have been summarized from the water quality criteria
documents prepared in support of various programs under
the Clean Water Act. In each case, however, the document
Is based on information and references available to the
Agency and which are referenced in each individual document.
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Table of Contents
Chemical Substance(Document Number) Page
Acetaldehyde(l) 1-1
Acetonitrile(2) 2-1
Acetophenone(3) 3-1
Acetyl Chloride(4) 4-1
Acrolein(S) ' 5-1
Acrylamide(Reserved)
Acrylonitrile(7) 7-1
Aldrin(8) 8-1
Allyl Alcohol(9) 9-1
Aniline (172) 172-1
Antimony(lO) 10-1
Arsenic(ll) 11-1
Asbestos(12) 12-5
Barium(13) 13-1
Benzal Chloride(14) 14-1
Benzene(lS) . 15-1
Benzidine(16) 16-1
Benz(a)anthracene(17) . 17-1
Benzo(b)fluoranthene(lS) 18-1
Benzo(a)pyrene(19) 19-1
Benzotrichloride(20) 20-1
Benzyl Chloride(21) 21-1
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Chemical Substance(Document Number) Page
Beryllium(22) . 22-1
*
Bis(2-chloroethoxy) Methane(23) 23-1
Bis(2-chloroethyl) Ether(24) 24-1
Bis(2-chloroisopropyl) Ether(25) 25-1
Bis(chloromethyl) Ether(26) 26-1
Bis(2-ethylhexyl) Phthalate(27) 27-1
Bromoform(28) 28-1
Broraonethane(29) 29-1
4-Bronophenyl Phenyl Ether(30) 30-1
Cadmium(31) 31-1
Carbon DisulfIde(32) 32-1
Carbon Tetrachloride (Tetrachloromethane)(33) 33-1
Chloral(34) 34-1
Chlordane(35) 35-1
Chlorinated Benzenes(36) 36-1
Chlorinated Ethanes(37) 37-1
Chlorinated Naphthalenes(38) 38-1
Chlorinated Phenols(39). 39-1
Chloroacetaldehyde(40) 40-1
Chloroalkyl Ethers(41) 41-1
Chlorobenzene(42) ' 42-1
p-Chlorb-m-cresol(43) 43-1
Chloroethane(44) 44-1
Chloroethene(Vinyl Chloride)(45) 45-1
-iii-
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Chemical Substance(Document Number) Page
2-Chioroethyl Vinyl Ether(46) 46-1
Chloroform (Carbon Trichlororaethane)(47) 47-1
Chlororaethane(48) 48-1
2-Chloronaph'thalene(49) 49-1
2-Chlorophenol(50) _ 50-1
Chromium(51) 51-1
Chrysene(52) • 52-1
Cresote(53) 53-1
Cresols and Cresylic Acid(54) 54-1
Crotonaldehyde(55) 55-1
Cyanides(56) 56-1
Cyanogen Chloride(57) 57-1
DDD(58) 58-1
DDE(59) 59-1
DDT(60) 60-1
Dibromochlororaethane(61) 61-1
•Di-n-butyl Phthalate(62) 62-1
Dibenzo(a ,h)anthracene( 63) 63-1
1,2-Dichlorobenzene(64) 64-1
l,3-Dichlorobenzene(65) . 65-1
1,4-Dichlorobenzene( 66) 66-1
Dichlorobenzenes(67) 67-1
3,3'-Dichlorobenzidine(68) 68-1
l,l-Dichloroethane(69) 69-1
-iv-
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Chemical Sub3tance(Pocument Number) ' Page
l,2-Dichloroethane(70) 70-1
l,l-Dichloroethylene(71) 71-1
trans-l,2-Dichloroethylene(72) 72-1
Dichloroethylenes(73) 73-1
Dichloromethane(74) 74-1
2,4-Dichlorophenol(75) 75-1
2,6-Dlchlorophenol(76) 76-1
2,4-Dichlorophenoxyacetic Acid (2,4-D)(77) 77-1
l,2-Dichloropropane(78) 78-1
Dlchloropropanes/Dichloropropenes(79) 79-1
Dichloropropanol(80) 80-1
l,3-Dichloropropene(81) 81-1
Dieldrin(82) 82-1
o,o-Diethyl Dithiophosphoric Acid(83) 83-1
o,o-T)iethyl-S-methyl Phosphorodithioate( 84) 81-1
Diethyl Phthalate(85) 85-1
Diraethylnitrosamine(86) 86-1
2,4-Dimethylphenol(87) 87-1
Dimethyl Phthalate(88) 88-1
Dinitrobenzenes(89) 89-1
4,6-Dinltro-o-creaol(90) 90-1
2,4-Diuitrophenol(91) 91-1
Dlnitrotoluene(92) 91-1
2,4-Dinitrotoluene(93) 93-1
-v-
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Chemical Substance(Document Number) Page
•
2,6-Dlnitrotoluene(94) 94-1
Di-n-octyl Phthalate(95) 95-1
Diphenylamlne (Reserved)
l,2-Diphenylhydrazlne(96) . 96-1
T)is>ulfoton(97) 97-1
Endosulfan(98) 98-1
Endrin(99) 99-1
Epichlorohydrin (l-Chloro-2,3-epoxypropane)(100) 100-1
Ethyl Methacrylate(lOl) 101-1
Ferric Cyanide(lOZ) 102-1
Fluoranthene(103) • 103-1
Formaldehyde(104) ' 104-1
Forric Acid(105) 105-1
Fumaronitrile(106) 106-1
Haloraethanes(107) 107-1
Heptachlor(lOS) 108-1
Heptachlor Epoxide(109) 109-1
Hexachlorobenzene(llO) • 110-1
Hexachlorobutadiene(lll) 111-1
Hexachlorocyclohexane(112) 112-1
garana-rHexachlorocyclohexane(113) 113-1
Hexachlorocyclopentadiene(114) 114-1
Hexachloroethane(llS) 115-1
Hexachlorophene(116) . 116 1
Hydrofluoric Acid(ll7) 117-1
-vi-
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Chemical Substance(Document Number) Page
Hydrogen Sulfide(118) 118-1
Indeno (1,2,3-cd) Pyrene(119) 119-1
Isobutyl Alcohol(120) 120-1
Lead(121) 121-1
Maleic Anhydride(122) 122-1
Maloaonitrile(123) 123-1
Mercury(124) 124-1
Methorayl(125) 125-1
Methyl Alcoho1(126) 126-1
S.S'-tnethylene-OjO.o1,o'-Tetraethyl Phosphorodithioate(127) 127-1
Methyl Ethyl Ketone(128) 128-1
Methyl Methacrylate(130) 130-1
Naphthalene(131) 131-1
l,4-Naphthoqulnone(132) 132-1
Nickel(133) 133-1
Nitrobenzene(134) 134-1
4-NItrophenol(135) 135-1
Nitrophenols(136) 136-1
Nitrosaoines(137) 137-1
N-Nitrosodiphenylamine(138) 138-1
N-Nitrosodi-n-propylamlne(139) - 139-1
Paraldehyde(140) 140-1
Pentachlorobenzene(141) 141-1
-vli-
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Chemical Substance(Document Number) Page
Pent.achloronitrobenzene(142) 142-1
Pentachlorophenol(143) 143-1
Phenol(l44) 144-1
Phenylenediamlne (Reserved)
Phorate(145) . 145-1
Phthalate Esters(146) 146-1
Phthalic Anhydride(147) 147-1
2-Picoline(148) 148-1
Polynuclear Aromatic Hydrocarbons(PAHs)(149) 149-1
Pyridine(lSO) 150-1
Quinones(151) 151-1
Resorcinol(152) 152-1
Selenium(153) 153-1
Silver(154) 154-1
TCDD(155) 155-1
1,1,1,2-Tetrachloroethane(156) 156-1
l,l,2,2-Tetrachloroethane(157) 157-1
Tetrachloroethylene(Perchloroethylene)(158) 158-1
Thallium(159) 159-1
Toluene(160) 160-1
2,4-Toluenediamine(161) 161-1
Toluene Diisocyanate(162) 162-1
Toxaphene(l63) 163-1
l,l,l-Trichloroethane(164) 164-1
-viii-
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Chemical. Substanee(Pocunent Number) Page
l,l,2-Trichloro.ethane(165) 165-1
%
Trichloroethylene(166) 166-1
Trichlorofluoromethane and Dichlorodifluororaethane(167) 167-1
2,4,6-Trichlorophenol(168) . 168-1
l,2,3-T-richloropropane(169) 169-1
0,0,0-Triethyl Phosphorothioate(170) 170-1
Trlnltrobenzene(171) 171-1
-ix-
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No. 1
Acetaldehyde
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
H
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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.
-------
ACETALDEHYDE
Summary
An increased incidence of malignant neoplasms was reported in
workers in an aldehyde factory. Acetaldehyde was found in
concentration of 1 to 7 mg/rn^ but there was no indication that
acetaldehyde was the causative factor for the cancers.
Equivacol results were obtained from a number of mutugenicity
assays.
I. INTRODUCTION
Acetaldehyde (CI^COH) is a clear, flammable liquid with a
pungent, fuity odor. It has the following physical/chemical
properties (Hawley, 1977; U.S. EPA, 1976a):
^.0
Chemical Structure: CH3 - C^^
^H
CAS No.: 75-07-0
Molecular Formula: C2H40
Boiling Point: 20.2°C
Melting Point: -123.5°C
Vapor Pressure: 740 mm (20°C)
Density: 0.7834 at 18eC/4°C
Octanol/Water
Partition Coefficient: 0.43
Vapor Density: 1.52
•
Solubility: soluble in water and most
organic solvents
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A review of the production range (Includes importation)
statistics for acetaldehyde (CAS No. 75-07-0) which was listed in
the initial TSCA Inventory (1977) has shown that between 1 billion
and 2 billion pounds of this chemical were produced/imported in
1977. *y
Acetaldehyde is used mainly as a chemical intermediate in the
production of paraldehydes, acetic acid, acetic anhydride, and a
variety of other chemicals (Hawley, 1977).
II. EXPOSURE
The NIOSH National Occupational Hazard Survey estimates that
2,430 workers are exposed to acetaldehyde annually (1976).
A. Environmental Fate
The available data do not indicate a potential for persis-
tance. and accumulation in the environment. While there is little
information on the environmental fate of acetaldehyde, the BOD/COD
of 0.72 confirms that acetaldehyde will readily biodegrade
(Verschueren, 1978).
As to its fate in air, aldehydes are expected to photodisso-
ciate rapidly and competively with their oxidation for a half-life
of 2 to 3 hours. Aldehydes do not persist in the atmosphere but
the fact that acetaldehyde is a component of vehicle exhaust may be
significant in its contribution to smog (U.S. EPA, 1977b).
This production range information does not include any production/
importation data claimed as confidential by the person(s) report-
ing 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 Regulation (40 CFR 710).
H
-------
B. Bioconcentration
Acetaldehyde has an octanol/water partition coefficient
of 0.43 indicating that it is highly hydrophilic and should not
accumulate (U.S. EPA, 1976).
C. Environmental Occurrence
Acetaldehyde is a normal intermediate product in the
respiration of higher plants; it occurs in traces in ripe fruits
and may form in alcoholic beverages after exposure to air. It has
been reported that acetaldehyde is found in leaf tobacco, ciga-
rette smoke, and automobile and diesel exhaust (U.S. EPA, 1977a).
Acetaldehyde has been reported in both finished drinking water
supplies and effluents from sewage treatment plants in several
locations throughout the U.S. (EPA, I976b).
III. PHARMACOKINETICS
Acetaldehyde which is the first occurring metabolite of ethanol
in mammals is produced in the liver and is often found in various
tissues after the consumption of alcohol (Obe and Ristow, 1977).
It is an intermediate product in the metabolism of sugars in the
body and hence occurs in traces in blood (EPA, I977b).
IV. HEALTH EFFECTS
A. Carcinogenic!ty
Watanabe and Sugimoto (1956) administered 0.5-5% acetalde-
hyde subcutaneously to rats for a period of 489 to 554 days. Four
of the 14 animals developed spindle cell carcinomas at the site of
injection.
•
An increased incidence of malignant neoplasms has been observed
in workers at an aldehyde factory who were exposed to acetaldehyde,
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butyraldehyde, crotonaldehyde, aldol, several alcohols, and longer
chain aldehydes. Acetaldehyde was found in concentrations of
1-7 mg/m3. Of the 220 people employed in this factory, 150 has
been exposed for more than 20 years. During the period 1967 to
1972, tumors were observed in nine males (all of whom were smokers).
The tumor incidences observed in the workers exceeded incidences of
carcinomas of the oral cavity and bronchogenic lung cancer expected
in the general population and, for the age group 55-59 years, the
incidence of all cancers in chemical plant workers. There is no
indication that acetaldehyde was the causative factor in the excess
incidence of cancer (Bittersohl, 1974; Bittersohl, 1975).
Acetaldehyde has been found positive in a variety of mutagenicity
tests: siter chromatid exchange in cultured human lymphocytes and
a Chinese hamster (ovary) cell line (Ristow and Obe, 1978; Obe and
Ristow, 1977); S. typhimirium (Ames Test); (Pol A~) E. colt
(Rosenkranz, 1977); and WP2 uvrA trp~) E. coli (Veghelyi et al.,
1978). It has, however, also been reported negative by other
investigators: S. typhimurium, with and without activation (Cotruvo
et al., 1977; Commoner, 1976; Laumbach e_t_ a_l_. , 1977); Saccharomyces
cerevisiae test for recombination (Cotruvo et al., JL977); and
Bacillus subtilis repair essay (Laumbach et al.,_1^77)._ Thus, of
ten reports of in vitro tests for the mutagenicity of acetaldehyde,
5 were positive and 5 were negative* Acetaldehyde was also found
to cross-link isolated calf thymus DNA (Ristow and Obe, 1978)..
C. Other Toxicity
*
1. Acute
-------
A table summarizing the acute toxicity of acetaldehyde
in cats and mice is found below:
Species
rat
rat
rat
rat
rat
mouse
mouse
Dose
I6,000ppm x 4 hrs.
4,000ppm x 4 hrs.
640 rag/kg
20,000ppm x 30 min.
1,930 mg/kg
560 mg/kg
1,232 mg/kg
Route
Result
Reference
ihl
ihl
s . c.
ihl
oral
s . c .
oral
lethal
lethal
LD50
LC50
LD50
LD50
LD50
Smyth, 1956
NIOSH, 1977
Skog, 1950
Skog, 1950
NIOSH, 1977
Skog, 1950
NIOSH, 1977
D. Other Relevant Data
Acetaldehyde is a mucous membrane irritant in humans
(Verschueren, 1978).
V. AQUATIC EFFECTS
A. Acute
The 24-hour median threshold limit (TLm) for acetaldehyde
pinperch is 70 mg/1. The 96-hour TLm in sunfish is 53 mg/1
(Verschueren, 1978).
VI. EXISTING GUIDELINES
A. Humans
The American Conference of Governmental and Industrial
Hygienists (ACGIH) has adopted a Threshold Limit Value (TLV) of
100 ppm for acetaldehyde. The OSHA standard in air is a Time
Weighted Average (TWA) of 200 ppm.
1-7
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REFERENCES
ACGIH (1977). American Conference of Governmental and Industrial
Hygienists, Threshold Limit Values for Chemical Substances and
Physical Agents in the Workroom Environment, Cincinnati, Ohio.
Bittersohl, G. (1974). Epdemiological investigations on cancer
in workers exposed to aldol and other aliphatic aldehydes. Arch.
Geschwalstforsch. 43:172-176.
Bittersohl, G. (1975). Env. Qual. Safety. 4:285-238 (as cited
in NCI, 1978).
Commoner, B. (1976). Reliability of bacterial mutagenesis
techniques to distinguish carcinogenic and non-carcinogenic
chemicals, EPA-600/1-76-002.
Cotruvo, J.A. -ej^ JL^. , (1977). Investigation of mutagenic effects
of products of ozonation reactions in water. Ann. N.Y. Acad.
Sci. 298:124-140.
Hawley, G.G. (1977). Condensed Chemical Dictionary. 9th edition.
Van Nostrand Reinhold Co.
Laumbach, A.D., e_t_ a^. (1977). Studies on the mutagenlcity of
vinyl chloride metabolites and related chemicals. Prev. Select.
Cancer. (Proc. Int. Symp.) 1:155-170.
NIOSH (1976). National Occupational Hazard Survey.
NIOSH (1977). Registry of Toxic Effects of Chemical Substances.
Obe, G., and H. Rlstow. (1977). Acetaldehyde, But Not Ethanol,
Induces Sister Chromatid Exchanges in Chinese Hamster Cells in
Vitro. Mutation Research. 56:211-213.
National Cancer Institute, Chemical Selection Working Group,
September 28, 1978.
OSHA (1976). Occupational Safety and Health Standards (29 CFR
1910), OSHA 2206.
Ristow, H., and G. Obe. (1978). Acetaldehyde Induces Cross-Links
in DNA and Causes Slster-Chromated Exchanges in Human Cells.
Mutation Research 58:115-119.
-------
Rosenkranz, H.S. (1977). Mutagenicity of halogenated alkanes and
their derivatives. Env. Hlth. Perspect. 21:79-84.
Skog, E. (1950). A toxicological investigation of lower aliphatic
aldehydes I. Toxicity of formaldehyde, acetaldehyde, propionaldehyde,
and butyraldehyde; as well as of acrolein and crotonaldehyde.
Acta Pharmacol. 6:29-318.
Smyth, H.F. (1956). An. Ind. Hyg. Assn. Quarterly, 17:144.
U.S. EPA (I976a). Preliminary Scoring of Selected Organic Air
Pollutants. EPA-450/3-77-008. PB 264-443.
U.S. EPA (I977a). Potential Industrial Carcinogens and Mutagens.
EPA-560/5-77-005.
U.S. EPA (I977b). Review of the Environmental Fate of Selected
Chemicals. EPA-560/5-77-003.
U.S. EPA (1979). Toxic Substances Control Act Chemical Substances
Inventory, Production Statistics for Chemicals on the Non-Confidential
Initial TSCA Inventory.
Veghelyi, P.V. et al. (1978). The fetal alcohol syndrome: symptoms
and pathogenesis. Acta Pediatr. Acad. Sci. Hung. 19:171-189.
Verschueren, K. (1978). Handbook of Environmental Data on Organic
Chemicals. Van Nostrand Reinhold Co., New York.
Watanabe, F. and S. Sugimoto (19.56). Study on the carcinogenic! ty
of aldehyde. 3rd Report. Four cases of sarcomas of rats appearing
in areas of repeated subcutaneous injections of acetaldehyde.
Gann. 47:599-601.
1-1
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No. 2
Ace ton!trlie
Health and Environmental Effects
U.S. ENVIRONJENTAL 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.
-------
ACETONITRILE
SUMMARY
Depending on the amount absorbed/ acetonitri le may cause
disorders in the central nervous system/ Liver/ kidneys, car-
diovascular system and gastrointestinal system/ regardless of
the route of administration. These effects are attributed to
the metabolic release of cyanide from the acetonitrile mole-
cule/ although the parent molecule itself may cause these ef-
fects.
This Hazard Assessment Profile was based largely on in-
formation obtained from NIOSH and its Criteria for a Recom-
mended Standard: Occupational Exposure to Nitrites/ (NIOSH/
1978).
The NIOSH 1972-1974 National Occupational Hazards Survey
estimates that about 26/000 workers are occupationa lly ex-
posed to ni tri les.
Major occupational exposures to nitrile occur by inhala-
tion of vapor or aerosols and by skin absorption. Adverse
effects of nitriles are also found from eye contact.
There is no available evidence to indicate that acetoni-
trile has mutagenic or carcinogenic activity. Two studies
have reported teratogenic effects in rats.
Unlike the immediate onset of cyanide toxicity/ nitrile
poisoning displays a delayed onset of symptoms.
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I. INTRODUCTION
Acetoni t r i Le CCHjCN) is a morion i t ri I e and falls into
the saturated aliphatic class of nitriles. It is a colorless
liquid and has a vapor pressure of 73 mm Hg at 20* C. It has
a molecular weight of 41.05 and a specific gravity of 0.786
CNIOSH, 1978).
When heated to decomposition, nitriles emit toxic fumes
containing cyanides (Sax,. 1968).
Acetonitrile was introduced to the commerical market in
1952, and its industrial uses lie in the manufacture of plas-
tics, synthetic fibres, elastomers, and solvents. Acetoni-
trile is used as a solvent in the extractive distillation
.that separates olefins from diolefins, butadiene from buty-
lene, and isoprene from isopentane.
In 1964, 3.5 million pounds of acetonitrile were con-
sumed industrially.
' II. EXPOSURE
A. Water and Food
Pertinent data were not found in the available lit-
erature.
B. Inhalation
Acetonitrile can be readily absorbed from oral mu-
cosa (McKee, et al. 1962; Dalhamn, et al. 1968).
In the workplace, acute poisoning and death have
I £*-
i been reported following the inhalation of acetonitrile
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C. Dermal
Dermal exposures to acetonitrile have caused ad-
verse reactions including death in some cases (NIOSH, 1978).
Acetonitrile has been reported to have been absorb-
ed through the intact skin of rabbits, yielding a dermal
LD5Q of 980 mg/kg (Pozzani, et al. 1959).
III. PHARMACOKINETICS
A. Absorption
x—•
Acetonitrile is a.component of cigarette smoke and
is absorbed by the oral tissues (McKee,. et al. 1962; Dalhamn,
et a I. 1968).
•—•
Humans have been shown to absorb acetonitrile di-
rectly through the skin and respiratory tract (Zeller,. et al.
1969; Amdur, 1959; Dequidt, et al. 1974)..
B. Distribution
Studies by McKee, et at. (1962) and Dalhamn, et al.
(1968) show th-at acetonitrile from cigarette smoking is re-
tained by the lungs.
Tissue distribution studies indicated that mononi-
triles (and acetonitrile, in particular) are distributed uni-
formly in the internal organs of humans and that cyanide me-
tabolites are found predominantly in the spleen, stomach and
skin, and to a lesser extent, in the liver, lungs, kidneys,
hearts, brain, muscle, intestines, and testes (Dequidt, et
al. 1974).
Haguenoer, et al. (1975) exposed three rats to *
2,800 or 25,000 ppm acetonitri le by inhalation. At 25,000
ppnr, all three rats died after 30 minutes. Chemical analysis
A.-5
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of the organs showed that the mean concentration of
acetonitrile in muscle was 136 pg/100 g of tissue and 2/438
ug/100 g of kidney tissue. High acetonitrile excretion or
possible renal blockage were postulated as the causes for the
high renal concentration.
Nitriles and their metabolic products have been de-
tected in urine/ blood and tissues (McKee/ et al. 1962).
C. Metabolism
Since human and animal studies report symptoms
characteristics of cyanide poisoning/ it is reasonable to
assume that a portion of the effects of exposure to acetoni-
tn'le is due to the release of the cyanide ion from the par-
ent compound (Zeller/ et al. 196~9; Amdur/ 1959; Pozzani/
1959).
After absorption/ nitriles may be metabolized to an
alpha cyanohydrin or to inorganic cyanide/ which is oxidized
to thiocyanate and is excreted in the urine. The C=N group
may be converted into a carboxylic acid derivative and ammon-
ia/ or may be incorporated into cyanocobalamine. Ionic cya-
nide also reacts with carboxyl groups and with disulfides
(McKee/ et al. 1962).
Haguenoer/ et al (1975) injected white male Wistar
rats with varying levels of acetonitrile ranging from 600
mg/kg to 2/340 mg/kg. A-t autopsy/ the internal organs showed
that the combined hydrogen cyanide consisted essentially of
thiocyanates/ cyanohydrins and cyanocoba I amines . '
0. Excretion
Acetonitrile is found in the morning urine of cigar-
ette smokers. Concentrations of acetonitrile range from 2.2
-------
of the organs showed that the mean concentration of
acetonitrile in muscle was 136 ^jg/100 g of tissue and 2,438
ug/10Q g of kidney tissue. High acetonitriLe excretion or
possible renal blockage were postulated as the causes for the
high renal concentration.
Nitriles and their metabolic products have been de-
tected in urine, blood and tissues (McKee, et al. 1962).
C. Metabolism
Since human and animal studies report symptoms
characteristics of cyanide poisoning, it is reasonable to
assume that a portion of the effects of exposure to acetoni-
trile is due to the release of the cyanide ion from the par-
ent compound CZeller, et al.. 1969; Amdur, 1959; Pozzani,
1959).
After absorption, nitriles may be metabolized to an
alpha cyanohydrin or to inorganic cyanide, which is oxidized
to thiocyanate and is excreted in the urine. The C=N group
may be converted into a carboxylic acid derivative and ammon-
ia, or may be incorporated into cyanocobalamine. Ionic cya-
nide also reacts with carboxyl groups and with disulfides
CMcKee, et al. 1962).
Haguenoer, et al (1975) injected white male Uistar
rats with varying levels of acetonitrile ranging from 600
mg/kg to 2,340 mg/kg. At autopsy, the internal organs showed
that the combined hydrogen cyanide consisted essentially of
thiocyanates, cyanohydrins and cyanocobaLamines. .
D. Excretion
Acetonitrile is found in the morning urine of cigar-
ette smokers. Concentrations of acetonitrile range from 2.2
JL-7
-------
ug/100 ml urine for those smoking three cigarettes per day up
to 20 jug/100 mL urine for heavy smokers (up to 2.5 packs per
day). The results showed that acetonitri le, once absorbed
into the body, can be excreted unchanged in the urine (NcKee,
et at. 1962).
Acetonitrile is also excreted unchanged in exhaled
air (Haguenoer, et al. 1975).
IV. EFFECTS
A. Carcinogenicity
Dorigan, et al. (1976) failed to show significant
carcinogenic effects in a two-year exposure study conducted
with rats.
8. Mutagenicity
Pertinent data were not found in the available lit-
erature.
C. Teratogenicity
Intraperitoneal (i.p.) administration of acetoni-
tri le to pregnant rats produced fetal malformations (Dorigan,
et al. 1976). Schmidt, et al. (1976) have determined skele-
tal abnormalities in rats following i.p. exposure to acetoni-
tri le.
D. Other Reproductive Effects
Pertinent data were not found in the available lit-
erature.
E. Chronic Toxicity
In an experiment to stimulate chronic occupational
exposure (seven hours per day, five days per week), 30 rats
were exposed to a concentration of 655 ppm acetonitrile for
-------
90 days. The rats exhibited bronchial inflammation, desqua-
matization and hypersecration of mucus, and hepatic and renal
lesions. Monkeys exposed by the same regimen, but to 350 ppm
acetonitrile for 91 days, experienced bronchitis and moderate
hemorrhage of the superior and inferior sagittal sinuses of
the brain (Pozzani, et al. 19S9).
Dogs exposed to acetonitrile at a concentration of
300 ppm for 91 days showed a reduction in body weight as well
as a reduction in hemoglobin and hematocrit values (Pozzani,,
et al. 1959).
Monkeys exposed to 660 ppm acetonitrile per day
showed poor coordination during the second week of exposure
and a monkey exposed to 330 ppm showed hyperexcitabi lity
toward the- end of the 13th week (Pozzani, et al. 1959).
The same investigators reported chronic LDgg
values of 0.85 and 0.95 ml/kg for female rats which i.p. ad-
ministration of acetonitrile.
G. Other Relevant Information
Dogs exposed with lethal quantities of acetonitrile
(16,000 ppm for four hours) showed blood cyanide levels rang-
ing from 305-433 ug/100 ml of blood after three hours (Poz-
zani, et al. 1959)..
V. AQUATIC TOXICITY
A. Acute
Observed 96-hour LC$Q values for the fathead
minnow (Pimephales promelas) are 1020 mg/l in hardwater a ad
1000 ml/I in softwater (Bringmann, 1976). For bluegills,
(Lepomi s mac roc hi rus) and guppies (Lebi stes reticulatus), the
-------
respective 96-hour values in softw.ater are 1850 mg/L and 1650
mg/l (Jones, 1971; Henderson, et at. 1960).
B. Chronic, Plant Effects, and Residue
Pertinent data were not found in the available lit-
erature.
C. Other Relevant Information
Acetonitrile has been observed to damage the bron-
chial epithelium of fish (Belousov, 1969). This compound,
when added to the aqueous environment of roaches and fil-
berts, disrupted blood circulation and protein metabolism and
induced hyperemia, hemorrhages, and the appearance of small
granules in the heart, brain, liver, and gills of fish. The
hepatic glycogen level decreased sharply. CHjCN induced-
death apparently resulted from circulatory disturbances and
necrobiotic changes in the cerebral neurons (Belousov, 1972).
Acetonitrile at a concentration of 100 mg/l inhib-
ited nitrificat ion in saprophytic organisms (Chekhovskaya,
1966).
VI. EXISTING GUIDELINES
A. Human
A federal occupational standard exists for acetoni-
trile and is based on the TLV for workplace exposure pre-
viously adopted by American Conference of Governmental and
Industrial Hygienists. This TLV is 40 ppm (70 mg/nH) and
is an eight-hour TWA.
•
3. Aquatic
Pertinent data were not found in the available lit-
erature.
-------
REFERENCES
Amdur, M.L. 1959. Accidental group exposure to acetoni-
triLes - A clinical study. J. Occup. Med. 1: 627.
American Conference of Governmental Industrial Hygienists.
Threshold limit values for chemical substances and physical
agents in the workroom environment, with intended changes for
1979.- Cincinnati, Ohio. 94 pp.
Belousov, Y..A. 1969. Effects of some chemical agents on the
histophysiological state of the bronchial epithelium. (Uch.
Zap. Yoroslav. Gos. Pedagog. Inst. USSR 62:126-129). Chem.
Abst. 97853c.
Belousov, Y.A. 1972. Morphological changes in some fish
organs during poisoning. Vlujanie Pestits. Dikikh Zhivotn.
41-45. Chem. Abst. 141567d, Vol. 80.
Bringmann, G_ 1976. Vergleichende Vefunde der Schadwirkung
wassergefahrdender. Stoffee gezen Bakterien (Speudomomas
putida) und Blaualgen (Microcystis aeruginosa) nwfa llwasser.
117-119.
Checkhovskaya, E.V., et. al. 196~6. Data for experimental
studies of toxicity of waste waters from aery lonitri le pro-
duction. (Vodosnabzh. Kanaliz. Gidrotekh. Sooruzh. nezhved.
Resp. Nauch. USSR SB 1: 83-88). Chem. Abst. 88437k.
Dalhamn, T., et al. 1968. Mouth absorption of various com-
pounds in cigarette smoke. Arch. Environ. Health 16: 831.
Dequidt, J., et al. 1974. Intoxication with acetonitrile
with a report on a fatal case. Eur. J. Toxicol. 7: 91.
Dirigan, et al. 1976. Preliminary scoring of selected
organic air pollutants. Environ. Prot. Agency, Contract No.
68-02-1495.
Grabois, B. 1955. Fatal exposure to methyl cyanide. NY
State Oep. Labor Oiv. Ind. Hyg. Won. Rev. 34: 1,7,3.
Haguenoer, J.M., et al.., 1975. Experimental acetonitrile
intoxications - I. Acute intoxicatios by the intraperitonea I
route.. Eur. J.. Toxicol. 8: 94.
Henderson, C., et a I. i960. The effect of some organic
cyanides (nitriles) on fish. Purdue Univ. Eng. Bull. Exp.
Ser. 106: 120.
Jones, H. 1971. Environmental control in the organic and*
petrochemical industries. Noyse Data Corp.
SL-ll
-------
McKee, H.C., et al. 1962. Acetonitrile in body fluids re-
lated to smoking. Public Health Rep. 77: 553.
NIOSH. 1978. NIOSH Criteria for a Recommended Standard:
Occupational Exposure to Nitriles. U.S. DHEW, Cincinnati.
Pozzani, V.C., et al. 1959. An investigation of the mammal-
ian toxicity of acetonitrile. J. Occup. Med. 1: 634.
Sax. N.I. 1968. Dangerous Properties of Industrial Materi-
als, 3rd ed. NY Van Nostrand Reinhold Co.
Schmidt/ W., et al. 1976. Formation of skeletal abnormali-
ties after treatment with aminoacetonitri le and cycy lophosph-.
amide during rat fetogenesis. (Verh. Anat. 71:635-638 Ger.)
Chem. Abst. 1515w.
Sunderman, F.W., and J.F. Kincaid. 1953. Toxicity studies
of acetone cyanohydrin and ethylene cyanohydrin. Arch. Ind.
Hyg. Occup. Med. 8: 371.
Zeller, H.V., et al. 1969. Toxicity of nitriles. Zentralbl
Arbirtsmed Arbeitsschutz. 19: 255.
-------
No. 3
Acetophenone
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
3-1
-------
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.
S-JL
-------
ACETOPHENONE
Summary
Acetophenone is present in various fossil fuel processes and products,
particularly coal and petroleum products. It is used as a flavoring agent
in products for human consumption and as an intermediate in organic
synthetic processes, particularly plastics manufacturing.
No data on the potential for carcinogenic, mutagenic, or teratogenic
effects or on the chronic toxicity of acetophenone were found in the
available literature.
There are no existing OSHA, NIOSH, or ACGIH standards or guidelines.
Acetophenone is a skin irritant and has been shown to cause severe eye irri-
tation in rabbits at microgram quantities. Acetophenone is highly toxic to
aquatic life
-------
I. INTRODUCTION
Acetophenone (1-phenylethanone, phenyl methyl ketone, acetyl-
benzene, benzoyl methide, hypnone, C^coo^; molecular weight 120.15)
is a liquid with a melting point of 20.5°C and is slightly soluble in
water. Acetophenone is used to impart a pleasant jasmine or orange-
blossom-like odor to perfumes, as a catalyst for the polymerization of ole-
fins, and in organic syntheses, especially as a photosynthesizer (Windholz,
1976). Additionally, it is used as a tobacco flavoring, as a solvent or
intermediate in the synthesis of Pharmaceuticals, and as a by-product of the
coal processing industry. Acetophenone is present in gasoline exhaust at
less than 0.1 to 0.4 ppm (Verschueren, 1977).
II. EXPOSURE
No data on levels of acetophenone in food or water or on other
potential (inhalation or dermal) exposures were found in the readily avail-
able literature.
III. PHARMACOKINETICS
Information on the absorption, distribution, metabolism, or ex-
cretion of acetophenone was not found in the readily available literature,
despite the fact that it is used in pharmaceutical preparations and in
tobacco, perfume, and other products for human comsumption.
IV. EFFECTS
A. Carcinogenic!ty, Mutagenicity, Teratogenicity, and Chronic Toxicity
Readily available data are extremely limited. One paper suggests
the possible mutagenicity of acetophenone due to its ability to cause DNA
breakage in bacterial systems following DNA photosensitization (Rahn, et
al. 1974). Because of the particular sensitivity of the bacterial system
to DNA breakage, this information by itself is insufficient to establish
acetophenone as a mutagenic agent.
-------
There is no additional data readily available on the potential for
carcinogenic, mutagenic, or teratogenic activity by acetophenone. No data
are available on chronic toxicity.
B. Acute Toxicity
Skin irritaion was observed in the rabbit at 10 mg/24 hrs. using
the draize procedure and at 515 mg when applied to the skin in the absence
of the absorbent gauze patch. Severe eye irritation was obtained in the
rabbit following application of 771 ug of acetophenene. The oral LD5Q in
rats was 900 mg acetophenone/kg, "while the lethal dose following intra-
peritoneal injection in mice was 200 mg/kg (NIOSH, 1978). Acetophenone is a
hypnotic in high concentrations and was used as an anesthetic in the last
century before less toxic substances were found (Kirk and Othmer, 1963).
C. Other Relevant Information
Based upon the retention time in a gas chromatographic/mass spec-
trographic column, Veith and Austin (1976) suggest a potential for bio-
accumulation of acetophenone. There is no additional information available
to verify this situation, however.
Microbial metabolism of acetophenone as the sole source of carbon
and energy has been demonstrated in pure culture (Cripps, 1975).
V. AQUATIC TOXICITY
Based upon reported values in the literature, acetophenone has
been shown to be highly toxic, to aquatic life, (U.S. EPA, 1979). LC5Q
values for fathead minnow are reported for the following time periods: 1
hour, greater than 200 mg/1; 24 hours, 200 mg/1; 48 hours, 163 mg/1; 72
hours, 158 mg/1; and 96 hours, 155 mg/1 (U.S. EPA, 1976).
Acetophenone has been reported to be a major constituent (36 per-
cent) of a weathered bunker fuel. This suggests that it may be present in
large quantity following spills of some bunker fuels (Guard, et al. 1975).
-------
Bunker fuels are highly variable form refinery to refinery; thus, a blanket
statement as to percentage composition of acetophenone or other constituents
cannot be made.
VI. EXISTING GUIDELINES AND STANDARDS
There are no existing guidelines and standards from OSHA, NIOSH,
or ACGIH. Similarily, no ambient water quality standards for acetophenone
exist.
-------
REFERENCES
Cripps, R.E. 1975. The microbial metabolism of acetophenone: metabolism
of acetophenone and some chloroacetophenones by an Arthrobacter species.
Biochem. Jour. 152: 233.
Guard, H.E., et al. 1975. Identification and potential biological effects
of the major components in the seawater extract of a bunker fuel. Bull.
Environ. Contam. Toxicol. 14: 395.
Kirk, R.E. and D.F. Othmer. 1963. Kirk-Othmer. Encyclopedia of Chemical
Technology. 2nd ed. J. Wiley and Sons, Inc., New York.
National Institute for Occupational Safety and Health. 1978. Registry of
Toxic Effects of Chemical Substances. E. Fairchild (ed.). U.S. Department
of Health, Education, and Welfare. Cincinnati, Ohio. -
Rahn, R.O., et al. 1974. Formation and chain breaks and thymine dimers in
ONA upon photosensitization at 313 nm with acetophenone, acetone, or benzo-
phenone. Photochem. Photobio. 19: 75.
U.S. EPA. 1976. Acute Toxicity of Selected Organic Compounds to Fathead
Minnows. EPA-600-3-76-097. U.S. EPA Environmental Research Lab., Duluth,
Minnesota.
U.S. EPA. 1979. Biological Screening of Complex Samples From In-
dustrial/Energy Processes. EPA-600-8-79-021. U.S. EPA, Research Triangle
Park, North Carolina.
Veith, G.O. and N.M. Austin. 1976. Detection and isolation of bioaccumu-
latable chemicals in complex effluents. In: L.H. Keith (ed.), Identifi-
cation and Analysis of Organic Pollutants in Water. Ann Arbor Science
Publishers, Inc., Ann Arbor, MI. p. 297.
Verschueren, K. 1977. Handbook of Environmental Data on Organic Chem-
icals. Van Nostrand Reinhold Company, New York.
Windholz, M. (ed.) 1976. Merck Index. 9th ed. Merck and Co., Rahway,
N.J.
3-7
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No. 4
Acetyl Chloride
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENC7
WASHINGTON, D.C. 20460
APRIL 30, 1980
y-/
U|
\, '
-------
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.
-------
ACETYL CHLORIDE
Summary
Acetyl chloride is an irritant and a corrosive. Cutaneous exposure
results in skin burns, while vapor exposure causes extreme irritation of the
eyes and mucous membranes. Inhalation of two ppm acetyl chloride has been
found irritating to humans. Death or permanent injury may result after
short exposures to small quantities of acetyl chloride. An aquatic toxicity
rating has been estimated to range from 10 to 100 ppm.
However, acetyl chloride reacts violently with water. Thus, its half-
life in ambient water should be short and exposure from water should be nil.
The degradation products should likewise pose no exposure problems if the pH
of the water remains stable.
y-3
-------
ACETYL CHLORIDE
I. INTRODUCTION
Acetyl chloride (ethanoyl chloride; CH^CQCl; molecular weight, 78.50)
is a colorless, fuming liquid with a pungent odor, a boiling point of
51-52°C, and a melting point of -112°C (Windholz, 1976). It is used as
an acetylating agent in testing for cholesterol and in the qualitative
determination of water in organic liquids. It is miscible with benzene,
chloroform, ether or glacial acetic acid (Windholr, 1976). In the presence
of water or alcohol, however, acetyl chloride hydrolyzes violently to form
hydrogen chloride and acetic acid. Phosgene fumes, which are highly toxic,
are emitted when acetyl chloride is heated to decomposition (Sax, 1975).
The 1975 U.S. annual production of acetyl chloride was approximately
4.54 x 10 grams (SRI, 1976). During transportation, this chemical should
be stored in a cool, well-ventilated place, out of direct sunlight, and away
from areas of high fire hazard; it should periodically be inspected (Sax,
1975). Acetyl chloride must be protected from water (Windholz, 1976).
II. EXPOSURE
Acetyl chloride reacts violently with water (see above). Thus, its
half-life in ambient water should be short and exposure from water should be
nil. - The degradation products should likewise pose no exposure problems if
the pH of the water remains stable. Internal exposure to acetyl chloride
will most likely occur through inhalation of the vapor, or, on rare occa-
sions, through ingestion. Skin absorption is very unlikely although severe
burns would be expected.
III. PHARMACOKINETICS
»
Pertinent data could not be located in the available literature.
t-f
-------
IV. EFFECTS
Acetyl chloride is an irritant and a corrosive. Cutaneous exposure
results in skin burns. Vapor exposure causes extreme irritation of the eyes
and mucous membranes (Windholz, 1976). Inhalation of 2 ppm acetyl chloride
was found irritating to humans (Handbook of Organic Industrial Solvents,
1961). Death or permanent injury may result after very short exposures to
small quantities of acetyl chloride (Sax, 1975).
Because the toxicity of acetyl chloride might be expected to pattern
that of its breakdown product hydrogen chloride (HCL), LCLQ value (the
lowest concentration of a substance in air which has been reported to cause
death in humans or animals) for HC1 might be indicative of its toxicity.
This value in humans is 1000 ppm for one minute (Mason, 1974).
Pertinent information could not be located in the available literature
regarding the carcinogenicity, mutagenicity, teratogenicity and chronic
toxicity of acetyl chloride.
V. AQUATIC TOXICITY
Acetyl chloride has been shown to be toxic to aquatic organisms in the
ranges of 10 to 100 ppm (Hann and Jensen, 1974). No other information has
been found in the literature.
VI. EXISTING GUIDELINES AND STANDARDS
No standards for acetyl chloride have been reported. However, a
ceiling limit of 5 ppm has been reported for hydrogen chloride (the most
irratating hydrolysis product of acetyl chloride) in industrial exposures.
(Mason, 1974).
-------
ACETYL CHLORIDE
REFERENCES
Handbook of Organic Industrial Solvents, 2nd ed. 1961. Cited in: Registry
of toxic effects of chemical substances. NIOSH (DHEW) Pub. No. 79-100, p. 4.
Hann, W. and P.A. Jensen. 1974. Water quality characteristics of hazardous
materials. Vol. 2. Texas A4M University.
Mason, R.V. 1974. Smoke and toxicity hazards in aircraft cabin furnish-
ings. Ann. Occup. Hyg. 17: 159.
Sax, N.I. 1975. Dangerous properties of industrial materials, 4th ed. Van
Nostrand Reinhold Co., New York, p. 355.
Stanford Research Institute. 1976. Chemical economics handbook.
Windholz, M. -(ed.) 1976. The Merck Index, 9th ed. Merck and Co., Inc.,
Rahway, N.J., p. 11.
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No. 5
Acroleln
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.
-------
ACROLEIN .
SUMMARY
Acrolein has not been shown to be a carcinogen or cocarcinogen in in-
halation experiments. Acrolein is mutagenic in some assay systems. Infor-
mation on teratogenicity is not available. The only reported chronic effect
of acrolein in humans is irritation of the mucous membranes. Chronic expo-
sure of Syrian golden hamsters to acrolein in the air caused reduced body
weight, gains and inflammation and epithelial '• metaplasia in the nasal
cavity. In addition, females had decreased liver weight, increased lung
weight, and slight hematologic changes.
Acrolein has been demonstrated to be acutely toxic in freshwater organ-
isms at concentrations of 57 to 160 ug/1. A single marine fish tested was
somewhat more resistant with a 48-hour LC5_. of 240 jug/1. Toxicity to
marine invertebrates was comparable to that of freshwater organisms.
-------
ACROLEIN
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Acrolein (U.S. EPA, 1979).
Acrolein (2-propenal; CH2=CHCHO; molecular weight 56.07) is a flamm-
able liquid with a pungent odor. It has the following physical and chemical
properties (Weast, 1975; Standen, 1967):
Melting Point -86.95QC
Boiling Point Range 52.5 - 53.5°C
Vapor Pressure 215mm Hgvat 20°C
Solubility Water: 210.8 percent by weight
at 20°C
Density 0.8410 at 20°C
Production (Worldwide) 59 kilotons (Hess, et al. 1978)
Capacity (Worldwide) 102 kilotcns/year
Capacity (United States) 47.6 kilotons/year
Acrolein is used as a biocide, crosslinking agent, and tissue fix-
ative. It is used as an intermediate throughout the chemical industry.
The fate of acrolein in water was observed in natural channel waters
(Bowmer and Higgins, 1976). No equilibrium was reached between dissipating
acrolein and degradation products, with the dissipating reaction apparently
being continued to completion. Degradation and evaporation appear to be the
major pathways for loss, while a smaller amount is lost through absorption
and uptake in aquatic organisms and sediments (Bowmer and Sainty, 1977;
Hopkins and Hattrup, 1974).
II. EXPOSURE
There is no available evidence that acrolein is a contaminant of pot-
able water or water supplies (U.S. EPA, 1979).
Acrolein is a common component of food. It is- commonly generated
during cooking or other processing, and is sometimes produced as an unwanted
-------
by-product in the fermentation of alcoholic beverages (Izard and Libermann,
1978; Kishi, et al. 1975; Hrdlicka and Kuca, 1965; Boyd, et al. 1965;
Rosenthaler and Vegezzi, 1955). However, the data are insufficient to
develop a conclusive measure of acrolein exposure from food processing or
cooking.
The U.S. EPA (1979) has estimated the weighted average bioconcentration
factor for acrolein to be 790 for the edible portions of fish and shellfish
consumed by Americans. This estimate is based on measured steady-state bio-
\
concentration studies in bluegills.
Atmospheric acrolein is generated as a combustion product of fuels and
of cellulosic materials (e.g., wood and cigarettes), as an intermediate in
atmospheric oxidation of propylene, and as a component of the volatiles pro-
duced by heating organic substrates (U.S. EPA, 1979). Acrolein is present
in urban smog; average concentrations of 0.012 - 0.018 mg acrolein/m and
peak concentrations of 0.030 - 0.032 mg acrolein/m were noted in the air
of Los Angeles (Renzetti and Bryan, 1961; Altshuller and McPherson, 1963).
Diesel exhaust emissions contained 12.4 mg acrolein/m ; trace amounts of
acrolein were present in samples taken from an area of traffic; and no acro-
lein was detected in ambient air from an open field (sensitivity of measure-
ment was below one part per million) (Bellar and Sigsby, 1970). Acrolein
content of smoke from tobacco and marijuana cigarettes ranged from 85 to 145
ug/cigarette (Hoffman, et al. 1975; Horton and Guerin, 1974). Acrolein was
detected at levels of 2.5 - 30 mg/m at 15 cm above the surface of pota-
toes or onions cooking in edible oil (Kishi, et al. 1975).
-------
III. .'HARMACOKINETICS
A. Absorption
Total respiratory tract retention of acrolein in anesthetized dogs
was 77 to 86 percent (Egle, 1972).
8. Distribution
Pertinent data were not found in the available literature.
C. Metabolism
Relatively little direct information is available on the metabolism
of acrolein. In vitro, acrolein can serve as a substrate for alcohol dehy-
drogenases from human and horse liver (Pietruszko, et al. 1973). In vivo
studies in rats indicate that a portion of subcutaneously administered acro-
lein is converted to 3-hydroxylpropylmercapturic acid (Kaye and Young, 1972;
Kaye, 1973). Acrolein undergoes both spontaneous and enzymatically cata-
lyzed conjugation with glutathione (Boyland and Chasseaud, 1967; Esterbauer,
et al. 1975). The low pH's encountered in the upper portions of the gastro-
intestinal tract probably would rapidly convert acrolein to saturated alco-
hol compounds (primarily beta propionaldehyde) (U.S. EPA, 1979). As several
of the toxic effects of acrolein are related to the high reactivity of the
carbon-carbon double bond, saturation of that bond should result in detoxi-
fication (U.S. EPA, 1979).
0. Excretion
In rats given single subcutaneous injections of acrolein, 10.5 per-
cent of the administered dose was recovered in the urine as 3-hydroxy-
propylmercapturic acid after 24 hours (Kaye and Young, 1972; Kaye, 1973).
S-6
-------
IV. EFFECTS
A. Carcinogenicity
One-year and lifespan inhalation studies with hamsters indicate
that acrolein is not a carcinogen or cocarcinogen (Feron and Kruysse, 1977;
National Cancer Institute, 1979).
B. Mutagenicity
Both positive and negative results have been obtained in muta-
genicity assays. Acrolein induced sex-linked mutations in Drosophila
melanoqaster (Rapoport, 1948) and was mutagenic for DNA polymerase-deficient
Escherichia coli (Bilimoria, 1975) and Salmonella typhimurium (Bignami, et
al. 1977). Mutagenic activity was not detected in the dominant lethal assay
in ICR/Ha Swiss mice (Epstein, et al. 1972) or in a strain of E. coli used
for detecting forward and reverse mutations (with or without microsomal
activation) (Ellenberger and Mohn, 1976; 1977). Acrolein was weakly muta-
genic for Saccharomyces cerevisiae (Izard, 1973).
C. Teratogenicity
Pertinent data were not found in the available literature.
C. Other Reproductive Effects
Exposure of male and female rats to 1.3 mg/m acrolein vapor for
26 days did not have a significant effect on the number of pregnant animals
or the number and mean weight of fetuses (Bouley, et al. 1976).
E. Chronic Effects
Little information is available on the chronic effects of acrolein
on humans. An abstract of a Russian study indicates that occupational expo-
sure to acrolein (0.8 to 8.2 mg/m ), methylmereaptan (0.003 to 5.6
•
mg/m ), methylmercaptopropionaldehyde (0.1 to 6.0 mg/m3), formaldehyde
(0.05 to 8.1 mg/m ), and acetaldehyde (0.48 to 22 mg/m3) is associated
S-7
-------
with irritation of the mucous membranes. This effect is most frequent in
women working for less than one and greater than seven years (Kantemirova,
1975). Acrolein is known to produce irritation of the eyes and nose (Albin
1962; Pattle and Cullumbine, 1956; Sim and Rattle, 1957) and is thought to
be responsible, at least in part, for the irritant properties of
photochemical smog (Altshuller, 1978; Schuck and Renzetti, 1960) and
cigarette smoke (Weber-Tschopp, et al. 1976a; 1976b; 1977).
In the only published chronic toxicity study on acrolein in animals
(Feron and Kruysse, 1977), male and female Syrian golden hamsters were ex-
•
posed to acrolein at 9.2 mg/m in air, seven hours per day, five days per
week, for 52 weeks. During the first week only, animals evidenced signs of
eye irritation, salivated, had nasal discharge, and were very restless.
During the exposure period, both males and females had reduced body weight
gains- compared to control groups. . Survival rate was unaffected. Slight
hematological changes, increased hemoglobin content and packed cell volume,
decreases in liver weight (-16 percent), and increases in lung weights (-1-32
percent) occurred only in females. In both sexes, the only pathological
changes in the respiratory tract were inflammation and epithelial metaplasia
in the nasal cavity.
In a study of subacute oral exposure, acrolein was added to the
drinking water of male and female rats at 5 to 200 mg acrolein/1 for 90 days
(Newell, 1958). NO hematologic, organ-weight, or pathologic changes could
be attributed to acrolein ingestion.
F. Other Relevant Information
Acrolein is highly reactive with thiol groups. Cysteine and other
»
compounds containing thiol groups antagonize the toxic effects of acrolein
-------
(Tillian, et al. 1976; Low, et al. 1977; Sprince, et al. 1978; Munsch, et
al. 1973;1974; Whitehouse and Beck, 1975). Ascorbic acid also antagonizes
the toxic effects of acrolein (Sprince, et al. 1978).
The effects of acrolein, on the adrenocortical response of rats
unlike those of DOT and parathion, are not inhibited by pretreatment with
phenobarbital and are only partially inhibited by dexamethason (Szot and
Murphy, 1970). Pretreatment of rats with acrolein significantly prolongs
hexobarbital and pentobarbital sleeping time (Jaeger and Murphy, 1973).
V. AQUATIC TOXICITY
A. Acute Toxicity
A relatively narrow range of acute toxicity to six species of
freshwater fish has been reported for acrolein (U.S. EPA, 1979). LC5Q
...values, ranged from 61 to 160 pg/1 with fathead minnows, (Pimephales
promelas), being most sensitive and largemouth bass, (Micropterus
salmoides), the most resistant of the species tested. Results from 7 static
bioassays varying from 24. to 96 hours in duration were reported. The fresh-
water invertebrate Daphnia magna was as sensitive to acrolein as freshwater
fish with 48-hour static LC_Q values of 59 and 80 /jg/1 being reported in
two individual studies. The longnose killifish, (Fandulus similis), was the
only marine species tested for acute toxicity of acrolein; a 48-hour flow-
__thrpugh LC^n of 150 pg/1 was obtained. The eastern oyster, (Crassostrea
virqinica), and adult brown shrimp, (Penacus aztecus), were the most sensi-
tive species tested an EC5Q value of 55 jjg/1 based on 50% decrease in
shell growth of oysters and an EC5Q value of 100 based on loss of equi-
librium of brown shrimp (Butler, 1965). Adult barnacles were more resistant
»
in static assays with 48-hour LC5Q values of 1,600 and 2,100 jug/1 being
reported.
57
-------
B. Chronic Toxicity
In a chronic life cycle test with the freshwater fathead minnow,
Pimephales promelas, survival of newly hatched second generation fry was
reduced significantly at 42 but not 11 ug/1, leading to a chronic value of
21.8 ug/1 (Macek, et al. 1976). A comparable value of 24 ug/1 was obtained
from reduced survival of three generations of Daphnia maqna. Chronic data
for marine organisms was not available.
C. Plant Effects
Pertinent data relating the phytotoxitity of freshwater marine
plants could not be located in the available literature.
0. Residues
A bioconcentration factor of 344 was obtained for radio labeled
acrolein administered to bluegills, (Lepomis macrochivas). A biological
half-life greater than seven days was indicated (U.S. EPA. 1979).
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived by the 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 use of subacute toxicological data for rats (no
observable effect level of 1.56 mg/kg body weight) and an uncertainty factor
of 1000, the U.S. EPA (1979) has derived a draft criterion of 6.50 pg/1 for
acrolein in ambient water. This draft criterion level corresponds to the
calculated (U.S. EPA, 1979) acceptable daily intake of 109 ug.
The ACGIH (1977) time-weighted average TLV for acrolein is 0.1 ppm
(0.25 mg/m ). The same value is recommended by OSHA (39 FR 23540). This
f-it
-------
standard was designed to "minimize, but not. entirely prevent, irritation to
all exposed individuals" (ACGIH, 1974).
The FDA permits acrolein as a slime-control substance in the manu-
facture of paper and paperboard for usage in food packaging (27 FR 46) and
in the treatment of food starch (28 FR 2676) at not more than 0.6 percent
acrolein.
B. Aquatic
The draft criterion for protecting freshwater organisms is 1.2 ug/1
as a 24-hour average not to exceed 2.7 ug/1. For marine life, the draft
criterion has been proposed as 0.88 ug/1, not to exceed 2.0 ug/1.
-------
ACROLEIN
REFERENCES
Albin, T. B. 1962. Page 234. In; C.W. Smith, ed. Handling
and toxicology, in acrolein. John Wiley and Sons, Inc.,
New York.
Altshuller, A. P. 1978. Assessment of the contribution
of chemical species to the eye irritation potential of photo-
chemical smog. Jour. Air Pollut.. Control Assoc. 28: 594.
Altshuller, A. R. , and S. P. McPherson. 1963. Spectrophoto-
metric. analysis of aldehydes in the Los Angeles atmosphere.
Jour. Air Pollut. Control Assoc. 13: 109.
v
American Conference of Governmental Industrial Hygienists.
1974. Documentation, of the threshold limit value. 3rd ed.
American Conference of Governmental Industrial Hygienists.
1977. Threshold limit values for chemical substances in
workroom air.
Bellar, T. A., and J. E. Sigsby. 1970. Direct gas chromato-
graphic analysis of low molecular weight substituted organic
compounds in emissions. Environ. Sci. Technol. 4: 150.
Bignami, M. , et al. 1977. Relationship between chemical
structure and mutagenic activity in some pesticides: The
use of Salmonella typhimurium and Aspergillus nidulans.
Mutat. Res. 4t»:
Bilimoria, M. H. 1975. Detection of mutagenic activity
of chemicals and tobacco smoke in bacterial system. Mutat.
Res. 31: 328.
Bouley, G., et al. 1976. Phenomena of adaptation in rats
continuously exposed to low concentrations of acrolein.
Ann. Occup. Hyg. 19: 27.
Bowraer, K. H. , and M. L. Higgins. 1976. Some aspects of
the persistence and fate of acrolein herbicide in water.
Arch. Environ. Con tarn. Toxicol. 5: 87.
Bowmer, K. H., and G. R. Sainty. 1977. Management of aqua-
tic plants with acrolein. Jour. Aquatic Plant Manage. 15:
40.
Boyd, E. N., et al. 1965. Measurement of monocarbonyl classes
in cocoa beans and chocolate liquor with special reference
to flavor. Jour. Food Sci. 30: 854.
**
S--/3L
-------
Boyland, E., and L. F. Chasseaud. 1967. Enzyme-catalyzed
conjugations of glutathione with unsaturated compounds.
Biochem. Jour. 104: 95.
Butler, P. A. 1965. Commercial fisheries investigations.
Effects of pesticides on fish and wildlife, 1964 research
findings Fish Wildl. Serv. U.S. Fish Wildl. Serv. Circ.
Egle, J. L., Jr. 1972.' Retention of inhaled formaldehyde,
propionaldehyde, and acrolein in the dog. Arch. Environ.
Health 25: 119.
Ellenberger, J., and G. R. Mohn. 1976. Comparative mutageni-
city testing of cyclophosphamide and some of its metabolites.
Mutat. Res. 38: 120.
Ellenberger, J., and G. R. Mohn. 1977. Mbtagenic activity
of major mammalian metabolites of cyclophosphamide toward
several genes of Escherichia coli. Jour. Toxicol. Enviorn.
Health 3: 637.
Epstein, S. S., et al. 1972. Detection of chemical mutagens
by the dominant lethal assay in the mouse. Toxicol. Appl.
Pharmacol. 23: 288.
Esterbauer, H., et al. 1975. Reaction of glutathione with
conjugated carbonyls. Z. Naturforsch. C: Biosci. 30c:
466.
Feron, V. J., and A. Kruysse. 1977. Effects of exposure
to acrolein vapor in hamsters simultaneously treated with
benzo (a)pyrene or diethylnitrosamine. Jour. Toxicol. Environ.
Health 3: 379.
Hess, L. B., et al. 1978. Acrolein and derivatives. Iri
Kirk-Othmer Encyclopedia of Chemical Technology. 3rd edT
Interscience Publishers, New York.
Hoffman, D., et al. 1975. On the carcinogenicity of mari-
juana 'smoke. Recent Adv. Phytochem. 9: 63.
Hopkins, D. M., and A. R. Hattrup. 1974. Field evaluation
of a method to detect acrolein in irrigation canals. U.S.
PB Rep. No. 234926/4GA. Natl. Tech. Inf. Serv.
Horton, A. D., and M. R. Guerin. 1974. Determination of
acetaldehydes and acrolein in the gas phase of cigarette
smoke using cryothermal gas chromatography. Tob. Sci. 18:
19-
Hrdlicka, J., and J. Kuca. 1965. The changes of carbonyl
compounds in the heat-processing of meat. Poultry Sci.
44:27.
-------
Izard, C. 1973. Recherches sur les effets mutagenes de
1' acroleine et des ses deux epoxydes: le glycidol et le
glycidal, sur Saecharomyces cerevisiae, C.R. Acad. Sci.
Ser. D. 276: 3(3771
Izard, C., and C. Libermann. 1978. Acrolein. Mutat. Res.
47: 115.
Jaeger, R. J., and S. D. Murphy. 1973. Alterations of
barbiturate action following 1,1-dichloroethylene, corti-
costerone, or. acrolein. Arch. Int. Pharmacodyn. Ther. 205:
281.
Kantemirova, A. E. 1975. Illness with temporary work dis-
ability in workers engaged in acrolein and raethylmercaptopro-
pionaldehyde (MMP) production. Tr. Volgogr. Cos. Med. Inst.
26: 79.. Chem. Abst. 88:.109868g.
Kaye, C. M. 1973.. Biosynthesis of raercapturic acids from
allyl alcohol, allyl esters, and acrolein. Biochem. Jour.
134: 1093.
Kaye, C. M., and L. Young. 1972. Synthesis of raercapturic
acids from allyl compounds in the rat. Biochem. Jour. 127:
87.
Kishi, M., et al. 1975. Effects of inhalation of the vapor
from heated edible oil on the circulatory and respiratory
systems in rabbits. Shokuhin Eiseigaku Zasshi. 16: 313.
Low, E.. S., et al. 1977. Correlated effects of cigarette
smoke components on alveolar macrophage adenosine triphos-
phatase activity and phagocytosis. Am. Rev. Respir. Dis..
115: 963.
Macek, K. J., et al. 1976. Toxicity of four pesticides
to water fleas and fathead minnows: Acute and chronic toxi-
city of acrolein, heptachlor, endosulfan, and tribluralin
to the water flea (Daphnia magna) and the fathead minnow
(Primephales promelas).EPAbTni/3-76-099. U.S. Environ.
Prot. Agency.
Munsch, N., et al. 1973. Effects of acrolein on DNA syn-
thesis i£ vitro. Fed. Eur. Biochem. Soc. Lett. 30: 286.
Munsch, N., et al. 1974. In vitro binding of tritium labeled
acrolein to regenerating rat liver DNA polymuase. Experi-
mentia 30: 1234.
National Cancer Institute. 1979. Personal communication
from Sharon Feeney.
Newell, G. W. 1958. Acute and subacute toxicity of acro-
lein. Stanford Res. Ins. SRI Project No. 5-868-2. Summar-
ized in Natl. Acad. Sci. 1977.
/://
-------
Pattle, R. E., and H. Cullumbine. 1956. Toxicity of some
atmospheric pollutants. Brit. Med. Jour. 2: 913.
Pietruszko, R., et al. 1973. Comparison of substrate specifi-
city of alcohol dehydrogenases from human liver, horse liver,
and yeast towards saturated and 2-enoic alcohols and alde-
hydes. Arch. Biochem. Biophys. 159: 50.
Rapoport., I. A. 1948. Mutations under the influence of
unsaturated aldehydes. Dokl. Akad. Nauk. (U.S.S.R.), 61:
713. Summarized in Izard and Libermann, 1978.
Renzetti, N. A., and R. J. Bryan. 1961. Atmospheric samp-
ling for aldehydes and eye irritation in Los Angeles smog
- 1960. Jour. Air Pollut. Control Assoc. 11: 421.
Rosenthaler, L., and G. Vegezzi. 1955. Acrolein in alco-
holic liquors. Z. Lebensm.-Untersuch. u. - Forsch. 102:
117.
Schuck, E. A., and N. A. Renzetti. 1960. Eye irritants
formed during photooxidation of hydro-carbons in the pre-
sence of oxides of nitrogen. Jour. Air Pollut. Control
Assoc. 10: 389.
Sim, V. M., and R. E. Pattle. 1957. Effect of possible
smog irritants on human subjects. Jour. Am. Med. Assoc.
165: 1908.
Sprince, H., et al. 1978. Ascorbic-acid and cysteine pro-
tection against aldehyde toxicants of cigarette smoke.
Fed. Proc. 37: 247.
Standen, A., ed. 1967. Kirk-Othmer Encyclopedia of Chemi-
cal Technology. Interscience Publishers, New York.
Szot, R. J., and S. D. Murphy. 1970. Phenobarbital and
dexamethasone inhibition of the adrenocortical response
of rats to toxic chemicals and other stresses. Toxicol.
Appl. Pharmacol. 17: 761.
Tillian, H. M., et al. 1976. Therapeutic effects of cys-
teine adducts of alpha, beta-unsaturated aldehydes on ehr-
lich ascites tumor of mice. Eur. Jour. Cancer 12: 989.
U.S. EPA. 1979. Ambient Water Quality Criteria: Acrolein.
(Draft)
Weast, R. C., ed. 1975. Handbook of chemistry and physics.
56th ed. CRC Press, Cleveland, Ohio.
Weber-Tschopp, A., et al. 1976a. Air pollution and irri-
tation due to cigarette smoke. Soz.-Praeventivmed 21: 101.
s-ur
-------
Weber-Tschopp, A., et al. 1976b. Objective and subjective
physiological effects of passive smoking. Int. Arch. Occup,
Environ. Health 37: 277.
Weber-Tschopp, A., et al. 1977. Experimental irritating
effects of acrolein on man. Int. Arch. Occup. Environ.
Health 40: 117.
Whitehouse, M. W., and F.W.J. Beck. 1975. Irritancy of
cyclophosphamide-derived aldehydes (acrolein, chloracetalde-
hyde) and their effect on lymphocyte distribution ui vivo;
Protective effect of thiols and bisulfite ions. Agents
Actions 5: 541.
5V*
-------
No. 7
Acrylonitrile
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
7-1
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards fron 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.
7-4
-------
SPECIAL NOTATION
U.S. EPA's Carcinogen Assessment Group (CAG) has evaluated
acrylonitrile and has found sufficient evidence to indicate
that this compound is carcinogenic.
7-3
-------
ACRYLONITRILE
Summary
Acrylonitrile is the most extensively produced aliphatic nitrile and
ranks 45th on the list of high-volume chemicals produced in the U.S. Chron-
ic exposure to acrylonitrile produces mild liver damage and functional dis-
orders of the central nervous system, cardiovascular and hemopoietic sys-
tems. Acrylonitrile has shown mutagenic activity in Drosophila and bacter-
ia. This compound is teratogenic in rats whether exposure is by inhalation
or ingestion in drinking water. There are both animal and epidemiologic
data to suggest "that acrylonitrile may be a human carcinogen.
The fathead minnow has an observed 96-hour LC-Q value ranging from
10,100 to 18,100 ug/1 depending on test condition and a 30-day LC5Q value
of 2,600 ug/1. For the freshwater invertebrate, Daphnia maqna, a reported
48-hour LC5Q value is 7,550 ug/1 with no adverse effects to concentrations
as high as 3,600 ug/1 in a life cycle test. A saltwater fish has an observ-
ed 96-hour LCcQ of 24,500 jug/1. A bluegill in a 28-day study bioconcen-
trated acrylonitrile 48-fold with a half-life of 4-7 days.
7-V
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ACRYLONITRILE
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Acrylonitrile (U.S. EPA, 1979).
Acrylonitrile (CH2=CHCN) is an explosive, flammable liquid having a
normal boiling point of 77°C and a vapor pressure of 80 mm Hg (20°C).
Currently, 1.6 billion pounds per year of acrylonitrile are manufactured in
the United States. The major use of acrylonitrile is in the manufacture of
copolymers for the production of acrylic and modacrylic fibers. Acryloni-
trile has been used as a fumigant; however, all U.S. registrations for this
use were voluntarily withdrawn as of August 8, 1978 (U.S. EPA, 1979).
II. EXPOSURE
A. Water
While no data on monitoring of water supplies for the presence of
acrylonitrile were found in the literature, potential problems may exist.
Possible sources of acrylonitrile in the aqueous environment are: (a) dump-
ing of chemical wastes, (b) leaching of wastes from industrial landfills,
(c) leaching of monomers from polymeric acrylonitrile, and (d) precipitation
from rain. Acrylonitrile is short-lived in the aqueous environment; a 10
ppm solution was completely degraded after 6 days in Mississippi River water
(Midwest Research Institute, 1977).
B. Food
There is no data on the levels of acrylonitrile in food. However,
acrylonitrile may contaminate food by leaching of the monomer from polyacry-
lonitrile containers (National Resources Defense Council, 1976). The U.S.
EPA (1979) has estimated the weighted average bioconcentration factor* for
-------
acrylonitrile to be 110 for the edible portions of fish and shellfish con-
sumed by Americans. This estimate is based on steady-state bioconcentration
studies in bluegills.
C. Inhalation
NIOSH (1978) estimated that 125,000 workers are exposed to acrylo-
nitrile each year. Acrylonitrile may be liberated to the atmosphere via
industrial processes or by the burning of polyacrylonitrile fiber (Monsanto,
1973). Data could not be found in the available literature regarding the
concentrations of acrylonitrile in ambient air.
III. PHARMACOKINETICS
A. Absorption
When orally administered to rats, essentially all of the acryloni-
trile is absorbed (Young, et al. 1977).
.8. Distribution
In rabbits, after administration of a 30 mg/kg dose, acrylonitrile
rapidly disappeared from the blood; only 1 mg/kg remained after 4 hours
(Hashimoto and Kanai, 1965). In rats the metabolites of acrylonitrile dis-
tributed to the stomach wall, erythrccytes, skin, and liver (Young, et al.
1977). .
C. Metabolism
Earlier reports (Giacosa, 1883; Maurice, 1900) indicated that most
aliphatic nitriles are metabolized to cyanide which is then detoxified to
thiocyanate. A more recent report concluded that acrylonitrile exerts its
toxicity by the metabolic release of cyanide ion, and that the relative abi-
lity of various species to convert CN~ to SCN" determined their suscep-
tibility to the toxic action of acrylonitrile (Brieger, et al. 1952). Other
facts, however, suggest that acrylonitrile toxicity is due in part to the
-------
acrylonitrile molecule itself or other unknown metabolite(s) rather than
just to the cyanide functional group (U.S. EPA, 1979). In a comprehensive
tracer study with rats Young, et al. (1977) found three uncharacterized
metabolites" as well as CCL after acrylonitrile administration. Also, cya-
noethylated mercapturic acid conjugates have been detected after administra-
tion of acrylonitrile (U.S. EPA, 1979).
D. Excretion
Urinary excretion of thiocyanate after acrylonitrile administration
ranges from 4-33 percent of the administered dose --depending on the species
(U.S. EPA, 1979). Urinary excretion also depends on route of administration
(Gut, et al. 1975).
IV. EFFECTS
A. Carcinogenicity
In two studies rats received acrylonitrile in the drinking water at
concentrations of 0, 35, 100 and 300 mg/1, which is equivalent to daily dos-
ages of approximately 4, 10, 30 mg/kg body weight respectively, excess mam-
mary tumors and tumors of the ear canal and nervous system were noted (Nor-
ris, 1977; Quast, et al. 1977). Both the intermediate and the highest doses
produced increased tumor incidences. In rats administered acrylonitrile in
olive oil by stomach tube at 5 mg/kg body weight 3 times per week for 52
weeks, a slight enhancement of the incidence of mammary tumors, forestomach
papillomas and acanthomas, skin carcinomas, and encephalic tumors has been
repprted (Maltoni, et al. 1977). Also, exposure of rats by inhalation (40,
20, 10, and 5 ppm for 4 hours daily, 5 times/week) for 52 weeks caused in-
creases in tumor incidence (Maltoni, et al. 1977). It should be pointed out
»
that possible impurities found in the acrylonitrile used by various investi-
gators might determine the carcinogenic effect. The specific role of these
impurities has not yet been determined -(U.S. EPA, 1979).
-------
Retrospective studies on workers in a textile fiber plant (O'Berg,
1977) and on workers in the polymerization recovery and laboratory areas of
a B.F. Goodrich plant (Monson, 1977) have shown higher than expected inci-
dences of cancers of all sites in workers exposed to acrylonitrile. The
greatest increase was noted with lung cancer. It should be noted that these
workers were exposed to other chemicals in their working environment.
B. Mutagenicity
Acrylonitrile is a weak mutagen in Drosophila melanoqaster (Benes
and Sram, 1969); although toxicity limited this testing. Milvy and Wolff
(1977) reported mutagenic activity for acrylonitrile in Salmonella typhimur-
ium with a mammalian liver-activating system. In Escherichia coli mutagenic
activity was observed without an activating system (Venitt, et al. 1977).
C. Teratogenicity
Studies in pregnant rats demonstrated that acrylonitrile adminis-
tered by gavage at 65 mg/kg/day caused fetal malformations (Murray, et al.
1976). These malformations included acaudea, short-tail, short trunk, miss-
ing vertebrae, and right-sided aortic arch. In a subsequent study, Murray,
et al. (1978) concludad that in pregnant rats exposed to 0, 40, or 80 ppm of
acrylonitrile by inhalation, teratogenic effects in the offspring were seen
at 80 ppm but not 40 ppm. Significant maternal toxicity was found at both
80 and 40 ppm, as well as in the previous study at 65 mg/kg/day.
0. Other Reproductive Effects
Pregnant rats receiving 500 ppm acrylonitrile in their drinking
«.
water showed reduced pup survival, possibly due to a maternal toxicity
(Beliles and Mueller, 1977).
-------
E. Chronic Toxicity
Knoblock, et al. (1972) observed a perceptible change in peripheral
blood pattern, functional disorders in the respiratory and cardiovascular
systems, and the excretory system, as well as signs of neuronal lesions in
the central nervous system of rats and rabbits breathing acrylonitrile (50
mg/m air) for 6 months. Babanov, et al. (1972) reported that inhalation
of acrylonitrile vapor (0.495 mg/m , 5 hours/day, 6 days/week) for 6
months resulted in central nervous system disorders, increased erythrocyte
count, and decreased leukocyte count in rats. Workers exposed for long per-
iods of time to acrylonitrile have subjective complaints including headache,
fatigue, nausea and weakness, as well as clinical symptoms of anemia, jaun-
dice, conjunctivitis and abnormal values of specific gravity of whole blood,
blood serum and cholinesterase values, urobilinogen, bilirubin, urinary pro-
tein and sugar (Sakarai- and Kusimoto, 1972). In another study, functional
disorders of the central nervous system, cardiovascular and hemopoietic sys-
tems were noted (Shustov and Mavrina, 1975). Sakarai and Kasumoto (1972)
concluded that acrylonitrile exposures at levels of 5-20 ppm caused mild
liver injury and probably a cumulative general toxic effect.
F. Other Relevant Information
HCN and CO were found to enhance acrylonitrile toxicity in experi-
mental animals (Yamamoto, 1976) as well as in workers engaged in acryloni-
trile production (Ostrovskaya, et al. 1976).
V. Aquatic Toxicity
A. Acute Toxicity
The 96-hour LC5Q values of fathead minnows (Pimephales promelas)
were 10,100 and 18,100 ug/1 for flow-through and static tests, respectively,
and 14,300 and 18,100 ug/1 for hard (330 mg/1) and soft (29 mg/1) waters,
7-r
-------
respectively (Henderson, et al. 1961). A reported 48-hour LC5Q for Daoh-
nia maqna is 7,550 ug/1 (U.S. EPA, 1978). The saltwater pinfish (Lagodon
rhbmboides) has an observed 96-hour LC5Q value of 24,500 jug/1 in a static
concentration unmeasured test (Oaugherty and Garrett, 1951).
B. Chronic Toxicity
Daphnia maqna has been exposed for its life cycle and the results
indicate no adverse effects at concentrations as high as 3,600 jug/1 (U.S.
EPA, 1978). Henderson, et al. (1961) observed a 30-day LC-g value of
2,600 pg/1 with Pimephales promelas (fathead minnows). No chronic test data
are available for saltwater species.
C. Plant Effects
Pertinent data could not be located in the available literature on
the sensitivity of plants to acrylonitrile.
D. Residues
In the only reported study, the bluegill (Lepomis macrochirus) was
exposed for 28 days and the determined whole body bioconcentration factor
was 48, with a half-life between 4-7 days (U.S. EPA, 1978).
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
The American Conference of Governmental Industrial Hygienists
threshold limit value (TLV) (ACGIH, 1974) for acrylonitrile is 20 ppm. In
»
January, 1978, the Occupational Safety and Health Administration (OSHA) an-
nounced an emergency temporary standard for acrylonitrile of 2 ppm averaged
-------
over an eight-hour period. Based on rat data (Norris, 1977; Quast, et al.
1977; Maltoni, et al. 1977), and using the "one-hit" model, the U.S. EPA
(1979) has estimated levels of acrylonitrile in ambient water which will re-
sult in specified risk levels of human cancer: •• ~
Exposure Assumptions Risk
(per day)
0
2 liters of drinking water
and consumption of 18.7
grams of fish and shellfish.
Consumption of fish and
shellfish only..
Levels and Corresponding Draft Criteria
10-7
0.008 x
10-* ng/1
0.016 x
10-* ng/1
10-6
0.08 x
10-* ng/1
0.16 x
10-* ng/1
10-5
0.8 x
10-* ng/1
1.6 x
10-* ng/1
B. Aquatic
For acrylonitrile, the draft criterion to protect freshwater aquat-
ic life is 130 ug/1 as a 24-hour average, and the concentration should not
exceed 300 ug/1 at any time. To protect saltwater species, the draft cri-
terion is 130 ug/1 as a 24-hour average, with the concentration not to exceed
290 ug/1 at any time (U.S. EPA, 1979).
-------
ACRYLONITRILE
REFERENCES
Babanov, G.P., et al. 1972. Adaptation of an organism
to acylonitrile at a low concentration factor in an indus-
trial environment. Toksikol. Gig. Prod. Neftekhim. 45:
58.
Beliles, R.P., and S. Mueller. 1977. Three-generation
reproduction study of rats receiving acrylonitrile in drink-
ing water. Acrylonitrile progress report second generation.
Submitted by Litton Bionetics, Inc. to the Manufacturing
Chemists Association. LBI Project No. 2660. November, 1977.
Benes, V., and R. Sram. 1969. Mutagenic activity of some
pesticides in Drosophila melanogaster. Ind. Med. Surg.
38: 442.
Brieger, et al. 1952. Acrylonitrile: Spectrophotometric
determination, acute toxicity and mechanism of action.
Arch. Indust. Hyg. Occup. Med. 6: 128.
Daugherty, P.M., Jr., and J.T. Garrett. 1951. Toxicity
levels of hydrocyanic acid and some industrial by-products.
Tex. Jour. Sci. 3: 391.
Giacosa, P. 1883. Toxicity of aliphatic nitriles. Hoppe-
Seyle 2: 95.
Hashimoto, K., and R. Kanai. 1965. Toxicology of acrylo-
nitrile: metabolism, mode of action, and therapy. Ind. Health
3: 30.
Henderson, C., et al. 1961. The effect of some organic
cyanides . (nitriles) on fish. Eng. Bull. Ext. Ser. Purdue
Univ. No. 106: 130.
Knobloch, K., et al. 1972. Chronic toxicity of acryloni-
trile. Med. Pracy 23: 243.
Maltoni, C., et al. 1977. Carcinogenicity bioassays on
rats of acrylonitrile administered by inhalation and by
ingestion. La Medicina del Lavoro 68: 401.
Meurice, J. 1900. Intoxication and detoxification of dif-
ferent nitriles. Arch. Internat. de Pharmacodynamie et
de Therapie 7: 2.
Midwest Research Institute. 1977. Sampling and analysis
of selected toxic substances. Section V. Sampling and
analysis protocol for acrylonitrile. Progress Report No.
13, Oct. 1-31, 1977. EPA Contract No. 68-01-4115, MRI Pro-
ject No. 4280-C(3).
-------
Milvy, P., and M. Wolff. 1977. Mutagenic studies with
acrylonitrile. Mutation Res. 48: 271.
Monsanto Company. July 19, 1973. Environmental Impact
of Nitrile Barrier Containers, LOPAC: A case study. Monsanto
Co. St. Louis, Missouri.
Monson, R.R. November 21, 1977. Mortality and Cancer Mo-
bidity among B.F. Goodrich White Male Union Members who
ever worked in Departments 5570 through 5579. Report to
B.F. Goodrich Company and to the United Rubber Workers.
Federal Register No. 43FR45762 (see OSHA Dockit H-108, ex-
hibits 67 and 163).
Murray, F.J., et al. 1976. Tertologic evaluation of acrylo-
nitrile monomer given to rats by gavage. Report from Toxi-
cology Research Lab., Dow Chem.
Murray, F.J., et al. 1978. Teratologic evaluation of in-
haled acrylonitrile monomer in rats. Report of the Toxi-
cology Research Laboratory, Dow Chemical U.S.A. Midland,
Michigan. May 31, 1978.
National Resources Defense Council. 1976. Pop bottles:
The plastic generation—a study of the environmental and
health problems of plastic beverage bottles, p. 33.
NIOSH. 1978. A Recommended Standard for Occupational Expo-
sure to Acrylonitrile. DREW (NIOSH) Publication No. 78-116,
U.S. Government Printing Office.
Norris, J.M. 1977. Status report on two-year study incor-
porating acrylonitrile in the drinking water of rats. Health
Environ. Res. The Dow Chemical Company.
O'Berg, M. 1977. Epidemiologic studies of workers exposed
to acrylonitrile: Preliminary results. E.I. Du Pont de
Nemours & Company.
Ostrovskaya, R.S., et al. 1976. Health status of workers
currently engaged in production of acrylonitrile. Gig.
T. Prof. Zabol. 6: 8.
Quast, J.F., et al. 1977. Toxicity of drinking water con-
taining acrylonitrile in rats: Results after 12 months.
Toxicology Res. Lab., Health and Environmental Res. Dow
Chemical U.S.A.
Sakarai, H., and M. Kusimoto. 1972. Epidemiologic Study
of Health Impairment Among AN Workers. Rodo Kagaku.48: .
273.
Shustov, V.Y., and E.A. Mavrina. 1975. Clinical picture
of chronic poisoning in the production of nitron. Gig. Tr.
Prof. Zabol 3: 27.
7-13
-------
Threshold Limit Values. 1974. TLV's: Threshold Limit
Values for Chemical Substances and Physical Agents in the
Work Room Environment with Intended Changes for 1974. Am.
Conf. Govern. Ind. Hyg.
U.S. EPA. 1978. In-depth studies on health and environ-
mental impacts of selected water pollutants. U.S. Environ.
Prot. Agency. Contract No. 68-01-4646.
U.S. EPA. 1979. Acrylonitrile: Ambient Water Quality
Criteria (Draft).
Venitt, S., et al. 1977. Mutagenicity of acrylonitrile
(cyanoethylane) in Escherichia coli. Mutation Res. 45:
283.
Yamamoto, K. 1976. Acute combined effects of HCN and CO,
with the use of combustion products from PAN (polyacrylo-
nitrile)—gauze mixtures. Z. Rechtsmed. 78: 303.
Young, J.D.,4et al. 1977. The pharmacokinetic and metabolic
profile of C-acrylonitrile given to rats by three routes.
Report of the Toxicological Research Laboratory. Dow Chemi-
cal. Midland, Michigan.
7-11
-------
No. 8
Aldrin
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. EPA1s Carcinogen Assessment Group (CAG) has evaluated
aldrin and has found sufficient evidence to indicate that
this compound is carcinogenic.
-------
ALDRIN •
Summary
Aldrin is a man-made compound belonging to the group of cyclodiene in-
secticides. The chronic toxicity of low doses of aldrin include shortened
lifespan, liver changes, and teratogenic effects. The induction of hepato-
cellular carcinoma in both male and female mice from the administration of
aldrin leads to the conclusion that it is likely to be a human carcinogen.
Aldrin has not been found mutagenic in several test systems although it did
induce unscheduled DNA synthesis in human fibroblasts. The World Health
Organization acceptable daily intake level for aldrin is 0.1 pg/kg/day.
Aldrin is rapidly converted to dieldrin by a number of fresh and salt-
water species. The overall toxicity of aldrin is similar to dieldrin. The
96-hour LC-Q values for freshwater fish vary from 2.2 to 37 pg/1 with in^
vertebrates being one order of magnitude less sensitive. Both marine fish
and plants were susceptible to levels of aldrin corresponding to those of
freshwater fish.
-------
ALDRIN
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Aldrin and Dieldrin (U.S. EPA, 1979a).
Aldrin is a white crystalline substance with a melting point of
104°C. It is soluble in organic solvents. The chemical name for aldrin
is 1,2,3,4,10,10-hexachloro-l,4,4a,5,8,8a-hexahydro-l,4,:5,8-exo-dimethano-
naphthalene. Aldrin is biologically altered in the environment to dieldrin,
a more stable and equally toxic form. For information concerning dieldrin
refer to the dieldrin hazard profile or the draft Ambient Water Quality Cri-
teria Document for Aldrin and Dieldrin (U.S. EPA, 1979a,b).
Aldrin was primarily used as a broad spectrum insecticide until 1974
when the U.S. EPA restricted its use to termite control by direct soil in-
jection, and non-food seed and plant treatment (U.S. EPA, 1979a). From 1966
to 1970 the use of aldrin in the United States dropped from 9.5 x 10 to
5.25 x 103 tons (U.S. EPA, 1979a). This decrease in use has been attri-
buted primarily to increased insect resistance to aldrin and to development
of substitute materials. Although the production of aldrin in the United
States is restricted, formulated products containing aldrin are imported
from Europe (U.S. EPA, 1979a).
II. EXPOSURE
A. Water
Aldrin has been applied to vast areas of agricultural land, and
aquatic areas in the United States and in most parts of the world. As a
result, this pesticide is found in most fresh and marine waters (U.S. EPA,
1979a). Levels of aldrin, ranging from 15 to 18 ng/1 or as high as 407 ng/1
-------
have been found in waters of the United States (U.S. EPA, 1976; leichten-
berg, et al. 1970). The half-life of aldrin in water one meter in depth has
been estimated to be 10.1 days (MacKay and Wolkoff, 1973).
B. Food
The estimated daily dietary intake of aldrin in 16 to 19 year old
males was estimated to be 0.001 mg in 1965 and only a trace amount in 1970
(Natl. Acad. Sci., 1975).
No direct measured bioconcentration factor for aldrin can be ob-
tained because it is rapidly converted to dieldrin by aquatic organisms
(U.S. EPA, 1979a). The U.S. EPA (1979a) has estimated the weighted average
bioconcentration factor of aldrin at 32. This estimate is based on the
octanbl/water partition coefficient for aldrin.
C. Inhalation
Aldrin enters the air through various mechanisms such as spraying,
wind action, water evaporation, and adhesion to particles (U.S. EPA, 1979a).
Ambient air levels of 8 ng/m of aldrin have been reported .(Stanley, et
al. 1971).
0. Dermal
Dermal exposure to aldrin is limited to workers employed during
its manufacture and use as a pesticide. Wolfe, et al. (1572) reported that
exposure in workers is mainly through dermal absorption rather than inhala-
tion. The ban on the manufacture of aldrin in the United States has greatly
reduced the risk of exposure.
III. PHARMACOKINETICS
A. Absorption
Pertinent data could not be located in the available literature
concerning the absorption of aldrin (U.S. EPA, 1979a).
-------
B. Distribution
The distribution of aldrin in humans or animals has not been ex-
tensively studied because aldrin is readily converted to dieldrin in vivo
via epoxidation (U.S. EPA, 1979a). For example, the blood plasma levels of
aldrin were lower than the corresponding blood plasma levels of dieldrin in
six workers just after chronic exposure to aldrin for five weeks (Mick, et
al. 1971).
C. Metabolism
The epoxidation of aldrin to dieldrin.. has been reported in many
organisms including man (U.S. EPA, 1979a). The reaction is NADPH-dependent
and the enzymes are heat-labile (Wong and Terriere, 1965). The metabolic
products of aldrin include dieldrin, as well as aldrin diol, and polar meta-
bolites excreted in the urine and feces (U.S. EPA, 1979a).
D. Excretion
Aldrin is excreted mainly in the feces and to some extent in the
urine in the form of several polar metabolites (U.S. EPA, 1979a). Ludwig,
et al. (1964) reported nine times as much radioactivity in the feces as in
the urine of rats chronically administered 14C-aldrin. A saturation level
was reached in these animals and concentrations of radioactivity in the body
decreased rapidly when feeding was terminated.
Specific values for the half-life of aldrin in humans were not
found in the available literature. However, in humans exposed to aldrin
and/or dieldrin the half-life of dieldrin in the blood was estimated to be
266 days (Jager, 1970). In another study with 12 volunteers ingesting vari-
ous doses of dieldrin, Hunter, et al. (1969) estimated the average dieldrin
half-life to be 369 days.
8-7
-------
IV. EFFECTS
A. Carcinogenicity
Aldrin has induced liver tumors in males and females in various
strains of mice according to reports of four separate feeding studies (Davis
and Fitzhugh, 1962; Davis, 1965; 43 FR 2450; Song and Harville, 1964). Ac-
cording to reports of five studies in two different strains of rats, aldrin
failed to induce a statistically significant carcinogenic response at all
but one site (Deichmann, et al. 1967, 1970; Fitzhugh, et al. 1964; Cleve-
land, 1966; 43 FR 2450).
The only information concerning the carcinogenic potential of
aldrin in man 'is an occupational study by Versteeg and Jager (1973). The
workers had been employed in a plant producing aldrin and dieldrin with a
mean exposure time of 6.6 years. An average time of 7.4 years had elapsed
since the end of exposure. No permanent adverse effects including cancer
were observed.
B. Mutagenicity
Aldrin was found not to be mutagenic in two bacterial assays (S^
typhimurium and §._ coli) with metabolic activation (Shirasu, et al. 1977).
Aldrin did, however, produce unscheduled DNA synthesis in human fibroblasts
with and without metabolic activation (Ahmed, et al. 1977).
C. Teratogenicity
Aldrin administered in single oral doses to pregnant hamsters
caused significant increases in hamster fetal death and increased fetal ano-
malies (i.e., open eye, webbed foot, cleft palate, and others). When a sim-
ilar study was done in mice at lower doses, teratogenic effects were also
•
observed, although these effects were less pronounced (Ottolenghi, et al.
1974).
-------
D. Other Reproductive Effects
Deichmann (1972) reported that aldrin and dieldrin (25 mg/kg diet)
fed to mice for six generations affected fertility, gestation, viability,
lactation and survival of the young.
E. Chronic Toxicity
The other effects produced by chronic administration of aldrin to
mice, rats, and dogs include shortened lifespan, increased liver to body
weight ratios, various changes in liver histology, and the induction of
hepatic enzymes (U.S. EPA, 1979a).
F. Other Relevant Information
Since aldrin and dieldrin are metabolized by way of mixed function
oxidase (MFO), any inducer or inhibitor of the MFO enzymes should affect the
metabolism of aldrin and dieldrin (U.S. EPA, 1979a).
When aldrin is administered with DDT, or after a plateau has been
reached in dogs with chronic DDT
-------
fathead minnows (Pimephales promelas) 32 and 37 jjg/1 (Henderson, et al.
1959). Acute toxicity varies greatly in freshwater invertebrates. In bio-
assays in which the aldrin concentrations were not measured, the observed
48-hour LC5Q -value for Daohnia pulex was 28 ^g/1 (Sanders and Cope, 1966),
and the observed 96-hour LC5Q values ranged from 4,300 to 38,500 ;jg/l for
scud, Gammarus spp. (Sanders, 1969, 1972; Gaufin, et al. 1965).
In flow-through exposures to aldrin, the 48 and 96-hour LC5Q
values for six saltwater fish species ranged from 2.0 to 7.2 pg/1. Inverte-
brate LC5Q values ranged from 0.37 to 33.0 jjg/1 (U:-S. EPA, 1979a).
B. Chronic Toxicity
No entire cycle or embryo-larval tests have been reported for any
fresh or saltwater species (U.S. EPA, 1979a).
C. Plant Effects
An aldrin concentration of 10,000 ^ig/1 reduced the population
growth in 12 days for water meal, Wolffia papulifera (Worthley and Schott,
1971). The productivity of a phytoplankton community was reduced 85 percent
after four hour exposure to l,000pg/l aldrin (Butler, 1963).
0. Residues
No freshwater or saltwater residue studies have been reported for
aldrin (U.S. EPA, 1979a).
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 current exposure level for aldrin set by the Occupational
Safety and Health Administration is a time-weighted average of 250 jjg/m
for skin absorption (37 FR 22139). In 1969, the U.S. Public Health Service
Advisory Committee recommended that the drinking water standard for aldrin
be 17 ^ig/1 (Mrak, 1969). The U.N. Food and Agricultural Organization/World
Health Organization acceptable daily intake for aldrin is 0.1 pg/kg/day
(Mrak, 1969).
The carcinogenicity data of the National Cancer Institute (1976)
(43 FR 2450) were used to calculate the draft water quality criterion for
aldrin which keeps the lifetime cancer risk for humans below 10" . The
concentration for aldrin is 4.6 x 10"2 ng/1 (U.S. EPA, 1979a).
B. Aquatic
Draft criterion has not been proposed directly for aldrin because
of its rapid conversion to dieldrin (U.S. EPA, 1979a).
-------
ALDRIN
REFERENCES
Ahmed, F.E., et al. 1977. Pesticide-induced ONA damage and its repair in
cultured human cells. Mutat. Res. 42: 161.
Butler, P.A. 1963. Commercial fisheries investigations. In: Pesticide and
wildlife studies: A review of Fish and Wildlife Service investigations
during 1961 and 1962. U.S. Fish Wildl. Serv. Circ. 167: 11.
Clark, C.R and R.I. Krieger. 1976. Beta-diethylaminoethyldiphenyl-
propylacetate (SKF 525-A) enhancement of tissue accumulation of aldrin in
mice. Toxicol. Appl. Pharmacol. 38: 315.
Cleveland, F.P. 1966. A summary of work on aldrin and dieldrin toxicity at
the Kettering Laboratory. Arch. Environ. Health. ^.3: 195.
Davis, K.J., 1965. Pathology report on mice for aldrin, dieldrin, hepta-
chlor, or heptachlor epoxide for two years. Internal Memorandum to Or. A.J.
Lehman. U.S. Food Drug Admin.
Davis, K.J. and O.G. Fitzhugh. 1962. Tumorigenic potential of aldrin and
dieldrin for mice. Toxicol. Appl. Pharmacol. 4: 187.
Oeichmann, W.B. 1972. Toxicology of DDT and related chlorinated hydro-
carbon pesticides. Jour. Occup. Med. 14: 285.
Oeichmann, W.B.j et al. 1967. Synergism among oral carcinogens in the
simultaneous feeding of four tumorigens to rats. Toxicol. Appl. Pharmacol.
11: 88.
Deichmann, W.B., et al. 1969. Retention of dieldrin and DDT in the tissues
of dogs fed aldrin and DDT individually and as a micture. Toxicol. Appl.
Pharmacol. 14: 205.
Oeichmann, W.B., et al. 1970. . Tumorigenicity of aldrin, dieldrin and en-
drin in the albino rat. Ind, Med. Surg. 39: 426.
Fitzhugh, O.G., et al. 1964. Chronic oral toxicity of aldrin and dieldrin
in rats and dogs. Food Cosmet. Toxicol. 2: 551.
Gaufin, A.R, et al. 1965. The toxicity of ten organic insecticides to var-
ious aquatic invertebrates. Water Sewage Works 12: 276.
Henderson, C., et al. 1959. Relative toxicity of ten chlorinated hydro-
carbon insecticides to four species of fish. Trans. Am. Fish. Soc. 88: 23.
Hunter, C.G., et al. 1969. Pharmacodynamics of Oieldrin (HEOD). Arch.
Environ. Health 18: 12.
Jager, K.W. 1970. Aldrin, dieldrin, endrin and telodrin: An epidemio-
logical and toxicological study of long-term occupational exposure.
Elsevier Publishing Co. Amsterdam.
-------
Katz, M. 1961. Acute toxicity of some organic insecticides to three
species of salmonids and to the threespine stickleback. Trans. Am. Fish.
Soc. 90: 264.
Leichtenberg, J.J., et al. 1970. Pesticides in surface waters in the
United States - A five-year summary, 1964-1968. Pestic. Monitor. Jour.
4: 71.
Ludwig, G., et al. 1964. Excretion and distribution of aldrin-l^C and
its metabolites after oral administration for a long period of time. Life
Sci. 3: 123.
Macek, K.J., et al. 1969. The effects of temperature on the susceptibility
of bluegills and rainbow trout to selected pesticides. Bull. Environ.
Contam. Toxicol. 4: 174.
MacKay, D. and A.W. Wolkoff. 1973. Rate of evaporation of low-solubility
contaminants from water bodies to atmosphere. Environ. Sci. Technol.
7: 611.
Mick, D.L., et al. 1971. Aldin and dieldrin in human blood components.
Arch. Environ. Health 23: 177.
Mrak, E.M. 1969. Report of the Secretary's commission on pesticides and
their relationship to environment health. U.S. Dept. Health, Edu. Welfare, '
Washington, D.C.
National Academy of Sciences, National Research Council. 1975. Vol. 1 Pest
control: An assessment of present and alternative technologies. Contem-
porary pest control practices and prospects. Natl. Acad. Sci. Washington,
O.C.
Ottolenghi, A.O., et al. 1974. Teratogenic effects of aldrin, dieldrin and
endrin in hamsters and mice. Teratology 9: 11.
Sanders, H.O. 1969. Toxicity of pesticides to the crustacean, Gammarus
Lacustris. Bur. Sport Fish. Wildl. Tech. Pap. No. 25.
Sanders, H.O. 1972. Toxicity of some insecticides to four species of mala-
costracan crustaceans. Bur. Sport Fish. Wildl. Tech. Pap. No. 66.
Sanders, H.O. and O.B. Cope. 1966. Toxicities of several pesticides to two
species of cladocerans. Trans. Am. Fish. Soc. 95: 165.
Shirasu, Y., et al. 1977. Mutagenicity screening on pesticides and modifi-
cation products: A basis of carcinogenicity evaluation. Page 267 in H.H.
Hiatt, et al. (eds.). Origins of Human Cancer. Cold Spring Harbor Lab. New
York.
Song, J. and W.E. Harville. 1964. The carcinogenicity of aldrin and diel-
drin on mouse and rat liver. Fed. Proc. 23: 336.
-------
Stanley, C.W., et al. 1971. Measurement of atmospheric levels of pesti-
cides. Environ. Sci. Technol. 5: 430.
U.S. EPA. 1976. National interim primary drinking water regulations. U.S.
Environ. Prot. Agency. Publ. No. 570/9-76-003.
U.S. EPA. 1979a. Aldrin/Oieldrin Ambient Water Quality Criteria Document.
Washington, D.C. (Draft).
U.S. EPA. 1979b. Environmental Criteria and Assessment Office. Dieldrin:
Hazard Profile. (Draft).
Versteeg, J.P.J. and K.w. Jager. 1973. Long-term occupational exposure to
the insecticides aldrin, dieldrin, endrin, and telodrin, Br. Jour. Ind.
Med. 30: 201.
Wolfe, H.R., et al. 1972. Exposure of spraymen to pesticides. Arch.
Environ. Health. 25: 29.
Wong, D.T. and -L.C. Terriere. 1965. Epoxidation of aldrin, isodrin, and
heptachlor by rat liver microsomes. Biochem. Pharmacol. 14: 375.
Worthley, E.G. and C.O. Schott. 1971. The comparative effects of CS and
various pollutants on freshwater phytoplankton colonies of Wolffia
papulifera Thompson. Dep. Army. Edgewood Arsenal Biomed. Lab. Task
IW662710-AD6302.
-------
No. 9
Allyl Alcohol
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.
-------
ALLYL ALCOHOL
Summary
Allyl alcohol is a severe irritant to the mucous membranes at high con-
centrations. Hepatotoxicity has been seen after oral and inhalation
exposures, however, results indicate that this effect may not be
cumulative. Allyl alcohol is also absorbed percutaneously.
Information on the carcinogenic, mutagenic, teratogenic or other repro-
ductive effects of allyl alcohol was not found in the^available literature.
Data concerning the effects of allyl alcohol to aquatic organisms were
not found in the available literature.
7-3
-------
I. INTRODUCTION
This profile is based on computerized searches of Toxline, Biosis
and Chemical Abstracts, and a review of other available appropriate
information sources as available.
Allyl alcohol (molecular weight-58.08) is a limpid liquid with
pungent odor. It is soluble in water, alcohol and ether, has a melting
point of -50°c and a boiling point of 96-97°C (Sax, 1979).
The major uses of allyl alcohol are in the manufacture of allyl
compounds, war gas, resins, and plasticizers (Windholz, 1976). Sixty kt.
are used in this country per year, of which 50 kt. are used to manufacture
glycerol (Kirk and Othmer, 1963).
After several years of storage, allyl alcohol polymerizes into a
substance that is soluble in chloroform but not water. When treated with
ether this substance becomes brittle (Windholz, 1976).
II. EXPOSURE
Pertinent data were not found in the available literature on air
or water exposure.
Esters of allyl alcohol are used as food flavorings. Natural de-
rivatives of allyl alcohol are widely distributed in vegetable material
(Lake, et al. 1978).
III. PHARMACOKINETICS
A. Absorption and Distribution
Pertinent data were not found in the available literature.
8. Metabolism
It has been suggested that allyl alcohol is completely metabolized
and that acrolein might be an intermediate metabolite (Browning, 1965). *The
rate of metabolism in rats was found to be about 23 mg/kg/hr. during con-
stant intravenous infusion (Carpanini, et al. 1978).
9-y
-------
C. Excretion
Allyl alcohol was not found in the urine of animals that had been
dosed subcutaneously or intravenously with the compound (Browning, 1965).
Other pertinent data were not found in the available literature.
IV. EFFECTS
A. Carcinogenicity, Mutagenicity, Teratogenicity, and Reproductive
Effects
Information on the carcinogenic effects of allyl alcohol was not
found in the available literature.
B. Chronic Toxicity
Lake, et al. (1978) administered allyl alcohol to rats by gastric
intubation. The rats were dosed daily for 1, 10, or 28 days. Liver homo-
genates from treated animals were analyzed for enzyme activity. Adminis-
tration for one day produced marked periportal necrosis, but repeated ad-
ministration for 10 or 28 days did not seem to increase the damage.
Allyl alcohol administration in the drinking water at a dose of 72
mg/kg/day caused weight loss, transient pulmonary rales, crustiness of the
eyelids, and local areas of liver necrosis (Browning, 1965).
Rats exposed to 40, 60, or 100 ppm of allyl alcohol by inhalation
showed signs of acute mucous membrane irritation, such as gasping and nasal
discharge. At the 100 ppm dose, the animals died after 10 exposures
(Browning, 1965). No gross toxicity was seen at 5 or 10 ppm, 5 days a week
for 13 months in rats, rabbits, guinea pigs, and dogs. However, mild
reversible degenerative changes in the liver and kidney were seen at the
seven ppm dose. A dose of 50 ppm was lethal to rats after 30 days
(Torkelson, et al. 1959).
-------
Carpanini, et al. (1978) gave rats doses of allyl alcohol 50, 100,
200, or 800 ppm im the drinking water for 15 weeks. Weight loss was seen in
males given 100, 200, or 800 ppm and females given 800 ppm. Food
consumption values were lower than the controls in males at 200 ppm and 800
ppm and females at 800 ppm. A dose-related decrease in water consumption
was seen in all treated animals. Minor changes were seen in the liver,
kidneys, and lungs of both treated and control groups upon histological
examination.
C. Acute Toxicity . v
Oral LD50's of allyl alcohol have been found to be
64-100 mg/kg for rats, 96-139 mg/kg for mice, and 52-71 mg/kg for rabbits;
43 mg/kg was lethal to dogs. Intraperitoneal LDgg's were 42 mg/kg for
rats and 60 mg/kg for mice. In rabbits an LD-g of 53-89 mg/kg was found
by percutan- eous absorption (Carpanini, et al. 1978). Inhalation of 1000
ppm was lethal to rabbits and monkeys after 3 to 4 hours. Erythema of the
conjunctiva and swelling of the cornea are seen in the eye. after exposure to
allyl alcohol, however, no permanent damage was noted. Application to the
skin caused only mild erythema. Intravenous injection produced a drop in
blood pressure. Injection of 40 minims in a 20 percent saline solution
caused fluctuations in the blood pressure, of rabbits resulting in violent
convulsions. Vomiting, diarrhea, convulsions, apathy, ataxia, lacrimation
and coma are seen after oral administration. Few cases of serious injury
due to inhalation have been reported, however, because concentrations that
would cause severe damage in a short period of time are painful to the eyes
and nose. Five ppm are detectable by irritation and 2 ppm by odor
»
(Browning, 1965).
Moderate air contamination has been found to cause lacrimation,
pain around the eyes and blurred vision in man lasting up to 48 hours
(Carpanini, et al. 1978).
• ^
9-C
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D. Other Relevant Information
Allyl alcohol has an unusual effect on the central nervous system
of mice and rats. The effect is seen as apathy, unwillingness to move,
anxiety, and no interest in escaping. It is apparently different from nar-
cosis seen with other agents (Dunlap, et al. 1958).
V. AQUATIC. TOXICITY
Pertinent data were not found in the available literature.
VI. EXISTING GUIDELINES
The recommended maximum atmospheric concentration (8 hours) is 2
ppm (Indust. Hyg. Assoc., 1963).
7-7
-------
REFERENCES
Browning, E.C. 1965. Toxicity and Metabolism of Industrial Solvents.
Elsevier Publishing Co., Amsterdam, p. 739.
Carpanini, F.M.B., et al. 1978. Short-term toxicity of allyl alcohol in
rats. Toxicol. 9: 29.
Dunlap, M.K., et al. 1958. The toxicity of allyl alcohol. A.M.A. Archives
of Indust. Health. 18: 303.
Industrial Hygiene Association. 1963. Hygienic Guide Series: Allyl
Alcohol. Indust. Hyg. Assoc. Jour. 24: 636.
Lake, B.C., et al. 1978. The effect of repeated administration on allyl
alcohol-induced hepatotoxicity in the rat. Biochem. Soc. Trans. 6: 145. .
Sax, N.I. 1979. Dangerous Properties of Industrial Materials. 5th ed.
Von Nostrand Reinhold Co., New York.
Torkelson, T.R., et al. 1959. Vapor toxicity of allyl alcohol as deter-
mined on laboratory animals. Indust. Hyg. Assoc. Jour. 20: 224.
Verschueren, K. 1977. Handbook of Environmental Data on Organic Chem-
icals. Von Nostrand Reinhold Co., New York.
Windholz, M. (ed.) 1976. Merck Index. 9th ed. Merck and Co., Inc.,
Rahway, New Jersey.
f-r
-------
No. 10
Antimony
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.
-------
ANTIMONY
Summary
The adverse health effects most commonly associated with exposure to
antimony are pulmonary, cardiovascular, dermal, and certain effects on
reproduction, development, arid longevity. Cardiovascular changes have
been well-established with exposure to antimony and probably represent
v
the most serious threat to human health. Antimony has not been assoc-
iated with carcinogenic effects. The lowest observed effect level for
antimony in the drinking water of rats was 5 ppm. A draft criterion of
145 jug/1 has been recommended for antimony in water based on an accep-
table daily intake of antimony from water, fish, and shellfish for man of
294 pg.
Antimony is highly toxic to aquatic organisms at a concentration
ranging from 19 mg/1 to 530 mg/1. Chronic values for antimony in fresh-
water organisms range from 0.8 mg/1 to 5.4 mg/1.
lo-J
-------
ANTIMONY
I. INTRODUCTION
This profile is based primarily on the Ambient Water Quality Criteria
Document for Antimony (U.S. EPA, 1979). The health hazards of antimony
and its compounds have also been recently reviewed by the National Ins-
titute for Occupational Safety and Health (NIOSH, 1?78).
Antimony (Sb; molecular weight 121.8) is a silvery, brittle, solid
belonging to group VB of the periodic table and lies between arsenic and
bismuth. It is classified as both a metal and a metalloid, and its prin-
cipal oxidation states are +3 and +5. Antimony has a boiling point of
1366°C and a melting point of 636°C. Most inorganic compounds of an-
timony are either only slightly water soluble or decompose in aqueous
media.
Antimony reacts with both sulfur and chlorine to form the tri-and
pentavalent sulfides and chlorides. Oxidation to antimony trioxide
(stibine), the major commercial oxide of antimony, is achieved under
controlled conditions.
Consumption of antimony in the United States is on the order of
40,000 metric tons per year (Callaway, 1969), of which half is obtained
from recycled scrap and the balance mainly imported. Use of antimony in
the United States is directed chiefly to the manufacture of ammunition,
storage batteries, matches and fireworks, and in the fire-proofing of
textiles.
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II. EXPOSURE
A. Water
Schroeder (1966) compiled data from surveys of municipal water
supplies in 94 cities and reported that levels averaged less than 0.2
pg/1 in finished water. In a related study, Schroeder and Kraemer (1974)
noted that tap water levels of antimony can be elevated in soft water
supplies due to leaching from plumbing.
B. Food
Because of the wide range of antimony levels in various types of
foods, it is not possible to accurately estimate an average dietary in-
take. Tanner and Friedman (1977) concluded that dietary intake of
antimony is negligible, based upon trace metal food monitoring data from
the U.S. Food and Drug Administration. However, in earlier studies, cal-
culated average dietary intakes were reported at 100 pg per day far man
(Schroeder, 1970) and in the range of 0.25 to 1.28 mg per day for insti-
tutionalized children (Murthy, et al. 1971). In one study on antimony
levels in Italian diets a mean daily value of several micrograms was re-
ported (Clemente, 1976).
C. Inhalation
Antimony is not generally found in ambient air at measurable
concentrations. National Air Sampling Network data for 1966 showed pos-
sibly significant levels at only four urban stations (0.042 to 0.085
pg/m3) (Schroeder, 1970; Woolrich, 1973).
D. Other Routes
The total body burden of antimony arising from all environmental
»
media is apparently very small relative to other trace metals (i.e.,
lead, mercury, cadmium) in the environment. Clemente (1976) published
lo-f
-------
limited data on fecal and urinary levels of antimon \ in selected Italian
populations and concluded that daily intakes were less than 2.0 ug/day.
In addition, data on the bioconcentration potential of antimony in fish
(U.S. EPA, 1978) indicate that no bioaccumulation is likely to occur.
The U.S. EPA (1979) has calculated the weighted average bioconcentration
factor (8CF) for antimony to be 1.4 for the edible portions of fish and
shellfish consumed by Americans. This estimate was based on 25-day bio-
concentration studies in bluegill.
Ill.PHARMACOKINETICS
Absorption of antimony in man and animals is mainly via the respir-
atory and gastrq-intestinal tracts. The extent of absorption is dependent
on factors such as solubility, particle size, and chemical forms
(Felicetti, et al. 1974a; 1974b). Absorption via the GI tract is of the
order of several percent with antimony trioxide, a relatively insoluble
compound , and presumably would be'much greater with soluble antimonials.
Blood is the main carrier for antimony, the extent of partition
between blood .compartments depending on the valence state of the element
and the animal species studied (Felicetti, et al. 1974a). The rodent ex-
clusively tends to concentrate trivalent antimony for long periods in the
erythrocyte (Djuric, et al. 1962). Whatever the species, it can gener-
ally be said that pentavalent antimony is borne by plasma and trivalent
antimony in the erythrocyte. Clearance of antimony from blood to tissues
is relatively rapid, and this is especially true in the case of paren-
teral administration and the use of pentavalent antimony (Casals, 1972;
Abdalla and Saif, 1962; El-8assouri, et al. 1963).
The tissue distribution and subsequent excretion of antimony is a
function of the valence state.
-------
In animals, trivalent antimony aerosols lead to highest levels in the
lung, skeleton, liver, pelt, and thyroid while pentavalent aerosols show
a similar distribution, with the exception of slower uptake by the liver
(Felicetti, et al. 1974a; 1974b; Thomas, et al. 1973).
Parenteral administration to animals shows trivalent antimony accumu-
lating in the liver and kidney as well as in pelt and thyroid (Molkhia
and Smith, 1969; Waitz, et al. 1965).
In man, non-occupational or non-therapeutic exposure shows very low
antimony levels in various tissues with little- evidence of accumulation
(Abdalla and Saif, 1962). Chemotherapeutic use leads to highest accumu-
lation in liver, thyroid, and heart for trivalent antimony.
The biological half-life of antimony in man and animals is a function
of route of exposure, chemical form, and oxidation state. The rat
appears to be unique in demonstrating a long biological half-time owing
to antimony accumulation in the erythrocyte. In other species, including
man, moderate half-times of the order of days have been demonstrated.
While most soft tissues do not appear to accumulate antimony, the skin
does show accumulation, perhaps because of its high content of sulfhydryl
groups. With respect to excretion, injection of trivalent antimony leads
mainly to urinary excretion in guinea pigs and dogs, and mainly fecal
clearance in hamsters, mice and rats.
Pentavalent antimony is mainly excreted via the kidney in most
species owing to its higher levels in plasma.
Unexposed humans excrete less than 1.0 jug antimony daily via urine,
while occupational or clinical exposure may result in markedly increased
amounts.
10-7
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IV. EFFECTS
A. Carcinogenicity
Antimony has not been tested for carcinogenic activity using an
appropriately designed chronic bioassay protocol. However, Shroeder
(1970) indicated that the chronic administration of antimony at 5 ppm in
the drinking water of rats, had no apparent tumorigenic effect. However,
the shortened life span of treated animals (average 106 to 107 days less
than controls) limits the usefulness of these data. Similar results were
also observed in a study with mice chronically exposed to antimony at 5
ppm in the drinking water (Kanisawa and Schroeder, 1569).
A single- epidemiologic investigation has been conducted into the
role of antimony in the development of occupational lung cancer (Oavies,
1973). This retrospective study, which was limited in scope, provided no
definitive information to support the possible role of antimony in lung
cancer development.
B. Mutagenicity
%
Antimony has not been tested for activity in standard muta-
genicity bioassays.
C. Teratogenicity
Little information is available concerning possible teratogenic
effects of antimony. In one study, Casals (1972) observed no effects,
i.e., no fetal abnormalities, following administration of a solution of
antimony dextran glycoside containing 125 or 250 mg Sb/kg to pregnant
rats on days 8 to 15 of gestation.
0. Other Reproductive Effects
»
Aiello (1955) observed a higher rate of premature deliveries*
among female workers engaged in antimony smelting and processing. In
-------
addition, dysmenorrhea was frequently reported among women workers.
Similarly, Belyaeva (1967) reported that a greater incidence of gyneco-
logical disorders was found among antimony smelter workers than in a con-
trol group (77.5 percent vs. 56 percent; significance unknown). Spon-
taneous late abortions occurred in 12 percent of the exposed females com-
pared to 4.1 percent among controls. Average urine levels of antimony
for exposed workers, however, were extremely high, ranging from 2.1 to
2.9 mg/100 ml. Antimony was also found in breast milk (3.3+ 2 mg/10),
placental tissue (3.2 to 12.6 mg/100 mg), amhiotic fluid (6.2 to 2.8
mg/100 mg), and umbilical cord blood (6.3 + 3 mg/100 ml).
In studies with rats exposed either to antimony dust (50 mg/kg,
i.p.) or to antimony trioxide dust (250 mg/m , 4 hours per day for 1.5
to 2 months), Belyaeva (1967) reported increased reproductive failure,
fewer offspring, and damage to the reproductive tissues (ovary and
uterus).
E. Chronic Toxicity
The toxic effects of exposure to antimony have been repeatedly
observed in both humans and experimental rodents. Pulmonary, cardio-
vascular, dermal, and certain effects on reproduction, development, and
longevity are among the health effects most commonly associated with an-
timony exposure.
Cardiovascular changes have been well established following ex-
posure to antimony and probably represent the most serious human health
effects demonstrated thus far (U.S. EPA, 1979). Air concentrations of
10-7
-------
antimony trisulfide exceeding 3 mg/cu m were associated with the induc-
tion of altered ECG patterns and some deaths attributed to myocardial
damage among certain .antimony workers (Brieger, et al. 1954). Also, in
parallel studies on animals, Brieger and coworkers (1954) observed ECG
alterations in rats and rabbits exposed to antimony in air at levels of
3.1 to 5.6 mg/m , 7 hours/day, 5 days/week for at least 6 weeks.
Gross and coworkers (1955) presented evidence for growth retardation
occurring when rats were chronically fed diets containing two percent
antimony trioxide. Other investigators (Schroeder, et al. 1970; Kanisawa
and Schroeder, 1969) reported that oral exposure to 5 ppm of antimony in
drinking water had no effect on the rate of growth of either rats or
mice.. However, the 5 ppm exposure level was effective in producing
slight but significant lifespan shortening in both rats and mice, and
altered blood chemistries in exposed rats. Therefore, the 5ppm exposure
level has been considered the "lowest observed effect level" in animals
that likely approximates the "no effect" level for antimony-induced ef-
fects on growth and longevity.
V. AQUATIC TOXICITY
A. Acute Toxicity
The'data base for antimony and freshwater organisms is small and
indicates that plants may be more sensitive than fish or invertebrate
species.
A 96-hour LCe« of 22,000 /jg/1 was reported for antimony tri-
chloride with the fathead minnow, whereas the value for bluegills and
antimony trioxide is above 530,000 ug/1 (U.S. EPA, 1979). For Daohnia
maqna a 48-hour LC^ value of 19,000 jug/1 and a 64-hour EC5Q value of
19,800 /jg/1 have been reported for antimony trichloride. Another 48-hour
-------
ECcn value for antimony trioxide and Daphnia magna has been reported to
be above 530,000 jug/1 (U.S. EPA, 1979).
B. Chronic Toxicity
No adverse effects on the fathead minnow were observed during an
embryo-larval test with antimony trioxide at the highest test concen-
tration of 7.5 jjg/1 (U.S. EPA, 1978). However, a comparable test with
antimony trichloride produced limits of 1,100 and 2,300 jug/1 for a
chronic value of 800 pg/1. A life cycle test with Daphnia magna and an-
timony trichloride produced limits of 4,200 and.. 7,000 jug/1 for a chronic
value of 5,400/jg/l (U.S. EPA, 1979). Pertinent information could not be
located in the available literature regarding chronic effects of antimony
on saltwater organisms.
C. Plants Effects
The 96-hour EC5Q values for chlorophyll a inhibition and re-
duction in cell number of the freshwater alga, Selenastrum capricornutum
are 610 and 630 pg/1, respectively. This indicates that aquatic plants
may be more sensitive than fish or invertebrate species (U.S. EPA,
1978). No inhibition of chlorophyll a reduction or in cell numbers of
the marine alga, Skeletonema costatum, were observed at concentrations as
high as 4,200;ug/l (U.S. EPA, 1978).
D. Residues
There was no bioconcentration of antimony by the bluegill above
control concentrations during a 28 day exposure to antimony. NO data
have been reported on bioconcentration of antimony in marine species.
VI EXISTING GUIDELINES AND STANDARDS
9
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 may
be changed.
A. Human
Existing occupational standards for exposure to antimony are
reviewed in the recently released NIQSH criteria document, Occupational
Exposure to.Antimony (U.S. Department of Health, Education and Welfare,
T978). "As stated in the NIOSH (1978) document, the American Conference
of Governmental Industrial Hygienists (ACGIH), in 1977, listed the TLV
for antimony as 0.5 mg/m3 along with a notice*- of intended change to a
proposed TLV of 2.0 mg/m for soluble antimony salts. The proposed TLV
was based mainly on the reports of Taylor (1966) and Cordasco (1974) on
accidental poisoning by antimony trichloride and pentachloride, respec-
tively. Proposed limits of 0.5 mg/m for handling and use of antimony
trioxide and 0.05 mg/m for antimony trioxide production were included
in the ACGIH (1977) notice of intended changes.
The Occupational Safety and Health Administration earlier adopted the
1968 ACGIH TLV for antimony of 0.5 mg/m3 as the Federal standard (29
CFR 1910.1000). This limit is consistent with limits adopted by many
other countries as described in Occupational Exposure Limits for Airborne
Toxic Substances - A tabular Compilation of Values from Selected Coun-
tries, a publication released by the International Labour Office in
1977. The NIOSH (1978) document also presented table of exposure limits
from several countries, reproduced here as Table 1; the typical
standard adopted was 0.5 mg/m .
-------
TABLE 1
HYGIENIC STANDARDS OF SEVERAL COUNTRIES FOR
ANTIMONY AND COMPOUNDS IN THE WORKING ENVIRONMENT
CountryStandardQualifications
(mg/m3)
FinlandONot stated
Federal Republic of Germany 0.5 8-hour TWA
Democratic Republic of Germany 0.5 Not stated
Rumania 0.5 Not stated
USSR 0.5 For antimony dust
0.3 For fluorides and
chlorides (tri-and
pentavalent); obli-
gatory control of HF
and HC1
1.0 For trivalent oxides
and sulfides
1.0 For pentavalent
oxides and sulfides
Sweden 0.5 Not stated
USA 0.5
8-hour TWA
Yugoslavia 0.5 Not stated
Modified from Occupational Exposure Limits in Airborne ToxicSub-
stances, International Labour Office.
The 0.5 mg/m level was also recommended as the United States occupa-
tional exposure standard by the NIOSH (1978) criteria document, based
mainly on estimated no-effect levels for cardiotoxic and pulmonary ef-
fects.
Based upon the data presented in the Ambient Water Quality Criteria
Document for Antimony (U.S. EPA, 1979), a recommended draft criterion of
145 pg/1 has been established. This value is based upon an acceptable
daily intake for man of 294 ug, derived from experimental animal studies
in which 5 ppm of antimony produced a slight shortening of lifespan with
no other deserved effects. An uncertainty factor of 100 was used in ex-
»
trapolating from animal data to human health effects.
10-13
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B. Aquatic
The draft criterion for Antimony to protect freshwater aquatic
life as derived using the Guidelines is 120 jug/1 as a 24 hour average and
the concentration should not exceed 1,000 /jg/1 at any time.
A saltwater criterion was not derived (U.S. EPA, 1979)
-------
ANTIMONY
REFERENCES
Abdalla, A., and M. Saif. 1962. Tracer studies with anti-
mony-124 i-n Irian. In; G.E.W. Walstenhalne and M. 0'Conner,
eds., Bilharziasis. Little Brown and Co., Boston, p. 287.
Aiello, G. 1955. Pathology of antimony. Folia Med., Naples
38: 100.
American Conference of Governmental Industrial Hygienists.
1977. Threshold limit values for chemical substances in
workroom air.
Belyaeva, A.P. 1967. The effect of antimony on reproduc-
tion. Gig. Truda Prof. Zabol 11: 32.
Brieger, H., et al. 1954. Industrial antimony poisoning.
Ind. Med. Surg. 23: 521.
Callaway, H.M. 1969. Antimony. In: The Encyclopedia Britan-
nica. Ency. Brit., Inc., 2: 20. "cliicago.
Casals, J.B. 1972. Pharmacokinetic and toxicological studies
of antimony dextran glycoside (RL-712). Brit. Jour. Pharmac.
46: 281.
Clemente, G.F. 1976. Trace element pathways from environ-
ment to man. Jour. Radioanal. Chem. 32: 25.
Cordasco, E.M. 1974. Newer concepts in the management
of environmental pulmonary edema. Angiology 25: 590.
Davies, T.A.L. 1973. The health of workers engaged in
antimony oxide manufacture—a statement. London, Department
of Employment, Employment Medical Adivsory Service, p. 2.
Djuric, D. , et al. 1962. The distribution and excretion
of trivalent antimony in the rat following inhalation.
Arch. Gewerbepath. Gewerbehyg. 19: 529.
El-Bassouri, M. , et al. 1963. Treatment of active urinary
schistosomiasis in children with sodium antimony dimercapto
succinate by the slow method. Trans. Roy. Soc. Trop. Med.
Hyg. 57: 136.
Felicetti, S.W., et al. 1974a. Metabolism of two valence
states of inhaled antimony in hamsters. Amer. Ind. Hyg.
Assoc. Jour. 355: 292. " '
Felicetti, S.W., et al. 1974b. Retention of inhaled anti-
mony-124 in the beagle dog as a function of temperature
of aerosol formation. Health Phys. 26: 525.
-------
Gross, et al. 1955. lexicological study of calcium halo-
phasphate phosphors and antimony tribxide. In: Acute and
chronic toxicity and some pharmacological aspects. Arch.
Indust. Health 11: 473.
International Labour Office. 1977. Occupational exposure
limits for airborne toxic substance - a tabular compilation
of values -from selected countries. Occupa'tional Health
Series No. 37. United Intarnational Labour Office, Geneva.
p. 44.
Kanisawa, M., and H.A. Schroeder. 1969. Life term studies
on the effect of trace elements of spontaneous tumors in
mice and rats. Cancer Res. 29: 892._
Molokhia, M.M., and H. Smith. 1969. Tissue distribution
of trivalent antimony in mice infected, with Schistosoma
Mansoni. Bull. WHO 40: 123. ~ '
Murthy, G.K., et al. 1971. Levels of antimony, cadmium,
chromium, cobalt, manganese and zinc in institutional total
diets. Environ. Sci. and Tech. 5: 436.
NIOSH. 1978. Criteria for a recommended standard: Occupa-
tional exposure to antimony. DHEW (NIOSH) G.P.O. No. 017-
033-00335-1.
Schroeder, H.A. 1966. Municipal drinking water and cardio-
vascular death rates. Jour. Amer. Med. Assoc. 195: 81.
Schroeder, H.A. 1970. A sensible look at air pollution
by metals. Arch. Environ. Health 21: 798.
Schroeder, H.A., and L.A. Kraemer. 1974. Cardiovascular
mortality, municipal water and corrosion. Arch. Enviorn.
Health 28: 303.
Schroeder, H.A., et al. 1970. Zirconium, niabium, antimony
and lead in rats: Life term studies. Jour. Nutr. 100: 59.
Tanner, J.T., and M.H. Friedman. 1977. Neutron activation
analysis for trace elements in foods. Jour. Radioanal.
Chem. 37: 529.
Taylor, P.J. 1966. Acute intoxication from antimony tri-
chloride. Br. Jour. Ind. Med. 23: 318.
Thomas, R.G., et al. 1973. Retention patterns of antimony
in mice following inhalation of particles formed at different
temperatures. Proc. Soc. Exp. Biol. Med. 144(2): 544.
-------
v^V
U.S. EPA. 1978. In-depth studies on health and environ-
mental impacts of selected water pollutants. U.S. Environ.
Prot. Agency, Contract No. 68-01-4646.
U.S. EPA. 1979. Antimony: Ambient Water Quality Criteria.
U.S. Environ. Prot. Agency, Washington, D.C.
Waitz, J.A'. , et al. 1965. Physiological disposition of
antimony after administration of Sb-labeled tartar emetic
to rats, mice and monkeys and the effects of tris (p- amino
phenyl) carbonium pamoate on this distribution. Bull. WHO
33: 537.
Woolrich, P.P. 1973. Occurrence of trace metals in the
environment: an overview. Amer. Ind. Hyg. Assoc. Jour. 34:
217.
16-17
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No. 11
Arsenic
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 (CAG) has evaluated
X
arsenic and has found sufficient evidence to indicate that
this compound is carcinogenic.
11-3
-------
ARSENIC
SUMMARY
Epidemiological studies have shown increased death rates
from lung,cancer in workers exposed to arsenic, probably
through inhalation. Other human studies have shown increased
skin cancers in non-occupationally exposed populations. In-
creased incidence of lymphomas and hemangioendotheliomas are
also occasionally reported.
Arsenicals have produced mutagenic effects in plants,
bacteria, in vitro- leukocyte cultures, and in the lymphocytes
of exposed humans. The teratogenic effects of arsenicals
have been demonstrated in many animal species. An increased
frequency of abortions in pregnant women exposed to arsenic
has been reported in a single study (U.S. EPA, 1979).
The chronic toxic effects of arsenic involve skin hyper-
keratosis, liver damage, neurological disturbances (including
hearing loss), and a gangrenous condition of the extremities
(Blackfoot disease). An increased mortality from cardiovas-
cular disease resulting from chronic arsenic exposure has
been suggested in two studies.
The data base for the toxicity of arsenic to aquatic or-
ganisms is more complete for freshwater organisms, where con-
centrations as low as 128 ug/1 have been acutely toxic to
freshwater fish. A single marine species produced an acute
value in excess of 8,000 ug/1. Based on one chronic life
cycle test using Daphnia magna, a chronic value for arsenic
was estimated at 853 ug/1.
thy
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ARSENIC
I. INTRODUCTION
This profile is based on the Ambient Water Quality Cri-
teria Document for Arsenic (U.S. EPA, 1979).
Arsenic is a gray, crystalline metalloid with a molecu-
lar weight of 74.92, a density of 5,727, a melting point (at
28 atmospheres) of 817°C, and a boiling point (sublimates) of
613°C (Weast, 1975). Arsenic exists in a variety of valence
states; the most common forms include pentavalent (arsenate),
trivalent (arsenite), and -3 valency (arsine). Properties of
some inorganic arsenic compounds are shown in Table 1.
Conditions of low pH, low oxidation-reduction potential,
and low dissolved oxygen in water favor formation of the
lower valency states (arsenite and arsine); more basic, oxy-
genated waters favor the presence of arsenate. Inorganic
arsenic can be converted to organic alkyl-arsenic acids and
to methylated arsines under both aerobic and anaerobic condi-
tions (U.S. EPA, 1979).
Arsenic and its compounds are used in the manufacture of
glass, cloth, and electrical semiconductors, as fungicides
and wood preservatives, as growth stimulants for plants and
animals, and in veterinary applications (U.S. EPA, 1976).
Production is currently 1.8 x 104 metric tons per year
(U.S. EPA, 1979).
Arsenic will persist in some form in the environment.
Inorganic arsenate is thermodynamically favored under normal
conditions over arsenite in water and is a more soluble form
(Ferguson and Gavis, 1972). Both arsenate and arsenite may
be precipitated from water by adsorption onto iron and alum-
-------
Table 1. Properties of Some Inorganic Arsenic Compounds
(Standen, 1967; U.S. EPA, 1976)
Compound
Formula
Water Solubility
Specific Properties
f
Arsenic trioxide As2°3
Arsenic pentoxide
Arsenic hydride
Arsenic(III) sulfide As4S6
Arsenic sulfido AS4S^
Arsenic(V) sulfide AsS
12 x 106 ug/1 @ 0°C
21 x 106 ug/1 @ 25°C
2300 x 106 ug/1 @ 20°C
20 ml/100 g cold water
520 ug/1 @ 18°C
Dissolves in water to form
arsenious acid (H3As03:
K = 8 x 10-1° @ 25°C)
Dissolves in water to form
arsenic acid (H3As04:Ki = 2.5 10~4
K2 = 5.6 x 10~8;
K3 = 3 x 10~13)
This compound and its methyl
derivatives are considered to
be the most toxic.
Burns in air forming arsenic
trioxide and sulfur dioxide;
.occurs naturally as orpiment.
Occurs naturally as realgar.
1400 ug/1 @ 0°C
-------
inum wompounds (U.S. EPA, 1979). Methylated arsines appear
to be volatile and sparingly soluble. Waters, containing high
organic matter may bind arsenic compounds to colloidal humic
matter (U.S. EPA, 1979).
II. EXPOSURE
Arsenic appears to be ubiquitous in 'the environment.
The earth's crust contains an average arsenic concentration
of 5 mgAg (U.S. EPA, 1976). The major sources of arsenic in
the environment are industrial, such as those in the smelting
of non-ferrous ores and in coal-fired power plants that uti-
lize fuel containing arsenic. Substantial arsenic contamina-
tion of water can occur from the improper use of arsenical
pesticides (U.S. EPA, 1979).
Based on available monitoring data, the U.S. EPA (1979)
has estimated the uptake of arsenic by adult humans from air,
water, and food:
Source mg/day
Maximum Conditions Minimum Conditions
Atmosphere .125 .001
Water 4.9 0.002
Food Supply .9 .007
Total 5.925 .010
Contaminated well water, seafood, and air near smelting
plants all present sources of high potential arsenic intake.
The U.S. EPA (1979) has estimated the weighted average
bioconcentration factor (BCF) for arsenic to be 2.3 in the
edible portions of fish and shellfish consumed by Americans.
*
This estimate was based on bioconcentration studies in fresh-
water fish.
11-7
-------
III. PHARMACOKINETICS
A. Absorption
The main routes by which arsenic can enter the body
are inhalation and ingestion. Particle size and solubility
greatly influence the biological fate of inhaled arsenic.
Falk and Kotin (1961) have reported that the optimal range of
particle size for deposition in the lower tracheobronchial
tree is 0.1 to 2 u« Larger particles are trapped by the
mucous membranes of the nose and throat and swallowed;
\
following this, the particles may be absorbed from the
gastrointestinal tract (U.S. EPA, 1979).
Human inhalation studies in terminal lung cancer
patients (Holland, et al. 1959) have indicated that 4.8 to
8.8 percent of inhaled arsenic-74 in cigarette smoke may be
absorbed. Radioactive arsenite inhaled in an aerosol solu-
tion by two patients showed 32 and 62 percent absorption, re-
spectively. Pinto, et al. (1976) studied arsenic excretion
in 24 workers exposed to the compound during copper smelting;
urinary arsenic levels were found to correlate significantly
with average airborne arsenic concentrations.
Water soluble arsenicals are readily absorbed through
the gastrointestinal tract. Studies with radioactive arse-
nate administered orally to rats have shown 70 to 90 percent
absorption from the gastrointestinal tract (Urakubo, et al.
1975; Dutkiewicz, 1977). Arsenic trioxide is only slightly
soluble in water and is not well absorbed. Theoretically,*
trivalent arsenicals should be less readily absorbed than
pentavalent forms due to reactivity with membrane components
-------
and lower solubility (U.S. EPA, 1979). However, investiga-
tors have reported high absorption of trivalent arsenic from
the gastrointestinal tract in humans (Bettley and O'Shea,
1975; Crecelius, 1977).
The absorption of arsenicals following dermal expo-
sure has been described in rats (Dutkiewicz, 1977) and humans
(Robinson, 1975; Garb and Hine, 1977).
Arsenic has been detected in the tissues (Kadowaki,
1960) and cord blood of newborns (Kagey, et al. 1977), and
thus transfers across the placenta in humans.
B. Distribution
Injection of radiolabelled arsenite in terminally
ill patients produced widespread distribution of the compound
(WHO, 1973). Hunter, et al. (1942) studied the distribution
of radioactive arsenicals in humans following oral and paren-
teral administration and found arsenic in the liver, kidney,
lungs, spleen, and skin during the first 24 hours after ad-
ministration. Levels of arsenic are maintained for long per-
iods in bone, hair'and nails (Kadowaki, 1960; Liebscher and
Smith, 1968) .
Tissue distribution of pentavalent arsenic has been
described in only a few animal studies; these studies indi-
cate only minor differences in distribution between trivalent
and pentavalent arsenicals (WHO, 1973).
-------
C. Metabolism
Studies with brain tumor patients given injections
of trivalent arsenic indicate that about 60 percent of the
total urinary arsenic was in the pentavalent state the first
day after, dosing (Mealey, et al. 1959). Braman and Foreback
(1973) have analyzed human urine samples and detected high
amounts of methylated forms (dimethyl arsenic acid and methyl
arsenic acid) . Analysis of the urine of one patient who in-
gested arsenic-contaminated wine indicated that 8 percent of
the initial dose was excreted as inorganic arsenic, 50 per-
cent was excreted as dimethyl arsenic acid, and 14 percent
was excreted as methyl arsenic acid (Crecelius, 1977).
The half-lives of inorganic and organic (methy-
lated) arsenicals in one patient have been reported as 10 and
30 hours, respectively (Crecelius, 1977).
D. Excretion
Arsenic is excreted primarily in the urine, with
small amounts removed in the feces and through normal hair
loss and skin shedding (U.S. EPA, 1979). Reports of minor
arsenic loss in sweat have also been made (Vellar, 1969).
Small amounts of radioactive arsenic (.003 to .35
percent) have been detected in expired air following adminis-
tration to rats (Dutkiewicz, 1977) and chickens (Overby and
Fredrickson, 1963).
IV. EFFECTS
A. Carcinogenicity
Epidemiological studies have shown an increased
mortality rate from respiratory cancer in workers exposed to
// - / 6
-------
arsenic during smelting operations (Lee and Fraumani, 1969?
Pinto and Bennett, 1963; Snegireff and Lombard, 1951; Kurat-
sune, et al. 1974). A retrospective study of Dow Chemical
employees indicated that workers exposed primarily to lead
arsenate and calcium arsenate showed increased death rates
from lung cancer and malignant neoplasms of the lymphatic and
hematopoietic systems (except leukemia) (Ott, et al. 1974).
A similar trend was noted in a study of retired
Allied Chemical workers (Baetjer, et al. 1975).
High rates of development of skin cancers have been
reported in' several studies of populations exposed to high
concentrations of arsenic in drinking water (Geyer, 1898;
Bergogilio, 1964; Tseng, et al. 1968).
Hemangioendothelioma of the liver associated with
exposure to arsenicals through ingestion has been reported in
several case studies (Roth, 1957; Regelson, et al. 1968).
Extensive experiments in animal systems with arsen-
icals administered in the diet or drinking water, or applied
topically or by intratracheal instillation failed to show
positive tumorigenic effects (U.S. EPA, 1979). However, two
recent reports have shown effects in animals. Schrauzer and
Ishmael (1974) indicated that feeding of sodium arsenite in
drinking water accelerated the rate of spontaneous mammary
tumor formation. Osswald and Goerttler (1971) found an
increase in leukemias and lymphomas in mice injected
repeatedly with sodium arsenate.
Animal studies on the skin tumor-promoting or co-
carcinogenic effects of arsenicals have produced negative
results (Raposo, 1928; Baroni, et al. 1963; Boutwell, 1963).
II -
-------
B. Mutagenicity
An increased incidence of chromosomal aberrations
has 'been found in persons exposed to arsenic occupationally
and medically (Petres, et al. 1970; Nordenson, et al. 1978;
Burgdorf, et al. 1977).
In vitro chromosomal changes following exposure to
arsenicals have been reported in root meristem cultures
(Levan, 1945) and in human leukocyte cultures (Petres and
Hundeiker, 1968; Petres, et al. 1970, 1972; Paton and
Allison, 1972).
Arsenate has been found to increase the frequency
of chromosome exchanges in Drosophila. Several organic ar-
senicals have a synergistic effect with ethylmethane sulfon-
ate in producing chromosome abnormalities in barley (Moutsh-
cen and Degraeve, 1965).
Sodium arsenate, sodium arsenite, and arsenic tri-
chloride produced positive mutagenic effects in a recorebinant
strain of Bacillus subtillus (Nishioka, 1975). Loforth and
Ames (1978) were unable to show mutagenic effects of trival-
ent and pentavelent arsenicals in the Ames Salmonella assay.
Arsenite exposure decreased the survival of E. coli after UV
damage of cellular PNA (Rossman, et al. 1975).
-------
C. Teratogenicity
i
ttordstrom, et al. (1978) have reported an increase
in the frequency of spontaneous abortions in pregnant women
living in the vicinity of a copper smelting plant; the expo-
V
sure environment was complex, involving several heavy metals
and sulfur dioxide.
Sodium arsenate has been shown to induce teratogen-
ic effects in the chick embryo (Ridgway and Karnofsky, 1952),
in golden hamsters (Perm and Carpenter, 1968; Ferm, et al.
\.
1971), in mice (Hood and Bishop, 1972), and rats '(Beaudoin,
1974). Malformations noted included exencephaly, anenceph-
aly, renal agenesis, gonadal agenesis, eye defects, and rib
and genitourinary abnormalities. Sodium arsenite injected
intraperitoneally into mice produced a lower incidence of
malformations than an equivalent dose of sodium arsenate
(Hood and Bishop, 1972; Hood, et al. 1977). Thacker, et al.
(1977) has noted that a higher oral dose of sodium arsenate
is needed to produce teratogenic effects in mice, when com-
pared to intraperitoneal doses.
Feeding of three generations of mice with low doses
of sodium arsenite in the chow failed to produce teratogenic
effects, but did decrease litter size (Schroeder and Mitch-
ener, 1971).
D. Other Reproductive Effects
Pertinent information could not be located in the
available literature regarding other reproductive effects.
•
E. Chronic Toxicity
A variety of chronic effects of arsenic exposure
has been noted. This includes a characteristic palmar-
-------
plantar hyperkeratosis and a gangrenous condition of the
hands and feet called Blackfoot disease (U.S. EPA, 1979).
Several clinical reports of liver damage in patients treated
with arsenical medication have been published (WHO, 1979).
An increased mortality from cardiovascular disease has been
noted in two epidemiological studies of smelter workers ex-
posed to high airborne arsenic (Lee and Fraumeni, 1969; U.S.
EPA, 1979). Neurological disturbances, including hearing
loss, in workers exposed to arsenicals have been reported
(WHO, 1979).
Effects of arsenicals on the hematopoietic system
following chronic exposure have also been noted (WHO, 1979).
These include disturbed erythropoiesis and granulocytopenia,
which may lead to impaired resistance to viral infections.
V. AQUATIC TOXICITY
A. Acute Toxicity
Seven static and seven flow-through bioassays from
.48 to 96-hours in duration provide a range of LC50 values
for freshwater fish of 290 to 150,000 ug/1. Hughes and Davis
(1967) demonstrated the most sensitive species as being blue-
gill fingerlings, Lepomis macrochirus, while Sorenson (1976)
reports that the most resistant species was the green sun-
fish, Lepomis cyanellus. Both species were tested in static
tests. Sanders and Cope (1966) provided the data for fresh-
water invertebrates in static bioassays. The cladoceran,
Simocephalus serrulatus, was the most sensitive with an 48-
*
hour LC50 value of 812 ug/1, while the stonefly, Ptaron-
arcys californica, was the most resistant species with an
h-IS
-------
LCgQ value of 22,040 ug/1. In marine, organisms, the chum
salmon, Onchorhynchus keta, had a 48-hour flow-through LC5Q
value of 8,331 ug/1 (Alderdice and Brett, 1957). Two marine
invertebrates were tested in 96 or 48-hour static-renewal or
static assays and produced the following LC5Q values: bay
scallop, Arqopecten irradiana, with 3,490 ug/1; and the em- .
bryos of the American oyster, Crassostrea virginica, with a
value of 4,330 ug/1.
B. Chronic Toxicity
One chronic life cycle freshwater test has provided
a chronic value of 853 ug/1 for arsenic to Daphnia magna.
Pertinent data could not be'located in the available litera-
ture for the chronic toxicity of arsenic to marine organisms.
C. Plant Effects
The lowest effective concentration recorded was 100
percent kill levels of 2,320 ug/1 for four species of fresh-
water algae.
D. Residues
Bioconcentration factors for five freshwater inver-
tebrate species and two fish species ranged from less than 1
to 17 (U.S. EPA, 1979) .
VI. EXISTING GUIDELINES AND STANDARDS
A. Hunan
Criteria for organic and inorganic arsenicals have
been derived. However, due to public comment questioning the
•
relevancy and accuracy of the studies used in the development
of these criteria, further review is necessary before final
recommendation.
-------
The OSHA tine-weighted average exposure criterion
for arsenic is 10 ug/m^.
B. Aquatic
For arsenic, the draft criterion for freshwater or-
ganisms is 57 ug/1, not to exceed 130 u<3/l. For marine or-
ganisms, the draft criterion is 29 ug/1, not to exceed 67
ug/1 (U.S. EPA,1^79).
-------
ARSENIC
REFERENCES
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arsenite to young chum salmon. Prog. Rep. Pacific Coast Stat.
Fish. Res.'Board Can. 108: 27.
Baetjer, A.M., et al. 1975. Cancer and occupational exposure
to inorganic arsenic. Page 393 j.n Abstracts. 18th Int. Cong.
Occup. Health Brighton, England, September 14-19.
Baroni, C., et al. 1963. Carcinogenesis tests of two inor-
ganic arsenicals. Arch. Environ.. Health 7: 668.
Beaudoin, A.R. 1974. Teratogenicity of sodium arsenate in
rats. Teratology 10: 153.
Bergoglio, R.M. 1964. Mortalidad por cancer en zonas de
aguas arsenicales de la Provincia de Cordoba, Republica Argen-
tina. Prensa Med. Argent. 51: 994.
Bettley, F., and J. O'Shea. 1975. The absorption of arsenic
and its relation to carcinoma. Brit. Jour. Dermatol. 92:
563.
Boutwell, R. 1963. A carcinogenicity evaluation of potassium
arsenite and arsenilic acid. Jour. Agric. Food Chem. 11:
381.
Braman, R.S., and C.C. Foreback. 1973. Methylated forms of
arsenic in the environment. Science 182:. 1247.
•
Burgdorf, W., et al. 1977. Elevated sister chromatic ex-
change rate in lymphocytes of subjects treated with arsenic.
Hum. Genet. 36: 69.
Crecelius, E.A. 1977. Changes in the chemical speciation of
arsenic following ingestion by man. Environ. Health Perspect.
19: 147.
Dutkiewicz, T. 1977. Experimental studies on arsenic absorp-
tion routes in rats. Environ. Health Perspect. 19: 173.
Falk, H.L., and P. Kotin. 1961. An assessment of factors
concerned with the carcinogenic properties of air pollutants.
Natl. Cancer Inst. Mon. 9: 81.
Ferguson, J.F., and J. Gavis. 1972. A review of the arsenic
cycle in natural waters. Water Res. 6: 1259. .
-------
Perm, V.H., and S.J. Carpenter. 1968. Malformation induced
by sodium arsenate. Jour. Reprod. Fertil. 17: 199.
Ferm, V.H., et al. 1971. The teratogenic profile of sodium
arsenate in the golden hamster. Arch. Environ. Health 22:
557.
Garb, L.G., and C..H. Hine. 1977. Arsenical neuropathy: Res-
idual effects following acute industrial exposure. Jour.
Occup. Med. 19: 567.
Geyer, L. 1898. Uber die chronischen Hautveranderungen beim
Arsenicismus und Betrachtungen uber die Massenerkrankungen in
Reichenstein in Schlesien. Arch. Derm. Syphilol. 43: 221.
Holland, R.H., et al. 1959. A study of inhaled arsenic-74 in
man. Cancer Res. 19: 1154.
\
Hood, R.D., and S.L. Bishop. 1972. Teratogenic effects of
sodium arsenate in mice. Arch. Environ. Health 24: 62.
Hood, R.D.,-et al. 1977. Effects in the mouse and rats of
prenatal exposure to arsenic. Environ. Health Perspect. 19:
219.
Hunter, F.T., et al. 1942. Radioactive tracer studies on
arsenic injected as potassium arsenite. jour. Pharmacol. Exp.
Ther. 76: 207.
Hughes, J.S., and J.T. Davis. 1967. Effects of selected
herbicides on bluegill sunfish. Pages 480-482. In Proc. 18th
Ann. Conf., S.E. Assoc. Game Fish Comm., October T8, 19, 20
and 21, 1964. Clearwater, Fla. Columbia, S.C.: S.E. Assoc.
Game Fish Comm. '
Kadowaki, K. 1960. Studies on the arsenic contents in organ-
tissues of the normal Japanese. Osaka City Med. Jour. 9:
2083.
Kagey, B., et al. 1977. Arsenic levels in maternal-fetal
tissue sets. Trace Subst. Environ. Health 11: 252.
Kuratsune, M., et al. 1974. Occupational lung cancer among
copper smelters. Int. Jour. Cancer 13: 552.
Lee, A.M., and J.F. Fraumeni, Jr. 1969. Arsenic and respira-
tory cancer in man: An occupational study. Jour. Natl. Can-
cer Inst. 42: 1045.
Levan, A. 1945. Cytological reactions induced by inorganic
salt solutions. Nature 156: 751.
11-17
-------
Liebscher, K., and H. Smith. 1968. Essential and nonessen-
tial trace elements. -A method of determining whether an ele-
ment is essential or nonessential in human tissue. Arch.
Environ. Health 17: 881.
Lofroth, G., and B. Ames. 1978. Mutagenicity of inorganic
compounds in Salmonella typhimurium; arsenic, chromium, and
selenium. Mutat. Res. 53: 65.
Mealey, J., Jr., et al. 1959. Radioarsenic in plasma,
urine, normal tissues, and intracranial neoplasms. Arch.
Neurol. Psychiatry 81: 310.
Moutshcen, J., and N . Degraeve. 1965. Influence of thiol—
nhibiting substances on the effects of ethyl methane sulphon-
ate (EMS) on chromosomes. Experientia 21: 200.
Nishioka, H. 1975. Mutagenic activities'" of metal compounds
in bacteria. Mutat. Res. 31: 185.
Nordenson, I., et al. 1978. Occupational and environmental
risks in and around a smelter in northern Sweden. II. Chro-
mosomal aberrations in workers exposed to arsenic. Hereditas
88: 47.
Nordstrom, S., et al. 1978. Occupational and environmental
risks in and around a smelter in northern Sweden. III. Fre-
quencies of spontaneous abortion. Hereditas 88: 51.
Osswald, H., and Kl. Goerttler. 1971. Laukosen bei der Maus
nach diaplacentarer und postnataler Arsenik-Applikation.
Dtsch. Gesmte-Path. 55: 289.
Ott, M.G., et al. 1974. Respiratory cancer and occupational
exposure to arsenicals. Arch. Environ. Health 29: 250.
Overby, L.R., and R.L. Fredrickson. 1963. Metabolic stabil-
ity of radioactive arsanilic acid in chickens. Jour. Agric.
Food Chem. 11: 378.
Paton, G.R., and A.C. Allison. . 1972. Chromosome damage in
human cell cultures induced by metal salts. Mutat. Res. 16:
332.
Petres, J., and M. Hundeiker. 1968. "Chromosomenpulverisa-
tion" nach Arseneinwirkung auf Zelljulturen _in vitro. Arch.
Klin. Exp. Dermatol. 231: 366.
Petres, J., et al. 1970. Chromosomenaberrationen an mensch-
lichen Lymphozyten bei chronischen Arsenchaden. Dtsh. Mecj.
Wochenschr. 95: 79.
Petres, J., et al. 1972. Zum Einfluss anorganischen Arsens
auf die DNS-Synthese menschlicher Lymphocyten _in vitro. Arch
Derm. Forsch. 242: 343.
-------
Pinto, S.S., and B.M. Bennett. 1963. Effect of arsenic tri-
oxide exposure on mortality. Arch. Environ. Health 7: 583.
Pinto, S.S., et al. 1976. Mortality experience of arsenic
exposed workers. Unpubl.
Raposo, L. 1929. Le cancer a 1'arsenie. C.P. Soc. Biol;
(Paris) 98: 86.
Regelson, W., et al. 1968. Hemangioendothelial sarcoma of
liver from chronic arsenic intoxication by Fowler's solution.
Cancer 21: 514.
Ridgway, L.P., and D.A. Karnovsky. 1952. The effects of
metals on the chick embryo: Toxicity and production of abnor-
malities in development. Annu. N.Y. Acad. Sci. 55: 203.
Robinson, T. 1975. Arsenical polyneuropathy due to caustic
arsenical paste. Brit. Med. Jour. 3: 139.
Rossman, T.-, et al. 1975. Effects of sodium arsenite on the
survival of UV-irradated Escherichia coli; Inhibition of a
rec A dependent function. Mutat. Res. 30: 157.
Roth, F. 1957. The sequelae of chronic arsenic poisoning in
Moselle vintners. German Med. Monthly 2: 172.
Sanders, H.O., and O.B. Cope. 1966. Toxicities of several
pesticides to two species of cladocerans. Trans. Am. Fish.
Soc. 95: 165.
Schrauzer, G., and D. Ishmael. 1974. Effects of selenium
and of arsenic on the genesis of spontaneous mammary tumors
in inbred C3H mice. Ann. Clin. Lab. Sci. 4: 441.
Schroeder, H.A., and M. Mitchener. 1971. Toxic effects of
trace elements on the reproduction of mice and rats. Arch.
Environ. Health 23: 102.
Snegireff, L.S., and O.M. Lombard. 1951. Arsenic and can-
cer. Observation in the metallurgical industry. AMA Arch.
Ind. Hyg. 4: 199.
Sorenson, E.M.B. 1976. Toxicity and accumulation of arsenic
in green sunfish, Lepomis cyanellus, exposed to arsenate in
water. Bull. Environ. Contam. Toxicol. 15: 756.
Sram, R., and V. Bencko. 1974. A contribution to the evalu-
ation of the genetic risk of exposure to arsenic. Cesk Hyg.
19: 308.
»
Standen, A. (ed.) 1967. Kirk-Othmer encyclopedia of chemi-
cal technology. Interscience Publishers, New York.
-------
Thacker, G., et al. 1977. Effects of administration routes
on arsenate teratogenesis in mice. Teratology 15: 30.
Tseng, W.P., et al. 1968. Prevalence of skin cancer in an
endemic area of chronic arsenicism in Taiwan. Jour. Natl.
Cancer Inst. 40: 453.
U.S. EPA. 1976. Arsenic and its compounds. EPA 560/6-76-
016. U.S. Environ. Prot. Agency, Washington, D.C.
U.S. EPA. 1979. Arsenic: Ambient Water Quality Criteria.
U.S. Environ. Prot. Agency, Washington, D.C.
Urakubo, G., et al. 1975. Studies in the fate of poisonous
metals in experimental animals (V). Body retention and ex-
cretion of arsenic. Jour. Food Hyg. Soc. Jpn. 16: 34.
\
Vellar, 0. 1969. Nutrient lopes through sweating. Thesis,
Universitetsforlaget, Oslo, Norway.
Weast, R.C. (ed.) 1975. Handbook of chemistry and physics.
56th ed. CRC Press, Cleveland, Ohio.
WHO. 1973. Environmental Health Criteria; Arsenic. World
Health Organization. Geneva.
•vr
I t-ltJL
-------
No. 12
Asbestos
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
I*-1
-------
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
asbestos and has found sufficient evidence to indicate that
this compound is carcinogenic.
/a-3
-------
ASBESTOS
Summary
Numerous studies indicate that asbestos fibers introduced into the
pleura, peritoneum, and trachea of rodents have induced malignant tumors.
The strongest evidence for the carcinogenicity of ingested asbestos is pro-
vided by epidemiology of human populations occupationally exposed to high
concentrations of airborne asbestos dust. Inhalation exposure to asbestos
dust is accompanied by ingestion because a high percentage of the inhaled
fibers are removed from the lung by mucociliary action and subsequently
swallowed. "Peritoneal mesothelioma, often in great excess, and modest ex-
cesses of stomach esophagus, colonrectal, and kidney cancer have been linked
to occupational exposure to asbestos.
Pertinent data on the acute or chronic effects of asbestos to aquatic
organisms were not found in the available literature.
-------
ASBESTOS
I. INTRODUCTION
This profile is based primarily upon the Ambient Water Quality Criteria
Document for Asbestos (U.S. EPA, 1979). In addition, valuable information
is available from recent reviews by the International Agency for Research on
Cancer (IARC, 1977) and the National Institute for Occupational Safety and
Health (NIOSH, 1977).
Asbestos is a broad term applied to numerous fibrous mineral silicates
composed of silicon, oxygen, hydrogen, and metal cations such as sodium,
magnesium, calcium, or iron. There are two major groups of asbestos, ser-
pentine (chrysotile or "white asbestos") and amphibole. Although chrysotile
is considered to be a distinct mineral, there are five fibrous amphiboles:
actinolite, amcsite ("brown asbestos"), anthophyllite, crocidolite ("blue
asbestos"), and tremolite. . The chemical composition of different asbestos
fibers varies widely, and typical formulas are presented in Table 1. Some
typical physical properties of three different mineral forms of asbestos are
presented in Table 2.
TABLE 1
TYPICAL FORMULAS FOR ASBESTOS FIBERS
1. Serpentines chrysotile
2. Amphiboles amosite
crocidolite Na/2(Mg,Fe) 5813022(0^)2
anthophyllite (Mg,Fe) 7813022(^)2
tremolite
actinolite
-------
TABLE 2.
TYPICAL PHYSICAL PROPERTIES OF CHRYSOTILE (WHITE ASBESTOS),
CROCIDOLITE (BLUE ASBESTOS), AND AMOSITE
Units Chrysotile Crocidolite Amosite
(white asbestos) (blue asbestos)
Approximate
diameter of micron
smallest fibers
Specific
gravity
Average
tensile Ib./inch2
strength
Modulus of Ib./inch2
elasticity
0.01
2.55
3.5 x 105
23.5 x 106
0.08
3.37
5 x 1Q5
27.0 x 106
0.1
3.45
1.75 x 105
23.5 x 106
Asbestos minerals, despite a relatively high fusion temperature, are
completely decomposed at temperatures of 1,000°C. Both the dehydroxyla-
tion temperature and decomposition temperature increase with increased MgO
content among the various amphibole species (Speil and Leineweber, 1969).
The solubility product constants for various Chrysotile fibers range
from 1.0 x 10 to 3 x 10~ . Most materials have a negative surface
charge in aqueous systems. However, since Chrysotile has a positive ( + )
charge, it will attract, or be attracted to, most dispersed materials. The
highly reactive surface of asbestos causes many surface reactions which are
intermediate between simple absorption and a true chemical reaction. The
absorption of various materials on the surface of Chrysotile supports the
premise that the polar surface of Chrysotile has a greater affinity for
polar molecules (e.g., H^O, NH ) than for non-polar molecules (Speil and
Leineweber, 1969).
-------
Of all the asbestos minerals, chrysotile is the most susceptible to
acid attack. It is almost completely destroyed within one hour in 1 N HCL
at 95°C. Amphibole fibers are much more resistant to mineral acids
(Lindell, 1972).
The resistance of the asbestos fibers to attack by reagents other than
acid is excellent up to temperatures of approximately 100°C with rapid
deterioration observed at higher temperatures. Chrysotile is completely de-
composed in concentrated KOH at 200°C. In general, organic acids have a
tendency to react slowly with chrysotile (Speil aYid Leineweber, 1969).
Chrysotile is the major type of asbestos used in the manufacture of as-
bestos products. These products include asbestos cement pipe, flooring pro-
ducts, paper products (e.g., padding), friction materials (e.g., brake lin-
ings and clutch facings), roofing products, and coating and patching com-
pounds. In 1975, the total consumption of asbestos in the U.S. was 550,900
thousand metric tons (U.S. EPA, 1979).
Of the 243,527 metric tons of asbestos discharged to the environment,
98.3 percent was discharged to land, 1.5 percent to air, and 0.2 percent to
water (U.S. EPA, 1979). Solid waste disposal by consumers was the single
largest contribution to total discharges. Although no process water is used
in dry mining of asbestos ore, there is the potential for runoff from asbes-
tos waste tailings, wet mining, and iron ore mining. Mining operations can
also contribute substantially to asbestos concentrations in water by air and
solid waste contamination. In addition to mining and industrial discharcss
of asbestos, asbestos fibers, which are believed to be the result of reck
outcroppings, are found in rivers and streams.
I3L-7
-------
II. EXPOSURE
A. Water
Asbestos is commonly found in domestic water supplies. Of 775 re-
cent samples analyzed by electron microscopy under the auspices of the U.S.
EPA, 50 percent showed detectable levels of asbestos, usually of the chryso-
tile variety (Millette, 1979). Nicholson and Pundsack (1973) measured aver-
age asbestos levels of 0.3 - 1.5 pg/1 in drinking water from two Eastern
United States river systems. Levels of 2.0 to 172.7 x 106 fibers/1 have
been reported in Canadian tap water, the highest levels being found in un-
filtered tap water near a mining area (Cunningham and Pontefract, 1971). In
other studies of Canadian drinking water levels of 0.1 to 4 x 10 fibers/1
have been reported (Kay, 1973). The U.S. EPA (1979) has concluded that
about 95 percent of water consumers in the United States are exposed to as-
bestos fiber concentrations of less than 10 fibers/1. The mass concen-
trations of chrysotile asbestos in the water of cities with less than 10°
fibers/1 are likely to be less than 0.01 pg/1, corresponding to an adult
daily intake of less than 0.02 ug. Pertinent data on the ability of aquatic
organisms to bioconcentrate asbestos from water were not located in the
available literature.
B. Food
There are scant data on the contribution of food products to popu-
lation asbestos exposure. However, asbestos fibers and talc, which some-
times contains asbestos as an impurity, may be used in the manufacture of
certain processed foods such as sugar, coated rice, vegetable oil and lard
(IARC, 1977). Cunningham and Pontefract (1971) reported that certain beers
and wines could contain asbestos fibers at levels similar to those found in
drinking water systems (10 to 10 fibers/1).
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C. Inhalation
Asbestos is present in virtually all metropolitan areas. Concen-
trations of asbestos in urban atmosphere are usually less than 10 ng/m ,
but may reach 100 ng/m-5 (Nicholson, et al. 1971; Nicholson and Pundesack,
1973; Sebastien, et al. 1976; IARC, 1977). Construction sites and buildings
fireproofed with loose asbestos material showed the most significant contam-
ination with individual measurements as high as 800 ng/m (Nicholson, et
al. 1975).
III. PHARMACOKINETICS
There are contradictory data concerning whether ingested asbestos
fibers are capable of passage across the gastrointestinal mucosa (Gross, et
al. 1974; Cooper and Cooper, 1978; Cunningham and Pontefract, 1973;
Cunningham, et al. 1977). Most ingested asbestos particles are excreted in
the feces (Cunningham, et al. 1976). However, at least one recent study
(Cook and Olson, 1979) indicates that ingestion of drinking water containing
amphibole fibers may result in the appearance of these fibers in the urine,
thus providing evidence for passage of asbestos across the human gastro-
intestinal tract.
Ingestion of asbestos fibers is accompanied by swallowing of many
fibers cleared from the respiratory tract by mucociliary action. More than
half the asbestos inhaled will likely be swallowed (U.S. EPA, 1979). The
deposition of asbestos fibers in the lung is a function of their diameter
rather than length, as about 50 percent of particles with a mass median dia-
meter of less than 0.1 urn will be deposited on nonciliated pulmonary sur-
faces. Deposition on nasal and pharyngeal surfaces becomes important as
mass median diameter approaches 1 jun and rises rapidly to become the domi-
nant deposition site for airborne particles 10 urn in diameter or greater
-------
(Brain and Volberg, 1974). Portions of inhaled asbestos fibers which are
not cleared by microciliary action may remain trapped in the lung for de-
cades (Pooley, 1973; Langer, 1973). However, the chrysotile content of the
lung does not build up as significantly as that of the amphiboles for simi-
lar exposure circumstances (Wagner, et al. 1974).
IV. EFFECTS
A. Carcinogenicity
All commercial forms of asbestos have demonstrated carcinogenic
activity in mice, rats, hamsters, and rabbits. 'Intraperitoneal injection of
various asbestos fibers has produced mesotheliomas in rats and mice (Maltoni
and Annoscia> 1974; Pott and Friedrichs, 1972; Pott, et al. 1976). In rats,
chronic inhalation of various types of asbestos have produced lung carcino-
mas and mesotheliomas (Reeves, et al. 1971, 1974; Gross, et al. 1967;
Wagner, et al. 1974; Davis, et al. 1978). Intrapleural injection of asbes-
tos fibers has produced mesotheliomas in rats, hamsters, and rabbits (Donna,
1970; Reeves, et al. 1971; Stanton and Wrench, 1972; Stanton, 1973; Wagner,
et al. 1973, 1977; Smith and Hubert, 1974). The oral administration of as-
bestos filter material reportedly caused malignancies in rats (Gibel, et al.
1976) although other feeding studies have produced equivocal results.
Occupational 'exposure .to chrysotile, amosite, anthophyllite, and
mixed fibers containing crocidolite has resulted in high incidences of human
lung cancers (Selikoff, et al. 1979; Seidman, et al. 1979; Enterline and
Henderson, 1973; Henderson and Enterline, 1979; IARC, 1977). Occupational
exposure to crocidolite, amosite, and chrysotile have also been associated
with a large incidence of pleural and peritoneal mesatheliomas. An excess
of gastrointestinal cancers has been associated in some studies witn expo-
sure to amosite, chrysotile, or mixed fibers containing crocidolite (Seli
I3.-I6
-------
koff, 1976; Selikoff, et al. 1979; Elmes -and Simpson, 1971; Henderson and
Enterline, 1979; Nicholson, et al. 1979; Seidman, et al. 1979; Newhouse and
Berry, 1979; McDonald and Liddell, 1979; Kogan, et al. 1972).
In the general environment, mesotheliomas have occurred in persons
living near asbestos factories and crocidolite mines and in the household
contacts of asbestos workers (Wagner, et al. 1960; Newhouse and Thomson,
1965). In addition, several studies have implicated asbestos in drinking
water with the development of cancer of the lung and digestive tract cancers .
(Mason, et al. 1974; Levy, et al. 1976; Cooper,'" et al. 1978, 1979). There
is convincing evidence to support the contention that asbestos exposure and
cigarette smoking act synergistically to produce dramatic increases in lung
cancer over that from exposure to either agent alone (Selikoff, et al. 1968;
Berry, et al. 1972).
In a study by Hammond, et'al. (1979) involving 17,800 insulation
workers, the death rate for non-smokers was 5.17 times that of a non-smoking
control population. The death rate was 53.24 times that of the non-smoking
control population or 4.90 times the death rate for a comparable group of
non-exposed smokers. Cancers of the larynx, pharynx and buccal cavity in
insulators were also found to be associated with cigarette smoking, together
with some non-malignant asbestos effects such as fibrosis and deaths due to
asbestosis.
B. Mutagenicity
In cultured Chinese hamster cells, chrysotile and crocidolite have
produced genetic damage and morphologic transformation (Sincock and
Seabright, 1975; Sincock, 1977). On the other hand, chrysotile, amosite,
and anthophyllite showed no mutagenic activity toward tester strains of §_._
coli or S^ typhimurium (Chamberlain and Tarmy, 1977).
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C. Teratogsnicity
Pertinent data on the possible teratogenic effects of asbestos were
not located in the available literature, although transplacental passage of
asbestos fibers has been reported (Cunningham and Pontefract, 1971, 1973).
D. Other Reproductive Effects
It is not known whether asbestos exposure may impair fertility or
interfere with reproductive success .(U.S. EPA, 1979).
E. Chronic Toxicity
The chronic ingestion of chrysotile by-rats (0.5 mg or 50 mg daily
for 14 months) produced no effects on the esophagus, stomach, or cecum tis-
sue, but histological changes were seen in the ileum, particularly of the
villi (Jacobs, et al. 1978).
The long-term disease entity, asbestosis, results from the inhala-
tion of asbestos fibers and is a chronic, progressive pneumoconiosis. It is
characterized by fibrosis of the lung parenchyma and produces shortness of
breath as the primary symptom. Asbestos has accounted for numerous cases of
occupational disablement during life as well as a considerable number of
deaths among worker groups. In groups exposed at lower concentrations such
as the families of workers, there is less incapacitation and although asbes-
tosis can occur, deaths have not been reported (Anderson, et al. 1976).
Extrapulmonary chronic effects reported include "asbestos corns"
from the penetration of asbestos fibers into the skin. NO chronic nonmalig-
nant gastrointestinal effects have been reported.
V. AQUATIC TOXICITY
Pertinent data concerning the effects of asbestos to either fresh-
water or marine organisms were not located in the available literature.
I a
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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
The current Occupational Safety and Health Administration (OSHA)
standard for an 8-hour time-weighted average (TWA) occupational exposure to
asbestos is 2 fibers longer than 5 microns in length per milliliter of air
(2f/ml or 2,000,000 f/m ). Peak exposures of up to 10 f/ml are permitted
for no more than 10 minutes (Fed. Reg., 1972). This standard has been in
effect since July 1, 1976, when it replaced an earlier one of 5 f/ml (TWA).
Great Britain also has a value of 2 f/ml as the accepted level, below wnich
no controls are required (BOHS, 1968). The British standard, in fact,
served as a guide for the OSHA standard (NIOSH, 1972).
The British standard was developed specifically to prevent asbes-
tosis among working populations; data were felt to be lacking that would
allow for determination of a standard for cancer (BOHS, 1968). Unfor-
tunately, among occupational groups, cancer is the primary cause of excess
death for workers (see "Carcinogenicity" section) with three-fourths or more
of asbestos-related deaths caused from malignancy. This fact has led OSHA
to propose a lower TWA standard of 0.5 f/ml (500,000 f/m3) (Fed. Reg.,
1975). The National Institute for Occupational Safety and Health (NIOSH),
in their criteria document for the hearings on a new standard, have proposed
a value of 0.1 f/ml (NIOSH, 1977). In the discussion of the NIOSH proposal,
it was stated that the value was selected on the basis of the sensitivity of
analytical techniques using optical microscopy and that 0.1 f/ml may not
neces
-------
sarily protect against cancer. Recognition that no information exists that
would define a threshold for asbestos carcinogenesis was also contained in
the preamble of the OSHA proposal. The existing standard in Great Britain
has been questioned by Peto (1978), who estimates that asbestos disease may
cause the death of 10 percent of workers exposed at 2 f/ml for a working
lifetime.
The existing federal standard for asbestos emissions into the en-
vironment prohibits "visible emissions" (U.S. EPA, 1975). No numerical
value was specified because of difficulty in monitoring ambient air asbestos
concentrations in the ambient air or in stack emissions. Some local govern-
ment agencies, however, may have numerical standards (e.g., New York, 27
ng/m ).
No standards for asbestos in foods or beverages exist even though
the use of filtration of such products through asbestos filters has been a
common practice in past years. Asbestos filtration, however, is prohibited
or limited for human drugs (U.S. FDA, 1976).
The draft recommended water quality criterion for asbestos par-
ticles (U.S. EPA, 1979) is derived from the substantial data which exists
for the increased incidence of peritoneal mesothelioma and gastrointestinal
tract cancer in humans exposed occupationally to asbestos. This derivation
assumes that much or all of this increased disease incidence is caused by
fibers ingested following clearance from the respiratory tract. Several
studies allow the association of approximate airborne fiber concentrations
to which individuals were exposed with observed excess peritoneal and gas-
trointestinal cancer. All of the inhaled asbestos is assumed to be even-
tually cleared from the respiratory tract and ingested.
-------
The draft criterion calculated to-keep the individual lifetime can-
cer risk below 10~ , is 300,000 fibers of all sizes/liter. The corres-
ponding mass concentration for chrysotile asbestos is approximately 0.05
ug/1. This criterion has not yet gone through the process of public review;
therefore, there is a possibility that the criterion may be changed.
B. Aqustic
Because no data are available on the aquatic toxicity of asbestos,
the U.S. EPA (1979) derived no aquatic criteria.
-------
ASBESTOS
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Brain, J.D., and P.A. Volberg. 1974. Models of lung retention
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Chamberlain, M. and E.M. Tarmy. 1977. Asbestos ana glass fibres
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Cook, P.M. and G.F. Olson. 1979. Ingested mineral fibers: Elimi-
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Cooper, R.C. and W.C. Cooper. 1.978. Public health aspects of
asbestos fibers in drinking water. Jour. Am. Water Works Assoc.
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Cooper, R.C., et al. 1978. Asbestos in domestic water supplies
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Cunningham, H.M. and R.D. Pontefract. 1971. Asoestos fioers
in beverages and drinking water. Nature (Lond.) 232: 332.
Cunningham, H.M. and R.D. Pontefract. 1973. Asbestos fibers
in beverages, drinking water and tissues: their passage through
the intestinal wall and movement through the body. Jour. Assoc.
Off. Analyt. Chem. 56: 97b.
Cunningham, H.M., et al.- 1976. Quantitative relationship of
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Davis, J.M.G., et al. 1978. Mass and number of fioers itt the
pathogenesis of asbestos-related lung disease in rats. Br. Jour.
Can. 37: o73.
-------
Donna, A. 1970. Tumori sperimentali da amiano di crisotilo,
crocidolite e amosite in ratto Sprague-Dawley. Med. Lavoro.
61: 1.
Elmes, P.O. ana M.J.C. Simpson. 1971. Insulation workers in
Belfast. III. Mortality 1940-66. Br. Jour. Ind. Med. 23: 226.
Enterline, P.E. ana V. Henaerson. 1973. Type of asbestos and
respiratory cancer in the asbestos industry. Arch. Environ.
Health. 27: 312.
Federal Register. 1972. Standard for exposure to asbestos dust.
Title 29, Chap. XVII, Part 1910-Occupational Safety and Health
Standards. June 7, Washington, D.C. 37: 11318.
Federal Register. 1975. Occupational exposure to asbestos;
notice of proposed rulemaking. Oct. 9, Washington, D.C. 49: 197.
Gibel, W., et al. 1976. Tierexperimentelle untersuchungen uber
eine kanzerogene wirkung von asbestfiltermaterial nach oraler
aufnahme. Arch. Geschwulstforsch. 46: 437.
Gross, P., et al. 1967. Experimental•asbestosis: The develop-
ment of lung cancer in rats with pulmonary deposits of chrysotile
asbestos dust. Arch. Environ. Health 15: 343.
Gross, P., et al. 1974. Ingested mineral fibres. Do they pene-
trate tissue or cause cancer? Arch. Environ. Health 29: 341.
Hammond, E.G., et al. 1979. Cigarette smoking and mortality
among U.S. asbestos insulation workers. Ann. N.Y. Acaa. Sci.
(In press; .
Henderson, V.I. and P.E. Enterline. 1979. Asbestos exposure
factors associated with excess cancer and respiratory disease
mortality. Ann. N.Y. Acad. Sci. (In press).
IARC Monographs on the Evaluation of Carcinogenic Risk of Chemi-
cals to Man. 1977. Asoestos. Vol. 14.
Jacobs, R., et al. 1978. Light and electron microscope studies
of the rat digestive tract following prolonged and short-term
ingestion of chrysotile asbestos. Br. Jour. Exp. Path. 59: 443.
Kay, G. 1973. Ontario intensifies search for asbestos in drinking
water. Water Pollut. Control 9: 33.
Kogan, P.M., et al. 1972. The cancer mortality rate among workers
of asbestos industry of the Urals. Gig. i Sanit. 37: 29.
*
Langer, A.M., et al. 1973. Identification of asbestos in human
tissues. Jour. Occup. Med 15: 287.
-------
Levy, B.S., et al. 1976. Investigating possible effects of
asbestos in city water: Surveillance of gastrointestinal cancer
incidence in Duluth, Minn. Am. Jour. Epidemiol. 103: 362.
Lindell, K.V. 1972. Biological effects of asbestos. Int.
Agency Res. Cancer, Lyon, France.
Maltoni, G. and C. Annoscia. 1974. Mesotheliomas in rats following
the intraperitoneal injection of crocidolite. In; W. Davis and
C. Maltoni, eds. Advances in tumour prevention, detection and
characterization. Vol. 1. Characterization of human tumours.
Excerpta Medica, Amsterdam.
Mason, T.J., et al. 1974. Asbestos-like fibers in Duluth water
supply. Relation to cancer mortality. Jour. Am. Med. Assoc.
228: 1019.
v
McDonald, J.C. and O.K. Liddell. 1979. Mortality in Canadian
miners and millers exposed to chrysotile, Ann. N.Y. Acad. Sci.
(In press).
Millette, J. 1979. Health Effects Res. Lab. (Personal communi-
cation) .
National Institute of Occupational Safety and Health. 1972.
Criteria for a recommended standard...Occupational exposure to
asbestos. DHEW (NIOSH) Pb. No. 72-10267.
Natioal Institute of Occupational Safety and Health. 1977.
Revised recommended asbestos standard. DHEW (NIOSH) Pub. No.
77-169.
Newhouse, M.L. and G. Berry. 1979. Patterns of disease among
long-term asbestos workers in the United Kingdom. Ann. N.Y.
Acaa. Sci. (In press).
Newhouse, M.L. and H. Thomson. 1965. Mesothelioma of pleura
and peritoneum following exposure to asbestos in the London area.
Br. Jour. Ind. Med. 22: 261.
Nicholson, W.J. 1971. Measurement of asbestos in amDient air.
Final report, Contract CPA 70-92. Natl. Air Pollut. Control
Admin.
Nicholson, W.J. and F.L. Pundsack. 1973. Asoestos in the envi-
ronment. Page 126 jLn_ P. Bogovski, et al. eds. Biological effects
of asoestos. IARC Sci. Publ. No. 8. Int. Agency Res. Cancer,
Lyon, France.
Nicholson, W.J., et al. 1971. AsDestos air pollution in New
York City. Page 136 _in H.M. England and W.T. Barry, eds. »Proc.
Second Clean Air Cong. Academic Press, New York.
Nicholson, W.J., et al. 1975. Asbestos contamination of the
air in puolic buildings. Final report, Contract No. 63-U^-iJ
-------
Nicholson, W.J., et al. 1979. Mortality experience of asbestos
factory workers: Effect of differing intensities of asbestos
exposure. Environ. Res. (In press).
Peto, J. 1978. The hygiene standard for asbestos. Lancet 8062: 484.
Pooley, F.DI 1973. Mesothelioma in relation to exposure. Page
222 iji P. Bogovski, et al. eds. Biological effects of asbestos.
IARC Sci. Publ. No. 8. Int. Agency Res. Cancer, Lyon, France.
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i.p.-injektion faserformiger staube. Naturwissenschaften. 59: 318.
Pott, F., et al. 1976. Ergebnisse aus tierversuchen zur kanzero-
genen wirkung faserformiger staube und ihre deutung im hinolick
auf die tumorentstehung beim menschen. Zbl. Bakt. Hyg., I Abt.
orig. B. 162: 467.
Reeves, A.L., et al. 1971. Experimental asbestos carcinogenesis.
Environ. Res. 4: 496.
Reeves, A.L., et al. 1974. Inhalation carcinogenesis from various
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par 1'asbeste. Rev. franc. Mai. resp. 4: 51.
Seidman, H., et al. 1979. Long-term observation following short-
term employment in an amosite asbestos factory. Ann. N.Y. Acad.
Sci. (In press).
Selikoff, I.J. 1976. Lung cancer and mesothelioma during prospec-
tive surveillance of 1249 asbestos insulation workers, 1963-1974.
Ann. N.Y. Acad. Sci. 271: 448.
Selikoff, I.J., et al. 1968. Asbestos exposure, smoking and
neoplasia. Jour. Am. Med, Assoc. 204: 106.
Selikoff, I.J., et al. 1979. Mortality experience of insulation
workers in the United States and Canada, 1943-1977. Ann. N.Y.
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Sincock, A.M. 1977. Ir± vitro chromosomal effects of asoestos
and other materials. In. Origins of human cancer. Cold Spring
Harbour, 1976.
Sincock, A.M. and M. Seabright. 1975. Induction of chromosome
changes in Chinese hamster cells by exposure to asbestos fibers.
Nature (Lond.) 257: 5o.
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a means for estimating carcinogenicity. Pages 92-101 in_ E. Karbe
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Speil, S. and J.P. Leineweber. 1969. Asbestos minerals in modern
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Stanton, M.F. 1973. Some etiological considerations of fibre
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effects of asnestos. Int. Agency Res. Cancer. IARC Sci. Publ.
No. 8.
Stanton, M.F. and C. Wrench. 1972. Mechanisms of mesothelioma
induction with asbestos and fibrous glass. Jour. Natl. Cancer
Inst. 48: 797.
U.S. EPA. 1975. National emission standards for hazardous air
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U.S. EPA. 1976. Quarterly report of the Environmental Research
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U.S. EPA. 1979. Asbestos: Ambient Water Quality Criteria.
Environmental Protection Agency, Washington, D.C.
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Wagner, J.C., et al. 1960. Diffuse pleural mesothelioma and
asbestos exposure in the north western Cape Province. Br. Jour.
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No. 13
Barium
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
/3-y
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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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BARIUM
SUMMARY
Water-soluble barium compounds are highly toxic to man. Fish and lower
species of marine organisms have been shown to bioaccumulate barium. The con-
centration of barium in sea water ranges around 20 ug/L, while that of drinking
water averages about 6 ug/L.
Soluble barium salts have a high acute toxicity. Small amounts of barium
can accumulate in the skeleton of humans and animals. Barium salts are strong
muscle stimulants: acute intoxication generally results in uncontrolled
contractions followed by partial or complete paralysis. Cardiac disturbances
including arrythmias can also occur. Barium dusts are irritant to nose,
throat and eyes. Baritosis (pneumoconiosis) occurs following chronic
inhalation of (fine) barium dusts. Barium sulfate used in barium enemas,
swallows and artificial orthopedic bones can result in tissue injury following
solubilization of the barium sulfate and/or soluble impurities. Potassium
acts as an antagonist for barium induced cellular disturbances. The TWA
for exposure to soluble barium compounds is 0.5 mg/m .
I. INTRODUCTION . . .
Barium (Ba; atomic weight 137.34) is a yellowish-white metal of the alkaline
earth group. It is relatively soft and ductile and may be worked readily.
Barium has a melting point of 729 C and a boiling point of 1640 C; its density
is 3.51 g/cm3 (Kunesh 1978).
Barium characteristically forms divalent compounds. At room temperature,
it combines readily and exothermically with oxygen and the halogens. It reacts
vigorously with water to form barium hydroxide, Ba(OH)_ (Kunesh 1978).
Barium occurs in nature chiefly as barite, crude BaSO^, and as witherite,
a form of BaCO,, both of which are highly insoluble salts. Only barite is
mined in this country (Kirkpatrick 1978).
A review of the production range (includes importation) statistics for
barium (CAS. No. 7440-39-3) which are listed in the initial TSCA Inventory,
(U.S. EPA 1979) has shown that between 100,000 and 900,000 pounds of this
chemical were produced/imported in 1977*.
*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).
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C. Environmental Occurrence
The flow of barium in the United States has been traced for the year 1969,
during which time consumption of barium totaled 1.87 billion pounds. It was
estimated that 30.8 million pounds of barium were emitted to the atmosphere.
Nearly 18 percent of the emissions resulted from the processing of barite, more
than 28 percent from chemical production, 26 percent from the combustion of
coal, and 23 percent from the manufacture of miscellaneous end products
(U.S. EPA 1972).
The concentration of barium in sea water is generally accepted as about
20 ug/L, with lower concentrations in the surface waters than at greater depths.
Barium ions are generally removed from solution quite rapidly by adsorption,
sedimentation and precipitation (U.S. EPA 1973). Concentrations of barium in
this country's drinking water supplies generally range from less than 0.6 ug/L
to about 10 ug/L, although a few midwestern and western states have had upper
limits of 100 to 300 ug/L (U.S. EPA 1976).
Due to the common use of barite as a weighting agent in drilling muds,
the resultant contamination of sediments near drilling sites was studied. The
average content of barium in benthic sediments from the Southern California Bight
was 637 parts per million (ppm), with a range from 43 to 1899 ppm. This area
includes active drilling sites where barium contamination is expected. The
concentration values were compared with the average 879 ppm barium found in
mainland intertidal sediments and the 388 ppm determined in the channel island
intertidal sediments. The lower barium content of the island sediments was
attributed to the volcanic soil of the islands; however, the higher barium
concentration of the mainland could not be traced to either natural or anthro-
pogenic origin. Due to variations in soil sources it is questionable whether
barium concentrations determined elsewhere could be used as reference values for
this study (Chow 1978).
In two studies correlating trace metal concentrations in the environment
with that in scalp hair of the inhabitants, barium was measured in the house
dust collected in four communities. Geometric mean values of barium determined
in house dust samples from the New York City area were as follows: 65.2 ug Ba/g
dust in Riverhead, 137.6 ug/g in Queens, and 312.4 ug/g in the Bronx (USEPA, 1978b)
The geometric mean value for barium measured in house dust in Ridgewood, New
Jersey was 330.0 ug/g (U.S. EPA 1978c).
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Barium and its compounds are used industrially as weighting agents in
oil and gas well drilling muds; as coloring agents in glass, ceramics, paint,
and pigments; as filler in rubber; and as antismoking agents in diesel
fuel (U.S. EPA 1972; NAPCA 1969). In medicine, barium sulfate is used as
an x-ray contrast medium because of its extreme insolubility and its ability to
absorb x-rays (Kirkpatrick 1978; U.S. EPA 1978a).
II. EXPOSURE :•••_
A. Environmental Fate
Due to the high reactivity of barium, it is not found in its elemental
state in the environment. In sea water, the naturally present sulfate and
carbonate tend to precipitate any water-soluble barium components. Thus, the
sediment usually has a higher concentration of barium than its corresponding
water source (Guthrie 1979) .
B. Bioconcentration
Due to the toxicity of soluble barium salts to man, the bioaccumulation
V
[ of the element has been a concern. Barium can be concentrated in goldfish by
; . a factor of 150. Concentration factors for barium listed in one study are
; 17,000 in phytoplankton, 900 in zooplankton, and 8 in fish muscle (U.S. EPA 1973).
i
I Thus, ingestion of fish by man can be a source of barium exposure.
j. Another study conducted on various species of marine organisms produced the
• following results (Guthrie 1979): Barnacles bioaccumulated about
I five times greater concentration of barium than was in the water, while oysters
! and clams contained concentrations of the element similar to that present in
i the water. Crabs and polychaetes were also analyzed for barium and were found
I to contain a significantly smaller quantity than that present in the sediment
i on which they dwell. However, no significant differences were noted between
i the concentration of barium in the two organisms and the concentrations in
the water column.
I In man, studies have been conducted to determine a correlation between barium
I in the environment, measured as house dust, and the concentration of barium found
in scalp hair of the inhabitants. A significant positive correlation has been
determined between the geometric mean concentrations of the element in house dust
': and hair. Other covariants of significant value measured in the studies were sex,
; hair length, and, in children less than 16 years old, age (U.S. EPA 1978b; U.S.
' EPA 1978c).
-------
Ill. PHARMACOKINETICS ,,.
Soluble barium is retained by muscle tissue for about 30 hours, after
which the amount of retained barium decreases slowly (NAPCA 1969) . Small
amounts of barium become irreversibly deposited in the skeleton. However,
the acceptance level is limited, as quantitative analysis of human bone
reveals no accumulation of barium from birth to death.... Barium levels
averaged 7 ug/g ashed bone. Very little barium is retained by the liver,
kidneys, or spleen, and practically none by the brain, heart, or hair.
Transient high concentrations are seen in the liver with lesser amounts in
lung and spleen following acute experimental dosing.
Barium administered orally or intraperitoneally as Bad. to weanling
male rats at doses of 1, 5, 25, or 125 mg/kg was taken up rapidly by the
soft tissues (30 mins), showed slow uptake by the skeleton (2 hrs) and was
excreted primarily in the feces (Clary and Tardiff, 1974) . No retention
data were reported.
133
Pulmonary clearance rates of inhaled radioactive Ba salts, ranged from
11
several hours for the soluble BaCl. to hundreds of days for Ba in fused
clay . Large amounts of barium were excreted in the feces; a lesser amount
was excreted in the urine. Although BaSO, is "Insoluble" in water, 50% of
133
BaSO, dissolved in a simulated biological fluid within 2-3 days, indicating
that solubilization is relatively rapid.
IV. HEALTH EFFECTS
A. Carcinogenicity
Bronchogenic carcinoma developed in rats injected with radioactive S
(unspecified dose) labelled barium sulfate (Patty 1963). BaSO^ powder (particle
size undefined) injected intrapleurally in female and male mice produced a
mesothelioma in only 1 out of 30 animals. No other pathological lesions were
investigated or reported. Saline controls (32) resulted in no mesotheliomas.
Barium sulfate had an oncogenie potency similar to that of glass powder and
•
aluminum oxide. It therefore appears likely that the observed tumor was due
to foreign-body-oncogenesis (Wagner).
-------
B. Acute and Chronic Toxicity
The soluble salts of barium are highly toxic when ingested. Barium chloride
and barium carbonate, two of the soluble compounds, have been reported to
cause toxic symptoms of a severe but usually nonfatal degree. Seven grams of
barium chloride (^4.5 g Ba) taken orally produced severe abdominal pain and
near-collapse, but not death (NAPCA 1969). However, Patty (1963) indicates
800 to 900 rag of barium chloride (550-600 mg Ba) to be a fatal, human dose.
Few cases of industrial poisoning from soluble barium salts have been reported.
Most of these have been cases of accidental ingestion (NAPCA 1969).
Ingested soluble barium compounds produce a strong stimulating effect on
all muscles of the body. The effect on the heart muscle is manifested by
irregular contractions followed by arrest of systolic action. Gastrointes-
tinal effects include vomiting and diarrhea. Central nervous system effects
observed include violent tonic and clonic spasms followed in some cases by
paralysis (NAPCA 1969).
Death resulting from barium exposure may occur in a few hours or a few
days, depending on the dose and solubility of the barium compound. A death
attributed to barium oxide poisoning has been reported. However, the usual
effect of exposure to dusts and fumes of barium oxide, barium sulfide, and
barium carbonate is irritation of eyes, nose, throat and the skin (NAPCA 1969).
Some of the BaSO, used in orthopedic bone cements has been shown to escape
into surrounding tissues (Rae 1977) . Mouse peritoneal macrophages exposed to
barium sulfate (10 particles.of unspecified size/macrophage) for periods up
to 144 hours showed a marked cytoplasmic vacuolization. Following cessation
of exposure only partial recovery occurred. No cell membrane damage was
observed (Rae 1977). The use of barium sulfate in barium swallows and
enemas \resulted in severe toxic ""affects on rupture of the intestinal tract
(Gardiner and Miller 1973, Bayer et al. 1974).
Inhalation of barium compounds is known to cause a benign respiratory
affliction (pneumoconiosis) called baritosis, which has been reported in
I workers exposed to finely divided barium sulfate in Italy, in barite miners
in the United States, Germany, and Czechoslovakia, and among workers exposed
to barium oxide. Generally, baritosis produces no symptoms of emphysema or
bronchitis, and lung function tests show no respiratory incapacity, although
some afflicted workers complain of dyspnea upon exertion. In the majority
of cases nodulation disappears if exposure to the barium compound is stopped
(NAPCA 1969). Aspirated BaSO, can result in granulomas of the lung and other
sites in man (Patty 1963) .
-------
Suicidal ingestion of a facial depilatory containing 15.8 g of BaS
resulted In paralysis of head, neck, arms, and trunk as well as respiratory
''.';.
paralysis. Therapy with MgSO,, saline and potassium resulted in recovery
within 24 hours (Gould et al. 1973).
Acute oral toxicity values for barium carbonate were: mouse LD = 200 mg/
kg; rat LD =» 50-200 mg/kg, LD5Q = 1480 + 340 mg/kg; rabbit ID = 170-300 mg/kg.
For barium chloride oral toxicity values were: mouse LD = 7-14 mg/kg; rat
LD = 355-533 mg/kg; rabbit LD = 170 mg/kg; dog LD = 90 mg/kg. For barium
flouride the acute oral LD for guinea pigs was 350 mg/kg (NAPCA 1969).
C. Other Relevant Information
Potassium acts as an in vitro antagonist of barium. Cardiac effects
such as arrythmias exerted by barium are also reversed rapidly by potassium.
Barium induces hypokalemia apparently by promoting a shift of potassium
from plasma into cells. The prolongation of action-potentials and depolariza-
tion of smooth and skeletal muscle by barium are thought to be due to
barium induced decreases in potassium conductance. In addition,, barium can
replace sodium to produce and/or prolong action potentials and can also
substitute for calcium in neurosecretory processes as described below (Peach 1975)
Barium chloride has been shown to cause arterial contractions in
_4
in vitro preparations of human digital arteries at concentrations of 10 to
10~ M (Jauernig and Moulds 1978). This activity was approximately 40 to 50
fold more than that of potassium chloride. At Bad- concentrations above 10~ M
contractions developed very slowly. The action of BaCl_ was inhibited by
^ _2
veraparmil, a calcium antagonist, at BaCl_ contractions below 10 M.
/3-r
-------
V. AQUATIC TOXICITY
According to an EPA report, experimental data indicate that in frtsh
and marine waters, the soluble barium concentration would need to exceed
50 mg/L before toxicity to aquatic life would be expected (U.S. EPA 1976).
Furthermore, in most natural waters, sufficient sulfate or carbonate is present
to precipitate barium in the water to a virtually insoluble, non-toxic
compound.
Soluble barium salts, however, are quite toxic. It has been reported
that 10 to 15 mg/L of barium chloride (9.9 mg/L Ba) was lethal to an aquatic
plant and two species of snails (species and origin unspecified). Bioassay
with this same barium salt showed the LCqf. for Coho Salmon to be 158 mg/L
(104 mg/L Ba) (U.S. EPA 1973).
VI. GUIDELINES
A. Human, Health
The OSHA Time Weighted Average for exposure to barium (soluble compound)
is 0.5 mg/rn3 (29 CFR 1910:1000).
B. Aquatic
There is no established criterion for barium in the aquatic environment.
The U.S. EPA (1973) suggests, however, that concentrations of barium equal
to or exceeding 1.0 mg/L constitute a hazard in the marine environment, and
levels less than 0.5 mg/L present minimal risk of deleterious effects.
a-f
-------
References
Bayer HP, Buhler F and Ostermeyer J, 1974. On the distribution of interstitial
and parenteral administered barium sulfate in the organism. Z. Rechtsmedizin
74: 207-215 (1974). (Ger.)
Chow T, Earl J, Reeds J, Hansen N, land Orphan V, 1978. Barium content of marine
sediments near drilling sites: A potent pollutant indicator. Marine Pollution
Bulletin. 9:97-99.
Clary JJ,.and Tardiff RG, 1974. The absorption, distribution and excretion of
orally administered 133-Bad., in weanling male rats. Toxicol. Appl. Pharmacol.
27:139.
Gardiner H and Miller RE, 1973. Barium peritonities. Am. J. Surgery 125:350-352.
Gould DB, Sortell MB and Lupariello AD. 1973. Barium sulfide poisoning. Arch.
Jut. Med. 132:891-894.
Guthrie RK, Ernst M, Cherry D, Murray H, 1979. Biomagnification of heavy metals
by organisms in a marine microcosm. Bull. Environm. Contam. Toxicol. 21:53-61.
Jauernig RA and Moulds RFJ. 1978. A human arterial preparation for studying the
effects of vasoactive-agents. Circ. Res. 42:363-358.
Kirkpatrick T. 1978. Sarium Compounds In. Kirk-Othmer1s Encyclopedia of
Chemical Technology, 3rd edition. John Wiley and Sons, Inc. New York. 3:463-479.
Kunesh CJ. 1978. Barium In Kirk-Othmer's Encyclopedia of Chemical Technology,
3rd edition. John Wiley and Sons, Inc. New York. 3:458-463.
NAPCA. 1969. Air Pollution Aspects of Barium and Its Compounds. National
Air Pollution Control Administration. PB 188 083.
Patty FA, Ed. 1963. Industrial Hygiene and Toxicology. Vol II. Toxicology.
2nd Edition. Interscience Publishers, New York; pp. 998-1002.
Peach MJ. 1975. Cations: Calcium, Magnesium, Barium, Lithium and Ammonium.
In: The Pharmaceutical Basis of Therapeutics. Goodman LS and Oilman A, Eds.
MacMillan Publishing Co., Inc. New York, pp. 791.
Rae.T, 1977. Tolerance of mouse macrophages in vitro to barium sulfate used in
orthopedic bone cement. Biomed. Mater. Res. 11:839-646.
U.S. Dept, of Labor. General Industry Standards Table Z-l. 29 CFR 1910:1000.
U.S. EPA 1972. National Inventory of Sources and Emissions - Barium, Baron,
Copper, Selenium, and Zinc 1969-Barium Section I. PB 210 676.
9
U.S. EPA 1973. Water Quality Criteria 1972. EPA-R-373-033.
-------
No. 14
Benzal Chloride
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
a-/
-------
No. 14
Benzal Chloride
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.
-------
BENZAL CHLORIDE
Summary
Benzal chloride has been reported to induce papillomas, carcinomas, and
leukemia in mice. Details of this work were not available for assessment.
Mutagenic effects of benzal chloride exposure have been reported in
Salmonella, Bacillus, and £_._ coll.
There is no available information on the teratogenic or adverse repro-
ductive effects of the compound.
-------
I. INTRODUCTION
Benzal chloride, CAS registry number 98-87-3, is a fuming, highly re-
fractive, colorless liquid. It is made by free radical chlorination of
toluene and has the following physical and chemical properties (Windholz,
1976; Verschueren, 1977):
Formula: C7H6C12
Molecular Weight: 161.03
Melting Point: -16°C
Boiling Point: 207°C
Density: 1.25614
Vapor Pressure: 0.3 torr ® 20°C
Solubility: alcohol, ether
insoluble in water
Benzal chloride is used almost exclusively for the manufacture of ben-
zaldehyde. It can also be used to prepare cinnamic acid and benzoyl chlor-
ide (Sidi, 1971).
II. EXPOSURE
A. Water
Benzal chloride is converted to benzaldehyde and hydrochloric acid
on contact with water (Sidi, 1971).
B. Food
Pertinent data could not be located in the available literature.
C. Inhalation
It is likely that the only source of benzal chloride in the air is
production facilities. The compound will hydrolyze in moist air to give
benzaldehyde and hydrochloric acid. Inhaled benzal chloride will probably
produce effects similar to those of inhaled hydrogen chloride.
»
D. Dermal
Benzal chloride is irritating to the skin (Sidi, 1971).
-------
III. PHARMACOKINETICS
Pertinent data on the pharmacokinetics of benzal chloride could not be
located in the available literature.
IV. EFFECTS
A. Carcinogenicity
In a study of Matsushita, et al. (1975) benzal chloride, along
with several other compounds, was found to induce carcinomas, leukemia, and
papillomas in mice. The details of the study were not available, but benzal
\
chloride was shown to possess a longer latency period than benzotrichloride
before the onset of harmful effects.
8. Mutagenicity
Yasuo, et al. (1978) tested the mutagenicity of several compounds
including benzal chloride in microbial assay systems which include the rec-
assay using Bacillus subtilis, the reversion assay using E_._ coli, and the
Ames assay using Salmonella typhimurium, with or without metabolic activa-
tion. Benzal chloride was positive in the rsc-assay without activation and
in the reversion assays using S^ typhimurium and §_._ coli with metabolic
activation.
C. Teratogenicity, Other Reproductive Effects and Chronic Toxicity
Pertinent data could not be located in the available literature.
D. Acute Toxicity
The oral LD^'s for mice and rats exposed to benzal chloride are
2,462 mg/kg and 3,249 mg/kg, respectively (NIOSH, 1978).
V. AQUATIC TOXICITY
Pertinent aquatic toxicity data could not be located in the available
literature.
-------
VI. EXISTING GUIDELINES AND STANDARDS
There are no existing guidelines or standards for exposure to benzal
chloride.
IV-<
-------
REFERENCES
Matsushito, H., et al. 1975. Carcinogenicities of the related compounds in
benzoyl chloride production. 49th Annual Meeting Japan Ind. Hyg. Soc., Sap-
pro, Japan, p. 252.
National Institute for Occupational Safety and Health. 1978. Registry of
Toxic Effects of Chemical Substances. NIOSH, OHEW Publ. No. 79-100.
Sidi, H. 1971. Benzyl Chloride, Benzal Chloride and Benzotrichloride. In;
Kirk-Othmer Encyclopedia of Chemical Technology, 2nd ed. Vol. 5, John Wiley
and Sons, New York. p. 281.
Verschueren, K. 1977. Handbook of Environmental Data on Organic Chemicals.
Van Nostrand Reinhold Co., New York. p. 127.
Windholz, M. (ed.) 1976. The Merck Index. 9th ed., Merck and Co., Inc.,
Rahway, New Jersey.
Yasuo, K., et al. 1978. Mutagenicity of benzotrichloride and related com-
pounds. Mutation Research 58: 143.
>¥-7
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No. 15
Benzene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON,' D.C. 20460
APRIL 30, 1980
is-i
-------
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 (CAG) has evaluated
benzene and has found sufficient evidence to indicate that
this compound is carcinogenic.
IS-*
-------
BENZENE -
Summary
Benzene is a widely used chemical. Chronic exposure to it causes
hematological abnormalities. Benzene is not mutagenic to bacteria, but
recent evidence shows it. to be carcinogenic, in animals. Also, benzene has
been shown to be leukemogenic in humans. There is suggestive evidence that
benzene may be teratogenic and may cause reduced fertility.
Benzene has been shown to be acutely toxic to aquatic organisms over a
concentration range of 5,800 to 495,000 pg/l. The marine fish striped bass
was the most sensitive species tested.
-------
BENZENE .
I. INTRODUCTION
This profile is based on the draft Ambient Water Quality Criteria Docu-
ment for Benzene (U.S. EPA, 1979).
Benzene (Benzol CgHg; molecular weight 78.1) is a volatile, color-
less, liquid hydrocarbon produced principally from coal tar distillation,
from petroleum by catalytic reforming of light naphthas, and in coal pro-
cessing and coal coking operations (Weast, 1972; Ayers and Muder, 1964; U.S.
EPA, 1976a). Benzene has a boiling point of -80.10C, a melting point of
5.5°C, a. water solubility of 1,780 mg/1 at 25°C, and a density of
0.87865 g/ml at 20°C. The broad utility spectrum of benzene includes its
use as: an intermediate for synthesis in the chemical and pharmaceutical
industries, a thinner for lacquer, a degreasing and cleaning agent, a sol-
vent in the rubber industry, an antiknock fuel additive, a general solvent
in laboratories and in the preparation and use of inks in the graphic arts
industries.
Current production of benzene in the U.S. is over 4 million metric tons
annually, and its use is expected to increase when additional production
facilities become available (Fick, 1976).
II. EXPOSURE
A. Water
A report by the National Cancer Institute (1977) noted benzene
levels of 0.1. to 0.3 ppb in four U.S. city drinking water supplies. One
measurement from a groundwater well in Jacksonville, Florida showed levels
higher than 100 ppb. One possible source of benzene in the aquatic environ-
»
ment is from cyclings between the atmosphere and water (U.S. EPA, 1976b).
Concentrations of benzene upstream and downstream from five benzene
-------
production or consumption plants ranged from less than 1.0 to 13.0 ppb, with
an average of 4.0 ppb (U.S. EPA, 1977a).
B. Food
Benzene has been detected in various food categories: fruits,
nuts, vegetables, dairy products, meat, fish, poultry, eggs, and several
beverages (Natl. Cancer Inst., 1977). NCI estimated that an individual
might ingest as much as 250 ug/day from these foods. The U.S. EPA (1979)
has estimated the weighted average bioconcentration factor of benzene for
the edible portion of fish and shellfish consumed by Americans to be 6.9.
This estimate is based on the octanol/water partition coefficient of benzene.
C. Inhalation
The respiratory route is the major source of human exposure to ben-
zene, and much of this exposure is by way of gasoline vapors and automotive
emissions. American gasolines contain, an average of 0.8 percent benzene (by
weight) (Goldstein, 1977a), and automotive exhausts contain an average of 4
percent benzene (by weight) (Howard and Durkin, 1974). Concentrations cf
benzene in the ambient air of gas stations have been found to be 0.3 to 2.4
ppm (Natl. Acad. Sci/Natl. Res. Council, 1977). Lonneman and coworkers.
(1968) measured an average concentration of 0.015 ppm in Los Angeles air
with a maximum of 0.057 ppm. The rural background level for benzene has
been reported as 0.017 ppb (Cleland and Kingsbury, 1977).
III. PHARMACOKINETICS
A. Absorption
The respiratory absorption of benzene by humans has been measured
several times .and found to be 40 to 50 percent retained on exposures to 110
ppm or less (Srbova, et al. 1950; Teisinger, at al. 1952; Hunter and Blair,
1972; Nomiyama and Nomiyama, 1974). Absorption was slightly less efficient,
Iff
-------
28 to 34 percent, on exposure to 6,000 ppm (Duvoir, et al. 1946).
Deichmann, et al. (1963) demonstrated that rats exposed to benzene (44 to 47
ppm) for long periods of time maintained blood benzene levels of approxi-
mately 4.25 mg/1.
B. Distribution
Free benzene accumulates in lipid tissue such as fat and bone
marrow, and benzene metabolites accumulate in liver tissue and bone marrow
(U.S. EPA, 1977b).
C. Metabolism
Benzene is metabolized by the mixed-function oxidase system to pro-
duce the highly reactive arene oxide (Rusch, et al. 1977). Arene oxide can
spontaneously rearrange to form phenol,, undergo enzymatic hydration followed
by dehydrogenation to form catechol or a glutathione derivative, or bind
covalently with cellular macromolecules. Evidence has accumulated that a
metabolite of benzene is responsible for benzene toxicity, in light of the
fact that a protection from benzene toxicity is afforded by inhibitors of
benzene metabolism (Nomiyama, 1964; Andrews, et al. 1977). The specific
metabolite that produces benzene toxicity has not yet been identified, but
likely candidates are benzene oxide, catechol, and hydroquinone, or the cor-
responding semiquinones (U.S. EPA, 1977b).
0. Excretion
Phenol measurement (free plus combined) of the urine of human vol-
unteers indicated that 50 to 87 percent of the retained benzene was excreted
as phenol (Hunter and Blair, 1972). The highest concentration of phenol was
found in the urine within about 3 hours .from termination of exposure.
Elimination via the lungs was no more than 12 percent of the retained 'dose.
-------
IV. EFFECTS
A. Carcinogenicity
On subcutaneous, dermal, oral, and inhalation exposure of rats and
mice to benzene, animal experiments have failed to support the view that
benzene is leukemogenic (U.S. EPA, 1979). Recent evidence suggests, how-
ever, that benzene is an animal carcinogen (Maltoni and Scarnato, 1579).
The evidence that benzene is a leukemogen for man is convincing and has re-
cently been reviewed by the Natl. Acad. Sci./Natl. Res. Coun. (1976), Natl.
Inst. Occup. Safety and Health (1977), and U.S.'- EPA (1977b). Vigliani and
Saita (1964) calculated a 20-fold higher risk of acute leukemia in workers
in northern Italy exposed to benzene. In some studies of acute leukemia
where benzene exposure levels have been reported, the concentrations have
generally been above 100 ppm (Aksoy, et al. 1972, 1974a,b, 1976a,b; Vigliani
and Fourni, 1976; Vigliani and Saita, 1964; Kinoshita, et al. 1965; Sellyei
and Kelemen, 1971). However, other studies have shown an association of
leukemic evidence to benzene levels less than 100 ppm (Infante et al., 1977;
Ott et al., 1978).
8. Mutagenicity
Benzene has not shown mutagenic activity in the
Salmonella/microsome in vitro bioassay (Lyon, 1975; Shahin, 1977; Simmon, et
al. 1977).
C. Teratogenicity
With rats exposed to 100 to 2,200 ppm benzene during days 6 to 15
of gestation some skeletal deformities were observed in their offspring
(Amer. Pet. Inst., 1978). Pregnant mice given single subcutaneous injec-
tions of benzene (3 ml/kg) on days 11 to 15 of gestation produced .fetuses
-------
with cleft palates, agnathia, and microagnathia, when delivered by caesarean
section on day 19 (Watanabe and Yashida, 1970).
D. Other Reproductive Effects
Gofmekler (1968) found complete absence of pregnancy in female rats
exposed continuously to 209.7 ppm benzene for 10 to 15 days prior to impreg-
nation. One of ten rats exposed to 19.8 ppm exhibited resorption of em-
bryos. The number of offspring per female exhibited an inverse relationship
to benzene exposure levels from 0.3 to 209.7 ppm.
E. Chronic Toxicity
In humans, pancytopenia (reduction of blood erythrocytes, leuko-
cytes, and platelets) has clearly been related to chronic benzene exposure
(Browning, 1965; Goldstein, 1977b; Intl. Labour Off., 1968; Snyder and
Kocsis, 1975).. Also, impairment of the immunological system has been re-
ported with chronic benzene exposure (Lange, et al. 1973a; Smolik, et al.
1973). Wolf, et al. (1956) reported that the no-effect level for blood
changes in rats, guinea pigs,. and rabbits was below 88 ppm in the air when
the animals were exposed for 7 hours per day for up to 269 days.
F. Other Relevant Information
In rabbits and rats injected subcutaneously with 0.2 mg/kg/day ben-
zene, the frequency of bone marrow mitosis with chromosomal aberrations in-
creased from 5.9 percent to 57.8 percent after an average of 18 weeks
(Kissling and Speck, 1971;. Dobrokhotov, 1972). In patients with benzene
induced aplastic anemia, lymphocyte chromosome damage, i.e., abnormal
karyo-type and deletion of chromosomal material, has been found (Pollini and
Cdlombi, 1964).
is-f
-------
V. AQUATIC TOXICITY
A. Acute
Acute toxicity values for freshwater fish are represented by
96-hour static LC5Q values of 20,000 to 22,490 ug/1 for the bluegill,
Lepomis macrochirus, to 386,000 ug/1 for the mosquitofish, Gambusia affinis,.
with goldfish, Carassius auratus, fathead minnows, Pimephales promelas, and
guppies, Poecilia reticulatius, being somewhat more resistant than the blue-
gill (U.S. EPA, 1979). Only one study was available for the acute effects
of benzene to freshwater invertebrates. A 48^hour static LC^ value of
203,000 jug/1 was obtained for the cladoceran Daphnia magna. LCeg values
for marine fish were reported as 5,800 and 10,900 ug/1 for striped bass,
Morone saxatilis. and 20,000 to 25,000 ^ig/1 for Pacific herring, Clupea
pallasi, and anchovy, Engraulis mordax, larvae. Marine invertebrates were
much more resistant with LC^ values of 27,000, 108,000, and 450,000 ^ig/1
reported for grass shrimp, Palaemonetes pugio, dungeness crab, Cancer
tnaqister, and the copepod, Tiqricopus californicus. respectively (U.S. EPA,
1979).
8. Chronic Toxicity
The only chronic toxicity test conducted on an aquatic species was
performed on the freshwater cladoceran, Daphnia magna. There were no ob-
served effects to these organisms at concentrations as high as 98,000 ug/1.
Pertinent information of the chronic effects of benzene on marine fish and
invertebrates could not be located in the available literature.
C. Plant Effects
A concentration of 525,000 jug/1 was responsible for a 50 percent
reduction in ceil numbers at 48-hours for the freshwater algae, Chlorella
vulqaris, while marine plants were reported as having growth inhibition at
-------
concentrations ranging from 20,000 to • 100,000 /jg/1 for the diatom,
Skeletonema costatum, with the dinoflagellate, Amohidinium carterae, and the
algae, Cricosohaera carterae, being intermediate in sensitivity with effec-
tive concentrations of 50,000 jug/1.
D. Residues
A bioconcentration factor of 24 was obtained for organisms with a
lipid content of 8 percent.
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
Existing air standards for occupational.exposure to benzene include
10 -ppm, an emergency temporary level of 1 ppm by the U.S. Occupational
Safety and Health Administration (Natl. Inst. Occup. Safety Health, 1974,
1977), and 25 ppm by the American Conference of Governmental Industrial
Hygienists (ACGIH, 1971). Based on human epidemiology data, and using a.
modified "one-hit" model, the EPA (1979) has estimated levels of benzene in
ambient water which will result in specified risk levels of human cancer:
Exposure Assumptions Risk Levels and Corresponding Draft Criteria
(per day)
0 10-7 10-6 10-5
2 liters of drinking water 0 0.15 jug/1 1.5 pg/1 15 pg/1
and consumption of 18.7
grams fish and shellfish.
Consumption of fish and 0 2.5jug/l 25 pg/1 250 /jg/1
shellfish only.
-------
8. Aquatic
Criterion for the protection of freshwater organisms have been
drafted at 3,100 ug/1 as a 24-hour average concentration not to exceed 7,000
jjg/1. For marine organisms criterion have been drafted as a 24-hour average
concentration of 920 pg/1 not to exceed 2,100 ug/1.
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BENZENE .
REFERENCES
ACGIH. 1971. Threshold limit values. American Conference of Governmental
Industrial Hygienists. Cincinnati, Ohio.
Aksoy, M., et al. 1972. Acute leukemia due to chronic exposure to benzene.
Am. Jour. Med. 52: 160.
Aksoy, M., et al. 1974a. Acute leukemia in two generations following
chronic exposure to benzene.. Hum. Hered. 24: 70.
Aksoy, M., et al. 1974b. Leukemia in shoe workers exposed chronically to
benzene. Blood 44: 837.
».
Aksoy, M., et al. 1976a. Combination of genetic factors and chronic expo-
sure to benzene in the aetiology of leukemia. Hum. Hered. 26: 149.
Aksoy, M.., et al. 1976b. Types of leukemia in chronic benzene poisoning.
A study in- thirty-four patients. Acta Haematologica 55: 65.
American Petroleum Institute. 1978. Table . 6 in Submission to Environ.
Health Comm. of the Sci. Advis. Board, U.S. Environ. Prot. Agency. Jan. 13,
1978.
Andrews,. L.S., et al. 1977... Biochem. Jour. 26: 293.
Ayers, G.W., and R.E. Muder. 1964. Kirk-Othmer encyclopedia of chemical
technology. 2nd ed. John Wiley and Sons, Inc., New York.
Browning, E. 1965. Benzene. In: Toxicity and metabolism of industrial
solvents. Elsevier Publishing Co., Amsterdam.
Cleland, J.G., and G.L. Kingsbury. 1977. Multimedia, environmental goals
for environmental assessment. EPA 600/7-77-136. U.S. Environ. Prot.
Agency, Washington, O.C.
Oeichmann, W.B., et al. 1963. The hemopoietic tissue toxicity of benzene
vapors. Toxicol. Appl. Pharmacol. 5: 201.
Dobrokhotov, v.B. 1972. The mutagenic influence of benzene and toluene
under experimental conditions. Gig. Sanit. 37: 36.
Duvoir, M.R., et al. 1946. The significance of benzene in the bone marrow
in the course of.benzene blood.diseases. Arch. Mai. Prof. 7: 77.
Fick, J.E. 1976.. To 1985: U.S. benzene supply/demand. Hydrocarbon Pro-
cessing. 55: 127.
Gofmekler, V.A. 1968. Effect in embryonic development of benzene and for-
maldehyde. Hyg. Sanit. 33: 327.
-------
Goldstein, B.D. 1977a. Introduction (Benzene toxicity: Critical review).
Jour. Toxicol. Environ. Health Suppl. 2: 1.
Goldstein, G.D. 1977b. Hematotoxicity in humans. Jour. Toxicol. Environ.
Health Suppl. 2: 69.
Howard, P.H., and P.R. Durkin. 1974. Sources of contamination, ambient
levels, and fate of benzene in the environment. EPA 560/5-75-005. U.S.
Environ. Prot. Agency, Washington, O.C.
Hunter, C.G., and 0. Blair. 1972. Benzene: Pharmakokinetic studies in
man. Ann. Occup. Hyg. 15: 193.
Infante, P.I., et al. 1977. Leukemia in benzene workers. Lancet. 2: 76.
International Labour Office. 1968. Benzene: Uses, toxic effects, substi-
tutes. Occup. Safety Health Ser., Geneva. v
Kinoshita, Y., et al.. 1965. A case of myelogenous leukemia. Jour. Japan
Haematol. Soe. 1965: 85.
Kissling, M., and B. Speck. 1971. Chromosomal aberrations in experimental
benzene intoxication. Helv. Med. Acta. 36: 59.
Lange, A., et al. 1973. Serum immunoglobulin levels in workers exposed to
benzene, toluene and xylene. Int. Arch. Arbeitsmed. 31: 37.
Lonneman, W.A., et al. 1968. Aromatic hydrocarbons in the atmosphere of
the Los Angeles basin. Environ. Sci. Technol. 2: 1017.
Lyon, J.P. 1975. Mutagenicity studies with benzene. Ph.D. thesis.
University of California.
Maltoni, C. and C. Scarnato. 1979. LaMedicina del Lavoro. 70(5): 352.
National Academy of Sciences/National Research Council. 1976. Health ef-
fects of benzene: A review. Natl. Acad. Sci., Washington, D.C.
National Academy of Sciences/National Research Council. 1977. Drinking
water and health. Natl. Acad. Sci., Washington, D.C.
National Cancer Institute. 1977. On occurrence, metabolism, and toxicity
including reported carcinogenicity of benzene. Summary rep. Washington,
D.C.
National Institute of Occupational Safety and Health. 1974. Criteria for a
recommended standard. Occupational exposure to benzene. U.S. Dep. Health
Edu. Welfare, Washington, O.C.
National.Institute of Occupational Safety and Health. 1977. Revised* recom-
mendation for an occupational exposure standard for benzene. U.S. Dept.
Health Edu. Welfare, Washington, D.C.
ff-'f '
-------
Nomiyama,. K. 1964. Experimental studies on benzene poisoning. Bull. Tokyo
Med. Dental Univ. 11: 297.
Nomiyama, K., and H. Nomiyama. 1974a. Respiratory retention, uptake and
excretion of organic solvents in man. Int. Arch. Arbertsmed. 32: 75.
Ott, M.G., et al. 1978. Mortality among individuals occupationally exposed
to benzene. Arch.. Environ. Health. 33: 3.
Pollini, G., and R. Colombi. 1964. Lymphocyte chromosome damage in benzene
blood dyscrasia. Med. Lav. 55: 641.
Rusch, G.M., et al. 1977. Benzene, metabolism. Jour. Toxicol. Environ.
Health Suppl. 2: 23.
Sellyei, M., and E. Kelemen. 1971. Chromosome study in a case of granu-
locytic leukemia with "Pelgerisation' 7 years 'after benzene pancytopenia.
Eur. Jour. Cancer 7: 83.
Shahin, M.M.' 1977. Unpublished results. The University of Alberta,
Canada. Cited in Mutat. Res. 47: 75.
Simmon, V.F., et al. 1977. Mutagenic activity of chemicals identified in
drinking water. 2nd Int. Conf. Environ. Mutagens, Edinburgh, Scotland,
July, 1977.
Smolik, R., et al. 1973. Serum complement level in workers exposed to ben-
zene, toluene and xylene. Int.. Arch. Arbeitsmed. 31: 243.
Snyder, R., and J.J. Kocsis. 1975. Current concepts of chronic benzene
toxicity. CRC Crit. Rev. Toxicol. 3: 265.
Srbova, J., et al. 1950. Absorption and elimination of inhaled benzene in
man. Arch. Ind. Hyg. 2: 1.
Teisinger, J., et al. 1952. The metabolism of benzene in man. Procovni
Lekarstvi 4: 175.
U.S. EPA. 1976a. Health effects of benzene: A review. U.S. Environ. Prot.
Agency, Washington, D.C.
U.S. EPA. 1976b. Air pollution assessment of benzene. Contract No. EPA
68-02-1495. Mitre Corp.
U.S. EPA. 1977a. Sampling in vicinity of benzene production and consump-
tion facilities. Preliminary report to Off. Tox. Subst. Battelle-Columbus
Laboratories.
U.S. EPA. 1977b. Benzene health effects assessment. U.S. Envirorv Prot.
Agency, Washington, D.C.
U.S. EPA. 1978. Environmental sources of benzene exposure: source contri-
bution factors. Contract No. 68-01-4635, Mitre Corp.
-------
U.S. EPA. 1979. Benzene: Ambient Water Quality Criteria. (Draft).
Vigliani, E.G., and A. Forni. 1976. Benzene and leukemia. Environ. Res.
11: 122.
Vigliani, E.G., and- G. Saita. 1964. Benzene and leukemia. New England
Jour. Med. 271: 872.
Watanabe, G.I., and S. Yoshida. 1970. The teratogenic effects of benzene
in pregnant mice. Act. Med. Biol. 19: 285.
Weast, R.C. 1972. Handbook of chemistry and physics. The Chemical Rubber
Co., Cleveland, Ohio.
Wolf, M.A., et al. 1956. Toxicological studies of certain alkylated ben-
zenes and benzene. Arch. Ind. Health 14: 387.
-------
No. 16
Benzldlne
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
16-1
-------
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. EPA1s Carcinogen Assessment Group (CAG) has evaluated
benzidine and has found sufficient evidence to indicate that
this compound is carcinogenic.
-------
BENZIDINE
Summary
Benzidine is a known carcinogen and has been linked to an in-
creased incidence of bladder cancer in humans and to cancers and
tumors in experimental animals. Benzidine is mutagenic in the Ames
assay and gives positive results in a test measuring DNA synthesis
inhibition in HeLa cells.
Pertinent data could not be located in --the available litera-
ture concerning the toxic effects of benzidine to aquatic organ-
isms.
-------
BENZIDINE
I. INTRODUCTION
Benzidine (4,4'-diaminobiphenyl) is an aromatic amine with
a molecular weight of 184.24. It exists at environmental tempera-
ture as a grayish-yellow, white, or reddish-gray crystalline
powder. Its melting point is 128°C, and its boiling point is
400°C. Benzidine's amino groups have pKa values of 4.66 and
3.57 (Weast, 1972). Two and one-half liter's of cold water will
dissolve 1 g of benzidine, and its solubility increases as water
temperatures rise.. Dissolution into organic solvents greatly
increases solubility. Benzidine is easily converted to and from
its. salt. Diazotization reactions involving benzidine will result
in colored compounds which are used as dyes in industry (U.S.
EPA, 1979} .
II. EXPOSURE
A. Water
Residential water supplies could be contaminated with
benzidine and its derivatives if the industrial effluent contain-
ing these chemicals were discharged into water supplies, however,
to date U.S. EPA (1979) finds no reports of such contamination.
B. Pood
While- food may become contaminated with benzidine due to
poor industrial, hygiene,. U.S. EPA (1979) reports that the ingestion
of contaminated food.is not a real, contribution to benzidine toxi-
city.
16-S
-------
The U.S. EPA (1979) has estimated a weighted average
bioconcentration factor (BCF) of 50 for benzidine, on octanol/water
partition coefficients and other factors.
C. Inhalation
Due to poor industrial hygiene and the use of open sys-
tems in the early days of the chemical and dye industries, inhala-
tion was formerly a principal route of entry for benzidine and its
derivatives into the body. At present workers wear respirators and
protective clothing to avoid exposure when cleaning equipment
(Haley, 1975).
0. Dermal
Skin absorption is. the most important route for entry of
benzidine into the body. Intact skin is easily penetrated by the
powdery benzidine base and is penetrated less readily by 3,3'-di-
methoxybenzidine and 3,3.'-dichlorobenzidine. High environmental
air temperatures and humidity increase skin absorption of benzi-
dine,1 3,3'-dimethoxybenzidine, 3,3'-dichlorobenzidine, and 3,3'-
dimethylbenzidine (U.S. EPA, 1979).
III. PHARMACOKINETICS
A. Absorption and Distribution
Benzidine is rapidly .absorbed into the bodies of intra-
veneously injected rats, with maximum concentrations of free
and bound benzidine occurring at two and three hours, respectively.
The highest concentration of benzidine was found in the blood
followed by the liver, kidney, spleen, heart, and lung (Soloimskaya,
1968) . Four hours after rats received intraperitoneal injections
of 100 mg benzidine/kg, high concentrations of the compound were
found in the stomach, stomach contents, and small intestine;
-------
12 hours after administration, benzidine was found in the small
intestine and its contents. Benzidine levels in the liver, the
target organ for toxicity in the rat, remained relatively high
and constant throughout the 12-hour period. The conjugated material,
indicative of the presence of metabolites, was high in urine
and tissues at 12 hours (Baker and Deighton, 1953) . In rats
given 20 rag of 3,3 '-dimethylbenzidine subcutaneously once a week
for eight weeks, amines were concentrated in the Zymbal's gland,
followed by the kidney, omentum, spleen, «nd liver (Pliss and
Zabezhinsky, 1970).
B. Metabolism and Excretion
The urine of humans exposed to benzidine contained a num-
ber of metabolites: N-hydroxyacetylamino benzidine, 3-hydroxyben-
zidine, 4-amino-4-oxybiphenyl, and mono- and diacetylbenzidine
(Engelbertz and Babel,. 1953; Troll, et al. 1963; Sciarini and
Meigs, 1961; Vigliani and Barsotti, 1962). Benzidine metabolites
in other species generally differ considerably from those in
humans, although 3-hydroxybenzidine and its conjugation products
are common to both animals and humans (Haley, 1975).
The half-life of benzidine in blood was 68 hours for
the rat and 88 hours for the dog. Rats, dogs, and monkeys ex-
creted 97, 96, and 83 percent, respectively, within one week
of an 0.2 rag/kg dose of benzidine. The respective excretion
rates for 3,3'-dichlorobenzidine were 98, 97, 88.5 percent.
Dogs and monkeys excreted free benzidine in the urine and dichloro-
•
benzidine in the bile while rats excreted both compounds via
the bile (Kellner, et al. 1973).
-------
Workers exposed to benzidine, who perspire freely and
have wet skin, contain a higher concentration of benzidine in the
urine (U.S. EPA, 1979). • •
IV. EFFECTS
A. Carcinogenicity
Benzidine is a proven human carcinogen. Its primary site
of tumor induction is the urinary bladder (U.S. EPA, 1979).
Workers exposed to benzidine have a carcinogenicity risk
14 times higher than that of the unexposed population (Case, et al.
1954). The incidence of bladder tumors in humans resulting from
occupational exposures to aromatic amines (benzidine) was first re-
searched in Germany in 1895. In the United States, the first cases
of this condition were: diagnosed in 1931 and reported in 1934.
A number of studies document the high incidence of blad-
der tumors in workers exposed to benzidine and other aromatic
amines (Gehrman, 1936; Case, et al. 1954; Scott, 1952; Deichmann
and Gerarde, 1969; Hamblin, 1963; Rye, et al. 1970; Int. Agency
Res. Cancer, 1972; Riches, 1972; Sax, 1975; Zavon, et al. 1973;
Mancuso and El-Attar, 1966, 1967; Kuzelova, et al. 1969; Billiard-
Duchesne, 1960; Vigliani and Barsotti, 1962; Forni, et al. 1972;
Tsuchiya, et al. 1975; Goldwater, et al. 1965). Initial exposure
concentration, exposure duration, and years of survival following
exposure as well as work habits and personal hygiene are involved
in the development of carcinomas where benzidine appears to be im-
plicated (Rye, et al. 1970).
Benzidine has also produced carcinogenic effects or
»
tumors in the mouse (hepatoma, lymphoma), the rat (hepatoma,
-------
carcinoma of the Zymbal's gland, adenocarcinoma, sarcoma, mammary
gland carcinoma), the hamster (hepatoma, liver carcinoma, chol-
angioma), the rabbit (bladder tumor, gall bladder tumor) and
the dog (bladder tumor) (Haley, 1975).
At present, there is no evidence indicating that 3,3'-di-
methylbenzidine, 3,3'-dimethoxybenzidine, or 3,3'-dichlorobenzi-
dine are human bladder carcinogens (Rye, et al. 1970).
B. Mutagenicity
In the Ames test, benzidine is mutagenic to Salmonella
typhimurium strains TA1537, TA1538, and TA98. Benzidine produces
positive results in a DNA synthesis inhibition test using HeLa
cells (Ames, et al. 1973; McCann, et al. 1975; Garner, et al. 1975;
U.S. EPA, 1978; U.S. EPA, 1979).
C. Teratogenicity
No teratogenic effects of benzidine have been reported in
humans. Mammary gland tumors and lung adenomas occurred in progeny
of female mice that received 8 to 10 mg of 3,3'-dimethylbenzidine
in. the last week of pregnancy. The tumors may have resulted from
transplacental transmission of the chemical or from its transfer to
neonates in milk from dosed mothers (Golub, et al. 1974).
D. Other Reprodutive Effects
Pertinent data could not be located in the available
literature.
E. Chronic Toxicity
Glomerulonephritis and nephrotic syndrome were produced
in Sprague-Dawley rats fed 0.043 percent N,N' -diacetylbenzidin-e, a
metabolite of benzidine, for at least two months (Harman, et al.
1952; Harman, 1971). Glomerulonephritis also developed in rats fed
if
-------
benzidine (Christopher and Jairam, 1970), and in rats receiving in-
jections either 100 mg subcutaneously or 100 or 200 mg intraper-
tioneally of N,N'-diacetylbenzidine. The severity of the lesions
in the later study was dose-related (Bremner and Tange, 1966).
Mice fed 0.01 and 0.08 percent benzidine dihydrochloride
exhibited decreased carcass, liver, and kidney weights, increased
spleen and thymus weights, cloudy swelling of the liver, vacuolar
degeneration of the renal tubules, and hyperplasia of the myeloid
elements in the bone marrow and of the lymphoid cells in the spleen
\
and thymic cortex. There was a dose dependent weight loss of 20
percent in males and 7 percent in females (Rao, et al. 1971).
P. Other Relevant Information
Dermatitis, involving both benzidine and its dimethyl
derivative, has .been reported in workers in the benzidine dyestuff
industry. Individual sensitivity played a large role in the de-
velopment of this condition (Schwartz, et al. 1947).
V. AQUATIC TOXICITY
Pertinent data could not be located in the available litera-
ture concerning the toxic effects of benzidine to aquatic 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 ambient water concentration standard for benzidine
is zero, due to potential carcinogenic effects of exposure to
16-10
-------
benzidine by ingestion of water and contaminated aquatic organisms.
U.S. EPA may set standards at an interim target risk level in
the range of IQ~^, 10, or 10 with respective corresponding'
criteria of 1.67 x 10~3 ug/1, 1.67 x 10~4, and 1.67 x 10~5 ug/1.
B. Aquatic
Criteria for the protection of freshwater or marine
aquatic organisms were not drafted, due to a lack of toxicological
evidence (U.S. EPA, 1979).
It'll
-------
BENZIDINE
REFERENCES
Ames, B. et al. 1973- Carcinogens are mutagens: A simple test system
combining liver homogenates for activation and bacteria for detection.
Proc. Natl. Acad. Sci. 70: 2281
Baker, R.K., and J.G. Deighton. 1953. The metabolism of benzidine in
the rat. Cancer Res. 13: 529.
Billiard-Buchesne, J.L. 1960. Cas Francais de tumeurs professionelles
de la vessie. Acta Unio Int. Contra Cancruzn (Belgium) 16: 284.
Bremner, D.A., and J. D. Tange. 1966. Renal and neoplastic lesions
after injection of N,N'-diacetylbenzidine. Arch. Pathol. 81: 146.
Case, R.A.M., et al. 1954. Tumours of the urinary bladder in workmen
engaged in the manufacture and use of certain dyestuff intermediates in
the British chemical industry: Part I. The role of aniline, benzidine,
alpha-naphthylamine and beta-naphthylamine. Br. Jour. Ind. Med. 11: 75.
Christopher, K.J., and B.T. Jairam. 1970. Benzidine
poisoning in white rats. Sci. Cult. (India) 36: 511.
Deichmann, W.B., and H.W. Gerarde. 1969. Toxicology of drugs and chemicals.
Academic Press, New York.
Englebertz, P., and E. Babel. 1953. Nachweis von benzidin und seinen
umwand. lungs produkten im harn und in organteilen. Zentr. Arbeitsmed.
Arbeitsschutz 3: 161.
Forni, A., et al. 1972. Urinary cytology in workers exposed to carcinogenic
aromatic amines: A six-year study. Acta Cytol. 16: 142.
Garner, et al. 1975- Testing of some benzidine anologies for microsomal
activation to bacterial mutagens. Cancer Let. 1: 39-
Gehrman, G.H. 1936. Papilloma and carcinoma of the bladder in dye workers.
Jour. Am. Med. Assoc. 107: 1436.
Goldwater, L.J., et al. 1965. Bladder tumors in a coal tar dye plant.
Arch. Environ. Health 11: 814.
Golub, N.I., et al. 1974. Oncogenic action of some nitrogen compounds
on the progeny of experimental mice. Bull. Exp. Biol. Med. (USSR) 78:
1402.
Haley, T.J. 1975. Benzidine revisited: A review of the literature and
problems associated with the use of benzidine and its congeners. Clin.
Toxicol. 8: 13.
-------
Hamblin, D.O. 1963- Aromatic nitro and amino compounds. Page 2105 in
D.W. Fassett and D.D. Irish, eds. Industrial hygiene and toxicology.
Vol. II. Interscience Publishers, New York.
Harman, J.W. 1971. Chronic glomerulonephritis and the nephrotic syndrome
induced in rats with M,N'-diacetylbenzidine. Jour. Pathol. (Scotland)
104: 119.
Harraan, J.W., et al. 1952. Chronic glomerulonephritis and nephrotic
syndrome induced in rats by M,N'-diacetylbenzidine. Am. Jour. Pathol.
28: 529.
International Agency for Research on Cancer. 1972. IARC monographs on
the evaluation of carcinogenic risk of chemicals to man. Vol. I. Lyon,
France.
^
Kellner, H .M., et al. 1973- Animal, studies on the kinetics of
benzidine and 3,3'-dichlorobenzidine. Arch. Toxicol. (West Germany)
31: 61.
Kuzelova, M., et al. 1969- Sledovani pracovniku zamestnanych pri
vyrobe benzidinu. Prac. Lek. (Czechoslovika) 21: 310.
Mancuso, T.F., and A.A. El-Attar. 1966. Cohort studies of workers
exposed to. betanaphthylamine and benzidine. Ind. Med. Surg. 35: 571.
Mancuso, T.F., and A.A. El-Attar. 1967. Cohort study of workers exposed
to betanaphthylamine and benzidine. Jour.. Occup. Med. 9: 277.
McCann, J., et al. 1975. Detection of carcinogens as. mutagens in the
Salmonella/microsome test: Assay of 300 chemicals. Proc. Natl. Acad.
Sci. 72: 5135.
Pliss, G.B., and M.A. Zabezhinsky. 1970. Carcinogenic properties of
orthotolidine (3,3'-dimethylbenzidine). Jour. Natl. Cancer Inst. 45: 283-
Rao, K.V.N., et al. 1971. Subacute toxicity of benzidine in the young
adult mice. Fed. Proc'. Am. Soc. Exp. Biol. 30: 344.
Riches, E. 1972. Industrial cancers. Nurs. Mirror (Great Br.) 134: 21.
Rye, W.A., et al. 1970. Facts and myths concerning aromatic diamine
curing agents. Jour. Occup. Med. 12: 211.
Sax, N.I. 1975. Dangerous properties of industrial materials. 4th ed.
Van Nostrand Reinhold Co., New York.
Schwartz, L. , et al.. 1947. Dermatitis in synthetic dye manufacture.
Page 268 in Occupational diseases of the skin. Lea and Febiger, Philadelphia,
Pa.
-------
Sciarini, L.J., and J.W. Meigs. 1961. The biotransformation of benzidine.
II. Studies in mouse and man. Arch. Environ. Health 2: 423.
Scott, T.S. 1952. The incidence of bladder tumours in a dyestuffs factory.
Br. Jour. Ind. Med. 9: 127.
Soloimskaya, E.A. 1968. The distribution of benzidine in rat organs and
its effect on the peripheral blood. Vopr.. Onkol. (USSR) 14: 51.
Troll, W., et al. 1963- N-hydroxy acetyl amino compounds, urinary metabolites
of aromatic amines in man. Proc. Am. Assoc. Cancer Res. 4: 68.
Tsuchiya, K., et al. 1975. An epidemiological study of occupational
bladder tumours in the dye industry of Japan. Br. Jour. Ind. Med. 32:
203.
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. Washington, D.C.
U.S. EPA. 1979. Benzidine: Ambient Water Quality Criteria. (Draft).
Vigliani, E.G., and M. Barsotti. 1962. Environmental tumors of the
bladder in some. Italian dyestuff factories. Acta Unio Int. Contra Cancrum
(Belgium) 18: 669.
Weast, R.C., ed. 1972. Handbood of chemistry and physics. 53rd ed. CRC
Press, Cleveland, Ohio.
Zavon, M.R., et al. 1973- Benzidine exposure as a cause of bladder
tumors. Arch. Environ. Health 27: 1.
-------
No. 17
Benz(a)anthracene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
17-1
-------
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
benz(a)anthracene and has found sufficient evidence to indi-
cate that this compound is carcinogenic.
-------
BENZ(a)ANTHRACZNS
SUMMARY
Benz(a)anthracene is a member of the polycyclic aro-
matic hydrocarbons (PAH) class. Although the PAH class
contains several,well-known potent carcinogens, benz(a)an-
thracene displays only weak carcinogenic activity. Benz(a)-
anthracene apparently does not display remarkable acute
or chronic toxicity other than the capability to induce
tumors on the skin of mice. Although exposure to benz(a)-
anthracene in the environment occurs in conjunc'tion with
exposure to other PAH, it is not known how these compounds
may interact in human systems. Furthermore, the specific
effects of benz(a)anthracene in humans are not known.
The only toxicity data for any of the polycyclic aro-
matic hydrocarbons is an 87 percent mortality of freshwater
fish exposed to 1,000 ug/1 benz(a)anthracene for six months.
-------
I. INTRODUCTION
This profile is based primarily on the Ambient Water
Quality Criteria Document for Polynuclear Aromatic Hydrocar-
bons (U.S. EPA, 1979a) and the Multimedia Health Assessment
Document for Polycyclic Organic Matter (U.S. EPA, 1979b).
Benz(a)anthracene (CngH,-) is °ns °f the family of
polycyclic aromatic hydrocarbons (PAH) formed as a result
of incomplete combustion of organic material. Benz(a)anthra-
cene has the following physical/chemical properties (U.S.
EPA, 1979b):
Melting point: 159.5-160.5°C
Boiling Point: 400°C _?
Vapor Pressue: 1.10 x 10 torr
PAH, including benz(a)anthracene, are ubiquitous in
the environment, being found in ambient air, food, water,
soils, and sediment (U.S. EPA, 1979b) . The PAH class con-
tains a number of potent carcinogens (e.g., benzo(a)pyrene),
weak carcinogens (e.g., benz(a)anthracene), and cocarcino-
gens (e.g., fluoranthene), as well as numerous non-carcino-
gens (U.S. EPA, 1979b).
PAH which contain more than three rings (such as benz(a)-
anthracene) are relatively stable in the environment, and
may be transported in air and water by adsorption to particu-
late matter. However, biodegradation and chemical treatment
are effective in eliminating most PAE in the environment.
The reader is referred to the PAH Hazard Profile for
•a more general discussion of PAH (U.S. EPA, 1979c).
17-S
-------
II. EXPOSURE
A. Water
Benz(a)anthracene levels in surface waters or
drinking water have not been reported. However, the concen-
tration of six representative PAH (net including benz(a)-
anthracene) in U.S. drinking water averaged 13.5 ng/1 (Basu
and Saxena, 1977, 1978).
- B. Food
Benz(a)anthracene has been detected in a wide
variety of foods including margarine (up to 29.5 ppb), smoked
fish (up to 1.7 ppb), yeast (up to 2C3 ppb) , and cooked
or smoked meat (up to 33.0 ppb) (U.S. EPA, 1979a). The
total intake of all types of PAH through the diet has been
estimated at 1.6 to 16 jag/day (U.S. EPA, 1979b) . The U.S.
EPA (1979a) has estimated the bioconcer.tration factor for
benz(a)anthracene to be 3,100 for the edible portions of
fish and shellfish consumed by Americans. This estimate
is based on the octanol/water partition coefficient of benz-
(a)anthracene.
C. Inhalation
Benz(a)anthracene has been repeatedly detected
in ambient air at concentrations ranging from 0.18 to 4.5.
ng/m3" (U.S. EPA, 1979a) . Thus, the hacan daily intake of
benz(a)anthracene by inhalation of anbient air may ber in
the range of 3.42 to 87.4 ng, assuming that a human breathes
19 m of air per day.
-------
III. PHARMACOKINETICS
There are no data available concerning the pharraaco-
kinetics of benz(a)anthracene, or other PAH, in humans.
Nevertheless, it is possible to make limited assumptions
based on the results of animal research conducted with sev-
eral PAH, particularly benzo(a)pyrene.
A. Absorption
The absorption of benz(a)anthracene in humans
has not been studied. However, it is known (U.S. EPA, 1979a)
that, as a class, PAH are well-absorbed across the respira-
tory and gastrointestinal epithelia. In particular, benz(a)-
anthracene was reported to be readily transported across
the gastrointestinal mucosa (Rees, et al., 1971). The high
lipid solubility of compounds in the PAH class supports
this observation.
B. Distribution
The distribution of benz(a)anthracene in mammals
has not been studied. However, it is known (U.S. EPA, 1979a)
that other PAH are widely distributed throughout the body
following their absorption in experimental rodents. Rela-
tive to other tissues, PAH tend to localize in body fat
and fatty tissues (e.g., breast).
C. Metabolism
Benz(a)anthracene, like other PAH, is metabolized
by the microsomal mixed-function oxidase enzyme system in
mammals (U.S. EPA, 1979b). Metabolic attack on one or more
•
of the aromatic double bonds leads to the formation of phenols
-------
and isomeric dihydcodiols by the intermediate formation
of reactive epoxides. Dihydrodiols are further metabolized
by microsomal mixed-function oxidases to yield diol epoxides,
compounds which are known to be biologically reactive inter-
mediates for certain PAH. Removal of activated intermediates
by conjugation with glutathione or glucuronic acid, or by
further metabolism to tetrahydrotetrols, is a key step in
protecting the organism from toxic interaction with cell
macromolecules. v
D. Excretion
The: excretion of benz (a) anthracene by'mammals
has not been studied. However, the excretion of closely
related PAH is rapid and occurs mainly via the feces (U.S.
EPA, 1979a). Elimination in the bile may account for a
significant percentage of administered PAH. However, the
rate of disappearance of various PAH from the body and
the principal routes of excretion are influenced both by
the structure of the parent compound and the route of admini-
stration (U.S. EPA, 1979a). It is unlikely that PAH will
accumulate in the body with chronic low-level exposures.
IV.. EFFECTS
A. Carcinogenicity
Benz(a)anthracene is recognized as a weak carcino-
gen in mammals (U.S. EPA, 1979a,b). It is a tumor initiator
on- the skin of mice, but failed to yield significant results
in the strain A mouse pulmonary tumor bioassay system.
*
IT-?
-------
B. Mutagenicity
Benz(a)anthracene has shown weak rnutagenic activity
in several test system, including Ames Salmonella assay,
somatic cells in culture, and sister chromatid exchange
in Chinese hamster cells (U.S. EPA, 1979b) ..
C. Teratbgenicity
Pertinent data could not be located in the avail-
able literature concerning the possible teratogenicity of
benz(a)anthracene. Other related PAH are apparently not
significantly teratogenic in mammals (U.S. EPA, 1979a).
D. Other Reproductive Effects
Pertinent data could not be located in the avail-
able literature.
E. Chronic Toxicity
The chronic toxicity of benz(a)anthracene has
not been extensively studied. The repeated injection of
benz(a)anthracene in mice for 40 weeks (total dose, 10 rag.)
had little apparent effect on longevity or organ weights
(U.S. EPA, 1979b).
V. AQUATIC TOXICITY
A. Acute
Pertinent data could not be located in the avail-
able information.
B. Chronic
No standard chronic toxicity data have been pre-
sented on freshwater or marine species. The only toxicity'
data available for benz(a)anthracene for fish is an 87 per-
-------
cent mortality on the freshwater bluecill sunfish, Lepomis
macrochirus, exposed to 1,000 ^ig/1 fcr six months (Brown,
et al., 1975).
C. Plant Effects
Pertinent data could not be located in the avail-
able information.
VI. EXISTING GUIDELINES AND STANDARE3
Neither the human nor the aquatic criteria derived
by U.S. EPA (1979a), which are summarized below, have gone
through the process of review; therefore, there is a pos-
sibility that these criteria will be changed.
A. Human
There are no established exposure criteria for
benz(a)anthracene. However, PAH as a class are regulated
by several authorities. The World Health Organization (1970)
has recommended that the concentration of PAH in drinking
water (measured as the total of fluorsn.thene, benzo(g,h,i)-
perylene, benzo(b)fluoranthene, benzc(>)fluoranthene, indeno-
(l,2,3-cd)pyrene, and benzo(a)pyrene) not to exceed 0.2
•ug/1. Occupational exposure criteria have been established
for coke oven emissions, coal tar products, and coal tar
pitch volatiles, all of which contain large amounts of PAH
including benz(a)anthracene (U.S. EPA, 1979a)..
The U.S'i- EPA (1979a) draft recommended criteria
for PAH in. water are based upon the ex-rapolation of animal.
carcinogenicity data for benzo (a) pyrsr.s and dibenz (a, h) anthra-
cene.
-------
B. Aquatic
Data were insufficient to propose criteria for
freshwater or marine environments.
-------
8ENZ(a)ANTHRACENE
REFERENCES
Basu, O.K., and J. Saxena. 1977. Analysis of raw and drinking water sam-
ples for polynuclear aromatic hydrocarbons. EPA PO No. CA-7-2999-A, and
CA-8-2275-B. Expo. Evalu. Branch, HERL, Cincinnati, Ohio.
Basu, O.K., and J. Saxena. 1978. Polynuclear aromatic hydrocarbons in
selected U.S. drinking waters and their raw water sources. Environ. Sci.
Technol. 12: 795.
Brown, E.R., et al. 1975. Tumors in fish caught in polluted waters: possi-
ble explanations. Comparative Leukemia Res. 1973. Leukemogenesis. Univ.
Tokyo Press/Karger, Basel, pp. 47-57. v
Rees, E.O., et al. 1971. A study of the mechanism of intestinal absorption
of benzo(a)pyrene. Biochem. Biophys. Act. 225: 96.
U.S. EPA. 1979a. Polynuclear Aromatic Hydrocarbons: Ambient Water Quality
Criteria (Draft), '
U.S. EPA. 1979b. Multimedia health assessment document for polycyclic or-
ganic matter. Prepared under "contract by J. Santodonato, et al., Syracuse
Research Corp.
U.S. EPA. 1979c. EnvironmentaT"Criteria and 'Assessment Office. Polynu-
clear Aromatic Hydrocarbons: Hazard Profile (Draft).
World. Health Organization. 1970. European standards fcr drinking water.
2nd. ed.j Geneva.
-------
No. 18
Benzo(b)£luo ranthene
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
benzo(b)fluoranthene and has found sufficient evidence to
indicate that this compound is carcinogenic.
-------
BEN ZO(b)FLUORANTHEN E
SUMMARY
Benzo(b)fluoranthene is a member of the polycyclic aro-
matic hydrocarbon (PAH) class. Numerous compounds in the PAH
class are well known for their carcinogenic effects in ani-
mals. Benzo(b)fluoranthene is carcinogenic to the skin of
mice and produces sarcomas when injected in mice. Very
little is known concerning the non-carcinogenic effects pro-
duced by chronic exposure to benzo(b)fluoranthene. Although
exposure to benzo(b)fluoranthene in the environment occurs in
conjunction with exposure to other PAH, it is not known how
these compounds may interact in human systems. Furthermore,
the specific effects of benzo(b)fluoranthene in humans are
not known.
Standard acute or chronic toxicity testing for aquatic
organisms has not been found in the available literature.
>*-
-------
BEN ZO(b)FLUORANTHEN E
I. ' INTRODUCTION
This profile is based primarily on the Ambient Water
Quality Criteria Document for Polynuclear Aromatic Hydrocar-
bons (U.S. EPA, 1979a) and the Multimedia Health Assessment
Document for Polycyclic Organic. Matter (U.S. EPA, 1979b).
Benzo(b)fluoranthene (C2QH12^ is one of the family
of polycyclic aromatic hydrocarbons (PAH) formed as a result
of incomplete combustion of organic material. Its physical/
chemical properties have not been well-characterized, other
than a reported melting point of 167°C (U.S. EPA, 1979b) .
PAH, including benzo(b)fluoranthene, are ubiquitous in
the environment, being found in ambient air, food, water,
soils, and sediment (U.S. EPA, 1979b). The PAH class con-
tains a number of potent carcinogens (e.g., benzo(a)pyrene),
moderately active carcinogens (e..g., benzo(b)f luoranthene) ,
weak carcinogens (e.g., benz(a)anthracene), and cocarcinogens
(e.g., fluoranthene), as well as numerous noncarcinogens
(U.S. EPA, 1979b) .
PAH which contain more than three rings (such as benzo-
(b)fluoranthene) are relatively stable in the environment and
may be transported in air and water by adsorption to particu-
• lar matter. However, biodegradation and chemical treatment
are effective in eliminating most PAH in the environment.
Refer to. the PAH Hazard Profile (U.S. EPA, 1979c) for a more
general treatment of PAH.
-------
II. EXPOSURE
A. Water
In a monitoring survey of U.S. drinking water, Basu
and Saxena (1977, 1978) were unable to detect benzo(b)fluor-
anthene. However, the concentration of six representative
*
PAH (fluoranthene, benzo(a)pyrene, benzo(g h i)perylene,
benzo(j)fluoranthene, benzo(k)fluoranthene, indeno(l,2,3-cd)
pyrene) averaged 13.5 ng/1.
B. Food
Levels of benzo(b)fluoranthene have not been re-
ported for food. However, the total intake .of all types of
PAH through the diet has.. been estimated at 1.6 to 16 ug/day
(U.S. EPA, 1979b).. The U.S. EPA (1979a) has estimated the
weighted average bioconcentration factor of benzo(b)fluor-
anthene to be 6,800 for the edible portion of fish and shell-
fish consumed by Americans. This estimate is based on the
octanol/water partition coefficient of benzo(b)fluoranthene.
C. Inhalation
Benzo(b)fluoranthene has been detected in ambient
air at concentrations ranging from 0.1 to 1.6 ng/m^ (Gordon
and Bryan, 1973). Thus, the human daily intake of benzo(b)-
fluoranthene by inhalation of ambient air may be in the range
of 1.9 to 30.4 ng, assuming that a human breathes 19 m^ of
air per day.
Ill. PHARMACOKINETICS
Pertinent data could not be located in the available
literature concerning the pharmacokinetics of benzo(b)fluor-
anthene, or other PAH, in humans. Nevertheless, it is pos-
-------
sible to make limited assumptions based on the results of
animal research conducted with several PAH, particularly
benzo(a)pyrene.
A. Absorption
The absorption of benzo(b)fluoranthene in humans or
other animals has not been studied. However, it is known
(U.S. EPA, 1979a) that, as a class, PAH are well-absorbed
across the respiratory and gastrointestinal epithelia. The
high lipid solubility of compounds in the PAH class supports
\
this observation.
B. Distribution
The distribution of benzo(b)fluoranthene in mammals
has not been studied. However, it is known (U.S. EPA, 1979a)
that other PAH are widely distributed throughout the body
following their absorption in experimental rodents.. Relative
to other tissues, PAH tend to localize in body fat and fatty
tissues (e.g., breast).
C. Metabolism
The metabolism of benzo(b)fluoranthene in mammals
has not been studied. Benzo(b)fluoranthene, like other PAH,
is most likely metabolized by the microsomal mixed-function
oxidase enzyme system in mammals (U.S. EPA, 1979b). Meta-
bolic attack, on one or more of the aromatic double bonds
leads to the formation of phenols and isomeric dihydrodiols
by the intermediate formation of reactive epoxides. Dihydro-
diols are further metabolized by microsomal mixed-function •
oxidases to yield diol epoxides, compounds which are known to
be biologically reactive intermediates for certain PAH. Re-
moval of activated intermediates by conjugation with gluta-
-------
thione or glucuronic acid, or by further metabolism to tetra-
hydrotetrols, is a key step in protecting the organism from
toxic interaction with cell macromolecules.
D. Excretion
The excretion of benzo(b)fluoranthene by mammals
has not been studied. However, the excretion of closely re-
lated PAH is rapid and occurs mainly via the feces (U.S. EPA,
1979a). Elimination in the bile may account for a signifi-
cant percentage of administered PAH. It is unlikely that PAH
«.
will accumulate in the body with chronic low-level exposures.
IV. EFFECTS
A. Carcinogenicity
Benzo(b)fluoranthene is regarded as a moderately
active carcinogen (U.S. EPA, 1979b). It is carcinogenic by
skin painting on mice, and by subcutaneous injection in mice
(U.S. EPA, 1979b; LaVoie, et al. 1979). The sarcomagenic
potency of benzo(b)fluoranthene is similar to that of benzo-
(a)pyrene (Buu-Hoi, 1964).
B. Mutagenicity
Benzo(b)fluoranthene is mutagenic in the Ames Sal-
monella assay in the presence of a microsomal activating sys-
tem (LaVoie, et al. 1979). It is also positive in the induc-
tion of sister-chromatid exchanges by intraperitoneal injec-
tion in Chinese hamsters (U.S. EPA, 1979b).
C. Teratogenicity
Pertinent data could not be located in the litera-
ture available concerning the possible teratogenicity of
-------
benzo(b)fluoranthene. Other related PAH are apparently not
significantly teratogenic in mammals (U.S. EPA, 1979a).
D. Other Reproductive Effects
Pertinent information could not be located in the
available literature.
E. Chronic Toxicity
Published data are not available regarding the non-
carcinogenic chronic effects of benzo(b)fluoranthene. It is
known, however, that exposure to carcinogenic PAH may produce
widespread tissue damage as well as selective destruction of
proliferating tissues (e.g., hematopoietic and lyraphoid sys-
tems) (U.S. EPA, 1979a).
V. AQUATIC TOXICITY
Pertinent information could not be located in the avail-
able literature.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
There are no established exposure criteria for
benzo(b)fluoranthene. However, PAH as a class are regulated
by several authorities. The World Health Organization has
recommended that the concentration of PAH in drinking water
(measured as the total of fluoranthene, benzo(g,h,ijperylene,
benzo(b)fluoranthene, benzo(k)fluoranthene, indeno(1,2,3-cd)'
pyrene, and benzo(a)pyrene) not exceed 0.2 ug/1. Occupa-
tional exposure criteria have been established for coke oven
emissions, coal tar products, and coal tar pitch volatiles/
all of which contain large amounts of PAH including benzo(b)-
fluoranthene (U.S. EPA, 1979a) .
-------
The tJ.S. EPA (1979a') draft recommended criteria for
PAH in water are based upon the extrapolation of animal car-
cinogenicity data for benzo(a)pyrene and dibenzc(a,h)anthra-
cene.
B. Aquatic
The criteria for freshwater and marine life have
not been drafted (U.S. EPA, 1979a).
-------
BENZO(b)R_UORANTHENE
REFERENCES
Basu, O.K. and 0. Saxena. 1977. Analysis of raw and drinking water sam-
ples for polynuclear aromatic hydrocarbons. U.S. Environ. Prot. Agency,
P.O. No. CA-7-2999-A. Exposure Evaluation Branch, HERL, Cincinnati, Ohio.
Basu, O.K. and J. Saxena. 1978. Polynuclear aromatic hydrocarbons in
selected U.S. drinking waters and their raw water sources. Environ. Sci.
Technol. 12: 795.
Buu-Hoi, N.P. 1964. New developments in chemical carcinogenesis by
polycyclic hydrocarbons and related heterocycles: A review. Cancer Res.
24: 1511.
v
Gordon, R.J. and R.J. Bryan. 1973. Patterns of airborne polynuclear hy-
drocarbon concentrations at four Los Angeles sites. Environ. Sci. Technol.
7: 1050.
La Voie, E., et al. 1979. A comparison of the mutagenicity, tumor-initiat-
ing activity and complete carcinogenicity of polynuclear aromatic hydrocar-
bons.. In: Polynuclear Aromatic Hydrocarbons, P.W. Jones and P. Leber (eds.)
Ann Arbor Science Publishers, Inc.
U.S. EPA. 1979a. Polynuclear Aromatic Hydrocarbons: Ambient Water Quality
Criteria. (Draft)
U.S. EPA. 1979b. Multimedia health assessment document for polycyclic or-
ganic matter. Prepared under contract by J. Santodonato, et al., Syracuse
Research Corp.
U.S. EPA. 1979c. Environmental Criteria and Assessment Office. Polynucle-
ar Aromatic Hydrocarbons: Hazard Profile. (Draft)
World Health Organization. 1970. European Standards for Drinking Water. 2nd
ed., Geneva.
-------
No. 19
Benzo(a)pyrene
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
benzo(a)pyrene and has found sufficient evidence to indicate
that this compound is carcinogenic.
-------
BENZO(a)PYRENE
Summary
The first chemicals shown to be involved in the development of cancsr
belong to the polynuclear aromatic hydrocarbons (PAH) class. Benzo(a)pyrene
is the most widely recognized and extensively studied of all carcinogenic
PAH. It is among the most potent animal carcinogens known and produces
tumors in virtually all species by all routes of administration.
Since humans are never exposed to only benzo(a)pyrene in the environ-
-ment, it is not possible to attribute human cancers solely to exposure to
benzo(a)pyrene. However," numerous epidemiologic studies support the belief
that carcinogenic PAH, including benzo(a)pyrene, are also human carcinogens.
Measured steady-state bioconcentration factors are not available for
freshwater or saltwater aquatic species exposed to benzo(a)pyrene. Standard
toxicity data for freshwater and saltwater aquatic life have not been re-
ported.
-------
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Polynuclear Aromatic Hydrocarbons (U.S. EPA, 1979a) and the Multimedia
Health Assessment Document for Polycyclic Organic Matter (U.S. EPA, 1979b).
Benzo(a)pyrene (C^cf1!^ ^s one °^ the ^i^7 °^ polynuclear aromat-
ic hydrocarbons (PAH) formed as a result of incomplete combustion of organic
material. Its physical and chemical properties have not been well-charac-
terized, other than a reported melting point of 178.8-179.3°C and a vapor
pressure of..5.49 x 10"9 mm Hg (U.S. EPA, 1979b). '•
PAH, including benzo(a)pyrene, are ubiquitous in the environment, being
found in ambient air, food, water, soils and sediment (U.S. EPA, 1979a).
The PAH class contains a number of potent carcinogens (e.g., benzo(a)py-
rene), moderately active carcinogens (e.g., benzo(b)fluoranthene), weak car-
cinogens (e.g., benz(a)anthracene), and cocarcinogens (e.g., fluoranthene),
as well as numerous noncarcinogens (U.S. EPA, 1975a).
PAH which contain more than three rings (such as benzo(a)pyrene) are
i
relatively stable in the environment and may be transported in air and
water by adsorption to particulate matter. However, biodegradation and
chemical treatment are effective in eliminating most PAH in the environment.
II. EXPOSURE
A. Water
Basu and Saxena (1977, 1978) have monitored various United States
drinking water supplies for the presence of PAH, including benzo(a)pyrene.
They reported that the average level of benzo(a)pyrene in drinking water was
0.55 nanograms/liter. This would result in a human daily intaks of benzo-
(a)pyrene from water of about 0.0011 jjg.
-------
••' V
B. Food
Benzo(a)pyrene has been detected in a wide variety of foods by
numerous investigators (U.S. EPA, 1979a). Benzo(a)pyrene levels are espe-
cially high' in cooked or smoked meats, where in certain cases (i.e., char-
coal-broiled steak) concentrations as high as 50 ppb have been reported
(Lijinsky and Ross, 1967). It has been estimated (U.S. EPA, 1979b) that the
daily dietary intake of benzo(a)pyrene is about 0.16 to 1.6 ug, and total
PAH intake is about 1.6 to 16 ug. The U.S. EPA (1979a) has estimated the
weighted average, bioconcentration factor for benzo(a)pyrene to be 6,800 for
the edible portions of fish and shellfish consumed by Americans. This esti-
mate is based-on the octanol/water partition coefficient for benzo(a)pyrene.
C. Inhalation
Benzo(a)pyrene levels have been routinely monitored in the ambient
atmosphere for many years. The average urban-rural ambient benzo(a)pyrene
concentration in the United States has been estimated at 0.5 nanograms/m
(U.S. EPA, 1979a). Thus, the human daily intake of benzo(a)pyrene by inhala-
tion of ambient air is about 9.5 nanograms, assuming that a human breathes
about 19 m of air per day.
III. PHARMACOKINETICS
Pertinent data could not be found in. available literature concerning
the pharmacokinetics of benzo(a)pyrene, or other PAH, in humans. Neverthe-
less, it is possible to make limited assumptions based on the results of
animal research conducted with several PAH, particularly benzo(a)pyrene.
A. Absorption
Toxicity data indicate that, as a class, PAH are capable of passage
across epithelial membranes (Smyth, et al. 1962). In particular, benzo(a)-
pyrene was reported to be readily transported across the intestinal mucosa
-------
(Rees, et al. 1971) and the respiratory membranes (Kotin, et al. 1969; Vai-
niok, et al. 1976).
8. Distribution
Benzo(a)pyrene becomes localized in a wide variety of body tissues
following its absorption (Kotin, et al. 1969). Due to its high lipid solu-
bility, benzo(a)pyrene localizes primarily in body fat and fatty tissues
(e.g., breast) (Schlede, et al. 1970a,b).
C. Metabolism
»
The metabolism of benzo(a)pyrene in mammals has been studied in
great detail (U.S. EPA, 1979a). 8enzo(a)pyrene, like other PAH, is metabo-
lized by the- microsomal mixed function oxidase enzyme system in mammals
(U.S. EPA, 1979b). Metabolic attack on one or more of the aromatic rings
leads to the formation of phenols and isomeric dihydrodiols by the interme-
diate formation of reactive epoxides. Dihydrodiols are further metabolized
by microsomal mixed function oxidases to yield diol epoxides, compounds
which are known to be ultimate carcinogens for certain PAH. Removal of
activated intermediates by conjugation with glutathione or glucuronic acid,
or by further metabolism to tetrahydrotetrols, is a key step in protecting
the organism from toxic interaction with cell macromolecules.
0. Excretion
The excretion of benzo(a)pyrene by mammals has been studied by sev-
eral groups of investigators. In general, the excretion of benzo(a)pyrene
and related PAH is rapid, and occurs mainly via the feces (U.S. EPA, I979a;
Schlede, et al. 1970a,b). Elimination in the bile may account for a signi-
ficant percentage of administered PAH. It is unlikely that PAH will accumu-
late in the body as a result of chronic low-level exposures.
-------
IV. EFFECTS
A. Carcinogenicity
The carcinogenic activity of benzo(a)pyrene was first recognized
decades ago, and since that time it has become a laboratory standard for the
production of experimental tumors which resemble human carcinomas in ani-
mals. The carcinogenic activity of benzo(a)pyrene is distinguished by sev-
eral remarkable features: (1) it is among the most potent animal carcino-
gens known, producing tumors by single exposures to microgram quantities;
(2) it acts both at the site of application and at organs distant to the
site of absorption; and (3) its Carcinogenicity has been demonstrated in
nearly every tissue and species tested, regardless of the route of admini-
stration (U.S. EPA, 1979a).
Oral administration of benzo(a)pyrene to rodents can result in
tumors of the forestomach, mammary gland, ovary, lung, liver, and lymphoid
and hematopoietic tissues (U.S. EPA, 1979a). Exposure to benzo(a)pyrene by
intratracheal instillation in rodents can also be an effective means of pro-
ducing respiratory tract tumors (Feron, et al. 1973). In addition, benzo-
(a)pyrene has remarkable potency for the induction of skin tumors in mice by
direct dermal application (U.S. EPA, 1979a).
Numerous epidemiologic studies support the belief that' carcinogenic
PAH, including benzo(a)pyrene, are responsible for the production of human
cancers both in occupational situations and among tobacco smokers (U.S. EPA,
1979b).
B. Mutagenicity
Benzo(a)pyrene gives positive results in nearly all mutagenicity
test systems including the Ames Salmonella assay, cultured Chinese hamster
cells, the sister-chromatid exchange test, and the induction of ONA repair
synthesis (U.S. EPA, 1979a).
-------
C. Teratogenicity and Other Reproductive Effects
Only limited data are available regarding the teratogenic effects
of benzo(a)pyrene or other PAH in animals. 8enzo(a)pyrene had little effect
on fertility or the developing embryo in several mammalian and non-mammalian
species (Rigdon and Rennels, 1964; Rigdon and Neal, 1965).
0. Chronic Toxicity
As long ago as 1937, investigators knew that carcinogenic PAH such
as benzo(a)pyrene produced systemic toxicity as manifested by an inhibition
of body growth in rats and mice (Haddow, et al... 1937). The target organs
affected by chronic administration of carcinogenic PAH are diverse, due
partly to extensive distribution in the body and also to the selective de-
struction of proliferating cells (e.g., hematopoietic and lymphoid system,
intestinal epithelium, testis) (Philips, et al. 1973).
V. AQUATIC TOXICITY
Pertinent data could not be located in the available literature.
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
There are no established exposure standards specifically for benzo-
(a)pyrene. However, PAH as a class are regulated by several authorities.
The World Health Organization (1970) has recommended that the concentration
of PAH in drinking water (measured as the total of fluoranthene, benzo(g,h,-
i)perylene, benzo(b)fluoranthene, benzo(k)fluoranthene, indeno(l,2,3-cd)py-
rene, and benzo(a)pyrene) not exceed 0.2 ug/1. Occupational exposure cri-
19-?
-------
teria have been established for coke oven emissions, coal tar products, and
coal tar pitch volatiles, all of which contain large amounts of PAH in water
based upon the extrapolation of animal carcinogenicity data for benzo(a)py-
rene and dibenz(a,h)anthracene. Levels for each compound are derived which
will result in specified risk levels of human cancer as shown in the table
below:
BaP
Exposure Assumptions Risk Levels and Corresponding Draft Criteria
(per day):- '
0 ID-7 10-* 10-5
2 liters of drinking water 0 0.097 0.97 9.7
and consumption of 18.7
grams of fish and shellfish.
Consumption of fish 0.44 4.45 44.46
and shellfish only.
Exoosure Assumotions
(per day)
2 liters of drinking water
and consumption of 18.7
grams of fish and shellfish.
Consumption of fish
and shellfish only.
DBA
Risk
0
0
Levels and
1C-7
0.43
1.96
Corresoonding
10-6
4.3
19.6
Draft Criteria
10-5
43
196
8 Aquatic
Guidelines are not available for benzo(a)pyrene in aquatic environ-
ments.
-------
BENZO(A)PYRENE
REFERENCES
Basu, O.K., -and J. Saxena. 1977. Analysis of raw and drinking
water samples for polynuclear aromatic hydrocarbons. EPA P.O. No.
CA-7-2999-A, and CA-8-2275-B, Expo. Evalu. Branch, HERL., Cincin-
nati.
Basu, O.K., and J. Saxena. 1978. Polynuclear aromatic hydrocarbons
in selected O.S. drinking waters and their raw water sources.
Environ. 3ci. Technol. 12: 795. ... . . ..
Feron, V.J., et al. 1973. Dose-response correlation for the induc-
tion of respiratory tract tumors in Syrian golden hamsters by in-
tratracheal instillations of benzo(a)pyrene. Europ. Jour. Cancer.
9: 387.
Haddow, A., et -al. 1937. The influence of certain carcinogenic and
other hydrocarbons on body growth in the rat. Proc. Royal Soc. B.
122: 477.
Kotin, P., et al. 1969. Distribution retention and elimination of
C -3, 4-benzopyrene after a<
Nat!. Cancer Inst. 23: 541.
T ;T
C -3, 4-benzopyrene after administration to mice and rats. Jour.
Lijinsky, W., and A.E. Ross. 1967. Production of carcinogenic
polynuclear hydrocarbons' in the cooking of food. Food Cosmet.
Toxicol. 5: 343. (
Philips, F.S. et al., 1973. In vivo cytotoxicity of polycyclic hy-
drocarbons. In: Pharmacology anathe future of man. Proc. 5th
Intl. Congr. PKarmacology, 1972, San Francisco. 2: 75.
Rees, E.G., et al. 1971. A study of the mechanism of intestinal
absorption of benzo(a)pyrene. Biochem. Biophys. Act. 255: 96.
Rigdon, R.H., and J. Neal. 1965. Effects of feeding benzo(a)py-
rene on fertility, embryos, and young mice. Jour. Natl. Cancer.
Inst. 32: 297.
Rigdon, R.H., and E.G. Rennels. 1964. Effect of feeding benzo-
pyrene on reproduction in the rat. Experientia. 20: 1291.
Schlede, E., et al. 1970a. Stimulatory effect of benzo(a)pyrene
and phenobarbital pretreatment on the biliary excretion of benzo-
(a)pyrene metabolites in the rat. Cancer Res. 30: 2398.
Schlede, E. , et al. 1970b. Effect of enzyme induction on' the
metabolism and tissue distribution of benzo(a)pyrene. Cancer Res.
30: 2893.
If-At
-------
Smyth, H.F., et al. 1962. Range - finding toxicity data: List II.
Am. Ind. Hyg. Jour. 23: 95.
U.S. EPA. 1979a. Polynuclear Aromatic Hydrocarbons: Ambient
Water Quality Criteria. (Draft).
U.S. EPA. 1979b. Multimedia Health Assessment Document for Poly-
cyclic Organic Matter. Prepared under contract by J. Santodonato
et al., Syracuse Research Corporation.
Vainioh, et al. 1976. The fate of intracheally installed benzo-
(a)pyrene in the isolated perfused rat lung of both control and 20-
methylcholanthrene pretreated. Res. Commun. Chem. Path. Pharmacol.
13: 259.
World Health Organization. 1970. European standards for drinking
water. 2nd ed. Revised. Geneva.
-------
tto. 20
Benzotrlchlorlde
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-ft.0-/
-------
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.
-------
BENZOTRICHLORIDE
Summary
Benzotrichloride has been shown to be mutagenic in a number of micro-
bial tests with and without metabolic activation.. One study has described
the carcinogenicity of benzotrichloride in mice. The lowest concentration
producing a lethal effect d-C^g) has been reported at 125 ppm for rats in-
haling benzotxichloride for four hours. Pertinent data for the toxic
effects to aquatic organisms were not found in the available literature.
10 -3
-------
I. INTRODUCTION
Benzotrichloride (CAS registry number 98-07-7), is a colorless, oily,
fuming liquid. It. is made by the free radical chlorination of boiling
toluene (Sidi, 1964; Windholz, 1976). Benzotrichloride has the following
physical and chemical properties (Windholz, 1976; Sidi, 1964):
Formula:
0
Molecular Weight: 155.48
Melting Point: -5°c
Boiling Point: 220. 8°C
Density: 1.375620
4
Solubility: alcohol, ether, benzene,
insoluble in water
Benzotrichloride is used extensively in the dye industry for the
production of Malachite green, Rosamine, Quinoline red, and Alizarine yellow
A. It can also be used to produce ethyl orthobenzoate (Sidi, 1964).
II. EXPOSURE
A. water
Benzotrichloride decompose in the presence of water to benzoic and
hydrochloric acids (Windholz, 1976).
B. Food
Pertinent data were not found in the available literature.
C. Inhalation
Pertinent data were not found in the available literature; how-
ever, significant exposure could occur in the workplace from accidental
spills. Benzotrichloride decomposes in moist air to benzoic and hydro-
chloric acids (Windholz, 1976).
0. Dermal
Benzotrichloride is irritating to the skin (Windholz, 1976).
-------
III. PHARMACOKINETICS
Pertinent pharmacokinetic data were not found in the available
literature.
IV. EFFECTS
A. Carcinogenicity
In a study by Matsushito and coworkers (1975), benzotrichloride
was found to Induce carcinomas, leukemia, and papillcmas in mice. The de-
tails of the study were not available for assessment.
B. Mutagenicity
Yasuq, et al. (1978) tested the mutagenicity of several compounds
including benzotrichloride in microbial systems such as the rec-assay using
Bacillus subtilis, reversion assays using £._ coii, and the Ames assay using
Salmonella typhimuriunv, with or without metabolic activation. Benzo-
trichloride was positive for mutagenicity in the rec-assay and was highly
positive on certain strains of §_._ coli and S._ typhimurium in the reversion
i
assay with metabolic activation, without metabolic activation, however,
benzotrichloride was only weakly positive in the latter assay.
C. Teratogenicity, Reproductive Effects, and Chronic Toxicity
Pertinent data were not found in the available literature.
0. Acute Toxicity
The lowest lethal concentration d-CLQ) for rats inhaling benzo-
trichloride is 125 ppm for four hours (Smyth, et al. 1951).
Benzotrichloride was severely irritating to the skin of rabbits
that received dermal applications of 10 mg for 24 hours and to the eyes of
rabbits that received instillations of 50 ug to the eye (Smyth, et al. 1951).
-------
V. AQUATIC TOXICITY
Pertinent data were not found in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
Existing'.quidelines and standards were not found in the available
literature.
-------
REFERENCES
Matsushitot H., et al. 1975. Carcincgenicities of the related compounds in
benzoyl chloride production. 49th Annu. Meeting Japan Ind. Hyg. Soc.,
Sappro, Japan, p. 252.
Sidi, H. 196A. Benzyl chloride, benzal chloride, benzotrichloride. In:
Xirk-Qthmer Encyclopedia of Chemical Technology. John Wiley and Sons, New
York, p. 281.
Smyth, H.F., et al. 1951. Range finding toxicity data: List IV. Amer.
Med. Assoc. Arch, of Ind. Health. 4: 119.
winohoiz, M. (ed.) 1976. Merck Index, 9th ed. Merck and Co., Inc.,
Rahvray, NJ.
Yasuo, K., et al. 1978. Mutagenicity of benzotrichloride and related com-
pounds. Mutat. Res. 58: 143.
20-?
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No. 21
Benzyl Chloride
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.
3/-A
-------
BENZYL CHLORIDE
Summary
Benzyl chloride has been shown to produce carcinogenic effects in rats
following subcutaneous administration and in mice following intraperitoneal
administration.
Weak mutagenic. activity of the compound has been demonstrated in the
Ames Salmonella assay and in £._ coll.
There is no available information on the possible teratogenic or ad-
verse reproductive effects of benzyl chloride.
Inhibition of cell multiplication in the alga, Microcystis aeruginosa,
started at 30 mg/1. Concentrations of 10 mg/1 and 17 mg/1 caused paralysis
in two species of fish.
aj-3
-------
I. INTRODUCTION
Benzyl chloride (alpha-chlorotoluene), CAS Registry number 100-44-7, is
a colorless-to-light yellow, clear, lachrymatory liquid and is made by free-
radical (photochemical) chlorination of tolene (Hawley, 1971; Austin, 1974).
It has the following physical and chemical properties (Windholz, et al.
1976; Hawley, 1971; Weast, 1972):
Formula:
. Molecular Weight: 126.59
Melting Point: -43°c
Boiling Point: 179°C
Density: Itl002!
Solubility: Miscible in alcohol, chloroform,
ether; insoluble in water
Production: approximately 89 million Ibs. 1977
(NIOSH, 1977)
i
Benzyl chloride is a moderately volatile compound with a vapor pressure
of 1 mm Hg at 22°C (NIOSH, 1978). The compound decomposes relatively
slowly in water with a 15-hour half-life of pH 7 (25°C) (NIOSH, 1978).
Benzyl chloride is used to make benzaldehyde through additional chlori-
nation and hydrolysis, but modest amounts are also used as a benzylating
agent for benzyl benzoate, n-butyl benzyl phthalate, benzyl ethyl aniline,
benzyl cellulose, components of dyes and perfumes-, and for production of
phenylacetic acid by benzyl cyanide (Austin, 1974).
II. EXPOSURE
A. water
Gruber (1975) reports that no benzyl chloride enters the water
from production.
a'-/
-------
8. Food
Pertinent data could not be located in the available literature.
C. Inhalation
Pertinent data were not found in the available literature; how-
ever,- benzyl chloride is used exclusively as a chemical intermediate in
manufacturing and exposure and is most likely limited to the workplace. As
such, the level of exposure is reported to be less than 1 ppm (NIOSH, 1978).
0. Dermal
»
Pertinent data could not be located in the available literature.
III. PHARMACOKINETICS
A. Absorption and Distribution
Pertinent data could not be located in the available literature.
8. Metabolism and Excretion
The major excretion product following ingestion of benzyl chloride
is a cysteine conjugate,•benzylmercapturic acid (Stekol, 1938, 1939; Witter,
1944; Barnes, et al. 1959; Knight and Young, 1958).
Bray, et al. (1958) administered benzyl chloride at 200 mg/kg body
weight orally to rabbits. Urine collected for 24 hours showed 86.4 percent
of the administered dose in the soluble fraction, with 49 percent as benzyl-
mercapturic acid, 20 percent as a glycine conjugate, 0.4 percent as glucosi-
duronic acid, and 17 percent as unconjugated benzoic acid. Maitrya and vyas
(1970) found 30 percent of the total oral dose of benzyl chloride to be ex-
creted by rats as hippuric acid.
Knight and Young (1958) found that benzyl chloride is converted
directly to benzyl mercapturic acid, unlike related compounds such as chlor-
inated benzenes, which form acid-labile precursors.
-------
Barnes, et al. (1959) found that 27 percent of the total oral dose
of benzyl chloride administered to rats was excreted as benzyl mercapturic
acid. This value compares with 49 percent excreted in rabbits (Bray, et al.
1958) and 4 percent in guinea pigs (Bray, et al. 1959).
Several studies have indicated that glutathione is the source of
.the thiol groups for mercapturic acid formation from benzyl chloride
(Bames, et al. 1959; Simkin and White, 1957; Anderson and Mosher, 1951;
•Waelsch and Rittenberg, 1942; Bray, et al. 1969; Beck, et al. 1964). The
turnover rate of glutathione in the liver was found to be 49 mg/100 g of
liver per hour (Simkin and White, 1957). An in vitro study by Suga, et al.
(1966) revealed that conjugation with glutathione can occur both enzymatic-
ally and non-«nzymatically in rat liver* preparations. The enzymic conjuga-
tion has also been observed in human liver preparations (Soyland and Chas-
seaud, 1969).
IV. EFFECTS
A. Carcinogenicity
Benzyl chloride was reviewed by IARC (1976) and found to be car-
cinogenic in rats. Oruckrey, et al. (1970) injected 14 rats subcutaneously
with benzyl chloride at 2.1 g/kg body weight (total dose) and 8 rats with
3.9 gAg body weight (total dose) during 51 weeks. Injection site sarcomas
were noted in three of the rats receiving the lower dose and six receiving
the higher dose; most of the tumors had metastasized to the lungs. The
vehicle of administration, arachis oil, did not produce local tumors.
Poirier, et al. (1975) administered intraperitoneal injections of
benzyl chloride in tricaprylin to three groups of 20 male and female A/Hes-
*
ton mice, three times per week for eight weeks, with total doses of 0.6,
1.5, and 2.0 g/kg body weight. After 24 weeks, all survivors were killed;
-------
lung tumors occurred in 4/15, 7/16, and 2/8 surviving mice in the three
groups, respectively. The average number of tumors per mouse was 0.26,
0.50, and 0.25, respectively. The incidence of tumors in mice receiving the
benzyl chloride was not significantly different from the results recorded
for untreated mice on the tricaprylin-vehicle treated mice.
B. Mutagenicity
McCann, et al. (1975a,b) found benzyl chloride to be weakly muta-
genic (less than 0.10 revertants/nanomole) when tested using the Ames assay
(Salmonella/microsomal activation).
. Rosenkranz and Poirier (1978), in a National Cancer Institute re-
port, found benzyl chloride to be marginally mutagenic in the Ames assay at
doses of 5 ul and 10 pi/plate without activation. Microsomal activation had
an inactivating effect on benzyl chloride. The investigators also evaluated
the DMA-modifying activity in bacterial systems using Escherichia coli pol A
mutants. A dose of 10 ul benzyl chloride, produced a positive mutagenic ef-
fect.
Benzyl chloride was found to be non-mutagenic in the Ames Salmo-
nella microsomal assay by Simmon (1579). The compound was mutagenic when
exposure was by vapor phase in a dessicator.
C. Teratogenicity, Other Reproductive Effects and Chronic Toxicity
Pertinent data could not be located in the available literature.
D. Acute Toxicity
A number of studies have been conducted on the acute toxicity of
benzyl chloride vapor to animals and were reviewed in a criteria document
prepared by NIOSH (1978). Respiratory tract inflammation and secondary in-
fections were observed in mice exposed to 390 mg/nP (LC5Q) for two tiours
and rats exposed to 740 mg/m^ (LC5Q) for two hours (Mikhailova, 1965).
It
re*
J/-7
-------
Rabbits exposed to 480 mg/m3 of benzyl chloride for eight hours/day for
six days suffered mild eye and nasal irritation by the sixth day, while cats
exposed to the same regimen suffered a loss of appetite in addition to eye
and respiratory tract irritation (Wolf, 1912). Death of a dog occurred
within 24 hours of exposure to 1,900 mg/nv5 of benzyl chloride for eight
hours. Corneal turbidity and irritation of the ocular, respiratory, and
oral mucosa were observed before death (Schutte, 1915). Mikhailova (1965)
observed hepatic changes and necrosis of the kidney in rats and mice exposed
to benzyl chloride at 100 mg/m^.
Landsteiner and Jacobs- (1936) investigated the sensitizing proper-
ties of benzyl chloride to guinea pigs. Benzyl chloride, in a saline solu-
tion (0.01 mg/animal) was injected intracutaneously twice per week for 12
weeks. Two weeks later, re-exposure revealed that benzyl chloride had a
sensitizing effect.
Occupational exposures to benzyl chloride have been reported by
several investigators (Wolf, 1912; Schutte, 1915; Mikhailova, 1971; Katz and
'Talbert, 1930; Watrous, 1947). Lacrimination, conjunctivitis, and irrita-
tion of the respiratory tract and eyes have been reported following exposure
to benzyl chloride vapor levels ranging from 6 to 8 mg/m3 for five minutes
to brief exposure at 23,600 mg/m3. Although no cases were reported in the
literature, liquid benzyl chloride has the potential for skin irritation
based on its release of hydrochloric acid upon hydrolysis. The odor thresh-
old and nasal irritation thresholds for benzyl chloride are 0.21 to 0.24
mg/m3 and 180 mg/nr5, respectively (Katz and Talbert, 1930; Leonardos, et
al. 1969).
-------
V. AQUATIC TOXICITY
A. Acute and Chronic Toxicity
Pertinent data could not be located in the available literature.
8. • Plant Effects
Inhibition of cell multiplication in Microcystis aeruqinosa start-
ed at 30 mg/1 (Bringmann and Kuhn, 1976).
C. Residues
Pertinent data could not be located in the available literature.
0. Other Relevant Information
Hiatt, et al. (1953) found that l.Q mg/1 of benzyl chloride pro-
duced no irritant response in marine fish, but 10 mg/1 caused a slight irri-
tant activity. This compound caused paralysis in the fish Trutta iridea and
Cvprinus carpio at concentrations of 10 mg/1 and 17 mg/1, respectively
(Meinck, et al. 1970),.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The American Conference of Governmental .and Industrial Hygienists
(ACGIH, 1977) recommends an occupational exposure limit of 1 ppm (5 mg/m^)
for benzyl chloride. The U.S. federal standard promulgated by OSHA is also
1 ppm (TWA) (29 CFR 1910.1000). NIQSH recommends an environmental exposure
limit of 5 mq/mj as a ceiling value for a 15-minute exposure (NIOSH, 1978).
3. Aquatic
NO guidelines to protect fish and saltwater organisms from benzyl
chloride toxicity have been established because of the lack of available
data.
-------
REFERENCES
American Conference of Governmental Industrial Hygienists. 1977. Threshold
Limit Values for Chemical Substances and Physical Agents in the Workroom
Environment. Cincinnati, Ohio.
Anderson, E.I. and W.A. Mosher. 1551. Incorporation of S35 from
-------
Katz, S.H. and E.J. Talbert. 1930. Intensities of odors and irritating
effects of warning agents for inflammable and poisonous gases, Paper 480.
U.S. Department of Commerce, Bureau of Mines. 37 pp.
Knight, R.H. and L. Young. 1558. Biochemical studies of toxic agents —
II. The occurrence of premercapturic acids. Biochem. Jour. 70: 111.
•-.. •
Landsteiner, k. and J. Jacobs. 1936. Studies on the sensitization of ani-
mals with simple chemical compounds, II. Jour. Exp. Med. 64: 625.
Leonardos, G., et al. 1969. Odor threshold determinations of 53 odorant
chemicals. Jour. Air Pollut. Control Assoc. 29: 91.
Maitrya, B.B. and C.R. Vyas. 1970. Studies on conjugation of organic com-
pounds in the rat. Ind. Jour. Biochem. 7: 284.
McCarm, a., et al. 1975a. Detection of carcinogens as mutagens ~ Bacter-
ial tester strains with R factor plasmids. Proc. Natl. Acad. Sci., USA.
72: 979.
McCann, J., et al. 1975b. Detection of carcinogens as mutagens in the Sal-
monella/microsome test — Assay of 300 chemicals. Proc. Natl. Acad. Sea..,
USA. 72: 5D5.
Meinck, f.., et al. 1970. Les eaux residuaires industrielles.
Mikhailova, T.v. 1965. Comparative toxicity of chloride derivatives of
toluene — Benzyl chloride, benzal chloride and benzotrichloride. Fed.
Proc. (Trans. Suppl.) 24: T877.
Mikhailova, T.V. 1971. Benzyl chloride In: ILQ Encyclopedia of
Occupational Health and Safety, Vol. 1. Geneva, International Labour
Office: 169.
National Institute for Occupational Safety and Health. 1977. Information
profiles on potential occupational hazards, benzyl chloride. OHEW, 210-77-
0120.
National Institute for Occupational Safety and Health. 1978. Criteria for
a Recommended Standard...Occupational Exposure to Benzyl Chloride. OHEY*
78-182.
Poirier, L.A., et al. 1975. Bioassay of alkyl halides and nucleotide base
analogs by pulmonary tumor response to strain A mice. Cancer Res. 35: 1411.
Rosenkranz, H.S. and L.A. Poirier. 1978. An evaluation of the mutagenicity
and DMA-modifying activity in microbial systems of carcinogens and noncarci-
nogens. . Unpublished report from U.S. Oept. of Health, Education and Wel-
fare, Public Health Service, National Institute of Health, National Cancer
Institute. 56 pp.
»
Schutte, H. 1915. Tests with benzyl and benzal chloride. Dissertation
translated from German. Wurzburg. Royal Bavarian Julius-iMaximilians uni-
versity, Franz Staudenraus Book Printing. 27 pp.
3.1- H
-------
Simkin, J.L. and K. White. 1957. The formation of hippuric acid — The
influence of benzoate administration on tissue glycine levels. Biochem.
Jour. 65: 574.
Simmon, V.F. 1979. In_ vitro mutagenicity assays of chemical carcinogens
and related .compounds with Salmonella typhimurium. Jour. Natl. Cancer Inst.
62: 893.
Stekol, J.A. 1938. Studies on the mercapturic acid synthesis in animals —
IX. Jour. aid. Chem. 124: 129.
Stekol, J.A. 1939. Studies on the mercapturic acid synthesis in animals —
XII. The detoxification of benzyl chloride, benzyl alcohol, benzaldehyde,
and S-benzyl homocysteine in the rabbit and rat. Jour. Biol. Chem.
128: 199.
Suga, T., et al. 1966. Studies on mercapturic acids, effect of some aro-
matic compounds on the level of glutathione and the activity of glutathion-
ase in the rat. Jour. Biochem. 59: 209.
Waelsch, H. and 0. Rittenberg. 1942. Glutathione — II. The metabolism of
glutathione studied with isotopic ammonia and glutamic acid. Jour. Biol.
Chem. 144: 53.
watrous, R.M. 1947. Health hazards of the pharmaceutical industry. Br.
Jour. 'Ind. Med. 4: 111.
Weast, R.C. 1972. Handbook of Chemistry and Physics, 53rd ed. Chemical
Rubber Company, Cleveland, Ohio.
Windholz, M., et al. 1976. Merck Index, 9th ed. Merck and Co., Inc., Rah-
way, New Jersey.
Witter, R.F. 1944. The metabolism of monobromobenzene, benzene, benzyl
chloride and related compounds in the rabbit. Ann Arbor, University of
Michigan, University Microfilms, Dissertation. 1-7, 32-35, 37-66, 93, 197,
113-118, 126-138.
Wolf, w. 1912. Concerning the Effect of Benzyl Chloride and Benzal Chlor-
ide on the Animal Organisms. Translation of dissertation from German, Wurz-
burg, Royal Bavarian Julius-Maximilians university. Franz Staudenraus Book
Printing, 25 pp.
-------
No. 22
Beryllium
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. SPA's Carcinogen Assessment Group (GAG) has evaluated
beryllium and has found sufficient evidence to indicate
that this compound is carcinogenic.
-------
BERYLLIUM
SUMMARY
Beryllium was shown to be carcinogenic in three animal
species, producing cancers of the lung and bone when admin-
istered by injection, inhalation, or intratracheal instilla-
tion. Ingestion of beryllium has failed to produce cancers
in animalsf possibly due to its poor gastrointestinal absorp-
tion. Several'epidemiology studies support the hypothesis
•
that beryllium is a human carcinogen.
Beryllium is toxic to freshwater organisms at concentra-
tions as low as 5.3 pg/1. Pertintent data for marine or-
ganisms were not found in the available literature (U.S.
EPA, 1979).
-------
BERYLLIUM
. I . INTRODUCTION
This profile is primarily based upon the Ambient Water
Quality Criteria Document for Beryllium (U.S. EPA, 1979).
Recent comprehensive reviews on the hazards of beryllium
have also been prepared by the National Institute for Occupa-
tional Safety and Health (NIOSH, 1972) and the International
Agency for Research on Cancer (IARC, 1972) .
Beryllium (Be; atomic weight 9.01) is--a dark gray metal
of the al'kaline earth family. Beryllium has the following
physical-chemical properties (IARC, 1972) :
Boiling point: 2970°C
Melting point: 1284 - 1300 C
Hardness: 60 - 125
Density: 1.84 - 1.85
Solubility: Soluble in acids and alkalis
World production of beryllium was reported as approximately
250 tons annually, but much more reaches the environment
as emissions from .coal burning operations (Tepper, 1972).
Most common beryllium compounds are readily soluble in water.
The hydroxide is soluble only to the extent of 2 rag/1 (Lange,
1956). Beryllium forms chemical compounds in which its
valence is -t-2. At acid pH, it behaves as a cation but forms
anionic complexes at pH greater than 8 (Krejci and Scheel,
1966) . The major source of beryllium in the environment
is the combustion of fossil fuels (Tepper, 1972). Beryl-
lium enters the waterways through weathering of rocks and
soils, through atmospheric fallout and through discharges
from industrial and municipal operations.
X.
-------
II. EXPOSURE
. A. Water
Kopp and Kroner (1967) reported the results of
trace metal analyses of 1,577 drinking water samples.obtained
throughout the United States. Beryllium was detected in
5.4 percent of the samples. Concentrations ranged from
0.01 to 1.22 ug/1, with a mean value of 0.19 ug/1.
B. Food
Beryllium has been detected in a- variety of vege-
tables, and in eggs, milk, nuts, bread, and baker's yeast
(Meehan and .Smythe, 1967; Petzow and Zorn, 1974). Measured
levels of beryllium were generally in the range of 0.01
to 0.5 ppm. Using the data for consumption and bioconcen-
tration for freshwater and saltwater fishes, mollusks, and
decapods, and the measured steady-state bioconcentration
factor (BCF) for beryllium in bluegills, the U.S. EPA (1979)
has estimated a weighted average BCF.for beryllium to be
19 for the edible portions of fish and shellfish consumed
by Americans.
C. Inhalation
The detection of beryllium in air is infrequent
and usually in trace amounts. In urban areas beryllium
levels may reach 0.008 ug/m , while in rural areas beryllium
concentrations have been measured at 0.00013 pg/m (Tabor
and Warren, 1953; National Air Sampling Network, 1968).
At a beryllium extraction plant in Ohio, beryllium concen- »
trations were generally around 2 ug/m"1 over a seven year
period (Breslin and Harris, 1959).
-------
III. PHARMACOKINETICS
Ingested beryllium is poorly absorbed within the gastro-
intestinal tract, presumably due to solubility problems
in the alimentary canal (HyslopT et al. 1943; Reeves, 1965).
When inhaled, soluble beryllium compounds are rapidly re-
moved from the lung, whereas insoluble beryllium compounds
can remain in the lung indefinitely (Van Cleave and Kaylor,
1955; Wagner, et al. 1969; Sprince, et al. 1976). When
parenterally administered, beryllium is di-stributed to all
tissues, although it shows preferential accumulation in
bone, followed by spleen, liver, kidney and muscle (Van
Cleave and Kaylor, 1955; Crowley, et al. 1949; Klemperer,
et al. 1952; Kaylor and Van Cleave, 1953; Spencer, et al.
1972). Absorbed beryllium tends to be either excreted in
the urine or deposited in kidneys and bone (Scott, et al.
1950). Once deposited in the skeleton, beryllium is removed
very slowly, with half-lives of .elimination reported to
be 1,210, 890, 1,770 and 1,270 days in mice, rats, monkeys,
and dogs, respectively (Furchner, et al. 1973).
IV. EFFECTS
A. Carcinogenicity
Beryllium was shown to be carcinogenic in three
animal species. Intravenous injection of beryllium, zinc
beryllium silicate, and beryllium phosphate produced osteo-
sarcomas in the rabbit (Gardner and Heslington, 1946; Dutra
#
and Largent, 1950; Komitowski, 1969; Fodor, 1971; IARC,
1972). Inhalation and intratracheal instillation of beryl-
-------
lium compounds have produced lung cancers in the rat and
monkey (Vorwald and Reeves, 1959; Vorwald, et al. 1966;
Reeves, et al. 1967). Ingestion of beryllium by rats and
mice has failed to induce tumors, possibly due to the poor
absorption of beryllium from the gastrointestinal tract.
Several epidemiological studies have failed to
establish a clear association between beryllium exposure
and cancer development (Stoeckle, et al. 1969; Mancuso,
1970; Niemoller, 1963). However, other recent studies sup-
port the hypothesis that beryllium is a human carcinogen
(Berg and Burbank, 1972; Wagoner, et al. 1978; Discher,
1978) .
B. Mutagenicity
Pertinent data were not found in the available
literature.
C. Teratogenicity
Beryllium has been implicated as a teratogen in
snails (Raven and Sprok, 1953) and has inhibited limb re-
generation in the salamander, Amblystoma punctatum (Thorton,
1950).
D. Other Reproductive Effects
Pertinent data were not found in the available
literature.
E. Chronic Toxicity
Chronic beryllium inhalation in humans produces
a progressive, systemic disease which may follow the ces-
sation of exposure by as long as five years (Tapper, et
-------
al. 1961; Hardy and Stoeckle, 1959). Symptoms include pneu-
monitis with cough, chest pain, and general weakness. Sy-
stemic effects include right heart enlargement with cardiac
failure, enlargement of liver and spleen, cyanosis, digital
clubbing, and kidney stones (Hall, et al. 1959). Chronic
beryllium disease can be produced in rats and monkeys by
inhalation of beryllium sulfate at 35 pg/m (Schepers, et
al. 1957; Vorwald, et al. 1966).
V. AQUATIC TOXICITY
A. Acute Toxicity
•
Acute toxicity data for beryllium for freshwater
fishes are taken from 22 static and 5 flow-through bioassays,
all 96 hours in duration. U.S. EPA (1979) presents the
most sensitive species, the guppy Poecilia reticulata, with
LC^Q values ranging from 71 to 17,500 jag/1. The data re-
flect that the toxicity of beryllium to freshwater fish
is decreased in hard water. This has also been confirmed
by U.S. EPA (1979) in the fathead minnow, Pimephales prome-
las, with LC^g values ranging from 82 to 11,000 ug/1. Acute
toxicity for aquatic invertebrates provides two 48-hour
LCen values of 7,900 and 2,500 ug/1, with water hardness
values of 180 and 200 jig/1 as CaCo^. The source of these
invertebrate studies is the same for chronic freshwater
studies. No data for acute toxicity to marine species was
found in the available literature.
-------
B. Chronic Toxicity
No chronic tests for freshwater fish were found
in the available literature. The clacioceran, Daphnia maqna,
was the only- freshwater species tested for chronic effects;
chronic values of less than 36 ug/1 and 5.3 ug/1 were ob-
tained by the U.S. EPA (1979). No chronic data for marine
species of fish or invertebrates was found in the available
literature.
C. Plant Effects \
The only plant study available reveals that the
green algae, Chlorella vannieli, displayed growth inhibition
at a concentration of 100,000 ug/1 (U.S. EPA, 197*).
D. Residues
Exposure of the bluegill for 28 days produced
a bioconcentration factor of 19 (U.S. EPA, 1978). No other
data was found in the available literature.
E. Other Relevant Information
The only marine data presented showed reduced
alkaline phosphatase activity in the mummichog, Fundulus
heteroclitus, at concentrations as low as 9 ug/1. A tera-
togenic response was observed by Evola-Maltese (1957) in
sea urchin embryos at concentrations of 9.010 ug/1.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The present standard for occupational exposure
to beryllium prescribes an 8-hour time-weignted average
-------
of 2.0 ug/m with a ceiling concentration of 5.0 pg/ra .
This is the same value recommended by the American Confer-
ence of Governmental Industrial Hygienists (1977). The
National Institute for Occupational Safety and Health (NIOSH,
1972) recommends that occupational exposure to beryllium
and its compounds not exceed 1 pg/m (8-hour time-weighted
average) with a ceiling limit of 5 ug/m (measured over
a 15 minute sampling period).
National Emission Standards for Hazardous Air
Pollutants set their criterion as not more than 10 g in
24 hours or emissions which result in maximum outplant con-
centrations of 0.01 pg/m , 30-day average (U.S. EPA, 1977).
Based on animal bioassay data for beryllium to
which the linear model was applied, the U.S. EPA (1979)
has estimated levels of beryllium in ambient water which
will result in carcinogenic risk for humans. As a result
of the public comments received, additional review and re-
evaluation of the data base is required before a final cri-
terion level can be recommended.
B. Aquatic
The U.S. EPA proposed a water quality standard
of 11 pg/1 for the protection of aquatic life in soft fresh-
water; 1,100 pg/1 for the protection of aquatic life in
hard freshwater; and 100 pg/1 for continuous irrigation
on all soils, except 500 mg/1 for irrigation on neutral
to alkaline lime-textured soils (U.S. EPA, 1977).
-------
The National Academy of Science/National Academy
of Engineering (1973) Water Quality Criteria recommendation
for marine aquatic life is: hazard level - 1.5 ug/1; minimal
risk of deleterious effects - 0.1 mg/1; and application
factor - 0.01 (applied to 96-hour LC^n) • Their recommenda-
tion for irrigation water is: 0.10 mg/1 for continuous use
on all soils.
The U.S. EPA (1979) has derived a draft criterion
for beryllium to protect freshwater aquatic organisms.
The 24-hour average concentration in ug/1 is dependent on
water hardness and is derived by the following equation:
££ 3 e(1.24 In (hardness) - 6.65)
The concentration not to be exceeded at any time is:
_, a (1.24 In (hardness) - 1.46)
CJ\ — e
No draft criterion was derived for marine organisms (U.S.
SPA, 1979). '
-------
BERYLLIUM .
REFERENCES
American Conference of Governmental Industrial Hygienists
1977. Threshold limit values for chemical substances in
workroom ai;r adopted by ACGIH for 1977. ACGIH, P.O. Box
1937, Cincinnati, Ohio 45201.
Berg, J.W., and F. Burbank. 1972. Correlations between
carcinogenic trace metals in water supply and cancer mor-
tality. Ann. N.Y. Acad. Sci. 199: 249.
Breslin, A.J., and W.B. Harris. 1959. Health protection
in beryllium facilities. Summary of ten years of experience.
AMA Arch Ind. Health 19: 596.
Crowley, J.F., et al. 1949. Metabolism of carrier-free
radioberyllium in the rat. Jour. Biol. Chem. 177: 975.
Discher, D.P. 1978. Letter to w.H. Foege, Director, Center
for Disease Control HEW (published in BNA Occupational Safety
and Health Reporter) 8: 853.
Dutra, F.R., and F.J. Largent. 1950. Osteosarcoma induced
by beryllium oxide. Am. Jour. Pathol. 26: 197.
Evola-Maltese, C. 1957. -Effects of beryllium on the develop-
ment and alkaline phosphatase activity of Paracentrotus
embryos. Acta Embryol. Morphol. Sxp. 1: 143.
Fodor, J. 1971. Histogenesis of bone tumors induced by
beryllium. Magyar Onkol. 15: 180.
Furchner, J.E., et al. 1973. Comparative metabolism of
radionucleotides in mammals. VIII: Retention of beryllium
in the mouse, rat, monkey, and dog. Health Physics 24:
293.
Gardner, L. U., and H.F. Heslington. 1946. Osteo-sarcoma
from intravenous beryllium compounds in rabbits. Fed. Proc.
5: 221.
Hall, T.C., et al. 1959. Case data from the beryllium
registry. AMA Arch. Ind. Health 19:100.
Hardy, H.L., and J.D. Stoeckle. 1959. Beryllium disease.
Jour. Chron. Dis. 9: 152.
Hyslop, F., et al. 1943. The toxicology of beryllium.
U.S. Pub. Health Serv. Natl. Inst. Health Bull. 181.
IARC. 1972. Monographs on the evaluation of carcinogenic
risk of chemicals to man. Beryllium: 1: 17.
-------
Kaylor, C.T., and C.D. Van Cleave. 1953. Radiographic
visualization of the deposition of radioberyllium in the
rat. Anat. Record 117: 467.
Klemperer, F.W., et al. 1952. The fate of beryllium com-
pounds in 'the rat. Arch, aiochem. Biophys. 41: 148.
Komitowski, D. 1969. Morphogenesis of beryllium-induced
bone tumors. Patol. Pol (suppl.) 1: 479.
Kopp, J.F., and R.C. Kroner. 1967. A five year study of
trace metals in waters of the United States. Fed. Water
Pollut. Control Admin., U.S. Dep. Inter., Cincinnati, Ohio.
Krejci, L.E., and L.D. Scheel. 1966. Ln H.E. Stokinger,
ed. Beryllium: Its industrial hygiene aspects. Academic
Press, Inc., New York.
Lange, N.A. ed. 1956. Lange's handbook of chemistry.
9th ed. Handbook Publishers, Inc., Sandusky, Ohio.
Mancuso, T.F. 1970. Relation of duration of employment
and prior illness to respiratory cancer among beryllium
workers. Environ. Res. 3: 251.
Meehan, W.R., and L.E. Smythe. 1967. Occurrence of beryl-
lium as a trace element in environmental materials. Environ.
Sci. Technol. 1: 839.
National Academy of Sciences, National Academy of Engineer-
ing. 1973. Water quality criteria 1972. A report. Natl.
Acad. of Sci., Washington, D.C.
National Air Sampling Network, Air Quality Data. 1968.
National Air Sampling Network, Durham, N.C., U.S. Dep. Health
Education and Welfare, Pub. Health Serv.
National Institute of Occupational Safety and Health. 1972.
Criteria for a recommended standard... .Occupational exposure
to beryllium. DHEW (NIOSH) ?ubl. No. 72-10806.
Niemoller, H.K. 1963. Delayed carcinoma induced by beryl-
lium aerosol in man. Int. Arch. Gewerbepthol. Gewerbehyg.
20: 18.
Petzow, G., and H. Zorn. 1S74. Toxicology of beryllium-
containing materials. Chemlxer Vig. 98: 236.
Raven, C.P., and N.S. Sprcn.<. 1953. Action of beryllium
on the development of Limnaei stagnalis. Chem. Abstr.
47: 6561.
-------
Reeves, A.L. 1965. Absorption of beryllium from the gastro-
intestinal tract. AMA Arch. Environ. Health 11: 209.
Reeves, A.L., et al. 1967. Beryllium carcinogenesis. I.
Inhalation exposure of rats to beryllium sulfate aerosol.
Cancer Res..27: 439.
Schepers, G.W.H., et al. 1957. The biological action of
inhaled beryllium sulfate. A preliminary chronic toxicity
study in rats. AMA Arch. Ind. Health 15: 32.
Scott, J.K., et al. 1950. The effect of added carrier
on the distribution an<
Biol. Chem. 172: 291.
y—
on the distribution and excretion of soluble Be. Jour.
Spencer, H.C., et al. 1972. Toxicological evaluation of
beryllium motor exhaust products. AMRL-TR-72-118. Aero-
medical Res. Lao. Wright-Patterson AFB, Ohio.
Sprince, N.L., et al. 1^76. Current (1975) problems of
differentiating between beryllium disease and. sarcoidosis.
Stoeckle, J.D., et al. 1969. Chronic beryllium disease:
Long-term follow-up of 60 cases and selective review of
the literature. Am. Jour. Med. 46: 545.
Tabor, B.C., and W.V. Warren. 1958. Distribution of cer-
tain metals in the atmosphere of some American cities.
Arch. Ind. Health. 17: 145.
Tepper, L.3. 1972. Beryllium. CRC critical reviews in
toxicology. 1: 235.
Tepper, L.B., et al. 1961. Toxicity of beryllium compounds.
Elsevier Publishing Co., New York.
Thornton, C.S. 1950. Beryllium inhibition of regenerations.
Jour. Exp. Zool. 114: 305.
U.S. EPA. 1977. Multimedia environmental goals for environ-
mental assessment. Vol. II. MEG charts and background inform-
ation. EPA-b0017-77-136b. U.S. Environ. Prot.Agency.
U.S. EPA. 1978. In-depth studies on health and environmental
impacts of selected water pollutants. U.S. Environ. Prot.
Agency, Washington, D.C.
U.S. EPA. 1979. Beryllium: Ambient Water Quality Criteria.
U.S. Environ. Prot. Agency, Washington, D.C.
Van Cleave, C.D., and C.T. Kaylor. 1955. Distribution,
retention and elimination of Be in the rat after intratra-
cheal injection. AMA Arch. Ind. Health 11: 375.
-------
Vorwald, A.J., and A.L. Reeves. 1959. ..Pathologic changes
induced by beryllium compounds. AMA. Arch. Ind. Health
19: 190.
Vorwald, A.J., et al. 1966. Experimental beryllium toxi-
cology, in H.E. Stokinger, ed. Beryllium, its industrial
hygiene aspects. Academic Press, New York.
Wagner, W.D., et al. 1969. Comparative inhalation toxicity
of beryllium ores bertranaite and beryl with production
of pulmonary tumors by beryl. Toxicol. Appl. Pharmacol.
15: 10.
Wagoner, J.K., et al. 1978. Beryllium: carcinogenicity
studies. Science 201: 298.
-------
No. 23
Bis(2-chloroethoxy)raethane
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.
-------
3IS(2-CHLOROETHOXY)METHANE
Summary
Pertinent data could not be located in the available literature search-
es on the mutagenic, carcinogenic, teratogenic, or adverse reproductive ef-
fects of bis(2-chloroethoxy)methane (BCEXM) in mammals. A closely related
compound, bis(2-chloroethoxy)ethane (BCEXE) has been shown to produce skin
tumors and injection site sarcomas in animal studies.
Pertinent information could, not be located in the available literature
on bis(2-chloroethoxy)methane toxicity to aquatic organisms.
-------
BIS( 2-CHLOROETHOXY )METHANE
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Chloroalkyl Ethers (U.S. EPA, 1979a).
The Chloroalkyl ethers are compounds in which a hydrogen atom in one or
both of the aliphatic ether chains are substituted with chlorine. Bis (2-
chloroethoxy)methane (3CEXM, dichloroethyl formal, C1CH2CH2-0-CH2-
is a colorless liquid at room temperature with a boiling
point of 218. 1°C and a specific gravity of 1.2339. The compound is
slightly soluble in water but miscible with most organic solvents.
The Chloroalkyl ethers have a wide variety of industrial uses in organ-
ic synthesis, treatment of textiles, the manufacture of polymers and insec-
ticides, as decreasing agents and solvents, and in the preparation of ion
exchange resins (U.S. EPA, 1979a).
The Chloroalkyl ethers, like BCEXM, have a higher stability in water
than the alpha Chloroalkyl ethers, which decompose. BCEXM is decomposed by
mineral acids.
II. EXPOSURE
NO specific information on exposure to BCEXM is available. The reader
is referred to a more general treatment of chloroalkyl ethers (U.S. EPA,
1979b). 3CEXM has been monitored in rubber plant effluents at a maximum
level of 140 mg/1 (Webb, et al. 1973). Bis-l,2-(2-chloroethoxy)ethane
(BCEXE), a closely related compound, has been reported in drinking water at
a maximum level of 0.03 ug/1 (U.S. EPA, 1975). Data on levels of BCEXM in
foods was not found in the available literature.
No bioaccumulation factor for BCEXM has been derived.
-------
III. PHARMACOKINETICS
Pertinent information could not be located in the available literature
on BCEXM. The reader is referred to a more general treatment of chloroalkyl
ethers. (U.sl EPA, 1979b).
IV. EFFECTS
A. Carcinogenicity
Pertinent information could not be located in the available litera-
ture on carcinogenic effects of BCEXM. The reader is referred to a more
general treatment of chloroalkyl ethers (U.S. EPA, I979b). A closely re-
lated compound, BCEXE, has been shown to produce skin tumors in mice and in-
jection site sarcomas (Van Ouuren, et al. 1972).
B. Mutagenicity, Teratogenicity, Other Reproductive Effects and Chron-
ic Toxicity
Pertinent data could not be located in the available literature for
BCEXM.
V. AQUATIC TOXICITY
Pertinent information could not be located in the available literature
on the aquatic toxicity of BCEXM.
VI. EXISTING GUIDELINES AND STANDARDS
No standards or recommended criteria exist for the protection of human
health or aquatic organisms to bis(2-chloroethoxy)methane.
-------
3IS( 2-CHLOROETHOXY)METHANE
RE
U.S. EPA., 1975. Preliminary assessment of suspected carcinogens in drink-
ing water:'Interim report to Congress, Washington, O.C.
U.S. EPA. 1979a. Chloroalkyl Ethers: Ambient Water Quality Criteria.
(Draft)
U.S. EPA. 1979b. Environmental Criteria and Assessment Office. Chloro-
alkyl Ethers: Hazard Profile. (Draft)
Van Ouuren, et al. 1972. Carcinogenicity of haloethers. II. Structure-
activity relationships of analogs of bis(chloromethyl)ether. Jour. Natl.
Cancer Inst. 48: 1431.
Webb, R.G., et al. 1973. Current practice in GC-MS analysis of organics in
water. Publ. EPA-R2-73-277. U.S. Environ. Prat. Agency, Carvallis, Oregon.
-------
No. 24
Bi3<2-chloroethyl)ether
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 infornation 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
bis(2-chloroethyl)ether and has found sufficient evidence to
•
indicate that this compound is carcinogenic.
-------
BIS(2-CHLOROETHYL)ETHER
Summary
Oral administration of bis(2-chloroethyl)ether (BCEE) did not produce
an increase of tumors in rats. Male mice showed a significant increase in
hepatomas after ingestion of BCEE. BCEE has also shown activity as a tumor
initiator for mouse skin.
Testing of BCEE in the Ames1 Salmonella assay, in E^ cpli, and in
Saccharomyces cerevisiae has shown that this compound induces mutagenic
effects.
There is no. available evidence to indicate that BCEE produces adverse
reproductive effects or teratogenic effects.
The data base for bis (2-chloroe thy Wether is limited to three studies.
The 96-hr LC5Q value for the bluegill is reported to be over 600,000 ;jg/l.
Adverse chronic effects were not observed with the fathead minnow at test
concentrations as high as 19,000 jug/1. A bioconcentration factor of 11 \yas
observed during a 14-day exposure of bluegills. The half-life was 4-7 days.
^t^-lf
-------
BIS( 2-CH.QRQETHYDETHER
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Chloralkyl Ethers (U.S. EPA, 1979a).
The chloroalkyl ethers are compounds in which a hydrogen atom in one or
both of the aliphatic ether chains are substituted with chlorine. 8is(2-
chloroethyl)ether (BCSE, molecular weight 143.01) is a colorless liquid at
room temperature with a boiling point of 176-178°C at 760 mm Hg, and a-
•
density of 1.213. The compound is practically insoluble in water, but is
miscible with most organic solvents (U.S. EPA, 1979a).
The chloroalkyl ethers have a wide variety of industrial and laboratory
uses in organic synthesis, in textile treatment, the manufacture of polymers
and insecticides, as degreasing agents, and in the preparation of ion ex-;
change resins (U.S. EPA, 1979a).
The B-substituted chloroalkyl ethers, such, as 3CEE, are generally more
stable and hence less reactive in aqueous systems than the a-substituted
compounds (U.S. EPA, 1979a).
for additional information regarding chloroalkyl ethers in general, the
reader is referred to the EPA/ECAO Hazard Profile on Chloroalkyl Ethers
(U.S. EPA 1979b).
II. EXPOSURE
The B-chloroalkyl ethers have been monitored in water. Industrial dis-
charges from chemical plants involved in the manufacture of glycol products,
rubber, and insecticides may contain high levels of BCEE (U.S. EPA, 1979a).
The highest concentration of SCEE in drinking water reported by the U.S.* EPA
-------
(1975) is Q.5 jjg/1. There is no evidence of the occurrence of the chloro-
alkyl ethers in the atmosphere; human exposure appears to be confined to
occupational settings.
Human exposure to chloroalkyl ethers via ingestion of food is unknown
(U.S. EPA, 1979a). The B-chloroalkyl ethers, due to their stability and low
water solubility, may have a high tendency to be bioaccumulated. The U.S.
EPA (1979a) has estimated the weighted average bioconcentration factor for
BCEE to be 25 for the edible portions of fish and shellfish consumed by
Americans. This estimate is based on a measured steady-state biocon-
centration factor using bluegills.
III. PHARMACOKINETICS
A. Absorption
Experiments with radiolabelled 8CEE have indicated that the com-
pound is readily absorbed following oral administration (Lingg, et al.
1978). Information on inhalation or dermal absorption of chloroalkyl ethers
is not available (U.S. EPA, 1979a).
B. Distribution
Pertinent information on the distribution of BCEE could not be
located in the literature.
C. Metabolism
The biotransformation of BCEE in rats following oral administration
appears to involve cleavage of the ether linkage and subsequent conjugation
with non-protein-free sulfhydryl groups, the major route, or with glucuronic
acid (Lingg, et al. 1978). Thiodiglycolic acid and 2-chloro-
ethanol-8-O-glucuronide were identified as urinary metabolites of BCEE in
rats.
-------
0. Excretion
BCEE administered to rats by intubation was eliminated rapidly in
the urine, with more than 60 percent of the compound excreted within 24
hours (Uingg',,et al. 1978).
IV. EFFECTS
A. Carcinogenicity
SCEE has shown activity as a tumor initiator in mouse skin (U.S.
EPA, 1979a). Preliminary results of an NCI study indicate that oral admin-
istration of BCEE does not produce an increase in tumor incidence in rats
(U.S. EPA, 1979a); however, mice administered BCEE by ingestion showed a
significant increase in hepatomas (Innes, et al. 1969).
B. Mutagenicity
Testing of the chloroalkyl ethers in the Ames1 Salmonella assay and.
in E^ coll have indicated that. BCEE induces mutagenic effects (U.S. EPA,
1979a). BCEE has also shown mutagenic effects in Saccharomvces cerevisiae
(Simmon, et al. 1977), but none were found in the heritable translocation
test for mice (Jorgenson, et al. 1977).
C. Teratogenicity, Chronic Toxicity and other Reproductive Effects
Pertinent information could not be located in the available liter-
ature.
0. Other Relevant Information
Acute physiological responses of the guinea pig to inhalation of
high concentrations of BCEE were congestion, emphysema, edema and hemorrhage
of the lungs (Shrenk, et al. 1933). Brief exposure of man to BCEE vapor, at
levels 260 ppm, irritated the nasal passages and eyes with profuse lacri-
mation. Deep inhalation produced nausea. The highest concentration, with no
noticeable effect was 35 ppm (Shrenk, et al. 1933).
A/-
-------
V. AQUATIC TOXICITY
A. Acute Toxicity
96-hr LC5Q value for the bluegill, Leoomis macrochirus, could not
be determined, for bis(2-chloroethy1)ether with exposure concentrations as
high as 600,000 ug/1 (U.S. EPA, 1978).
3. Chronic Toxicity
An embryo-larval test has been reported with bis(2-chloroethyl)
ether and the fathead minnow, Pimeohales promelas. Adverse effects were not
*
observed at test concentrations as high as 19,000 ug/1 (U.S. EPA, 1978).
C. Plant Effects
Pertinent data could not be located in the available literature.
0. Residues
A bioconcsntration factor of 11 was determined during a 14-day ex- 4
posure of bluegills to bis(2-chloroethyl)ether. The half-life was 4-7 days.
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
Based on the results of an animal carcinogenesis bioassay, and
using a linear, non-threshold model, the U.S. EPA (1979a) has estimated that
an ambient water level of 0.42 ug/1 will present an increased risk of 10" 3
or less for BCEE, assuming water and the injection of contaminated aquatic
organisms to be the only sources of exposure.
-------
The 8-hour, time-weighted average threshold limit value (TLV-TWA)
for 8CEE determined by the American Conference of Governmental Industrial
Hygienists (ACGIH, 1978) is 5 ppm for 8CEE.
3. Aquatic
Freshwater or saltwater criteria cannot be derived for bis(2-chlo-
roethyDether because of insufficient data (U.S. EPA, 1979a).
-------
aiS( 2-CHLQRQETHYDETHER
REFERENCES
American Conference of Governmental Industrial Hygienists. 1978. Threshold
limit values for chemical substances and physical agents in the workroom
environment with intended changes for 1978. Cincinnati, Ohio.
Fishbein, L. 1977. Potential industrial carcinogens and mutagens. Publ.
EPA-56075-77-005, Off. Toxic Subst. Environ. Prot. Agency, Washington, O.C.
Innes, J.R.M., et al. 1969. Bioassay of pesticides and industrial chem-
icals for tumorigenicity in mice: A preliminary note. Jour. Natl. Cancer
Inst. 42: 1101.
•
Jorgenson, T.A., et al. 1977. Study of the mutagenic potential of
bis(2-chloroethyl) and bis(2-chloroisopropyl) ethers in mice by the heri-
table translocation test. Toxicol. Appl. Pharmacol. 41: 196.
Lingg, R.O., et al. 1978. Fate of bis (2-chloroethyl)ether in rats after
acute oral administration. Toxicol. Appl. Pharmacol. 45: 248.
Schrenk, H.H., et al. 1933. Acute response of guinea pigs to vapors of
some new commercial organic compounds. VII. Oichloroethyl ether. Pub.
Health Rep. 48: 1389.
Simmon, V.F., et al. 1977. Mutagenic activity of chemicals identified in
drinking water. In: 0. Scott, et al. (ed.) Progress in genetic toxicology.
Elsevier/North HoITand Biomedical Press, New York.
U.S. EPA. 1975. Preliminary assessment of suspected carcinogens in drink-
ing water. Rep. Cong. U.S. Environ. Prot. Agency, Washington, D.C.
U.S. EPA. 1977a. National organic monitoring survey. General review of
results and methodology: Phases I-III. U.S. Environ. Prot. Agency, Off.
Water Supply, Tech. Support Div. Presented before Water Supply Res. Oiv.
Phys. Chem. Removal Branch, Oct. 21.
U.S. EPA. 1977b. Potential industrial carcinogens and mutagens. Office of
Toxic Substances. EPA-560/5-77-005. Washington, O.C.
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. U.S. Environ. Prot. Agency, Contract No.
68-1-4646.
U.S. EPA. 1979a. Chloroalkyl Ethers: Ambient Water Quality Criteria.
(Draft)
U.S. EPA. 1979b. Environmental Criteria and Assessment Office. Hazard
Profile: Chloroalkyl Ethers. (Draft).
Van Ouuren, 3.L. 1969. Carcinogenic apoxides, lactones, and haloethers and
their mode of action. Ann. N.Y. Acad. Sci. 163: 633.
-------
Van Ouuren, 8.L.. et al. 1969. Carcinogenicity of haloethers. jour. Natl.
Cancer Inst. 43: 481.
Van Ouuren, B.L., et al. 1972. Carcinogenicity of haloethers. II. Struc-
ture-activity . relationships of analogs of bis(chloromethyl)ether. Jour.
Mat-i ranear Inst. 48: 1431.
-------
Mo. 25
3ia(2-ChloroisopropyI)ether
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
3LS-./
-------
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.
-------
BIS(2-CHLOROISOPROPYL)ETHER
Summary
Preliminary results from an NCI carcinogenesis bioassay do not show an
increase in tumors following oral administration of bis(2-chloroisopropyl)-
ether (8CIE).
BCIE has produced mutagenic effects in two bacterial test systems (Sal-
monella and E^ coli) but has failed to show mutagenicity in one mammalian
study.
No information is available on the teratogenic or adverse reproductive
effects of BCIE.
Chronic exposure to BCIE has produced liver damage in animals.
Data on the toxicity of bis(2-chloroisopropyl)ether to aquatic' organ-
isms are not available.
-3
-------
BIS(2-CHLOROISOPROPYL)ETHER
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Chloroalkyl Ethers (U.S. EPA, 1979a).
The Chloroalkyl ethers are compounds in which a hydrogen atom in one or
both of the aliphatic ether chains .are substituted with chlorine. Bis(2-
chloroisopropyl)ether (BCIE, molecular weight 171.07) is a colorless liquid
at room temperature with a boiling point of 187-188°C at 760 mm Hg. The
compound is practically insoluble in water but is miscible with organic sol-
vents.
•
The Chloroalkyl ethers have a wide variety of industrial and laboratory
uses in organic synthesis, treatment of textiles, the manufacture of poly-
mers and insecticides, as degreasing agents, and in the preparation of ion
exchange resins (U.S. EPA, 1979a).
The beta-chloroalkyl ethers, like BCIE, are more stable in aqueous sys-
tem than the alpha-chloroalkyl ethers, which decompose rapidly. For addi-.
tional information regarding the Chloroalkyl ethers as a class, the reader
is referred to the Hazard Profile on Chloroalkyl Ethers (U.S. EPA, 1979b).
II. EXPOSURE
The beta-chloroalkyl ethers have been monitored in water. Industrial
discharges from chemical plants involved in the manufacture of glycol pro-
ducts, rubber, and insecticides may present high effluent levels (U.S. EPA,
1979a). The highest concentration of BCIE monitored in drinking water by
the U.S. EPA (1975) was reported as 1.58 jug/1.
The concentrations of Chloroalkyl ethers in foods have not been moni-
tored. The beta-chloroalkyl ethers, however, due to their relative stabili-
ty and low water solubility, may have a high tendency to be bioaccumulated.
-------
The U.S. EPA (1979a) has estimated the weighted average bioconcentration
factor for bis(2-chloroisopropyl)ether to be 106 for the edible portions of
fish and shellfish consumed by Americans. This estimate is based on the
octanol/wate-r partition coefficient.
III. PHARMACOKINETICS
A. Absorption
Experiments with radio-labeled BCIE have indicated that the com-
pound is readily absorbed following oral administration (Smith, et al.
1977). No information on inhalation or dermal absorption of the chloroalkyl
ethers is available (U.S. EPA, 1979a).
B» Distribution
Species differences in the distribution of radio-labeled BCIE have
been reported by Smith, et al. (1977). Monkeys retained higher amounts of
radioactivity in the liver, muscle, and brain than did rats. Urine and ex-
pired air from monkeys also contained higher levels of radioactivity than
those determined in the rat. Blood levels of BCIE in monkeys reached a peak
within 2 hours following oral administration and then declined in a biphasic
manner (t 1/2 = 5 hours and 2 days, respectively).
C. Metabolism
Urinary metabolites of labeled BCIE identified in studies with rats
included l-chloro-2-propanol, propylene oxide, 2-(l-methyl-2-chloro-ethoxy)
propionic acid, and carbon dioxide (Smith, et al. 1977).
0. Excretion
Smith, et al. (1977) found that in the rat, 63.36 percent, 5.37
percent, and 15.96 percent of a 30 mg orally-administered dose of BCIE were
recovered after 7 days in the urine, feces, and expired air, respectively.
In the monkey, the corresponding figures were 28.61 percent, 1.19 percent,
and Q percent, respectively.
-------
IV. EFFECTS
A. Carcinogenicity
Preliminary results of an NCI carcinogenicity bioassay indicate
that oral administration of 8CIE does not produce an increase in tumor inci-
dence (U.S. EPA, 1979a).
B. Mutagenicity
Testing of BCIE in the Ames Salmonella assay and in E.. coli have
indicated that the compound shows mutagenic activity (U.S. EPA, 1979a).
BCIE did not show mutagenic effects in the murine heritable translocation
test (Oorgenson, at al. 1977).
C. Teratogenicity and Other Reproductive Effects
Pertinent data could not be located in the available literature.
0. Chronic Toxicity
Chronic oral exposures of mice to BCIE produced centrilobular liver
necrosis in mice. The major - effects in rats were pulmonary congestion and
pneumonia (U.S. EPA, 1979a).
E. Other Relevant Information
Several chloroalkyl ethers show initiating activity and therefore
may interact with other agents to produce skin papillomas (Van 'Duuren, et
al. 1969, 1972); however, data specific to BCIE is not available.
V. AQUATIC TOXICITY
Pertinent data could not be located in the available literature,
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
BCIE is an isomer of a group of chloroalkyl ethers which have been
shown to have,,carcinogenic potential. BCIE has been shown to be mutagenic;
however, definitive proof of carcinogenicity has not been demonstrated. The
available data is presently under review and a definitive determination as
to the carcinogenicity of this isomer cannot be made at this time.
B. Aquatic
No draft criteria to protect fish and saltwater aquatic organisms
from bis(2-chloroisopropyl)ether toxicity have been derived (U.S. EPA, 1979).
-------
BIS(2-CHLOROISOPROPYL)ETHER (8CIE)
REFERENCES
Jorgenson, T., et al. 1977. Study of the mutagenic potential of bis(2-
chloroethyl) and bis(2-chloroisopropyl) ethers in mice by the heritable
translocation test. Toxicol. Appl. Pharmacol. 41: 196.
Smith, C., et al. 1977. Comparative metabolism of haloethers. Ann. N.Y.
Acad. Sci. 298: 111.
U.S. EPA. 1975. Preliminary assessment of suspected carcinogens in drink-
ing water: Interim report to Congress, Washington, O.C.
U.S. EPA. 1979a. . Ghloroalkyl Ethers: Ambient Water Quality Criteria.'
(Draft)
U.S. EPA. 1979b. Environmental Criteria and Assessment Office. Chloro-
alkyl Ethers: Hazard Profile. (Draft)
Van Duuren, B., et al. 1969. Carcinogenicity of haloethers. Jour. Natl.
Cancer Inst. 43: 481.
Van Duuren, 8., et al. 1972. Carcinogenicity of haloethers. II. Struc-
ture-activity relationships of analogs of bis(chloroethyl)ether. Jour.
Natl. Cancer Inst. 48: 1431.
-------
V
No. 26
Bis(Chloronethyl)ether
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-I
-------
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
bis(chlorotnethyl)ether and has found sufficient evidence to
indicate that this compound is carcinogenic.
-------
BIS(CHLOROMETHYL)ETHER
Summary
9is(chloromethyl)ether (BCME) has been shown to produce tumors in ani-
mals following administration by subcutaneous injection, inhalation, or der-
mal application. Epidemiological studies of workers in the United States,
Germany, and Japan who were exposed to BCME and chloromethyl methyl ether
(CMME) indicate that these compounds are human respiratory carcinogens.
BCME has produced mutagenic effects in the Ames1 Salmonella assay and
in ,§., coli. Increased cytogenetic abnormalities have been observed in the
lymphocytes of workers exposed to BCME and CMME; this effect appeared to be
reversible.
There is no available evidence to indicate that the chloroalkyl ethers
produce adverse reproductive effects or teratogenic effects.
Information has not been found on the toxicity of bis(chloromethyl)
ether to aquatic organisms. The hazard profiles on the hafloethers and the
chloroalkyl ethers should be consulted for the toxicity of related compounds.
-------
BIS(CHLOROMETHYL)ETHER
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Chloroalkyl Ethers (U.S. EPA, 1979a).
The Chloroalkyl ethers are compounds in which hydrogen atoms in one or
both of the aliphatic ether chains are substituted with chlorine. Bis-
(chloromethyl)ether, (BCME; molecular weight 115.0), is a colorless liquid
at room temperature with a boiling point of 104°C at 760 mm Hg, and a den-
sity of 1.328. The compound immediately nydrolyies in water, but is misci-
ble with ethanol, ether, and many organic solvents (U.S. EPA, 1979a).
The Chloroalkyl ethers have a wide variety of industrial and laboratory
uses in organic synthesis, textile treatment, the manufacture of polymers
and insecticides, the preparation of ion exchange resins, and as degreasing
agents (U.S. EPA, 1979a).
While BCME is very unstable in water, it appears to be relatively sta-
ble in the atmosphere (Tou and Kallos, 1974). Spontaneous formation of 3CN€
occurs in the presence of both hydrogen chloride and formaldehyde (Frankel,
et al. 1974). For additional information regarding the Chloroalkyl ethers
in general, the reader is referred to the BWECAO Hazard Profile on Chloro-
alkyl Ethers (U.S. EPA, 1979D).
II. EXPOSURE
As might be expected from the reactivity of BCME in water, monitoring
studies have not detected its presence in water. Human exposure by inhala-
tion appears to be confined to occupational settings (U.S. EPA, 1979a).
Data for human exposure to ctrloroalkyl ethers by ingestion of food is
»
not available, nor is data relevant to human dermal exposure to chloralkyl
ethers (U.S. EPA, I979a).
-------
The U.S. EPA (1979a) has estimated the- weighted average bioconcentra-
tion factor for BCME to be 31 for the edible portions of fish and shellfish
consumed by Americans. This estimate is based on the octanol/water parti-
tion coefficient.
III. PHARMACOKINETICS
There is no specific information relating to the absorption, distribu-
tion, metabolism, or excretion of BCME (U.S. EPA, 1979a). Because of the
high reactivity and instability of BCME in aqueous systems, it is difficult
to generate pharmacokinetic parameters.
IV. EFFECTS
A. Carcinogenicity
BCME has been shown to produce tumors in several animal systems.
Inhalation exposure of male rats to' BCME produced malignant respiratory
tract tumors (Kuschner, et al. 1975), while dermal application to mouse skin
led to the appearance of skin tumors (Van Duuren, et al. 1963). Administra-
tion of BCME to newborn mice by ingestion has been shown to increase the
incidence of hepatocellular carcinomas in males (Innes, et al. 1969).
Epidemiological studies of workers in the United States, Germany,
and Japan who were occupationally exposed to BCME and CMME have indicated
that these compounds are human respiratory carcinogens (U.S. EPA, 1979a).
BCME has been shown to accelerate the rate of lung tumor formation
in strain A mice following inhalation exposure (Leong, et al. 1971). BCME
has also shown activity as a tumor initiating agent for mouse skin (Slaga,
et al. 1973).
B. Mutagenicity
»
Testing of the chloroalkyl ethers in the Ames Salmonella assay and
in §_._ coli have indicated that SCME produced direct mutagenic effects (U.S.
EPA, 1979a).
-------
The results of a study on the incidence of cytogenetic aberrations
in the lymphocytes of workers exposed to 8CME and CCME indicate higher fre-
quencies in this cohort. Follow-up indicates that removal of workers from
exposure led" to a decrease in the frequency of aberrations (Zudova and
Landa, 1977).
C. Teratogenicity and Other Reproductive Effects
Pertinent data could not be located in the available literature
regarding teratogenicity and other reproductive effects.
0. Chronic Toxicity
Chronic occupational exposure to CMME contaminated with BCME has
produced bronchitis in workers (U.S. EPA, 1979a). Cigarette smoking has
been found to act synergistically with this type of exposure to produce
bronchitis (Weiss, 1976, 1977).
E. Other Relevant Information
The initiating activity of several chloroalkyl ethers indicates
that these compounds will interact with other agents to produce skin papil-
lomas (Van Ouuren, et al. 1969, 1972).
V. AQUATIC TOXICITY
Pertinent information could not be found in the available literature
regarding aquatic toxicity for freshwater or marine species.
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
Based on animal carcinogenesis data, and using a linear, non-
threshold model, the U.S. EPA (1979a) has recommended a maximum permissible
-------
concentration of BCME for ingested water at .02 ng/1. Assuming water is the
only source of exposure, compliance to this level should limit the risk car-
cinogenesis to not more than 10" .
Based on animal studies, the 8-hour, time-weighted threshold limit
value (TLV-TVIA) has been recommended for BCME as one ppb by the American
Conference of Governmental and Industrial Hygienists (1978).
8. Aquatic
Criterion for the protection of freshwater or marine aquatic organ-
isms were not drafted due to lack of toxicological'-evidence.
-------
BIS(CHLOROMETHYL)ETHER
REFERENCES
American Conference of Governmental Industrial Hygienists.
1978. Threshold limit values for chemical substances and
physical agents in the workroom environment with intended
changes for 1978. Cincinnati, Ohio.
Frankel, L.S., et al. 1974. Formation of bis(chloromethyl)
ether from formaldehyde and hydrogen chloride. Environ.
Sci. Techno!. 8: 356.
Innes, J.R.M., et al. 1969. Bioassay of pesticides and
industrial chemicals for tumorigenicity in'-mice: A prelimi-
nary note. Jour. Natl. Cancer Inst. 42: 1101.
Kuschner, M.-f et al. 1975. Inhalation carcinogenicity
of alpha halo ethers. III. Lifetime and limited period
inhalation studies with bis(chloromethyl)ether at 0.1 ppm.
Arch. Environ. Health 30: 73.
Leong, B.K.J., et al. 1971. Induction of lung adenomas
by chronic inhalation of bis(chloromethyl)ether. Arch.
Environ. Health 22: 663.
Slaga, T.J., et al. 1973. Macromolecular synthesis fol-
lowing a single application of alkylating agents used as
initiators of mouse skin tumorigenesis. Cancer Res. 33:
769.
Tou, J.C., and G.J. Kallos. 1974. Kinetic study of the
stabilities of chloromethyl methyl ether and bis(chloromethyl)
ether in humid air. Anal. Chem. 46: 1866.
U.S. EPA. 1979a. Chloroalkyl Ethers: Ambient Water Quality
Criteria (Draft).
U.S. EPA. 1979b. Environmental Criteria and Assessment
Office. Hazard Profile: Chloroalkyl Ethers (Draft).
Van Duuren, B.L., et al. 1968. Alpha-haloethers: A new
type of alkylating carcinogen. Arch. Environ. Health 16:
472.
Van Duuren, B.L., et al. 1969. Carcinogenicity of halo-
ethers. Jour. Natl. Cancer Inst. 43: 481.
»
Van Duuren, B.L., et al. 1972. Carcinogenicity of halo-
ethers. II. . Structure-activity relationships of analogs
of bis(chloromethyl)ether. Jour. Natl. Cancer Inst. 48:
1431.
-------
Weiss, W. 1976. Chloromethyl ethers, cigarettes, cough
and cancer. Jour. Occup. Med. 18: 194.
Weiss, W. 1977. The forced end-expiratory flow rate in
Chloromethyl ether workers. Jour. Occup. Med. 19: 611.
Zudova, Z.V and K. Landa. 1977. Genetic risk of occupa-
tional exposures to haloethers. Mutat. Res. 46: 242.
-------
No. 27
Bis ( 2-ethylexyDphthalate
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.
-------
BIS-(2-ETHYLHEXYL)PHTHALATE
SUMMARY
Bis-'(-2-ethylhexyl)phthalate has been shown to produce
rautagenic effects in the Ames Salmonella assay and in the
dominant lethal assay.
Teratogenic effects in rats were reported following
interperitoneal (i.p.) administration and oral administra-
tion of bis-(2-ethylhexyl)phthalate. Additional reproductive
effects produced by bis-(2-ethylhexyl)phthalate include
impaired implantation and parturition, and decreased fertility
in rats. Testicular damage and decreased spermatogenesis
have been reported in rats, following i.p. or oral adminis-
tration, and in mice, given bis-(2-ethylhexyl)phthalate
by oral intubation.
Evidence has not been found indicating that bis-(2-
ethylhexyDphthalate has carcinogenic effects. Chronic
animal feeding studies of bis-(2-ethylhexyl)phthalate have
shown effects on the liver and kidneys.
Bis-(2-ethylhexyl)phthalate is acutely, toxic to fresh-
water invertebrates at a concentration of 11,000 ^ag/1.
The same species has been shown to- display severe reproduc-
tive impairment when exposed to concentrations less than
3 ug/1.
-------
. BIS-(2-ETHYLHEXYL)PHTHALATE
I. INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria Document for Phthalate Esters (U.S. EPA, 1979).
Bis-(2-ethylhexyl)phthalate, most commonly referred
to as di-(2-ethylhexyl)phthalate, (DEHP) is a diester of
the ortho form of benzene dicarboxylic acid. The compound
has a molecular weight of 391.0, specific gravity of 0.985,
boiling point of 386.9°C at 5 mm Hg, and is insoluble in
water (U.S. EPA, 1979).
DEHP is widely used as a plasticizer, primarily in
the production of polyvinyl chloride (PVC) resins. As much
as 60 percent by weight of PVC materials may be plasticizer
(U.S. EPA, 1979). Through this usage, DEHP is incorporated
into such products as wire and cable covering, floor tiles,
swimming pool liners, upholstery, and seat covers, footwear,
and food and medical packaging materials (U.S International
Trade Commission, 1978).
In 1977, current production was 1.94 x 10 tons/year
(U.S. EPA, 1979).
Phthalates have been detected in soil, air, and water
samples; in animal and human tissues; and in certain vegeta-
tion. Evidence from _in_ vitro studies indicates that certain
bacterial flora may be capable of metabolizing phthalates
to the monoester form (Englehardt, et al. 1975).
-------
II. EXPOSURE
Phthalate esters appear in all areas of the environ-
ment. Environmental release of the phthalates may occur
through leaching of plasticizers from ?VC materials, vola-
tilization of phthalates from PVC materials, and the inciner-
ation of PVC items. Sources of human exposure to phthalates
include contaminated foods and fish, and parenteral adminis-
tration by use of PVC blood bags, tubings, and infusion
devices (U.S. EPA, 1979).
Monitoring studies have indicated that phthalate concen-
trations in water are mostly in the ppm range, or 1-2 ug/liter
(U.S. EPA, 1979). Air levels of phthalates in closed rooms
that have PVC tiles have been reported to be 0.15 to 0.26
mg/m (Peakall, 1975)-. Industrial monitoring has measured
air levels of phthalates from 1.7 to 66 mg/m (Milkov, et
al. 1973). Levels of DEHP have ranged from not detect-
able to' 68 ppm in foodstuffs (Tomita, et al. 1977). Cheese,
milk, fish and shellfish present potential sources of high
phthalate intake (U.S. EPA, 1979). Estimates of parenteral
exposure of patients to DEHP during use of PVC medical appli-
ances have indicated approximately 150 mg DEHP exposure
from a single hemodialysis course. An average of 33 mg
DEHP exposure is possible during open heart surgery (U.S.
EPA, 1979).
The U.S. EPA (1979) has estimated the weighted average
»
bioconcentration factor for DEHP to be.95 for the edible
portions of fish and shellfish consumed by Americans. This
3.7-S
-------
estimate is based on the measured steady-state bioconcentra-
tion studies in fathead minnow.
III. PHASMACOKINETICS
A. Absorption
The phthalates are readily absorbed from the intes-
tinal tract, the peritoneal cavity, and the lungs (U.S.
EPA, 1979). Daniel and Bratt (1974) found that seven days
following oral administration of radiolabelled DEHP, 42
percent of the dose was recovered in the urine and 57 per-
cent recovered in the feces of rats. Bilary excretion of
orally administered DEHP has been noted by Wallin, et al.
(1974). Limited human studies indicate that 2 to 4.5 per-
cent of orally administered DEHP was recovered in the urine
of volunteers within 24 hours (Shaffer, et al. 1945). Lake,
et al. (1975) have suggested that orally administered phtha-
lates are absorbed after metabolic conversion to the mono-
ester form in the gut.
Dermal absorption of DEHP in rabbits has been
reported at 16 to 20 percent of the initial dose within
three days following administration (Autian, 1973).
B. Distribution
Studies in rats injected with radiolabelled DEHP
have shown that 60 to 70 percent of the administered dose
was detected in the liver and lungs within 2 hours after
administration (Daniel and Bratt, 1974). Wadell, et al.
(1977) have reported rapid accumulation of labelled DEHP
in the kidney and liver of rats after i.v. injection, fol-
lowed by rapid excretion into the urine, bile, and intes-
-------
tine. Seven days after i.v. administration of labelled
DEHP to mice, levels of compound were found preferentially
in the lungs and to a lesser extent in the brain, fat, heart,
and blood (Autian, 1973).
An examination of tissue samples, from two deceased
patients who had received large volumes of transfused blood,
detected DEHP in the spleen, liver, lungs, and abdominal
fat (Jaeger and Rubin, 1970).
Injection of pregnant rats with labelled DEHP
has shown that the compound may cross the placental barrier
(Singh, et al. 1975).
C. Metabolism
Various metabolites of DEHP have been identified
following oral feeding to rats (Albro,. et al. 1973). These
results indicate that DEHP is initially converted from the
diester to the monoester, followed by the oxidation of the '
monoester side chain forming two different alcohols. The
alcohols are oxidized to the corresponding carboxylic acid
or ketone. Enzymatic cleavage of DEHP to the monoester
may take place in the liver or the gut (Lake, et al. 1977).
This enzymatic conversion has been observed in stored whole
blood indicating widespread distribution of metabolic activ-..
ity (Rock, et al. 1978).
D. Excretion
Excretion of orally administered DEHP is virtually
»
complete in the rat within 4 days (Lake, et al. 1975).
Major excretion is through the urine and feces, with biliary
a 9-
-------
excretion increasing the content of DEEP (or metabolites)
in the intestine (U.S. EPA, 1979). Schulz and Rubin (1973)
have noted an increase in total water soluble metabolites
of labelled DEHP in the first 24 hours following injection
into rats. Within one hour, eight percent of the DEHP was
found in the liver, intestines and urine. After 24 hours,
54.6 percent was recovered in the intestinal tract, excreted
feces and urine, and only 20.5 percent was recovered in or-
ganic extractable form. Blood loss of DEHP showed a biphasic
o
pattern, with half-lives of 9 minutes and 22 minutes, respec-
tively (Schulz and Rubin, 1973).
IV. EFFECTS
A. Carcinogenicity
Pertinent data could not be located in the avail-
able literature.
B. Mutagenicity
Testing of DEHP in the Ames Salmonella assay has .
shown no mutagenic effects (Rubin, et al. 1979). Yagi,
et al. (1978) have indicated that DEHP is not mutagenic
in a recombinant strain of Bacillus, but the monoester meta-
bolite of DEHP did show some mutagenic effects. Results
of a dominant lethal assay in mice indicate that DEHP has
a dose and time dependent mutagenic effect (Singh, et al.
1974).
C. Teratogenicity
DEHP has been shown to produce teratogenic .effects
in rats following i.p. administration (Singh, et al. 1972).
-------
Following oral administration there was a significant reduc-
tion in fetus weight at 0.34 and 1.70 g/kg/day.
D. .Other Reproductive Effects
Effects on implantation and parturition have been.
observed in pregnant rats injected intraperitoneally with
DEHP (Peters and Cook, 1973). A three-generation repro-
duction study in rats has indicated decreased fertility
iri rats following-maternal treatment with DEHP (Industrial
Bio-Test, 1978).
Testicular damage has been reported in rats ad-
ministered DEHP i.p. or orally. Seth, et al. (1976) found
degeneration of the seminiferous tubules and changes in
spermatagonia; testicular atrophy and morphological damage
were noted in rats fed DEHP (Gray, et al. 1977; Yamada,
et al, 1975). Otake, et al. (1977) noted decreased sperma-
togenesis in mice administered DEHP by intubation.
E. Chronic Toxicity
Oral feeding of DEHP produced increases in liver
and kidney weight in several animal studies (U.S. EPA, 1979).
Chronic exposure to transfused blood containing DEHP has
produced liver damage in monkeys (Kevy, et al. 1978). Lake,
et al. (1975) have produced liver damage in rats by adminis-
tration of mono-2-ethylhexyl phthalate.
F. Other Relevant Information
Several animal studies have demonstrated that
•
pce-treatment of rats with DEHP produced an increase in
hexobarbital sleeping times (Daniel and Bratt, 1974; Rubin
and Jaeger, 1973; Swinyard, et al. L976).
317-7
-------
V. AQUATIC TOXICITY
A. Acute Toxicity
Only one acute study on the freshwater cladoceran
(Daphnia magna) has produced a 96-hour static LC^Q value
of 11,000 ug/1 (U.S. EPA, 1978). Freshwater fish or marine
data have not been found in the literature.
B. Chronic Toxicity
Chronic studies involving the rainbow trout (Salmo-
gairdneri) provided a chronic value of 4.2 ug/1 in an embryo-
larval assay (Mehrle and Mayer, 1976). Severe reproductive
impairment was observed at less than 3 ug/1 in a chronic
Daphnia magna assay (Mayer and Sanders, 1973).
C. Plant Effects
Pertinent information could not be located in
the available literature.
D. Residues
Bioconcentration factors have been obtained for
several species of freshwater organisms: 54 to 2,680 for
the scud (Gamarus pseudolimnaeus); 14 to 50 for the sowbug
(Ascellus brevicaudus); 42 to 113 for the rainbow trout
(Salmo gairdneri); and 91 to 886 for the fathead minnow
(Pimephales promelas) (U.S. EPA, 1979).
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived
by U.S. EPA (1979), which are summarized below, have gene
»
through the process of public review; therefore, there is
a possibility that these criteria will be changed.
-------
A. Human
Based on "no effect" levels observed in chronic
feeding studies in rats or dogs, the U.S. EPA has calculated
an acceptable daily intake (ADI) level for DEEP of 42 mg/day.
The recommended water quality criteria level for
protection of human health is 10 mg/1 for DEEP (U.S. EPA,
1979).
B. Aquatic
Criterion was not drafted for either freshwater
•
or marine environments due to insufficient data.
SL7-//
-------
BIS-(2-ETHYLHEXYL) PHTHALATE
REFERENCES
Albro, P.VI., et al. 1973. Metabolism of-diethylhexyl phthal-
ate by rats. Isolation and characterization of the urinary
metabolites. Jour. Chromatogr. 76: 321.
Autian, J. 1973. Toxicity and health threats of phthalate
esters: Review of the literature. Environ. Health Perspect.
June 3.
Daniel, J.W., and H. Bratt. 1974. The absorption, metabo-"
lism and tissue distribution of di(2-ethylhexyl) phthalate
in rats. Toxicology 2: 51.
Engelhardt, G., et al. 1975. The microbial metabolism
of di-n-butyl phthalate and related dialkyl phthalates.
Bull. Environ. Contam. Toxicol. 13: 342.
Gray, J., et al. 1977. Short-term toxicity study of di-
2-ethylhexyl phthalate in rats. Food Cosmet. Toxicol. 65:
389.
Industrial Bio-Test. 1978. Three generation reproduction
study with di-2-ethylhexyl phthalate in albino rats. Plastic
Industry News 24: 201.
Jaeger, R.J., and R.J. Rubin. 1970. Plasticizers from
plastic devices: Extraction, metabolism, and accumulation
by biological systems. Science 170: 460.
Kevy, S.V., et al. 1978. Toxicology of plastic devices
having contact with blood. Rep. N01 H3 5-2906, Natl. Heart,
Lung and Blood Inst. Bethesda, Md.
Lake, B.G., et al. 1975. Studies on the hepatic effects
of orally administered di-(2-ethylhexyl) phthalate in the
rat. Toxicol. Appl. Pharmacol. 32: 355.
Lake, B.G., et al. 1977. The in vitro hydrolysis of some
phthalate diesters by hepatic ami intestinal preparations
from various species. Toxicol. Appl. Pharmacol. 39: 239.
Mayer, F.L., Jr., and H.O. Sanders. 1973. Toxicology of
phthalic acid esters in aquatic organisms. Environ. Health
Perspect. 3: 153.
Mehrle, P.M., and F.L. Mayer. 1976. Di-2-ethylhexyl phtha'l-
ate: Residue dynamics and biological effects in rainbow
trout and fathead minnows. Pages 519-524. ^n Trace sub-
stances in environmental health. University of Missouri
Press, Columbia.
-------
Milkov, L.E., et al. 1973. Health status of workers ex-
posed to phthalate plasticizers in the manufacture of artifi-
cial leather and films based on PVC resins. Environ. Health
Perspect. Jan. 175.
\
Otake, T.',. et al. 1977. The effect of di-2-ethylhexyl
phthalate (DEHP) on male mice. I. Osaka-Fuitsu Koshu Eisei
Kenkyusho Kenkyu Hokoku, Koshu Eisei Hen 15: 129.
Peakall, D.B. 1975. Phthalate esters: Occurrence and
biological effects. Residue Rev. 54: 1.
Peters, J.W., and R.M. .Cook. ..1973. ..Effects of phthalate
esters on reproduction of rats. Environ. Health Perspect.
Jan. 91.
Rock, G., et al. 1978. The accumulation of mono-2-ethyl-
hexyl phthalate (MEHP) during storage of whole blood and
plasma. Transfusion 13: 553.
Rubin, R.J., and R.J. Jaeger. 1973. Some pharmacologic
and toxicologic effects of di-2-ethylhexyl phthalate (DEHP)
and other plasticizers. Environ. Health Perspect. Jan.
53.
Rubin, R.J., et al. 1979. ' Ames mutagenic assay of a series
of phthalic acid esters: Positive response of the dimethyl
and diethyl esters in TA 100. Abstract. Soc. Toxicol. Annu.
Meet. New Orleans, March 11.
Schulz, C.O., and R.J. Rubin. 1973. Distribution, metabo-
lism and excretion of di-2-ethylhexyl phthalate in the rat.
Environ. Health Perspect. Jan. 123.
Seth, P.K., et al. 1976. Biochemical changes induced by
di-2-ethylhexyl phthalate in rat liver. Page 423 ui Enviorn-
raental biology. Interprint Publications, New Dehli, India.
Shaffer, C.B., et al. 1945. Acute and subacute toxicity
of di(2-ethylhexyl) phthalate with note upon its metabolism.
Jour. Ind. Hyg. Toxicol. 27: 130.
Singh, A.R., et al. 1972. Teratogenicity of phthalate esters
in rats. Jour. Pharmacol. Sci. 51: 51.
Singh, A.R., et al. 1974. Mutagenic and antifertility
sensitivities of mice to di-2-ethylhexyl phthalate (DEHP)
and dimethoxyethyl phthalate (DMEP). Toxicol. Appl. Pharmacol.
29: 35.
Singh A.R., et al. 1975. Maternal-fetal transfer of I4c-
v i /l
di-2-ethylhexyl phthalate ai
Jour. Pharm. Sci. 64: 1347.
i «
di-2-ethylhexyl phthalate and C-diethyl phthalate in rats.
3.7-13
-------
Swinyard, E.A., et al. 1976. Nonspecific effect of bis(2-
ethylhexyl) phthalate on hexobarbital sleep time. Jour.
Pharmacol. Sci. 65: 733.
Tomita, I., et al. 1977. Phthalic acid esters in various
foodstuffs and biological materials. Ecotoxicology and
Environmental Safety 1: 275.
U.S. EPA. 1978. In-depth studies on health and environ-
mental impacts of selected water pollutants. U.S. Environ.
Prot. Agency, Contract No. 68-01-4646.
U.S. EPA. 1979. Phthalate Esters: Ambient Water Quality
Criteria (Draft).
U.S. International Trade Commission. 1978. Synthetic or-
ganic chemicals, U.S. production and sales. Washington,
D.C.
•
Waddell, W.M., et al. 1977- The distribution in mice of
intravenously administered C-di-2-ethylhexyl phthalate
determined by whole-body autoradiography. Toxicol. Appl.
Pharmacol. 39: 339.
Wallin, R.F., et al. 1974. Di(2-ethylhexyl) phthalate •
(DEHF) metabolism in animals and post-transfusion tissue
levels in man. Bull. Parenteral Drug. Assoc. 28: 278.
Yagi, Y., et al. 1978. Embryotoxicity of phthalate esters
in mouse. Proceedings of the First International Congress
on Toxicology, Plaa, G. and Duncan, W., eds. Academic Press,
N.Y. p. 59.
Yamada, A., et al. 1975. Subacute toxicity of di-2-ethyl-
hexyl phthalate. Trans. Food Hyg. Soc. Japan, 29th Meeting
p. 36.
*7i#'
-------
No. 28
Bromoform
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.
-------
If9
BROMOFORM
SUMMARY
Bromoform has been detected in finished drinking water in
the United States and Canada. It is believed to be formed by the
haloform reaction that may occur during water chlorination.
Broraoform can be removed -from drinking water via treatment with
activated carbon. Natural sources (especially red algae) produce
significant quantities of bromoform. There is a potential for
bromoform to accumulate in the aquatic environment because of its
resistance to degradation. Volatilization is likely to be an
important means of environmental transport.
Bromoform gave positive results in mutagenicity tests with
Salmonella typhimurium TA100. In a short-term in vivo oncogen-
icity assay it caused a significant increase in tumor incidence
at one dose level.
Inhalation of bromoform by humans can cause irritation of
the respiratory tract and liver damage. Respiratory failure is
the primary cause of death in- bromoform-related fatalities.
I. INTRODUCTION
This profile is based primarily on the Ambient Water Quality
Criteria document for halomethanes (U.S. EPA 1979b).
Bromoform (tribromomethane; CHB^) is a colorless, heavy
»
liquid similar in odor and taste to chloroform. Bromoform has
the following physical/chemical properties -(Weast, 1974):
-------
Molecular Weight: 252.75
Melting Point: 8.3'C
Boiling Point: 149.5'C (at 760 ram Hg)
Vapor Pressure: 10 ram Fig al 34'C
Solubility: slightly soluble in water;
soluble in a variety of
organic solvents.
A review of the production range (includes importation)
statistics for bromoform (CAS Ho. 75-25-2) which is listed in the
initial TSCA Inventory (1979a) has shown that between 100,000 and
900,000 pounds of this chemical were produced/imported in 1977.—'
Bromoform'is used as a chemical intermediate; solvent for
waxes, greases, and oils; ingredient in fire-resistant chemicals
and gauge fluids (U.S. EPA 1978a; Hawley, 1977).
II. EXPOSURE
A. Environmental Pate
Bromoform gradually decomposes on standing; air and light
accelerate decomposition (Windholz, 1976). The vapor pressure of
bromoform, while lower than that for chloroform and other chloro-
alkanes, is, nonetheless, sufficient to ensure that volatiliza-
tion will be an important means of environmental transport. The
This production range information does not include any produc-
tion/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).
-------
half-life for hydrolysis of bromoform is estimated at 636 years.
Bromoforra should be much more reactive in the atmosphere. Oxi-
dation by HO radical will result in a half-life of a few months
in the troposphere (U.S. EPA, 1977).
3. Bioconcentration
The bioconcentration factor for bromoform in aquatic organ-
isms that contain about 8% lip id is estimated to be 48. The
weighted average bioconcentration factor for bromoform in the
edible portion of all aquatic organisms consumed by Americans is
estimated to be 14 (U.S. EPA, 1979b).
C. Environmental Occurence
The National Organics Reconnaissance Survey detected bromo-
form in the finished drinking water of 26 of 80 cities, with a
maximum concentration of 92 ug/1. Over 90% of the samples con-
tained 5 ug/1 or less. No bromoform was found in raw water
samples (Syraons _et_ aA., 1975). Similarly, the EPA Region V
Organics Survey found bromoform in 14% of the finished drinking
water samples and none in raw water (U.S. EPA, 1975). Using a
variety of sampling and analysis methods, the National Organic
Monitoring "Survey found bromoform in 3 of 111, 6 of 118, 38 of
113, 19 of 106, and 30 of 105 samples with mean concentrations
ranging from 12-28 ug/1 (U.S. EPA, 1978b). A Canadian survey of
drinking water found 0-0.2 ug/1 with a median concentration of
0.01 ug/1 (Health and Welfare Can., 1977).
»
The National Academy of Sciences (1978) concluded that water
chlorination, via the haloforra reaction, results in the produc-
tion of trihalomethanes (including bromoforn) from the organic
precursors present in raw water.
-------
Significant quantities of bromoforra are also produced from
natural sources, especially red algae. For example, the essen-
tial oil of Asparagopsis taxiformis (a red marine algae eaten by
Hawaiians) contains approximately 80% bromoform (Burreson et al.,
1975).
.III. PHARMACOKINETICS
Bromoform is absorbed through the lungs, gastrointestinal
tract, and skin. Some of the absorbed bromoform is metabolized
in the liver to inorganic bromide ion. Bromide is found in
tissues and urine following inhalation or rectal administration
of bromoform (Lucas, 1929). Metabolism of bromoform to carbon
monoxide has also been reported (Ahmed, 1977). Recent studies
show that phenobarbital-induced rats metabolize bromoform to, A
(COC\J
carbonyl bromide (COBr2)f the brorainated analog of phosgene pPuirt
mi., f 1979).
IV. HEALTH EFFECTS
A. Carcinogenicity
Bromoform caused a significant increase in tumor incidence
at one dose level in a short-term in vivo oncogenicity assay
known as the strain A mouse lung adenoma test. The increase was
observed at a dose of 48 mg/kg/injection with a total dose of
1100 rag/kg. The tumor incidence was not increased significantly
at doses of 4 mg/kg (total dose of 72 mg/kg) or 100 mg/kg (total
dose of 2400 mg/kg) (Theiss ^t_ _al_. , 1977.
-------
B. Mutagenicity
Bromoforn was mutagenic in S. typhimurium strain TA 100
(without metabolic activation) (Simmon, 1977).
C. Other Toxicity
Rats inhaling 250 rag/m3 bromoform for 4 hr/day for 2 months
developed impaired liver and kidney function (Dykan, 1962).
In humans, inhalation of bromoform causes irritation.to the
respiratory tract. Mild cases of bromoform poisoning may cause
only headache, listlessness, and vertigo. Unconsciousness, loss
of reflexes, and convulsions occur in severe cases. The primary
cause of death from a lethal dose of bromoform is respiratory
failure. Pathology indicates that the chemical causes fatty
degenerative and centrolobular necrotic changes in the liver
(U.S. PHS, 1955).
Acute animal studies indicate impaired function and
pathological changes in the liver and kidneys of animals exposed
to bromoform (Kutob and Plaa, 1962; Dykan, 1962).
V. AQUATIC EFFECTS
A. Fresh Water Organisms
The 96-hr LCgg (static) in bluegill sunfish is 29.3 mg/1.
The 48-hr LC^Q (static) for Daphnia magna is 46.5 mg/1. The.96-
hr ECegS for chlorophyll A production and cell number in S.
capricornutum are 112 og/1 and 116 mg/1, respectively (U.S. EPA,
»
1978a). (See also Section II.B.)
X
-------
B. Marine Organisms
The 96-hr LC^Q (static) in sheepshead minnow is 17.9 mg/1.
The 96-hr LC'50 (static) in mysid shrimp is 20.7 mg/1. The EC5Qs
for chlorophyll A production and cell number in S. costatum are,
respectively, 12.3 mg/1 and 11.5 mg/1 (U.S. EPA, 1978a).
VI. EXISTING GUIDELINES
A. Human
The OSHA standard for bromoform in air is a time weighted
average (TWA) of 0.5 ppm (39CFR23540).
The Maximum Contaminant Level (MCL) for total trihalometh-
anes (including bromoform) in drinking water has been set by the
D.S. EPA at 100 ug/1 (44FR68624). The concentration of bromoform
produced by chlorination can be reduced by treatment of drinking
water with powdered activated carbon (Rook,11974). This is the
technology that has been proposed by the EPA to meet this
standard.
B. Aquatic
The proposed ambient water criterion for the protection of
fresh water aquatic life from excessive bromoform exposure is 840
ug/1 as a 24-hour average. Bromoform levels are not to exceed
1900 ug/1 at any time. The criterion for the protection of
marine life is 180 ug/1 (24 hr avg), not to exceed 1900 ug/1
(U.S. EPA, 1979b).
-------
REFERENCES
Ahmed, A.E.f ^t_ _al_. 1977. Metabolism of haloforms to carbon
monoxide/ I.' In vitro studies. Drug Metab. Dispos., _5_:198. (as
cited in U.S. EPA, 1979b).
Burreson, B.J., R.E. Moore, P.P. Roller 1975. Haloforras in the
essential oil of the alga Asparagopsis taxiformis (Rhodophyta).
Tetrahedron Letters, _7_:473-476. (as cited in NAS, 1978).
Dykan, V.A. 1962. Changes in liver and kidney, functions due to
methylene bromide and bromoform. Nauchn. Trucy Ukr Nauchn. -
Issled. Inst. Gigieny Truda i Profyabolevanii 29:82. (as cited
in U.S. EPA, 1979b).
Hawley, G.G. ed. 1971. Condensed Chemical Dictionary. 8th ed.
Van Mostrand Reinhold Co.
Health and Welfare Canada 1977. Environmental Health Direc-
torate national survey of halomethane in drinking water. (as
cited in U.S. EPA, 1979b).
Kutob, S.D., G.J. Plaa 1962. A procedure for estimating the
hepatotoxic potential of certain industrial solvents, ?ox. Appl.
Pharm., _4_:354. (as cited in U.S. EPA, 1979b) .
Lucas, G.H.W. 1929. A study of the fate and toxieity of bromine
and chlorine containing anesthetics, J. Pharm. Exp. Therap.,
_3_4:223-237. (as cited in WAS, 1978).
National Academy of Sciences 1977. Drinking Water and Health,
Part II, Chapters 6 and 7, Washington, D.C.
National Academy of Sciences 1978. Nonfluorinated Halomethanes
in the Environment, Washington, D.C.
Pohl, L.R. _et_ _al_. 1979. Oxidative bioactivation of haloforms
into hepatotoxins, prepublication.
Rook, J.J. 1974. Formation of haloforms during chlorination of
natural waters. J. Soc. Water Treat. Examin. 23 (Part 2):234-
243.
Simmon, V.F. 1977. Mutagenic activity of chemicals identified
in drinking water. In Progress in genetic toxicology, S. Scott
^Jt_al_. eds. (as cited in U.S. EPA, 1979b).
Symons, J.M et al. 1975. National organics reconnaissance '
survey for halogenated organics (NORS). J. Amer. Water Works
Assoc. j57_:634-647. (as cited in MAS, 1978).
Theiss, J.C. _et_ _al_. 1977. Test for carcinogenicity of organic
contaminants of United States drinking waters by pulmonary tumor
response in strain A mice, Can. Res., ^7_:2717. (as cited in U.S.
EPA, 1979b).
-------
U.S. EPA 1975. Formation of Halogenated Organics by Chlorina-
tion of Water Supplies. EPA-600/1-75-002, PB 241-511. (as cited
in WAS, 197-8).
U.S. EPA 1977. Review of the environmental fate of selected
chemicals, EPA-560/5-77-0033.
U.S. EPA 1978a. Indepth studies on health and environmental
impacts of selected water pollutants, contract no. 68-01-4646,
Washington, D.C. (as cited in U.S. EPA, 1979b).
U.S. EPA 1978b. The National Organic Monitoring Survey, Office
of Water Supply, Washington, D.C.
U.S. EPA 1979a. Toxic Substances Control Act Chemical Substance
Inventory, Production Statistics for Chemicals on the Non-Confi-
dential Initial TSCA Inventory.
U.S. EPA 1979b. Halomethanes, Ambient Water Quality Criteria.
PB 296 797.
U.S. Public Health Service 1955. The halogenated hydrocarbons:
Toxity and potential dangers. No, 414. (as cited in U.S. EPA,
1979b).
Weast, R.C. ed. 1972. CRC Handbook of Chemistry and Physics.
CRC Press, Inc., Cleveland, Ohio.
Windholz, M. ed. 1976. The Merck Index, 9th ed., Merck and Co.,
Inc., Ranway, N.J.
-------
No. 29
Bromomethane
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
a,*-/
-------
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.
-------
BROMOMETHANE
Summary
On acute exposure to bromomethane, neurologic and psychiatric
abnormalities may develop and persist for months or years. There is
no information on the chronic toxicity, carcinogenicity, or terato-
genicity of bromomethane. Bromomethane has been shown to be mutagenic
in the Ames SU_ typhimurium test system.
Acute LCijQ values have been reported in two tests as 12,000 and
11,000 }ig/l for a marine and freshwater fish, respectively.
-------
BROMOMETHANE
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria
Document for Halomethanes (U.S. EPA, 1979a).
Bromomethane (CH^Br, methyl bromide, monobromomethane, and
embafume; molecular weight 9^-9^) is a colorless gas. Bromomethane
has a melting point of -93-6°C, a boiling point of 3-56°C, a specific
gravity of 1.676 g/ml at -20°C, and a water solubility of 17.5 g/1
at 20°C (Natl. Acad. Sci., 1978). Bromomethane has been widely used
as a fumigant, fire extinguisher, refrigerant, and insecticide (Kantarjian
and Shaheen, 1963). Today the major use of bromomethane is as a
fumigating agent. Bromomethane is believed to be formed in nature,
with the oceans as a primary source (Lovelock, 1975). The other
major environmental source of bromomethane is from its agricultural
use as a soil, seed, feed and apace fumigant. For additional information
regarding Halomethanes as a class the reader is referred to the
Hazard Profile on Halomethanes (U.S. EPA, 1979b).
II. EXPOSURE
A. Water
The U.S. EPA (1975) has identified bromomethane qualitatively
in finished drinking waters in the U.S. There are, however, no data
on its concentration in drinking water, raw water, or waste water
(U.S. EPA, 1979a).
B. Food
There is no information on the concentration of bromomethane
in food. Bromomethane residues from fumigation decrease rapidly
through loss to the atmosphere and reaction with protein to form
-------
inorganic bromide residues. With proper aeration and product processing,
most residual bromomethane will rapidly disappear due to methylation
reactions and volatilization (Natl. Acad. Sci., 1978; Davis, et al.
1977). There are no bioconcentration data for bromomethane (U.S.
EPA, 1979a).
C. Inhalation
Saltwater atmospheric background concentrations of bromomethane
averaging about 0.00036 mg/m3 have been reported (Grimsrud and Rasmussen,
1975; Singh, et al. 1977). This'is higher than reported average
continental background and urban levels and suggests that the oceans
are a major source of global bromomethane (Natl. Acad. Sci., 1978).
Bromomethane concentrations of up to 0.00085 mg/m3 may occur outdoors
locally with light traffic, as a result of exhaust containing bromomethane
as a breakdown product of ethylene dibromide, which is used in leaded
gasoline (Natl. Acad. Sci., 1978).
III. PHARMACOKINETICS
A. Absorption
Absorption of bromomethane most commonly occurs via the
lungs, although it can also occur through the gastrointestinal tract
and the skin (Davis, et al. 1977; von Oettingen, 1964).
B. Distribution
Upon absorption, blood levels of residual non-volatile
bromide increase, indicating rapid uptake of bromomethane or its
metabolites (Miller and Haggard, 19^3). Bromomethane is rapidly
distributed to various tissues and is broken down to inorganic bromide*.
Storage, only as bromides, occurs mainly in lipid-rich tissues.
-------
C. Metabolism
Evidently the toxicity of bromomethane is mediated by the
bromomethane molecule itself. Its reaction with tissue (methylation
of sulfhydfyl groups in critical cellular proteins and enzymes)
results in disturbance of intracellular metabolic functions, with
irritative, irreversible, or paralytic consequences (Natl. Acad.
Sci., 1978; Davis, et al. 1977; Miller and Haggard, 1943).
D. Excretion
Elimination of bromomethane is rapid initially, largely
through the lungs. The kidneys eliminate much of the remainder as
bromide in the urine (Natl. Acad. Sci., 1978).
IV. EFFECTS
Pertinent information relative to the carcinogenicity, teratogenicity
or other reproductive effects, or chronic toxcity of brqmomethane
were not found in the available literature.
A. Mutagenicity
Simmon and coworkers (1977) reported that bromomethane was
mutagenic to Salmonella typhimurium strain TA100 when assayed in a
dessicator whose atmosphere contained the test compound. Metabolic
activation was not required, and the number of revertants per plate .
was directly dose-related.
B. Other Relevant Information
In several species, acute fatal poisoning has involved
marked central nervous system disturbances with a variety of manifestations:
ataxia, twitching, convulsions, coma, as well as changes in lung, liver,
-------
heart, and kidney tissues (Sayer, et al. 1930; Irish, et al. 1940;
Gorbachev, et al. 1962; von Qettingen, 1964). Also, residual bromide
in fumigated food has produced some adverse effects in dogs (Rosenblum,
et al. 1960).
V. AQUATIC TOXICITY.
Two acute toxicity studies on one freshwater and one marine
fish species were reported with LC5Q values of 11,000 ug/1 for freshwater
*
bluegill (Lepomis maerochirus) and an LC5Q value of 12,000 jig/1 for
the marine tidewater silversides (Menidia beryllina) .(U.S. EPA,
1979a). Pertinent information relative to aquatic chronic toxicity
or plant effects for bromomethane were not found in the available
literature.
71. 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 current OSHA standard for occupational exposure to
bromomethane (1976) is 80 mg/m^; the American Conference of Governmental
Industrial Hygienist's (ACGIH, 1971) threshold limit value is 78
mg/m3. The U.S. EPA (1979a) draft water quality criteria for bromomethane
is 2 ug/1. Refer to the Halomethane Hazard Profile for discussion
of criteria derivation (U.S. EPA, 1979b).
-------
B. Aquatic Toxicity
The draft criterion for protecting freshwater life is a
24-hour average concentration of 140 ^g/1, not to exceed 320 ug/1.
The marine criterion is 170 ug/1 as a 24-hour average, not to exceed
380 jig/1.
-------
BROMOMETHANE
References
American Conference of Governmental and Industrial Hygienists. 1971.
Documentation of the threshold limit values for substances in workroom
air. Cincinnati, Ohio.
Davis, L.N., et al. 1977- Investigation of selected potential environmental
contaminants: monohalomethanes. EPA 560/2-77-007; TH 77-535. Final
rep. June, 1977, on Contract No. 68-01-4315. Off. Toxic Subst. U.S.
Environ. Prot. Agency, Washington, D.C.
Gorbachev, E.M., et al. 1962. Disturbances in neuroendocrine regulation
and oxidation-reduction by certain commercial poisons. Plenuma Patofiziol
Sibiri i Dal'n. Vost. Sb. 88.
• *
Grimsrud, E.P., and R.A. Rasmussen. 1975. Survey and analysis of halocarbons
in the atmosphere by gas chromatography-oass spectrometry. Atmos. Environ. 9:
1014.
Irish, D.D., et al. 1940. The response attending exposure of laboratory
animals to vapors of methyl bromide. Jour. Ind. Hyg. Toxicol. 22': 218.
Kantarjian, A.D., and A.S. Shaheen. 1963. Methyl bromide poisoning with nervous
system manifestations resembling polyneuropathy. Neurology 13: 1054.
Lovelock, (J.E. 1975. Natural halocarbons in the air and in the sea. Nature
256: 193-
Miller, D.P., and H.W. Haggard. 1943. Intracellular penetration.of bromide as
feature in toxicity of alkyl bromides. Jour. Ind. Hyg. Toxicol. 25: 423-
National Academy of Sciences. 1978. Nonfluorinated halomethanes in the
enviornment. Washington, D.C.
Occupational Safety and Health Administration. 1976. General industry standards.
OSHA 2206, revised January 1976. U.S. Dep. Labor, Washington., D.C.
Rosenblum, I., et al. 1960. Chronic ingestion by dogs of methyl bromide-
fumigated foods. Arch. Enviorn. Health 1: 3'6-
Sayer, R.R., et al. 1930. Toxicity of dichlorodiflouromethane. U.S Bur. Mines
Rep. R.I. 3013.
Simmon, 7.F. et al. 1977. Mutagenic activity of chemicals identified in drinking
water. S. Scott, et al., eds. In; Progress in genetic toxicology.
•
Singh, H.B., et al. 1977. Urban-non-urban relationships of halocarbons, S?5,
•NjO and other atmospheric constituents. Atinos. Environ. 11: 819.
U.S. EPA. 1975- Preliminary assessment of suspected carcinogens in drinking
water, and appendicies. A report to Congress, Washington,D.C.
U.S. EPA. I979a. Halomethanes: Ambient Water Quality Criteria. (Draft).
U.S. EPA, 1979b. Environmental Criteria and Assessment Office. Halomethanes:
Hazard Profile.
-------
von Qettingen, W.F. 1964. The halogenated hydrocarbons of industrial and
toxicological importance. Slsevier Publ. Co., Amsterdam.
-------
No. 30
4-Bromophenyl Phenyl Ether
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.
-------
4-Bromophenyl phenyl ether
SUMMARY
Very little information on 4-bromophenyl phenyl ether exists. 4-Bromophenyl
phenyl ether has been identified in raw water, in drinking water and in river
water. 4-Bromophenyl phenyl ether has been tested in the pulmonary adenoma
assay, a short-term carcinogenicity assay. Although the results were negative,
several known carcinogens also gave negative results. No other health effects
were available. 4-Bromophenyl phenyl ether appears to be relatively toxic
to freshwater aquatic life: a 24-hour average criterion of 6.2 ug/L has been
proposed.
I. INTRODUCTION
4-Bromophenyl phenyl ether (BrC,H,OC,H_; molecular weight 249.11) is a
liquid at room temperature; it has the following physical/chemical properties
(Weast 1972):
Melting point: 18.72°C
Boiling point: 310.14°C (760 mm Hg)
163°C (10 mm Hg)
Density: 1.420820 ,
Solubility: Insoluble in water; soluble in ether
No information could be found on the uses of this substance.
A review of the production range (includes importation) statistics
for 4-bromophenyl phenyl ether (CAS Nol 101-55-3) which is listed in the initial
TSCA Inventory (1979) has shown that between 0 and 900 pounds of this chemical
were produced/imported in 1977.*
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).
-------
II. EXPOSURE
No specific Information relevant to the environmental fate of 4-bromophenyl
phenyl ether-was found In the literature. A U.S. EPA report (1975a) Included this
substance in a category with several other drinking water contaminants consid-
ered to be refractory to biodegradation (i.e., lifetime greater than two years
in unadapted soil; point sources unable to be treated biologically). However,
the authors did not present or reference experimental data to support the inclu-
sion of 4-bromopheny phenyl ether in this category. U.S. EPA (1975a) estimated
that three tons of 4-bromophenyl phenyl ether are discharged annually.
4-Bromophenyl phenyl ether has been identified as a contaminant in finished
drinking water on three occasions, in raw water on one occasion and in river
water on one occasion. No quantitative data were supplied (U.S. EPA, 1976). Fri-
loux (1971) and U.S. EPA (1972) have also reported the presence of 4-bromophenyl
phenyl ether in raw and finished water of the lower Mississippi River (New
Orleans area). Again, no quantitative data were supplied. U.S. EPA (1975) sug:-
gest that 4-bromophenyl phenyl ether may be formed during the chlorination of
treated sewage and drinking water.
III. PHAEMACOKINETICS
No information was located.
IV. HEALTH EFFECTS
A. Carcinogenicity
Three groups of 20 male mice were administered intraperitoneal doses
(23, 17 or 18 doses, respectively) of 4-bromophenyl phenyl ether in tricaprylin,
vehicle three times a week for 3 weeks (Theiss et al. 1977). The total doses
were 920, 1700, or 3600 mg/kg, respectively. Animals were sacrificed at 24
weeks from the start of the experiment. Incidences of lung adenomas were not
significantly increased, as compared with vehicle controls. However, this short-
term assay should not be considered indicative of the nononcogenieity of 4-
bromophenyl phenyl ether as several known oncogens tested negative in this assay.
-------
7. AQUATIC TOXICXTY
A. Acute
An unadjusted 96 hour LC-Q of 4,940 ug/L was determined by exposing
bluegills to 4-bromophenyl phenyl ether (Table 1). Adjusting this value for test
conditions and species sensitivity, a Final Fish Acute Value of 690 ug/L is obtained
(U.S. EPA, undated).
Exposure of Daphnia magna, yielded an unadjusted 43 hour LC_Q of 360 ug/L
(Table 2). The Final Invertebrate Acute Value (and the Final Acute Value) for
4-bromophenyl phenyl ether is 14 ug/L (U.S. EPA, undated).
B. Chronic
In an embryo-larval test using the fathead minnow (in which survival and
growth were observed), a chronic value of 61 ug/L was obtained for 4-bromophenyl
phenyl ether exposure (Table 3). Dividing by the species sensitivity factor
(6.7), a Final Fish Chronic Value of 9.1 ug/L is derived. Since no other
Information is available, this value is also the Final Chronic Value (U.S. EPA,
undated).
VI. EXISTING GUIDELINES
A. Aquatic
A 24 hour average concentration of 6.2 ug/L (6.2 ug/L = 0.44 x 14 ug/L
(Final Acute Value)) is the recommended criterion to protect freshwater aquatic
life. The maximum allowable concentration should not exceed 14 ug/L at any
time (U.S. EPA, undated).
-------
Table 1. Freshwater fish acute values
Organism
Bluegill,
Lepomis macrochirus
Bioassay Test
Method* Cone
S U
Chemical
.** Description
4-Bromophenyl-
phenyl ether
Time
(hrs)
96
LC50
(ug/L.)
4,940
Adjusted
LC50
(ug/L)
2,700
-M
* S => static
** U » unmeasured
•
Geometric mean of adjusted values: 4-Bromophenylphenyl ether * 2,700 ug/L
2,700
3.9
690 ug/L
Table 2. Freshwater invertebrate acute values
Organism
Cladoceran,
Daphnia aagna
Bioassay Test
Method* Cone.**
S U
Chemical
Description
4-3romophenyl-
phenyl ether
Time
(hrs)
48
LC50
(ug/L)
360
.Adjusted
LC50
(ug/L)
300
* S - static
** U =» unmeasured
Geometric mean of adjusted values:
300 ., /T
- - U ug/L
4-Bromophenyl phenyl ether » 300 ug/L
Table 3. Freshwater fish chronic values, 4-Bromophenyl phenyl ether
Organism
Fathead minnow,
P 1m ep hales promelas
Limits
Test* (ug/L)
E-L 89-167
Chronic
Value
(ug/L)
61
61
* E-L » embryo-larva
Geometric mean of chronic values =• 61 ug/L 7—, =9.1 ug/L
o. /
Lowest chronic value = 61 ug/L
30-6
-------
BIBLIOGRAPHY
Friloux J. L971. Petrochemical wastes as a pollution problem In the lower
Mississippi River. Paper submitted to the Senate Subcommittee on Air and Water
Pollution, April 5 (as cited in U.S. EPA, 1975b) .
Theiss JC, Stoner GD, Shlmkin MB, Weisfaurger EK. 1977. Test for carcinogenicity
of organic contaminants of United States drinking waters by pulmonary tumor
response in strain A mice. Cancer Research 37:2717-2720.
U.S. EPA. 1972 Industrial pollution of the Lower Mississippi River in
Louisiana Region VI. Surveillance and Analysis Division (as cited in U.S.
EPA, I975b).
U.S. EPA. 1975a. Identification of organic compounds in effluents from industrial
sources. EPA-560/3-75-002, PB 241 641.
U.S. EPA. 1975b. Investigation of selected potential environmental contaminants:
Haloethers. EPA-560/2-75-006.
U.S. EPA. 1976. Frequency of organic compounds identified in water. EPA-
600/4-76-062.
U.S. EPA. 1979. Toxic Substances Control Act Chemical Substance Inventory.
Production Statistics for Chemicals on the Non-Confidential Initial TSCA Inventory.
U.S. EPA. (undated). Ambient Water Quality Criteria Document on Haloethers,
Criteria and Standards Division, Office of Water Planning and Management. PB
296-796.
Weast, RC (ed.). 1972. Handbook of Chemistry and Physics, 53rd. ed. The
Chemical Rubber Co., Cleveland, OH.
-------
No. 31
Cadmium
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. EPA1 s Carcinogen Assessment Group (GAG) has evaluated
cadmium and has found sufficient evidence to indicate that
this compound is carcinogenic.
-------
CADMIUM
Summary
The major non-occupational routes of human cadmium exposure are through
food and tobacco smoke. Drinking water also contributes relatively little
to the average daily intake.
Epidemiological studies indicate that cadmium exposure may increase the
mortality level for cancer of the prostate. Long-term feeding and inhal-
ation studies in animals have not produced tumors, while intravenous admin-
istration of cadmium has produced only injection site tumors. Mutagenic
effects of cadmium exposure have been seen in animal studies, bacterial sys-
tems, in vitro tests, and in the chromosomes of occupationally exposed
workers.
Cadmium has produced teratogenic effects in several species of animals,
possibly through interference with zinc metabolism. Testicular necrosis and
neurobehavioral alterations in animals following exposure during pregnancy
have been produced by cadmium in animals.
Chronic exposure to cadmium has produced emphysema and a characteristic
syndrome (Itai-Itai disease) following renal damage and osteomalacia. A
causal relationship between chronic cadmium exposure and hypertension in
humans has been suggested but not confirmed.
Cadmium is acutely toxic to freshwater fish at levels as low as 0.55
tig/1. Freshwater fish embryo/larval stages tended to be the most sensitive
to cadmium. Marine fish were generally more resistant than freshwater
fish. The long half-life of cadmium in aquatic organisms has been postu-
lated, and severe restrictions to gill-tissue respiration have been obs'erved
at concentrations as low as 0.5jug/l.
J/-V
-------
CADMIUM
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Cadmium (U.S. EPA, 1979).
Cadmium is a soft, bluish-silver-white metal, harder than tin but
softer than zinc. The metal melts at 321°C and shows a boiling point of
765°C (U.S. EPA, 1978b). Cadmium dissolves readily in mineral acids.
Some of the physical/chemical properties of cadmium and its compounds are
summarized in Table 1 (U.S. EPA, 1978b).
Cadmium is currently used in electroplating, paint and pigment
manufacture, and as a stabilizer for plastics (Fulkerson and Goeller, 1973).
Current production: 6000 metric tons (1968) (U.S. EPA, 1978b)
Projected production; 12,000 metric tons (2000) (U.S. EPA, 1978b)
Since cadmium is an element, it will persist, in some form in the
environment. Cadmium is precipitated from solution by carbonate, hydrox-
ide, and sulfide ions (Baes, 1973); this is dependent on pH and on cadmium
concentration. Complexing of cadmium with other anions will produce soluble
forms (Samuelson, 1963). Cadmium is strongly adsorbed to clays, muds, humic
and organic materials and some hydrous oxides (Watson, 1973), all of which
lead to precipitation from aqueous media. Cadmium corrodes slightly in air,
but forms a protective surface film which prevents further corrosion (U.S.
EPA, 1978b).
II. EXPOSURE
Cadmium is universally associated with zinc and appears with it in
natural deposits (Hem, 1972). Major sources of cadmium release into the
»
environment include emissions from metal refining and smelting plants, in-
cineration of polyvinyl chloride plastics, emissions from use of fossil
t
*4
31-S
-------
Table 1. Sutnu rrO|>crtleu of Cadmium and Its Important Compounds
Solubility
Primary Molecular Physical j Melting Boiling In watur
iiiie or uclBlit llcnulty ututc. • point point 20*C
Ciiiu|-muiJ occurrence For an In (£/iaolo) (B/U!) 20*C (*C) (*C) (g/llter)
llii.liuliin Cuilultiu nickel C.d 112.4 tt.6 Sllvur metal 321 765 Inuolublc
i
r
Cii.lniliin Swelling plant CdO 12B.4 7.0 Drown powder i Dttcoupouea 0.01)015
iml.le in coal toii.hu:,- «' ut 900
1 Inn en I a a I on '•
Ca.lmlinu I'lijiiiciit (or CdS 144.5 4.8 Yellow crystal 1750 Decomposes 0.0013
I'uiiiinila; jilioa-
C luii a .
i:,i,liuliim fruit tree CdSO, 20B.5 4.7 Uhlte 1000 755
bull. iiu luwlclJe cryatalllne
Ca.lmluia Turf treat- CdCO-j 172.4 4.3 IHilte powder Uuconpoaea 0.001
L'iiili>M>iii u wen i " or crystalline below 500
Solubility
In oilier
sol vent a
Soluble lit
acid and"
Soluble In
acid and
Nil-, milta
Soluble In
acid, very
ullulitly
soluble In
HII^OIl
Insoluble
In acid
and alocliol
Soluble In
acid and
KCN, Kit.
suits
Acute I.etluil
9 wu/w lu Hie
appro«liuiite
Iblliul cuncen-
t rut Ion lu wan,
lulialuil an fuuiu
50 IIIB/W IK tlie
lullial concen-
tration In wun,
Inbalud; 72
|.II5U (oral)
27 uiB/kg dog.
II) (lillb-
ciitdneoiiu)
-------
Table 1. Soiuu I'tupui I leu of Catlialuu onj Itu Important CunipounJs (Cont'd)
1'iluuiy llalccular
in. u oi weight Dcilulty
i:i.»i|>uim5|) (oral)
Inuoliiblo In
alcohol
Soluble In
uclJ and KCII
(III.,-i J.n.i U.M.,|.| U.I fiuia Uuuat, 19)1
-------
fuels, use of certain phosphate fertilizers, and leaching of galvanized iron
pipes (U.S. EPA, 1978b). The major non-occupational routes of human expo-
sure to cadmium are through foods and tobacco smoke (U.S. EPA, 1979),
Based on' available monitoring data, the U.S. EPA (1979) has estimated
the uptake of cadmium by adult humans from air, water, and food:
Adult
Source jug/day
Maximum conditions
Air-ambient .008 mg/day
Air-smoking 9.0'
Foods 75.0
Drinking water 20.0
Total 304.008
Minimum conditions
Air-ambient 0.00002
Air-smoking 0
Food 12.0
Drinking water 1.0
Total 13.00002
The variation of cadmium, levels in air, food, and water is quite exten-
sive as indicated above. Leafy vegetables, contaminated water, and air near
smelting plants all present sources of high potential exposure. The U.S.
EPA (1979) has estimated the weighted average, bioconcentration factor of
cadmium to be 17 in the edible portions of fish and shellfish consumed by
Americans.
III. PHARMACOKINETICS
A. Absorption
The main routes by which cadmium can enter the body are inhalation
and ingestion. Particle size and solubility greatly influence the biolog-
ical fate of inhaled cadmium. When a large proportion of particles are in
-------
the respirable range, up to 25% of the inhaled amount may be absorbed (EPA,
1979). Cadmium fumes may have an absorption of up to 50%, and it is esti-
mated that up to 50% of cadmium in cigarette smoke may be absorbed (WHO,
1977; Elinder-, et al. 1976). Large particles are trapped by the mucous mem-
branes and may eventually be swallowed, resulting in gastrointestinal
absorption (EPA, 1979).
Only a small proportion of ingested cadmium is absorbed. Two human
studies using radiolabelled cadmium have indicated mean cadmium absorption
from the gastrointestinal tract of 6% and 4.6% (Rahola, et al. 1973;
McLellan, et al. 1978). • Various dietary factors interact with cadmium ab-
sorption; these include calcium levels (Washko and Cousins, 1976), vitamin 0
levels (Worker and Migicovsky, 1961), zinc, iron, and copper levels (Banis,
et al. 1969). and ascorbic acid levels (Fox and Fry, 1970). Low protein
diets enhance the uptake of cadmium from the gastrointestinal tract (Suzuki,
et al. 1969).
Dermal absorption of cadmium appears to occur to a small extent;
wahlberg (1965) has determined that up to 1.8 percent of high levels of cad-
mium chloride were absorbed by guinea pig skin.
Cadmium levels have been determined in human embryos (Chaube, et
al. 1973) and in the blood of newborns (Lauwerys, 1978), indicating passage
of cadmium occurs across the placental membranes.
B. Distribution
Cadmium is principally stored in the liver, kidneys, and pancreas
with higher levels initially found in the liver (WHO Task Group, 1977).
continued exposure leads to accumulation in all of these organs; levels as
-------
high as 200-300 mg/kg wet weight may be found in the renal cortex. This
storage appears to be dependent on the association of cadmium with the
cadmium binding protein, metallothionen (Nordberg et al., 1975).
Animal studies indicate that following intraperitoneal or intra-
venous administration of cadmium most of the compound is found in the blood
plasma. After 12-24 hours the plasma is cleared and most of the compound is
associated with red blood cells (U.S. EPA, 1978b).
The cadmium body burden of humans increases with age (Friberg, et
•
al. 1974) from very minimal levels at birth to an average of up to 30-40 mg
by the age of 50 in non-occupationally exposed individuals. Liver accumu-
lation continues through the last decades of life, while kidney concen-
trations increase until the fourth decade and then decline (Gross, et al.
1976). The pancreas and salivary glands also contain considerable concen-
trations of cadmium (Nordberg, 1975). Smoking effects the body burden of
cadmium; levels in the renal cortex of smokers may be double those found in
non-smokers (Elinder, et al. 1976; Hammer, et al. 1971).
C. Metabolism.
Pertinent data were not found in the available literature.
D. Excretion
Since only about 6 percent of ingested cadmium is absorbed, a large
proportion of the compound is eliminated by the feces (U.S. EPA, a or b).
Some biliary excretion of cadmium has been demonstrated in rats (Stowe,
1976); this represented less than 0.1 percent of a subcutaneously adminis-
tered dose.
Urinary excretion of cadmium is approximately 1-2 mg/day in the
»
general population (Imbus, et al. 1963; Szadkowski, et al. 1969). Occupa-
tionally exposed individuals may show markedly higher urinary excretion
3HO
-------
levels (Friberg, at al. 1974). A modest increase in human urinary excretion
of cadmium has been noted with increasing age (Katagiri, et al. 1971).
Additional sources of cadmium loss are through salivary excretion
and shedding of hair (U.S. EPA, 1979).
Biological half-life calculations for exposed workers have given
values of up to 200 days (urine). Direct comparisons of urinary excretion
levels and estimated body burden using Japanese, American, and German data,
suggest a half-time- of 13-47 years. Using more complex metabolic models,
Frieberg, et al. • 1974 concluded that the biologic half-time is probably
10-30 years. . The most recent estimate of biologic half-time is 15.7 years
by Ellis (1979).
IV. EFFECTS
A. Carcinogenicity
The results of several epidemiology studies of the relationship of
cancer to occupational exposure to cadmium are summarized in Table 3 (U.S.
EPA-, 1978a). The only consistent trend seen in these studies is an
increased incidence of prostate cancer in cadmium-exposed workers. A recent
study by Kjellstrom, et al. (1979) of 269 cadmium-nickel battery factor/
workers found increased•cancer mortality from nasopharyngeal cancer (signif-
icant) and increased mortality trends for prostate, lung, and colon-rectum
cancers (not significant). After reviewing these studies, EPA (1979) has
concluded that cadmium cannot be definitely implicated as a human carcino-
gen with the available data.
Animal experiments with the administration of cadmium by subcu-
taneous or intravenous injection have demonstrated that cadmium produces
31-11
-------
injection site sarcomas and testicular tumors (Leydigiomas) (see Table 2;
U.S. EPA, 1978a). A large number of metals and irritants produced compar-
able injection site sarcomas. Long term feeding and inhalation studies with
cadmium have not produced tumors (Schroeder, et al. 1964, Levy, et al. 1973;
Decker, et al. 1958; Anwar, et al. 1961; Paterson, 1947; Malcolm, 1972)
At the present time, the draft ambient water quality criterion for
protection of human health is based on the toxicity of cadmium rather than
on any carcinogenic effects. Though the studies summarized above qualita-
tively indicate a -carcinogenic potential for cadmium, quantitatively, the
issue has not been resolved.
B. Mutagenicity
An increased incidence of chromosomal aberrations has been noted in
workers occupationally exposed to cadmium and in Japanese patients suffering
cadmium toxicity (Itai-Itai disease) (Bauchinger, et al. 1976; Bui, et al.
1975; Oeknudt and Leonard, 1976; Shiraishi and Yoshida, 1972).
Cadmium has been shown to produce mutagenic effects in vitro and in
vivo in several systems (see Table 4; U.S. EPA, 1978 a or b). These effects
include induction of point mutations in bacterial systems, chromosome aberr-
ations in cultured cells and cytogenetic damage in vivo, and promotion of
error prone base incorporation in DNA in vitro. Several investigators have
been unable to show dominant lethal effects of cadmium in mice (Epstein, et
al. 1972; Gillivod and Leonard, 1975; Suter, 1975). Point mutation studies
with cadmium in Orosophila have also produced negative findings (Shabalina,
1968; Friberg et al., 1974; Sorsa and Pfeiffer, 1973).
C. Teratogenicity
•
Damage to the reproductive tract resulting from a single dose of
parenterally administered cadmium chloride (2 mg/kg) have been observed in
-------
TABLE 2
STUDIES OH CADMIUM CARCINOGENESIS IN EXPERIMENTAL ANIMALS*
Authors
Animals
Compounds and routes
Tumora
lleath £t al. , 1962; Heath and Daniel, 1964 Kats
Kazantzls, 1063; Kazantzla and Hanbury, 1966 Rats
tladdow £t aJL. , 1964; Roe ejt al. , 1964 Rats
fiutlirle, 1964
-------
TABLE 3
SUMMARY OF RESULTS OF HUMAN EPIDEMIOLOGY STUDIES OF CANCER EFFECTS
ASSOCIATED UITH OCCUPATIONAL EXPOSURES TO CADMIUM
Population
(U'oup Studied
Mattery factory
uoikei's
Mattery factory
xvidkei a
Cadmium smelter
workers
Itubber industry
Cadmium Compound
Exposed To
Cadmium oxide
Cadmium oxide
Cadmium oxide,
others
Cadmium oxide
Incidences of
All Cancers
High
Normal
High
High
Incidences of
Lung Cancer
Normal
Normal
High
Normal
Incidences of
Prostrate Cancer
High
High
High
High
Reference
Potts (1965)
i
Kipling and
Uaterhouse
(1967)
Lemon et al .
(1976)
McMichael et al.
workers
(1976)
-------
rats, rabbits, guinea pigs, hamsters, and mice (Parizek and Zahor, 1956;
Parizek, 1957; Meek, 1959). This susceptibility appears to be genetically
regulated since different strains of mice show differential susceptibility
(Wolkowski,''1975).
Teratogenic effects of cadmium compounds administered parenterally
have been reported in mice (Eto, et al. 1975), hamsters (Perm and Carpenter,
1968; Mulvihill, et al. 1970; Ferm, 1971; Gale and Ferm, 1973) and rats
(Chernoff, 1973; 8arr, 1973). Oral administration of cadmium (10 ppm) has
»
demonstrated texatogenic effects in rats (Schroeder, and Mitchener, 1971),
but no teratogenicity has been reported in rats and monkeys (Cuetkova, 1970;
Pond and Walker, 1975; Willis, et al. 1976; Campbell and Mills, 1974).
0. Other Reproductive Effects
Rats in late pregnancy are apparently more sensitive to cadmium
than non-gravid animals or those immediately post-partum. A single dose of
2-3 mg/kg of body weight given during the last 4 days of pregnancy resulted
in high mortality (76 percent).
In addition to the ernbryotoxic effects of cadmium indicated in
Section C, persisting effects of cadmium exposure during pregnancy on postu-
lated development and growth of offspring have been observed. This includes
neurobehavioral alteration in newborn rats (Chowdbury and Lauria, 1976) and
growth deficiencies in lambs (U.S. EPA, 197Sa).
E. Chronic Toxicity
Friberg (1948, 1950) observed emphysema in workmen exposed to cad-
mium dust in an alkaline battery factory. This finding has subsequently
been well documented (U.S. EPA, 1979).
-------
TABLE 4
SUMMARY OF MUTAGENICITY TEST RESULTS
iiystcu
Genetic Effect
Reported
Mutageuicity
References
Systems la vitro
Iliiuuin cells
se Hamster Cells
Chromosomal damage
Point mutation
Point mutation
Jh. subtil is recoiublnant Gene mutation
assay
Polyuucleotides Base mispairing
Shlralshl zt_ al.'t 1972
Costa e£ al., 1976
Takahoshl, 1972
Nlshloka, 1975
Slrover and Loeb, 1976
Ihuiiau leukocytes
Iliiiiiau luiikocytuu
Human leukocytes
Iliiiiiau leukocytes
.'O oocytes
Mitiiuiia 1 a
»'c
Systems in vivo
CUromosomal damage
Ctu'omosomal damage
Chromosomal damage
Chromosomal damage
Altered spermatogenesls
Cytogenetic damage
Dominant lethal mutations
Dominant lethal mutations
Dominant lethal mutations
Chromosomal abnormalities
Sex-linked recessive lethal
+
+
Shirashi and Yoshlda, 1972
Bui et._al., 1975
Deknudt and Leonard, 1975
liauchinger et al., 1976
Lee and Dixon, 1973
Shimada et_ al., 1976
Epstein et^ al. , 1972
Gllliavod and Leonard, 1975
Suter, 1975
Shimada e£ al., 1976
Soraa and Pfeifer, 1973
-------
rats, rabbits, guinea pigs, hamsters, and mice (Parizek and Zahor, 1956;
Parizek, 1957; Meek, 1959). This susceptibility appears to tie genetically
regulated since different strains of mice show differential susceptibility
(Wolkowski,'1975).
Teratogenic effects of cadmium compounds administered parenterally
have been reported in mice (Eto, et al. 1975), hamsters (Ferm and Carpenter,
1968; Mulvihill, et al. 1970; Ferm, 1971; Gale and Ferm, 1973) and rats
(Chernoff, 1973; Barr, 1973). Oral administration of cadmium (10 ppm) has
•
demonstrated teratogenic effects in rats (Schroeder and. Mitchener, • 1971),
but no teratogenicity has been reported in rats and monkeys (Cuetkova, 1970;
Pond and Walker, 1975; Willis, et al. 1976; Campbell and Mills, 1974).
0. Other Reproductive Effects
Rats in late pregnancy are apparently more sensitive to cadmium
than non-gravid animals or those immediately post-partum. A single dose of
2-3 mg/kg of body weight given during the last 4 days of pregnancy resulted
in high mortality (76 percent).
In addition to the embryotoxic effects of cadmium 'indicated in
Section C, persisting effects of cadmium exposure during pregnancy on postu-
lated development and growth of offspring have been observed. This includes
neurobehavioral alteration' in newborn rats (Chowdbury and Lauria, 1976) and
growth deficiencies in lambs (U.S. EPA, 1978a).
E. Chronic Toxicity
Friberg (1948, 1950) observed emphysema in workmen exposed to cad-
mium dust in an alkaline battery factory. This finding has subsequently
been well documented (U.S. EPA, 1979).
-------
TABLE 4
SUMMARY OF MUTACENICITY TEST RESULTS
Tcul System
Genetic Effect
Reported
Mutageulclty
References
lluiiiaii eel la
Chinese llama ter Cella
j^. cercvlijiae
diilit:
Systems In vitro
Chromosomal damage
Point mutation
Point mutation
assay
I'olynucleotldcs
u recombInant Gene mutation
Base mispalrlng
Shiraishi £t ai.'. 1972
Coata e£ al.. 1976
Takahoshi, 1972
NishioUa, 1975
Slrover and Loeb, 1976
Human leukocytes
Human luukocytes
Human leukocytes
Human leukocytes
Uiit s|>efiiiatogonia
tloii:;e OOCytes
Ihniue breeding
tluu:,e breeding
l-kiuue breeding
H.iuuiial a
I), ii.elai
Systems in vivo
Chromosomal damage
Chromosomal damage
Chromosomal damage
Chromosomal damage
Altered spermatogenesls
Cytogenetic damage
Dominant lethal mutations
Dominant lethal mutations
Dominant lethal mutations
Chromosomal abnormalities
Sex-linked recessive lethal
Shirashi and Yoshlda, 1972
Bui ££ al., 1975
Deknudt and Leonard, 1975
Bauchinger et al., 1976
Lee and Dixon, 1973
Shlmada ££ al., 1976
Epstein et^ al. , 1972
Gilllavod and Leonard, 1975
Suter, 1975
Shlmada ££ al., 1976
Soraa and Pfelfer, 1973
-------
Chronic cadmium exposure produces renal tabular damage that is
characterized by the appearance of a characteristic protein 9B2-micro-
globulin) in the urine. Renal damage has been estimated to occur when
cadmium levels in the renal cortex reach 200 mg/kg (Kjellstron, 1977).
Itai-Itai disease is the result of cadmium induced renal damage plus ostao-
malacia (U.S. EPA, 1978a).
Exposure to high ambient cadmium levels may contribute to the etio-
logy of hypertension (U.S. EPA, 1979). Several studies, however, have been
unable to show a correlation between 'renal levels of cadmium and hyper-
•
tension (Morgan 1972; Lewis, et al. 1972; Beevers, et al. 1976).
Friberg (1950) and Blejer (1971) have noted abnormal liver function
tests in workers exposed to cadmium; however, these workers were occupa-
tionally exposed to a variety of agents.
The immunosuppressive effects of cadmium exposure, including an in-
creased susceptibility to various infections, have been reported in several
animal studies (Cook, et al. 1975; Xoller, 1973; Exon, et al. 1975).
V. AQUATIC TOXICITY
A. Acute Toxicity
Acute toxicity in freshwater fish has been studied in a number of
96-hour bioassays consisting of one static renewal, 22 static, and 19 flow-
through tests. LC5Q values ranged from 1 ug/1 for stripped bass larvae
(Roccus saxatilus) (Hughes, 1973) to 73,500 for the fathead minnow
(Pimephales promelas) (Pickering and Henderson, 1966). Increased resistance
to the toxic action of cadmium in hard waters was observed. The Up-
values for freshwater invertebrates ranged from 3.5 for Cladoceran
»
(Simoeohalus serrulatus) to 28,000 pg/1 for the mayfly (Eohemerella grandis
qrandis). Acute LC-0 values for marine fish ranged from 1,600 ug/1 for
31-17
-------
larval Atlantic silversides (Menidia menida) (Middaugh and Dean, 1977) to
114,000 yg/1 for juvenile mummichog (Fundulus heteroclitus) (Voyer, 1975).
Intraspecific and life stage differences have shown that larval stages of
the Atlantic silversides and mummichog are four times more sensitive than
adults under the same test conditions (Middaugh and Dean, 1977). Marine
invertebrates are more sensitive to cadmium than are marine fishes. LC--.
values ranged from 15.5 ug/1 for the mysid shrimp (Nimmo, et al. 1977a)- te-
46,600 for the fiddler crab (Uca puqilator) (O'Hara, 1973).
B. Chronic Toxicity
Chronic values for freshwater fish ranged from 0.9 ;jg/l in a brook
trout (Salvelinus fontinalis) embryo larval assay (Sauter, et al. 1976) to
50 jug/1 in a life cycle (or partial life cycle) assay for the bluegill
(Lepomis marcochirus) in hard water (Eaton, 1974). Salmonids were in
general the most sensitive species examined. Data for freshwater inverte-
brates depend on a single jug/1 obtained for Daphnia maqna (Biesinger and
Christensen, 1972). NO chronic studies were available for cadmium effects
in marine fishes. The only marine invertebrates data reported was the
chronic value of 5.5 jug/1 for the mysid shrimp, Mvsidoosis bahia. In this
animal' no measurable effects on brood appearance in the pouch, release,
average number per female, or survival were observed at concentrations of
4.8 jug/1.
C. Plant Effects
Effective concentrations for freshwater plants ranged from 2 jug/1,
which causes a 1C fold growth rate decrease in the diatom, Asterionella
formosa (Conway, 1973), to 7,400 jug/1, which causes a 5C& root weight,inhi-
bition in Eurasian water-milfoil (Myrioohvllum soicatum). In marine algae,
-------
96-hour EC5Q growth rate assays yielded values of 160 and 175 ug/1 for
Cvclotslla nana and Skeletonema costatum respectively (Gentile and Johnson,
1974).
0. Residues
Bioconcentration factors ranged from 151 for brook trout to 1,988
for the flagfish (Jordanella floridae). One characteristic of cadmium tox-
icity in aquatic organisms was the passible long half-life of the chemical
in certain tissues of exposed brook trout even after being placed in clean
water for several weeks. Testicular damage to adult mallards was observed
when fed 20 mg/kg cadmium in the diet for 90 days. In marine organisms •
bioconcentration values ranged from 37 for the shrimp Cranqon crangon to
1,230 for the American oyster, Crassostrea virginica (Schuster and Pringle,
1969).
E. Miscellaneous
Several studies on marine organisms have demonstrated significant
reduction in gill-tissues respiratory rates in the cunner, Tautoqolabrus
adepersus, the winter flounder, Pseudopleuronectes americanus, and the
stripped bass, Morone saxatilis, at concentrations as low as 0.5 ug/1.
VI. EXISTING GUIDELINES
A. Human
It is not recommended that cadmium be considered a suspect human
carcinogen for purposes of calculating a water quality criterion (U.S. EPA,
1979).
The EPA Primary Drinking Water Standard for protection of human
health is 10 ug/1. This level was also adopted as the draft ambient water
*
quality criterion (U.S. EPA, 1979).
3M9
-------
The OSHA time-weightad average exposure criterion for cadmium is
100 ;jg/m .
B. Aquatic
The draft criterion proposed for freshwater organisms to cadmium
has been prepared following the Guidelines, and is listed according to the
following equation:
Q(0.867 In-(hardness) - '4.38)
for a 24-hour average and not to exceed the level described by the following
equation:
(1.30 In-(hardness) - 3.92)
e
The proposed marine criterion derived following the Guidelines is 1.0 jjg as
a 24-hour average not to excaed 16 ^ig/1 at any time (U.S. EPA, 1979).
3/-3J
-------
CADMIUM
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•>
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»
Chernoff, N. 1973. Teratogenic effects of cadmium in rats.
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-------
Chowdbury, P. and D.B. Lauria. 1976. Influence of cadmium and
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Fern, V. and S. Carpenter. 1963. The relationship of cadmium
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Pox, M.R.S. and 3.E. Fry. 1970. Cadmium toxicity decreased
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-------
Friberg, L. 1948a. Proteinuria and kidney injury among workers
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Gale, T. and V. Ferm. 1973. Skeletal malformations resulting
from cadmium treatment in the hamster. Biol. Neou. 23: 149.
Gentile, J. and M. Johnson. 1974. EPA Semi-annual Rep., Narra-
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Gilliavod, N. and A. Leonard. 1975. Mutagenicity tests with
cadmium in the mouse. Toxicology 5: 43.
Gross, S.B., et al. 1976. Cadmium in liver, kidney and hair
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Hammer, D.I., et al. 1971. Hair trace metal levels and environ-
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Imbus, H.R., et al. 1963. Boron, cadmium, chromium and nickel
•in blood and urine. Arch. Environ. Health. 6: 286.
Katagiri, Y., et al. 1971. Concentration of cadmium in urine
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Kjellstrom, T., et al. 1979. Mortality and cancer morbidity
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-------
Levy, L.S., et al. 1973. Absence of prostatic changes in rts
exposed to cadmium. Ann. Occup. Hyg. 16: 111.
Lewis, G.P., et al. 1972. Cadmium accumulation in man: Influence
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Malcolm, D. 1972. Potential carcinogenic effect of cadmium
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31-
-------
Paterson, J.C. 1947. Studies on the toxicity of inhaled cad-
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*
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31* if
-------
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109
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•
Weast, R.C. (ed.) 1975. Handbook of chemistry and physics,
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-------
WHO Task. Group. 1977. Environmental health aspects of cadmium.
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Jour. Nutr. 75: 222.
- *a fr
-------
LB-.44-1
No. 32
Carbon Bisulfide
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
OCTOBER 30, 1980
32-1
-------
CARBON BISULFIDE
I. PHYSICAL-AND CHEMICAL PROPERTIES
*
CS2 (FW 76.14) is soluble in water at 0.294% (20°C), and
chelates trace metals, especially Cu and Zn. It is a colorless,
volatile, and extremely flammable liquid at RT. CS£ has no
odor wh'en pure.
II. PRODUCTION AND USE
C$2 is produced in petroleum and coal tar refining. Its
principal uses are as a solvent in the manufacture of rayon,
rubber, chemicals, solvents, and pesticides.^ In 1974, 782
2
million pounds of CSo were produced in the United States. In
1971, 53% was used in production of viscose rayon and cellphane
and 25% for manufacture of CC]^.
III. EXPOSURE
CS2 was detected in 5 of 10 water supplies surveyed by
the EPA.3 NIOSH25 estimates that in the U.S. 20,000 employees
are potentially exposed to CS2«
III. PHARMACOKINETICS
A. Absorption; Absorption differs with species and
route of administration^; inhalation and skin absorption are
the most important routes for humans (31).
B. Distribution; Large concentrations of both free
and bound C$2 are found in brain (guinea pig) and peripheral
nerves (rats) of exposed animals. The ratio of bound to
32-2
-------
free C$2 is brain 3:1. Blood and fatty tissues contain mainly
bound CS2> while liver contains €82 mainly in the free (unbound)
•C. Metabolism; C$2 is 90% metabolized by the P-450
system to inorganic sulfate.^ A portion of the S released by
CS2 is thought to react with SH groups of cysteine residues
in the microsomal proteins to form hydro-sulfide-6
D. Excretion; small amounts of CS2 metabolites such as thiourea,
5-mercaptothioazolidone, and inorganic constituents are excreted
in urine.^ Inhalation studies have shown that 18% of the
C&2 inhaled is exhaled unchanged. Of the remaining inhaled
dose, 70% is excreted as free or bound €82 and urinary
sulfates, and 30% is stored in the body and slowly excreted
as CS2 and its metabolites.
V. EFFECTS ON MAMMALS
A. Carcinogenicity: .No available data.^
B. Mutagenicity; No available data.^
C. Teratogenicity; Bariliah et al.8 showed that
inhalation of 10 mg/m^ is lethal to embryos before and after implan-
tation. CS2 at 2.2 mg/m3 inhaled for 4 hours/day was toxic to dams,
and embryotoxic if administered . during gestation, and had no effect
on male rats.^ Inhalation of lower concentrations (0.34 mg/1 for
210 days) caused disturbances of estrus.^-^ Topical application of
CS2 induced teratogenic effects in rats. In a dominant lethal
test, inhalation of 10 mg/m^ by male rats before copulation
proved lethal to embryos.8
32-3
-------
D. 'Toxicity
1. Humans
%
C$2 causes damage to the central and peripheral
nervous systems and may accelerate the development of, or
worsen, coronary heart disease.31
The lowest lethal concentration has been reported as
4,000 ppm in 30 minutes.H In the same study, a person sub-
jected to a concentration of 50 mg/m^ for 7 years had CMS
effects. Moderate chronic exposure of humans at less than
65 mg/m^ for several years has been reported by Cooper^ to
cause polyneuropathy. In a study by Baranowska et al.^3
humans have been shown to absorb 8.8-37.2 mg from an aqueous
solution containing 0.33-1.67 gm/1. This was over a period of
1 hour of hand-soaking.
In poisoning due to continued exposure at fairly low
levels (0.9-378 ppm)31 neuritis and visual disturbances are
the most common symptoms.31>32 Sensory changes, sensations
of heaviness and coldness, "veiling" of objects, pain in
affected limbs, are often followed by gradually increasing
loss of strength. Mental symptoms varying in severity
(excitation, irritability, personality changes, insomnia,
and even insanity) may occur.32
There are several studies on cardiovascular effects
of CS2 exposure.26"29 Heinberg et al.26'27 report signifi-
cantly elevated rates of coronary heart disease mortality,
angina, and high blood pressure in viscose rayon workers.
A five year follow-up again reported increased
32-4
-------
coronary heart disease mortality and higher than expected
incidences of total infarctions, nonfatal infarctions and angina.
t
In a-n 8-year followup in 1976, Heinberg-^O found no excess
coronary heart disease mortality during the last 3 years of the
study.
1 2. Other species.
IP injection of 400 mg/kg was the lowest lethal
dose in guinea pigs.14 An IV LD50 of 694 mg/kg in mice was
reported by Hylen and Chin.^-5
Toxic effects have been observed at doses as low as 1.7 mg/kg
in rabbits.^ Rats showed toxic SC effects at 1 mg/kg.17-19
Vinxsgr adov^O showed that 1 ppm in drinking water was nontoxic
to rabbits; 70 ppm was fatal.
In a chronic study, Paterni et al.^1 found that 6
mg/kg/day produced toxic effects in rabbits. The lowest
lethal chronic dose for rabbits was shown to be 0.1 ml 3
times a week for 7 months. ^ Applied topically, €82 produced
higher incidence of
anemia in female than in male rats, and teratogenic•effects (see above)
r\ <5 ' o
were observed. When rats inhaled C$2 at 10 mg/m , abnormalities
of genitourinary and skeletal systems were noted. In addition,
disturbances of ossification and blood formation and dystrophic
changes in liver and kidney were noted.8
VI. EXISTING GUIDELINES AND STANDARDS
The NAS^ did not recommend limits for drinking water
32-5
-------
because estimates of effects of chronic oral exposure cannot be
made with any confidence.
The current OSHA PEL is 20 ppm (62 mg/m3), with a
ceiling concentration of 30 ppm (93 mg/m3) for an 8-hour
day, 5 day work week.25 -jhe NIOSH2^ recommended standard
is 3 mg/m3.24
32-6
-------
REFERENCES (CS2)
1. U.S. EPA, Identification of organic compounds in effluents
from industr-ial-- sour ces , 1975.
2. U.S. International Trade Commission, Syn. Org. Chem., 1974.
3. U.S. EPA,'Preliminary Assessment of suspected carcinogens
in drinking water. Report to Congress. EPA 560/14-75-005;
?B 260961, 1975.
4.' NAS, Drinking Water and Health, 1977.
5. Dalve et ai., Chem. Biol. Inter. 10_:347-361, 1975.
6. . CatigusMxi and Neal, BBRC j65_(2): 629-636, 1975.
7. Theisinger, Am. Ind. Hyg. Assoc. 3^(2):55-61, 1974.
8. Bariliah et al. , Anat. Gistol. Embriol. £8_(5 ): 77-81, 1975.
9, Sal'nikova and "Chirkova, Gig. Tr. Prof. Zabol L2:34-37,
1974.
10. Rbzewiski et al., Med. Pr . ^(2)1133-139, 1973.
11. Registry of Toxic Effects of Chemical Substances, 1975.
12. Cooper, Food Cosmet. Toxicol. _14_:57-59, 1976.
13. Baranowska et al., Ann. Acad. Med. Lodz j^:169-174, 1966.
(cited in Chem. Abs. 7£:31443W, February 24, 1969).
14-. Davidson and Feinlab, Am. Heart J. 8_3( 1): 100-114, 1972.
15. Hylin and Chen, Bull. Environ. Contam. Toxicol.
_3(6):322332, 1968.
16." Merck Index, 1968.
17. Okamoto, Tokyo Jikeikai Ika Daigaku Zasshi 74;1184-1191.
1959.
18. Freundt et al. , Int. Arch Arbeitsmed. _32_: 297-303, 1974.
19. Freundt et al., Arch. Toxicol. ^2:233-240, 1974.
20. Vinogradov, Gig. Sanit. .31(1):13-18, 1966.
21. Paterm et al., Folia Med. 41:705-722, 1958.
32-7
-------
32-7
22. Michalova et al., Arch. Gewerbepath. Gewerbehyg.
_16_:653-665,. 1959.
«
23. Gut. Prac. Lek. 2l(10):453-458, 1969.
24. NIOSH. .-Criteria for a Recommended Standard CS2>
May, 1977.
25. 29 CFR 1910.1000.
26. Hernberg, Br. J. Ind. Med. 21_7_: 313-325, 1970.
27. Hernberg et al., Work Env. Health J5_:ll-16, 1971.
28. Hernberg et al., Work Env. Health ^0_: 93-99 , 1973.
29. Tolonen et al., Br . J..Ind. Med . .^2:1-10 , 1975.
30. Heinberg et al. , Work Env. Health _2:27-30, 1976.
31. Proctor, N.H. and J. P. Hughes, Chemical Hazards of
the Workplace. Lippincott, N.Y., 1978.
32. Sax, V. I. Dangerous Properties of Industrial
Materials. Van Nostrand Reinhold, N.Y., 5th edition,
1979.
32-8
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No. 33
Carbon Tetrachloride (Tetrachlororaethane)
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 (CAG) has evaluated
carbon tetrachloride and has found sufficient evidence to
indicate that this compound is carcinogenic.
•33-3
-------
CARBON TETRACHLORIDE
Summary
Carbon tetrachloride (CC1J is a haloalkane with a wide range of in-
dustrial and chemical applications. Toxicological data for non-human mam-
mals are extensive and show that CC1. causes liver and kidney damage, bio-
chemical changes in liver function, and neurological damage. CCl^ has
been found to induce liver cancer in rats and mice. Mutagenic effects have
not been observed and teratogenic effects have not been conclusively demon-
strated.
The data base on aquatic toxicity is limited. LC5Q (96-hour) values
for bluegill range from 27,300 to 125,000 pg/1 in static tests. For Daphnia
magna. the reported 48-hour EC5Q is 35,200 jug/1. The 96-hour LC5Q fqr
the tidewater silverside is 150,000 pg/1. An embryo-larval test with the
fathead minnow showed no adverse effect from carbon tetrachloride concentra-
tions up to 3,400 jug/1.. No plant effect data are available. The bluegill
bioconcentrated carbon tetrachloride to a factor of 30 times within 21 days
exposure. The biological half-life in the bluegill was less than 1 day.
-------
CARBON TETRACHLORIDE
I. INTRODUCTION
Carbon tetrachloride (CC14) is a haloalkane with a wide range of in-
dustrial and chemical applications. Approximately 932.7 million pounds are
produced at 11 plant sites in the U.S. (U.S. EPA, 1977b; Johns, 1976). The
bulk of CC1* is used in the manufacture of fluorocarbons for aerosol pro-
pellants. Other uses include grain fumigation, a component in fire extin-
guisher solutions, chemical solvent, and a degreaser in the dry cleaning in-
dustry (Johns, 1976).
Carbon tetrachloride is a heavy, colorless liquid at room temperature.
Its physical/chemical properties include: molecular weight, 153.82; melting
point, -22.99°C; solubility in water, 800,000 jug/1 at 25°C; and vapor
pressure, 55.65 mm Hg at 10°C. CCl^ is relatively non-polar and miscir
ble with alcohol, acetone and most organic solvents.
Carbon tetrachloride may be quite stable under certain environmental
conditions. The hydrolytic breakdown of CC14 in water is estimated to re-
quire 70,000 years for 50 percent decomposition (Johns, 1976). This decom-
position is accelerated in the presence of metals such as iron (Pearson and
McConnell, 1975). Hydrolytic decomposition as a means of removal from water
is insignificant when compared with evaporation. In one experiment the
evaporative half-life of CCl^ in water at ambient temperatures was found
to be 29 minutes (Dilling, et al. 1975), but this is highly dependent on ex-
perimental conditions, such as surface area to bulk volume ratios. For ad-
ditional information regarding Halomethanes as a class, the reader is refer-
red to the Hazard Profile on Halomethanes (U.S. EPA, 1979b).
-------
II. EXPOSURE
A. Water
CC1. has been found in many water samples including rain, sur-
face, potable, and sea, in the sub-part per billion range (McConnell, et al.
1975). The National Organics Monitoring Survey (NOMS) found CC14 in 10
percent of 113 public water systems sampled, with mean values ranging from
2.4-6.4jjg/l (U.S. EPA, 1977a).
Although CC14 is a chlorinated hydrocarbon, it is not produced in
finished drinking water as a result of the chlorination process (Natl. Res.
Coun., 1977,1978).
B. Food
Carbon tetrachloride has been detected in a variety of foodstuffs
other than fish and shellfish in levels ranging from 1 to 20 pg/kg (McCon-
nell, et al. 1975).
Results of various studies on CC1. fumigant residues in food in-
dicate that the amount of residue is dependent upon fumigant dosage, storage
conditions, length of aeration and the extent of processing (U.S. EPA,
1979a). Usually, proper storage and aeration reduce CC1 residues to
trace amounts.
The U.S. EPA (1979a) has estimated the weighted average bioconcen-
tration factor for carbon tetrachloride to be 69 for the edible portions of
fish and shellfish consumed by Americans. This estimate is based on measur-
ed steady-state bioconcentration studies in bluegills.
C. Inhalation
The occurrence of CCl^ in the atmosphere is due largely to the
»
volatile nature of the compound. Concentrations of CC1, in continental
and marine air masses range from .00078 - .00091 mg/m . Although some
-------
higher quantities (.0091 mg/m3) have been measured in urban areas, concen-
trations of CC14 are universally widespread with little geographic varia-
tion (U.S. EPA, 1979a).
III. PHARMACOKINETICS
A. Absorption
CCl^ is readily absorbed through the lungs, and more slowly
through the gastrointestinal tract (Nielsen and Larsen, 1965). It can also
be absorbed through the skin. The rate and amount of absorption are enhanc-
ed with the ingestion of fat and alcohol (Nielson and Larson, 1965; Moon,
1950). Robbins (1929) found that considerable amounts of CC14 are absorb-
ed from the small intestine, less from the colon, and little from the stom-
ach. Absorption from the gastorintestinal tract appears to vary by species,
i.e., it occurs more rapidly in rabbits than dogs. .
8. Distribution
The organ distribution of CC1. varies with the route of adminis-
tration, its concentration, and the duration of exposure (U.S. EPA, 1979a).
After oral administration to dogs, Robbins (1929) found the highest
concentrations of CCl^ in the bone marrow. The liver, pancreas and spleen
had one-fifth the amount found in the bone marrow. The highest concentra-
tions of CC1. after inhalation, however, were found in the brain (Von Qet-
tingen, et al. 1949,1950). After inhalation of CC14 by monkeys, the high-
est levels were detected in fat, followed by liver and bone marrow (McColli-
ster, et al. 1950). McConnell, et al. (1975) found human tissue levels of
CCl^ to range as follows: kidney, 1-3 mg/1; liver, 1-5 mg/1 and fat, 1-13
.ng/1.
On the cellular level, McClean, et al. (1965) found CC1. in all
cell fractions with higher concentrations in ribosomes.
3J-7
-------
C. Metabolism
When CC1. is administered to mammals, it is metabolized to a
small extent, the majority being excreted through the lungs. The metabo-
lites include chloroform, hexachloroethane, and carbon dioxide. These meta-
bolites play an important role in the overall toxicity of CCl^ (U.S. EPA,
1979a). Some of the CC14 metabolic products are also incorporated into
fatty acids by the liver and into liver microsomal proteins and lipids (Gor-
dis, 1969).
The chemical pathology of liver injury induced by CCl^ is a re-
sult of the initial homolytic cleavage of the C-C1 bond which liberates tri-
chloromethyl- and chlorine-free radicals (Fishbein, 1976). The next step
may be one of two conflicting reactions: direct attack via alkylation on
cellular constituents (especially sulfhydryl groups), or peroxidative decom-
position of lipids of the endoplasmic reticulum as a key link between the
initial bond cleavage and the pathological phenomena 'characteristic of
CC14 (Butler, 1961; Tracey and Sherlock, 1968).
0. Excretion
The largest portion of absorbed CC1. is rapidly excreted. Ap-
proximately 50-79 percent of absorbed radioactive CC14 is eliminated
through the lungs, and the remainder is excreted in the urine and feces. No
CCl^ was detected in the blood or in the expired air, 48 hours and 6 days,
respectively, after CCl^ inhalation (Beamer, et al. 1950). CCl^ is ex-
creted as 85 percent parent compound, 10 percent carbon dioxide, and smaller
quantities of other products including chloroform (NRC, 1977).
IV. EFFECTS
•
A. Carcinogenicity
CCl^ has been shown to be carcinogenic in rats, mice, and ham-
sters via subcutaneous injection, intubation, and rectal instillation (U.S.
-------
EPA, 1979). Current knowledge lead to the conclusion that carcinogenesis is
a non-threshold, non-reversible process. However, some scientists do argue
that a threshold may occur.
Rueber and Glover (1970) administered injections of 1.3 ml/kg of
body weight of a 50 percent solution of CC14 in corn oil to rats, two
times per week until death. Carcinoma of the liver were present in 12/15
(80 percent) Japanese male rats, 4/12 (33 percent) Wistar rats, and 8/13 (62
percent) Osborne-Mendel rats, whereas Black Rats or Sprague-Oawley rats did
not develop carcinomas. The incidence of cirrhosis of the liver also dif-
fered with the strain of the rat. Carcinoma of the liver tended to develop
along with mild or moderate, ' rather than severe cirrhosis of the liver.
When administered with CC14, methylcholanthrene (a potent enzyme inducer)
was found to increase the incidence of nyperplastic hepatic nodules and
early carcinomas in rats (Rueber, 1970). Females were found to be more sus-
ceptible to the development of nyperplastic nodules and carcinomas.
The National Cancer Institute (1976) studied the carcinogenic ef-
fect of CC14 in male and female mice (1,250 mg/kg or 2,500 mg/kg of body
weight, oral gavage 5 times/week/78 weeks). Hepatocellular carcinomas were
found in almost all of the mice receiving CCl^. Andervant and Ounn (1955)
transplanted 30 CCl^-induced tumors into mice. They observed growth in 28
of the hepatomas, through 4 to 6 transplant generations.
B. Mutagenicity
Conclusive evidence on the mutageniciity of CC1. has not been re-
ported. Kraemer, et al. (1976) found negative results using the Ames bac-
terial reversion tests. However, they explain that halogenated hydrocarbons
#
are usually negative in the Ames test.
t
•3
33-
-------
C. Teratogenicity
Very little data are available concerning the teratogenic effects
of CC14. Schwetz, et al. (1974) found CC14 to be slightly embryotoxic,
and to a certain degree retarded fetal development, when administered to
rats at 300 or 1,000 mg/1 for 7 hr/day on days 6 through 15 of gestation.
Bhattacharyya (1965) found that subcutaneous injection occasionally gave
rise to changes in fetal liver.
D. Other Reproductive Effects
Pertinent data concerning other reproductive effects of CCl^ were
not encountered in the available literature.
E. Chronic Toxicity
Cases of chronic poisoning have been reported by Butsch (1932),
Wirtschafter (1933), Strauss (1954), Von Oettingen (1964), and others. The
clinical picture of chronic CCl^ poisoning is much less characteristic
than that of acute poisoning. Von Oettingen (1964) has done an excellent
job of reviewing the symptoms. Patients suffering from this condition may
complain of fatigue, lassitude, giddiness, anxiety, and headache. They suf-
fer from paresthesias and muscular twitchings, and show increased reflex ex-
citability. They may be moderately jaundiced, have a tendency to hypogly-
cemia, and biopsy specimens of the liver may show fatty infiltration. Pa-
tients may complain of a lack of appetite, nausea, and occasionally of diar-
rhea. In some instances, the blood pressure is lowered and is accompanied
by pain in the cardiac region and mild anemia. Other patients have develop-
ed pain in the kidney region, dysuria, and slight nocturia, and have had
urine containing small amounts of albumin and a few red blood cells. Burn-
»
ing of the eyes and, in a few instances, blurred vision are frequent com-
plaints of those exposed. If these symptoms are not pronounced, or of long
-------
standing, recovery usually takes place upon discontinuation of the exposure
if the proper treatment is received (Von Oettingen, 1964).
Reports on pathological changes in fatalities from CCl^ poison-
ings are generally limited to findings in the liver and kidneys. The brain
and lungs may be edematous. The intestines may be hyperemic and covered
with numerous petechial hemorrhages and the spleen may be enlarged and hy-
peremic. Occasionally the adrenal glands may show degenerative changes of
the cortex and the heart may undergo toxic myocarditis (Von Oettingen, 1564).
F. Other Relevant Information
The toxic effects of CCl^ are potentiated by both the habitual
and occasional ingestion of alcohol (U.S. EPA, 1979a). Pretreatment of lab-
oratory animals with ethanol, methanol, or isopropanol increases the suscep-
tibility of the liver to CC14 (Wei, et al. 1971; Traiger and Plaa, 1971). .'
Hafeman and Hoekstra (1977) reported that protective effects
against CCl.-induced lipid peroxidation are exhibited by vitamin E, sele-
nium, and methionine.
According to Oavis (1934), very obese or undernourished persons or
those suffering from pulmonary diseases, gastric ulcers or a tendency to
vomiting, liver or kidney diseases, diabetes or glandular disturbances, are
especially sensitive to the toxic effect of CCl^ (Von Oettingen, 1964).
V. AQUATIC TOXICITY
A. Acute Toxicity
Two studies have investigated the acute toxicity of carbon tetra-
chloride to bluegills (Leoomis macrochirus) in static tests. The determined
LC5Q varied from 27,300 jjg/1 to 125,000 pg/1 (Dawson, at al. 1977; U.S.
»
EPA, 1978). With Daonnia maona. the reported 48-hr. EC5Q is 35,200 jjg/1
(U.S. EPA, 1978). The 96-hr. LC50 for the tidewater silversides (Menidia
bervilina) is 150,000 jjg/1 (Dawson, et al. 1977).
-------
B. Chronic Toxicity
An embryo-larval test with the fathead minnow (Pimeohales promelas)
showed no adverse effect from carbon tetrachloride concentrations up to
3,400 ug/L (U.S. EPA, 1978). Other chronic data are not available.
C. Plant Effects
There are no data in the available literature describing the ef-
fects of carbon tetrachloride on freshwater or saltwater plants.
D. Residues
The bluegill bioconcentrated carbon tetrachloride to a factor of 30
times within 21 days. The biological half-life in these tissues was less
than 1 day.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived by U.S. EPA
(1979a), which are summarized below, have been reviewed; therefore, there is
a possibility that these criteria will be changed.
A. Human
The American Conference of Governmental Industrial Hygienists
(1971) recommends a threshold limit value (TLV) of 10 mg/m3 for CC14,
with peak values not to. exceed 25 mg/m even for short periods of time.
The Occupational Safety and Health Administration adopted the American Na-
tional Standards Institute (ANSI, 1967) standard Z37.17 - 1967 as the Feder-
al standard for CC14 (29 CFR 1910.1000). This standard is 10 mg/m3 for
an 8-hour TWA, with an acceptable ceiling of 25 mg/m and a maximum peak
for 5 minutes in any 4-hour period of 200 mg/m .
The draft ambient water quality criteria for carbon tetrachloride
has been set to reduce the human carcinogenic risk levels to 10, 10"°
or 10" (U.S. EPA, 1979a). .The corresponding criteria are 2.6 jjg/1, 0.26
33-t
-------
ug/1, and 0.025 jjg/1, respectively. Refer to the Halomethane Hazard Profile
for discussion of criteria derivation (U.S.. EPA, 1979b).
B. Aquatic
For carbon tetrachloride, the drafted criteria to protect fresh-
water aquatic life is 620 ug/1 as a 24-hour average and the concentration
should never exceed 1,400 ug/1 at any time. To protect saltwater aquatic
life, the drafted criterion is 2,000 ug/1 as 24-hour average and the concen-
tration should not exceed 4,600 ug/1 at any time (U.S. EPA, 1979a).
-------
No. 34
Chloral
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.
-------
CHLORAL
Summary
Chloral (trichloroacetaldehyde) is used as an intermediate in the manu-
facture of DDT, methoxychlor, DDVP, naled, trichlorfon, and TCA. Chloral is
readily soluble in water, forming chloral hydrate. Chloral hydrate decom-
poses to chloroform with a half-life of two days. Chloral hydrate has been
used as a therapeutic agent due to its hypnotic and sedative properties.
Chloral (as chloral hydrate) has been identified in chlorinated water
samples at concentrations as high as 5.0 jug/1. Chloral hydrate is formed
through the chlofination of natural humic substances in the raw water. At-
mospheric chloral concentrations up to 273.5 mg/nv3 have been reported from
spraying and pouring of polyurethanes in Soviet factories. Similar data on
exposure levels in U.S. plants were not found in the available literature.
Specific information on the pharmacokinetic behavior,, carcinogenicity,
mutagenicity, teratogenicity, and other reproductive effects of chloral was
not found in the available literature. However, the pharmacokinetic be-
havior of chloral may be similar to chloral hydrate where metabolism to tri-
chloroethanol and trichloroacetic acid and excretion via the urine (and pos-
*
sibly bile) have been observed. Chloral hydrate produced skin tumors in 4
of 20 mice dermally exposed. Information on the chronic or acute effects of
chloral in humans was not found in the available literature. Chronic ef-
fects from respiratory exposure to chloral as indicated in laboratory
animals include reduction of kidney function and serum transaminase activ-
ity, change in central nervous system function'.'(unspecified), decrease in
-------
antitoxic and enzyme-synthesizing function of the liver, and alteration of
morphological characteristics of peripheral blood. Slowed growth rate, leu-
kocytosis and changes in arterial blood pressure were also observed. Acute
oral LD5Q values in rats ranged from 0.05 to 1.34 g/kg.
U.S. standards and guidelines for chloral were not found in the avail-
able literature.
-------
CHLORAL
ENVIRONMENTAL FATE
Chloral (trichloroacetaldehyde) is freely soluble in water, forming
chloral hydrate (Windholz, et al. 1576). Chloral hydrate was identified in
drinking water from 6 of 10 cities sampled (Keith, 1976). The author postu-
lated that chloral hydrate was formed by the chlorination of other compounds
during the addition of chlorine to the water supplies. Chloral hydrate was
not identified prior to chlorination. Chloral hydrate may be formed by the
chlorination of ethanol or acetaldehyde ana1 may occur as an intermediate in
the reaction involving the conversion of ethanol to chloroform as follows:
Ethanol - Acetaldehyde - Chloral - Chloral hydrate - Chloroform
Chloral hydrate decomposes to chloroform with a half-life of 2 days at pH 8
and 35°C (Luknitskii, 1575). Rook (1574) demonstrated the formation of
haloforms from the chlorination of natural humic substances in raw water.
Chloral polymerizes under the influence of light and in the presence of
sulfuric acid, forming a white solid trimer called metachloral (Windholz,
1576). Dilling, et al. (1576) studied the effects of chloral on the decom-
position rates of trichloroethylene, NO, and N02 in the atmosphere and ob-
served that chloral increases the photodecomposition rate of trichloro-
ethylene to a greater extent than it does NO or N02.
-------
CHLORAL
I. INTRODUCTION
This profile is based on literature searches in Biological Abstracts,
Chemical Abstracts, MEDLINE, and TOXLINE.
Chloral [Cl^cCHO], also referred to as trichloroacetaldehyde, anhy-
drous chloral, and trichloroethanol, is an oily liquid with a pungent, ir-
ritating odor. The physical properties of chloral are: molecular weight,
147.39; melting point, -57.5°C; boiling point, 97.75°C at 760 mm Hg;
density, 1.5121 at 20/4°C (Weast, 1976). The compound is very soluble in
water, forming chloral hydrate, and is soluble in alcohol and ether.
Industrial production of chloral involves direct chlorination of ethyl
alcohol followed by treatment with concentrated sulfuric acid (Stanford
Research Institute, 1976). Production may also occur by direct chlorination
of either zetaldehyde or paraldehyde in the presence of antimony chloride.
Prior to 1572, essentially all chloral produced was used in the manufacture
of DOT. Production of chloral was greatest in 1963 at 79.8 million pounds,
decreasing to 62.4 million pounds in 1969. Production data after 1969 were
not reported. Consumption of chloral for DDT manufacture was estimated at
25 million pounds in 1975, with an additional 500,000 pounds used in the
»
manufacture of other pesticides, including methoxychlor, ODVP, naled, tri-
chlorfon, and TCA (trichloroacetic acid). Mel'nikov, et al. (1975) identi-
fied chloral as an impurity in chlorofos.
Chloral is also used in the production of chloral hydrate, a thera-
peutic agent with hypnotic and sedative effects used prior to the intro-
r
duction of barbituates. Production of U.S.P. (pharmaceutical) grade chloral
hydrate was estimated to be 300,000 pounds per year in 1975 (Stanford
Research Institute, 1976).
-------
II. EXPOSURE
Boitsov, et al. (1970) noted that chloral is evolved in spraying and
pouring of polyurethane. The authors reported chloral concentrations as
high as 273.5 mg/nr in Soviet factories. Similar information on atmos-
pheric occupational exposure to chloral in Western countries was not found
in the available literature.
Chloral exposure from water occurs as chloral hydrate. Keith (1976)
reported chloral hydrate concentrations ranging from 0.01 ;jg/l to 5.0 jjg/1
in chlorinated drinking water supplies of six of ten U.S. cities studied.
The mean concentration of chloral hydrate in drinking water for the six
cities was 1.92 jug/1.
Chloral hydrate has been used as a hypnotic and sedative agent. Alco-
hol synergistically increases the depressant effect of the compound, creat-
ing a potent depressant commonly referred to as "Mickey Finn" or "knockout
drops". Addiction to chloral hydrate through intentional abuse of the com-
pound has been reported (Goodman and Oilman, 1970).
III. PHARMACOKINETICS
A. Absorption
Specific information on the absorption of chloral was not found in
»
the available literature. Goodman arid Gilman (1970) reported that chloral
hydrate readily penetrates diffusion barriers in the body.
B. Distribution
Specific information on the distribution of chloral was not found
in the available literature. Goodman and Gilman (1970), reporting on the
distribution of chloral hydrate from oral administration, noted its presence
in cerebrospinal fluid, milk, amniotic fluid, and fetal blood. The auth'ors
-------
noted that other investigators were unable to detect significant amounts of
chloral hydrate in the blood after oral administration (owing probably to
its rapid reduction).
C. Metabolism
Information on the metabolic reaction of chloral is obtained in-
directly through a metabolic study of trichloroethylene (Henschler, 1577).
The author reported that trichloroethylene oxidizes to a chlorinated epoxide
which undergoes molecular rearrangement to chloral, which is further metabo-
lized to either trichloroethanol or trichloroacetic acid. The rearrange-
ment, detected by in vivo studies, is hypothesized to occur by a catalytic
action of the trivalent iron of P-450.
Goodman and Oilman (1970) noted that chloral hydrate is reduced to
trichloroethanol in the liver and other tissues, including whole blood, with
the reaction catalyzed by alcohol dehydrogenase. Additional trichloro-
ethanol is converted to trichloroacetic acid. Chloral hydrate may be di-
rectly oxidized to trichloroacetic acid in the liver and kidney.
0. Excretion
Both chloral aid chloral hydrate are metabolized to trichloro-
ethanol or trichloroacetic acid (Goodman and Oilman, 1970; Henschler,
«
1977). Trichloroethanol is then conjugated and excreted in the urine as a
glucuronide (urochloralic acid) or is converted to trichloroacetic acid and
slowly excreted in the urine. The glucuronide may also be concentrated and
excreted in the bile. The fraction of the total dose excreted as trichloro-
ethanol, glucuronide, and trichloroacetic acid is quite variable, indicating
other possible routes of elimination. ;'
-------
IV. EFFECTS
A. Carcinogenicity
. Specific information on the carcinogenicity of chloral was not
found in the available literature. However, Keith (1976) reported skin
tumors in 4 of 20 mice dermally exposed to chloral hydrate (4 to 5 percent
solution in acetone). Further interpretation of the results and discussion
of the study methodology were not given.
B. Mutagenicity, Teratogenicity, and Other Reproductive Effects
Specific information on the mutagenicity,•teratogenicity, and re-
productive effects of chloral was not found in the available literature.
C. Chronic Effects
Rats receiving 0.1 mg/kg chloral exhibited a reduction of kidney
function and serum transaminase after seven months' exposure (Kryatov,
1970). No physiological effects were observed in rats receiving 0.01 mg/kg
chloral for periods of seven months. The route of exposure was not reported.
Chronic respiratory exposure of rats and rabbits to chloral at 0.1
mg/1 (100 mg/nr) produced changes in central nervous system function, de-
creased antitoxic and enzyme synthesizing function of the liver, and altered
morphological characteristics of peripheral blood (Pavlova, 1975). Boitsov,
et al. (1970) reported slowed growth rate, leukocytosis, decreased albumin-
globulin ratio, and changes in arterial blood pressure and central nervous
system responses (unspecified) following prolonged respiratory exposure of
mice to chloral at 60 mg/m3.
Goodman and Oilman (1970) reported gastritis, skin eruptions, and
parenchymatous renal injury in patients suffering from chronic chloral hy-
• .• _
drate intoxication. Habitual use of chloral hydrate may result in the
-------
development of tolerance, physical dependence, and addiction. Death may oc-
cur either as a result of an overdose or a failure of the detoxification
mechanism due to hepatic damage.
F. Acute Toxicity
According to Hann and Jensen (1974), the human acute oral LD,.n
of chloral is between 50 and 500 mg/kg.
Kryatov (1970) reported the following LD5Q values for chloral:
mice, 0.850 g/kg; rats, 0.725 g/kg; and guinea pigs, 0.940 g/kg. The routes
of exposure were not stated. Verschueren (1977) reported an oral LD5Q for
rats of 0.05 to 0.4 g/kg, while Pavlov (1975) reported an acute oral LD5Q
of 0.94 and 1.34" g/kg for mice and rats, respectively. Pavlov (1975) also
reported inhalation LC5Q values of 25.5 g/m3 and 44.5 g/m3 for mice
and rats, respectively. Boitsov, et al. (1970) reported an LD5Q Of 0.710
g/kg in mice. The route of exposure was not stated. Hawley (1971) reported
that chloral is a highly toxic, strong irritant and noted ingestion or in-
halation may be fatal. Information on acute toxic effects from occupational
exposure to chloral was not found in the available literature.
G. Other Relevant Information
Verschueren (1977) reported an odor threshold concentration of
chloral in water of 0.047 ppm. The author also reported an inhibition of
cell multiplication in Pseudomonas sp. at a chloral hydrate concentration of
1.6 mg/1.
V. AQUATIC TOXICITY
A. Acute Toxicity
Verschueren (1977) reported inhibition' of cell multiplication in
Microcystis sp. at 78 mg/1 chloral hydrate. Hann and Jensen (1974) rariked
the 96-hour Tl_m aquatic toxicity of chloral in the range from 1 to 10 ppm.
-------
B. Chronic Toxicity
Information on the chronic aquatic toxicity of chloral was not
found in the available literature.
C. Plant Effects
Shimizu, et al. (1574) reported chloral inhibited the growth of
rice stems by 63.4 percent relative to controls, but slightly stimulated
root growth. The concentration of chloral in water culture was not reported.
D. Residue
Keith (1976) identified chloral hydrate In chlorinated drinking
water in six of ten cities sampled. The sample locations and concentrations
of chloral hydrate identified were: Philadelphia, PA, 5.0 pg/1; Seattle,
WA, 3.5 jjg/1; Cincinnati, OH, 2.0 ug/1; Terrebonne Parish, LA, 1.0 jug/1; New
York City, NY, 0.02 jug/1; Grand Forks, NO, 0.01 jug/1.
E. Other Relevant Information
Hann and Jensen (1974) ranked the aesthetic effect of chloral on
water as very low (zero), noting that the chemical neither pollutes waters
nor causes aesthetic problems.
VI. EXISTING GUIDELINES AND STANDARDS
Boitsov, et al. (1970) reported a maximum recommended chloral concen-
tration in workroom air of 0.22 mg/1 (220 mg/m-5) (USSR). Kryatov (1970)
reported a maximum recommended permissible concentration in bodies of water
as 0.2 mg/1 (USSR). Verschueren (1977) reported a maximum allowable chloral
concentration of 0.2 mg/1 in Class I waters used for drinking, but the
nation applying this standard was not identified.
-------
References
Boitsov, A.N., et al. 1570. lexicological evaluation of chloral in the
process of its liberation during spraying and pouring of polyurethane
foams. Gig. Tr. Prof. Zabol. 14: 26. (Chemical Abstracts CA 73:96934P).
Oilling, W.L., et al. 1576. Organic photochemistry-simulated atmopsheric
photcdecomposition rates of methylene chloride, 1,1,1-trichloroethane, tri-
chloroethylene, tetrschloroethylene, and other compounds. Environ. Sci.
Technol. ID: 351.
Goodman, L.S. and A. Gilman. 1970. The Pharmacological Basis of Therapeu-
tics. The MacMillan Co., New York. p. 123.
Hann, R.W. and P.A. Jensen. 1974. Water Quality Characteristics of Hazard-
ous Materials. Texas A and M Univ., College Station, TX.
Hawley, G.G. 1971. Condensed Chemical Oistionary, 8th ed. Von Nostrand
Reinhold Co., New York. p. 195.
Henschler, D. 1977. Metabolism and mutagenicity of halogenated olefins - a
comparison of structure and activity. Environ. Health Perspec. 21: 61.
Keith, L.H. (ed.) 1976. Identification and Analysis of Organic Pollutants
in Water. Ann Arbor Science Publishers, Inc., Ann Arbor, Michigan, p. 351.
Kryatov, I.A. 1970. Hygienic assessment of sodium salts of p-chlorobenzene
sulfate and chloral as contaminating factors in bodies of water. Gig.
Sanit. 35:14. (Chemical Abstracts CA 73:69048).
Luknitskii, F.I. 1975. The chemistry of chloral. Chem. Rev. 75: 259.
Mel'nikov, N.N., et al. 1975. Identification of impurities in technical
chlorofos. Khim. Sel'sk. Khoz. D: 142. (Chemical Abstracts CA 82:165838K).
Pavlova, L.P. 1975. Toxicological characteristics of trichloroacetal-
dehyde. Tr. Azerb. Nauchno-Issled. Inst. Gig. Tr. Pro. Zabol. JO: 99.
(Chemical Abstracts CA 87:19499611).
Rook, J.J. 1974. Formation of haloforms during chlorination of natural
waters. Water Treatment Exam. 23: 234.
Shimizu, K., et al. 1974. Haloacetic acid derivatives for controlling
Gramineae growth. Japan 7432,063 (Cl.A Oln) 27 Aug. 1974, Appl. 70 77, 535,
05 Sep. 1970 (Chemical Abstracts CA 82:81709F).
Stanford Research Institute. 1976. Chemical Economics Handbook. Stanford
Research Institute, Menlo Park, CA. p. 632.2030A-.'_
Verschueren, K. 1977. Handbook of Environmental Data on Organic CKem-
icals. Von Nostrand Reinhold Co., New York. p. 170.
-------
Weast, R.C. (ed.) 1976. Handbook of Chemistry and Physics. CRC Press,
Cleveland, OH. p. C-76.
Windholz, M., et al. 1976. The Merck Index. Merck and Co., Inc., Rahway,
N.J. p. 1,236.
-------
No. 35
Chlordane
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. BPA's Carcinogen Assessment Group (GAG) has evaluated
chlordane and has found sufficient evidence to indicate
that this compound is carcinogenic.
-------
CHLORDANE '
Summary
Chlordane is an organochlorinated cyclodiene insecticide commonly used
as a formulation consisting of 24% trans-, 19% cis-chlordane, 10% hepta-
chlor, 21.5% chlordenes, 7% nonachlor, and 18.5% of other organochlorinated
material. Since heptachlor is also an insecticide and is more toxic than
chlordane, technical chlordane is generally more toxic than pure chlordane.
Pure chlordane, which is a cis/trans mixture of isomers, induces liver
cancer in mice and is mutagenic in some assays. Chlordane has not been shown
to be teratogenic. Little information is available on chronic mammalian
toxicity. Repeated doses of chlordane produced alterations in brain poten-
tials and changes in some blood parameters. Chlordane is a convulsant.
Chlordane and its toxic metabolite oxychlordane accumulate in adipose tissue.
Ten species of freshwater fish have reported 96-hr LC5Q values rang-
ing from 8 to 1160 pg/1. Freshwater invertebrates appear to be more resis-
tant to chlordane, with observed 96-hr LC-Q values ranging from 4 to 40
jjg/1. Five species of saltwater fish have LC5Q values of 5.5 to 160 ug/1,
and marine invertebrate LC5Q values range between 0.4 and 480 pg/1.
Chronic studies involving the bluegill Oaphnia maqna gave an LC50 of 1.6
wg/i.
-------
CHLOROANE
INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Chlordane (U.S. EPA, 1979).
Chlordane is a broad spectrum insecticide of the group of organochlori-
nated polycyclic hydrocarbons called cyclodiene insecticides. Chlordane has
been used extensively over the past 30 years for termite control in homes
and gardens, and as a control for soil insects.
Pure Chlordane (l,2,4,5,6,7,a,8-octachloro-2,3,3a,4,7,7a-hexahydro-<4,7-
methanoindene) is a pale yellow liquid having the empirical formula C,Q-
H-Clg and a molecular weight of 409.8. It is composed of a mixture of
stereoisomers, with the cis- and trans- forms predominating, commonly refer-
red to as alpha- and gamma-isomers, respectively.) The solubility of pure
Chlordane in water is approximately 9 jjg/1 at 25°C (U.S. EPA, 1979).
Technical grade Chlordane is a mixture of chlorinated hydrocarbons with
a typical composition of approximately. 24 percent trans(gamma)-Chlordane, 19
percent cis(alpha)-Chlordane, 10 percent heptachlor (another insecticidal
ingredient), 21.5 percent chlordene isomers, 7 percent nonachlor, and 18.5
percent closely related chlorinated hydrocarbon compounds. Technical chlor-
»
dane is a viscous, amber-colored liquid with a cedar-like odor. It has a
vapor pressure of 1 x 10~ mm Hg at 25°C. The solubility of technical
Chlordane in water is 150 to 220 pg/1 at 22°C (U.S. EPA, 1979).
Production of Chlordane was 10,000 metric tons in 1974 (41 FR 7559;
February 19, 1976). Both uses and production volume have declined exten-
/
sively since the issuance of a registration .suspension notice by the U.S.
EPA (40 FR34456; December 24, 1975) for all food, crop, home, and 'garden
-------
uses of chlordane. However, use of chlordane for termite control and limit-
ed usage (through 1980) as an agricultural insecticide are still permitted
(A3 FR 12372; March, 1978).
Chlordane persists for prolonged periods in the environment (U.S. EPA,
1979). Photo-cis-chlordane can be produced in water and on plant surfaces
by the action of sunlight (Benson, et al. 1971) and has been found to be
twice as toxic as chlordane to fish and mammals (Ivie, et al. 1972; Podow-
ski, et al. 1979). Photo-cis-chlordane (5 ng/1) is accumulated more (ca.
20%) by goldfish (Carassius auratus) than chlordane (5 ng/1) itself (Ducat
and Khan, 1979).
Air transport of chlordane has been hypothesized to account for resi-
dues in Sweden (Jansson, et al. 1979). Residues in agricultural soils may
be as high as 195 ng/g dry weight of soil (Requejo, et al. 1979).
II EXPOSURE
A. Water
Chlordane has been detected in finished waters at a maximum concen-
tration of 8 ;jg/l (Schafer, et al. 1969) and in rainwater (Bevenue, et al.
1972; U.S. EPA, 1976). There have been reports of individual household
wells becoming contaminated after a house is treated with chlordane for ter-
mite control (U.S. EPA, 1979). A recent contamination of a municipal water
system has been discussed by Harrington, et al. (1978). Chlordane has also
been detected in rainwater (U.S. EPA, 1976).
B. Food
Chlordane has been found infrequently in food supplies since 1965,
when the FDA began systematic monitoring for -chlordane (Nisbet, 1976). The
only quantifiable sample collected was 0.059 mg chlordane/kg measured in a
sample of grain in 1972 (Manske and Johnson, 1975). In the most recently
-------
published results (for 1975), chlordane was not detected (Johnson and
Manske, 1977). Fish are thought .to represent the most significant dietary
exposure. The average daily uptake from fish is estimated at 1 ;jg (Nisbet,
1976).
The U.S. EPA (1979) has estimated the weighted average bioconcen-
tration factor for chlordane to be 5,500 for the edible portions of fish and
shellfish consumed by Americans. This estimate was based on measured steady-
state bioconcentration studies in the sheepshead minnow (Cyprinodon varieqa-
tus).
Eighty-seven percent of 200 samples of milk collected in Illinois
from 1971 to .1973 were positive for chlordane. The average concentration
was 50 pg/1 (Moore, 1975 as reviewed by Nat. Acad. Sci., 1977). Cyclo-
dienes, such as chlordane, apparently are ingested with forage and tend to
concentrate in lipids. Oxychlordane, a metabolite of chlordane and hepta-
chlor, was found in 46 percent of 57 human milk samples collected during
1973-74 in Arkansas and Mississippi. The mean value was 5 jug/1, and the
maximum was 20 ug/1 (Strassman and Kutz, 1977).
C. Inhalation
In a survey of the extent of atmospheric contamination by pesti-
cides, air was sampled at nine localities representative of both Durban and
agricultural areas. Chlordane was. not detected in any samples (Stanley, et
al. 1971). In a larger survey, 2,479 samples were collected at 45 sites in
16 states. Chlordane was detected in only two samples, with concentrations
of 84 and 204 ng/m (Nisbet, 1976). The vapor concentrations to which
spray operators are exposed have not been estimated.
-------
D. Dermal Effects
Chlordane can be absorbed through the skin to produce toxic effects
(Gosselin, et al. 1976). Spray operators, chlordane formulators and farmers
may be exposed. Chlordane has been known to persist for as long as two
years on the hands (Kazen, et al. 1974). Dermal LD5Q values in rats range
from 530 to 700 mg/kg (U.S. EPA, 1979).
'ill. PHARMACOKINETICS
A. Absorption
Gastrointestinal absorption of chlordane- in rats ranged from 6 per-
cent with a single dose to 10-15 percent with smaller daily doses (Barnett
and Dorough, 1974).
B. Distribution
In a study of the distribution of chlordane and its metabolites
using radioactive carbon, the levels of residues in the tissues were low,
except in the fat (Barnett and Dorough, 1974). Rats were fed 1, 5, and 25
mg chlordane/g in food for 56 days. Concentrations of chlordane residues in
fat, liver, kidney, brain, and muscle were 300, 12, 10, 4, and 2 percent,
respectively, of the concentration in the diet. All residues declined
steadily for 4 weeks, at which time concentrations were reduced about 60
percent. During the next four weeks, residues declined only slightly.
C. Metabolism
Mammals metabolize chlordane to oxychlordane, via 1,2-dichloro-'
chlordene which is about twenty times more toxic than the parent compound
and persists in adipose tissue (Polen, et al. 1971; Tashiro and Matsumura,
f
1978; Street and Blau, 1972). Oxychlordane cart degrade to form l-hydroxy-2-
*
cyclochlordenes, and l-hydroxy-2-chloro-2,3-epoxy-chlordenes (Tashiro and
Matsumura, 1978). In general, the metabolism of chlordane takes olace via a
-------
series of oxidative enzyme reactions. None of the metabolic intermediates
(except for oxychlordane) and end products are more toxic than chlordane
(Barnett and Oorough, 1974; Tashiro and Matsumura, 1977; Mastri, et al.
1969). Trans-nonachlor, a major impurity in technical chlordene, is con-
verted to trans-chlordane in rats, but this is not important in humans.
This explains the fact that trans-nonachlor accumulates in humans but not in
rats (Tashiro and Matsumura, 1978). A very small amount of cis- or trans-
chlordane can be converted to heptachlor in rat liver (Tashiro and Matsu-
mura, 1977).
0. Excretion
Chlordane is primarily excreted in the feces of rats, only about
six percent of the total intake being eliminated in the urine. Urinary ex-
cretion of chlordane in rabbits is greater than excretion in the feces (Nye
and Dorough, 1976).
The half-life of chlordane in a young boy was reported to be ap-
proximately 21 days (Curley and Garrettson, 1969), while for rats it was 23
days (Barnett and Oorough, 1974). The half-life of chlordane in the serum
of a young girl was 88 days (Aldrich and Holmes, 1969).
IV. EFFECTS
A. Carcinogenicity
Hepatocellular carcinomas were induced in both sexes of two strains
of mice fed pure (95%) chlordane (56.2 mg/kg) in the diet for 80 weeks (Na-
tional Cancer Institute, 1977; Epstein, 1976). In contrast to findings with
mice, a significantly increased incidence of hepatocellular carcinomas did
not appear in rats administered chlordane. Dosages were near the maximum
permissible (National Cancer Institute, 1977).
3r-
-------
B. Mutagenicity
Pure or technical chlordane induced unscheduled ONA synthesis in
the SV-40 transformed human fibroblast cell line VA-4. Metabolic activation
eliminated this effect (Ahmed, et al. 1977). Chlordane did not induce muta-
tions in the dominant lethal assay in mice (Arnold, et al. 1977).
While neither pure cis-chlordane nor pure trans-chlordane was muta-
genic in the Ames Salmonella microsome assay, technical grade chlordane was
mutagenic. Microsomal activation did not enhance the mutagenic activity
(Simmon, et al. 1977).
C. Teratogenicity
Chlordane was found not to be teratogenic in rats when fed at con-
centrations of 150 to 300 mg/kg during gestation (Ingle, 1952).
0. Other Reproductive Effects
Pertinent data could not be located in the available literature.
E. Chronic Toxicity
There appears to be little information on chronic mammalian toxi-
city. Daily injections of 0.15 to 25 mg chlordane/kg in adult rats resulted
in dose-dependent alterations of brain potentials (Hyde and Falkenberg,
• 1976). As changes were directly related to length of exposure, it was con-
cluded that chlordane may be a cumulative neurotoxin. Length of exposure
was not specified. Repeated doses of chlordane given to gerbils produced
changes in serum proteins, blood glucose, and alkaline and acid phosphatase
activities (Karel and Saxena, 1976). Again, duration of treatment was not
specified.
F. Other Relevant Information
Carbon tetrachloride produced more extensive hepatocellular necro-
sis in chlordane-pretreated rats than in rats which were not pretreated
(Stenger, et al. 1975). Rats suffered greater cirrhosis when chlordane (50
-------
ug/kg/day) exposure for ten weeks followed prior exposures of ten weeks for
carbon tetrachloride above (110 mg/1) or with chlordane (Mahon and Oloffs,
1979). Quail treated with chlordane followed by endrin had considerably
more chlordane residues in their brains than did quail treated with chlor-
dane alone (Ludke, 1976). Quail pretreated with 10 mg/kg chlordane exhibit-
ed decreased susceptibility to parathion (Ludke, 1977). Chlordane is a con-
vulsant and emetic. It induces twitching, seizures and electroencephalo-
graphic dysrhythmia in humans. Acute symptoms can be alleviated with pheno-
barbital. Acute oral LD-Q values for the rat range from 100 to 112 mg/kg
(U.S. EPA, 1979). The no observable effect level was found to be 2.5 mg/kg/
day over 15 days (Natl. Acad. Sci., 1977).
Chlordane inhibits growth of human viridans streptococci of the
buccal cavity. Complete inhibition of growth occurred at 3 ppm, and about
20 percent inhibition was seen at 1 ppm (Goes, et al. 1978).
V. AQUATIC TOXICITY
. A. Acute Toxicity
Ten species of freshwater fish have reported 96-hr LC5Q values
ranging from 8 to 1160 jjg/1 resulting from technical and pure chlordane
exposure with a geometric mean of 16 ug/1. Rainbow trout, Salmo gairdneri
»
(Mehrle, et al. 1974) was the most sensitive species tested, the channel
catfish (Ictalurus punctatus) the least sensitive. The freshwater inverte-
brates were more sensitive to chlordane, with a reported LC5_ value rang-
ing from 4.0 for freshwater shrimp Palaemonetes kadiakensis (Sanders, 1972)
to 40 jjg/1 (Gammarus fasciatus), with a geometric mean of 0.36 ug/1. In
^
goldfish (Carassius auratus). only 0.13 percent of cis-chlordane is metabo-
lized in 24 hours. Only 0.61 percent is converted after 25 days.' Some
metabolites were chlordene chlorohydrin and monohydroxy derivatives (Fercz
and Khan, 1979).
-------
The LCcg's for four species of saltwater fish, sheepshead minnows
(Cyprinodon veriegatus), striped bass (Morone saxatilis), pinfish (Lagodon
rhomboides), and white mullet (Mugil curema), ranged from 5.5 to 24.5 jug/1.
The three-spine stickleback (Gasterosteus aculeatus) yielded 96-hr LC5Q
values which ranged from 90-160 pg/1 (Katz, 1961). Invertebrate LC5Q val-
ues ranged from 0.4 for the pink shrimp, Penaeus duorarum (Parrish, et al.
1976) to 480 jug/1. The geometric mean of the adjusted LC5Q values for in-
vertebrates was 0.18jug/l (U.S. EPA, 1979).
B. Chronic Toxicity
In a life cycle bioassay involving freshwater organisms, the chron-
ic values for. the bluegill Lepomis macrochirus (Cardwell, et al. 1977) was
1.6jug/l. In two tests involving the sheepshead minnow, Cyprinodon variega-
tus, the chronic values were 0.63 ug/1 for the life cycle test (Parrish, et
al. 1978) and 5.49 jug/1 for an embryo-level test (Parrish, et al. 1976).
Many blood parameters (clotting time, mean corpuscular hemoglobin
and cholesterol level) are lowered after the teleost, Sacco-branchus fossil-
us, is exposed to 120 pg/1 of chlordane for 15 to 60 days (Verna, et al.
1979). Similar results were obtained in Labeo rohita at doses — 23 pg/1
after 30 to 60 day exposures (Bansal, et al. 1979).
C. Plant Effects . *
A natural saltwater phytoplankton community suffered a 94 percent
decrease in productivity during a 4-hour exposure at 1,000 jjg/1 (Butler,
1963).
D. Residues
In Daphnia magna, chlordane was bioconcentrated 6,000-fold after
seven days' exposure and 7,400-fold by scuds (Hyallela azteca) after 85 days
of exposure (Cardwell, et al. 1977). After 33 days' exposure, the fresh-
^^fa*
-------
water alga (Oedegonium sp.) bioconcentrated chlordane 98,000-fold; Physa
sp., a snail, concentrated it 133,000-fold (Sanborn, et al. 1976). Equili-
brium bioconcentration factors for the sheepshead minnow ranged from 6,580
to 16,035 (Goodman, et al. 1978; Parrish, et al. 1976).
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The issue of the carcinogenicity of chlordane in humans is being
reconsidered; thus, there is a possibility that the criterion for human
health will be changed. Based on the data for qarcinogenicity in mice (Ep-
stein, 1976), and using the "one-hit" model, the U.S. EPA (1979) has esti-
mated levels of chlordane in ambient water which will result in risk levels
of human cancer as specified in the table below.
Exposure Assumptions Risk Levels and Corresponding Draft Criteria
(per day)
0 10-7 10-* 10-5
2 liters of drinking water 0 .0.012 ng/1 0.12 ng/1 1.2 ng/1
and consumption of 18.7
grams fish and shellfish.
Consumption of fish and 0 0.013 ng/1 0.13 ng/1 1.3 ng/1
shellfish only.
The ACGIH (1977) adopted a time-weighted average value of 0.5
mg/m for chlordane, with a short-term exposure limit (15 minutes) of 2
mg/m .
A limit of 3 ug/1 for chlordane in drinking water is suggested
under the proposed Interim Primary Drinking Water Standards (40 FR 11990,
March 14, 1975).
^
Canadian Drinking Water Standards --(.Dept. Natl. Health Welfare,
»
1968) limit chlordane to 3 ug/1 in raw water supplies.
-------
8. Aquatic
For chlordane, the proposed criterion to protect freshwater aquatic
life is 0.024 /jg/1 for a 24-hour average, not to exceed 0.36 pg/1 at any
time (U.S. EPA, 1979). For saltwater aquatic species, the draft criterion
is 0.0091 jug/1 for a 24-hour average, not to exceed 0.18 pg/1 at any time
(U.S. EPA, 1979).
-HJ3-
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CHLORDANE
REFERENCES
Ahmed, F.E., et al. 1977. Pesticide induced DNA damage
and its repair in cultured human cells. Mutat. Res. 42:
161.
Aldrich, F.D., and J.H. Holmes. 1969. Acute chlordane
intoxication in a child. Arch. Environ. Health 19: 129.
ACGIH. 1977. TLVs thresholds limit values for chemical
substances in workroom air adopted by the American Confer-
ence of Governmental Industrial Hygienists for 1977. Cincin-
nati, Ohio. v
Arnold, D.W., et al. 1977. Dominant lethal studies with
technical chlordane, HCS-3260, and heptachlor: heptachlor
epoxide. Jour. Toxicol. Environ. Health 2: 547.
Bansal, S.K., et al. 1979. Physiological dysfunction of
the haemopoletic system in a freshwater teleost, Rabeo ro-
hita, following chronic chlordane exposure. Part 1.Altera-
tions in certain haemotological parameters. Bull. Environ.
Contain. Toxicol. 22: 666.
Barnett, J.R., and H.W. Dorough. 1974. Metabolism of chlor-
dane in rats. Jour. Agric. Food Chera. 22: 612.
Benson, W.R., et al. 1971. Chlordane photoalteration pro-
ducts: Their preparation and identification. Jour. Agric.
Food Chem. 19: 857.
Bevenue, A., et al. 1972. Organochlorine pesticides in-
rainwater Oahu, Hawaii, 1971-72. Bull. Environ. Contam.
Toxicol. 8: 238. «
Butler, P.A., et al. 1953. Effects of pesticides on oy-
sters. Proc. Shell Fish. Assoc. 51: 23.
Cardwell, R.D., et al. 1977. Acute and chronic toxicity
of chlordane to fish and invertebrates. EPA Ecol. Res.
Ser., U.S. Environ. Prot. Agency, Duluth, Minn.
Curley, A., and L.K. Garrettson. 1969. Acute chlordane
poisoning. Arch. Environ. Health 18: 211.
Department of National Health and Welfa're. 1963. Canadian
drinking water standards and objectives. Ottawa, Canada.
Ducat, D.A. and M.A.Q. Khan. 1979... Absorption and elimina-
tion of C-cis-chlordane and C-photo-cis-chlordane by
goldfish, Carassius auratus. Arch. Enviorn. Contam. 8: 409.
-1.
-------
Epstein, S.S. 1976. Carcinogenicity of heptachlor and
chlordane. Sci. Total Environ. 6: 103.
Feroz, M., and M.A.Q. Khan. 1979. Fate of 14C-cis-chlor-
dane in goldfish, Carassius auratus. Bull. Enviorn. Contam.
Toxicol. 23: 64.
Goes, T.R., et al. 1978. In vitro inhibition of oral Viri-
dous streptococei by chlordane. Arch. Environ. Contam.
Toxicol. 7: 449.
Goodman, L., et al. 1978. Effects of heptachlor and toxa-
phene on laboratory-reared embryos and fry of the sheepshead
minnow. Proc. 30th Annu. Conf. S.E. Assoc. Game Fish Comm.
Gosselin, R.E., et al. 1976. Clinical toxicology of commer-
cial products. 4th ed. Williams and Wilkdns Co., Baltimore,
Md.
Harrington, J.M., et al. 1978. Chlordane contamination
of a municipal water system. Environ. Res. 15: 155.
Hyde, K.M., and R.L. Falkenberg. 1976. Neuroelectrical
disturbance as indicator of chronic chlordane toxicity.
Toxicol. Appl. Pharmacol. 37: 499.
Ingle, L. 1952. Chronic oral toxicity of chlordane to
rats. Arch. Ind. Hyg. Occup. Med. 6: 357.
Ivie, G.W., et al. 1972. Novel photoproducts of heptachlor
epoxide, trans-chlordane and trans-nonachlor. Bull. Environ.
Contam. Toxicol. 7: 376.
Jansson, B., et al. 1979. Chlorinated terpenes and chlor-
dane components found in fish, guilleiuot and seal from
Swedish waters. Chemosphere 8: 181.
Johnson, R.D., and D.D. Manske. 1977. Pesticide and .other
chemical residues in total diet samples (XI). Pestic. Monitor.
Jour. 11: 116.
Karel, A.K., and S.C. Saxena. 1976. Chronic chlordane
toxicity: effect on blood biochemistry of Meriones hurrianae
Jerdon, the Indian desert gerbil. Pestic. Biochem. Physiol.
6: 111.
Katz, M. 1961. Acute toxicity of some organic insecticides
to three species of salmonids and to the threespine stickle-
back. Trans. Am. Fish. Soc. 90: 264. '
Kazan C. , et al. 1974. Persistence of pesticides on ttie
hands of some occupationally exposed people. Arch. Environ.
Health 29: 315.
-------
Ludke, J.L. 1976. Organochlorine pesticide residues associ-
ated with mortality: additivity of chlordane and endrin.
Bull. Environ. Contain. Toxicol. 16: 253.
Ludke, J.L. 1977. DDE increases the toxicity of parathion
to coturnix quail. Pestic. Biochem. Physiol. 7: 28.
Mahon, D.C., and P.C. Oloffs. 1979. Effects of subchronic
low-level dietary intake of chlordane on rats with cirrhosis
of the liver. Jour. Environ. Sci. Health B14: 227.
Manske, D.D., and R.D. Johnson. 1975. Pesticide residues
in total diet samples (VIII). Pestic. Monitor. Jour. 9: 94.
Mastri, C., et al. 1969. Unpublished data. In 1970 evalua-
tion of some pesticide residues in food. Foo"3~Agric. Org.
United Nations/World Health Org. *•
Mehrle, P.M., et al. 1974. Nutritional effects on chlor-
dane toxicity in rainbow trout. Bull. Enviorn. Contam.
Toxicol. 2: 513
Moore, S., III. 1975. Proc. 27th Illinois Custom Spray
Operators Training School. Urbana.
National Academy Science. 1977. Drinking water and health.
Washington, D.C.
National Cancer Institute. 1977. Bioassay of chlordane
for possible carcinogenicity. NCI-CG-TR-8.
Nisbet, I.C.T. 1976. Human exposure to chlordane, hepta-
chlor, and their metabolites. Contract WA-7-1319-A. U.S.
Environ. Prot. Agency.
Nye, D.E., and H.W. Dorough. 1976. Fate of insecticides
administered endotracheally to rats. Bull. Environ. Contam.
Toxicol. 15: 291. *
Parrish, P.R., et al. 1976. Chlordane: effects on several
estuarine organisms. Jour. Toxicol. Environ. Health 1:
485.
Parrish, P.R., et al. 1978. Chronic toxicity of chlordane,
trifluralin and pentachlorophenol to sheepshead minnows
(Cyprinodon variegatus). EPA 600/3-78-010: 1. U.S. Environ.
Prot. Agency.
f
Podowski, A.A., et al. 1979. Photolysis of heptachlor
and cis-chlordane and toxicity of their photoisomers to
animals. Arch. Environ. Contam. Toxicol. 8: 509.
Polen, P.3., et al. 1971. Characterization of oxychlor-
dane, animal metabolites of chlordane. Bull. Enviorn. Contam.
Toxicol. 5: 521.
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Requejo,' A.G., et al. 1979. Polychlorinated biphenyls
and chlorinated pesticides in soils of the Everglades National
Park and adjacent agricultural areas. Environ. Sci. Technol.
13:
Sanborn, J.R., et al. 1976. The fate of chlordane and
toxaphene in a terrestrial-aquatic model ecosystem. Environ.
Entomol. 5: 533.
Sanders, H.O. 1972. Toxicity of some insecticides to four
species of malacostracan crustaceans. U.S. Dept. Interior.
Fish Wildlife Tech. p. 66, August.
Schafer, M.L., et al. 1969. Pesticides in drinking water'.
Environ. Sci. Technol. 3; 1261.
Simmon, V.F., et al. 1977. Mutagenic ac-tivity of chemicals
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Environ. Mutagens, Edinburgh, Scotland, July 1977.
Stanley, C.W. , et al. 1971. Measurement of atmospheric
levels of pesticides. Environ. Sci. Technol. 5: 430.
Stenger, R.J., et al. 1975. Effects of chlordane pretreat-
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Mol. Pathol. 23: 144.
Strassman, S.C., and F.W. Kutz. 1977. Insecticide residues
in human milk from Arkansas and Mississippi, 1973-74. Pestic.
Monitor. Jour. 10: 130.
Street, J.E., and S.E. Blau. 1972. Oxychlordane: accumu-
lation in rat adipose tissue on feeding chlordane isomers
or technical chlordane. Jour. Agric. Food Chem. 20: 395.
Tashiro, S., and F. Matsumura. 1977. Metabolic routes
of cis- and trans-chlordane in rats. Jour. Agric. Food
Chem. 25: 872. »
Tashiro, S., and F. Matsumura. 1978. Metabolism of trans-
nonachlor and related chlordane components in rat and man.
Arch. Enviorn. Contam. Toxicol. 7: 413.
U.S. EPA. 1976. Consolidated heptachlor/chlordane hearing.
Fed. Register 41: 7552.
U.S. EPA. 1979. Chlordane: Ambient Water Quality Criteria
(Draft) .
Verna, S.R., et al. 1979. Pesticide induced haemotological
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Bull. Environ. Contam. Toxicol. 22: 467.
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LB:42-1
No. 36
Chlorinated Benzenes
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
OCTOBER 30, 1980
36-1
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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.
36-2
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CHLORINATED BENZENES
Summary
%
The chlorinated benzenes are a group of compounds with a
wide variety of physical and chemical characteristics depending
on the degree of chlorination. As chlorination increases, the
persistence of the compound in the environment increases. On
chronic exposure liver and kidney changes are noted, and the
degree of toxicity increases with the degree of chlorination.
The chlorinated benzenes have not been shown to be teratogens or
mutagens. Only hexachlorobenzene has been demonstrated to be
carcinogenic in laboratory animals.
Aquatic toxicity data indicate a trend to increasing toxicity
with increasing chlorination for all species tested. For the
bluegill, for example, the following 96-hour LC5Q values; have
been noted: chlorobenzene, 15,900 ug/1; 1,2,4-trichlorobenzene,
200 ug/1. Other freshwater and saltwater fish, invertebrates
and plants are generally less sensitive to chlorobenzenes than
the bluegill. The sheephead minnow yielded a chronic value of
14.5 ug/1 for 1,2,4,Stetrachlorobenzene in an embryo-level
test. After 28 days of exposure, the bioconcentration factors
for the bluegill for pentachlorobenzene and 1,2,4,5-tetrachloro-
benzene were 3,400 and 1,800, respectively.
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CHLORINATED BENZENES
I. INTRODUCTION
«
This profile is based inpart on the Ambient Water Quality
Criteria Document for Chlorinated Benzenes (U.S. EPA, 1980).
This document summarizes the general properties of the chlori-
nated benzenes. For further information on monochlorobenzene,
1, 2,4-trichlorobenzene, or hexachlorobenzene, refer to the specific
EPA/ECAO Hazard Profiles for these compounds. For detailed
information on the other chlorinated benzenes refer to the Ambient
Water Quality Document (U.S. EPA, 1980).
The chlorinated benzenes, excluding dichlorobenzenes*, are
monochlorobenzene (CgH3Cl), 1, 2,4-trichlorobenzene (0^3013),
1,3,5-trichlorobenzene (CgH3Cl3), 1,2,3,4-tetrachlorobenzene
(CgH2Cl4), 1,2,3,5-tetrachlorobenzene (C6H2C14), 1,2,4,5-
tetrachlorobenzene (CgH2Cl4), pentachlorobenzene (€5015) and
hexachlorobenzene (0^015). All chlorinated benzenes are colorless
liquids or solids with a pleasant aroma. The most important
properties imparted by chlorine to these compounds are solvent
power, viscosity and moderate chemical reactivity. Viscosity
and nonflammability tend to increase with degree of chlorination.
Vapor pressures and water solubility decrease progressively with
the degree of chlorination (U.S. EPA, 1980).
*the health and environmental effects of dichlorobenzenes are
discussed in HEBD's Nos. 64-67.
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The current production, based on annual production in the
U.S., was 139,105 kkg of monochlorobenzene in 1975, 12,849 kkg of
1, 2,4,-trichlorobenzene, 8,182 kkg of 1, 2, 4, 5-tetrachlorobenzene
and 318 kkg of hexachlorobenzene in 1973 (West and Ware, 1977;
EPA, 1975a). The remaining chlorinated benzenes are produced
mainly as by-products from the production processes for the above
four chemicals. Chlorinated benzenes have many and diverse uses
in industry depending upon the individual properties of the
specific compound. Some uses are as solvents, chemical inter-
mediates, flame retardants, and plasticizers.
11. EXPOSURE
A. Water
Mono-, tri-, and hexachlorobenzene have been detected
in ambient water. Because of its high volatility, monochlorobenzene
has a short half-life of only 5.8 hours (Mackay and Leinonen,
1975). However, hexachlorobenzene has an extremely long residue
time in water, appearing to be ubiquitous in the aqueous environment.
Monochlorobenzene has been detected in "uncontaminated" water at
levels of 4.7 ug/1. Both trichlorobenzene and hexachlorobenzene
have been detected in drinking waters at concentrations of 1.0
ug/1 and 4 to 6 ng/1 respectively (U.S. EPA, 1980). There is no
information available on the concentration of the other chlorinated
benzenes in water.
B. Food
There is little data on the consumption of chlorinated
benzenes in food. All the chlorinated benzenes appear to
36-5
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concentrate in fat, and can be absorbed by plants from contaminated
soil. Both pentachlorobenzene and hexachlorobenzene have been
detected in meat fat (e.g. Stijve, 1971; Ushio and Doguchi,
1977). Hexachlorobenzene, the most extensively studied compound,
has been found in a wide variety of foods from cereals to milk
(including- human breasjt milk), eggs, and meat. The U.S. EPA
(1980) has estimated the weighted bioconcentration factors for
freshwater species:
' Weighted
Chemical bioconcentration factor
monochlorobenzene 13
1,2,4-trichlorobenzene 182
1,2,3,5-tetrachlorobenzene 1,800
pentachlorobenzene 3,400
hexachlorobenzene 22,000
These estimates were based on the octanol/water parti-
tion coefficients of the chlorinated benzenes.
C. Inhalation
There is no available data on the concentration of
chlorinated benzenes in ambient air with the exception of
measurements of aerial fallout of particulate bound 1,2,4-
trichlorobenzene in southern California. Five sampling sites
showed median levels of 1,2,4-trichlorobenzene of less than
11 ng/ra2/day (U.S. EPA, 1980). The primary site of inhalation
exposure to chlorinated benzenes is the workplace in industries
utilizing and/or producing these compounds.
III. PHARMACOKINETICS
A. Absorption
There is little data on the absorption of orally
administered chlorinated benzenes. It is apparent from the
36-6
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toxicity of orally administered compounds that absorption does
take place, and tetrachlorobenzene has been shown to be absorbed
relatively efficiently by rabbits (Jondorf, et al. 1958).
Pentachlorobenzene was absorbed poorly after subcutaneous injection
(Parke and Williams, 1960). Hexachlorobenzene was absorbed poorly
from an orally administered aqueous solution (Koss and Kornasky,
1975), but with high efficiency when administered in oil (Albro
and Thomas, 1974). The more highly chlorinated compounds in food
products selectively partition into the lipid portion and are
absorbed far better than those in the aqueous portion (U.S. EPA,
1980).
B. Distribution
The chlorinated benzenes are lipophilic compounds, with
greater lipophilic tendencies in the more highly chlorinated
compounds. The predominant uptake site is either suspected or
known to be the lipid tissues of the body (Lee and Metcalf,
1975; U.S. EPA, 1980).
C. Metabolism
•
The chlorinated benzenes are metabolized in the liver
by the NADPH-cytochrome P-448 dependent microsomal enzyme system
(Ariyoshi, et al. 1975? Koss, et al. 1976). At least for
monochlorobenzene, there is evidence that toxic intermediates are
formed during metabolism (Kohli, et al. 1976). Various conjugates
and phenolic derivatives are the primary excretory end products
of chlorinated benzene metabolism. Conjugates of the more highly
chlorinated compounds, such as hexachlorobenzene, are only formed
to a limited extent, and their metabolism is relatively slow.
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D. Excretion
The less-chlorinated benzenes are excreted as polar
metabolites or conjugates in the urine. An exception occurs with
monochlorobenzene is an exception: in the rabbit, 27 percent of
an administered dose appeared as unchanged compounds in expired
air (Williams, 1959). The two highly chlorinated compounds,
pentachlorobenzene and hexachlorobenzene, are predominately
•
eliminated in unchanged form by fecal excretion (Koss and Koransky,
1975; Rozman, et al. 1979). The biological half-lives of these
two compounds are extremely long in comparison to those of the
less-chlorinated compounds (U.S. EPA, 1980).
IV. EFFECTS
A. Carcinogencity
The carcinogenic potential of mono- and tetrachlorobenzene
have not been investigated (U.S. EPA, 1980). In one study,
trichlorobenzene was not shown to produce any significant increase
in liver tumors (Gotto, et al. 1972). There is one report, not
critically evaluated by EPA (1980), which alludes to the carcino-
gencity of pentachlorobenzene in mice and the absence of this
activity in rats and dogs (Preussman, 1975). Life-time feeding
studies in hamsters (Cabral, et al. 1977) and mice (Cabral, et
al. 1978) have demonstrated the carcinogenic activity of hexa-
chlorobenezene. However, shorter term studies failed to demonstrate
an increased tumor incidence in strain A mice or ICR mice (Theiss,
et al. 1977; Shirai, et al. 1978). Chlorobenzene has been tentative-
ly selected for long-term bioassay testing by NCI (U.S. EPA, 1978b).
36-8
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B. Mutagenicity
There are no reports of studies conducted to evaluate
the mutagenic potential of tri-,tetra- and pentachlorobenzene*
Chlorobenzene causes mutations in S.antibioticus, and chromosomal
damage and mitotic inhibition in root tips of higher plants, and
is not mutagenic in the fungus A.nidulans (U.S. EPA, 1978b).
Hexachlorobenzene was assayed for mutagenic activity in the
dominant lethal assay, and shown to be inactive (Khera, 1974).
C. Teratogenicity
There are no available reports on the teratogenic
potential of mono-, tri-, and tetra-, Chlorobenzene (U.S. EPA,
1980). Khera (1974) concluded that hexachlorobenzene is not a
teratogen when given to CD-I mice at 50 mg/kg/day on gestation
days from 7 to 11. Pentachlorobenzene, however, induces a dose-
related incidence of sternebral defects in rats (Khera, 1975).
D. Other Reproductive Effects
Both penta- and hexachlorobenzene pass through
the placenta and cause fetal toxicity in rats (Grant, et al.
1977). The distribution of hexachlorobenzene in the fetus appears
to be the same as in the adult,, with the highest concentration
in fatty tissue.
E. Chronic Toxicity
There are no available data on the chronic effects of
pentachlorobenzene (U.S. EPA, 1979). Mono- and trichlorobenzene
product histological changes in the liver and kidney (Irish,
1963; Coate, et al. 1977). Chlorobenzene (orally administered at
250 mg/kg for 3 days) caused liver dysfunction and porphyria
36-9
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(U.S. EPA, 1978b). There is also evidence for liver damage
occurring with prolonged exposure of rats and dogs to tetrachloro-
benzene (Fomenko, 1965? Braun, et al. 1978). Hexachlorobenzene
has caused histological changes in the livers of rats (Koss, et al.
1978). In humans exposed to undefined amounts of hexachlorobenzene
for an undetermined time, porphyrinuria has been shown to occur
(Cam and Nigogosyan, 1963).
F. Other Relevant Information
Chlorinated benzenes appear to-increase the activity of
microsomal NADPH-cytochrome P-450 dependent enzyme systems.
V. ACUATIC TOXICITY (U.S. EPA, 1980)
A. Acute Toxicity
The dichlorobenzenes are covered in a separate EPA/ECAO
hazard profile and will not be covered in this disucssion on
chlorobenzenes.
All data reported for freshwater fish are from 96-hour
static toxicity tests. Pickering and Henderson (1966) reported
96-hour LCso values for goldfish, guppies and bluegills to be
51,620, 45,530, and 24,000 ug/1, respectively, for chlorobenzene.
Two 96 hour LCso values for chlorobenzene and fathead minnows ar«
33,930 ug/1 in saltwater and 29,120 ug/1 in hard water. Reported
96-hour values for the bluegill exposed to chlorobenzene, 1,2,4-
trichlorobenzene, 1,2,3,5- and 1,2,4,5-tetrachlorobenzenes and
pentachlorobenzene are 15,900, 3,360, 6,420, 1,550, and 250
ug/1, respectively (U.S. EPA, 1978). These data indicate increasing
toxicity with chlorination, except for monochlorobenzene. ECsg
(48 hour) values reported for Daphnia magna are: chlorcb'enzene
36-10
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86,000 ug/1, 1,2,4-trichlorobenzene 50,200 ug/1, 1,2,3,5-tetra-
chlorobenzene 9,710 ug/1, and pentachlorobenzene 5,280 ug/1.
Toxicity tests with the sheepshead minnow, Cyprinodon
variegatus, performed with five chlorinated benzenes under static
conditions and yielded the following 96-hour LCso values:
chlorobenzene 10,500 ug/1, 1,2,4-trichlorobenzene 21,400 ug/1,
1,2,3,5-tetrachlorobenzene 3,670 ug/1, 1,2,4,5 tetrachlorobenzene
840 ug/1, and pentrachlorobenzene 835 ug/1. As with sheepshea^
minnows, sensitivity of the mysid shrimp, Mysidopsis bahia, to
chlorinated benzenes generally increases with increasing chlori-
nation. The reported 96-hour LCso values are as follows:
chlorobenzene 16,400 ug/1, 1,2,4-trichlorobenzene 450 ug/1,
1, 2,3,5-tetrachlorobenzene 340 ug/1, 1,2,4,5-tetrachlorobenzene
1,480 ug/1, and 160 ug/1 for pentachlorobenzene.
B. Chronic Toxicity
Chronic toxicity data are not available for freshwater
fish or invertebrate species. Only one saltwater species*
Cyprinodon variegatus, has been chronically exposed to any of the
chlorinated benzenes. In an embryo-level test, the limits for
1,2,4,5-tetrachlorobenzene are .92 to 180 ug/1, with a final
chronic value of 64.5 ug/1.
C. Plant Effects
The green freshwater algae Selenastrum capricornutum
has been exposed to five chlorinated benzenes. Based on cell
number, the 96-hour ECso values are as follows: chlorobenzene
220,000 ug/1, 1,2,4-trichlorobenzene 36,700 ug/1, 1,2,3,5-
tetrachlorobenzene 17,700 ug/1, 1,2,4,5-tetrachlorobenzene 46,800
36-11
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ug/l, and pentachlorobenzene 6,780 ug/1.
D. Residues
»
No measured bioconcentration factor (BCF) is available
for chlorobenzen.es. However, the average weighted BCF of 13 was
calculated from octanol-water partition coefficient and other
factors. .(See above) (U.S. EPA, 1980).
VI. EXISTING GUIDELINES AND STANDARDS
A. Hunan
Monochlorobenzene: The American Conference of Governmental
Industrial Hygienists (ACGIH, 1971) threshold limit value for
monochlorobenzene is 75 ppm. The U.S. EPA ambient water quality
criterion for monochlorobenzene is 20 ug/1 based on the threshold
concentration for odor and taste, and 488 ug/1 based on its toxic
effects (U.S. EPA, 1980).
Trichlorobenzene: The American Conference of Governmental
Industrial Hygienists (ACGIH, 1977) threshold limit value for
1,2,4-trichlorobenzene is (5 ppm). Because of the insufficiency
of available information for trichlorobenzene U.S. EPA (1980)
determined that a criterion could not be derived using the
guidelines in effect in 1980.
Tetrachlorobenzene: The U.S. EPA (1980) ambient water
quality criterion for 1,2,4,5-tetrachlorobenzene based on its
toxic effects, is 38 ug/1.
Pentachlorobenzene: The U.S. EPA (1979) ambient water
quality criterion for pentachlorobenzene based on its toxic
effects is 74 ug/1.
36-12
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Hexachlorobenzene: The value of 0.6 ug/kg/day
was suggested by FAO/WHO as a reasonable upper limit for residues
in food for human consumption (FAO/WHO, 1974). The Louisiana
State Department of Agriculture has set the tolerated level of
hexachlorobenzene in meat fat at 0.3 mg/kg (U.S. EPA, 1976). The
FAO/WHO recommendations for residues in foodstuffs were 0.5
mg/kg in fat for milk and eggs, and 1 mg/kg in fat for meat and
poultry (FAO/WHO, 1974). For maximum protection of human health
from the potential carcinogenic effects of hexachlorobenzene
through ingestion of contaminated water and contaminated aquatic
organisms, the ambient water criterion is 0.72 ug/1 (10-7 incremental
lifetime risk)(U.S. EPA, 1980).
36-13
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CHLORINATED BENZENES
REFERENCES
Albro, PiW., and R. Thomas. 1974. Intestinal absorption of
hexachlorobenzene and hexchlorocyclohexane isomers in rats.
Bull. Environ. Contain. Toxicol. 12: 289.
American Conference of Governmental Industrial Hygienists. 1971.
Documentation of the threshold limit values for substances in
workroom air. 3rd ed.
Ariyoshi, T., et al. 1975a. Relation between chemical structure
and activity. I. Effects of the number of chlorine atoms in
chlorinated benzenes on the components of drug metabolizing
systems and hepatic constituents. Chera. Pharm. Bull. 23: 817.
Braun, W.H./ et al. 1978. Fharraacokinetics and toxicological
evaluation of dogs fed 1,2,4,5-tetrachlorobenzene in the diet for
two years. Jour. Environ. Pathol. Toxicol. 2:225.
Cabral, J.R.P., et al. 1977. Carcinogenic activity of hexachloro-
benzene in hamsters. Nature (London) 269:510.
Cabral, J.R.P., et al. 1978. Carcinogenesis study in mice with
hexachlorobenzene. Toxicol Appl. Pharmacol. 45:323.
Cam, C., and G. Nigogosyan. 1963. Acquired toxic porphyria cutanea
tarda due to hexchlorobenzene. Jour. Am. Med. Assoc. 183:88.
Coate, W.B., et al. 1977. Chronic.inhalation exposure of rats,
rabbits and monkeys to 1,2,4-trichlorobenzene. Arch. Environ.
Health. 32:249.
Fomenko, v.N. 1965. Determination of the maximum permissible
concentration of tetrachlorobenzene in water basins. Gig. Sanit.
30:8.
Food and Agriculture Organization. 1974. 1973 evaluations of some
pesticide residues in food. FAO/AGP/1973/M/9/1; WHO Pestic. Residue
Ser. 3. World Health Org., Rome, Italy, p. 291.
Gott, M., et al. 1972. Hepatoma formation in mice after admini
stration of high doses of hexchlorocyclohexane isomers. Chemosphere
1L279.
36-14
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Grant, D.L., et al. 1977. Effect of hexachlorobenzene on re-
production in the rat. Arch. Environ. Contain. Toxicol 5:207.
Irish, D.D. 1963. . Halogenated hydrocarbons: II. Cyclic. In
Industrial Hygiene and Toxicology, Vol. II, 2nd ed., F.A. Patty,
(ed.) Interscience, New York. p. 1333.
Jondorf, W.R., et al. 1958. Studies in detoxication. The
metabolism of halogenobenzenes 1,2,3,4-, 1,2,3,5- and 1,2,4,5-
tetrachlorobenzenes. Jour.Biol. Chem. 69:189.
Khera, K.S.- 1974. Teratogenicity and dominant lethal "studies
on hexachlorobenzene in rats. Food Cosmet. Toxicol. 12:471.
Khera, K.S. and D.C. Villeneuve. 1975. Teratogenicity studies on
halogenated benzenes (pentachloro-, pentanitro-, and hexabromo-)
in rats. Toxicology. 5:117.
Kohli, I., et al. 1976. The metabolism of higher chlorinated
benzene isomers. Can. Jour. Biochem. 54:203.
Koss, G. , and W. Koransky. 1975. Studies on the toxicology of
hexachlorobenzene. I. Pharmacokinetics. Arch. Toxicol. 34:203.
Koss, G., et al. 1976. Studies on the toxicology of hexachloro-
benzene. II. Identification and determination of metabolites.
Arch. Toxicol. 35:107.
Koss, G., et al. 1978. Studies on the toxicology of hexachloro-
benzene. III. Observations in a long-term experiment. Arch.
Toxicol. 40:285.
Lu, P.Y., and R.L. Metcalf. 1975. Environmental fate and biode-
gradability of benzene derivatives as studied in a model aquatic
ecosystem. Environ. Health Perspect. 10:269.
Mackciy, D. , and P.J. Leinonen. 1975. Rate of evaporation of low-
solubility contaminants from water bodies to atmosphere. Environ.
Sci. Technol. 9:1178.
Parke, D.C., and R.T. Williams. 1960. Studies in detoxification
LXXXI. Metabolism of halobenzenes: (a) Penta- and hexachloro-
benzene: (b) Further ob-servations of 1,3,5-trichlorobenzene.
Biochem. Jour. 74:1.
Parrish, P.R., et al. 1974. Hexachlorobenzene: effects on several
estuarine animals. Pages 179-187 In; Proc. 28th Annu. Conf. S.E.
Assoc. Game Fish Comm.
36-15
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Pickering, Q'.H. , and C. Henderson. 1966. Acute toxicity of some
important petrochemicals to fish. Jour. Water Pollut. Control
Fed. 38:1419.
»
Preussmann, R. 1975. Chemical carcinogens in the human environ-
ment. Hand. Allg. Pathol. 6:421.
Rozman, K., et al. 1979 Metabolism and pharmacokinetics of penta-
chlorobenzene in rhesus monkeys. Bull. Environ. Contarn. Toxicol.
22:190.
Shirai, T., et al. 1978. Hepatocarcinogenicity of polychlorinated
terphenyl (PCT) in ICR mice and its enhancement by hexachlorobenzene
(HCB). Cancer Lett. 4:271.
Stijve, T. 1971. Determination and occurrence of hexachlorobenzene
residues. Mitt. Geb. Lebenmittelunters. Hyg. 62:406.
Theiss, J.C., et al. 1977. Test for carcinogenicity of organic
contaminants of United States drinking waters by pulmonary tumor
resopnse in strain A mice. Cancer Res. 37:2717.
U.S. EPA. 1975. Survey of Industrial Processing Data: Task I,
hexachlorobenzene and nexachlorobutadiene pollution from chlorocarbon
processes. Mid. Res. Inst. EPA, Off. Toxic Subs. Contract, Washington,
D.C.
U.S. EPA. 1976. Environmental contamination from hexachlorobenzene.
EPA-560/6-76-014. Off. Tox. Subst. 1-27.
U.S. EPA. 1978. In-depth studies on health and environmental impacts
of selected water pollutants. U.S. Environ. Prot. Agency, Contract
No. 68-01-4646.
U.S. EPA. 1978b. Initial Report of the TSCA Interagency Testing
Committee to the Administrator, EPA. EPA 560-10-78/001.
t
U.S. EPA. 1979. Ambient Water Quality Criteria for EPA 440/5-80-028.
Ushio, F., and M. Doguchi. 1977. Dietary intakes of some chlorinated
hydrocarbons and heavy metals estimated on the experimentally prepared
diets. Bull. Environ. Contain. Toxicol. 17:707.
West, W.L., and S.A. Ware. 1977. Preliminary Report, Investigation
of Selected -Potential Environmental Contaminants: Halogenated Ben-
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Williams, R.T. 1959. The metabolism of halogenated aromatic hydro-
carbons. Page 237 In; Detoxication mechanisms. 2nd ed. John Wiley
and Sons, New York.
36-16
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No. 37
Chlorinated Ethanes
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
37-1
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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 (CAG) has evaluated
chlorinated ethanes and has found sufficient evidence to
indicate that this compound is carcinogenic.
37-3
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CHLORINATED ETHANES
SUMMARY
Four of the chlorinated ethanes have been shown to
produce tumors in experimental animal studies conducted
by the National Cancer Institute (NCI). These four are
1,2-dichloroethane, 1,1,2-trichloroethane, 1,1,2,2-tetra-
chloroethane, and hexachloroethane. Animal tumors were
also produced by administration of 1,1,1-trichloroethane,
\
but this bioassay is being repeated due to premature deaths
in one initial study.
Two of the chlorinated ethanes, 1,2-dichloroethane
and 1,1,2,2-tetrachloroethane, have shown mutagenic activity
in the Ames Salmonella assay and in E. coli. 1,2-Dichloroethane
.has also shown mutagenic action in pea plants and in Drosophila.
No evidence is available indicating that the chlocoethanes
produce teratogenic effects. Some toxic effects on fetal
development have been shown following administration of
1,2-dichloroethane and hexachloroethane.
Symptoms produced by toxic exposure to the chloroethanes
include central nervous system disorders, liver and kidney
damage, and cardiac effects.
Aquatic toxicity data for the effects of chlorinated
ethanes to freshwater and marine life are few. Acute studies
have indicated that hexachloroethane is the most toxic of
the chlorinated ethanes reviewed. Marine organisms tend
»
to be more sensitive than freshwater organisms with acute
toxicity values as low as 540 ug/1 being reported.
-------
CHLORINATED ETHANES
I . INTRODUCTION
This profile is based on the draft Ambient Water Quality
Criteria Document for Chlorinated Ethanes (U.S. EPA, 1979).
The chloroethanes (see table 1) are hydrocarbons in
which one or more of the hydrogen atoms have been replaced
by chlorine atoms. Water solubility and vapor pressure
decrease with increasing chlorination, while density and
melting point increase. Monochloroethane is a gas at room
temperature, hexachloroethane is a solid, and the remaining
compounds are liquids. All chloroethanes show some solubility
in water, and all, except monochloroethane, are more dense
than water.
The chloroethanes are used as solvents, cleaning and
degreasing agents, in the manufacture of plastics and textiles,
and in the chemical synthesis of a number of compounds.
Current production:
monochloroethane 335 x 103 tons/yr in 1976
"1,2-dichloroethane 4,000 x 10^ tons/yr in 1976
1,1,1-trichloroethane 215 x 10 tons/yr in 1976
The chlorinated ethanes form azeotropes with toater
(Kirk and Othmer, 1963). All are very soluble in organic
solvents (Lange, 1956) . Microbial degradation of the chlorin-
ated ethanes has not been demonstrated (U.S. EPA, 1979).
II . EXPOSURE
The chloroethanes are present in raw and finished waters
due primarily to industrial discharges. Small amounts of
the chloroethanes may be formed by chlorination of drinking
water or treatment of sewage. Water monitoring studies
3-7-5
-------
have shown the following levels of various chloroethanes:
1,2-dichloroethane, 0.2-8 ug/1; 1,1,2-trichloroethane, 0.1-
8.5 ug/1; 1,1,1,2-tetrachloroethane, 0.11 ;ag/l (U.S. EPA,
1979). In general, air levels of chloroethanes are produced
by evaporation of volatile chloroethanes widely used as
degreasing agents and in dry cleaning operations (U.S. EPA,
1979). Industrial monitoring studies have shown air levels
of 1,1,1-trichloroethane ranging from 1.5 to 396 ppm (U.S.
EPA, 1979).
s
TABLE 1
Chloroethanes and Synonyms
Synonyms
Compound Name
Monochloroethane
1,1,-Dichloroethane
1,2-Dichloroethane
1,1,1-Trichloroethane
1,1,2-Tr ichloroethane
1,1,1,2-Tetrachloroethane
1,1,2,2-Tetrachloroethane
Pentachloroethane
Hexachloroethane
Chloroethane
Ethylidene Dichloride
Ethylene Dichloride
Methyl Chloroform
Ethane Trichloride
Tetrachloroethane
Acetylene Tetrachloride
Pentalin
Perchloroethane
Ethyl chloride
Ethylidene Chloride^
Ethylene Chloride
Chlorothene
Vinyl Trichloride
Sym-Yetrachloroethane
Ethane Pentachloride
Sources of human exposure to chloroethanes include
water, air, contaminated foods and fish, and dermal absorption.
•
The two most widely used solvents, 1,2-dichloroethane and
1,1,1-trichloroethane, are the compounds most often detected
in foods. Analysis of several foods indicated I,1,1-trichloro-
37-6
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ethane levels of 1-10 ug/kg (Walter, et al. 1976), while
levels of 1,2-dichloroethane found in 11 of 17 species have
been reported to be 2-23 ug/g (Page and Kennedy, 1975) .
Fish and shellfish have shown levels of chloroethanes in
the nanogram range (Dickson and Riley, 1976).
The U.S. EPA (1979) has derived the following weighted
average bioconcentration. factors for the edible portions
of fish and shellfish consumed by Americans: 1,2-dichloro-
ethane, 4.6; 1,1,1-trichloroethane, 21; 1,1,2,2-tetrachloro-
«.
ethane, 18; pentachloroethane, 150; hexachloroethane, 320.
These estimates were based on the measured steady-state
bioconcentration studies in bluegill. Bioconcentration
factors for 1,1,2-trichloroethane (6.3) and 1,1,1,2-tetrachloro-
ethane (18) were derived by EPA (1979) using octanol-water
partition coefficients.
III. PHARMACOKINETICS
A. Absorption
The chloroethanes are absorbed rapidly following
ingestion or inhalation (U.S. EPA, 1979). Dermal absorption
is thought to be slower in rabbits based on studies by Smyth,
et al. (1969). However, rapid dermal absorption has been
seen in guinea pigs with the same trichloroethane (Jakobson,
et al. 1977).
Human studies on the absorption of inhaled 1,1,2,2-
tetrachloroethane indicate that the compound is completely
absorbed after exposure to trace levels of radiolabeled
vapor (Morgan, et al. , 1970, 1972). At higher exposure
levels absorption is rapid in man and animals, but obviously
not complete.
37-7
-------
B. * Distribution
Studies on the distribution of 1,1,1-trichloroethane
in mice following inhalation exposure have shown levels
in the. liver to be twice that found in the kidney and brain
(Holmberg, et al. 1977). Postmortem examination of human
tissues showed 1,1,1-trichloroethane in body fat (highest
concentration) kidneys, liver, and brain (Walter, et al.
1976). Due to the lipid solubility of chloroethanes, body
distribution may be expected to be widespread. Stahl, et
V
al. (1969) have noted that human tissue samples of liver,
brain, kidney, muscle, lung, and blood contained 1,1,1-tri-
chloroethane following acute exposure, with the liver contain-
ing the highest concentration.
Passage of 1,1,1,2-tetrachloroethane across the
placenta has been reported by Truhaut, et al. (1974) in
rabbits and rats.
C. Metabolism
The metabolism of chloroethanes involves both
enzymatic dechlorination and hydroxylation to corresponding
alcohols (Monster, 1979; Truhaut, 1972). Oxidation reactions
may produce unsaturated metabolites which are then transformed
to the alcohol and ester (Yllner, 1971 a,b,c,d).
Metabolism appears to involve the activity of
the mixed function oxidase enzyme system (Van Dyke and Wineman,
1971). Animal experiments by Yllner (1971 a,b,c,d,e) indicated
that the percentage of administered 'compound metabolized
*
decreased with increasing dose, suggesting saturation of
metabolic pathways.
-------
D. Excretion
The chloroethanes are excreted primarily in the
urine and in expired air (U.S. EPA, 1979). As much as 60
to 80 percent of an inhaled dose of 1,1,1-trichloroethane
(70 or 140 ppm for 4 hours) was expired unchanged by human
volunteers (Monster, et al. 1979). Animal studies conducted
by Yllner (1971 a,b,c,d) indicate that largest amount of
chloroethanes, administered by intraperitoneal (i.p.) injec-
tion is excreted in the urine; this is followed by expira-
tion (in the changed or unchanged form), with very little
excretion in the feces. Excretion appears to be rapid,
since 90 percent of i.p. administered doses of 1,2-dichloro-
ethane or 1,1,2-trichloroethane were eliminated in the first
24 hours (U.S. EPA, 1979). However, the detection of chloro-
ethanes in postmortem tissue samples indicates that some
portion of these compounds persists in the body (Walter,
et al. 1976).
IV. EFFECTS
A. Carcinogenicity
Several chlorinated ethanes have been shown to
produce a variety of tumors in rats and mice in experiments
utilizing oral administration. Tumor types observed after
compound administration include squamous cell carcinoma
of the stomach, hemangiosarcoma, adenocarcinoma of the mam-
mary gland, and hepatocellular carcinoma (NCI, 1978a,b,c,d) .
The four chlorinated ethanes which have been classified
as carcinogens based on animal studies are: 1,2-dichloro-
ethane, 1,1,2-trichloroethane, 1,1, 2,2-tetrachloroethane,
37-?
-------
and hexachloroe thane. Increased tumor production was also
noted in animals treated with 1,1,1-trichloroe thane, but
high mortality during this study (NCI, 1977) caused retest-
ing of the compound to be initiated. Iri vitro transforma-
tion of rat embryo cells and subsequent fibrosarcoma produc-
tion by these cells when injected ir\ vivo, indicate that
1,1,1-trichloroe thane does have carcinogenic potential (Price,
et al. 1978) .
B. Mutagenicity
v
Two of the chlorinated ethanes, 1,2-dichloroethane
and 1,1,2,2-tetrachloroethane, have shown mutagenic activity
in the Ames Salmonella assay and for DNA polymerase deficient
strain of E. coli (Brem, et al. 1974). In these two systems,
1,1,2,2-tetrachloroethane showed higher mutagenic activity
than 1,2-dichloroethane (Rosenkranz, 1977).
Mutagenic effects have been produced by 1,2-dichloro-
ethane in pea plants (Kirichek, 1974) and in Drosophila
(Nylander, et al. 1978). Several metabolites of dichloro-
ethane (chloroacetaldehyde, chloroethanol, and S-chloroethyl
cysteine have also been shown to produce mutations in the
Ames assay (U.S. EPA, 1979).
Testing of hexachioroethane in the Ames Salmonella
assay or in a yeast assay system failed to show any mutagenic
activity (Weeks, et al. 1979) .
C. Teratogenicity
Inhalation exposure of pregnant rats and mice
to 1,1, 1-tr ichloroethane was shown to produce some soft
37-1-0
-------
tissue and skeletal deformities; this incidence was not
judged statistically significant by the Fisher Exact proba-
bility test (Schwetz, et al. 1975).
Testing of hexachloroethane administered to rats
by intubation or inhalation exposure did not show an increase
in teratogenic effects (Weeks, et al. 1979). Inhalation
exposure of pregnant rats to 1,2-dichloroethane also failed
to demonstrate teratogenic effects (Schwetz, et al. 1974;
Vozovaya, 1974).
D. Other Reproductive Effects
Decreased litter size, reduced fetal weights and
a reduction in live births have been reported in rats exposed
to 1,2-dichloroethane (57 mg/m m four hours/day, six days/week)
by inhalation (Vozovaya, 1974). 1,1-Dichloroethane retarded
fetal development at exposures of 6,000 ppm. (Schwetz, et
al. 1974). Higher fetal resorption rates and a decreased
number of live fetuses per litter were observed in rats
following administration of hexachloroethane by intubation
(15, 48 or 260 ppm, 6 hours/day) or inhalation (50, 100
*
or 500 mg/kg/day) (Weeks, et al. 1979).
E. Chronic Toxicity
Neurologic changes and liver and kidney damage
have been noted following long term human exposure to 1,2-
dichloroethane (NIOSH, 1978). Cardiac effects (overstimulation)
have been noted following human exposure' to 1,1-dichloroethane
(U.S. EPA, 1979).
Central nervous system disorders have been reported
in humans exposed to 1,1,1-trichloroethane. Symptoms noted
7t
37-11
-------
were altered reaction time, perceptual speed, manual dexterity,
and equilibrium (U.S. EPA, 1979).
Animal studies indicate that the general symptoms
of toxicity resulting from exposure to the chloroethanes
involve effects in the central nervous system, cardiovascular
system, pulmonary system, and the liver and kidney (U.S.
EPA, 1979) . Laboratory animals and humans exposed to chloro-
ethanes show similar symptoms of toxicity (U.S. EPA, 1979).
Based on data derived from animal studies, the
\
U.S. EPA (1979) has concluded that the relative toxicity
of the chloroethanes is as follows: 1, 2-dichloroe thane >
1,1,2, 2- tetr achloroethane ^"1,1,2-tr ichloroe thane >hexachloro-
ethane 1 , 1-dichloroe thane ;> 1 , 1 , 1-tr ichloroe thane > monochloro-
ethane.
F. Other Relevant Information
The hepatotoxicity of 1,1', 2-trichloroethane was
increased in mice following acetone or isopropyl alcohol
pretreatment (Traiger and Plaa, 1974) . Similarly, ethanol
pretreatment of mice increased the hepatic effects of 1,1,1-
trichloroethane (Klassen and Plaa, 1966).
Hexobarbital sleeping times in rats were reported
to be decreased following inhalation exposure to 1,1,1-tri-
chloroethane (3,000 ppm) , indicating an effect of the compound
on stimulation of hepatic microsomal enzymes (Fuller, et
al. 1970) .
V. AQUATIC TOXICITY
9
A. Acute Toxicity
Acute toxicity studies were conducted on three
species of freshwater organisms and two marine species.
37-
-------
For freshwater fish, 96-hour static LC50 values for the
bluegill sunfish, Lepomis macrochirus, ranged from 980 pg/1
hexachloroethane to 431,000 ug/1 1,2-dichloroethane, while
the range of 48-hour LC5Q values for the freshwater inverte-
brate Daphnia magna was 8,070 ug/1 to 218,000 ug/1 for hexa-
chloroethane and 1,2-dichloroethane respectively. Among
marine organisms, the sheepshead minnow (Cyprinodon vagie-
gatus) produced LC^Q values ranging from 2,400 pg/I for
hexachloroethane to 116,000 ug/1 for pentachloroethane.
The marine mysid shrimp (Mysidopsis bahia) produced LCrg
values ranging from 940 ug/1 for hexachloroethane to 113,000
ug/1 for 1,2-dichloroethane. The general order of acute
toxicities for the chlorinated ethanes reviewed for fresh-
water fish is: hexachloroethane (highest toxicity) , 1,1,2,2-
tetrachloroethane, 1,1,2-trichloroethane, pentachloroethane,
and 1,2-dichloroethane (U.S. EPA, 1979).
B. Chronic Toxicity
The only chronic study available for the chlori-
nated ethanes is for pentachloroethane1 s chronic effects
on the marine shrimp (Mysidopsis bahia) , which produced
a chronic value of 580 ug/1 (U.S EPA, 1978).
C. Plant Effects
Effective EC^g concentrations, based on chlorophyll
a and cell numbers for the freshwater algae Selenastrum
capriconutum ranges from 87,000 ug/1, for hexachloroethane
to 146,000 ug/1 for 1,1, 2, 2-tetrachloroethane, with penta-
chloroethane being intermediate in its phytotoxicity . For
the marine algae Skeletonema costatum, a greater sensi-
37-13
-------
tivity was indicated by effective EC50_ concentrations based
on cell numbers and chlorophyll a ranging from 6,230 ug/1
for 1,1,2,2-tetrachloroethane and 7,750 ug/1 for hexachloro-
ethane to 58,200 ug/1 for pentachloroethane.
D. Residues
The bioconcentration value was greatest for hexa-
chloroethane with a value of 139 ug/1 being reported for
bluegill. Bioconcentration values of 2, 3, and 9 were obtained
for 1,2-dichloro, 1,1,2,2-tetrachloro, and 1,1,1-trichloro-
\
ethane for bluegills. 1,1-,2-Trichloroe thane and 1,1,1,2-
tetrachloroethane used the octanol/water coefficients to
derive BCF's of 22 and 62, respectively.
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 may be changed.
A. Human
Based on the NCI carcinogenesis bioassay data,
and using a linear, non-threshold model, the U.S. EPA (1979)
has estimated levels of four chloroethanes in ambient water
that will result in an additional cancer risk of 10~3: 1,2-
dichloroe thane, 7.0 ug/1; 1,1,2-trichloroethane, 2.7 ug/1;
1,1,2,2-tetrachloroethane, 1.3 pg/1; hexachloroethane, 5.9
ug/1. A draft ambient water quality - criterion to protect
human health has been derived by EPA for 1,1,1-tr ichloro-
ethane based on mammalian toxicity data at the level of
15.7 mg/1.
J7-/Y
-------
Insufficient mammalian toxicological data prevented
derivation of a water criterion for monochloroethane, 1,1-
dichloroethane, 1,1,1,2-tetrachloroethane, or pentachloro-
ethane (U.S. EPA, 1979}.
The following compounds have had eight hour, TWA
exposure standards established by OSHA: monochloroethane,
1,000 ppm; 1,1-dichloroethane, 100 ppm; 1,2-dichloroethane,
50 ppm; 1,1,1-trichloroethane, 350 ppm; 1,1,2-trichloroethane,
10 ppm; 1,1,2,2-tetrachloroethane, 5 ppm; hexachloroethane,
1 ppm.
B. Aquatic
Criteria for protecting freshwater organisms have
been drafted for five of the chlorinated hydrocarbons: 62
pg/1 (average concentation) not to exceed 140 pg/1 for hexa-
chloroethane; 170 pg/1 not to exceed 380 pg/1 for 1,1,2,2-
tetrachloroethane; 440 pq/l not to exceed 1,000 ,ug/l for
pentachloroethane; 3,900 ug/1 not to exceed 8,800 pg/1 for
1,2-dichloroethane; and 5,300 pg/1 not to exceed 12,000
pg/1 for 1,1,1-trichloroethane. For marine organisms, cri-
teria have been drafted as: 7 pg/1 (average concentration)
not to exceed 16 pg/1 for hexachloroethane; 38 pg/1 not
to exceed 87 pg/1 for pentachloroethane; 70 ug/1 not to
exceed 160 pg/1 for 1,1,2,2-tetrachloroethane; 240 pg/1
not to exceed 540 pg/1 for 1,1,1-trichloroethane; and 880
pg/1 not to exceed 2,000 pg/1 for 1,2-dichloroethane.
-------
CHLORINATED ETHANES
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-------
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Ethylene dichloride (1,2-dichloroethane). Current Intelli-
gence Bull. 25. DFEW (NIOSH) Publ. No. 78-149.
Nylander, P.O., et al. 1978. Mutagenic effects of petrol in
Drosophilia irielanoaaster. I. Effects of benzene of and 1,2-
dichloroethane. Mutat. Res. 57: 163.
Page, B.D., and P.P.C. Kennedy. 1975. Determination of
mthylene chloride, ethylene dichloride, and trichloroethylene
as solvent residues in spice oleoresins, using vacuum distil-
lation and electron-capture gas chromatography. Jour.
Assoc. Off. Anal. Chen. 58: 1062.
*
Price, P.J., et al.' 1978. Transforming activities of tri-
chloroethylene and proposed industrial alternatives. I_n
vitro. 14: 290.
Rosenkranz, H.S. 1977. Mutagenicity of halogenated alkanes
and their derivatives. Environ. Health Perspect. 21: 79.
Schwetz, B.A., et al. 1974. Embryo- and fetotoxicity of in-
haled carbon tetrachloride, 1,1,-dichloroethane, and methyl
ethyl ketone in rats. Toxicol. Appl. Pharmacol. 28: 452.
Schwetz, B.A., et al. 1975. Effect of maternally inhaled.
trichloroethylene, perchloroethylene, methyl chloroform, and
methylene chloride on embryonal and fetal development in mice
and rats. Toxicol. Appl. Pharmacol. 32: 84.
-------
Smyth, H.F., Jr., et al. 1969. Range-finding toxicity data:
list VII. Am. Ind. Hyg. Assoc. Jour. 30: 470.
Stahl, C.J., et al. 1969. Trichloroethane poisoning: ob-
servations on the pathology and toxicology in six fatal
cases. Jour. Forensic Sci. 14: 393.
Traiger, G.J., and G.L. Plaa. 1974. Chlorinated hydrocarbon
toxicity. Arch. Environ. Health 28: 276.
Truhaut, R. 1972. Metabolic transformations of 1,1,1,2-
tetrachloroethane in animals (rats, rabbits). Chem. Anal.
(Warsaw) 17: 1075.
Truhaut, R., et al. 1974. Toxicological study of 1,1,1,2-
tetrachloroethane. Arch. Mai. Prof. Med. Trav. Secur. Soc.
35: 593.
U.S. EPA. 1978. In-depth studies on health and environ-
mental impacts of selected water pollutants. U.S. Environ.
Prot. Agency. Contract No. 68-01-4646.
U.S. EPA. 1979. Chlorinated Ethanes: Ambient Water Quality
Criteria (Draft).
Van Dyke, R.A., and C.G. Wineman. 1971. Enzymatic dechlori-
nation: Dechlorination of chloroethanes and propanes J^n
vitro. Biochem. Pharmacol. 20: 463.
Vozovaya, M.A. 1974. Development o^ progeny of two genera-
tions obtained from female rats subjected to the action of
dichloroethane. Gig. Sanit. 7: 25.
Walter, P., et al. 1976. Chlorinated hydrocarbon toxicity
(1,1,1-trichloroethane, trichloroethylene, and tetrachloro-
ethylene): a monograph. PE Rep. PB-257185. Natl. Tech.
Inf. Serv., Springfield, Va.
*
Weeks, M.H., et al. 1979. The toxicity of hexachloroethane
in laboratory animals. Am. Ind. Hyg. Assoc. Jour. 40: 187.
Yllner, S. 1971a. Metabolism of 1, 2-dichloroethane-14C
in the mouse. Acta. Pharraacol. Toxicol. 30: 257.
Yllner, S. 1971b. Metabolism of 1,1,2-trichloroethane-l,2-
^•4C in the mouse. Acta. Pharnacol. Toxicol. 320: 248.
Yllner, S. 1971c. Metabolism of 1,1,1,2-tetrachloroethane
in the mouse. Acta. Pharmacol. Toxicol. 29: 471.
Yllner, S. 1971d. Metabolism of 1,1,2,2-tetrachloroethane-
^4C in the mouse. Acta. Pharmacol. Toxicol. 29: 499.
Yllner, S. 1971e. Metabolism of pentachloroethane in the
mouse. Acta. Pharmacol. Toxicol. 2^: 481.
37- It
-------
No. 38
Chlorinated Naphthalenes
Health and Environmental Effects
O.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.
-------
CHLORINATED NAPTHALENE5
Summary
Chlorinated naphthalenes have been used in a variety of industries,
usually as mixtures. Chronic toxicity varies with the degree of chlori-
nation, with the more highly chlorinated species being more toxic. The
clinical signs of toxicity in humans are damage to liver, heart, pancreas,
gall bladder, lungs, adrenal glands, and kidney. No animal or human studies
have been presented on the carcinogenicity, mutagenicity, or teratogenicity
of polychlorinated naphthalenes.
Very little data on aquatic toxicity are available for individual
chlorinated naphthalenes. 48-Hour and 96-hour LC^Q values of octachloro-
naphthalene over 500,000 /ug/1 have been reported for Daphnia magna and the
bluegill, respectively. A freshwater alga also resulted in a 96-hour LC5Q
value for octachloronaphthalene of over 500,000 jLig/1.
Toxicity studies with aquatic organisms are confined to tests with 1-
chloronaphthalene on one freshwater fish and two algal species (one fresh
and one saltwater). All tests have reported 96-hour LC5Q values of be-
tween 320 and 2,270 jjg/1. Exposure of sheepshead minnow to 1-chloronaphtha-
*
lene in an embryo-larval study resulted in a chronic value of 328 ug/1.
-------
CHLORINATED NAPTHALENES
I. INTRODUCTION
This profile is based on the draft Ambient Water Quality Criteria Docu-
ment for Chlorinated Naphthalenes (U.S. EPA, 1979).
Chlorinated naphthalenes consist of two fused six carbon-membered aro-
matic rings where any or all of the eight hydrogen atoms can be replaced
with chlorine. The physical properties of the chlorinated naphthalenes are
generally dependent on the degree of chlorination. Melting points range
from 17°C for 1-chloronaphthalene to 198°C- for 1,2,3,4-tetrachloro-
naphthalene. As the degree of chlorination increases, the specific gravity,
boiling point, fire and flash points all increase, while the vapor pressure
and water solubility decrease. Chlorinated naphthalenes have been used as
the paper impregnant in automobile capacitors (mixtures of tri- and tetra-
chloronaphthalenes), and as oil additives for engine cleaning, and in fabric
dyeing (mixtures of mono- and dichloronaphthalenes). In 1956, the total
U.S. production of chlorinated naphthalenes was approximately 3,175 metric
tons (Hardie, 1964).
II. EXPOSURE
A. Water
To date, polychlorinated naphthalenes have not been identified in
drinking waters (U.S. EPA, 1979). However, these compounds have been found
in waters or sediments adjacent to point sources or areas of heavy poly-
chlorinated biphenyl contamination.
B. Food
Polychlorinated naphthalenes appear to be biomagnified in the aqua-
tic ecosystem, with the degree of biomagnification being greater for the
more highly chlorinated polychlorinated compounds (Walsh, et al. 1977).
-------
Erickson, at al. (1978) also noted a higher relative biomagnification of the
lowest chlorinated naphthalenes by the fruit of apple trees grown on contam-
inated soil. The U.S. EPA (1979) has estimated the weighted average biocon-
centration factor for Halowax 1014 (a mixture of chlorinated naphthalenes)
to be 4,800 for the edible portions of fish and shellfish consumed by
Americans. This estimate is based on measured non-steady-state bioconcen-
tration studies in brown shrimp.
C. Inhalation
Erickson, et al. (1978) found ambient -air concentrations of poly-
chlorinated naphthalenes ranging from 0.025 to 2.90 pg/m near a poly-
chlorinated naphthalene plant. Concentrations of trichloronaphthalene were
as high as 0.95 ug/m , while hexachloronaphthalene concentrations never
exceeded 0.007 jug/m .
III. PHARMACOKINETICS
A. Absorption
Pertinent data could not be located in the available literature.
B. Distribution
In the rat fed 1,2-dichloronaphthalene, the chemical and its metab-
olites were found primarily in the intestine, kidney, and adipose tissue
»
(Chu, et al. 1977).
C. Metabolism
There appears to be appreciable metabolism in mammals of poly-
chlorinated naphthalenes containing four chlorine atoms or less (U.S. EPA,
1979). Cornish and Block (1958) investigated the excretion of polychlori-
nated naphthalenes in rabbits and found 79 percent of 1-chloronaphthalene,
93 percent of dichloronaphthalene, and 45 percent of tetrachloronaphthalene
-------
were excreted in the urine as metabolites .of the parent compounds. Metab-
olism may involve hydroxylation alone or hydroxylation in combination with
dechlorination. In some cases, an arene oxide intermediate may be formed
(Ruzo, et al. 1976).
D. Excretion
In rats fed 1,2-dichloronaphthalene, initially more of the chemical
and its metabolites were found in the urine; however, by the end of seven
days a greater proportion had been excreted in the feces (Chu, et al. 1977).
In the first 24 hours, 62 percent of the dose was excreted in the bile, as
compared to 18.9 percent lost in the feces. This suggests that there is an
appreciable reabsorption and enterohepatic recirculation of this particular
chlorinated naphthalene.
IV. EFFECTS
NO animal or human studies have been reported on the carcinogenic!ty,
mutagenicity, or teratogenicity of chlorinated naphthalenes. No other re-
productive effects were found in the available literature.
A. Chronic Toxicity
Chronic dermal exposure to penta- and hexachlorinated naphthalenes
causes a form of chloracne which, if persistent, can progress to fprm a cyst
or sterile abcess (Jones, 1941; Shelley and Kligman, 1957; Kleinfeld, et al.
1972). Workers exposed to these two isomers complained of eye irritation,
headaches, fatigue, vertigo, nausea, loss of appetite, and weight loss
(Kleinfeld, et al. 1972). More severe exposure to the fumes of polychlori-
nated naphthalenes has produced severe liver damage, together with damage to
the heart, pancreas, gall bladder, lungs, adrenal glands, and kidney tubules
(Greenburg, et al. 1939). Chronic toxicity in animals appears to be quali-
tatively the same (U.S. EPA, 1979). Polychlorinated naphthalenes containing
-------
three or fewer chlorine atoms were found to be nontoxic, while tetrachloro-
naphthalene resulted in mild liver disease at levels as high as 0.7 mg/kg/-
day; the higher chlorinated naphthalenes produce more severe disease at
lower doses (Bell, 1953). Because of their insolubility, hepta- and octa-
chloronaphthalene were less toxic when given in suspension than when given
in solution.
8. Other Relevant Information
Drinker, et al. (1937) showed enhancement of hepatoxicity of a mix-
ture of ethanol/carbon tetrachloride in rats pretreated with 1.16 mg/m of
a penta-Xhexachloronaphthalene mixture in air for six weeks. In a similar
study trichloronaphthalene was inactive.
V. AQUATIC TOXICITY
A. Acute Toxicity
The 96-hour LC^ value reported for the bluegill, Lepomis
macrochirus, exposed to 1-chloronaphthalene is 2,270 jug/1 (U.S. EPA, 1978).
With saltwater species, exposure of the sheepshead minnow, Cyprinodon
variqatus, and mysid shrimp, Mysidopsis bahia_, to 1-chloronaphthalene pro-
vided 96-hour LC50 values of 1,290 and 370 Jjg/l, respectively. Daphnia
maqna and the bluegill, Lepomis macrochirus, have a slight sensitivity to
octachloronaphthalene, ' with respective 48-hour and 96-hour I_C50 values
greater than 530,000pg/l (U.S. EPA, 1978).
B. Chronic Toxicity
In the only chronic study reported (embryo-larval), exposure of
1-chloronaphthalene to the sheepshead minnow resulted in a chronic value of
329 jjg/1 (U.S. EPA, 1978).
-------
C. Plant Effects
A freshwater alga, Selenastrum capricomutum, and a saltwater alga,
Skeletonema costatum, when exposed to 1-chloronaphthalene, both produced 96-
hour EC5Q values ranging from 1,000 to 1,300 ug/1 based on cell numbers.
Octachloronaphthalene exposure to Selenastrum caprlcornutum re-
sulted in a 96-hour EC^g value of over 500,000 jug/1 based on cell numbers
(U.S. EPA, 1978).
0 . Residues
Pertinent data could not be located in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The only standards for polychlorinated naphthalenes are the ACGIH
Threshold Limit Values (TLV) adopted by the Occupational Safety and Health
Administration and are as follow:
ACGIH (1977)
Threshold Limit Values
Trichloronaphthalene
Tetrachloronaphthalene
Pentachloronaphthalene
Hexachloronaphthalene
Octachloronaphthalene
5
2
0.5
0.2
0.1
mg/m3
mg/m3
mg/m3
mg/m3 •
mg/m3
There are no state or federal water quality or ambient air quality standards
for chlorinated naphthalenes.
The U.S. EPA is presently evaluating, the available data and has
recommended that a single acceptable daily intake (ADI) of 70 ug/man/day be
used for the tri-, tetra-, penta-, hexa-, and octa-chlorinated naphthalenes.
*
This ADI will be used to derive the human health criteria for the chlori-
nated naphthalenes.
-------
B. Aquatic
For 1-chloronaphthalene, the draft criterion to protect freshwater
aquatic life is 29 pg/1 as a 24-hour average, not to exceed 67 pg/1 at any
time. For saltwater aquatic species, the draft criteron is 2.8 jug/1 as a
24-hour average, not to exceed 6.4/jg/l at any time (U.S. EPA, 1979).
-------
CHLORINATED NAPHTHALENE
REFERENCES
American Conference of Governmental Industrial Hygienists.
1977. TLVs Threshold Limit Value for chemical substances and
physical agents in the workroom environment with intended
changes. Cincinnati, Ohio.
Bell, W.S. 1953. The relative toxicity of the chlorinated
naphthalenes in experimentally produced bovine hyperkeratosis
(X-disease). Vet. Met. 48: 135.
Chu, I., et al. 1977. Metabolism and tissue distribution of
(1,4,5,—J-4C)-l,2-dichloronaphthaline in rats. Bull.
Environ. Contain. Toxicol. 18: 177.
«.
Cornish, H.H., and W.D. Block. 1958. Metabolism of chlori-
nated naphthalenes. Jour. Biol. Chem. 231: 583.
Drinker, C.K., et al. 1937. The problem of possible sys-
temic effects from certain chlorinated hydrocarbons. Jour.
Ind. Hyg. Toxicol. 19: 283.
Erickson, M.D., et al. 1978. Sampling and analysis for
polychlorinated naphthalenes in the environment. Jour.
Assoc. Off. Anal. Chem. 61: 1335.
Greenburg,. L., et al. 1939. The systemic effects resulting
from exposure to certain chlorinated hydrocarbons. Jour.
Ind. Hyg. Toxicol. 21: 29.
Hardie, D.W.F. 1964. Chlorocarbons and chlorohydrocarbons:
Chlorinated Naphthalenes. pp. 297-303 In; Kirk-Othmer, En-
cyclo. of Chemical Technology. 2nd ed. John Wiley and Sons,
Inc., New York.
Jones, A.T. 1941. The etiology of acne with special prefer-
ence to acne of occupational origin. Jour. Ind. Hyg. Toxi-
col. 23: 290.
Kleinfeld, M., et al. 1972. Clinical effects of chlorinated
naphthalene exposure. Jour. Occup. Med. 14: 377.
Ruzo, L., et al. 1976. Metabolism of chlorinated naphtha-
lenes. Jour. Agric. Food Chem. 24: 581.
Shelley, W.B., and A.M. Kligman. 1957. The experimental
production of acne by penta- and hexa'chlcronaphthalenes.
A.M.A. Arch. Derm. 75: 689.
33--; a
-------
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, Washington, D.C.
U.'s. EPA. 1979. Chlorinated Naphthalenes: Ambient Water
Quality Criteria. (Draft).
Walsh, G.E., et al. 1977. Effects and uptake of chlorinated
naphthalenes in marine unicellular algae. Bull. Environ.
Contain. Toxicol. 18: 297.
-------
LB:46
No. 39
Chlorinated Phenols
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D. C. 20460
October 30, 1980
39-1
-------
DISCLAIMER
This report represents a survey of the potential health and
environmental hazards from exposure to the subject chemical. The
information contained in the report is drawn chiefly from secondary
sources and available reference documents. Because of the limita-
tions of such sources, this short profile may not reflect all
available information including all the adverse health and environ-
mental impacts presented by the subject chemical. This document
has undergone scrutiny to ensure its technical accuracy.
39-2
-------
SPECIAL NOTATION
This document discusses the health and environmental effects
of some of the di, tri, and tetra-substituted chlorinated phenols.
The health effects of p-chloro-m-cresol, 2-chlorophenol, 2,4- and
2,6-dichlorophenol, 2,4,6-trichlorophenol, and pentachlorophenol are
discussed in HEBD's nos. 43, 50, 75, 76, 143, and 168, respectively.
The National Cancer Institute (1979) recently published the results
of a bioassay indicating that 2,4,6-trichlorophenol induces cancer
in rats and mice.
39-3
-------
CHLORINATED PHENOLS
SUMMARY
Mammalian data supporting chronic effects for most of these
compounds is limited. Except for trichlorophenol, there are not
sufficient data to indicate whether any of the other chlorinated
phenols are carcinogens. In skin painting studies, 3-chlorophenol
and 2,4,5-trichlorophenol promoted papillomas. Tetrachlorophenol
was not teratogenic or embryolethal in animals, but showed question-
able fetotoxic effects. Chronic exposure to 4-chlorophenol produced
myoneural disorders in humans and animals. Adverse health effects
have been noted in workers exposed to 2,4,5-trichlorophenol.
Workers chronically exposed to tetrachlorophenol and pentachloro-
phenol, perhaps contaminated with small amounts of chlorodibenzo-
dioxins, developed severe skin irritations, respiratory difficulties,
and headaches.
Chlorophenols are uncouplers of oxidative phosphorylation,
and- affect carbohydrate metabolism. Several affect the nervous
system, causing convulsions.
The tainting of rainbow trout flesh has been demonstrated at
exposures of 15 to 84 ug/1 for several of the chlorinated phenols.
39-4
-------
I. INTRODUCTION
This profile is based in part on the Ambient Water Quality
Criteria Document for Chlorinated Phenols (U.S. EPA, 1980).
The chlorinated phenols represent a group of commercially
produced substituted phenols and cresols also referred to as chloro-
phenols or chlorocresols. The compounds p-chloro-m-cresol,
2,4- and 2,6-dichlorophenols, 2,4,6-trichlorophenol, and penta-
chlorophenol are discussed in separate hazard profiles.
Purified chlorinated phenols are colorless, crystalline
solids (with the exception of 2-chlorophenol which is a liquid),
while the technical grades may be light tan or slightly pink due
to impurities. Chlorophenols have pungent odors. In general,
the volatility of chlorinated phenols decreases and the melting
and boiling points increase as the number of substituted chlorine
atoms increases. Although the solubility of chlorinated phenols
in aqueous solutions is relatively low, it increases markedly
when the pH of the solution exceeds their specific pKa. The solu-
bilities of chlorinated phenols and chlorocresols (with the
exception of 2,4,6-trichloro-m-cresol) range from soluble to very
soluble in relatively non-polar solvents such as benzene and
petroleum ether (U.S. EPA, 1980).
The chlorinated phenols that are most important commercially
are 4-chlbrophenol, 2,4,-dichlorophenol, 2,4,5-trichlorophenol,
2,3,4-tetrachlorophenol, pentachlorophenol, and 4-chloro-o-cresol.
Many of the chlorophenols have no commercial application but are
39-5
-------
produced to some extent as byproducts of the commercially important
compounds. The highly toxic polychlorinated dibenzo-p-dioxins
«
may be formed during the chemical synthesis of some chlorophenols.
During the chlorination of drinking waters and wastewater effluents,
chlorophenols may be inadvertently produced (U.S. EPA, 1980).
Chlorinated phenols are used as intermediates in the synthesis
of dyes, pigments, phenolic resins, pesticides, and herbicides.
Certain chlorophenols are used directly as flea repellants, fungi-
cides, wood preservatives, mold inhibitors, antiseptics, disinfect-
ants, and antigumming agents for gasoline.
Chlorinated phenols undergo photolysis in aqueous solutions
as a result of ultraviolet irradiation; photodegration leads to
the substitution of hydroxyl groups in place of the chlorine atoms
with subsequent polymerization (U.S..EPA, 1980). Microbial degra-
dation of chlorophenols has been reported by numerous investigators
(U.S. EPA, 1980).
3-CHLOROPHENOL and 4-CHLOROPHENOL
II. EXPOSURE
Monochlorophenols have been found in surface waters in the
Netherlands at concentrations of 2 to 20 ug/1 (Piet and DeGrunt,
1975). Ingestion of chlorobenzene can give rise to internal
exposure to 2-, 3-, and 4-chlorophenols, as chlorobenzene is
metabolized to monochlorophenols (Lindsay-Smith, et al. 1972).
No data were found demonstrating the presence of monochlorophenol
in food.
39-6
-------
For 4-chlorophenol the U.S. EPA has estimated the weighted
average bioconcentration factor for the edible portions of all
aquatic organisms consumed by Americans to be 12. This estimate
is base don the octanol/water partition coefficient.
Data were not found in the available literature regarding
inhalation exposure.
III. PHARMACOKINETICS
Systematic studies of the pharmacokinetics of 3- or 4-chloro-
phenol are not available. Dogs excreted 87 percent of administered
4-chlorophenol in the urine as sulfuric and glucuronic conjugates
(Karpow, 1893, as cited in U.S. EPAf 1980).
IV. EFFECTS
A. Carcinogenicity
Information is not adequate to determine whether 3- or
4-chlorophenol posses carcinogenic properties. A 20 percent solu-
tion of 3-chlorophenol promoted papillomas when repeatedly applied
to the backs of mice after initiation with dimethylbenzanthrene
(Boutwell and Bosch, 1959).
B. Mutagenicity, Teratogenicity and Other Reproductive Effects
Pertinent data cannot be located in the available litera-
ture regarding mutagenicity, teratogenicity and other reproductive
effects.
C. Chronic Toxicity
Rats exposed 6 hrs/day for four months to 2 mg 4-chloro-
phenol/n\3 showed a temporary weight loss and increased myoneural
39-7
-------
excitability. Body temperature and hematological parameters were
not altered (Gurova, 1964). Workers exposed to 4-chlorophenol
* ,*
had a significantly higher incidence of neurological disorders
when compared with unexposed workers in the same plant. Peripheral
nerve stimulation studies showed increased myoneural excitability
in exposed workers. The minimum detection distance in a two-point
touch discrimination test was also increased (Gurova, 1964).
D. Other Relevant Information
3- and 4-Chlorophenol are weak uncouplers of oxidative
phosphorylation (U.S. EPA, 1980).
2,5-DICHLOROPHENOL, 3,4-DICHLOROPHENOL,
and 3,5-DICHLOROPHENOL
II. EXPOSURE
Unspecified dichlorophenol (DCP) isomers have been detected
in concentrations of 0.01 to 1.5 ug/1 in Dutch surface waters
(Piet and DeGrunt, 1975). Dichlorophenols have been found in flue
gas condensates from municipal incinerators (Olie, et al., 1977).
No data on exposure from foods or the dermal route were found.
Exposure to other chemicals can result in exposure to dichlorophenols
(i.e., dichlorobenzenes,. lindane, and the alpha and delta isomers
of 1,2,3,4,5,6-hexachlorocyclohexane are metabolized by mammals
to dichlorophenols) (Kohle, et al.f 1976; Foster and Saha, 1978).
III. PHARMACOKINETICS
Pharmacokinetic data specific to these dichlorophenol isomers
39-8
-------
could not be located in the available literature. It is reasonable
to assume that the dichlorophenol isomers are absorbed through
•
the skin and from the gut, and rapidly eliminated as are other
chlorophenols (U.S. EPA, 1980).
IV EFFECTS
A. .Carcinogenicity
Pertinent data cannot be located in the available
literature; 2,4-DCP has been selected for bioassay.
B. Mutagenicity
None of the dichlorophenols were found to be mutagenic
in the Ames test with or without microsomal activation (Rasanen
and Hattula, 1977). Mutagenicity in mammalian test systems has
not been studied (U.S. EPA, 1980).
C. Teratogenicity, Other Reproductive Effects and Chronic
Toxicity
Pertinent data cannot be located in the available litera-
ture regarding teratogenicity, other reproductive effects and
chronic toxicity.
•
D. Other Relevant Information
Phenol, and the lower chlorinated phenols, including
2,6-dichlorophenol are convulsants (Farquharson, et al, 1958);
the latter readily penetrates the bovine lens capsule (Ismail
et al., 1976), and inhibits oxidative phosphorylation in that
tissue (Korte et al., 1976). The significance of these results
is as yet unknown.
39-9
-------
TRICHLOROPHENOLS*
I. EXPOSURE
Trichlorophenols have been detected in surface waters in
Holland at concentrations ranging from 0.003 to 0.1 ug/1 (Piet
and DeGrunt, 1975). 2,4,5-Trichlorophenol can be formed from the
chlorination of phenol in water (Burttschell et al., 1959).
One possible source of trichlorophenol exposure for humans
is through the food chain, as a result of the metabolism by
grazing animals of ingested chlorophenoxy acid herbicides 2,4,5-T
(2,4,5-trichlorophenoxyacetic acid) and Silvex (2-(2,4,5-trichloro-
phenoxy)-propionic acid). Residues of these herbicides on sprayed
forage are estimated to be 100-300 ppm. Studies in which cattle
and sheep were fed these herbicides at 300, 1000, and 2000 ppm
(Clark et al*, 1976) showed the presence of 2,4,5-trichlorophenol
in various tissues. In lactating cows fed 2,4,5-T at 100 ppm, an
occasional residue of 0.06 ppm or less of trichlorophenol was
detected in milk (Bjerke et al., 1972).
Exposure to other chemicals such as trichlorobenzenes, lindane,
the alpha and delta isomers of 1,2,3,4,5,6- hexachlorocyclohexane,
isomers of benzene hexachloride, and the insecticide Ronnel can
result in exposure to trichlorophenols via metabolic degradation
of the parent compound (U.S. EPA, 1980).
*The health and environmental effects of 2,4,6-trichlorophenol
are more extensively discussed in HEBD No. 168.
39-10
-------
The U.S. EPA (1980) has estimated the weighted average
bioconcentration factors for the edible portions of all aquatic
organisms consumed by Americans to be 130 to 2,4,5-trichlorophenol
and 110 for 2,4,6-trichlorophenol. These estimates are based on
the octanol/water partition coefficients for these chemicals.
Trichlorophenols are found in flue gas condensates from
municipal incinerators (Olie et al., 1977).
Most commercial trichlorophenols and their derivatives contain
appreciable amounts of the contaminant 2,3,7,8-tetrachlorodibenzo-
p-dioxin (TCDD) and/or its homologues (U.S. EPA, 1980). The
presence of this highly toxic contaminant caused the U.S. EPA to
publish a Rebuttable Presumption Against Registration (RPAR) and
Continued Registration of Pesticide Products Containing 2,4,5-T
(43 PR 17116). The published RPAR indicated that 2,4,5-trichloro-
phenol is also the subject of a separate potential RPAR.
III. PHARMACOKINETICS
A. Absorption and Distribution
The oral LDsg in the rat has been variously reported as 820
and 2960 mg/kg (U.S. EPA 1980). Information dealing with tissue
distribution after administration of trichlorophenols could not
be located in the available literature. Feeding of 2,4,5-T and
Silvex to sheep and cattle produced high levels of 2,4,5-trichloro-
phenol in liver and kidney and low levels in muscle and fat (Clark
et al., 1976).
39-11
-------
B. Metabolism
.Pertinent data could not be located in the available
*
literature.
C. Excretion
In ratsf 82 percent of an administered dose (1 ppm in
the diet for" 3 days) of 2,4,6-trichlorophenol was eliminated in
the urine and 22 percent in the feces. Radiolabeled feces was
not detected in liver, lung or fat obtained 5 days after the last
dose (Rorte, et al., 1976). The approximate blood half-life for
2,4,5-trichlorophenol is 20 hours, after dosing of sheep with
Erbon (an herbicide which is metabolized to 2,4,5-trichlorophenol)
(Wright et al., 1970).
2,4,5-Trichlorophenol was detected in 1.7 percent of
urine samples collected from the general population (Kutz et al.,
1978).
IV. EFFECTS
A. Carcinogenicity
A 21 percent solution of 2,4,5-trichlorophenol in
acetone promoted papillomas but not carcinomas in mice after
initiation with dimethylbenzanthrene (Boutwell and Bosch, 1959).
2,3,5-, 2,3,6-, 2,4,5-, and 2,4,6-Trichlorophenol were not found
to be mutagenic in the Ames test with and without microsomal
activation (Rasanen and Hattula, 1977). 2,4,6-Trichlorophenol
induces cancer in rats and mice (NCI, 1979).
C. Teratogenicity and Other Reproductive Effects
Pertinent data could, not be located in the available
literature regarding teratogenicity and other reproductive effects.
39-12
-------
D. Chronic Toxicity
When rats were fed 2/4,5-trichlorophenol (99 percent
pure) for 98 days (McCollister et al., 1961), levels of 1000 mg
trichlorophenol/kg feed (assumed to be equivalent to 100 rag/kg body
weight) or less produced no adverse effects as judged by behavior^
mortality, food consumption, growth, terminal hematology, body and
organ weights, and gross or microscopic pathology. At 10,000 mg/kg
diet (1000 mg/kg body weight), growth was slowed in females. Histo-
pathologic changes were noted in liver and kidney. There were no
hematologic changes. At 3000 mg/kg feed (300 mg/kg body weight),
milder histopathologic changes in liver and kidney were observed.
The histopathologic changes were considered to be reversible.
Adverse health effects including chloracne, porphyria cutanea-
tarda with hyperpigmentation, hirsutism and urinary excretion of
porphyrins were described in workers involved in the manufacture of
2,4,5-D and 2,4,5-T (Bleiberg, et al., 1964). It is possible that
some of these symptoms represent 2,3,7,8-tetrachlorodibenzo-p-dioxin
toxicosis (U.S. EPA, 1980).
•
E. Other Relevant Information
Studies on the subcellular effects of trichlorophenols
shows them to be powerful uncouplers of oxidative phosphorylation.
2,4,5-Trichlorophenol readily penetrates the bovine eye lens (Ismael,
1975), and affects the carbohydrate metabolizing system of that
tissue (Korte et al., 1976).
39-13
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TETRACHLOROPHENOL
II. EXPOSURE
There are three isomers of tetrachlorophenol: 2,3,4,5-,
2,3,5,6, and, most importantly, 2,3,4,6-tetrachlorophenol. Commer-
cial pentachlorophenol contains 3 to 10 percent tetrachlorophenol
(Goldstein et al., 1977; Schwetz et al., 1974). Commercial tetra-
chlorophenol contains pentachlorophenol (27 percent) and toxic non-
phenolic impurities such as chlorodibenzofurans and chlorpdioxin
isomers (Schwetz et al., 1974). The presence of tetrachlorophenol
in drinking water has not been documented (U.S. EPA, 1980). Exposure
to other chemicals such as tetrachlorobenzenes can result in exposure
to tetrachlorophenols via degradation of the parent compound (Kohli
et al., 1976).
Data could not be located in the available literature on
ingestion from foods. The U.S. EPA (1980) has estimated a weighted
average bioconcentration factor for 2,3,4,6-tetrachlorophenol of
320 for the edible portion of aquatic organisms consumed by Americans.
This estimate is based on the octanol/water partition coefficient
of 2,3,4,5-tetrachlorophenol.
Tetrachlorophenols have been found in flue gas condensates
from municipal incinerators (Olie et al., 1977).
II. PHARMACOKINETICS
A. Absorption and Distribution
Pertinent data could not be located in the available
literature regarding absorption and distribution.
39-14
-------
B. Metabolism and Excretion
In rats, over 98 percent of an intraperitoneally administere^
%
dose of 2,3,4,6-tetrachlorophenol was recovered in the urine in 24
hours. About 66 percent was excreted as the unchanged compound and
35 percent as tetrachloro-p-hydroquinone. About 94 percent of the
intraperitoneal dose of 2,3,4,6-tetrachlorophenol was recovered in
the urine in 24 hours, primarily as the unchanged compound with
trace amounts of trichloro-p-hydroquinone. Fifty-one percent of
the intraperitoneal dose of 2,3,4,5-tetrachlorophenol was recovered
in the urine in 24 hours, followed by an additional 7 percent in
the second 24 hours, primarily as the unchanged compound with trace
amounts of trichloro-p-hydroquinone. In these experiments, the
urine was boiled to split any conjugates (Alhborg and Larsson, 1978).
Fungi methylate pentachlorophenols to the corresponding anisoles,
(U.S. EPA, 1980). The chronic health effects consequences of
these compounds are not known, and the possibility of methylation
in mammalian liver or intestine has not been documented.
A. Carcinogenicity
Pertinent data could not be located in the available
literature.
B. Mutagenicity
2,3,4,6-Tetrachlorophenol was reported to be nonmutagenic in
the Ames test, both with and without microsomal activation (Rasanen
et al., 1977).
39-15
-------
C. -Teratogenicity
Tetrachlorophenol did not induce teratogenic effects in
*
rats at doses of 10 or 30 mgAg administered on days six through 15
of gestation (Schwetz et al., 1974).
D. Other Reproductive Effects
Tetrachlorophenol produced fetotoxic effects (subcutaneous
edema and delayed ossification of skull bones) in rats at doses of
10 and 30 mg/kg administered on days six through 15 of gestation
(Schwetz, et al., 1974).
E. Chronic Toxicity
Sawmill workers exposed to wood dust containing 100-800
ppm 2,3,4,6-tetrachlorophenol, 30-40 ppm pentachlorophenol, 10-50
ppm chlorophenoxyphenols, 1-10 ppm chlorodibenzofurans and less
than 0.5 ppm chlorodibenzo-p-dioxins developed severe skin irrita-
tions, respiratory difficulties and headaches (Levin et al., 1976).
No toxicity studies of 90 days or longer were found in
the available literature.
F. Other Relevant Information
2,3,4,6-Tetrachlorophenol is a strong uncoupler of
oxidative phosphorylation, and affects mixed function oxidases
(U.S. EPA, 1980).
CHLORINATED PHENOLS
I. AQUATIC TOXICITY
A. Acute Toxicity (U.S. EPA, 1980)
The acute toxicity of eight chlorophenols was determined
39-16
-------
in nine bioassays. Acute 96-hour LC$Q values for freshwater fish
ranged from 30 ug/1 for the fathead minnow, Pimephales promelas,
for 4-chloro-3-methylphenol to 9,040 ug/1 for the fathead minnow
for 2,4,6-trichlorophenol. Among the freshwater invertebrates,
toxicity for Daphnia magna was tested with seven chlorophenols
in eight 48-hour static bioassays. Acute LV^Q values ranged from
290 ug/1 for 2,3,4,6-tetrachlorophenol and 4-chloro-2-methylphenol
to 6,040 ug/1 for 2,4,6-trichlorophenol. Acute 96-hour static 1>C$Q
values in the sheepshead minnow ranged from 1,660 ug/1 for 2,4,5-
trichlorophenol to 5,350 ug/1 for 4-chlorophenol. The only marine
invertebrate species acutely tested has been the mysid shrimp,
Hysidopsis bahia, with acute 96-hour static LCso values reported
as: 3,830 ug/1 for 2,4,5-trichlorophenol; 21,900 ug/1 for 2,3,5,6-
tetrachlorophenol, and 29,700 ug/1 for 4-chlorophenol.
B. Chronic Toxicity (U.S. EPA, 1980)
No data other than that presented in the specific hazard
profile for 2-chlorophenol, 2,4-dichlorophenol, and pentachlorophenol
were available for freshwater organisms. An embryo-larval study
provided a chronic value of 180 ug/1 for sheepshead minnows,
Cyprinodon variegatus, exposed to 2,4-dichloro-6-methylphenol.
C. Effects on Plants (U.S. EPA, 1980)
Effective concentrations for 15 tests on four species of
39-17
-------
freshwater plants ranged from chlorosis LCso of 603 ug/1 for 2,3,4,6-
tetrachlorophenol to 598,584 ug/1 for 2-chloro-6-raethylphenol in
« /
the duckweed, Lemna minor. The marine algae, Skeletonema costaturn,
has been used to assess the relative toxicities of three chlorinated
phenols. Effective concentrations, based on chlorophyll a content
and cell-growth, of 440 and 500 ug/1 were obtained for 2,3,5,6-tetra-
chlorophenol. 2,4,5-Trichlorophenol and 4-chlorophenol were roughly
two and seven times as potent, respectively, as 2,3,5,6-tetrachloro-
phenol.
D. Residues
Steady-state bioconcentration factors have not been
calculated for the chlorinated phenols. However, based upon octanol/
water partition coefficients, the following bioconcentration factors
have been estimated for aquatic organisms with a lipid content of
eight percent: 41 for 4-chlorophenol; 440 for 2,4,5-trichlorophenol;
380 for 2,4,6-trichlorophenol; 1,100 for 2,3,4,6-tetrachlorophenol;
and 470 for 4-chloro-3-methylphenol (U.S. EPA, 1980).
E. Miscellaneous
The tainting of fish flesh by exposure of rainbow trout,
Salmo gairdneri, to various chlorinated phenols has derived a range
of estimated concentrations not impairing the flavor of cooked fish
from 15 ug/1 for 2-chlorophenol to 84 ug/1 for 2,3-dichlorophenol
(U.S. EPA, 1980).
II. EXISTING GUIDELINES AND STANDARDS
Water quality criteria recommended for chlorinated phenols by
the U.S. EPA (1980) are given in the following table:
38-18
-------
Recommended Water Quality Criteria
Compound
Human Health
Criterion from
Organoleptic
Effects
(ug/1)
Criterion from
Toxicological
Data
(ug/1)
Aquatic Life
(ug/1.)
Monochlorophenols
3-chlorophenol 0.1
4-chlorophenol 0.1
Dichlorophenols
2,3-dichlorophenol 0.4
2,4-dichlorophenol 0.3
2,5-dichlorophenol 0.5
2,6-dichlorophenol 0.2
3,4-dichlorophenol 0.3
Trichlorophenols
2,4,5-trichlorophenol 1.0
2,4,6-trichlorophenol 2.0
Tetrachlorophenols
2,3,4,6-tetrachlorophenol 1
2,3,5,6-tetrachlorophenol
none
none
none
3.09
none
none
none
1600
12(c)
none
29,700(b)
970(a)
(a) Chronic toxicity value, freshwater
(b) Acute toxicity value, saltwater
(°) Based on NCI carcinogenesis bioassay
39-19
-------
CHLORINATED PHENOLS
REFERENCES
*
Ahlborg, U.G., and K. Larsson. 1978. Metabolism of tetrachloro-
phenols in the rat. Arch. Toxicol. 40: 63.
Bleiberg, J., et al. 1964. Industrially acquired porphyria.
Arch. Dermatol. 89: 793.
Boutwell, -R.K., and D.K. Bosch. 1959. The tumor-promoting action
of phenol and related compounds for mouse skin. Cancer Res. 19: 413.
Clark, D.E., et al. 1976. Residues of chlorophenoxy acid herbicides
and their phenolic metabolites in tissues of sheep and cattle.
Jour. Agric. Food Chem. 23: 573.
Foster, T.S., and J.G. Saha. 1978. The in vitro metabolism of
lindane by an enzyme preparation from chicken liver. Jour. Environ.
Sci. Health. 13: 25.
Goldstein, J.A., et al. 1977. Effects of pentachlorophenol on
hepatic drug-metabolizing enzymes and porphyria related to contamina-
tion with chlorinated dibenzo-p-dioxins and dibenzofurans. Biochem.
Pharmacol. 26: 1549.
Gurova, A.I. 1964. Hygienic characteristics of p-chlorophenol in
the aniline dye industry. Hyg. Sanita. 29: 46.
Ismail, R., et al. 1975. Permeability of the isolated bovine lens
capsule for environmental chemicals. Exp. Eye Res. 20: 179.
Karpow, G. 1893. On the antiseptic action of three isomer chloro-
phenols and of their salicylate esters and their fate in the
metabolism. Arch. Sci. Bid. St. Petersburg. 2: 304. Cited by
W.F. von Oettingen, 1949.
Kohli, J., et al. 1976. The metabolism of higher chlorinated
benzene isomers. Can Jour. Biochem. 54: 203.
Korte, I., et al. 1976. Studies on the influences of some environ-
mental chemicals and their metabolites on the content of free
adenine nucleotides, intermediates of glycolysis and on the activities
of certain enzymes of bovine lenses in vitro. Chemosphere. 5: 131.
Kutz, F.W., et al. 1978. Survey of pesticide residues and their
metabolites in urine from the general population. Pages 363-369 In;
K. Rango Rao, ed. Pentachlorophenol: Chemistry, pharmacology and
environmental toxicology, Plenum Press, New York.
39-20
-------
CHLORINATED PHENOLS
REFERENCES (Continued)
Levin, J.O., et al. 1976. Use of chlorophenols as fungicides in
sawmills. Scan. Jour. Work Environ. Health. 2: 7l.
Lindsay-Smith, Jr., et al. 1972. Mechanisms of mammalian hydroxyla-
tion: Some novel metabolites of chlorobenzenes. Xenobiotica 2: 215.
McCollis'ter, D.D., et al. 1961. Toxicolpgic information on 2,4,5-
trichlorophenol. Toxicol. Appl. Pharmacol. 3: 63.
National Cancer Institute. 1979. Bioassay of 2,4,6-trichlorophenol
for possible carcinogencity NCI-CG-TR-155.
Olie, K., et al. 1977. Chlorodibenzo-p-dioxins and chlorodibenzo-
flurans are trace components of fly ash and flue gas of some
municipal incinerators in the Netherlands. Chemosphere. 8:445.
Piet, G.J., and F. DeGrunt. 1975. Organic chloro compounds in
surface and drinking water of the Netherlands. Pages 81-92 In;
Problems raised by the contamination of man and his environment.
Comm. Eur. Communities, Luxembourg.
Rasanen, L., and M.L. Hattula. 1977. The mutagenicity of MCPA
and its soil metabolites, chlorinated phenols, catechols and some
widely used slimicides in Finland. Bull. Environ. Contam. Toxicol.
18:565.
Schwetz, B.A., et al. 1974-. Effect of purified and commercial
grade tetrachlorophenol on rat embryonal and fetal development.
Toxicol. Appl. Pharmacol. 28: 146.
U.S. EPA. 1980. Chlorinated Phenols: Ambient Water Quality
Criteria. EPA 440/5-80-032.
Wright, F.C., et al. 1970. Metabolic and residue studies with 2-
(2,4,5-trichlorophenoxy)-ethyl 2,2-dichloropropionate. Jour. Agric.
Food Chem. 18: 845,
39-21
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No. 40
Chloroacetaldehyde
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
~_L7
-/
-------
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.
-------
CHLOROACETALDEHYDE
Summary
No carcinogenic effects were observed in female ICR Ha Swiss mice follow-
ing administration of chloroacetaldehyde via dermal application or subcutaneous
injection. Mutagenic effects, varying from weak to strong, have been reported
in the yeasts Schizosaccharomyces pombe and Saccharomyces cerivisiae and in
certain Salmonella bacterial tester strains. There is no evidence in the
available literature to indicate that chloroacetaldehyde produces teratogenic
«.
effects. Occupational exposure studies have shown chloroacetaldehyde to be a
severe irritant of the eyes, mucous membranes and skin.
Data concerning the effects of chloroacetaldehyde on aquatic organisms
were not found in the available literature.
1)0-3
-------
CHLOROACETALDEHYDE
I. INTRODUCTION
Chloroacetaldehyde (C,H,C10) is a clear, colorless liquid with a pungent
^ O
odor. Its physical properties include: boiling point, 90.0-100.1°C (40 per-
cent sol.); freezing point, -16.3°C (40 percent sol.); and vapor pressure, 100
mm at 45°C (40 percent sol.). Synonyms for Chloroacetaldehyde are:
monochloroacetaldehyde, 2-chloroacetaldehyde and chloroaldehyde. It is soluable
in water, acetone and methanol. Primary uses of Chloroacetaldehyde include:
».
use as a fungicide, use in the manufacture of 2-aminothiazole, and use in the
removal of bark from tree trunks.
II. EXPOSURE
No monitoring data are available to indicate ambient air or water levels
of Chloroacetaldehyde, nor is any information available on possible exposure
from food.
Occupational routes of human exposure to Chloroacetaldehyde are primarily
through inhalation and skin absorption.
Bioaccumulation data on Chloroacetaldehyde were not found in the available
literature. However, 2-chloroacetaldehyde is known to be a chemically reactive
compound and its half-life in aqueous solution has been reported as slightly
greater than 24 hours (Van Duuren et al., 1972).
III. PHARMACOKINETICS
A. Absorption
Exposure to Chloroacetaldehyde is primarily through inhalation and
skin absorption.
Chloroacetaldehyde proved to be very lethal by inhalation. In an inhalation
study conducted by Lawrence et al. (1972), mice were placed in a chloroacetaldehyde-
free chamber and air containing Chloroacetaldehyde vapor was then passed
-------
through the chamber. The time of exposure required to kill 50% of the animals,
LTcQ, was 2.57 min. (the chamber atmosphere was calculated to have reached 45%
equilibrium within that time.)
In comparison studies conducted on chloroacetaldehyde and 2-chloroethanol,
chloroacetaldehyde was reported as exhibiting greater irritant activity, but
having lesser penetrant capacity (Lawrence et al., 1972).
B. Distribution
Information on the distribution of chloroacetaldehyde was not found
*.
in the available literature.
C. Metabolism
Chloroacetaldehyde appears to be a metabolite of a number of compounds
including 1,2-dichloroethane, chloroethanol and vinyl chloride (McCann et al.,
1975).
Johnson (1967) conducted in vitro studies on rat livers, the results of
which indicated that S-carboxymethylglutathione was probably formed via
chloroacetaldehyde metabolic action. Based upon these studies, Johnson suggested
that the same metabolic mechanism was operative in the j_n vivo conversion of
chloroethanol to S-carboxymethylglutathione.
In recent studies, Watanabe et al. (1976a,b) reported that chloro-
acetaldehyde would conjugate with glutathione and cysteine leading ultimately
to the types of urinary metabolites found in animals exposed to vinyl chloride.
The authors reported that as nonprotein free sulfhydral concentrations are
depleted, the alkylating metabolites, one of which is chloroacetaldehyde, are
likely to react with protein, ONA and RNA, eliciting proportionally greater
toxicity. This is in agreement with other studies conducted on vinyl chjoride
metabolism (Hefner et al., 1975; Bolt et al., 1977).
/_ —
-------
Chloroacetaldehyde was shown to cause the destruction of lung hemoprotein,
cytochrome P450, as well as liver microsomal cytochrome P450, with no requirement
for NAOPH (Harper and Patel, 1978). The results suggested that the aldehydes
tested, one of which was Chloroacetaldehyde, were the toxic intermediates
which inactivated pulmonary enzymes following exposure to some environmental
agents.
D. Excretion
Information specifically on the rates and routes of Chloroacetaldehyde
\
elimination was not found in the available literature. Studies on vinyl
chloride and ethylene dichloride, however, indicate that Chloroacetaldehyde,
as an intermediate metabolite, may ultimately convert to a number of urinary
metabolites—including chloroacetic acid, S-carboxymethylcysteine and thiodiacetic
acid—depending on the particular metabolic pathway involved in the biotransforma-
tion of the parent compound (Johnson, 1967; Yllner, 1971; Watanabe, 1976a,b).
IV. EFFECTS
A. Carcinogenicity
In a study on the carcinogenic activity of alkylating agents, Van
Duuren et al. (1974) exposed female ICR Ha Swiss mice to 2-chloroacetaldehyde
(assayed as diethylacetal). The routes of administration were via skin and
subcutaneous injection. The authors reported no significant tumor induction.
Later studies confirmed these findings (Goldschmidt, personal communication,
1977). However, in a report by McCann et al. (1975), the authors stated that
previous reports of changes of respiratory epithelium in lungs of rats exposed
to Chloroacetaldehyde were suggestive of premalignant conditions.
B. Mutagenicity
Many studies have been reported which show that Chloroacetaldehyde
exhibits varying degrees of mutagenic activity (Huberman et al., 1975; Border
-------
and Webster, 1976; Elmore et al., 1976; Rosenkranz, 1977). Lopn'eno et al.
(1977) reported that 2-chloroacetaldehyde showed only feeble genetic activity
when tested in the yeasts Schizosaccharomyces pombe and Saccharomyces cerevisiae.
However, McCann et al. (1975) reported that chloroacetaldehyde was quite
effective in reverting Salmonella bacterial tester strain TA 100, but did not
revert TA 1535. In a later study, Rosenkranz (1977) found that
2-chloroacetaldehyde did display some mutagenic activity towards TA 1535.
In a study conducted by Elmore et al. (1976) the authors reported that
•<.
the chloroacetaldehyde monomer and monomer hydrate were more mutagem'cally
active that the dimer hydrate and the trimer.
Rannug et al. (1976) reported that the mutagenic effectiveness of
4
chloroacetaldehyde is about 10 times higher than expected from kinetic data.
C. Teratogenicity and Other Reproductive Effects
Pertinent information could not be found in the available literature.
0. Chronic Toxicity
No chronic information could be found in the available literature.
However, extensive toxicity studies conducted by Lawrence et al. (1972) revealed
some subacute effects of chloroacetaldehyde on Sprague-Oawley and Black Bethesda
rats. Groups of rats received .001879 and .003758 ml/kg of chloroacetaldehyde
(representing 0.3 and 0.6 of the acute LD50 dose, respectively) daily for 30
consecutive days. Hematologic tests at the end of 30 days showed that there
was a significant decrease in hemoglobin, hematocrit, and erthrocytes in the
high dose group; the low dose group showed an increase in monocytes accompanied
by a decrease in lymphocytes. The animals were sacrificed and organ-to-body
weight ratios were calculated. Ratios for both brain and lungs were significantly
•
greater in the low dose group, while the high dose group showed a significant
increase in the brain, gonads, heart, kidneys, liver, lungs and spleen.
-------
Histological examination did not reveal any abnormalities attributable to
chloroacetaldehyde except for the lungs which showed more severe bronchitis,
bronchiolitis and bronchopneumonia than were seen in controls.
In another subacute (subchronic) study, chloroacetaldehyde was administered
to rats in doses of .00032, .00080, .00160 and .00320 ml/kg, three times a
week for 12 weeks. Hematologic determinations showed no significant differences
between controls and the two lower dose groups, while animals administered
.0016 ml/kg showed a decrease in red cell count and lymphocytes and an increase
in segmented neutrophiles; the highest dose group showed a significant decrease
in red blood cells and hemoglobin with an increase in clotting time and segmented
neutrophiles. Organ-to-body weight ratios were determined for several organs
and, although there were some significant differences from controls, there
were no apparent dose-related responses.
D. Acute Toxicity
Lawrence et al. (1972) conducted a series of acute toxicity tests on
ICR mice, Sprague-Oawley and Black Bethesda rats, New Zealand albino rabbits
and Hartlez strain guinea pigs. The results were reported as follows: the
LD5Qs (ml/kg) for chloroacetaldehyde administered intraperitoneally ranged
from .00598 in mice to .00464 in rabbits; the LD50s (ml/kg) for chloroacetaldehyde
administered intragastrically were reported as .06918 in male mice, .07507 in
female rats and .08665 in male rats; the dermal LD50 (ml/kg) in rabbits was
reported as .2243; and the inhalation LT5Q in mice was reported as 2.57 min.
E. Other Relevent Information
Case studies show that contact with a strong solution of chloroacetaldehyde
in the human eye will likely result in permanent impairment of vision and skin
contact with a potent solution will result in burns (Proctor and Hughes,
1978).
-------
V. AQUATIC TOXICITY
Data concerning the effects of chloroacetaldehyde on aquatic organisms
were not found in the available literature.
VI. EXISTING GUIDELINES
The 8-hour, TWA occupational exposure limit established for chloroacetaldehyde
is 1 ppm. This TLV of 1 ppm was set to prevent irritation (ACGIH, 1976).
-------
CHLOROACETALDEHYDE
References
1. American Industrial Hygiene Association. 1976. Threshold limit values
for substances in workroom air. 3rd ed. p. 48. Cincinnati. Cited in
Proctor and Hughes, 1978.
2. Bolt, H. M. et al. 1977. Pharmacokinetics of vinyl chloride in the rat.
Toxicology. 2:179.
3. Border, E. A., and I. Webster. 1977. The effect of vinyl chloride
monomer, chloroethylene oxide and chloroacetaldehyde on DNA synthesis in
regenerating rat liver. Chem. Biol. Interact.•• 17:239.
4. Elmore, J. 0. et al. 1976. Vinyl chloride mutagenicity via the metabolites
chlorooxirane and chloroacetaldehyde monomer hydrate. Biochim. Biophys.
Acta. 442:405.
5. Harper, C., and J. M. Patel. 1978. Inactivation of pulmonary cytochrome
P 450 by aldehydes. Fed. Proc. 37:767.
6. Hefner, R. E., Jr. et al. 1975. Preliminary studies of the fate of inhaled
vinyl chloride monomer in rats. Ann. N.Y. Acad. Sci. 246:135.
7. Huberman, E. et al. 1975. Mutation induction in Chinese hamster V79
cells by two vinyl chloride metabolites, chloroethylene oxide and
2-chloroacetaldehyde. Int. J. Cancer. 16:639.
8. Johnson, M. K. 1967. Metabolism of chloroethanol in the rat. Biochem.
Pharmacol. 16:185.
9. Lawrence W. H. et al. 1972. Toxicity profile of chloroacetaldehyde. J.
Pharm. Sci. 61:19.
i
10. Loprieno, N. et al. 1977. Induction of gene mutations and gene conversions
by vinyl chloride metabolites in yeast. Cancer Res. 36:253.
11. McCann, J. et al. 1975. Mutagenicity of chloroacetaldehyde, a possible
metabolic product of 1,2-dichloroethane (ethylene dichloride), chloroethanol
(ethylene chlorohydrin), vinyl chloride, and cyclophosphamide. Proc.
Nat. Acad. Sci. 72:3190.
12. Proctor, N. H., and J. P. Hughes. 1978. Chemical hazards of the workplace.
p. 160. Lippincott Co., Philadelphia.
13. Rannug, U. et al. 1976. Mutagenicity of chloroethylene oxide,
chloroacetaldehyde, 2-chloroethanol and chloroacetic acid, conceivable
metabolites of vinyl chloride. Chem. Biol. Interact. 12:251.
14. Rosenkranz, H. S. 1977. Mutagenicity of halogenated alkanes and their
derivatives. Environ. Health Perspect. 21:79.
-------
15. Van Duuren, B. L. et al. 1972. Carcinogenicity of halo-ethers. II.
Structure-activity relationships of analogs of bis-(chloromethyl) ether.
J. Nat. Cancer Inst. 48:1431.
16. Van Duuren, B. L. et al. 1974. Carcinogenic activity of alkylating
agents. J. Nat. Cancer Inst. 53:695
14
17. Watanabe, P. G. et al. 1976a. Fate of C vinyl chloride after single
oral administration in rats. Toxicol. Appl. Pharmacol. 36:339.
Watanabe, P. G. et al. 1976b. Fate of 14C vinyl chloride folli
inhalation exposure in rats. Toxicol. App. Pharmacol. 37:49.
Yllner, S. 1970. Metaboli:
Pharmacol. Toxicol. 30:69.
Yllner, S. 1971. Metaboli:
Pharmacol. Toxicol. 30:257.
18. Watanabe, P. G. et al. 1976b. Fate of C vinyl chloride following
icol
14
19. Yllner, S. 1970. Metabolism of chloroacetate -1- C in the mouse. Acta
14
20. Yllner, S. 1971. Metabolism of 1,2-dichloroethane- C in the mouse. Acta
it
-------
No. 41
Chloroalkyl Ethers
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 (CAG) has evaluated
chloroalkyl ethers and has found sufficient evidence to
indicate that this compound is carcinogenic.
-------
CHLOROALKYL ETHERS
SUMMARY
Bis(chlororaethyl)ether (BCME), chloromethyl methyl ether
(CMME), and bis(2-chloroethyl)ether (BCEE) have shown carcin-
ogenic effects in animal studies following administration by
various routes. Epidemiological studies in the United States/
Germany/ and Japan have indicated that workers exposed to
BCME and CMME developed an increased incidence of respiratory
tract tumors.
Testing of BCME, CMME, BCEE, and bis(2-chloroisopropyl)-
ether (BCIE-) in the Ames Salmonella assay and in Jj. coli have
indicated that these compounds have mutagenic activity. Cy-
togenetic studies of lymphocytes from workers exposed to BCME
and CMME have reported an increased frequency of aberrations,
which appear to be reversible.
There is no available evidence to indicate chloroalkyl
ethers produce adverse reproductive or teratogenic effects.
The information base for freshwater organisms and chloro-
alkyl ethers is limited to a few toxicity tests of 2-chloro-
ethyl vinyl ether and bis(2-chloroethyl)ether. The reported
96-hour LC50 value for bis(2-chloroethyl)ether in the.
bluegill is greater than 600,000 ug/1. A "no effect" value
of 19,000 ug/1 was observed using the fathead minnow in an
embryo-larval test. Bis(2-chloroethyl)ether has a reported
bioconcentration factor of 11 in a 14-day exposure to blue-
gills. The half-life is from four to seven days. The re-*
ported 96-hour LC50 value for the bluegill and 2-chloro-
ethyl vinyl ether is 194,000 ug/1.
-------
CHLOROALKYL ETHERS
I. INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria Document for chloroalkyl ethers (U.S. EPA, 1979).
The chloroalkyl ethers are compounds with a hydrogen
atom in one or both of the aliphatic ether chains substituted
by a chlorine atom. The chemical reactivity of these com-
pounds varies greatly, depending on the nature of the ali-
phatic groups and the placement of the chlorine atoms. The
most reactive compounds are those with short aliphatic groups
and those in which chlorine substitution is closest to the
ether oxygen (alpha-chloro) (U.S. EPA, 1979).
As an indication of their high reactivity, chloromethyl
methyl ether (CMME), bis(chloromethyl)ether (BCME) , 1-chloro-
ethyl ethyl ester, and 1-chloroethyl methyl ether decompose
rapidly in water. The beta-chloroethers, bis(2-chloroethyl)-
ether (BCEE) and bis(2-chloroisopropyl)ether (BCIE) are more
stable in aqueous systems; they are practically insoluble in
water but miscible with most organic solvents (U.S. EPA,
1979).
The chloroalkyl ethers have a wide variety of industrial
and laboratory uses in organic synthesis, textile treatment,
the manufacture of polymers and insecticides, in the prepara-
tion of ion exchange resins, and as degreasing agents (U.S.
EPA, 1979) .
While the short chain alpha-chloroalkyl ethers (BCME,.
CMME) are very unstable in aqueous systems, they appear to be
relatively stable in the atmosphere (Tou and Kallos, 1974).
Bis(chloromethyl)ether will form spontaneously in the pres-
-------
ence of both hydrogen chloride and formaldehyde (Frankel, et
al. 1974).
II. EXPOSURE
The beta-chloroalkyl ethers have been monitored in
water. Industrial effluents from chemical plants involved in
the manufacture of glycol products, rubber, and insecticides
may contain high levels of these ethers (U.S. EPA, 1979).
The highest concentrations in drinking water of bis(2-chloro-
ethyl)ether, bis(2-chloroisopropyl)ether, and bis-l,2-(2-
chloroethoxy)ethane (BCEXE) reported by the U.S. EPA (1975)
are 0.5, 1.58, and 0.03 ug/lr respectively. The average con-
centration of these compounds in drinking water is in the
nanograra range (U.S. EPA, 1979). Chloroalkyl ethers have
been detected in the atmosphere, and human inhalation expo-
sure appears to be limited to occupational settings.
The Chloroalkyl ethers have not been monitored in food
(U.S. EPA, 1979). The betachloroalkyl ethers, because of
their relative stability and low water solubility, may have a
tendency to be bioaccumulated. The U.S. EPA (1979) has esti-
mated the weighted bioconcentration factor to be 25 for' the
edible portions of fish and shellfish consumed by Americans.
This is based on the measured steady-state bioconcentration
studies in bluegills. Bioconcentration factors for BCME (31)
and BCIE (106) have been derived using a proportionality con-
stant related to octanol/water partition coefficients (U.S.
EPA, 1979). Dermal exposure for the Chloroalkyl ethers has
not been determined (U.S. EPA, 1979).
-------
III. PHARMACOKINETICS
A. Absorption
Experiments with radio-labelled BCIE and BCEE in
female rats and monkeys have indicated that both compounds
are readily absorbed in the blood following oral administra-
tion (Smith, et al., 1977; Lingg, et al., 1978). Pertinent
data could not be located in the available literature re-
trieved on dermal or inhalation absorption of the alkyl
ethers.
B. Distribution
Species differences in the distribution of radio-
labelled BCIE have been reported by Smith, et al. (1977).
Monkeys, as compared to rats, retain higher amounts of radio-
activity in the liver, muscle, and brain. Urine and expired
air from the rat contained higher levels of radioactivity
than those found in the monkey. Blood levels of BCIE in mon-
keys reached a peak within two hours following oral adminis-
tration and then declined in a biphasic manner (t]y2's
= 5 hours and 2 days for the first and second phases, respec-
tively).
C. Metabolism
The biotransformation of BCEE in rats following
oral administration appears to involve cleavage of the ether
linkage and subsequent conjugation (Lingg, et al., 1978).
Thiodiglycolic acid and chloroethanol-D-glucuronide were
identified as urinary metabolites of BCEE. Metabolites of*
BCIE identified in the rat included l-chloro-2-propanol, pro-
pylene oxide, 2-(l-methyl-2-chloroethoxy)-propionic acid, and
carbon dioxide (Smith, et al., 1977).
-------
D. Excretion
BCEE administered orally to rats was excreted
rapidly, with more than 60 percent of the compound excreted
within 24 hours. Virtually all of this elimination was via
the urine (Lingg, et al., 1978).
IV. EFFECTS
-'X
A. Carcinogenicity
There are several studies with bis(chloromethyl)-
ether (BCME), chloromethyl methyl ether (CMME), and bis(2-
chloroethyl)ether (BCEE) that show carcinogenic effects.
BCME induced malignant tumors of the male rat respiratory
tract following inhalation exposure (Kuschner, et al.,
1975). Application of BCME and BCEXE to the skin of mice
produced skin tumors (Van Duuren, et al., 1968), while subcu-
taneous injection of BCME to newborn mice induced pulmonary
tumors (Gargus, et al., 1969).
Oral administration of bis(2-chloroethyl)ether (BCEE) to
mice has been shown to increase the incidence of hepatocellu-
lar carcinomas in males (Innes, et al., 1969).
Epidemiological studies of workers in the United States,
Germany, and Japan who were occupationally exposed to BCME
and CMME have indicated these compounds are human respiratory
carcinogens (U.S. EPA, 1979).
Both BCME and CMME have been shown to accelerate the
rate of lung tumor formation in Strain & mice following inha-
lation exposure (Leong, et al., 1971). BCME and BCEE have'
shown tumor initiating activity for mouse skin, while CMME
showed only weak initiating activity (U.S. EPA, 1979).
-------
Preliminary results of a National Cancer Institute
study indicate that oral administration of BCIE does not pro-
duce an increase in tumor incidence (U.S. EPA, 1979).
B. Mutagenicity
Testing of the chloroalkyl ethers in the Ames Sal-
monella assay on jE. coli have indicated that BCME, CMME,
BCIE, and BCEE all produced mutagenic effects (U.S. EPA,
1979). BCEE has also been reported to induce mutations in
Saccharomyces cerevisiae (U.S. EPA, 1979). Neither BCEE nor
BCIE showed mutagenic effects in the heritable translocation
test in mice (Jorganson, et al. 1977). An increase in cyto-
genetic aberrations in the lymphocytes of workers exposed to
BCME and CMME was reported by Zudova and Landa (1977); the
frequency of aberrations decreased following the removal of
workers from exposure.
C. Teratogenicity and Other Reproductive Effects
Pertinent data could not be located in the avail-
able literature.
D. Chronic Toxicity
Chronic occupational exposure to CMME contaminated
with BCME has produced bronchitis in workers (U.S. EPA,
1979). Cigarette smoking has been found to act synergisti-
cally with CMME exposure to produce bronchitis (Weiss, 1976,
1977).
Animal studies have indicated that chronic exposure
to BCIE produces liver necrosis in mice. Exposure in rats'
causes major effects on the lungs, including congestion and
pneumonia (U.S. EPA, 1979).
-------
E. Other Relevant Information
The initiating activity of several chloroalkyl
ethers indicates that these compounds may interact with other
agents to produce skin papillomas (Van Duuren, et al., 1969,
1972).
V. AQUATIC TOXICITY
A. Acute Toxicity
The reported static 96-hour LC5Q value for the
bluegill (Lepomis macrochirus) with 2-chloroethyl vinyl ether
(concentration unmeasured) is 194,000 ug/1 (U.S. EPA, 1978).
The 96-hour LC50 values for the bluegill could not be de-
termined in a static test for bis(2-chloroethyl)ether with
exposure concentrations as high as 600,000 ug/1. The concen-
tration of the ether was not monitored during the bioassay.
Pertinent data could not be located in the available litera-
ture on saltwater species.
B. Chronic Toxicity
An embryo-larval test was conducted with bis(2-
chloroethyl)ether and the fathead minnow, (Pimephales prome-
las) . Adverse effects were not obs'erved at test concentra-
tions as high as 19,000 ug/1.
C. Plant Effects
Pertinent data could not be located in the avail-
able literature.
D. Residues
Using bis(2-chloroethyl)ether, a bioconcentratioh
factor of 11 was determined during a 14-day exposure of blue-
gills (U.S. EPA, 1979). The half-life was observed to be
between four and seven days.
-------
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 may be changed.
A. Human
Based on animal carcinogenesis bioassays, and using
a linear, nonthreshold model, the U.S. EPA (1979) has esti-
mated the following ambient water levels of chlorpalkyl
ethers which will produce an increased cancer risk of
10~5: BCIE, 11.5ug/l; BCEE, 0.42 ug/1; and BCME 0.02
ng/1.
Eight-hour TWA exposure values (TLV) for the fol-
lowing chloroalkyl ethers have been recommended by the Ameri-
can Conference of Governmental and Industrial Hygienists
(ACGIH, 1978): BCME, 1 ppb; BCEE, 5 ppm.
B. Aquatic
Freshwater and saltwater drafted criteria have not
been derived for any chloroalkyl ethers because of insuffi-
i
cient data (U.S. EPA, 1979).
-------
CHLOROALKYL ETHERS
REFERENCES
American Conference of Governmental Industrial Hygienists.
1978. Threshold limit values for chemical substances and
physical agents in the workroom environment with intended
changes for 1978. Cincinnati, Ohio.
Frankel, L.S., et al. 1974. Formation of bis (chloromethyl)
ether from formaldehyde and hydrogen chloride. Environ. Sci.
Technol. 8: 356.
Gargus, J.L., et al. 1969. Induction of lung adenomas in
newborn mice by bis(chloromethyl) ether. Toxicol. Appl.
Pharmacol. 15: 92.
Iones, J.R.M., et al. 1969. Bioassay of pesticides and in-
dustrial chemicals for tumorigenicity in mice: A preliminary
note. Jour. Natl. Cancer Inst. 42: 1101.
Jorgenson, T.A., et al. 1977. Study of the mutagenic poten-
tial of bis(2-chloroethyl) and bis (2-chloroisopropyl) ethers
in mice, by the heritable translocation test. Toxicol. Appl.
Pharmacol. 41: 196.
Kuschner, M., et al. 1975. Inhalation carcinogenicity of
alpha halo esthers. III. Lifetime and limited period inhala-
tion studies with bis(chloromethyl)ether at 0.1 ppm. Arch
Environ. Health 30: 73.
Leong, B.K.J., et al. 1971. Induction of lung adenomas by
chronic inhalation of bis(chloromethyl)ether. Arch. Environ.
Health 22: 663.
Lingg, R.D., et al. 1978. Fate of bis(2-chloroethyl)ether
in rats after acute oral administration. Toxicol. Appl.
Pharmacol. 45: 248.
Smith, C.C., et al. 1977. Comparative metabolism of halo-
ethers. Ann. N.Y. Acad. Sci. 298: 111.
Tou, J.C., and G.J. Kallos. 1974. Kinetic study of the sta-
bilities of chloromethyl methyl ether and bis(chloromethyl)-
ether in humid air. Anal. Chem. 46: 1866.
U.S. EPA. 1975. Preliminary assessment of suspected carcin-
ogens in drinking water. Rep. Cong. U.S. Environ. Prot.
Agency, Washington, D.C.
»
U.S. EPA. 1978.. In-depth studies on health and environmen-
tal impacts of selected water pollutants. U.S. Environ.
Prot. Agency, Contract No. 68-01-4646.
-------
U.S. EPA. 1979. Chloroalkyl Ethers: Ambient Water Quality
Criteria. (Draft).
Van Duuren, B.L., et al. 1968. Alpha-haloethers: A new type
of alkylating carcinogen. Arch. Environ. Health 16: 472.
Van Duuren, B.L., et al. 1969. Carcinogenicity of halo-
ethers. Jour. Natl. Cancer Inst. 43: 481.
Van Duuren> B.L., et al. 1972. Carcinogenicity of halo-
ethers. II. Structure-activity relationships of analogs of
bis(chloromethyl)ether. Jour. Natl. Cancer Inst. 48: 1431.
Weiss, W. 1976. Chloromethyl ethers, cigarettes,, cough and
cancer. Jour. Occup. Med. 18: 194.
Weiss, W. 1977. The forced end-expiratory flow rate in
chloromethyl ether workers. Jour. Occup. Med. 19: 611.
Zudova, Z., and K. Landa. 1977. Genetic risk of occupation-
al exposures to haloethers. Mutat. Res. 46: 242.
Sf
-------
No. 42
Chlorobenzene
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.
-------
CHLOROBENZENE
Summary
There is little data on the quantities of chlorobenzene in air, water
and food, although this compound has been identified in these media. Chron-
ic exposure to chlorobenzene appears to cause a variety of pathologies under
different experimental regimens; however, the liver and kidney appear to be
affected in a number of species. There have been no studies conducted to
evaluate the mutagenic, teratogenic, or carcinogenic potential of chloro-
benzene.
Four species of freshwater fish have 96-hour LC-n values ranging from
24,000 to 51,620 jug/1. Hardness does not significantly affect the values.
In saltwater, a fish and shrimp had reported 96-hour LC-Q values of 10,500
;jg/l and 6,400 pg/1, respectively. No chronic data involving chlorobenzene
are available. Algae, both fresh and saltwater, are considerably less sen-
sitive to chlorobenzene toxicity than fish and invertebrates.
-------
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Chlorinated Benzenes (U.S. EPA, 1979).
Chlorobenzene, most often referred to as monochlorobenzene (MCB;
CgH5Cl; molecular weight 112.56), is a colorless liquid with a pleasant
aroma. Monochlorobenzene has a melting point of -45.6°c, a boiling point
of 131-132°C, a water solubility of 488 mg/1 at 25°C, and a density of
1.107 g/ml. Monochlorobenzene has been used as a synthetic Intermediate in
the production of phenol, DDT, and aniline. It is also used as a solvent in
the manufacture of adhesives, paints, polishes, waxes, diisocyanates,
Pharmaceuticals and natural rubber (U.S. EPA, 1979).
Data on current production derived from U.S. International Trade Com-
mission reports show that between 1969 and 1975, the U.S. annual production
of monochlorobenzene decreased by 50 percent, from approximately 600 million
pounds to approximately 300 million pounds (U.S. EPA, 1977).
II. EXPOSURE
A. Water
Based on the vapor pressure, water solubility, and molecular weight
of Chlorobenzene, Mackay and Leinonen (1975) estimated the half-life of
evaporation from water to be 5.8 hours. Monochlorobenzene has been detected
in ground water, "uncontaminated" upland water, and in waters contaminated
either by industrial, municipal or agricultural waste. The concentrations
ranged from 0.1 to 27 jug/1, with raw waters having the lowest concentration
and municipal waste the highest (U.S. EPA, 1975, 1977). These estimates
should be considered as gross estimates of exposure, due to the volatile
nature of monochlorobenzene.
-------
B. Food
The U.S. EPA (1979) has estimated the weighted average bioconcen-
tration factor of monochlorobenzene to be 13 for the edible portions of fish
and shellfish consumed by Americans. This estimate was based on octanol/-
water partition coefficients.
C. Inhalation
Data have not been found in the available literature which deal
with exposure to chlorobenzene outside of the industrial working environment.
III. PHARMACOKINETICS
A. Absorption
There is little question, based on human effects and mammalian
toxicity studies, that chlorobenzene is absorbed through the lungs and from
the gastrointestinal tract (U.S. EPA, 1977).
B. Distribution
Because chlorobenzene is highly lipophilic and hydrophobic, it
would be expected that it would be distributed throughout total body water
space, with body lipid providing a deposition site (U.S. EPA, 1979).
C. Metabolism
Chlorobenzene is metabolised via an NADPH-cytochrome P-448 depen-
i
dent microsomal enzyme system. The first product, and rate limiting step,
is a epoxidation; this is followed by formation of diphenolic and monophe-
nolic compounds (U.S. EPA, 1979). Various conjugates of these phenolic
derivatives are the primary excretory products (Lu, et al. 1974). Evidence
indicates that the metabolism of monochlorobenzene results in the formation
of toxic intermediates (Kohli, et al. 1976). Brodie, et al. (1971) induced
microsomal enzymes with phenobarbital and showed a potentiationin in 'the
toxicity of monochlorobenzene. However, the use of 3-methylcho-
-------
lanthrene to induce microsomal enzymes provided protection for rats (Oesch,
et al. 1973). The metabolism of chlorobenzene may also lead to the forma-
tion of carcinogenic active intermediates (Kohli, et al. 1976).
D. Excretion
The predominant route of elimination is through the formation of
conjugates of the metabolites of monochlorobenzene and elimination of these
conjugates by the urine (U.S. EPA, 1979). The types of conjugates formed
vary with species (Williams, et al. 1975). In the rabbit, 27 percent of an
administered dose appeared unchanged in the expired air (Williams, 1959).
IV. EFFECTS
Pertinent data could not be located in the available literature on the
carcinogenicity, mutagenicity, teratogenicity, or other reproductive effects
of chlorobenzene.
A. Chronic Toxicity
Data on the chronic toxicity of chlorobenzene is sparse and some-
what contradictory. "Histopathological changes" have been noted in lungs,
liver and kidneys following inhalation of monochlorobenzene (200, 475, and
1,000 ppm) in rats, rabbits and guinea pigs (Irish, 1963). Oral administra-
tion of doses of 12.5, 50 and 250 mg/kg/day to rats produced little patholo-
gical change, except for growth retardation in males (Knapp, et al. 1971).
B. Other Relevant Information
Chlorobenzene appears to increase the activity of microsomal NADPH-
cytochrome P-A50 dependent enzyme systems. Induction of microsomal enzyme
activity has been shown to enhance the metabolism of a wide variety of
drugs, pesticides and other xenobiotics (U.S. EPA, 1979).
-------
V. AQUATIC TOXICITY
A. Acute Toxicity
Pickering and Henderson (1966) reported observed 96-hour LC5Q
values for goldfish, Carassius auratus, guppy, Poecilia reticulatus. and
bluegill, Lepomis macrochirus, to be 51,620, 45,530, and 24,000 pg/1,. re-
spectively, for chlorobenzene. Two 96-hour LC^g values for chlorobenzene
and fathead minnows, Pimephales promelas, are 33,930 ug/1 in soft water (20
mg/1) and 29,120 jug/1 in hard water (360 mg/1), indicating that hardness
does not significantly affect the acute toxicity -of chlorobenzene (U.S. EPA,
1978). With Daphnia maqna, an observed 48-hour EC-Q value of 86,000 pg/1
was reported.' In saltwater studies, sheepshead minnow had a reported un-
adjusted LC^Q (96-hour) value of 10,500 ;ug/l, with a 96-hour EC5Q of
16,400 ug/1 for mysid shrimp (U.S. EPA, 1978).
B. Chronic Toxicity
NO chronic toxicity studies have been reported on the chronic
toxicity of chlorobenzene and any salt or freshwater species.
C. Plant Effects
The freshwater alga Selenastrum capricomutum is considerably less
sensitive than fish and Daphnia magna. Based on cell numbers, the species
has a reported 96-hour EC5g value of 224,000 ;ug/l. The saltwater alga,
Skeletonema costatum, had a 96-hour EC5Q) based on cell numbers of 341,000
/jg/1.
D. Residues
A bioconcentration factor of 44 was obtained assuming an 8 percent
lipid content of fish.
y-7
-------
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
The American Conference of Governmental Industrial Hygienists
(ACGIH, 1971) threshold limit value for chlorobenzene is 350 mg/m3. The
acceptable daily intake (ADI) was calculated to be ..1.008 mg/day. The U.S.
EPA (1979) draft water criterion for chlorobenzene is 20 pg/1, based on
threshold concentration for odor and taste.
B. Aquatic
For chlorobenzene, the drafted criterion to protect freshwater
aquatic life is 1,500 jug/1 as a 24-hour average; the concentration should
not exceed 3,500 jug/1 at any time. To protect saltwater aquatic life, a
draft criterion of 120 jug/1 as a 24-hour average with a concentration not
exceeding 280 pg/1 at any time has been recommended (U.S. EPA, 1979).
-------
CHLOROBENZENE
REFERENCES
American Conference of Governmental Industrial Hygienists.
1971. Documentation of the threshold limit values for sub-
stances in workroom air. 3rd. Ed.
Brodie, B.B., et al. 1971. Possible mechanism of liver ne-
crosis caused by aromatic organic compounds. Proc. Natl.
Acad. Sci. 68: 160.
Irish, D.D. 1963. Halogenated hydrocarbons: II. Cyclic.
^n?Industrial Hygiene and Toxicology, Vol. II, 2nd Ed., ed.
F.A. Patty , Interscience, New York. p. 1333.
Knapp, W.K., Jr., et al. 1971. Subacute oral toxicity of
monochlorobenzene in dogs and rats. Topxicol. Appl. Pharraa-
col. 19: 393.
Kohli, I., et al. 1976. The metabolism of higher chlori-
nated benzene isomers. Can. Jour. Biochem. 54: 203.
• Lu, A.Y.H., et al. 1974. Liver microsomal electron trans-
port systems. III. Involvement of cytochrome b5 in the
NADH-supported cytochrome p5-450 dependent hydroxylation of
chlorobenzene. Biochem. Biphys. Res. Comm. 61: 1348.
Mackay, D., and P.J. Leinonen. 1975. Rate of evaporation of
•low-solubility contaminants from water bodies to atmosphere.
Environ. Sci. Technol. 9: 1178.
Oesch, F., et al. 1973. Induction activation, and inhibition
of epoxide hydrase. Anomalous prevention of chlorobenzene-
induced hepatotoxicity by an inhibitor of epoxide hydrase.
Chem. Biol. Interact. 6: 189.
Pickering, Q.H., and C. Henderson. 1966. Acute toxicity of
some important petrochemicals to fish. Jour. Water Pollut.
Control Fed. 38: 1419.
U.S. EPA. 1975. Preliminary assessment of suspected carcin-
ogens in drinking water. Report to Congress. Environ.
Prot. Agency, Washington, D.C.
U.S. EPA. 1977. Investigation of selected potential envi-
ronmental contaminants: Halogenated benzenes. EPA 560/2-77-
004.
U.S. EPA. 1978. In-depth studies on health and environmen-
tal impacts of selected water pollutants. U.S. Environ.'
Prot. Agency, Contract No. 68-01-4646.
-------
U.S. EPA. 1979. Chlorinated Benzenes:.Ambient Water Quality
Criteria (Draft).
Williams, R.T. 1959. The metabolism of halogenated aromatic
hydrocarbons. Page 237 in Detoxication mechanisms. 2nd ed.
John Wiley and Sons, New York.
Williams, R.T., et al. 1975. Species variation in the meta-
bolism of some organic halogen compounds. Page 91 InfA.D.
Mclntyre and C.F. Mills, eds. Ecological and toxicological
research. Plenum Press, New York.
-------
No. A3
p-Chloro-m-cresol
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.
-------
p-CHLORO-m-CRESOL
SUMMARY
p-Chloro-m-cresol has been found to be susceptible to biodegradation
under aerobic conditions in a synthetic sewage sludge. It has been found
to be formed by the chlorination of waters receiving effluents from electric
power-generating plants and by the chlorination of the effluent from a
domestic sewage treatment facility.
Very little information on the health effects of p-chloro-m-cresol
was located. p-Chloro-m-cresol has been characterized as very toxic
in humans, although support for this statement is 'limited. In rats, a
subcutaneous LO^g of 400 mg/kg and an oral LDL of 500 mg/kg have been
reported.
I. INTRODUCTION
p-Chloro-m-cresol (4-chloro-3-raethylphenol; C_H_C10; molecular
weight 142.58) is a solid (dimorphous crystals) at room temperature. The
pure compound is odorless, but it has a phenolic odor in its most common, impure
form. Its melting point is 55.5°C and its boiling point is 235°C.
It is soluble in water and many organic solvents (Windholz 1976).
A review of the production range (includes importation) statistics
for p-chloro-m-cresol (CAS No. 59-50-7) as listed in the initial TSCA
Inventory (U.S. EPA 1979) shows that between 10,000 and 90,000 pounds of
this chemical were produced/imported in 1977.
p-Chloro-m-cresol is used as an external germicide and as a preserva-
tive for glues, gums, paints, inks, textiles and leather goods (Hawley 1971).
It is also used as a preservative in cosmetics (Wilson 1975, Liem 1977).
EPA (1973) indicates that p-chloro-m-cresol is "cleared for use in adhesives
used in food packaging."
*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 Con-
fidential Business Information. The data submitted for the TSCA Inventory,
including production range information, are subject to the limitations con-
tained in the Inventory Reporting Regulations (40 CFR 710).
-------
II. EXPOSURE
A. Environmental Fate
Voets et al. (1976) reported that p-chloro-ra-cresol was quite susceptible
to microbial breakdown under aerobic conditions in an organic medium
(synthetic sewage sludge) , while degradation under aerobic conditions in a
mineral solution (simulating oligotrophic aquatic systems) was relatively
difficult. No degradation was observed in either system under anaerobic
conditions.
B. Bioconcentration
No studies on the bioconcentration potential of this compound were
found. Based on its solubility, p-chloro-m-cresol would not be expected
to have a high bioconcentration potential .
C. Exposure
Human exposure to p-chloro-m-cresol occurs through its presence in
certain cosmetics and in a variety of other consumer products in which
it is used as a preservative (Wilson 1975, Liem 1977).
p-Chloro-m-cresol has been found to be formed by the chlorination
of water from a lake and a river receiving cooling waters from electric
power-generating plants, at concentrations of 0.2 ug/1 and 0.7 ug/1, res-
pectively. It has also been found to be formed by the chlorination of the
effluent from a domestic sewage treatment facility at a concentration of
1.5 ug/1 (Jolley et al. 1975).
III. PHARMACOKINETICS
No information was found.
! IV. HEALTH EFFECTS
Very little toxicological data for p-chloro-m-cresol was available. The
subcutaneous LDc0 f°r p-chloro-m-cresol in rats is 400 rag/kg (NIOSH 1975).
The oral LD for p-chloro-m-cresol in rats is 500 mg/kg. In mice the
LiO
intraperitoneal LD is 30 mg/kg and the subcutaneous LD is 200 mg/kg
L»O Lo
-------
(U.S. DHEW 1978). One author has rated p-chloro-m-cresol as very toxic,
with a probable lethal dose to humans of 50-500 mg/kg. (Von Oettingen
as quoted in Gosselin et al. 1976). p-Chloro-m-cresol was also reported
as non-irritating to skin in concentrations of 0.5 to; 1.0% in alcohol.
V. AQUATIC TOXICITY
A. Acute
The only information available is that for Daphnia pulex. The
96-hour LC50 for p-chloro-m-cresol exposure is 3.1 mg/L (Jolley et al. 1977),
VI. GUIDELINES
No guidelines for exposure to p-chloro-m-cresol were located.
-------
References
Gosselin RE et al. 1976. Clinical Toxicology of Commercial Products.
Fourth Edition.
Hawley GG (Ed.) 1971. Condensed Chemical Dictionary, 8th Edition. Van
Nostrand Reinhold Co.
Jolley RL. , Jones G, Pitt WW, and Thompson JE. 1975. Chlorination of
Organics in Cooling Waters and Process Effluents. In Proceedings of the
Conference on the Environmental Impact of Water Chlorination, Oak Ridge,
Tennessee, Oct. 22-24, 1975, published July 1976.
Jolley RL, Gorchev H, Hamilton DH. 1978. Water Chlorination Environmental
Impact and Health Effects In Proceedings of the Second Conference on the
Environmental Impact of Water Chlorination, Gatlinburg, Tenn. 1977.
Liem DH. 1977. Analysis of antimicrobial compounds, in cosmetics, Cosmetics
and Toiletries, 92: 59-72.
National Institute of Occupational Safety and Health. 1975. Registry of
Toxic Effects of Chemcial Substances. 1978 Edition. DHEW (NIOSH) Publication
79-100, Rockville, MD.
U.S. EPA. 1973. EPA Compendium of Registered Pesticides, Vol. II, Part I,
Page P-01-00.01.
jt . U.S. EPA. 1979. Toxic Substances Control Act Chemical Substance Inventory,
•f Production Statistics for Chemicals on the Non-Confidential TSCA Inventory.
Voets JP, Pipyn P, Van Lancker P, and Verstraete W. 1976. Degradation of
microbicides under different environmental conditions. J. Appl. Bact.
40:67-72.
'
Wilson, CH. 1975. Identification of preservatives in cosmetic products by
thin layer chromatography. J. Soc. Cosraet. Chem. , 26:75-81.
i
Windholz M. ed. 1976. The Merck Index, Merck & Co., Inc., Rahway, New Jersey.
-------
No. 44
Chloroethane
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.
-------
CHLOROETHANE
SUMMARY
There is no available evidence which indicates that
monochloroethane produces carcinogenic, rnutagenic, or terato-
genic effects. Symptoms produced by human poisoning with
monochloroethane include central nervous system depression,
respiratory failure, and cardiac arrhythmias. The results of
animal studies indicate that liver, kidney, and cardiac toxi-
city may be produced by monochloroethane.
«.
Data examining the toxic effects of chloroethane on
aquatic organisms were not available.
-------
CHLOROETHANE
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 have been replaced by chlorine atoms.
Water solubility and vapor pressure decrease with increasing
chlorination, while density and melting point increase.
Monochloroethane (chloroethane, M.W. 64.52) is a gas at room
temperature. The compound has a boiling point of 13.1°C, a
melting point of -138.7°C, a specific gravity of 0.9214, and
a solubility of 5.74 g/1 in water (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 1976 production of monochloroethane was 335 x 10^
tons/year (U.S. EPA, 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. Snail amounts of the
chloroethanes may be formed by chlorination of drinking water
-------
or treatment of sewage. Air levels of chloroethanes are
produced by evaporation of these volatile compounds widely
used as degreasing agents and in dry cleaning operations
(U.S. EPA, 1979a).
Sources of human exposure to chloroethanes include
water, air, contaminated foods and fish, and dermal absorp-
tion. Fish and shellfish have shown levels of chloroethanes
in the nanogram range (Dickson and Riley, 1976). Data on the
levels of monochloroethanes in foods is not available.
An average bioconcentration factor for monochloroethane
in fish and shellfish has not been derived by the EPA.
III. PHARMACOKINETICS
Pertinent data could not be located in the available
literature on monochloroethane for absorption, distribution,
metabolism, and excretion. However, the reader is referred
to a more general treatment of chloroethanes (U.S. EPA,
1979b), which indicates rapid absorption of chloroethanes
following oral or inhalation exposure; widespread distribu-
tion of the chloroethanes throughout the body; enzymatic de-
chlorination and oxidation to the alcohol and ester forms;
and excretion of the chloromethanes primarily in the urine
and expired air. Specifically for monochloroethane, absorp-
tion following dermal application is minor; and excretion
appears to be rapid, with the major portion of the injected
compound excreted in the first 24 hours (U.S. EPA, 1979a)
-------
IV. EFFECTS
Pertinent data could not be located in the available
literature on monochloroethane for carcinoqenicity, mutageni-
city, teratogenicity and other reproductive effects.
A. Chronic Toxicity
Hunan symptons of monochloroethane poisoning indi-
cate central nervous system depression, respiratory failure,
and cardivascular symptoms, including cardiac arrhythmias
(U.S. EPA, 1979a). Animal toxicity has indicated kidney dam-
age and fatty infiltration of the liver, kidney, and heart
(U.S. EPA, 1979a).
V. AQUATIC TOXICITY
Pertinent data could not be located in the available
1iterature.
VI. EXISTING GUIDLINES AND STANDARDS
A. Human
The eight-hour TWA standard prepared by OSHA for
monochloroethane is 1,000 ppm.
Sufficient data are not available to derive a cri-
terion to protect human health from exposure to monochloro-
ethane in ambient water.
B. Aquatic
There are not sufficient toxicological data to cal-
culate exposure criteria.
-------
CHLOROETHANE
REFERENCES
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.
Kirk, R., and Othmer, 0. 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.
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.F. Wineman. 1971. Enzymatic dechlorination:
Dechlorination of chloroethanes and propanes in vitro. Biochem.
Pharmacol. 20: 463.
-------
No. 45
Chloroethene
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.
-------
CHLOROETHENE
(VINYL CHLORIDE)
Summary
Vinyl chloride has been used for over 40 years in the produc-
tion of polyvinyl chloride. Animal studies indicate that vinyl
chloride is not teratogenic, but it has been found to be mutagenic
in several biologic test systems. Vinyl chloride has been found to
be carcinogenic in laboratory animals and has Joeen positively asso-
ciated with angiosarcoma of the liver in humans. Recently "vinyl
chloride disease", a multisystem disorder, has been described in
workers exposed to vinyl chloride.
Data are lacking concerning the effects of vinyl chloride
in freshwater and saltwater aquatic life.
yr-J
-------
CHLOROETHENE
(VINYL CHLORIDE)
I. INTRODUCTION
Vinyl chloride (CH2CHC1; molecular weight 62.5) is a highly
flammable chloro-olefinic hydrocarbon which emits a sweet or
pleasant odor, and has a vapor density slightly more than twice
that of air. Its physical properties include: melting point,
-153.8°C; and solubility in water, O.llg/100 g at 28°C. It is
soluble in alcohol and very soluble in ether and carbon tetra-
chloride (Weast, 1972). Many salts of metals (including silver,
copper, iron, " platinum, iridium) have the ability to complex
with vinyl chloride resulting in its increased solubility in
water. Conversely, alkali metal salts, such as sodium or potas-
sium chloride, may decrease the solubility of vinyl chloride
in aqueous solutions (Fox, 1978).
Vinyl chloride has been used for over 40 years in the produc-
tion of polyvinyl chloride (PVC), which in turn is the most widely
used material in the manufacture of plastics. Production of vinyl
chloride in the U.S. reached slightly over 5 billion pounds in 1977
(U.S. Int. Trade Comm,-1978).
Vinyl chloride and polyvinyl chloride are used in the manufac-
ture of numerous products in. building and construction, the automo-
tive industry, for electrical wire insulation and cables, piping,
industrial and household equipment, packaging for food products,
medical supplies, and are depended upon heavily by the rubber,
paper and glass industries (Maltoni, 1976a).
In the U.S. about 1500 workers were employed in monomer syn-
thesis and an additional 5000 in polymerization operations (Fal.k,
-------
et al. 1974). As many as 350,000 workers were estimated to be asso-
ciated with fabricating plants (U.S. EPA, 1974). By 1976, it was
estimated that worldwide nearly one million persons were associated
with manufacturing goods derived from PVC (Maltoni, 1976a).
Potential sources of population exposure to vinyl chloride are
emissions from PVC fabricating plants, release of monomers from
various plastic products, and emissions from the incineration of
PVC products (U.S. EPA, 1975).
II. EXPOSURE
«.
A. Water
Small amounts of vinyl chloride may be present in public
water supplies as a result of industrial waste water discharges.
The levels of vinyl chloride in effluents vary considerably de-
pending on the extent of in-plant treatment of waste water. Vinyl
chloride in samples of waste water from seven areas ranged from
0.05 ppm to 20 ppm, typical levels being 2-3 ppm (U.S. EPA, 1974) .
The low solubility and high volatility of vinyl chloride tend to
limit the amounts found in water; however, the presence of certain
salts may increase the solubility and therefore could create situa-
tions of concern (U.S..EPA, 1975).
Polyvinyl chloride pipe.used in water distribution sys-
tems provides another source of low levels of vinyl chloride in
drinking water. In a study by the U.S. EPA of five water distribu-
tion systems which used PVC pipes, water from the newest, longest
pipe system had the highest vinyl chloride concentration (1.4 ug/1)
while the two oldest systems only had traces of vinyl chloride • (0.3
;jg/l and 0.6 pg/1) (Dressman and McFarren, 1978) . The National
-5
-------
Science Foundation (NSF) has adopted a voluntary standard of 10 ppmj
or less of residual monomer in finished pipe and fittings. Three
times a year NSF samples water supplies in several cities. In
1977, more than 95 percent of the samples conformed to the stan-
dard; however, levels of 5.6 ug/1 and 0.27 /jg/1 vinyl chloride have
been detected in at least two cities.
B. Food
Small quantities of vinyl chloride are ingested by humans
when the entrained monomer migrates into foods packaged in PVC
wrappings and containers. The solubility of vinyl chloride in
foods packaged in water is low (0.11 percent)/ however, the monomer
is soluble in alcohols and mineral oil. In 1973, the U.S. Treasury
Department banned the use of vinyl chloride polymers for packaging
alcoholic beverages (Int. Agency Res. Cancer, 1974). The FDA anal-
yzed a number of PVC packaged products in 1974. The concentrations
ranged from "not detectable" to 9,000 ppb.
The U.S. EPA (1979) has estimated the weighted average
bioconcentration factor of vinyl chloride to be 1.9 for the edible
portions of fresh and shellfish consumed by Americans. This esti-
mate was based on the octanol/water coefficient of vinyl chloride.
C. Inhalation
Inhalation of vinyl chloride is the principal route of
exposure to people working in or living near vinyl chloride indus-
tries. After 1960, Dow Chemical Co. was successful in reducing ex-
posures to workers to about 25 ppm level, though levels up to 500
•
ppm still occurred. Inhalation exposures drastically dropped after
appropriate controls were instituted following case reports of
vinyl chloride induced angiosarcoma of the liver in workers and ex-
perimental animals (U.S. SPA, 1979). " •
-------
III. PHARMACOKINETICS
A. Absorption
Vinyl chloride is rapidly absorbed through the lungs and
enters the blood stream (Duprat, et al. 1977).
B. Distribution
The liver of rats accumulates, the greatest percentage
of vinyl chloride and/or metabolites of vinyl chloride 72 hours
after a single oral dose (Watanabe, et al. 1976). Ten minutes
after a 5-minute inhalation exposure to vinyl chloride at 10,000
ppm, the compound was found in the liver, bile duct, stomach,
and kidney of - rats (Duprat, et al. 1977). Immediately after
exposure by inhalation to C-vinyl chloride at 50 ppm for 5
14
hours, the percent incorporated as C/radioactivity per gram
of tissue was highest for kidney (2.13), liver (1.86), and spleen
(0.73). Forty-eight hours after the beginning of exposure, labeled
material could still be detected in these tissues.
C. Metabolism
Detoxification of vinyl chloride takes place primarily in
the liver by oxidation to polar compounds which can be conjugated
to glutathione and/or cysteine (Hefner, et al. 1975). These cova-
lently bond metabolites are then excreted in the urine.
Vinyl chloride is metabolized extensively by rats _iri vivo
and the metabolic pathways appear to be saturable. The postulated
primary metabolic pathway involves alcohol dehydrogenase and, for
rats, appears to be saturated by exposures to concentrations ex-
ceeding 220 to 250 ppm. In rats exposed to higher concentrations,
metabolism of vinyl chloride is postulated to occur via a secondary
-------
pathway involving epoxidation and/or peroxidation. Present data
indicates that vinyl chloride is metabolized to an activated car-
cinogen electrophile and is capable of covalent reaction with
nucleophilic groups or cellular macromolecules (U.S. EPA, 1979).
There is ample evidence that the mixed function oxidase
(MFO) system may be involved in the metabolism of vinyl chloride.
Rat liver microsomes catalyze the covalent binding of vinyl chlor-
ide metabolites to protein and nucleic acids; chloroethylene
oxide is thought to be the primary microsomal metabolite capable
of alkylating these cellular macromolecules (Kappus, et al. 1975;
1976; Laib and Bolt, 1977). Hathway (1977) reports in vitro
depurination of calf thymus DMA by chloroacetaldehyde identical
to that observed in hepatocyte DNA following the administration
of vinyl chloride to rats in vitro.
D. Excretion
Watanabe, et al. (1976) monitored the elimination of
vinyl chloride for 72 hours following a single oral dose adminis-
tered to rats. The total 14-,-activity recovered at each dose level
ranged from 82-92 percent. At a dose level of 1 mg/kg, 2 percent
was exhaled as vinyl chloride, 13 percent was exhaled as carbon
dioxide, 59 percent was eliminated in the urine and 2 percent in
the feces. Excretion of vinyl chloride at a dose level of 100 mg/kg
was 66 percent exhaled as vinyl chloride, 2.5 percent as carbon
dioxide, 11 percent in the urine and 0.5 percent in the feces. Ad-
ministration by inhalation produced almost the same results.
»
Green and Hathway (1975) found that more than 96 percent
14
of 250 ug C-vinyl chloride administered via intragastric, intra-
-------
venous or intraperitoneal routes was excreted within 24 hours. The
rats given vinyl chloride by the intragastric -route exhaled 3.7
percent as vinyl chloride, 12.6 percent as CO-; 71.5 percent
of the labeled material was in the urine and 2.8 percent in the
feces. Intravenous injections resulted in 9.9 percent exhaled
as vinyl chloride, 10.3 percent as C02; 41.5 percent in the urine
and 1.6 percent in the feces.
IV. EFFECTS
A. Carcinogenicity
The carcinogenicity of vinyl chloride has been investi-
gated in several animal studies. Viola, et al. (1971) induced skin
epidermoid carcinomas, lung carcinomas or bone steochrondromas in
24/25 male rats exposed to 30,000 ppm vinyl chloride intermittently
for 12 months. Tumors appeared between 10 and 11 months. Caputo,
et al. (1974) observed carcinomas and sarcomas in all groups of
male and female rats inhaling various concentrations of vinyl
chloride except those exposed to 50 ppm.
Maltoni and Lefemine (1974a,b; 1975) reported on a
series of experiments concerning the effects on rats, mice, and
hamsters of inhalation- exposure to vinyl chloride at concentra-
tions ranging from 50 to 10,000 ppm for varying periods of time.
The animals were observed for their entire lifetime. Angiosar-
comas of the liver occurred in all three species, as well as
tumors at several other sites. A differential response between
the sexes was not reported.
•
Maltoni (1976b) observed four subcutaneous angiosar-
comas, four zymbal gland carcinomas, and one nephroblastoma in
- 9
-------
66 offspring of rats exposed by inhalation 4 hours/day to 10,000
or 6,000 ppm vinyl chloride from the 12th to 18th day of gesta-
tion. Liver angiosarcomas were also observed in rats administered
vinyl chloride via stomach tube for 52 weeks.
Recent experiments by Lee, et al. (1977) with rats
and mice confirm the carcinogenicity of vinyl chloride. Each
species was exposed to 50,250 or 1000 ppm vinyl chloride or 55
ppm vinylene chloride 6 hr/day, 5 days/week for 1-12 months.
After 12 months, bronchioalveolar adenomas, .mammary gland tumors,
and angiosarcomas in the liver and other sites developed in mice
exposed to all-three dose levels of vinyl chloride. Rats exposed
to 250 ppm or 100 ppm vinyl chloride developed angiosarcoma in
the liver, lung and other sites (Lee, et al. 1978).
The primary effect associated with vinyl chloride expo-
sure in man is an increased risk of cancer in several organs in-
cluding angiosarcoma of the liver. Liver angiosarcoma is an ex-
tremely rare liver cancer in humans, with 26 cases reported annual-
ly in the U.S. (Natl. Cancer Inst., 1975). Human data on the car-
cinogenic effects of vinyl chloride have been obtained primarily
from cases of occupational exposures of workers. The latent period
has been estimated to be 15-20 years; however, recent case reports
indicate a longer average latent period (Spirtas and Kaminski,
1978) .
A number of epidemiological studies of vinyl chloride
have been reported (U.S. EPA, 1979). Tabershaw/Cooper Associates
(1974) found no increase in the overall mortality rate for vinyl
chloride workers nor significant increases in standard mortality
-------
rates (SMR's) for malignant neoplasms. Reexamination of this
data by Ott, et al. (1975) including more clearly defined expo-
sure levels confirmed the previous findings: no increase over
that expected for malignant neoplasms in the low exposure group
(TWA 10-100 ppm vinyl chloride) and a non-significant increase
in deaths due to malignant neoplasms in the high exposure group
(TWA, greater than 200 ppm).
However, liver cancer death were twelve-fold, and brain
cancer deaths were five-fold greater than, that expected in a
study by Wagoner (1974). Likewise, Monson, et al. (1974) found
death due to cancer to be 50 percent higher than expected in
vinyl chloride workers who died from 1947-1973, including a 900
percent increase in cancers of the liver and biliary tract.
In the most recent update of the NIOSH register, a total
of 64 cases of hepatic angiosarcoma have been identified worldwide
among vinyl chloride exposed industrial workers (Spirtas and Kamin-
ski, 1978). Twenty-three of these cases were reported in the
United States. Six cases were documented since 1975.
B. Mutagenicity
Vinyl chloride has been found to be mutagenic in a number
of biological systems including: metabolically activated systems
using Salmonella typhimurium; back mutation systems using
Escherichia coli; forward mutation and gene coversion in yeast; and
germ cells of Drosophila and Chinese hamster V79 cells (U.S. EPA,
1979) .
The dominant lethal assay was used to test the mutag'eni-
city of inhaled vinyl chloride in mice. Levels as high as 30,000
t
-11
-------
ppm (6 hours/day for 5 days) yielded negative results (Anderson, et
al. 1976).
Several investigators have observed a significantly
higher incidence of chromosomal aberrations in the lymphocytes of
workers chronically exposed to high levels of vinyl chloride
(Ducatman, et al. 1975; Purchase, et al. 1975; Funes-Cravioto, et
al. 1975).
C. Teratogenicity
Animal studies using mice, rats and rabbits, indicate
that inhalation of vinyl chloride does not induce gross teratogenic
abnormalities in offspring of mothers exposed 7 hours daily to con-
centrations ranging from 50 to 2,500 ppm (John, et al. 1977); how-
ever, excess occurrences of minor skeletal abnormalities were
noted. Increased fetal death was noted at the higher exposure
levels. These findings were confirmed by Radike, et al. (1977a)
who exposed rats to 600-6,000 ppm vinyl chloride, 4 hours daily on
the 9th to the 21st day of gestation.
Further examination is needed of reported high rates of
congenital defects in three small communities in which vinyl chlor-
ide polymerization plants are located (U.S. EPA, 1979).
D. Other Reproductive Effects
No effect on fertility in mice was noted in a dominant
lethal assay conducted by Anderson, et al. (1976).
E. Chronic Toxicity
There are numerous clinical indications that chronic
exposure to vinyl chloride is toxic to humans (U.S. EPA, 1979).
Hepatitis-like changes, angioneurosis, Raynaud's syndrome, derma-
-------
titis, acroosteolysis, thyroid insufficiency, and hepatomegaly
have been reported around the world. Other long term effects
include functional disturbances of the central nervous system
with adrenergic sensory polyneuritis (Smirnova and Granik, 1970);
thrombocytopenia, splenomegaly, liver malfunction with fibrosis,
pulmonary changes (Lange, et al. 1974); and alterations in serum
enzyme levels (Makk, et al. 1976).
F. Other Relevant Information
Pretreatment of rats with pyrazole' (an alcohol dehydro-
genose inhibitor) and ethanol inhibits the metabolism of vinyl
chloride (Hefner, et al. 1975). This indicates the involvement
of alcohol dehydrogenose in the metabolism of vinyl chloride.
The chronic ingestion of alcohol was found to increase
the incidence of liver tumors and tumors in other sites in in-
dividuals exposed to vinyl chloride (Radike, 1977b).
Jaeger (1975) conducted experiments to determine the
interaction between vinylidene chloride (1,1-DCE) and vinyl chloride.
In this experiment, the effects of 4-hour exposures to 200 ppm
of 1,1-DCE and 1,000 ppm vinyl chloride were less than if 1,1-
DCE was given alone.
V. AQUATIC TOXICITY
A. Pertinent information relevant to acute and chronic toxi-
city, plant effects and residues for vinyl chloride were not found
in the available literature.
-------
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The current federal OSHA standard for vinyl chloride is 1
ppm (TWA) with a maximum of 5 ppm for a period of no longer than 15
minutes in 1 day. (39 FR 35890 (Oct. 4, 1979)).
In 1974, a notice to cancel registrations of pesticide
spray products containing vinyl chloride as a prop'ellant was issued
(39 FR 14753 (April 26, 1974)). Other aerosol products, such as
hair spray, utilizing vinyl chloride as a propellant were banned
from the market in the U.S. and other countries (Int. Agency Res.
Cancer, 1974). "The U.S. EPA proposed in 1975 and 1976 an emission
standard of 10 ppm vinyl chloride at the stack for industry.
The draft ambient water quality criterion for vinyl
chloride has been set to reduce the human lifetime cancer risk
level to 10"5, 10~6 and 10"7 (U.S. EPA, 1979). The corresponding
criteria are 517 /jg/1, 51.7 pg/1 and 5.17 pg/1, respectively. The
data base from which this criterion has been derived is currently
being reviewed, therefore, this criteria to protect human health
may change.
B. Aquatic
Fresh or salt water criteria could not be derived because
of insufficient data (U.S. EPA, 1979).
-------
CHLOROETHENE
(VINYL CHLORIDE)
REFERENCES
Anderson, D., et al. 1976. Vinyl chloride: dominant lethal studies in male
CD-I mice. Mutat. Red. 40: 359.
Caputo, A., et al. 1974. Oncogenicity of vinyl chloride at low concentra-
tions in rats and rabbits. IRCS 2: 1582.
Dressman, R.C. and E.F. McFarren. 1978. Determination of vinyl chloride
migration from polyvinyl chloride pipe into water. Am. Water Works Assoc.
Jour. 70: 29.
Ducatman, A., et al. 1975. Vinyl chloride exposure and human chromosome
aberrations. Mutat. Rec. 31: 163.
Duprat, P., et al. 1977. Metabolic approach to industrial poisoning:
blood kinetics and distribution of l^C-vinyl chloride monomer (VCM).
Toxicol Pharmacol. Suppl. 142.
Falk, H., et al. 1974. Hepatic disease among workers at a vinyl chloride
polymerication plant. Jour. Am. Med. Assoc. 230: 59.
Fox, C.R. 1978. Plant uses prove phenol recovery with resins. Hydrocarbon
processing. November, 269.
Funes-Cravioto, F., et al. 1975. Chromosome aberrations in workers exposed
to vinyl chloride. Lancet 1: 459.
Green, T. and D.E. Hathway. 1975. The biological fate in rats of vinyl
chloride in relation to its oncogenicity. Chem. Biol. Interactions.
11: 545.
Hathway, D.E. 1977. Comparative mammalian metabolism of vinyl chloride and
vinylidene chloride in relation to oncogenic potential. Environ. Health
Perspect. 21: 55.
Hefner, R.E., Jr., et al. 1975. Preliminary studies of the fate of inhaled
vinyl chloride monomer in rats. Ann. N.Y. Acad. Sci. 246: 135.
International Agency for Research on Cancer. 1974. Monograph on the evalu-
ation of carcinogenic risk of chemicals to man. Vol. 7. Lyon, France.
Jaeger, R.J. 1975. Vinyl chloride monomer: comments on its hepatotoxicity
and interaction with 1,1-dichloroethylene. Ann. N.Y. Acad. Sci. 246: 150.
John, J.A., et al. 1977. The effects of maternally inhaled vinyl chloride
on embryonal and fetal development in mice, rats and rabbits. Toxicol.
Appl. Pharmacol. 39: 497.
-------
Kappus, H., et al. 1975. Rat liver microsomes catalyse covalent binding of
chloride to macromolecules . Nature 257: 134.
Kappus, H., et al. 1976. Liver microsomal uptake of (l^C) vinyl chloride
and transformation to protein alkylating metabolites in vitro. Toxicol.
Appl. Pharmacol. 37: 461.
Laib, R.J. and H.M. Bolt. 1977. Alkylation of RNA by vinyl chloride meta-
bolites in vitro and in vivo: formation of l-N^-ethenoadenosine . Toxico-
logy 8: 185.
Lange, C.E., et al. 1974. The so-called vinyl chloride sickness-and-occu-
pationally-related systemic sclerosis? Int. Arch. Arbeitsmed. 32: 1.
Lee, C.C., et al. 1977. Inhalation toxicity of vinyl chloride and vinyli-
dene chloride. Environ. Health Perspect. 21: 25.
*.
Lee, C.C., et al. 1978. Carcinogenicity of vinyl chloride and vinylidene
chloride. Jour. Toxicol. Environ. Health 4: 15.
Makk, L., et al. 1976. Clinical and morphologic features of hepatic angio-
sarcoma in vinyl chloride workers. Cancer 37:149.
Maltoni, C. 1976a. Carcinogenicity of vinyl chloride: Current results.
Experimental evidence. Proc. 6th Int. Symp. Biological Characterization of
Human Tomours, Copenhagen May 13-15, 1975. Vol. 3 Biological characteriza-
tion of human tumours, 1976. American Elsevier Publishing Co., Inc., New
York.
Maltoni, C. 1976b. Predictive value of carcinogenesis bioassays. Ann.
N.Y. Acad. Sci. 271: 431.
Maltoni, C. and G. Lefemine. 1974a. Carcinogenicity bioassays of vinyl
chloride. I. Research plan and early results. Environ. Res. 7:387.
Maltoni, C. and G. Lefemine. 1974b. La potentiality dei saggi sperimentali
mella predizion; dei rischi oncogeni ambiental: Un esemplo: 11 chlorure di
vinile. Acad. Natl. Lincei. 56: 1.
Maltoni, C. and G. Lefemine. 1975. Carcinogenicity assays of vinyl chlor-
ide: Current results. Ann. N.Y. Acad. Sci. 246: 195.
Monson, R.R., et al. 1974. Mortality among vinyl chloride workers. Pre-
sented at Natl. Inst. Environ. Health Sci. Conf., Pinehurst, N.C., July
29-31.
National Cancer Institute Monograph 41. 1975. Third national cancer sur-
vey: incidence data.
Ott, M.G., et al. 1975. Vinyl chloride exposure in a controlled industrial
environment: a long-term mortality experience in 595 employees. Arch. Envi-
ron. Health 30: 333.
-------
Purchase, I.F.H., et al. 1975. Chromosomal and dominant lethal effects of
vinyl chloride. Lancet 28: 410.
Radike, M., et al. 1977a. Transplacental effects of vinyl chloride in
rats. Annual Report. Center for the Study of the Human Environment. USPHS-
ES-00159. Dept. Environ. Health, Med. College, University of Cincinnati.
Radike, M.J., et al. 1977b. Effect of ethanol and vinyl chloride on the
induction of liver tumors: preliminary report. Environ. Health Perspect.
21: 153.
Smirnova, N.A. and N-.P. Granik. 1970. Long-term. side effects of acute
occupational poisoning by certain hydrocarbons and their derivatives. Gig.
Tr. Prof. Zabol. 14: 50.
Spirtas, R. and R. Kaminski. 1978. Angiosarcoma of the liver in vinyl
chloride/polyvinyl chloride workers. Update of the NIOSH Register. Jour.
Occup. Med. 20: 427.
Tabershaw/Cooper Assoc., Inc. 1974. Epidemiologic study of vinyl chloride
workers. Final report submitted to Manufacturing Chemists Assoc., Washing-
ton, O.C. Berkeley, Calif.
U.S. EPA. 1974. Preliminary assessment of the environmental problems asso-
ciated with vinyl chloride and polyvinyl chloride. EPA 560/4-74-001. Natl.
Tech. Inf. Serv., Springfield, Va.
U.S. EPA. 1975. A scientific and technical assessment report on vinyl
chloride and polyvinyl chloride. EPA-600/6-75-004. Off. Res. Dev., U.S.
Environ. Prot. Agency, Washington, D.C.
U.S. EPA. 1979. Vinyl Chloride: Ambient Water Quality Criteria. (Draft).
U.S. International Trade Commission. 1978. Synthetic organic chemicals.
U.S. Production and Sales, 1977. Publ. 920. U.S. Government Printing Of-
fice, Washington, D.C.
Viola, P.L., et al. 1971. Oncogenic response of rat skin, lungs, bones to
vinyl chloride. Cancer Res. 31: 516.
Wagoner, J.E. 1974. NIOSH presented before the environment. Commerce Comm.
U.S. Senate, Washington, D.C.
Watanabe, P.G., et al. 1976. Fate of (14C) vinyl chloride after single
oral administration in rats. Toxicol. Appl. Pharmacol. 36: 339.
Weast, R.C. (ed.) 1972. Handbook of chemistry and physics. CRC Press,
Cleveland, Ohio.
-------
No. 46
2-Chloroethyl Vinyl Ether
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.
-------
2-CHLOROETHYL VINYL ETHER
SUMMARY
Very little information is available for 2-chloroethyl vinyl ether. It
appears to be relatively stable except under acidic conditions. There is some
potential for bioconcentration of the compound in exposed organisms. No expo-
sure data were available, although 2-chloroethyl vinyl ether has been identified
in industrial effluent discharges.
The acute toxicity of 2-chloroethyl vinyl ether is relatively low: oral
LD5Q: 250 mg/kg; dermal LD5Q 3.2 ml/kg; LCLQ: 250 ppm (4 hrs). Eye irrita-
tion has been reported following exposure to 2-chloroethyl vinyl ether. No
other data on health effects were available.
I. INTRODUCTION.
2-Chloroethyl vinyl ether (C1CH_CH-OCH=CH_; molecular weight 106.55) is a
liquid having the following physical/chemical properties (Windholz, 1976; Weast,
1972; U.S. EPA, 1979c):
Boiling point (760 mm Hg): 109°C
Melting point: -70°C
Density: 1.047520
Solubility: Soluble in water to the extent
of 6g/L; very soluble in
alcohol and ether
The compound finds use in the manufacture of anesthetics, sedatives, and
cellulose ethers (Windholz, 1976).
A review of. the production range (includes importation) statistics for 2-
chloroethyl vinyl ether (CAS No. 110-75-8) which is listed in the initial TSCA
inventory (1979a) has shown that none of this chemical was produced or imported
in 1977*.
*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 (40CFR710).
-------
II. EXPOSURE
A. Environmental Rate
The 0-chloroalkyl ethers have been shown to be quite stable to hydrolysis
and to persist for extended periods without biodegradation (U.S. EPA, 1979b).
2-Chloroethyl ethyl ether (a B-chloroalkyl other) is stable to sodium hydroxide
solutions but will undergo hydrolysis in the presence of dilute acids to acet*
aldehyde and 2-chloroethanol (Windholz 1976). Conventional treatment systems
may be inadequate to sufficiently remove the g-chloroalkyl ethers once present
in water supplies (U.S. EPA 1979b; U.S. EPA 1975).
B. Bioconcentration
A calculated bioconcentration factor of 34.2 (U.S. EPA, 1979b) points to
some potential for 2-chloroethyl vinyl ether accumulation in exposed organisms.
C. Environmental Occurrence
There is no specific information available on general population exposure
to 2-chloroethyl vinyl ether. The compound has been identified three times in
the water of Louisville, Kentucky (3/74): twice in effluent
facturing plants and once in the effluent from a latex plant (U.S. EPA 1976). No
concentration levels were given.
NIOSH, utilizing data from the National Occupational Hazards Survey
(NOHS 1977) has compiled a listing summarizing occupational exposure to 2-
chloroethyl vinyl ether (Table 1). As shown, NIOSH estimates 23,473 people
are exposed annually to the compound. The number of potentially exposed indi-
viduals is greatest for the following areas: fabricated metal products; whole-
sale trade; leather, rubber and plastic, and chemical products.
III. PHARMACOKINETICS
»
Vinyl ethers readily undergo acid catalysed hydrolysis to give alcohols and
aldehydes, e.g., 2-chloroethyl vinyl ether is hydrolyzed to 2-chloroethanol and
acetaldehyde (Salomaa et al. 1966).
-------
TABLE 1
PROJECTED NUMBERS BY INDUSTRY
HAZARD
SIC
CODE
25
28
30
31
34
35
36
37
38
39
50
73
DESCRIPTION
84673 Chloroethyl Vinyl Ether, 2-
DESCRIPTION
Furniture and fixtures
Chemicals and allied products
Rubber and plastic products
Leather and leather products
Fabricated metal products
Machinery, except electrical
Electrical equipment and supplies
Transportation equipment
Instruments and related products
Miscellaneous manufacturing industries
Wholesale trade
Miscellaneous business services
ESTIMATED
PLANTS
ESTIMATED
PEOPLE
ESTIMATED
EXPOSURES
920
1,683
1,669
2,279
9,149
35
432
553
299
240
6,194
20
I
TOTAL
2,059
23,473
23,473
-------
IV. HEALTH EFFECTS
A. Mutagenicity
Although no information on the mutagenicity of 2-chloroethyl vinyl ether was
available, its hydrolysis product, 2-chloroethanol, has been shown to be muta-
genic in Salmonella typhimurium TA 1535 (Bannug et al. 1976), TA100 and TA98
(McCann et al. 1976), as well as Klebsiella pneumonia (Voogd et al. 1972).
B. Other Toxicity
Very little toxicological data for 2-chloroethyl vinyl ether is available.
The oral LD5Q for 2-chloroethyl vinyl ether in rats is 250 mg/kg (U.S. EPA, 1975,
Patty 1963). Dermal exposure to the shaven skin of rabbits for 24 hours resulted
in an LD5Q of 3.2 mL/kg (U.S. EPA, 1976). The acute inhalation toxicity of
2-chloroethyl vinyl ether in rats was determined following single four-hour
exposures. The lowest lethal concentration was 250 ppm (U.S. EPA, 1975). In a
similar inhalation study, 1/6 rats exposed by inhalation to 500 ppm died during
the 14-day observation period (U.S. EPA, 1975).
Primary skin irritation and eye irritation studies have also been conducted
for 2-chloroethyl vinyl ether. Dermal exposure to undiluted 2-chloroethyl vinyl
ether did not cause even slight erythema. Application of 0.5 mL undiluted 2-
chloroethyl vinyl ether to the eyes of rabbits resulted in severe eye injury
(U.S. EPA, 1975).
V. AQUATIC TOXICITY
A. Acute
The adjusted 96-hour LC__ for blue gill exposure to 2-chloroethyl vinyl
ether is 194,000 ug/L (U.S. EPA, 1979b). Dividing by the species sensitivity
factor (3.9), a Final Fish Acute Value of 50,000 ug/L is obtained (Table 1).
•
There is no data on invertebrate or plant exposure.
VI. EXISTING GUIDELINES
No guidelines were located.
-------
Table 2. Freshwater fish acute values (U.S. EPA, 1979b)
Adjusted
Bioassay Test Chemical Time ^so ^50
Organism Method Cone.** Description (hrs) (ug/L) (ug/L)
Bluegill, S U 2-chloroethyl 96- 354,000 194,000
Lepomis macrochirus vinyl ether
* S = static
** U = unmeasured
Geometric mean of adjusted values: 2-chloroethyl vinyl ether » 194,000 ug/L
. 50,000
-------
References
Lange NA (ed.). 1967. Lange's Handbook of Chemistry, rev. 10th ed., New York:
McGraw-Hill Book Co. '
McCann J, Simmon V., Streitwieser D, Ames BN. 1975. Mutagenicity of chloro-
acetaldehyde, a possible metabolic product of 1,2-dichloroethane-. (ethylene
dichloride), chloroethanol (ethylene chlorohydrin), vinyl chloride and cyclo-
phosphamide. Proc. Nat. Acad. Sci. 72:3190-3193.
National Occupational Hazard Survey (NOHS) 1977 Vol. Ill, U.S. DHEW, NIOSH,
Cincinnati, Ohio (Special request for computer printout: 2-chloroethyl vinyl
ether Dec. 1979)
Rannug U., Gothe R. Wachtmeister CA. 1976. The mutagenicity of chloroethylene
oxide, chloroacetaldehyde, 2-chloroethanol and chloroacetic acid, conceivable
metabolites of vinyl chloride. Chem-Biol, Interactions 12:251-263.
Salomaa P, Kankaanpera A. Lajunen M. 1966. Protolytic cleavage of vinyl
ethers, general acid catalysis, structural effects and deuterium solvent isotope
effects. Acta Chemica Scand. 20:1790-1801.
U.S. EPA, 1975. Investigation of selected potential environmental
contaminants: Haloethers. EPA 560/2-75-006.
U.S. EPA, 1976. Frequency of organic compounds identified in water. EPA 600/4-
76-062.
U.S. EPA, 1979a. Toxic Substance Control Act, Chemical Substance Inventory,.
Production Statistics for Chemicals on the Non-Confidential Initial TSCA Inventory.
U.S. EPA, 1979b. Ambient Water Quality Criteria Document on Chloroalkyl Ethers.
PB 297-921.
U.S. EPA, 1979c. Ambient Water Quality Criteria Document on Haloethers. PB 296-796.
Voogd CE, Jacobs JJJAA, van der Stel JJ. 1972. On the mutagenic action of
dichlorvos. Mutat. Res. 16:413-416.
Weast RC (ed.). 1972. Handbook of Chemistry and Physics, 53rd ed. The Chemical
Rubber Co., Cleveland, OH.
Windholz M. (ed.). 1976. The Merck Index, 9th ed. Merck & Co. Inc., Rahway, NJ.
-------
No. 47
Chloroform (Carbon Trlchlorotnethane)
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. EPA1 s Carcinogen Assessment Group (GAG) has evaluated
chloroform and has found sufficient evidence to indicate
that this compound is carcinogenic.
-------
CHLOROFORM
SUMMARY
Chloroform has been found to induce hepatocellular
carcinomas in mice and kidney epithelial tumors in rats.
Hepatomas have also been induced in mice, but necrosis may
be a prerequisite to tumor formation. Bacterial assays
involving chloroform have yielded no mutagenic effects.
Chloroform has produced teratogenic effects when administered
to pregnant .rats.
Reported 96-hour LCcn values for two common freshwater
fish range from 43,800 to 115,000 ug/1 in static tests.
A 48-hour static test with Daphnia magna yielded an LC5Q
of 28,900 pg/1. The observed 96-hour LC5Q for the saltwater
pink shrimp is 81,500 ug/1. In a life cycle chronic test,
the chronic value was 2,546 ug/1 for D£Enn-'-a. magna. Per-
tinent information on chloroform toxicity to plants could
not be located in the available literature. In the only
residue study reported, the bluegill concentrated chloroform
six times after a 14-day exposure. The tissue half-life
was less than one day suggesting that residues of chloroform
would not be an environmental hazard to aquatic life.
7-y
-------
CHLOROFORM
I. INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria Document for Chloroform (U.S. EPA, 1979a).
Chloroform (CHC13; molecular weight 119.39) is a clear,
colorless liquid with a pleasant, etheric, non-irritating
odor and taste (Hardie, 1964; Windholz, 1976). It has the
following physical/chemical properties (Hardie, 1964; Irish,
1972; Windholz, 1976):
Boiling Point: 61-62°C
Melting Point: -63.5°C
Flash Point: none (none-flammable)
Solubility: Water - 7.42 x 10° ;jg/l at 25°C
Miscible with alcohol, benzene,
ether, petroleum ether, carbon
tetrachloride, carbon disulfide,
and oils.
Vapor Pressure: 200 mm Hg at 25 C
Current Production: 1.2 x 10 metric tons/year (U.S.
EPA, 1978a).
Chloroform is currently used either as a solvent or
as an intermediate in the production of refrigerants (prin-
cipleus), plastics, and Pharmaceuticals (U.S. EPA, 1975)'.
Chloroform is relatively stable under normal environ-
mental conditions. When exposed to sunlight, it decomposes
slowly in air but is relatively stable in water. The mea-
sured half-life for hydrolyis was found to be 15 months
(Natl. Acad. Sci., 1978a). Degradation in water can occur
in the presence of metals and is accelerated by aeration
(Hardie, 1964).
-------
For additional information regarding halomethanes as
a class the reader is referred to the Hazard Profile on
halomethanes (U.S. EPA, 19795).
II. EXPOSURE
Chloroform appears to be ubiquitous in the environment.
A major source of chloroform contamination is from the chlor-
ination of water and wastewater (U.S. EPA, 1975; Bellar,
et al., 1974). Industrial spills may occasionally be a
pulse source of transient high level contamination (Nat.
Acad. Sci., 1978a; Neely, et al., 1976; Brass and Thomas,
1978).
Based on available monitoring data including informa-
tion from the National Organics Monitoring Survey (NOMS),
the U.S. EPA (1978b) has estimated the uptake of chloroform
by adult humans from air, water, and food:
Source
Atmosphere
Water
Food Supply
Total
Atmosphere
Water
Food Supply
Total
Atmosphere
Water
Food Supply
Total
Adult
mg/yr
Maximum Conditions
204
343
16
563
Minimum Conditions
0.41
0.73
2.00
3.14
Mean Conditions
20.0
64.0
9.00
93
Percent
uptake
36
61
3
TUTT
13
23
64
100.
22
69
10
iod.
00
do
00
-------
A similar estimate, not using NOMS data, has been made by
the National Academy of Sciences (Nat. Acad. Sci., 1978a).
The U.S. EPA (1979a) has estimated the bioconcentration
factor for chloroform to be 14 for the edible portions of
fish and shellfish consumed by Americans. This estimate-
is based on measured steady-state bioconcentration studies
in bluegills.
III. PHARMACOKINETICS
A. Absorption
The efficiency of chloroform absorption by the
gastrointestinal tract is virtually 100 percent in humans
(Fry, et al., 1972). The corresponding value by inhalation
is 49 to 77 percent (Lehmann and Hassegawa, 1910). Quantita-
tive estimates of dermal absorption efficiency were not
encountered. Since chloroform was used as an anesthetic
via dermal administration, some dermal absorption by humans
can be assumed (U.S. EPA, 1979a).
B. Distribution
Chloroform is transported to all mammalian body
organs and is also transported across the placenta. Strain
differences for chloroform distribution in mice have been
documented by Vessell, et al., (1976).
C. Metabolism
Most absorbed chloroform is not metabolized by
mammals. Toxication, rather than detoxication, appears
•
to be the major consequence of metabolism and probably involves
mixed-function oxidase (MFO) enzyme systems. This observa-
-------
tion is based on enhancement of chloroform toxicity by MFO
inducers and the diminution of toxicity by MFO inhibitors
(Ilett, et al., 1973, McLean, 1970). At least in the liver,
covalent binding of a metabolite to tissue is associated
with tissue damage (Lavigne and Marchand, 1974). Limited
human data (two people) suggest that about 50 percent of
absorbed chloroform is metabolized to C02 (Fry, et al. ,
1972; Chiou, 1975).
D. Excretion
In humans, the half-life of chloroform in the
blood and expired air is 1.5 hours (Chiou, 1975). Most
unchanged chloroform and C02 generated from chloroform are
eliminated via the lungs. Chlorine generated from chloroform
metabolism is eliminated via the urine (Taylor, et al.,
1974; Fry, et al., 1972).
IV. EFFECTS
A. Carcinogenicity
Eschenbrenner and Miller (1945) demonstrated that
oral doses of chloroform administered over a 16-month period
induced hepatomas in strain A mice. Based on variations
in dosing schedules, these researchers concluded that necro-
sis was prerequisite to tumor induction.
In the National Cancer Institute bioassay of chloro-
form (NCI, 1976), hepatocellular carcinomas were induced
in mice (Table 1) and kidney epithelial tumors were induced
in male rats (Table 2), following oral doses over extended
periods of time.
-------
Ten epidemiologic studies have been conducted
on the association of human exposure to chloroform and/or
other trihalomethanes with cancer. A review of these studies
by the National Academy of Sciences (NAS, 1978b) indicated
that these studies suggest that higher concentrations of
trihalomethanes in drinking water may be associated with
an increased frequency of cancer of the bladder. One of
these studies (McCabe, 1975) claimed to demonstrate a statis-
tically significant correlation between age, sex, race,
adjusted death rate for total cancer, and chloroform levels.
B, Mutagenicity
Chloroform yielded negative results in the Ames
assay (Simmon, .et al. 1977).
C. Teratogenicity
At oral dose levels causing signs of maternal
toxicity, chloroform had fetotoxic effects on rabbits (100
mg/kg/day) and rats (316 mg/kg/day) (Thompson, et al., 1974).
Fetal abnormalities (acaudia, imperforate anus, subcutaneous
edema, missing ribs, and delayed ossification) were induced
when pregnant rats were exposed to airborne chloroform at
489 and 1,466 mg/m , 7 hrs/day, on days 6 to 15 of gestation.
At 147 mg/m , the only effects were significant increases
in delayed skull ossification and wavy'ribs (Schwetz, et
al., 1974).
J
-------
Table 1. Hepatocellular Carcinoma Incidence in Mice'
Controls Low
Colony Matched Dose
Male 577/~ 1718* 138 mg/kg 18750
(6%) (6%) (30%)
High
Dose
277 mg/kg 34/45
(98%)
Female
1/80
(1%)
0/20
(0%)
238
mg/kg
36/45
477
mg/kg 39/41
(95%)
Table 2. Statistically Significant Tumor Incidence in Rats'
Controls
Colony Matched
Kidney 0/99 0/19
epithelial
tumors/animals
P value 0.0000 0.0016
Males
Low
Dose
High
Dose
90 mg/kg 4/50 180/mg/kg 12/50
(8%) (24%)
Source: National Cancer Institute, 1976.
D. Other Reproductive Effects
Pertinent data could not be located in the avail-
able literature.
E. Chronic Toxicity
The NIOSH Criteria Document (1974) tabulates data
on the effect of chronic chloroform exposure in humans.
The primary target organs appear to be the liver and kidneys,
with some signs of neurological disorders. These effects
have been documented only with occupational exposures.
-------
With the exception of the possible relationship to cancer
(Section IV.A), chronic toxic effects in humans, attribut-
able to ambient levels of chloroform, have not been documented.
The chronic effects of chloroform in experimental
mammals is similar to the effects seen in humans: liver
necrosis and kidney degeneration (Torkelson, et al., 1976;
U.S. EPA, 1979a).
F. Other Relevant Information
Ethanol pretreatment of mice reportedly enhances
the toxic effects of chloroform on the liver (Kutob and
Plaa, 1961); as does high fat and low protein diets (Van
Oettingen, 1964; McLean, 1970). These data were generated
using experimental mammals.
V. AQUATIC TOXICITY
A. Acute Toxicity
Bentley, et al. (1975) observed the 96-hour LC5Q
values for rainbow trout, (Salmo gairdneri), of 43,800 and
66,800 ^jg/1 and for bluegills (Lepomis macrochirus) , 100,000
to 115,000 jjg/1,- all in static tests. A 48-hour static
test with Daphnia magna resulted in an LC,-n of 28,900 ug/1
(U.S. EPA 1979a). The observed 96-hour LC5Q for the pink
shrimp (Panaeus duorarum) is 81,500 ^ag/1. (Bentley, et
al.,' 1975) .
B. Chronic Toxicity
The chronic effects of chloroform on Daphnia magna
were determined using flow-through methods with measured
concentrations. The chronic effect level was 2,546 pg/1
(U.S. EPA, 1979a). No other chronic data were available.
-------
C. Plant Effects
Pertinent information could not be located in
the available literature concerning acute chronic toxicity
of chloroform to plants.
D. Residues
In the only residue study reported, the bluegill
(Lepomis macrochirus) bioconcentrated chloroform six times
after a 14-day exposure (U.S. EPA, 1979a). The tissue half-
life was less than one day.
VI. EXISTING GUIDELINES AND STANDARDS
Both the human health and aquatic criteria derived
by U.S. EPA (1979a), which are summarized below, are being
reviewed; therefore, there is a possibility that these crite-
ria may be changed.
A. Human
Based on the NCI mice data, and using the "one-
hit" model, the EPA (1979a) has estimated levels of chloro-
form in ambient water which will result in specified risk
levels of human cancer:
Exposure Assumption Risk Levels and Corresponding Criteria
(per~Bay) ~ " _, ,
0 10 ' 10 ° 10 3
2 liters of drinking 0 0.021 ug/1 0.21 pg/1 2.1 ug/1
water and consumption
of 18.7 grams fish and
shellfish.
»
Consumption of fish 0 0.175 /jg/1 1.75 ug/1 17.5
shellfish only.
-------
The above risks assume that drinking water treatment
and distribution will have no impact on the chloroform con-
centration.
The NIOSH time-weighted average exposure criterion
for chloroform is 2 ppm or 9.8 mg/m .
The FDA prohibits the use of chloroform in drugs, cos-
metics, or food contact material (14 FR 15026, 15029 April
9, 1976).
Refer to the Halomethane Hazard Profile for discussion
of criterion derivation (U.S. EPA, 1979b).
B. Aquatic
For chloroform, the draft criterion to protect
freshwater aquatic life, based on chronic invertebrate toxi-
city, is 500 pg/1 as a .24-hour average and the concentration
should not (based on acute effects) exceed 1,200 /ig/1 at
any time (U.S. EPA, 1979a). To protect saltwater aquatic
life, the concentration of chloroform should not exceed
620 jag/1 as a 24-hour average and the concentration should
not exceed 1,400 ^ig/1 at anytime (U.S. EPA, 1979a) . These
were calculated from an experiment on a marine invertebrate.
-------
CHLOROFORM
REFERENCES
Bellar, T.A., et al. 1974. The occurrence of organohalides in chlorinated
drinking water. Jour. Am. Water Works Assoc. 66: 703.
Bentley, R.E., et al. 1975. Acute toxicity of chloroform to bluegill
(Lepomis macrochirus), rainbow trout, (Salmo qairdneri), and pink shrimp
(Penaeus duorarumTT Contract No. WA-6-99-1414-8. U.S. Environ. Prot.
Agency.
Brass, H.J. and R.F. Thomas. 1978. Correspondence with Region III. Tech.
Support Div., U.S. Environ. Prot. Agency, Washington, O.C.
Chiou, W.L. 1975. .Quantitation of hepatic and pulmonary first-pass, effect
and its implications in pharmacokinetic study. I. Pharmacokinetics of
chloroform in man. Jour. Pharmacokin. Biopharmaceu. 3: 193.
Eschenbrenner,' A.B. and E. Miller. 1945. Induction of hepatomas in mice by
repeated oral administration of chloroform, with observations on sex dif-
ferences. Jour. Natl. Cancer Inst. 5: 251.
Fry, B.J., et al. 1972. Pulmonary elimination of chloroform and its meta-
bolites in man. Arch. Int. Phartnacodyn. 196: 98.
Hardie, O.W.F. 1964. Chlorocarbons and chlorohydrocarbons: chloroform.
^n: Kirk-Othmer encyclopedia of chemical technology. 2nd ed. John Wiley
and Sons, Inc., New York.
Ilett, K.F., et al. 1973. Chloroform toxicity in mice: Correlation of
renal and hepatic necrosis with covalent binding of metabolites to tissue
macromolecules. Exp. Mol. Pathol. 19: 215.
Irish, O.D. 1972. Aliphatic halogenated hydrocarbons. Ln: Industrial
hygiene and toxicology. 2nd ed. John Wiley and Sons, Inc., New York.
Kutob, S.D. and G.L. Plaa. 1961. The effect of acute ethanol intoxication
on chloroform-induced liver damage. Jour. Pharmacol. Exp. Ther. 135: 245.
Lavigne, J.G. and C. Marchand. 1974. The role of metabolism in chloroform
hepatotoxicity. Toxicol. Appl. Pharmacol. 29: 312.
Lenmann, K.B.. and Hassegawa. 1910. Studies of the absorption of chlori-
nated hyrocarbons in animals and humans. Archiv. fuer Hygiene. 72: 327.
McCabe, L.J. 1975. Association between trihalomethanes in drinking water
(NORS data) and mortality. Draft report. U.S. Environ. Prot. Agency.
»
McLean, A.E.M. 1970. The effect of protein deficiency and microsomal en-
zyme induction by DDT and phenobarbitone on the acute toxicity of chloroform
and pyrrolizidine alkaloid retrorsine. Brit. Jour. Exp. Pathol. 51: 317.
-------
National Academy of Sciences. 1978a. Nonfluorinated halomethanes in the
environment. Environ. Studies Board, Natl. Res. Council, Washington, O.C.
National Academy of Sciences/National Research Council. 1978b. Epidemiolo-
gical studies of cancer frequency and certain organic constituents of drink-
ing water - A review of recent literature for U.S. Environ. Prot. Agency.
National Cancer Institute. 1976. Report on carcinogenesis bioassay of
chloroform. Natl. Tech. Inf. Serv. PB-264018. Springfield, Va.
National Institute for Occupational Safety and Health. 1974. Criteria for
a recommended standard...Occupational exposure to chloroform. NIOSH Publ.
No. 75-114. Oept. Health Educ. Welfare, Washington, O.C.
Neely, W.8., et al. 1976. Mathematical models predict concentration-time
profiles resulting from chemical spill in river. Environ. Sci. Technol.
10: 72.
Schwetz, 8.A., et al. 1974. Embryo and fetotoxicity of inhaled chloroform
in rats. Toxicol. Appl. Pharmacol. 28: 442.
Simmon, J.M., et al. 1977. Mutagenic activity of chemicals identified in
drinking water. In: 0. Scott, et al., (ed.) Progress in genetic toxico-
logy. Elsevier/North Holland Biomedical Press, New York.
Taylor, O.C., et al. 1974. Metabolism of chloroform. II. A sex difference
in the metabolism of (l^C)-chloroform in mice. Xenobiotica 4: 165.
Thompson, D.J., et al. 1974. Teratology studies on orally administered
chloroform in the rat and rabbit. Toxicol. Appl. Pharmacol. 29: 348.
Torkelson, T.R., et al. 1976. The toxicity of chloroform as determined by
single and repeated exposure of laboratory animals. Am. Ind. Hyg. Assoc.
Jour. 37: 697.
U.S. EPA. 1975. Development document for interim final effluent limita-
tions guidelines and new source performance standards for the significant
organic products segment of the organic chemical manufacturing point source
category. EPA-440/1-75/045. U.S. Environ. Prot. Agency, Washington, O.C.
U.S. EPA. 1978a. 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. 1978b. Office of Water Supply. Statement of basis and purpose
for an amendment to the national interim primary drinking water regulations
on trihalomethanes. Washington, O.C.
U.S. EPA. 1979a. Chloroform: Ambient Water Quality Criteria Document.
(Draft)
»
U.S. EPA. 1979b. Environmental Criteria and Assessment Office. Chloro-
form: Hazard Profile. (Draft)
-------
Van Oettingen, W.F. 1964. The hydrocarbons of industrial and toxicological
importance. Elsevier Publishing Co., New York.
Vessell, E.S., et al. 1976. Environmental and genetic factors affecting
the response of laboratory animals to drugs. Fed. Am. Soc. Exp. Biol. Proc.
35: 1125.
Windholz, M., ed. 1976. The Merck Index. 9th ed. Merck and Co., Inc.,
Rahway, N.J.
-------
No. 48
Chloromethane
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-S7H-
-------
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.
-------
CHLOROMETHANE
SUMMARY
Chloromethane is toxic to humans by its action on the
central nervous system. In acute toxicity, symptoms consist
of blurring vision, headache, vertigo, loss of coordination,
slurring of speech, staggering, mental confusion, nausea,
and vomiting. Information is not available on chronic toxicity,
teratogenicity,. or carcinogenicity. Chloromethane is highly
rautagenic to the bacteria, Salmonella typhimurium.
Only three toxicity tests have been conducted on three
species of fish yielding acute values ranging from 147,000
to 300,000 pg/1. Tests on aquatic invertebrates or plants
have not been conducted.
-------
CHLOROMETHANE
I. INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria Document for Halomethanes (U.S. EPA, 1979a).
Chloromethane (CH.,C1; methyl chloride; molecular weight
50.49) is a colorless, flammable, almost odorless gas at
room temperature and pressure (Windholz, 1976). Chloromethane
has a melting point of -97.7°C, a boiling point of -24.2°C,
a specific gravity of 0.973 g/ml at -10°C, and a water solubi-
lity of 5.38 x 10 pg/1. It is used as a refrigerant,
a methylating agent, a dewaxing agent, and catalytic solvent
in synthetic rubber production (MacDonald, 1964). However,
its primary use is as a chemical intermediate (Natl. Acad.
Sci., 1978). Chloromethane is released to the environment
by manufacturing and use emissions, by synthesis during
chlorination of drinking water and municipal sewage, and
by natural synthesis, with the oceans as the primary site
(Lovelock, 1975). For additional information regarding
the halomethanes as a class, the reader is referred to the
Hazard Profile on Halomethanes (U.S. EPA, 1979b).
II. EXPOSURE
A. Water
The U.S. EPA (1975) has identified Chloromethane
qualitatively in finished drinking waters in the U.S. How-
ever, there are no data on its concentration in drinking
water, raw water, or waste-water (U.S. EPA, 1979a), probably'
because it is more reactive than other chlorinated methanes
(Natl. Acad. Sci., 1978).
-------
B. Food
There is no information on the presence of chloro-
raethane in food. There is no bioconcentration factor for
chloromethane (U.S. EPA, 1979a).
C. Inhalation
Saltwater atmospheric background concentrations
of chloromethane averaging about 0.0025 mg/m have been
reported (Grimsrud and Rasmussen, 1975; Singh, et al. 1977).
This is higher than reported average continental background
and urban levels and suggests, that the oceans are a major
source of global chloromethane (National Acad. Sci., 1978).
Localized sources, such as burning of tobacco or other com-
bustion processes, may produce high indoor-air concentra-
tions of chloromethane (up to 0.04 mg/m ) (Natl. Acad. Sci.,
1978) . Chloromethane is the predominant halomethane in
indoor air, and is generally in concentrations two to ten
times ambient background levels.
III. PHARMACOKINETICS
A. Absorption
Chloromethane is absorbed readily via the lungs,
and to a less significant extent via the skin. Poisonings
involving gastrointestinal absorption have not been reported
(Natl. Acad. Sci., 1977; Davis, et al., 1977).
B.. Distribution
Uptake of chloromethane by the blood is rapid
but results in only moderate blood levels with continued
exposure. Signs and pathology, of intoxications suggest
-------
wide tissue (blood, nervous tissue, liver, and kidney) distri-
bution of absorbed chloromethane (Natl. Acad. Sci., 1978).
C. Metabolism
Decomposition and sequestration of chloromethane
result primarily by reaction with sulfhydryl groups in intra-
cellular enzymes and proteins (Natl. Acad. Sci., 1977).
IV. EFFECTS
A. Carcinogenicity
Pertinent information could not be located in
the available literature.
B. Mutagenicity
Simmon and coworkers (1977) reported that chloro-
methane was mutagenic to Salmonella tryphimurium strain
TA 100 when assayed in a dessicator whose atmosphere contained
the test compound. Metabolic activation was not required,
and the number of revertants per plate was directly dose-
related. Also, Andrews, et al. (1976) have demonstrated
that chloromethane was mutagenic to S_._ typhimurium strain
TA1535 in the presence and absence of added liver homogenate
preparations.
C. Teratogenicity and Other Reproductive Effects
Information on positive evidence of teratogenisis
or other reproductive effects was not available in the literature,
D. Chronic Toxicity
Under prolonged exposures to chloromethane (dura-
»
tion not specified) increased mucous flow and reduced mucosta-
-------
tic effect of other agents (e.g., nitrogen oxides) were
noted in cats (Weissbecker, et al., 1971).
E. Other Relevant Information
In acute human intoxication, chloromethane pro-
duces central nervous system depression, and systemic poison-
ing cases have also involved hepatic and renal injury (Hansen,
er al., 1953; Spevac, et al., 1976).
V. AQUATIC TOXICITY
A. Acute Toxicity <•
A single 96-hour static renewal test serves as
the only acute study for freshwater providing an adjusted
LC^g value of 550,000 ug/1 for the bluegill sunfish (Lepomis
macrochirus). (Dawson, et al., 1977). Studies on fresh-
water invertebrates were not found. For the marine fish,
the tidewater silversides (Menidia beryllina), a 96-hour
static renewal assayed provided an LC5Q value of 270,000
ug/1 (Dawson, et al., 1977). Acute studies on marine inverte-
brates were not found.
B. Chronic Toxicity
In a review of the available literature, chronic
testing with chloromethane has not been reported.
C. Plant Effects
Pertinent information could not be located in the
available literature.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human 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 possibly that these criteria may be changed.
A. Human
OSHA (1976) has established the maximum acceptable
time-weighted average air concentrations for daily eight-
hour occupational exposure at 210 mg/m . The U.S. EPA (1979a)
Draft Water Quality Criteria for Chloromethane is .2 ug/1.
Refer to the Halomethanes Hazard Profile for discussion
of criteria derivation (U.S. EPA, 1979b) . *-
B. Aquatic
Criterion recommended to protect freshwater or-
ganisms have been drafted as 7,000 ug/1, not to exceed 16,000
ug/1 for a 24-hour average concentration. For marine life,
the criterion has been drafted as 3,700 ^ug/1, not to exceed
8,400 pg/1 as a 24-hour average concentration.
i
-------
CHLOROMETHANE
REFERENCES
Andrews, A.W., et al. 1976. A comparison of the rautagenic
properties of vinyl chloride and methyl chloride. Mutat.
Res. 40: 273.
Davis, L.N., et al. 1977. Investigation of selected poten-
tial environmental contaminants: monohalomethanes. EPA
560/2-77-007; TR 77-535. Final rep. June, 1977, of Contract
No. 68-01-4315. Off. Toxic Subst., U.S. Environ. Prot.
Agency, Washington, D.C.
Dawson, G.W., et al. 1977. The acute toxlcity of 47 indus-
trial chemicals to fresh and saltwater fishes. Jour. Hazard.
Mater. 1: 303.
Grimsrud, E.P., and R.A. Rasmussen. 1975. Survey and an-
alysis of halocarbons in the atmosphere by gas chromatography
mass spectrometry. Atmos. Environ. 9: 1014.
Hansen, H., et al. 1953. Methyl chloride intoxification:
Report of 15 cases. AMA Arch. Ind. Hyg. Occup. Med. 8:
328.
Lovelock, J.E. 1975. Natural halocarbons in the air and
in the sea. Nature.256: 193.
MacDonald, J.D.C. 1964. Methyl chloride intoxication.
Jour. Occup. Med. 6: 81.
National Academny of Sciences. 1977. Drinking water and
health. Washington, D.C.
National Academy of Sciences. 1978. Nonfluorinated halo-
methanes in the environment. Washington, D.C.
Occcupational Safety and Health Administration. 1976.
General industry standards. OSHA 2206, revised January,
1976. U.S. Dep. Labor, Washington, D.C.
Simmon, V.F., et al. 1977. Mutagenic activity of chemicals
identified in drinking water. S. Scott, et al., (eds.) In;
Progress in genetic toxicology.
Singh, H.B., et al. 1977. Urban-non-urban relationships
of halocarbons, SFg, M 0 and other atmospheric constituents'
Atmos. Environ. 11: 819.
-------
Spevac, L. , et al. 1976. Methyl chloride poisoning in
four members of a family. Br. Jour. Ind. Med. 33: 272.
U.S. EPA. 1975. Preliminary assessment of suspe-..:.ed cac •' '.no-
gens in drinking water, and appendices. A report to Co ngr ;_•:.; s,
Washington, D.C.
U.S. EPA. 1979a. Halomethanes: Ambient Water Quality Cri-
teria (Draft).
U.S. EPA. I979b. 2nviror.-p.2r.ta]. Criteria ar-:5 Assessment
Office. Halomathanas: Ha:;a.rd Profile (Draft) .
Weissbecker, L., et al. 1971. Cigarette smoke and tracheal
mucus transport rate: Isolation of effect of components
of smoke. Am. Rev. Resp. Dis. 104: 182. .
Windhoiz, M., (ed.) 1976. The Merck Index. M.^tck and Co.,
Rahwav, N.J.
-------
No. 49
2-Chlo ronaphthalene
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.
-------
2-CHLO RONAPHTHALZNE
SUMMARY
Monochlorinated naphthalenes are relatively insoluble in
water. They can be slowly degraded by bacteria and are subject
to photochemical decomposition. Monochlorinated naphthalenes
appear to bioconcentrate in plants and animals exposed to the
substances. 2-Chloronaphthalene has been identified as a pol-
lutant in a variety of industries.
No information was located on the carcinogenicity, mutagen-
icity,. or teratogenicity of 2-chloronaphthalene or other mono-
chlorinated naphthalenes. The metabolism of some chlorinated
naphthalenes, however, proceeds through an epoxide mechanism. If
an epoxide is formed as an intermediate in the metabolism of 2-
chloronaphthalene, it could react with cellular macromolecules
possibly resulting in cytotoxicity, mutagenicity, oncogenicity,
or other effects.
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria
Document for Chlorinated Naphthalenes (U.S. EPA, 1979b).
2-Chloronaphthalene (C,QHyCl; molecular weight 162) is a
crystalline solid with a melting point of 61°C and a boiling
point of 256"C. Its density at 16°C is 1.27. It is insoluble in
»
water and soluble in many organic solvents (Weast; 1972 and
Hardie, 1964).
-------
A review of the production range (includes importation)
statistics for 2-chloronaphthalene (CAS. No. 91-58-7) which is
listed in the inital TSCA Inventory (1979a) has shown that
between 1,000 and 9,000 pounds of this chemical were
produced/imported in 1977 ._V
Monochloronaphthalenes and mixtures of mono- and dichloro-
naphthalenes have been used for chemical-resistant gauge fluids
and instrument seals, as heat exchange fluids, high-boiling
specialty solvents (e.g., for solution polymerization), color
dispersions, engine crankcase additives to dissolve sludges and
gums, and as ingredients in motor tuneup compounds. Monochloro-
naphthalene was formerly used as a wood preservative (Dressier,
1979).
II. EXPOSURE
A. Environmental Fate
Polychlorinated naphthalenes do not occur naturally in the
environment. Potential environmental accumulation can occur
around points of manufacture of the compounds or products
containing them, near sites of disposal of polychorinated
naphthalene-containing wastes, and, because polychlorinated
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).
-------
biphenyls (PCBs) are to some extent contaminated by polychlori-
nated naphthalenes (Vos _et_ _al_. 1970; Bowes _et_ _al_. 1975) near
sites of heavy PCS contamination.
Because polychlorinated naphthalenes are relatively insol-
uble in water, they are not expected to migrate far from their
point of disposition. The use of mono- and dichlorinated naphtha-
lenes as an engine oil additive and as a polymerization solvent
in the fabric industry suggests possible contamination of soil or
water.
Walker and Wiltshire (1955) found that soil bacteria when
first grown on naphthalene could also grow on 1-chloronaph-
thalene, producing a diol and chlorosalicylic acid. Canonica et
al. (1957) found similar results for 2-chloronaphthalene. Okey
and Bogan (1965) studied the utilization of chlorinated sub-
strates by activated sludge and found that naphthalene was
degraded at a fairly rapid rate, while 1-and 2-chloronaphthalenes
were handled more slowly.
Ruzo ^t_ _al_. (1975) studied the photodegradation of 2-chloro-
naphthalene in methanol. The major reaction pathways seen were
dechlorination and dimerization. Jaffe and Orchin (1966) indi-
cated that any 2-chloronaphthalene present at the surface of
water could be degraded by sunlight to naphthalene. In the
aquatic environment, 2-chloronaphthalene can exist as a surface
film, be adsorbed by sediments, or accumulated by biota.
tff-S
-------
B. Bioconcentration
Monochlorinated naphthalenes appear to bioconcentrate in the
aquatic environment. Adult grass shrimp (Palaemonetes pugio)
were exposed to a mixture of mono- and dichloro naphthalenes for
15 days. The concentration of chloronaphthalenes detected in the
shrimp was 63 times that of the experimental environment. When
removed from the contaminated environment, however, the concen-
tration in the shrimp returned to virtually zero within 5 days
(Green and Neff, 1977).
Erickson _et_ _al_. (1978a) reported a higher relative biocon-
centration of the lower chlorinated naphthalenes in the fruit of
apple trees grown on contaminated soil. The soil was found to
have a polychlorinated naphthalene level of 190 ug/kg of which
1.6 ug/kg consisted of monochloronaphthalenes. While the apples
grown on this soil had only 90 ug/kg of polychlorinated naphtha-
lenes, the level of monochloronaphthalene was 62 ug/kg.
C. Environmental Occurrence
2-Chloronaphthalene has been identified as a pollutant in a
variety of industries, e.g. organic chemical, rubber, power
generation, and foundries (U.S. EPA, 1979c).
Chlorinated naphthalenes have been found more consistently
in air and soil samples than in associated rivers and streams
(Erickson et_ al_., 1978b). The air samples contained mainly the
mono-, di- and trichlorinated naphthalenes, while soil contained
»
mostly the tri-, tetra- and pentachlorinated derivatives.
To date polychlorinated naphthalenes have not been identi-
fied in either drinking water or market basket food. The Food
and Drug Administration has had polychlorinated naphthalene
-------
monitoring capability for foods since 1970, but has not reported
their occurrence in food (U.S. EPA, 1975).
III. PHARMACOKINETICS
Ruzo et^ al^. (1976b) reported the presence of 2-chloronaph-
thalene in the brain, kidney, and liver of pigs six hours after
injection. Small concentrations of 3-chloro-2-naphthol, a
metabolite , were seen in the kidney and liver with large amounts
occurring in the urine and bile. The metabolism of some chlori-
nated napthalenes proceeds through an epoxide mechanism (Ruzo et
al. 1975, 1976ab; Chu et al., 1977ab).
IV. HEALTH EFFECTS
A. Teratogenicity, Mutagenicity, and Carcinogenicity
No information was located on the Carcinogenicity, muta-
genicity, or teratogenicity of polychlorinated naphthalenes.
If an epoxide is formed as an intermediate in the metabolism
of 2-chloronaphthalene, it could react with cellular macromole-
cules. Binding might occur with protein, RNA, and DNA resulting
in possible cytotoxicity, mutagenicity, oncogenicity, or other
effects (Garner, 1976; Heidelberger, 1973; Wyndham and Safe,
1978).
B. Other Toxity
In man, the first disease recognized as being associated
•
with occupational exposure to higher polychlorinated naphthalenes
was chloracne. Occurrence of this disease was associated with
the manufacture or use of polychloronaphthalene-treated electri-
cal cables. Kleinfeld et al. (1972) noted that workers at
-------
an electric coil manufacturing plant had no cases of chloracne
while using a mono- and dichloronaphthalene mixture. When a
tetra-/pentachlorinated naphthalene mixture was substituted for
the original mixture, 56 of the 59 potentially exposed workers
developed chloracne within a "short" time.
The lower chlorinated naphthalenes appear to have low acute
toxicity. Mixtures of mono-/dichloronaphthalenes and tri-/tetra-
chloronaphthalenes at 500 mg/g in a mineral oil suspension
applied to the skin of the human ear caused no response over a
30-day period. A mixture of penta-/hexachloronaphthalenes given
under the same conditions caused chloroacne (Shelley and Kligman,
1957).
The oral LD50 for rats and mice is 2078 mg/kg and 886 mg/kg
respectively (NIOSH, 1978). No mortality or illness was reported
in rabbits given 500 mg/kg orally (Cornish and Block, 1958).
V. AQUATIC EFFECTS
The LC50 (ppb) of a mixture of 60% mono- and 40% dichloro-
naphthalenes in grass shrimp (Palaemonetes pugio)is as follows:
72-hr 96-hr
post larval stage - 449
adult 370 325
(Green and Neff, 1977)
VI. EXISTING GUIDELINES
There are no existing guidelines for 2-chloronaphthalene.
-------
BIBLIOGRAPHY
Bowes, G. W. j|t__al/ 1975. Identification of chlorinated diben-
zofurans in. American polychlorinated biphenyls. Nature 256, 305.
(as cited in U.S. EPA, 1979b).
Canonica, L. ^t_ ^1_. 1957. Products of microbial oxidation of
some substituted naphthalenes. Rend. 1st. Lombardo Sci. 91, 119-
129 (Abstract).
Cornish H.H., and W.D. Block. 1958. Metabolism of chlorinated
naphthalenes. J. Biol. Chem. 231, 583. (as cited in U.S. EPA,
1979b).
Chu, I., et al. 1977a. Metabolism and tissue distribution of
(1,4,5,8-^^fF-l*2-dichloronaphthalene in rats. Bull. Environ.
Contain. Toxicol. 18, 177. (as cited in U.S. EPA, 1979b) .
Chu, I., et al. 1977b. Metabolism of chloronaphthalenes. J.
Agric. Food Chem. 25, 881. (as cited in U.S. EPA, 1979b).
Dressier, H. 1979. Chlorocarbons and chlorohydrocarbons:
chlorinated naphthalenes. In. Standen A. ed. Kirk-Othmer
Encyclopedia of Chemical Technology, 3rd ed. New York: John Wiley
and Sons, Inc.
Erickson, M.D. , _et_ _al_. 1978a. Sampling and analysis for
polychlorinated naphthalenes in the environment J. Assoc. Off.
Anal. Chem. 61, 1335. (as cited in U.S. EPA, 1979b).
Erickson, M.D., et al. 1978b. Development of methods for
sampling and analysis of polychlorinated naphthalenes in ambient
air. Environ. Sci. Tech. 12(8), 927-931.
Garner, R.C. 1976. The role of epoxides in bioactivation and
carcinogenesis. In; Bridges, J. W. and L. F. Chasseaud, eds.
Progress in drug metabolism, Vol. 1. New York: John Wiley and
Sons. pp. 77-128.
Green, F. A., Jr. and-J. M. Neff. 1977. Toxicity, accumulation,
and release of three polychlorinated naphthalenes (Halowax 1000,
1013, and 1099) in postlarval and adult grass shrimp,
Palaemonetes pugio. Bull. Environ. Contain. Toxicol. 14, 399.
Hardie, D.W.F. 1964. Chlorocarbons and chlorohydrocarbons:
chlorinated naphthalenes. In: Kirk-Othmer Encyclopedia of .
Chemical Technology, ,2nd ed. John Wiley and Sons. Inc., New York.
Heidelberger, C. 1973. Current trends in carcinogenesis. Proc.
Fed. Am. Soc. Exp. Biol. 32,2154-2161.
Jaffe, H. H. and M. Orchin. .1966. Theory and aplication of
ultraviolet spectroscopy. Wiley Pub. New York, 624pp.
-------
Kleinfeld, M., _e_t _al_. 1972. Clinical effects of chlorinated
naphthalene exposure. J. Occup. Med. 14,377-379. (as cited in
U.S. EPA, 1979b).
National Institute of Occupational Safety and Health. 1978.
Registry of Toxic Effects of Chemical Substances. DREW Publ. No.
79-100.
Okey, R. W. and R. H. Bogan. 1965. Apparent involvement of
electronic mechanisms in limiting raicrobial metabolism of
pesticides. J. Water Pollution Contr. Fedr. 37, 692.
Ruzo, L.O., et al. 1975. Hydroxylated metabolites of chlo-
rinated naphthalenes (Halowax 1031) in pig urine. Chemosphere 3,
121-123.
Ruzo, L. 0., _et_ _al_. 1976a. Metabolism of chlorinated
naphthalenes. . J. Agric. Food Chem. 24, 581-583.
Ruzo, L.O., _et_ _alL. 1976b. Uptake and distribution of
chloronaphthalenes and their metabolities in pigs. Bull.
Environ. Contain. Toxicol. 16(2), 233-239.
Shelley, W. B., and A. M. Kligman. 1957. The experimental
production of acne by penta-and hexachloronaphthalenes. A.M.A.
Arch. Dermatol. 75, 689-695. (as cited in U.S. EPA, 1979b).
U.S. EPA. 1975. Environmental Hazard Assessment Report:
Chlorinated Naphthalenes. (EPA 560/8-75-001).
U.S. EPA. 1979a. Toxic Substances Control Act Chemical
Substance Inventory, Production Statistics for Chemicals on the
Non-Confidential Initial TSCA Inventory, .
U.S. EPA. 1979b. Ambient Water Quality Criteria: Chlorinated
Naphthalenes. PB-292-426.
U.S. EPA. Unpublished data obtained from the U.S. EPA
Environmental Research Laboratory, Athens, Georgia, February 22,
I979c.
Vos, J.G., ^st_ _al_. 1970. Identification and toxicological evalu-
ation of chlorinated dibenzofurans and chlorinated naphthalenes
in two commercial polychlorinated biphenyls. Food Cosmet.
Toxicol. 8_, 625. (as cited in U.S. EPA, 1979b)
Walker, N. and G.H. Wiltshire. 1955. The decomposition of 1-
chloro- and 1-bromonaphthalene by soil bacteria. J. Gen.
Microbiol. 12, 478-483.
-------
Weast, R.C., ed. 1972. CRC Handbook of Chemistry and Physics.
CRC Press, Inc., Cleveland, Ohio.
Wyndham, D., and S. Safe. 1978. In vitro metabolism of 4-
y?-//
-------
No. 50
2-Chlorophenol
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.
-------
2-CHLOROPHENOL
SUMMARY
Insufficient data exist to indicate that 2-chlorophenol
is a carcinogenic agent. 2-Chlorophenol appears to act as a
nonspecific irritant in promoting tumors in skin painting
studies. No information is available on mutagenicity, tera-
togenicity, or subacute and chronic toxicity. 2-Chlorophenol
is a weak uncoupler of oxidative phosphorylation and a con-
vulsant.
2-Chlorophenol is acutely toxic to freshwater fish at
concentrations ranging from 6,590 to 20,170 ug/1. No marine
studies are available. Concentrations greater than 60 ug/1
have been reported to taint cooked rainbow trout flesh in
flavor impairment studies.
-------
I. INTRODUCTION
This profile is based primarily on the Ambient Water
Quality Criteria Document for 2-Chlorophenol (U.S. EPA,
1979) .
2-Chlorophenol (ortho-chlorophenol) is a liquid having
the empirical formula CgHgCl (molecular weight: 128.56).
It has the following physical/chemical properties (Rodd,
1954; Judson and Kilpatrick, 1949; Sax, 1975; Stecher, 1968;
Henshaw, 1971):
Melting Point: 8.7°C
Boiling Point Range: 175-176°C
Vapor Pressure: 1 mm Hg at 12.1°C
Solubility: Slightly soluble (lg/1)
in water at 25°C and
neutral pH
2-Chlorophenol is a commercially produced chemical used
as an intermediate in the production of higher chlorophenols
and phenolic resins and has been utilized in a process for
extracting sulfur and nitrogen compounds from coal (U.S. EPA,
1979).
2-Chlorophenol undergoes photolysis in aqueous solutions
as a result of UV irradiaton (Omura and Matsuura, 1971;
Joschek and Miller, 1966). Laboratory studies suggest that
microbial oxidation could be a degradation route for 2-chlo-
rophenol (Loos, et al., 1966; Sidwell, 1971; Nachtigall and
Butler, 1974). However, studies performed by Ettinger and
Ruchhoft (1950) on the persistency of 2-chlorophenol in sew-
age and polluted river water indicated that the removal of
»
monochlorophenols requires the presence of an adapted micro-
flora.
-------
II . EXPOSURE
A. Water
The generation of waste from the commercial produc-
tion and use of 2-chlorophenol (U.S. EPA, 1979) and the inad-
vertent synthesis of 2-chlorophenol due to chlorination of .
water contaminated with phenol (Aly, 1968: Barnhart and Camp-
bell, 1972; Jolley, 1973; Jolley, et al., 1975) are potential
sources of contamination of water with 2-chlorophenol. How-
ever, no data regarding 2-chlorophenol concentrations in fin-
ished drinking water are available (U.S. EPA, 1979).
B. Food
Information on levels of 2-chlorophenol in foods is
not available. Any contamination of foods is probably indi-
rect as a result of use and subsequent metabolism of phenoxy-
alkanoic herbicides (U.S. EPA, 1979). Although residues of
2,4-dichlorophenol were found in tissues of animals fed 2,4-D
and nemacide containing food (Clark, et al. 1975); Sherman,
et al. 1972), no evidences were cited to indicate the pres-
ence of 2-chlorophenol; moreover, there was no contamination
of 2-chlorophenol in milk and cream obtained from cows fed
2,4-D treated food (Bjerke, et al. 1972).
The potential for airborne exposure to 2-chloro-
phenol in the general environment, excluding occupational ex-
posure, has not been reported (U.S. EPA, 1979).
The U.S. EPA (1979) has estimated the weighted
average bioconcentration factor for 2-chlorophenol and the'
edible portion of fish and shellfish consumed by Americans at
-------
490. This estimate is based on measured steady state biocon-
centration studies in bluegills.
C. Inhalation
Pertinent data regarding concentrations of 2-chloro-
phenol in ambient air could not be found, in the available
literature.
III. PHARMACOKINETICS
A. Absorption
Data dealing directly with the absorption of 2-
chlorophenol by humans and experimental animals has not been
found. Chlorophenol compounds are generally considered to be
readily absorbed, as would be expected from their high lipid
solubility and low degree of ionization at physiological pH
(Doedens, 1963; Farquharso'n, et al., 1958). Toxic ity studies
indicate that 2-chlorophenol is absorbed through the skin.
B. Distribution
Pertinent data regard.ing tissue distribution of 2-
chlorophenol was not located in the available literature.
C. Metabolism
Data regarding the metabolism, of 2-chlorophenol in
humans was not available (U.S. EPA, 1979). Based on experi-
mental work in two species, it appears that the metabolism of
2-chlorophenol in mammals is similar to that of phenol in
regard, to the formation and excretion of sulfate and glucur-
onide conjugates (Von Oettingen, 1949; Lindsay-Smith, et al.
#
1972) Conversion of chlo.robenzene to monochlorophenols,
including 2-chlorophenol, has been shown J.n vitro with rat
-------
liver (Selander, et al. 1975) and in vivo> with rabbits
(Lindsay-Smith, et al. 1972).
D. Excretion
Studies on rate and route of excretion for
2-chlorophenol in humans were not available. Dogs excreted
87 percent of administered 2-chlorophenol in the urine as
sulfate and glucuronide conjugates (Von Oettingen, 1949).
The same metabolites were found in the urine of rabbits after
administration of chlorobenzene (Lindsay-Smith, et al. 1972);
however, out of the total free and conjugated chlorophenols
only 6 percent were present as 2-chlorophenol.
IV. EFFECTS
A. Carcinogenicity
Insufficient data exist to indicate that 2-chloro-
phenol is a carcinogen. In the only study found (Boutwell
and Bosch, 1959), 2-chlorophenol promoted skin cancer in mice
after initiation with dimethylbenzanthracene and when repeat-
edly applied at a concentrations high enough to damage the
skin. 2-Chlorophenol was not carcinogenic when applied re-
peatedly without initiation with dimethylbenzanthracene, but
did induce a high incidence of papillomas and no carcinomas.
Information regarding mutagenicity, teratogenicity,
other reproductive effects and chronic toxicity could not be
found in the available literature.
F. Other Relevant Information
2-Chlorophenol is a weak uncoupler of oxidative
phosphorylation (Mitsuda, et al., 1963) and a convulsant
(Farquharson, et al., 1958; Angel and Rogers, 1972).
.TO-/
-------
V. AQUATIC TOXICITY
A. Acute Toxicity
Acute studies on four species of fish have produced
96-hour static LC50 values ranging from 6,590 ug/1 in the
bluegill (Lepomis macrochirus) (U.S. EPA, 1978) to 20,170
ug/1 to the guppy (Poecilia reticulatus). Juvenile bluegills
were more sensitive in a static renewal assay with an LC50
value of 8,400 ug/1. The fathead minnow (Pimephales prome-
las) was the only freshwater fish tested in a flow through
system and gave an LC5Q value of 12,380 ug/l» Daphnia
magna has been found to have 48-hour static LC5Q values
of 2,580 ug/1 and 7,430 ug/1. No data concerning the effects
of 2-chlorophenol to marine fish or invertebrates are avail-
able.
B. Chronic Toxicity
Effects were not obtained in a chronic embryo-
larval test of 2-chlorophenol at concentrations as high as
1,950 ug/1 for the freshwater fathead minnow. Additional
chronic studies are not available.
C. Plant Effects
The only plant assay available provides an effec-
tive concentration of 500,000 ug/1 in chlorophyll reduction
in the algae, Chlorella pyrenoidosa.
D. Residues
. A measured bioconcentration factor of 214 has been
obtained for the bluegill. The half-life was less than one
day, indicating a rapid, depuration rate for 2-chlorophenol.
-------
E. Miscellaneous
Flavor impairment of the edible portion of fish
exposed to 2-chlorophenol has been reported. The highest
concentration of 2-chlorophenol in the exposure water which
would not impair the flavor of cooked rainbow trout (Salmo
gairdneri) has been estimated at 60 ug/1 Shumway and
Palensky, 1973).
VI. EXISTING GUIDLINES AND STANDARDS
Neither the human health nor the aquatic criteria de-
rived 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 may be changed.
A. Human
Based on the prevention of adverse organoleptic ef-
fects, the U.S. EPA (1979) draft interim criterion recommend-
ed for 2-chlorophenol in ambient water is 0.3 ug/1. There
are no other standards or guidelines for exposure to 2-chlo-
rophenol.
B. Aquatic
Based on the tainting of fish, the draft criterion
to protect freshwater organisms from 2-chlorophenol is 60
ug/1 as a 24-hour average, not to exceed 180 ug/1 at any
time. No criterion was derived for marine life (U.S. EPA,
1979) .
SO'f
-------
2-CHLOROPHENOL
REFERENCES
Aly, O.M. 1968. Separation of phenols in waters by thin
layer chromatography. Water Res. 2: 587.
Angel, A., and K.J. Rogers. 1972. An analysis of the con-
vulsant activity of substituted benzenes in the mouse. Toxi-
col. Appl. Pharmacol. 21: 214.
Barnhart, E.L., and G.R. Campbell. 1972. The effect of
chlorination on selected organic chemicals. U.S. Government
Printing Office, Washington, D.C.
Bjerke, E.L., et al. 1972. Residue study of phenoxy herbi-
cides in milk and cream. Jour. Agric. Food Chera. 20: 963.
Boutwell, R.K., and O.K. Bosch. 1959. The tumor-promoting
action of phenol and related compounds for mouse skin.
Cancer Res. 19: 413.
Clark, D.E., et al. 1975. Residues of chlorophenoxy acid
herbicides and their phenolic metabolites in tissues of sheep
and cattle. Jour. Agric. Food Chem. 23: 573.
Doedens, J.D. 1963.. Chlorophenols. Page 325 _in Kirk-Othmer
encyclopedia of chemical technology. John Wiley and Sons,
Inc., New York.
Ettinger, M.B., and C.C. Ruchhoft. 1950. Persistence of
monochlorophenols in polluted river water and sewage dilu-
tion. U.S. Pub. Health Serv., Environ. Health Center, Cin-
cinnati, Ohio.
Farquharson, M.E., et al. 1958. The biological action of
chlorophenols. Br. Jour. Pharmacol. 13: 20.
Henshaw, T.B. 1971. Adsorption/filtration plant cuts
phenols from effluent. Chem. Eng. 76: 47.
Jolley, R.L. 1973. Chlorination effects on organic
constituents in effluents from domesti'c sanitary sewage
treatment plants. Ph.D. dissertation. University of
Tennessee.
Jolley, R.L., et al. 1975. Chlorination of cooling water: A
source of environmentally significant chlorine-containing
organic compounds. Proc. 4th Natl. Symp. Radioecology.
Corvallis, Ore. •
Joschek, H.I., and S.I. Miller. 1966. Photoclea.vage of
phenoxyphenols and bromophenols. Jour. Am. Chem. Soc. 88:
3269.
-------
Judson, C.M., and M. Kilpatrick. 1949. The effects of sub-
stituents on the dissociation constants of substituted
phenols. I. Experimental measurements in aqueous solutions.
Jour. Am. Chem. Soc. 74: 3110.
Lindsay-Smith, J.R., et al. 1972. Mechanisms of mammalian
hydroxylation: Some novel metabolites of chlorobenzene.
Xenobiotica 2: 215.
Loos, M.A., et al. 1966. Formation of 2,4-dichlorophenol
and 2,4-dichlorophenoxyacetate by Arthrobacter Sp. Can.
Jour. Microbiol. 13: 691.
Mitsuda, H., et al. 1963. Effect of chlorophenol analogues
on the oxidative phosphorylation in rat liver mitochondria.
Agric. Biol. Chem. 27: 366.
Nachtigall, H., and R.G. Butler. 1974. Metabolism of
phenols and chlorophenols by activated sludge microorganisms.
Abstr. Annu. Meet. Am. Soc. Microbiol. 74: 184.
Omura, K., and T. Matsuura. 1971. Photoinduced reactions -
L Photolysis of halogenophenols in aqueous alkali and in
aqueous cyanide. Tetrahedron 27: 3101.
Rodd, E.H. 1954. Chemistry of carbon compounds. III-A.
Aromatics. Elsevier Publishing Co., Amsterdam.
Sax, H.I. 1975. Dangerous properties of industrial mate-
rials. 4th ed. Van Nostrand Reinhold Co., New York.
Selander, H.G., et al. 1975. Metabolism of chlorobenzene
with hepatic microsomes and soluble cytochrome P45Q Sys-
tem. Arch. Biochem. Biophys. 168: 309
Sherman, J., et al. 1972. Chronic toxicity and residues
from feeding nemacide 0 (2-,4-dichlorophenol) 0, 0-diethylphos-
phorothioate to laying hens. Jour. Agric. Food Chem. 23:
617.
Shumway, D.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. Government Printing Office,
Washington, D.C.
Sidwell, A.E. 1971. Biological treatment of chlorophenolic
wastes - the demonstration of a facility for the biological
treatment of a complex chlorophenolic waste. Water Pollut.
Control Res. Ser. 12130 EKG.
»
Stecher, P.G., ed. 1968. The Merck Index. 8th ed. Merck
and Co., Rahway, N.J.
So-11
-------
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. 2-Chlorophenol: Ambient Water Quality Cri-
teria (Draft).
Von Oettingen, W.F. 1949. Phenol and its derivatives: the
relation between their chemical constitution and their effect
on the organism. Natl. Inst. Health Bull. 190: 193.
-------
SJ-45-01
No. 51
Chr omium
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
October 30, 1980
51-1
-------
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. Be-
cause 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 sub-
ject material. This document has undergone scrutiny to ensure
its technical accuracy.
51-2
-------
CHROMIUM
Summary
Hexavalent chromium (CrVI), at low concentrations in water,
has a deleterious effect on the growth of fish, aquatic inver-
tebrates, and certain species of algae. For the most sensi-
tive aquatic species, Daphnia magna, a final chronic no-effect
level of less than 10 ug/1 has been derived by the U.S. EPA.
For trivalent Cr(Crlll) toxic effects are more pronounced in soft
than in hard water; chronic no-effect levels are derived as a
function of water hardness.
Several hexavalent Cr compounds have produced tumors
in animal studies. Human epidemiology studies indicate a
possible etiology of Cr exposure in the production of lung
tumors in occupationally exposed workers. Trivalent Cr has
•
not shown carcinogenic effects.
Mutagenic effects, including cytogenetlc effects in
exposed workers, have been reported for hexavalent chromium
compounds. Trivalent chromium compounds were not mutagenic
in the Ames bacterial assay. Teratogenic effects of chromium
have been reported in a single study and have not been
confirmed.
Impairment of pulmonary function has been reported in
chrome electroplating workers subject to chronic chromium
exposure. However, exposure to multiple agents complicates
the interpretation of this finding.
51-3
-------
CHROMIUM
I. INTRODUCTION
«
This profile is in large part based on the Ambient
Water Quality Criteria Document for Chromium (U.S. EPA, 1980).
Chromium (Cr) is a steel gray, lustrous, hard metal that
melts at 1857 + 20°C, boils at 2672°C, and has a specific
gravity of 7.18 to 7.20 at 20 °C (Weast, 1974). Cr compounds
exist in a variety of oxidation states; the most commonly
occurring are those of the trivalent and hexavalent states.
Physical properties of some Cr compounds are summarized in
Table 1.
Cr compounds are utilized in the paint and dye industries
as pigments and mordants, in metallurgy for the production of
stainless steel and other alloys, in the chrome tanning of
leather goods, in the production of high melting refractory
materials, and for chrome plating.
Hexavalent Cr compounds are relatively water soluble and
are readily reduced to more stable and insoluble trivalent
forms by reaction with organic reducing matter. Trivalent
chromium forms stable hexacoordinate complexes with a great
variety of ligands (water, ammonia, urea, halides, sulfates,
ethylene diamine, organic acids). In neutral and basic
solutions, trivalent Cr may form polynuclear bridge compounds
that eventually precipitate. Hexavalent Cr exists in solution
as a component of an anion (hydrochromate, chromate, or
dichromate) and does not precipitate from alkaline solution.
51-4
-------
The specific anionic form of hexavalent Cr is dependent on •
pH - in the acid range hydrochromate predominates, while in
the alkaline range the predominant form is chromate (Trama
and Benoit, 1960). Cr VI occurs naturally in alkaline soft
waters (Robertson, 1975) and in aerated sea water (Fukai,
1967; Cutshall et. al., 1965; Emerson et. al., 1979). The
oxidation of CR III is expected to occur on energetic grounds
(Carlin, 1965; U.S. EPA, 1977). In fact, .however, oxidation
takes place only very slowly in natural waters, except in the
presence of Mn02 (Schroeder and Lee, 1975; U.S. EPA, 1978).
Under laboratory conditions oxidation does occur (Schroeder
and Lee, 1975; Stephens, 1977). In contrast, the reduction
of Cr VI to Cr III occurs rapidly in lake waters (Schroeder
and Lee, 1975).
It seems probable that in most waters, especially under
neutral or slightly acid conditions-, Cr VI is reduced to Cr
III, the hydroxy complexes of which precipitate out and/or
are absorbed onto clays and other soil elements (N.A.S.,
1974; U.S. EPA, 1978).
Since Cr is an element, it persists indefinitely in the
environment in some form. Trivalent Cr compounds are more
likely to accumulate in sediments, while hexavalent forms
remain soluble and dissipate with the water flow (U.S. EPA, 1980)
II. EXPOSURE
Large amounts of hexavalent Cr are produced and utilized
51-5
-------
in industry, primarily as chromates and dichromates (U.S.
EPA, 1980). Industrial processes consumed 320,000 metric
tons of Cr metal alone in 1972.
Much of the detectable chromium in air and water is
presumably derived from industrial processes. Levels of
total Cr in the air exceeding 0.10 mg/m^ were reported
from 59 of 186 urban areas examined (U.S. EPA, 1973). Air
levels in non-urban areas generally fall below detection
limits. Mean concentration of Cr in 1577 samples of surface
water was determined as 9.7 ug/1 (Kopp, 1969). Cr is naturally
distributed in the continental crust at an average concentration
of 125 rag/kg (N.A.S., 1974).
Based on available monitoring data, the U.S. EPA (1980)
has estimated the uptake of Cr by adult humans from air,
water and food:
Source Uptake ug/day
Atmosphere 1
Water 20
Food Supply 50-100
121
A different estimate for self-selected diets was 280ug/day
(NAS, 1974). It is often stated that the American diet may
be marginally deficient in Cr. Since a MDR has not yet been
established (Mertz, 1978), and since absorption factors (see
below) are as yet poorly understood, this statement is open
to question.
51-6
-------
Table \. Physical Hropertlea of Typical Chromium Compounds
Compound
On 1 da t ion stale 0
Chromium car bony 1
In benzene
clirouiium(O)
Oxidation slate * 1
i>lu( Llpliunyl )-
chromium (1)
lull Ida
Oxidation slale * 2
Cliroiuuua acclatu
Chroiiious chloride
Clironous ammonium
auH'alu
Oxidation stale » 3
Chromic chloride
Chruwlo acclyl-
Ciirunic |iolasslum
aiill'dlb (chroma
it 1 UOl )
Clirttulu uhlurldu
Cliruin i^^li 1 or 1 du
llull.t^^H'.llU
Formula Appearance
(Cr(CO>6 Colorless
cryatala
(CJI, ),.Cr Droun
b b f. . ,
crystals
(C. II^C,!!, )_CrI Orange plates
Cr,(C II 0 )U-2II,0 Red crystals
223212
CrCl White
cryatala
CrSO|(.(Hlllt)2SO||.6ll20 Blue cryatala
CrCl. Urlght purple
* plates
Cr(CII-.COCIICOCM ) Hed-vlolet
J 3 * cryatala
KCr(SO( )_• )2H_0 Deep purple
crystals
(Cr(ll Ot.Cl )CI-2II20 Urlght eruun
cryatala
(Cr(ll.,0)6)Cl3 V»olot
crystals
Crystal ayatom Density
and space group (g/cm )
Orlhorhoinblo, C:! 1*77. a
£r 10
Cubic, Pa.. . 1.519
3
1-'17.«
Monoollnlo, C2./Q 1.79
Tetragonal, DJ! 2.93
Ml*
S
HonooUnlc, C.
•a __c
•* » rviOrD o n-»
lloxa^oital, D. 2.U7-C
Honoollnlo 1.3M
£
Cubic, A 1.U261(-
(1 ID
Trial Inlcor 1.B3525
uonoclinlo
llhoiabohudral, 0,.
Halting Dolling
point Pglnt
150 151
(decomposed) (decomposed)
(sealed tube)
281-21)5 Sublimes 150
(vacuum)
178 Decomposes
•
815 1120
Sublimes 685
208 315
89
( Inoongruent )
95
90
Solubility
Slightly soluble In
CC1U; Insoluble in
U20, (C2H5)20,
Insoluble In ILO;
soluble in C II,
b o
Soluble In
C2">j0"« c»,"ijM
Slightly soluble In
II 0; soluble In
aolida
Soluble In II-,O to blue
solution, absorbs U
Soluble In U.,0,
absorbs Q
Insoluble In U.,0.
soluble In presence
ol' Cr
Insoluble In II .,0; ...
soluble In C,|l .
0 6
Soluble In IIO
Soluble In II^O, green
solution turning
groen-vlolut
Soluble In H.,0, violet
solution turning
uruun-vlolbl^
-------
Compound 'Formula
throoiic oildu Cr.O-
* J
Oxidation atate » 1
Chromium (IV) oxide CrO,
£
Chroulua(IV) CrCli,
L-tllurldu
Oxidation state * 5
barium chrouate(lV) Ua..(CrOh).
J 1 «
Oxidation slate * 6
Chronlum(Vl) CrO
oxldb
Cliri.uyl chloride CrO.Cl.
Ammonium (HII.KCr 0
dlclirowjlu
rolaaunim *2Cr2°7
dtuhrouule
Sodium dl chroma le ll' Ci-0 • 211-0
1
Potassium chruraute K CrO^
Ziudluo uhromate lla^CrO.
Potassium chloro- KCrO^Cl
chruuate
!illvur uliroualu Ig CrO^
* 1
.
ll.irluiu cliroiiiiile liuCi-O.
'1
Appearance
Green powder
or crystals
Dark Drown or
black powder
Dtack-green
crystals
Huby-red
crystals
Cherry-red
liquid
Red-orange
crystals
Orange-red
crystals
Orauge-rcd
crystals
follow
crystals
Yellow
crystals
Orange
crystals
Iliiroon
crystuls
Main yellow
solid
Crystal aystea Density
and apace group (g/cm )
llhombohcdral, D,. $.22^
IU
Tutragonul, »,!. 4.90
(calculated)
Stable only at
.high temp.
Same aa
Ca.-d'O. )
J H 2
•
Ortliorhomblo, C?' 2'725
3
1.9I1525
Honocllnlo 2.l552c
•
Trlollnlo . 2.676.,.
Honoollnlo ''^''"pS
3
Orlhorhouiblo 2.TW &
17
Ortliorhoiuhlo. D ' 2.723-,^
Monocllnlo 2.*I97^(|
"
Monocllnlc 5.625,,.-
25
Orthorhoinblo 4.'I90.>|.
'•>
Melting Dolling
point point
2135 oa. 3000
Deooopoaea
to Cr20
630
*
197 Decomposes
..'
-96.5 115.0
Deoonpoaea
390 Decomposes
01.6 Decomposes
(tnoongruont)
971
792
Decomposes
Deoonposoa
Solubility
Insoluble
Soluhle In act da to
CrJ* and Cr°*
Slightly decomposes
In ILO; soluble In
dllnCe acids to
Cr1* and Cr
Very aoluble In ll.0|
aoluble In CD
COCII, (Cll C0)^5
Insoluble In ll^Oi
liydrolyxesi Soluble
In CS 001
Soluble In U.,0
Soluble In H.,0
Very soluble In U.,0
Soluble In H.,0
Soluble In U.,0
Soluble In U.,0,
hydrolyxes
Very alightly aoluble
In ILO; soluble In
dilute acids
Very slightly aol'ubla
In II. ,0; soluble In
strung acids
-------
Compound Formula
Strontium chroma te SrCrO^
Lead chroma te PbCrO^
Appearance
Yellow solid
Yellow solid
Orange solid
lied solid
Crystal system Density
and apace group (g/cn )
Honoollnlo. C*^ 3'fl95i5
Ortliorhomblc _
Honoollnlo, CJL 6-l2|5
Tetragonal
He 1 ting boiling
point ' point
(°0 (°C)
Decomposes
U'lM
Solubility
Slightly soluble In
II 0; soluble In
dilute aclda
Practically insoluble
In II 0} soluble in
strong aclda
Source: Adapted fron U.S. EPA, I97B.
-------
The U.S. EPA (1980) has derived a bioconcentration factor
(BCF) of 11 for chromium.
III. PHARMACOKINETICS
A. Absorption
• The efficiency of Cr absorption by the gastroin-
testinal tract is a function of the oxidation and chemical
forms of the compound and the presence of other dietary
constituents, and poorly understood intestinal epithelial
barriers (U.S. EPA, 1980; Mertz, 1978). Oral administration
of trivalent Cr results in little absorption. In order to be
assimilated chromium must be present in the form of an organic
complex with nicotinic acid termed glucose tolerance factor (GTF)
(Mertz, 1969; 1971; 1978). Inorganic Cr is poorly assimilated
(a few per cent) (Mertz, 1969; 1971). Cr from animal sources is
.much better utilized than that from vegetables, in which it may
occur in high concentrations (Mertz, 1978). Dermal absorption of
Cr does not contribute greatly to total body load, except in
•
situations where toxic external concentrations have produced
ulceration (U.S. EPA, 1980). Pulmonary exposure to Cr, which can
be significant in some industrial situations, leads to prolonged
retention at this site (Baetjer, et al. 1959). Under most conditions,
however, the contribution of the inhalation route to total absorbed
Cr is small (U.S. EPA, 1980).
B. Distribution
Analysis of the metabolism and distribution of Cr
51-10
-------
is complicated by the fact that the methods available for the
estimation of Cr at low levels do not adequately distinguish
between its different forms (U.S. EPA 1980; 1978). In
addition, difficulties of interpretation arise from the fact
that cellular constituents reduce Cr to the trivalent form
(Petrilli and DeFlora 1978; Nakamuro 1978).
Absorbed Cr is primarily transported bound to siderophilin,
a metal transport protein which predominantly binds iron.
The organ distribution of Cr is highly dependent on the
chemical form administered. For instance, while trivalent Cr
does not extensively cross the placental barrier, when admin-
istered to pregnant rats in completed form (GIF), it is
taken up by the fetus. The highest concentrations of Cr
accumulate in skin, lung, muscle and fat (Mertz 1969, Casarett
and Doull, 1979). Pulmonary Cr arises from inhalation, and
does not equilibrate with other body stores. Cr concentration
in tissues other than lungs decline somewhat with age (Mertz 1969)
Hexavalent Cr is reduced to the trivalent form in skin.
In the blood little hexavalent Cr is detected. The reticulo-
endothelial system, liver, spleen, testis and bone marrow
have an affinity for trivalent Cr, (Mertz 1969); chromates
are bound largely to red blood cells (Mertz 1969). Inside
cells, about half of the Cr is in the nucleus.
C. Metabolism
Analysis of chromium metabolism is complicated by
the extensive binding of chromium to tissue components
51-11
-------
(enzymes, proteins, nucleic acids) and by the inability of
*
analytical methods to distinguish between the different forms
of chromium (U.S. EPA, 1978; 1980).
Studies of the kinetics of radiochromium distribution in
humans .indicated three major accumulation and clearance
components (Lim, 1978). Animal studies with radioactive
chromium trichloride injected intravenously showed that heart,
lung, pancreas, and brain retain only 10 to 31 percent of
their initial radioactivity after four days. Spleen, kidney,
testis and epididymls concentrate chromium (Hopkins, 1965).
Average urinary and blood concentrations are 0.4 and 2.8
ug/lOOg, respectively (Casarett and Ooull, 1979). Because of
rapid clearance, blood concentration is not an indicator of
Cr intake (Mertz, 1971).
D. Elimination
Chromium turnover in humans appears to be very slow
(National Academy of Sciences, 1974). One component of
i
chromium elimination has been calculated to have a half-life
of 616 days (Taylor, 1975). In rats, three compartments
for trlvalent chromium have been estimated to have half-
lives of 0.5, 5.9, and 83.4 days, respectively (Mertz, et al. ,
1965).
Chromium is excreted in both urine and feces. Urinary
excretion is the major route of elimination, accounting
for recovery of 80 percent of injected chromium (Mertz, 1969).
Up to 20 percent of intravenously injected trivalent chromium
was found in the feces of rats (Visek, et al. 1953). Milk
51-12
-------
also contributes to excretion (Casarett, 1979).
IV.. EFFECTS
A. Carcinogenicity
Carcinogenicity of various hexavalent Cr compounds
in humans has been well documented (U.S. EPA, 1980). EPA1s
Carcinogen Assessment Group (CAG) has determined that there
is substantial evidence that hexavalent Cr compounds are
carcinogenic in man. Six epidemiologic studies, conducted
at five different locations, of 1200 chromate workers provide
strong evidence that inhalation of Cr VI produces lung cancer
(U.S. EPA, 1978; 1980). One study (Taylor, 1966) also showed
an increase in digestive cancer. In rats and hamsters
inhalation studies using calcium chromates have produced
cancer (Laskin, 1973), and Cr VI is carcinogenic when implanted
in intrabronchial pellets, as well as by subcutaneous and
intramuscular injection in mice and rats. However, the
Carcinogenicity of Cr VI has not been tested by oral admini-
stration (U.S. EPA, 1980).
The determination of the Carcinogenicity of Cr VI compounds
rests mainly on epidemiologic studies (see above) of employees
in industries which use or produce chromates. Cr III compounds
are used principally in the manufacture of ferrochrome,
chromite bricks and steel, in leather tanning and in lithography,
Data on the Carcinogenicity of trivalent Cr are felt to be
inadequate (Heimann, 1976). Rats showed a weak carcinogenic
response to chromic (Cr III) acetate (Hueper and Payne, 1962;
51-13
-------
Maltoni, 1974). Cr may be a co-carcinogen or promoter:
chromium carbonyl is a mild synergist for benzo(a)pyrene in
the production of carcinomas in tracheal grafts in rats
(Lave and Mass, 1977). Such effects could be important in
the development of lung cancer following pulmonary exposure
to chrornates.
B. Mutagenicity
Cytogenetic effects in workers exposed to welding
fumes have been attributed to inhaled chromium (Hedenstedt, et
al., 1977). These effects have also been reported in chromate
production workers (Bigalief, et al., 1977).
Cr compounds induce chromosomal aberrations in human and
animal leukocytes, and mutations in bacteria and yeasts (U.S.
EPA, 1980; Petrilli and DeFlora, 1978a,b; Nakumoro 1978).
In these tests Cr VI compounds have much higher activity
than Cr III compounds. Under some assay conditions cellular
reducing agents (ascorbic acid, NADH, NADPH, GSH) prevent Cr
VI mutagenicity by reducing it to CR III (Petrilli and
DeFlora, 1977; 1978a, b). Nakamuro, however (1978) found
that Cr (III) acetate, nitrate and chloride induce chromosomal
damage in cultured human leukocytes, and are bacterial mutagens,
C. Teratogenicity
Embryonic abnormalities have been produced in the
developing chicken by direct injection of trivalent or
hexavalent chromium into the yolk sac or onto the chorioallan-
toic membrane (Ridgway and Karnofsky, 1952). This effect
51-14
-------
has not been further investigated, and is worrisome because
of the reported placental permeability to complexed Cr (Mertz
1969).
D. Other Reproductive Effects
Pertinent information could not be located in the
available literature.
E. Chronic Toxicity
Except as regards the carcinogenicity of Cr VI,
the concentrations of Cr encountered in the normal environment
do not constitute a human health hazard. However, acute
and chronic toxicity problems associated with exposure to Cr
are of concern in the industrial environment. These effects
have been reviewed (NIOSH, 1975; EPA, 1980), and include
damage to liver, kidney, skin, respiratory passages and lungs
(U.S. EPA, 1978, 1980; NAS 1974, 1977; NIOSH, 1975). Allergic
dermatitis is a pronounced property of both tri- and hexavalent
Cr compounds (EPA, 1980; Casarett and Doull, 1979).
Subtle changes in pulmonary function have been observed
in workers employed in electroplating (Bovett et. al.f 1977).
Cr VI causes ulceration and perforation of the nasal systems,
chronic rhinitis and pharyngitis, but these effects have been
observed only in workers chronically exposed to relatively
high concentrations of chromates (NIOSH, 1975).
V. AQUATIC TOXICITY
A. Chronic Toxicity
No data for chronic toxicity of trivalent chromium
51-15
-------
for freshwater fishes is available. The geometric mean of
chronic toxicity values for the freshwater invertebrate
Daphnia magna is based on data from a single study, and is
reported as 445 ug/1. No chronic data for trivalent chromium
for freshwater algae are available.
Chronic embryo-larval tests on six species of fresh
water fish exposed to Cr VI resulted in values ranging from
37 to 72 ug/1 for rainbow trout (Salmo gairdneri) and lake
trout, Salvelinus mamaycush. White suckers, Catostomus
conunersoni, and channel catfish, Ictalurus punctatus, were
intermediate in sensitivity and northern pike, Esox lucius,
and bluegills, Lepomis macrochirus, were least sensitive
with chronic values of 360 and 368 ug/1 respectively. In
life cycle or partial life cycle tests, both the rainbow trout
and snook trout, Salvelinus fontinalis, were sensitive with
chronic values of 265 ug/1. Chronic testing of hexavalent
chromium in Daphnia magna found significant survival and
fecundity changes at concentrations as low as 10 ug/1. The
effects of hexavalent chromium .on the freshwater algae,
Ch1amydomonas reinhardi, were recorded at levels as low as 10
ug/1. The Eurasian watermilfoil displayed the greatest
resistance to hexavalent chromium, even at levels as high as
9,900 ug/1.
There are no chronic toxicity data available for trivalent
chromium compounds in marine fish, invertebrates or algae.
The only available bioconcentration data for freshwater
51-16
-------
species are from studies on rainbow trout, and indicate a
bioconcentration factor of 1 for potassium chromate. Marine
bioconcentration factors in three species of bivalve molluscs,
Mytilus edulis, (34) , Crassostrea Virginia (166) , and Mya arenaria ,
(152), give a 'geometric mean of 114. The weighted average BEF
is 11 (U.S. EPA, 1980).
B. Acute Toxicity
The acute toxicity of trivalent. chromium compounds
has been examined extensively. The 96-hour LCso values
for 14 tests ranged from 3,330 to 71,900 ug/1 and correlates
with the hardness of water over a range of 20 to 360 ug/1 (as
CaC03) in 11 species of freshwater fish. The guppy Poecilia
reticulata was most sensitive and the bluegill the most
resistant. Among eight species of freshwater invertebrates,
acute 96-hour LCso values ranged from 2,000 to 64,000 ug/1.
For hexavalent chromium 96-hour LCso values ranged from
17,600 ug/1 in the fathead minnow, Pimephales promelas, in
soft water to 195, --- ug/1 for large mouth bass, Micropteus
salmoider, in hard water. The 96-hour LCso values for
freshwater invertebrates exposed to hexavalent chromium ranged
from 3,100 ug/1 in the rotifer, Philodina acuticornis, to
12,000 ug/1 in the rotifer, Philodina roseola.
There are no pertinent acute toxicity data available
regarding the toxicity of Cr III compounds to marine species.
The acute toxicity data for hexavalent chromium to marine
fishes resulted in 96-hour LCso values of 30,000 to 30,000
51-17
-------
ug/1 for the speckled sanddab, Citharichthys stigmaeus, and
91,000 ug/1 for .the mummichog, Fundulus heteroclitus. In-
%
vertebrates appeared more sensitive to hexavalent chromium
than marine fish. The 96 hour LCso values for hexavalent
chromium ranged from 2,000 ug/1 for the polychaete worm,
Nereis vinens, to 105,000 ug/1 for the mud snail, Nassarius
obsoleutus, in static bioassays.
The U.S. EPA (1978) offers an extensive review of the
environmental effects of chromium compounds in freshwater and
marine organisms.
VI. EXISTING GUIDELINES
Standards promulgated by various U.S. agencies are
summarized in Table I.
Based on animal data indicating carcinogenic effects of
chromium VI and estimates of lifetime exposures from
consumption of both drinking water and aquatic life forms,
the U.S. EPA (1980) has estimated that the concentrations of
hexavalent chromium in ambient water should be no greater
»
than 7.1 ng/1 to keep the lifetime risk of cancer below 1 in
100,000. This risk calculation is based on the conservative
assumption that ingestion of Cr VI can cause cancer. EPA's
Water Quality Criteria Document (U.S. EPA 1980) discusses
this and' alternative assumptions.
The OSHA time-weighted average exposure criterion for
chromium (carcinogenic compounds) is 1 ug/m3; for the "non-
carcinogenic" classification of chromium compounds the
criterion is 25 ug/m3 (OSHA 1979).
51-18
-------
TABLE 1
Recommended or Established Standards for Cr in the United States
MEDIUM
CHEMICAL
SPECIES
REFERENCE
STANDARD
Drinking Water
Domestic Water Supply
Fresh Water (aquatic
life)
Ambient Water Quality
Criteria
Livestock Water
Work Place AIR
Cr VI
total chromium
total chromium
total chromiumc
Cr VIC
Cr VI
care inogenic
Cr VIa
noncarcinogenic
Cr VIa
soluble chromic
and chromous salts
metal and insoluble
salts
U.S. Public Health
Service (1962)
U.S. EPA (1976)
U.S. EPA (1976)
U.S. EPA (1980)
U.S. EPA (1980)
Nat'l. Acad. Sci.
(1972) and Nat'l.
Acad. Eng. (1972)
Nat'l. Inst. Occup.
Safety and Health
(1975)
Nat'l. Inst. Occup.
Safety and Health
(1975)
29 CFR 1910.1000
29 CFR 1910.000
50 ug/1
50 ug/1
100 ug/1
50 ug/1
0.007 ug/1
1 mg/1
1 ug/m3
25 ug/m3 TWAb
50 ug/m3 ceiling
0.5 mg/m3
1.0 mg/ m3
aCarcinogenic compounds
mono-or dichromates of
>ime-weighted average
. , - ^ ~
are here taken to include all forms of Cr VI other
H, Li, Na, K, Rb, Cs, and NH4.
than CrO3 and
-------
For the protection of aquatic species, proposed water
t
criteria for both trivalent and hexavalent chromium in fresh-
water and marine environments have been prepared in accordance
with the Guidelines for Deriving Water Quality Criteria
(Federal Register 43_: 21506, May 18, 1975 and Federal Register
£3_:29028, July 5, 1978). In freshwater environments the
proposed criterion for hexavalent chromium is 10 ug/1, not to
exceed 110 ug/1, and the proposed criterion for trivalent Cr
is given a Chronic Final Value represented by the following
equation:
C.F.V. = e (0.83 In (water hardness) = 2.94)
The proposed criterion for trivalent chromium in marine
environments could not be determined by criteria established
in the Guidelines.
51-20
-------
References
Baejter, A., et al. 1959. The distribution and retention
of chromium in men and animals. AMA Arch. Ind. Health 20: 126.
Bigalief, A., et al. 1977. Evaluation of the mutagenous
activity of chromium compounds. Gig. Tr. Prof. abol. 6: 37.
Bovett, P., et al. 1977. Spirometric alterations in workers
in the chromium electroplating industry. Int. Arch. Occup.
Environ. Health 40: 25.
Carlin, R. L., ed. 1965. Transition Metal Chemistry, Marcel
Dekker, N.Y.; Volume I.
Cassarett, L. J• and J. Doull. 1979. Toxicology, The Basic
Science of Poisons. MacMillan, N.Y., Second edition, 1979.
Cutshall, N., Johnson, V. and C. Osterberg. 1965. Chromium
51 in sea water; chemistry. Science 152: 202-203.
Emerson, S., Cranton, R. E. and P. S. Liss. 1979. Redox
species in a reducing fjord: equilibrium and kinetic
considerations. Deep Sea Res. 26A: 859-878.
Fukai, R. 1967. Valency state of chromium in sea water.
Nature 213: 901.
Hedenstedt, A., et al. 1977. .Mutagenicity of fume particles
from stainless steel welding. Scand. J. Work. Environ. Health
3: 203.
Heimann, H. 1976. Chromates and cancer. Presented at the
International Conference on Health Hazards in the Painting
Trades. Geneva, Switzerland, September 23-24.
Hopkins, L. 1965. Distribution in the rat of physiological
amounts of injected Cr-51 (III) with time. Am. J. Physiol.
209: 731.
Hueper, W. C. and W. W. Payne. 1962. Experimental studies
in metal carcinogenesis. Chromium, nickel, iron, arsenic.
Arch. Environ. Health. 5: 445-562.
Kopp, J. 1969. The occurrence of trace elements in water
In; Trace Substances in Environmental Health III, University
of Missouri, Columbia, MO. p. 59.
51-21
-------
Lane, B. and M. Mass. 1977. Carcinogenic!ty and co-
car cinogenicity. of chromium carbonyl in heterotropic tracheal
grafts. Cancer Res. 37: 1476.
Laskin, S., et al. 1970. Studies in pulmonary carcinogenesis
in; Inhalation Carcinogenesis, M. Hanna, P. Nettlesheim,
J. Gilbert (eds.). U.S. Atomic Energy Commission, p. 321.
Lim, T. 1978. The kinetics of the trace element chromium
(III) in the human body. Paper presented at 2nd International
Congress of Nuclear Medicine and Biology", Washington, D.C.
Maltoni, C., G. Lefemine, P. Chieco and D. Caretti. 1974.
La cancerogenes; ambientale e professionale: nuove prospective
.alia luce della cancerogenes; da cloruro de vinile. Osp. Vita
1: 4-66. (Quoted in Petrilli and DeFlora, 1978).
Mertz, W., et al. 1965. Biological activity and fate of
trace quantities of intravenous chromium (III) in the rat.
Amer. J. Physiol. 209: 484.
Mertz, W., et al. 1969. Chromium occurrence and function
in biological systems. Physiol. Rev. 49: 163.
Mertz, W. 1978. Trace elements. Contemporary Nutrition.
3(2): 48-49.
Mertz W. and E.E. Roginski, 1971. Chromium metabolism: the
glucose tolerance factor, in Nutrition, Newer Trace Elements,
W. Mertz and W.E. Cornatzer. Marcel Dekker, Inc., N.Y.
Nakamuro, K., K. Yoshikawa, Y. Sayato and, H. Kirata. 1978.
Comparative Studies of chromosomal aberration and mutagenicity
of trivalent and hexavalent chromium. Mutat. Res. 58: 175-181.
National Academy of Sciences. 1974. Medical and -biological
effects of environmental pollutants: Chromium. Washington, D.C.
National Institute for Occupational Safety and Health (NIOSH).
1975. Criteria for a recommended standard occupational
exposure to chromium (VI). U.S.D.H.E.W. Publications #76-129.
OSHA. 1979. 29 CFR 1910.1000 (1979).
Petrilli, F. L. and S. DeFlora. 1978. Metabolic de-
activation of hexavalent chromium mutagenicity. Mutat.
Res. 54: 139-147.
51-22
-------
Petrilli, F., and S. DeFlora. 1977. Toxicity and mutagenicity
of he.xavalent chromium in Salmonella typhimur ium. Appl.
Environ. Microbiol. 33: 805.
Ridgway, L. and D- Karnofsky. 1952. Effects of metals in
the chick embryo - toxicity and production of abnormalities
in development. Ann. N.Y. Acad. Sci. 55: 203.
Robertson, F. N. 1975. Hexavalent chromium in the groundwater
in Paradise Valley, Arizona. Groundwater. 516-527.
Schroeder, H., et al. 1962. Abnormal trace metals in man-
chromium. J. Chronic Pis. 15: 941.
Stephens, R.D., D.L. Storm and K.C. Ting, 1977. Environmental
Oxidation of Chromium. California Department of Health,
Hazardous Materials Section, Berkeley CA 94704.
Taylor, F. 1966. The relationship of mortality and duration
of employment as reflected by a cohort of chromate workers.
Am. J. Pub. Health. 56: 218.
Trama, F. and R. Benoit. 1960. Toxicity of hexavalent
chromium to bluegills. J. Water Pollut. Control Fed. 37: 868.
U.S. EPA. 1973. Air quality data for metals - 1968 and 1969.
EPA document #APTD 1467.
U.S. EPA. 1978. Reviews of the environmental effects of
pollutants: Chromium. EPA document #600/1-78-023.
U.S. EPA. 1980. Ambient Water Quality Criteria for Chromium,
EPA 440/5-80-035. October.
Venitt, S. and L. Levy. 1974. Mutagenicity of chromates in
bacteria and its relevance to chromate carcinogenesis. Nature
250: 493.
Visek, W., et al. Metabolism of Cr-51 by animals as in-
fluenced by chemical state. Proc. Soc. Exp. Biol. Med. 84: 610
Weast, R. 1974. Handbook of Chemistry and Physics, 55th ed.,
CRC Press, Cleveland, Ohio p. 2216.
51-23
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No. 52
Chrysene
Health and Environmental Effects
O.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. EPA1s Carcinogen Assessment Group (GAG) has evaluated
chrysene and has found sufficient evidence to indicate that
this compound is carcinogenic.
-------
CHRYSENE
Summary
Chrysene is a member of the polynuclear aromatic hydrocarbons (PAH)
class. Numerous compounds in the PAH class are well-known as potent animal
carcinogens. However, chrysene is generally regarded as only a weak carcin-
ogen to animals. There are no reports available concerning the chronic
toxicity of chrysene. Although exposure to chrysene in the environment oc-
curs in conjunction with exposure to other PAH, it is not known how these
compounds may interact in human systems.
No standard toxicity data for chrysene are available for freshwater or
marine organisms.
-------
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Polynuclear Aromatic Hydrocarbons (U.S. EPA, 1979a) and the Multi-media
Health Assessment Document for Polycyclic Organic Matter (U.S. EPA, 1979b).
Chrysene (ciaHi2^ *s one of the fasn^y of polynuclear aromatic
hydrocarbons (PAH) formed as a result of incomplete combustion of organic
material. Its physical/chemical properties have not been well-character-
ized, other than a reported melting point of 254°C and a boiling point of
448°C (U.S. EPA, 1979b).
PAH, including chrysene,. are ubiquitous in the environment, being found
in ambient air, food, water, soils, and sediment (U.S.. EPA,. 1979b). The PAH
class contains a number of potent carcinogens (e.g., benzo(a)pyrene), moder-
ately active carcinogens (e.g., benzo(b)fluoranthene), weak carcinogens
(e.g., chrysene), and cocarcinogens (e.g., fluoranthene), as well as numer-
ous non-carcinogens (U.S. EPA, 1979b).
PAH which contain more than three rings (such as chrysene) are rela-
tively stable in the environment. and may be transported in air and water by
adsorption to particulate matter. However, biodegradation and chemical
treatment are effective in eliminating most PAH in the environment.
The reader is referred to the PAH Hazard Profile for more general dis-
cussion of PAH (U.S. EPA, 1979c).
II. EXPOSURE
A. 'water
•Levels of chrysene are not routinely monitored in water. However,
the concentration. of six representative PAH (benzo(a)pyrene, fluoranthene,
»
benzo(k)fluoranthene, benzo(j)fluoranthene, benzo(g,h,i)perylene, and inde-
no(l,3-cd)pyrene) in U.S. drinking water averaged 13.5 ng/1 (Basu and Sax-
ena, 1977,1978).
-------
B. Food
Chrysene has been detected in a wide variety of foods such as coco-
nut oil (12 ppb), and smoked or cooked meats (up to 66 ppb) (U.S. EPA,
1979b). Although it is not possible to accurately estimate the human diet-
ary intake of chrysene, it has been concluded (U.S. EPA, 1979b) that the
daily dietary intake for all types of PAH is in the range of 1.6 to 16 ug.
The U.S. EPA (1979a) has estimated the weighted average. bioconcentration
factor for chrysene to be 3,100 for the edible portion of fish and shellfish
consumed by Americans. This estimate is based on the octanol/water parti-
tion coefficient for chrysene.
C. Inhalation
Chrysene is commonly found in ambient air. Measured concentrations
of chrysene have reportedly been in the range of 0.6 to 4.8 ng/m (Gordon,
1976; Fox and Staley, 1976). Thus, the human daily intake of chrysene by
inhalation of ambient air may be in the range of 11.4 to 91.2 ng, assuming
that a human breathes 19 m of air per day.
III. PHARMACOKINETICS
Pertinent data could not be located in the available literature con-
cerning the pharmacokinetics of chrysene or other PAH in humans. Neverthe-
less, it is possible to make limited assumptions based on the results of
animal research conducted with several PAH, particularly benzo(a)pyrene.
A. Absorption
The absorption of chrysene in humans has not been studied. How-
ever, it is known (U.S. EPA, 1979a) that, as a class, PAH are well-absorbed
across the respiratory and gastrointestinal epithelia. In particular, chry-
»
sene was reported to be readily transported across the gastrointestinal
mucosa (Rees, et al. 1971). The high lipid solubility of compounds in the
PAH class supports this observation.
-------
8. Distribution
The distribution of chrysene in mammals has not been studied. How-
ever, it is known (U.S. EPA, 1979a) that other PAH are widely distributed
throughout the body following their absorption in experimental rodents.
Relative to other tissues, PAH tend to localize in body fat and fatty tis-
sues (e.g., breast).
C. Metabolism
Limited work on the metabolism of chrysene has been conducted, as
part of an investigation into the mechanism of its bioactivation to a muta-
gen/carcinogen (Wood, et al. 1977).
Chrysene, like other PAH, is apparently metabolized by the microso-
mal mixed-function oxidase enzyme system in mammals (U.S. EPA, 1979b).
Metabolic attack, on one or more of the aromatic double bonds leads to the
formation of phenols,.and isomeric dihydrodiols by the intermediate forma-
tion of reactive epoxides. Dihydrodiols are further metabolized by microso-
mal mixed-function oxidases to yield dial epoxides, compounds which are
known, to be biologically reactive intermediates for certain PAH. Removal of
activated intermediates by conjugation with glutathione or glucuronic acid,
or by further metabolism to tetrahydrotetrols, is a key step in protecting
the organism from toxic interaction with cell macromolecules.
0. Excretion
The excretion of chrysene by mammals has not been studied. How-
ever, the excretion of closely related PAH is rapid, and occurs mainly via
the feces (U.S. EPA, 1979a). Elimination- in the bile .may account for a sig-
nificant percentage of administered PAH. However, the rate of disappearance
»
of various PAH from the body, and the principal routes of excretion, are in-
-------
fluenced both by the structure of the parent compound and the route of admi-
nistration (U.S. EPA, 1979b). It is unlikely that PAH will accumulate in
the body with chronic low-level exposures.
IV. EFFECTS
A. Carcinogenicity
Chrysene is regarded as a weak animal carcinogen (U.S. EPA, 1979b).
LaVoie and coworkers (1979) reported that chrysene can act.as both a tumor
initiator and as a complete carcinogen on the skin of mice.
B. Mutagenicity
Chrysene is positive in the Ames Salmonella assay in the presence
of a metabolizing enzyme system (LaVoie, et al. 1979; Wood, et al. 1977).
Chrysene is also positive in the induction of sister-chromatid exchanges in
Chinese hamster cells (Roszinsky-Kocher, et al. 1979).
C. Teratogenicity
Pertinent data could not be located in the available literature
concerning the possible teratogenicity of chrysene. Other related PAH are
apparently not significantly teratogenic in mammals (U.S. EPA, 1979a).
D. Other Reproductive Effects and Chronic Toxicity
Pertinent data could not be located in the available literature re-
garding other reproductive effects and chronic toxicity.
V. AQUATIC TOXICITY
The only data concerning the effects of chrysene to aquatic organisms
is a single bioconcentration factor of 8.2 (24-hour) for the marine clam
(Ranqia cuneata) (Neff, et al. 1976). No standard aquatic toxicity data for
chrysene either in acute or chronic studies are available for freshwater or
»
marine species.
-------
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
There are no established exposure criteria for chrysene. However,
PAH as a class are regulated by several authorities. The World Health Or-
ganization has recommended that the concentration of PAH in drinking water
(measured as the total of fluoranthene, benzo(g,h,i)perylene, benzo(b)fluor-
anthene, benzo(h)fluoranthene, indeno(l,2,3-cd)pyrene, and benzo(a)pyrene)
Tnot exceed 0.2 jug/1. Occupational exposure criteria have been established
for coke oven emissions, coal tar products,, and coal tar pitch volatiles,
all of which contain large amounts of PAH including chrysene (U.S. EPA,
1979a).
The U.S. EPA (1979a) draft recommended criteria for PAH in water
are based upon the extrapolation of animal carcinogenicity data for benzo-
(a)pyrene and dibenz(a,h)anthracene.
8. Aquatic
Data is insufficient for drafting freshwater or marine criterion.
-------
CHRYSENE
REFERENCES
Basu, D.K., and J. Saxena. 1977. Analysis of raw and drinking
water samples for polynuclear aromatic hydrocarbons. EPA P.O. No.
CA-7-2999-A, and CA-8-2275-B, Expo. Evalu. Branch, HERL, Cincin-
nati.
Basu, O.K., and J. Saxena. 1978. Polynuclear aromatic hydrocar-
bons in selected U.S. drinking waters and their raw water sources.
Environ. Sci. Technol. 12: 795.
Fox, M.A., and S.W. Staley. 1976. Determination of polycyclic
aromatic hydrocarbons in atmosphere particulate matter by high
pressure liquid chromatography coupled with flourescence tech-
niques. Anal. Chem. 48: 992.
Gordon, R.J., '1976. Distribution of.airborne polycyclic aromatic
hydrocarbons throughout Los Angeles. Environ. Sci. Technol.
10: 370.
Lasnitzki, A., and Woodhouse, D.C. 1944. The effect of 1:2:5:6-
Dibenzanthracene on the lymph-nodes of the rat. Jour. Anat.
78: 121.
LaVoie, E., et al. 1979. A comparison of the mutagenicity tumor-
initiating activity and complete carcinogenicity of polychlorin-
ated aromatic hydrocarbons In; Polynuclear Aromatic Hydrocarbons,
P.W. Jones and P. Leber (eds.). Ann Arbor Science Publishers.
Neff, J.M., et al. 1976. Accumulation and release of petroleum-
derived aromatic hydrocarbons by four species of marine animals.
Mar. Biol. 38: 279.
Rees, E. 0., et al. 1971. A study of the mechanism of intestinal
absorption of benzo(a)pyrene. Biochem. Biophys. Act. 225: 96.
Roszinsky - Kocher, et al. 1979. Mutagenicity of PAH's. Induc-
tion of cister-chromatied exchanges in vivo. Mutation Research.
66: 65.
U.S. EPA. 1979a. Polynuclear Aromatic Hydrocarbons: Ambient
Water Quality Criteria (Draft).
U.S. EPA. 1979b. Multimedia Health Assessment Document for Poly-
cyclic Organic Matter. Environmental Criteria and Assessment
Office, Research Triangle Park, N.C. Prepared by Syracuse Research
Corporation.
U.S. EPA. 1979c. Environmental Criteria and Assessment Office.
Hazard Profile: Chlorinated Ethanes (Draft).
-------
Wood A.W., et al. 1977. Metabolic Activation of Libenzo(ah)an-
thracene and its Dihydrodiols to Bacterial Mutagens. Cancer Res.
38: 1967.
World Health Organization. 1970. European standards for drink-
ing waters. 2nd edition. Revised. Geneva.
-------
No. 53
Creosote
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 (CAG) has evaluated
creosote and has found sufficient evidence to indicate that
this compound is carcinogenic.
-------
; CREOSOTE
I. INTRODUCTION
Creosote is a coal-tar distillate used mainly as a wood preservative.
It is highly toxic to wood-destroying organisms and has a low evaporation
rate (Farm Chemicals Handbook, 1977). In 1972, an estimated 521,000 tonnes
(575,000 tons) were produced by six companies at 25 sites in the United
States (von Rumker, et al. 1974). About 90 percent of the creosote is sold
to the wood-preservation industry; the remainder is burned as fuel (von Rum-
ker, et al. 1974).
Creosote's other pesticidal uses are as an herbicide, an insecticide,
an acaricide,' an arachnicide, a fungicfde, a tree dressing, a disinfectant,
and. a horse repellent (Table 1).
TABLE 1.
USES AND SITES FOR CREOSOTE
(Cummings, 1977)
Use
Preservative
Insecticide
(screwworm)
Acaricide (mites)
Arachnicide (ticks)
Herbicide
Fungicide
Insecticide
(Certain insects, worms,
moths and borers)
Horse repellent
Disinfectant
Site
Wood
Horses and mules
Poultry and horses.
Poultry and horses
Along roads, highways, and fences;
farms; flower beds
Rope, canvas, tarpaulins, tree wounds
Tree dressing
Wood stalls, mangers, gates, fence
rails, posts, trees, trailer sites
Outhouses, water closets, garbage
cans, feeding and watering equipment
-------
Creosote is produced by the distillation of coal tar obtained from the
coking of c'oal. The composition of creosote is highly variable and depends
on the composition of the coal used to make the tar, the design and operat-
ing conditions of the coke oven (e.g., gas collection system, temperature,
coking time), and the design and operating condition of the still (e.g.,
feed rate, temperature, and blending of tar distillation fractions) (43 FR
48154, 1978).
Continuous tar distillation at temperatures of up to 400°C produces
fractions typically ranging from crude benzene bo residue pitches (von Rum-
ker, et al. 1974). A common distillation temperature for creosote is about
200 to 400°C (Hawley, 1977; von Rumket, et al. 1974). The creosote frac-
tion is a mixture of organic compounds, mainly liquid and solid cyclic hy-
drocarbons, including two-ring and polynuclear aromatic hydrocarbons (PAH)
•(Table 2). Among the PAH, phenanthrene represents 12 to 14 percent of the
composition of creosote (Considine, 1976). 6enzo(a)pyrene (BaP) is present
at a concentration of about 200 ppm (Guerin, 1977).
II. EXPOSURE
A. Water
Each year an estimated 60 to 115 million pounds (27,000-52,000
tonnes) of creosote are discharged in wastewater treatment sludges by creo-
sote producers. At large tar distillation plants, wastewater streams con-
taining creosote are treated on-site and/or conveyed to public sewage treat-
ment facilities. Wastewater sludges treated on-site are transferred to
landfill or burial sites (von Rumker, et al. 1974),. The estimated flux of
2
creosote from these disposal sites ranges from 0.75 kg/m /hr to 11.0
kg/m2/yr (U.S. EPA, 1980). In 1972, about one billion pounds ("455,000
-------
TABLE 2.
PHYSICAL AND CHEMICAL PROPERTIES OF CREOSOTE
Synonyms: Brick oil, coal tar oil, creosote oil, creosotum, cresylic creo-
sote, dead oil, heavy oil, liquid pitch oil, naphthalene oil, tar
oil, wash oil
Structural and Empirical Formula: Consists principally of liquid and solid
cyclic hydrocarbons; contains substantial amounts of naphthalene
and anthracene; 12-14 percent phenanthrene; 200 ppm benz(a)pyrene
Molecular Weight: —
Description: Dark- brown green, yellowish or colorless above 38°C, naph-
thenic. odor; soluble in alcohol, benzene toluene; immiscible
with water
Specific Gravity and/or Density: d25 more than 1.076
25
Melting and/or Boiling Points: Common distillation range 200 to 400°C
Stability: Overall degradation rate (0.48/day) = same as microbial degra-
dation
Solubility (water): approx. 5 g/1; sed . /Z_
n20 . 1
Vapor Pressure: —
•Bioconcentration Factor (8CF) and/or
Octanol/water partition coefficient (Kow): BCF =0.6
KQW = i.o
Source: Hawley, G.G., 1977; Windholz, 1976; U.S. EPA, 1980; Lopedes, 1978
-------
tonnes) of creosote were used to preserve railroad ties, marine pilings and
utility poles (NIOSH, 1977a).
Some of the organics present in creosote are moderately soluble.
Creosote partitions between sediments and water in a ratio of 1:5. It is
considered stable in groundwater, but decomposes at an estimated rate of 90
percent in five days in river water flowing 50-250 miles. About 99 percent
decomposed in a lake environment in one year (U.S. EPA, 1980).
Creosote migrates from treated wood into the environment, but the
impact of this migration is unknown. Creosote-was found to have a vapor
loss of 27.5 and 15.2 percent from the outer two inches of seasoned and
green poles, respectively; high residue creosote was estimated to have a
10.3 and 4.4 vapor loss, respectively. Creosote losses to the aquatic envi-
ronment are the greatest during the first years after installation. One
eight-year study is summarized below (43 FR 48154, 1978).
Creosote Loss
Year pounds/linear foot
1 0.31
2 0.05
3 0.06
4 0.22
4-8 • 0.15 (average)
B. . Food
Naiussat and Auger (1970) found that PAHs in a contaminated lagoon
accumulated to the greatest extent in species near the top of the food
chain. One of these compounds, BaP, has been reported to accumulate in mus-
sels (about 50 pg/kg; 20 times background) taken from creosote-treated pil-
ings (43 FR 48154, 1978). Elevated levels of BaP in mussels growing near
#
creosoted timbers or pilings suggest that creosote is a significant source
of BaP in the' marine environment. This suggestion was supported by compari-
-------
sons of gas chromatography profiles of polycyclic aromatic hydrocarbons iso-
lated from mussels and creosoted wood (Dunn and Stich, 1976).
High levels of PAH have been found in commercial seafoods grown in
impoundments constructed of creosoted wood.. Commercial samples of oysters,
clans, and mussels were found to contain BsP at concentrations generally
less than 10 ng/g (wet weight). PAHs were also found in cockels, abalone,
scallops, lobster, and shrimp. Levels of BaP and other related PAHs were
found to be inversely related to the ability of the species to metabolize
PAH, except in the case of lobster. Unexpectedly high levels were found in
all edible -meat, of lobsters maintained in commercial tidal compounds con-
structed of creosoted timber: up to 281 ng/g BaP, 303 ng/g chrysene, 222
ng/g benzo(a)anthracene, 261 ng/g benzo(b)fluoranthene, 153 ng/g dibenz-
(a,h)anthracene, and B7 ng/g indeno(l,2,3-cd)pyrene (Dunn and Fee, 1979).
III..PHARMACOKINETICS
A. Absorption
Creosote, is. (readily) absorbed through the skin and mucous mem-
branes (NIOSH, 1977b).
IV. EFFECTS
A. Carcinogenicity
Creosote has been associated with several occupational cases of
skin cancer over a 50-year period (Farm Chemicals Handbook, 1977); its role
in human cancer is still not-clearly understood (NIOSH, 1977b).
Henry (1947), Lenson (1956), 0'Donovan (1920), Cookson (1924), and
Mackenzie (1898) described various kinds of workers who were occupationally
exposed to creosote and developed skin tumors. Dermal application of creo-
sote produced skin tumors in mice (Woodhouse, 1950; Poel and Kammer, 19*57;
Lijinsky, et al. 1956;. Boutwell and Bosch, 1958; Roe, et al. 1958). Roe, et
-------
al. (1558) also found that dermal application of creosote to mice produced
lung tumors. Boutwell and Bosch (1958) found that creosote had the ability
to initiate tumor formation when applied for a limited period prior to
treatment with croton oil. Sail and Shear (1940) found that the number of
skin tumors was increased by dermal treatment with creosote and benzo(a)py-
rene over the number of tumors produced by benzo(a)pyrene or creosote alone.
There is considerable evidence to show that creosote produces tumors in
mice; that creosote, when applied dermally, is a tumor-initiating agent when
followed by dermal treatment with croton oil (Boutwell 'and Bosch, 1958);
that creosote accelerates the tumor production caused by benzo(a)pyrene
(Sail and Shear, 1940); and that workers occupationally exposed to creosote
developed tumors (Table 3). These studies have not yet demonstrated a cor-
relation between the carcinogenic potency of creosote oils and the content
of benzpyrene (Patty, 1963).
Results from dose response studies are summarized below (NIOSH,
1977a).
Concentration
and duration Effects
100% 3x/wk Skin carcinomas in 82%,
28 wk tumors in 92%
20-80% 3x/wk Skin carcinomas in 88%,
6-44 wk tumors in 100%
100% 2x/wk Skin and lung tumors
21 wk in 74%
1DO% 3x/wk Skin tumors in 50%
70 wk
*•
10-100% 2x/wk* Skin tumors in 38-74%
70 wk
2% 2x/wk* No tumors
70 wk
*Creosote plus 1 percent 7,12-dimethylbenz(a)anthracene.
-------
TABLE 3.
SUMMARY TABLE ON ONCOGENICITY OF CREOSOTE
A. Human Case Reports
Substance
and Type
Authors Year of Exposure
Occupation
of Exposed
Individual(s)
Type of Tumor
Response
Mackenzie 1896 Handling of
Creosote
0'Donovan 1920 Handling of
Creosote
Cookson 1924 Handling of
Creosote
Henry 1947 Handling of
Creosote
Lenson 1956 Painting of
Creosote
Worker who dipped Warty elevation on arms;
railway ties in papillomatous swellings
creosote on scrotum
Workers who creo- Skin cancer
soted timbers
Creosote factory
worker
Squamous epitheliomata
on hand; epitheliomatous
deposits in liver, lungs,
kidneys and heart walls
37 men of various Cutaneous epitheliomata
occupations
Shipyard worker
Malignant cutaneous
tumors of the face
B. Animal Studies
Dermal Exposure
Authors
Sail and
Shear
Woodhouse
Lijinsky,
et al.
Poel and
Kammer
Boutwell
and Bosch
Roe,
et al.
Year
1940
1950
1956
1957
1958
1953
Substance
Tested
Creosote and
benzo(a)pyrene
Creosote oil
#1 creosote
oil
Blended creo-
sote oils;
Light creosote
oil
Creosote
(Carbasota)
Creosote oil
(Carbasota)
Animal and
Strain
Mice (Strain A)
Mice (Albino;
Undefined strain)
Mice - Swiss
Mice (C57L
Strain)
Mice (C57L.
Strain)
Mice (Albino -
random bred)
Mice (Strain
Undefined)
Type of Tumor
Response
Accelerated tumor forma-
tion
Papillomas and carcinomas
Papillomas and carcinomas
Papillomas and carcinomas
metastatic growths in
lungs and lymph nodes
Papillomas
Papillomas and carcinomas
Skin and lung tumors
-------
B. Mutagenicity
Simmon and Poole (1978) found that, following metabolic activation
by Arochlor 1254-stimulated rat liver homogenate, both the creosote PI and
the coal tar-creosote P2 produced a mutagenic dose-response and a doubling
above background mutation rate with Salmonella typhimurium strains TA 1537,
TA 98, and TA 100. Mitchell and Tajiri (1978) found that, following meta-
bolic activation by Arochlor 1254-stimulated rat liver homogenate, creosote
PI and coal tar creosote P2 increased the number of forward mutations at the
thymidine kinase locus of L5178Y mouse lymphoma cells in a dose-related man-
ner. There is considerable evidence which proves that creosote PI and P2
*
cause mutations in Salmonella typhimurium strains TA 1537, TA 98 and TA 100,
and in L5178Y mouse lymphoma cells.
C. Teratogenicity and Other Reproductive Effects .
Investigations utilizing pregnant swine indicate that direct con-
tact with lumber freshly treated with creosote would produce acute toxico-
sis, resulting in extensive mortality in newborn swine. The direct contact
of the pregnant sow with lumber freshly treated with creosote provides suf-
ficient dermal absorption to cause fetal deaths and weak pigs at birth.
Creosote is extremely toxic to young swine; the degree of toxicity lessens
as the pigs become older (Schipper, 1961).
D. Chronic and Acute Toxicity
Skin contact with creosote or exposure to its vapors may cuase
burning, itching, papular and vasicular eruptions, or gangrene. Eye injur-
ies can include keratitis, conjunctivitis, and "corneal abrasion (Patty,
1963). Exposed skin shows increased susceptibility to sunburn, an effect
•
attributed to photo-toxic substances usually present in commercial grades of
creosote. Eventually, exposed skin areas become hyperpigmented (NIOSH,
1977b).
-II
-------
Serious systemic effects, including cardiovascular collapse and
death, have been observed only after ingestion (NIOSH, 1977b). Fatalities
have occurred within 14 to 36 hours after ingestion of 7 grams by adults or
1 to 2 grams by children. Symptoms of systemic illness include salivation,
vomiting, respiratory difficulties, vertigo, hypothermia, cyanosis, and mild
convulsion (Patty, 1963). Once widely used in medicine, occasional in-
stances of self-medication are still reported and sometimes lead to chronic
visual disturbances, hypertension, and gastrointestinal bleeding (NIOSH,
1977b).
The oral LD5Q in rats is estimated at 725 mg creosote per kilo-
gram body weight (mg/kg). The reported UX for dogs, cats, and rabbits
is 600 mg/kg (Fairchild, 1977).
V. AQUATIC TOXICITY
Ellis (1943) found fish kills occurring at creosote concentrations as
low as 6.0 mg/1 in less than 10 hours. Applegate, et al. (1957), using
small numbers of subjects, found that concentrations of 5.0 mg/1 produced no
mortalities in rainbow trout (Salmo qainneri), bluegill (Lepomis macro-
chirus), or lamprey larvae (Petromyzon marinus).
The 8-day LDeg of a 60:40 mixture of creosote and coal tar in bob-
white quail (Colinus virqinianus) was reported to be about 1,260 ppm; in the
mallard duck (Anas platyrhynchos), 10,388 ppm. The 24-hour 50 percent medi-
um tolerance limit (Tl-5g) of the creosote/coal tar mixture was 3.72 ppm in
rainbow trout (Salmo qainneri) and 4.42 ppm in the bluegill (Lepomis macro-
chirus). The 24-hour TL5Q concentrations in goldfish (Carrasius auratus)
and rainbow trout were 3.51 and 2.6 ppm, respectively (Webb, 1975).
-------
VI. EXISTING GUIDELINES AND STANDARDS
The Office of Toxic Substances of EPA has issued RPAR on creosote and
is continuing preregulatory assessment under Section 6 of the Federal Insec-
ticide, Fungicide and Rodenticide Act.
A time-weighted average creosote concentration of 0.1 mg/m^ has been
recommended for occupational air exposure.
The aquatic toxicity rating for creosote is reported as TLm96 = IQ_]_
ppm (Fairchild, 1977).
Jfl
-------
REFERENCES
Applegate, V.C., et al. 1957. Toxicity of 4,346 chemicals to larval Ian-
preys and fishes. Oept. of Interior, Special Sci. Rept. No. 207.
Boutwell, R.K. and O.K. Bosch. 1558. The carcinogenicity of creosote oil:
its role in the induction of skin tumors in mice. Cancer Res. 18: 1171.
Considine, O.M. (ed.) 1576. Van Nostrand's Scientific Encyclopedia, 5th
ed. Van Nostrand Reinhold Co., New York.
Cookson, H.A. 1524. Epithelioma of the. skin after prolonged exposure to
creosote. Brit. Med. Jour. 68: 368.
Cummings, W. 1577. Use of profile for coal tar derivatives (exclusive of
wood preservatives). Mentioned in 43 FR 48211, 1578.
Dunn, B.P. and J. Fee. 1579. Polycyclic aromatic hydrocarbon carcinogens
in commercial seafoods. Jour. Fish Res. Board Can. 36: 1469.
Dunn, B.P. and H.F. Stich. 1976. Monitoring procedures for chemical car-
cinogens in coastal waters. Jour. Fish Res. Board Can. 33: 2040.
Ellis, M.M. 1543. Stream pollution studies in the State of Mississippi.
U.S. Dept. of Interior, Special Sci. Rept. No. 3.
Fairchild, E.J. 1577. Agricultural chemicals and pesticides: A subfile of
the NIOSH registry of toxic effects of chemical substances. U.S. Oept. of
HEW,. July.
Farm Chemicals Handbook. 1577. Meister Publishing Company, Willoughby,
Ohio.
Guerin, M.R. 1577. Energy sources of polycyclic aromatic hydrocarbons.
Oak Ridge National Laboratory.
Haw ley, G.G. 1977. The Condensed Chemical Dictionary, 9th ed. Van Nos-
trand Reinhold Co., New York.
Henry, S.A. 1947. Occupational cutaneous cancer attributable to certain
chemicals in industry. Brit. Med. Bull. 4: 398.
Lenson, N. 1556. Multiple cutaneous carcinoma after creosote exposure.
New Engl. Jour. Med. 254: 520.
Lijinsky, W., et al. 1556. A study of the chemical constitution and car-
cinogenic action of creosote oil. Jour. Natl. Cancer Inst. 18: 687.
Lopedes, O.N. (ed.) 1578. Dictionary of Scientific and Technical Terms,
2nd ed.
Mackenzie, S. 1858. Yellow pigmentary strains of haemorrhagic origin and a
class of tar eruption. Brit. Jour. Derm. 10: 417.
-------
Mitchell, A.D. and D.T. Tajiri. 1978. In vitro mammalian mutagenicity as-
says of creosote PI and P2. SRI International. EPA Contract No. 68-01-2458.
Naiussat, P. and C. Auger. 1570. Distribution of benzo(a)pyrene and pery-
lene in various organisms of the Cliperton Lagon ecosystem. C.R. Acad.
Siv., Ser. D. 270: 2702.
National Institute for Occupational Safety and Health. 1977a. Criteria for
a Recommended Standard: Occupational exposure to coal tar products. DHEW
(NIOSH) Publ. No. 78-107.
National Institute for Occupational Safety and Health. 1977b. Health Haz-
ard Evaluation Determination. DHEW (NIOSH) Publ. No. 75-117-372.
0'Donovan, W.J. 1920. epitheliomatous ulceration among tar workers. Brit.
Jour. Derm. Syphilis. 32: 215.
Patty, F.A. 1963. Industrial Hygiene and Toxicology, Vol. 2, 2nd ed.
Interscience, New York.
Poel, W.E. and A.G. Kammer. 1957. Experimental carcinogenicity of coal-tar
fractions. The carcinogenicity of creosote oils. Jour. Natl. Cancer Inst.
18: 41.
Roe, F.J.C., et al. 1958. The carcinogenicity of creosote oil. The induc-
tion of lung tumors in mice. Cancer Res. 18: 1176.
Sail, R.D. and M.J. Shear. 1940. Studies in carcinogenesis. XII. Effect
of the basic fraction of creosote oil on the production of tumors in mice by
chemical carcinogens. Jour. Natl. Cancer Inst. 1: 45.
Schipper, I.S. 1561. The toxicity of wood preservatives for swine. Am.
Jour. Vet. Res. 22: 401.
Simmon, V.F. and D.C. Poole. 1978. In vitro microbiological mutagenicity
assay of creosote PI and. creosote P2. SRI International. EPA Contract No.
68-10-2458.
U.S. EPA. 1980. Aquatic fate and transport estimates for hazardous chemi-
cal exposure assessments. Environmental Research Laboratory, Athens, Geor-
gia.
von Rumker, R., et al. 1974. Production, distribution, use and environ-
mental impact potential of selected pesticides. Report No. EPA 540/1-74-
001. U.S. Environ. Prot. Agency, Office of Water and Hazardous Materials,
Office of Pesticide Programs.
Webb, D.A. 1975. Environmental aspects of creosote. Proceedings American
Wood-Preservation Association. 7: -176.
»
Windholz, M. 1976. The Merck Index, 9th ed. Merck and Co., Inc., Rahway,
New Jersey.
-------
Woodhouse, O.L. 1950. The carcinogenic activity of some petroleum frac-
tions and extracts; comparative results in tests on mice repeated after an
interval of eighteen months. Jour. Hygiene. 48: 121.
-------
No. 54
Cresols and Cresylic Acid
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.
-------
SJ-27-12
Cresol and Cresylic Acid
I. INTRODUCTION
Cjresols are methyl phenols with methyl group at the
o-, p-, m- position. It has a molecular weight of 108, a
melting point of between 11-35°C and a boiling point of
between 191-203°C. It is slightly soluble in water, but
soluble in alcohols, glycols, dilute alkalis, ether and
chloroform. Cresylic acid is the refined product from coal
tar and contains the three isomers of cresol (the crude
product from coal tar is creosote).
Cresols are quite stable in soil due to their antimicro-
bial properties. o-cresol is degraded in air to quinones and
dihydroxybenzene by 03 with an estimated half-life of 1 day.
The m- and p- isomers are expected to behave similarly.
Cresols are used as disinfectants, agricultural chemicals,
solvents, chemical intermediates, metal cleaners, and motor
oil additives. p-cresol is permitted in U.S. as a food
flavoring and for fragrance in soaps, lotions and perfumes.
Annual production if 150 million pounds. NIOSH1 estimates
that the annual environmental release of the mixed isomers is
30 million pounds.
II. PHARMACOKINETICS
«•
Cresols are rapidly metabolized and thus unlikely to bio-
accumulate in mammals.2
III. EFFECTS ON MAMMALS
A. Carcinogenicity: CAG^ concluded that the data base
-------
for this chemical is weak. No data exist on which to determine
carcinogenesis in mice. The literature cites three case
reports of cancer in humans occupational/ exposed.
B. Mutagenicity: CAG^ concluded that cresols cause
chromosome fragmentation in plants. No other mutagenicity
studies have been done.
C. Toxieity; They are corrosive to the skin and
mucuous membranes and moderately toxic by ingestion and dermal
exposure. The organs affected are CNS, liver, lung, kidneys,
stomach, eyes, and heart. No epidemiological studies of
workers have been done.^-
IV. EXISTING GUIDELINES
The current occupational standard (TWA) is 5 ppm. NIOSH^
recommends a lowering to 2.3 ppm.
-------
DOSSIER
ON
CSZSOLS'
BY
Clement Associates, Inc.
1055 Tnomas Jefferson Street, NW
Washingtonr•D.C. 20007
December, 1977
Contract No. NSF-C-ENV77-15417
Prepared, for
TSCA Interagency Testing Committee
Washington, O.C.
-------
FOREWORD
This dossier has been prepared by Clement Associates, Inc.
(Clement), in partial fulfillment of Contract NSF-C-SNV77-15417,
sponsored by the National Science Foundation, to provide techni-
cal support to the Toxic Substances Control. Act (TSCA) Interagency
Testing Committee. The Committee is charged with the responsibility
for making recommendations to the Administrator of. the Environmental
Protection. Agency (EPA) regarding chemical substances or mixtures
which should be given priority by SPA for testing to determine ad-
verse effects on. man or the environment.
The dossier was designed to provide the Committee with infor-
mation on the chemical's physical.and chemical properties, exposure
characteristics/ and biological properties in sufficient detail to
support an. .informed' judgment on whether the substance should be given
priority for testing.. The dossier is not intended to represent a com-
prehensive critical review. 'Such a.review could not be performed with
the constraints imposed upon the Committee (and, therefore, the con-
tractor) by the statutory deadlines of TSCA.
Faced with the task of preparing dossiers which could be quick-
ly assembled and yet contain sufficient information for the Commit-
tee's purposes,. Clement proceeded along the following lines.
Literature searches were conducted using the National Library
of Medicine's TOXLINE and the Environmental Mutagen Information
Center (EMIC) automated data banks.. Each reference on a list of
sources of general information (see "General References" in biblio-
graphy) was reviewed. Further- references and information were
obtained from monographs, criteria documents, reviews, and reports
available from government agency files and trade association li-
braries. Information received in response to the Committee's July
1977 Federal Register notice requesting information on certain
substances was reviewed. Clement scientists relied upon, their own
knowledge of the literature- to augment the data sources.
In general, secondary sources were relied upon in preparing
.the: dossiers. When an article was judged to con-tain information
of major- significance or to. require a critical.* re view the primary
source was consulted. The text makes clear whether a primary or
secondary source of information was used.
-------
KEY TO ABBREVIATIONS
TCLo - Lowest published toxic concentration
- the concentration of a substance in air which has
been reported to produce any toxic effect in animals
or humans over any given exposure time.
TDLo - Lowest published toxic dose
- the lowest dose of a substance introduced by any
route other'than inhalation over any given period
of time that has been reported to produce any toxic
. effect in animals or humans.
LCLo - Lowest published lethal concentration'
- the lowest concentration of a substance, other than
an LC50, in air that has been reported to have
caused, death in humans or animals over any given
exposure time.
LDLo - Lowest published lethal dose
- the lowest dose of a substance other than LD50
introduced by any route other than inhalation over
any given period of time that has been reported to
have caused death in humans or animals.
LC50 - Median lethal concentration
- the concentration of a test material that kills 50
per cent of an experimental animal population
within a given time period.
LD50 - Median lethal dose
- the dose of a test material, introduced by any route
other than inhalation, that kills 50'percent of an
experimental animal population within a. given time
period.
LT50 - Median Lethal Response Time
•Statistical estimate of the time from dosage to the
death of 50 percent of the organisms in the population
subjected to a toxicant under specified conditions.
TLm - Median tolerance limit
- the concentration of a test material at which 50 per
cent of an experimental animal population are able
to survive for a specified time period.
TLV®- Threshold limit value
- the airborne concentration of a substance to which
nearly all workers may be repeatedly exposed day
after day without adverse effect.
-------
TLV^TWA - Threshold limit value - tine weighted average
- the time-weighted average concentration of a .
substance for an 8-hour workday or 40-hour
workweek, to which nearly all workers may be
repeatedly exposed, day after day, without
adverse effect.
TLV^STZL- Threshold limit value - short term exposure limit-
- the .maximal concentration of a substance to which
workers can be exposed for up to 15 minutes
without suffering acute or. chronic toxic effects.
. No more than four excursions per day are per- •
mitted. There must be at least 60 minutes
between•exposure periods. The daily TLV-TWA
must not be exceeded.
«• • . •
BOO - Biochemical oxygen demand
-a measure of the presence of organic materials
which will be oxidized biologically in bodies
of water.
NOHS Occupational Exposure:
- Rank
- an ordering of the approximately 7000 hazards
occurring in the workplace from most common to
least common .
- Estimated number of persons exposed
-•includes full- and part—time workers.. For hazards
ranked 1 through 200, the figure projected to
national statistics by NIOSH is given; for the re.-
maining hazards the number of people exposed given
in the survey was multiplied'by a -fixed number to
give a rough estimate of national exposure. The
fixed number used, --30--/ is derived from the sta-
tistical sampling technique used in this survey.
i - insoluble
ss . — slightly soluble
s - soluble
vs - very soluble
00 - soluble in all proportions
bz - benzene
chl - chloroform
-------
eth - ether
peth - petroleum ether'
ace - acetone
lig - ligroin
ale - alcphol•
CC1, - carbon tetrachloride
4
dil. aUc. - dilute alkalis
/
..'••••^
CS2 - carbon disulfide
os -— organic solvents
oos - ordinary organic solvents
-------
CRESOLS '
AN OVERVIEW
There are three isomers of cresol: o-cresol, m-cresoi,
and o-cresol.,^All three isomers as well as mixtures are art-
icles of commerce .> Cresols are solid or liquid at room tem-
perature (melting points 11-35°C). They are slightly soluble
ia water and soluble ±a"organic solvents.
Total annual production of cresols in the United States is
probably in. excess, of 100 million pouncs. They are used for
a wide variety of purposes/ including uses as disinfectants,
solvents,, in ore flotation, and as intermediates in the pro-
duction of phosphate esters and phenolic resins. The number
of persons occupationally exposed to cresols is estimated to
be two million. They are also present in a number of con-
sumer products.,, including disinfectants, metal cleaners, ana
motor oil additives.
Cresols are manufactured both from petroleum and from
'coal. The composition of the commercial products depends
on the method of production and upon the degree of. refining.
Cresols are sold in a wide variety of grades,- varying- in com-
position, 'color, and boiling ranger Technical grade cresols
f
commonly contain xylenols and phenol. A less refined pro-
duct called creosote oil contains 10-20% by volume of tar from
the coking process.
-------
Cresols are relatively easily metabolized by mammals 'and
*
micro-organisms and are unlikely to undergo significant bio-
accumulation. They are moderately toxic to mammals by ingestion
and dermal exposure, and are corrosive to skin and other tissues.
No data are available on their toxicity by inhalation. Little
11
information is available on effects of chronic exposure.
• *
In one experiment all 'three isomers of cresol were re-
ported to promote the carcinogenicity of dimethylbenzanthracene
on mouse skin. m-Cresol caused developmental abnormalities in*
toad embryos. Otherwise, no significant information is avail-
able on the potential carcinogenicity, mutagenicity, or terato-
genicity of cresols.
Cresols have a broad spectrum of toxicity to micro-organisms
and are used as disinfectants and fungicides. There is little
other information on their potential toxicity to wildlife.
-------
CTESQLS
BART I
.INFORMATICS?
I. 'Cresol (mixed isomers)
1.1 Identification CAS No. 001319773
-NIOSHNo. G059500
1.2 Synonyms and»tTrade Names
Cresylic acid; methyl phenol; hydroxytoiuene;
trieresol; cresylol
(G23,G21,G16)
.1..3 Chemical Formula and Molecular Weight
OH
C7HgO Mol. Wt. 108.15
(G23)
1.4 Chemical and Physical Properties •
1..4.1 Description; Admixture of isomers -in which
. m-isomer predominates, obtained
rrom coal tar or petroleun;
colorless, yellow or pinkish
liquid; phenolic odor; combustible;
becomes darker with age and on
exposure.to light.
(G21,G23)
1.4.2 Boiling Point; 191 - 203° C (G21)
1.4.-3 Melting Point; . 11 - 35° C ' ' (G21)
1.4.4 Absorption Spectrometry;
No information found in sources searched
y
1.4.5 Vapor Pressure; No information found in sources searched
1.4.6 Solubility; Soluble in alcohol, glycol,
" dilute alkalis, ether, chloro-
form;
Slightly soluble in water
(G21,G2S)
1.4.7 Octanol/Water Partition Coefficient;
Log ?-..+. s 2.70' (estimate)
-------
1.5 Production ana Use
1,5.1 Production:
60 Million Ibs (1968)
80 Million Ibs (1973)
(G25)
1.5,2 Use:
As a disinfectant; intermediate in manufactur-
ing of phenolic resins, tricresyl phosphate,
salicylaldehyde, coumarin, and herbicides; as
an ore flotation agent; as a textile scouring .^.
agent; as an organic intermediate; as a- -^-~""'
factant
Quantitative Distribution af Uses
Phosphate esters
Magnet wire
Antioxidants
Resins
Exports
Cleaning and disinfectant
compounds
Ore flotation
Miscellaneous
Percent
22
15
15
15
10
6
6
11
100
Consumer Product Information;
. Cresol is present in:
automotive parts cleaner
metal cleaner, stripper, degreaser
disinfectant
motor oil additive
carbon remover
embalming supplies
Estimates
1,S.J, Release Rate;
30.4 Million Ibs
l.£,2 HOHS Occupational Exposure :
Rank: 105
Estimates no. of persons exposed t
(G21)
(G25)
(G35)
(G2S)
1,9 14, 000
6
(G29)
-------
C3ESOT.S
H. m-Cresol
1.1 Identification CAS No. : 000108394
NIOSH No. : G061250
1.2 Synonyms and Trade Names
i
ra-Cresylic acid; n«ethylphenoi; 3-roethylphenol; l-hydroxy-3-^nethyl-
benzene; nt-kresoi; ro-oxytoluene
~ ' (G16)
i> *
1.3 Chemical Formula and Molecular Weight
CH
C-H-0 M3l. wt. 108.15
(G22)
*
1.4 Chemical and Physical Properties
1.4.1 Description; Colorless to yellowish liquid; phenol-like
odor '
1.4.2 Boiling Point; 202.2° C ' . (G22)
1.4.3 Malting Point; -11.5° C '" (G22)
1.4.4 Absorption Spectronstry:
=214, 271,277,
logfc =3.79,3.20,3.27 ' (G22)
1.4.5 Vapor Pressure; 1 ma at 52.08 C (G22)
1.4.6 Solubility; Slightly soluble in water; *
• • Soluble in- hot water, organic solvents;
. . ' ' Soluble in all proportions in alcohol, ether.,
acetone, benzene and carbon' tetrachloride
(G22)
»
1.4.7' OctanolA?ater Partition Coefficient;
log' P^. = 2.37
-------
Production and Use
No information found in sources searched
1.5,2 Use; In disinfectants and fuaicants;. in photographic
developers, explosives (G22)
•t
1.6 Exposure Estimates
i
1.6.1 Release Hate; .
No information found in grn_gr!ag ^^gchgd
. 1.6.2. NOES Occsatlcna?. 5c»sure;
Rank: 2731 '
no. o£ r*>i'5j.iins exccsed: 9,000*
estimate (G29)
1.7 Manufacturers
Kappers Co., Inc.. . (G24)
-------
CRESOLS
m. oHZresol
1.1 Identification CAS No. .000095487
NIOSH No. G063000
1.2 Synonyms and Trade Names
o-Cresylic acid'; o-methyl phenol; 2-nethyl phenol?
orthocresol; l-hydroxy-2-raethylbenzene; o-hydroxy-
toluene; o-methylphenol; o-oxytoluene; 2-hydroxy- '
toluene ~~
(G16)
5
1.3 Chemical Formula and Molecular Weicht
C7HgO Mol. Wt. 108.15
CG22)
1.4 Chemical and Physical Properties
1.4.1 Description; White crystals; phenol-like odor;
combustible; becomes dark with age
and exposure to air and light.
(G23,G21)
. 1.4.2 Boiling Point;- 190.95° C (G22)
1.4.3 Melting Point; 30.94° C ' (G22)
1.4.4 Absorption Spectrometry;
\ Wcl uSZT A «•. A •> M c MM*
A Max s 219' 275 m*
log i = 3.71, 3.22 (G22)
1.4.5 Vapor Pressure: 1 mm at 38.2° C (G22)
1.4.6 Solubility; Soluble in water and ordinary^
'.' organic solvents;
Very soluble Jn alcohol and ether;
Soluble in' all proportions ir.
acetone, benzene, caraon tetracnloride
(G22)
-------
1.4.7 Octanol/Water Partition .Coefficient:
1.5 Production and Use
I.S.I Production:
Poct =3.40
49..70U Million Ibs
20.481 Million ibs
22.IS7 Million Ibs
(1972)
(1975)
(1976)
1.5.2 User
Disinfectant; solvent
1.6 Exposure Estimates
1.6.1 Release Rate: 15.b Million Ibs
(CIS)
(G28)
(G24)
(G24)
(G23)
(G28)
1.6.2 NOHS Occupational Exposure:
Rank: 1480
Estimates no. of persons exposed: 52/000*
*rough estimate (G29)
1.7 Manufacturers
from coal tar:
Koppers Co., Inc. *
Perro Corp.
from petroleum:
Mericnem Co.
Ferro Corp.
Sherwin-Williams Co.
(G24J
-------
CSESOLS
IV. £-Cresol
1.1 Identification CAS No.: 000106445
NIOSH NO.: G064750
1.2 Synonyms and frrade Names
i
4-Cresol; £-cresylic acid; l-hydroxy-4-roethylbenzene; £-
hydroxy toluene; 4 -hydroxy toluene; £-Kresol; l-methyl-4-
hydroxybenzene; £-methylphenol; 4-methyiphenol; £-oxyto-
luene; para-cresol; pa^ramethyl phenol "~
(G16)
1.3 Chemical Formula and Molecular Weight
OH
' C HO Mol. wt. 108.15
7 8
CH
3 (G22)
1.4 Chemical and Physical Properties
1.4.1 Description; ' Crystalline mass? phenol-like
" odor
(G21)
1.4.2 Boiling Point; 201.9° C ' (G22)
1.4.3 Melting Point; 34.8° C (G22)
• 1.4.4 Absorption Spectrometry ;
log £ » 3.23 (G22)
y
1.4.5 Vapor Pressure: 1 mm at 53.0° C (G22)
1.4.6 Solubility; Slightly soluble in water;
' Soluble 'in hot water, organic solvents;
Soluble in all proportions in. alcohol,
ether, acetone, benzene and carbon
tetrachloride
(G22)
1.4.7 Octanol/Water Partition Coefficient
poct = 2-35 '
-------
1.5 Production and Use
1.5.1 Production;
No information found in sources searched -
1.5.2. Use; As a chemical- intermediate (G24)
1.6 Exposure Estimate
1.6.1 Release Rate;
No information found in sources searched
1.6.2 NOES Occupational Exposure
Rank: 2466
. • Estimated no. of persons exposed:. 14,000*
•rough estimate
CG29)
1.7 Manufacturers
Sherwin-Williams Co.
(G24)
-------
CBFSOIfi
SUMMMTC OF QIARAOTERISTICS
Name
Solubility
Cresol s in ale, glycol,
(mixed isomers) Ail. alk, eth,
chl.
ss in II-O
o-Cresol
m-Cresol
LogP
oct
2.70
ci
s in H20 and COS,
vs in ale and eth.
oo in ace, bz, OCl..
3.40
ss in 1!2O; s in hot 2.17
lUO, os;^0 in ale,
eth, bz, aoe, OCl.
ss in I120| s in
hot II2O, bsf?o in
ale, eth, bz, ace,
L4
'2.35
Estimated
Environmental
Release
(Million Ibs)
30.4
15.6
Production
(Million Ibs)
t
~60 (1968)
— 80 (1973)
49.7 (1972)
20,481(1975)
22.187(19761
Estimated no.
of persons
exposed
(occupational)
1,914,000
52,000
9,000
14,000
Use
Disinfectant; phenolic
resins; tricresyl «^x>s-
pliate; ore flotation;
textile scouring agent;
organic intermediate;
mfg. of salicylaldehyde
coumarin, and herbicides
surfactant
Disinfectant, solvent
In disinfectants, fumi-
gants, pliotographic
developers, explosives
cyclic intermediate
No information found in sources searched.
-------
CRESOLS
PART II.
BIOLOGICAL PROPERTIES
^
2.1 Bioaccumulation
Log octahol/water partition, coefficients are 3.40, 2.37, and
2.35 for the a-, m-, and £-isomers, respectively (CIS). The high
partition coefficient of the £-isomer is due to the steric effect
of the methyl group on the hydroxyl group. The high octanol/ .
water partition coefficients of the cresols indicate that bio-
accumulation in aquatic organisms is a possibility, but specific
data on such bioaccumulation are not available. . By analogy with
phenol, which appears to be completely eliminated from the body
within 24 hours (G19), it is expected that cresols would not be
bioaccumulated in mammals'. Cresols in waste waters near indust-'
rial plants are reported to undergo rapid biodegradation (G14),
which indicate-s that cresols, like phenol, are relatively easily
metabolized.
2.2 Contasanants and Envircroental Degradation or Conversion
Products
Cresols are sold in a wide variety of technical and special
grades, classified by color and distillation range (G2S). The
composition of the various materials depends upon the starting
material and the method of production. A major source of cresols
is the. tar-acid oil obtained as a by-product of coking of. coal (G25)
Cresols (boiling above 204°C)/ available as a mixture of o-,
m-, and p_-isbmers from tar acids, are called cresylic acid. A less
refined product called creosote- oil contains i.0-20% by volume of
the tar from the coking process; it is used as a wood preservative
(G2S). Creosote oil may contain polynuclear aromatic hydrocarbons.
Xylenols and phenol are common impurities (or ingredients) of tech-
nical grade cresols (G25).
-------
The high environmental stability of the cresols in soils
(owing to their antimicrobial properties) contributes to their
widespread use as wood perservatives. £-Cresol is degraded by
the hydroxyl radical and ozone in air and by organic peroxide
radicals in water; half life estimates are less than 1 day in
air and 10 days in water (G14) . The m- and p_-isomers are ex-
pected to behave similarly. Environmental degradation is likely
to be by air oxidation to give quinones and dihydroxybenzenes (G14)
'»
Biodegfadation'products of cresols by sewage microorganisms
include carbon dioxide, methane, 3-methylcatechol, 2-hydroxy-6-
oxahepta-2,4-dienoic acid, oxalic acid, pyrocatechol,carboxylic
acid, and salicylic acid (G14). By analogy with phenol, cresols •
may be methylated in tije environment to form the corresponding
anisoles. • • .
2.3 Acute Toxicity
The NIOSH Registry of Toxic Effects of Chemical Substances
(G16) reports the acute toxicity of cresols as follows:
Substance Parameter
Cresol
o-Cresol
"^*
LD50
LD50
LD50
LD50
LD50 •
LDLo
LDLo-
LDLO
LD50
LDLo
LDLo
LDLo
LDLo
m-Cresol
LD50
LD50
LD50
LD50
LDLo
LDLo
LDLO
LD50
LDLO
LDLo
LDLO
LDLo
Dosage
1454 mgAg
861 mgAg
121 mgAg
1100 mgAg
344 mgAg
410 mgAg
55 mgAg
940 mgAg
1380 mgAg
450 mgAg
180 mgAg
360 mgAg
200 mgAg
242 mgAg
620 mgAg
350 mgAg
828 mgAg
450 mgAg
180 mgAg
1400 mgAg
2050 mgAg
500 mgAg
280 mgAg
100 mgAg
250 mgAg
Animal
rat
mouse
rat
rat
mouse
mouse
cat
rabbit
rabbit
rabbit
rabbit
guinea pig
frog •*
rat '
rat
rat
mouse
mouse
cat
rabbit
rabbit
rabbit
rabbit
guinea pig
frog
Route
oral
oral
oral
skin
oral
subcutaneous
subcutaneous
oral
skin '
subcutaneous
intravenous.
intraperitoneal
subcutaneous
oral
skin
unknown
oral »
subcutaneous
subcutaneous
oral
skin
subcutaneous
intravenous
intraperitoneal
.subcutaneous
-------
(continued)
Substance Parameter Dosage Animal . Route
p_-Cresol LD50 207 mg/kg rat oral
LD50 705 mg/kg rat ' skin
LD50 344 mg/kg mouse . oral
LOLo • 150 mg/kg mouse subcutaneous
LD50 160 mg/kg mouse unknown
LD.LO ' _ 80 mg/kg cat subcutaneous
LDLo * 620 mg/kg rabbit . oral
LD50 • 301 mg/kg .rabbit skin
LDLo 300 mg/kg rabbit subcutaneous
LDLo 180 mg/kg rabbit intravenous
LDLo 100 mg/kg ' guinea pig intraperitoneal
LDLo • • 150 mg/kg frog subcutaneous
Cresols are rated as moderately toxic to humans (G4). Acute
exposures can cause muscular weakness, gastroenteric disturbances,
severe depression, collapse, and death (G38). Organs attacked by
cresols include the central nervous system, liver, kidneys, lungs,
pancreas, spleen, eyes, heart, and skin (G38).. The type of exposure
to cresols determines, in part,, the toxic effects. Cresols are highly
corrosive to any tissues they contact (G5) and are readily absorbed
by skin and mucous membranes. Systemic effects, including death,
occur after dermal exposure-. Because their vapor pressure is low
at 25°C, cresols do .not usually constitute an acute inhalation
hazard. No-data are available on the toxicity of cresol vapors to
humans (G39).
- In animals, cresol toxicity varies with the isomer, the species
and the route of exposure. Reported LDSOs- vary from a low of 121
mg/kg ia the rat (oral, pj-cresol) to a high of 2050 mg/kg in the
rabbit (skiiu m-cresol) (G16). Evidence for different biological.
effects of the three isomers includes the observation that, the ratios
between the LDSOs of the least toxic and most -toxic isomexs vary from
as low as 1.8 (cutaneous, rat) to as high as 6.8 (cutaneous,'rabbit).
Furthermore, £-cresol, but neither o- nor m-cresol, produced.
permanent, pigment loss in the hair of mice (1).
2.4 Other Toxic Effects
Chronic poisoning from absorption of cresols through the skir.,
-------
mucous membranes or respiratory tract has not bean well studied.
Campbell (2) presented incomplete studies showing that exposure
of mice to an atmosphere saturated with cresylic acid vapors for
1 hr/day on consecutive days caused irritation of the nose and
eyes./ and death in some animals. Uzhdavini e£ al. (3) performed
poorly documented studies on the chronic effects of oj-cresol in-
halation. In mice, £hey found evidence for: tail necrosis; slowed
weight gain; cellular degeneration of the CNS; respiratory tract
hyperemia, edema, proliferation of cellular elements, and hemor-
rhagic patche's; myocardial fiber degeneration; and protein deposits
in liver and kidney cells. In rats, they reported alterations in
a conditioned reflex, and alterations in both peripheral blood and
bone marrow elements.
The Threshold Limit Value established by the ACGIH for cresols
is 5 ppm (Gil).
2.5 Carcinogenicity
o, m, and p_-Cresol have been reported to promote the carcino-
genicity of dimethyIbenzanthracene (DMBA) in skin tests with mice
(4). They were slightly less active as promoters than phenol in
this experiment (see table below).
No. mice Avg. no. % survivors
survivors/ papillomas with
Promoter* original no. per survivor papilloma
Benzene Control 12/12 0 0
20% phenol 22/27 1.50 64
20% o-cresol 17/27 1.35 59
' 20% m-cresol 14/29 0.93 50
20% £-cresol 20/28 0.55 35 - '
* Initiator: 0.3% DMBA in acetone. Promoter in benzene.
Data at 12 weeks.
No carcinogenicity tests conducted with cresols alone have been
found in the searched literature.
-------
2.6 Mutagenicity
In onion root tips, however, m- and p_-cresol' produced cyto-
logical abnormalities including stickiness, erosion,, pycnosis,
C-mitosis, polyphoidy, and chromosome fragmentation(5). o-Cresol
did not appear as active (5). These chromosomal effects do not
necessarily imply that the cresols will have genetic activity in
mammals. No other mutagenicity studies were found in the searched
literature.
• . -. •
2.7 Tera'togenicity
No systematic studies of the teratogenic potential of the
cresols have been found. The only information available is
on the effect of m-cresol on embryos of a toad (Xenopus laevis)
at the neural tube stage of development (6). Concentrations of
20 to 80 ppm, m-cresol caused two developmental- abnormalities:
edema, and tail flexion..
2.8 Metabolic Information
Very little is known about the metabolic fate of cresols
in mammals. .One study showed that the cresols are excreted in
rabbit urine primarily as oxygen conjugates: 60-72% as
ether glucuronides and 10-15% as ethereal sulphates (7).
Paper chromatography shoved that o- and m-cresol are
hydroxylated and that pj-cresol forms £-hydroxybenzoic acid
p_-Cresol glucuronide was isolated from the. urine of rabbits
dosed by stomach tube with pj-cresol, whereas^o- and m-cresol
were metabolized to 2,,5-dihydroxytoluene (7) . No studies
have been traced of the biological effect of these and other
possible metabolites of the cresols.
-------
2.9 Ecological Effects
The 96-hour LC50 of o-cresol to channel catfish (Ictalurus
punctatus) is reported to be 67 mg/1 (8). In tests with
perch and sunf^.sh,.lethal concentrations (not LCSOs) were
determined in 1 hgur exposures. In perch (Perca fluviatilis),
lethal concentrations for o-, m- and £-cresols were in the
range 10-20 ppm (9). The Aquatic .Toxicity Rating (96-hour
TLm, species unspecified) for cresols is listed as LO-1 ppm
(G16). Although o-cresol is less toxic to juvenile Atlantic
salmon (Salmo salar) than p_-cresol, the salmon avoided
o-cresol more efficiently (10).
Cresols have a broad spectrum of toxicity to microorganisms,
They are used as disinfectants and as fungicides to protect
materials such as wood. They are also reported to be active
against mycoplasmas (11), viruses (12), and .plant galls (13).
2.10 Current Testing and Evaluation
A criteria document on cresols is planned for completion
in 1977 by NIOSH.
-------
REFERENCES
1. Shelley, W. B. o-Cresol: cause of ink-induced hair depitaent-
ation in mice. ""Brit. J. Dematol. 90:169-174 (1974).
2. Campbell, J. Petroleum cresylic acids - a study of their toxi-
city and the* toxicity of cresylic disinfectants. Soap Sanit.
Chem. 17:103-111 (1941).
3. Dzhdavini/ E.R., Astafyeva, l.K., Mamayeva, A.A. and Bakhtizina,
G.Z. Inhalation toxicity of o-cresol. Tr. Ufiia. Nauchno-Issled
Inst. Gig. Profzabol. 7:115-119 (1972). (Russian)
4. Bontwell, R.K., and Bosch, O.K. The tumor-promoting action of
phenol'and related compounds for mouse skin. Cancer Res.
19:413-424 .(1959).
5. Sharma, A.K. and Ghosh, S. Chemical basis of the action of
cresols and nitrophenols on chromosomes. The Nucleus 8:183-
190 (1965).
6. Johnson, D.A. The effects' of meta-cresol on the embryonic
development of the African.Clawed Toad, Xenoous laevis.
J. Ala. Acad. Sci. 44:177 (1973).
7. Bray, E.G., Thorpe, W.V., and White, K. Metabolism of
- derivatives of toluene.. 4. Cresols.. Biochem. J. 46:275-
278 (1950). . v
8. Clemens, H.P., and Sneed, K.E. Lethal dose of several com-
mercial chemicals for fingerling channel catfish. U.S. Fish.
Wildlife Serv. Spec. Sci. Rep. Fisheries 316 (1959). .
9-. Jones, J.R.E. Fish'.and River Pollution. Butterworths, London
(1964). Pp 118-153.
10. Zitko, V., and Carson, W.G. Avoidance of organic solvents
and substituted phenols by juvenile Atlantic salmon. Fish-
eries Res.. Board Can. MS* Rep. 1327 (1974)..
.- ' >
11.. Kihara/K., Sasaki, T., and Arima, S. Efeect of antiseptics
and detergents on Mycoplasma. Igaku 7.Q Seibutsugaku, 83:5-8
(1971).
12. Sellers, R. F. The inactivation of foot-and-mouth disease
virus by chemicals and disinfectants. Vet. Rec., 83:504-506
(1963).
13. Schrothr M.N. and Hildebrand, B.C. A chemotherapeutic treatment
for selectively eradicating crovm gall and olive knot neoplasms.
Phytopath. 53':848-854 (1954).
-------
GENERAL REFERENCES
Gl. Browning, E. Toxicity and Metabolism of Industrial Solvents.
Elsevier, Amsterdam (1965).
'•
G2. Browning, E. Toxicitv of Industrial Metals, 2nd ed. Apoleton-
Century-Crofts, New York (1969).
G3. Fairhall, L.T. Industrial' Toxicology, 2nd ed. Williams •
& Wilkins Co. (1969).
• -
G4. Sax, N.I. Dangerous Properties of Industrial Materials,
3rd-«d. Reinnold Publishing Corp., New York (1975).
G5. Chemical Safety Data Sheets. Manufacturing Chemists Asso-
ciation, Washington, D.C.
G6. Industrial Safety Data Sheets. National Safety Council,
Chicago, Illinois.
G7. Shepard, T.H, Catalog of Teratogenic Agents. Johns Eopkins
University Press, Baltimore (1973).
G8. Thienes, C.L.. & Haley, T.J. Clinical Toxicology. Lea &
Febiger, Philadelphia (1972).
G9. IARC Monographs on the Evaluation of Carcinogenic Risk of
Chemicals to Man. Lyon, France. WHO, International Agency
for Research on Cancer.
G10. Debruin, A. Biochemical Toxicology of Environmental Agents.
Elsevier/North-Holland, Inc., New York (1976).
Gil. Threshold Limit Values for Chemical Substances^and Physical
Agents in the Workroom Environment with Intended Changes
for 1976. American Conference of Government Industrial
Hygienists.
Jr
G12. Chemicals Being- Tested for Carcinogenicity by the Bioassay
Program, DCCP. National Cancer Institute (1977).
G13. Information Bulletin on the Survey of Chemicals Being Tested
For Carcinogenicity, No. 6. WHO, Lyon, France (1976) ,
G14. Brown, S.L., et_ al_. Research Program on Hazard Priority
Ranking of Manufactured Chemicals, Phase II - Final Report
to National' Science Foundation. Stanford Research Institute,
'Menlo Park, California (1975).
-------
G15. Dorigan, J., et al. Scoring of Organic Air Pollutants,
Chemistry, Production and Toxicity of Selected Synthetic
Organic Chemicals. MITSZ, MTR-7243 (1976)t
.G16. NIOSH Registry of Toxic Effects of Chemical Substances (1976).
G17. Kirk-Othmer Encyclopedia of Chemical Technology. Edited
Standen,A(ed.),Interscience Publishers, New York (1963, 1972). .
>,
G18. Survey of Compounds Which Have Been Tested for Carcinogenic
Activity Through 1972-1973 Volume. DHEW Publication No.
NIH73-453, National Cancer Institute, Rockville, Maryland.
G19. Criteria for a Recommended Standard - Occupational Exposure
to .... / praparea ny NIOSH .
: .
G20. Suspected Carcinogens - A. subfile of the NIOSH Toxic Sub-
stance List (1975).
G21. The Condensed Chemical. Dictionary, 9th ed. Van Nostrand
Reinhold Co., New York (1977).
G22. Handbook of Chemistry and Physics , 57th ed. The Chemical
Rubber Company, Cleveland, Ohio (1976).
G23. The Merck Index, 9th ed. Merck & Co., Inc., Rahway, N.J.
(1976) .
G24. Synthetic Organic Chemicals, United States Production and
Sales. 1966-76. ' U.S. International Trade Commission, U.S.
Government Printing Office, Washington, D.C.
G25. Lowenheim, F.A. & Moran, M.K.. Faith. Keyes, and Clark's
Industrial Chemicals, 4th ed. John wiley & Sons, New York
(1975).
G25. Gosselin, Hodge, Smith &. Gleason. -Clinical Toxicology of
Commercial Products, 4th ed. The Williams and Wilkins Co.,
Baltimore (1976).
G27. Chemical Consumer Hazard Information System. Consumer Product
Safety Commission, Washington, D.C. (1977)^
G23. A Study of Industrial Data on Candidate Chemicals for Test-
ing. Stanford Research Institute, Palo Alto, California (1976,7)
G29. National Occupational Hazards Survey (NOHS). National
Institute for"Occupational Safety and Health, Cincinati '
Ohio (1976).
G30. The Aldrich Catalog/Handbook of Organic and 3lochs-teals.
.Aldrich' Chemical Co., Inc. (1977-78).
-------
G31. McCutcheon's Functional Materials 1977 Annual. McCutcheon
Division, MC Publishing Co. (1977).
G32. Hampel & Hawley. The Encyclopedia of Chemistry. 3rd ed.
Van Nostrand Reinhold Co., New YorK 11973} .
G33. Casarett, L. J. & Doull, J. Toxicology, the Basic Science
of Poisons., Macmillan Publishing Co." Inc., New York (1975).
G34. "EPA/Office of Research and Development, Chemical Production.
G35. CTCP/Rochester Computer Service. (See Reference No. G26.)
G36. Leo, A., Hansch, C. & Elkins, D. Partition coefficients.
and their uses. . Chem. Rev. 71:525-616 (1971).
G37. 1977-78 OPD Chemical Buyers Directory.
G38. Patty, F.A. Industrial Hygiene and Toxicology, Vol. 2, 2nd ed.
Wiley Interscience, New York (1963)..
G39. Directory of Chemical Producers. Stanford Research Institute,
Menlo Park, California (1977).
-------
No. 55
Crotonaldehyde
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.
-------
CROTONALDEHYDE
SUMMARY
Crotonaldehyde is not expected to be overly persistent in
water or the atmosphere. It is not expected to bioconcentrate.
It has been detected in finished drinking water and in sewage
treatment plant, effluents.
An increased incidence of malignant neoplasms has been
observed in workers at an aldehyde factory who were exposed to
crotonaldehyde, among other substances. There is, however, no
indication that crotonaldehyde was the causative factor in the
excess incidence of cancer.
Pathologic change was observed in the testes of mice receiv-
ing crotonaldehyde in the drinking water (0. 2 g/1) for one month.
I. INTRODUCTION
Crotonaldehyde (CH3CH=CHCHO; molecular weight 70.1) is a
water-white, mobile liquid with a pungent, suffocating odor
(Hawley, 1977). It has the following physical/chemical
properties (U.S. EPA, 1979a; Hawley, 1977):
Boiling Points 102"C
Melting Point: -60°C
Vapor Pressure: 19 mm Hg at 20"C
Solubility: very soluble in water;
also soluble in many
organic solvents.
-------
A review of the production range (includes importation)
statistics for crotonaldehyde (CAS No. 4170-30-3) which was
listed in the initial TSCA Inventory (1979b) has shown that
between 1 million and 8 million pounds of this chemical were
produced/imported in 1977.—'
Crotonaldehyde is used as an intermediate in the manufacture
of n-butanol and crotonic and sorbic acids; solvent in the
purification of mineral oil; intermediate in resin and rubber
antioxidant manufacture; and in organic syntheses (NCI, 1978).
Other uses.are as a warning agent in fuel-gas, insecticides,
leather tanning, production of rubber accelerators, and as an
alcohol denaturant (Hawley, 1977).
II. ENVIRONMENTAL FATE
Formaldehyde, the simplest aldehyde, is almost entirely
hydrated in water, thus it is nonvolatile and is inactive toward
photochemical dissociation. Higher aldehydes, such as crotonal-
dehyde, are less hydrated in water, more volatile, and somewhat
active toward photochemical degradation (Calvert and Pitts,
1966). Crotonaldehyde is expected to be oxidized in water at the
double bond to form keto aldehydes and cleavage products (U.S.
EPA, 1977). Crotonaldehyde biodegrades at a slow to moderate
This production range information does not include any pro-
duction/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 Inven-
tory, including production range information, are subject to
the limitations contained in the Inventory Reporting Regula-
tions (40 CFR 710).
-------
rate; acclimated bacteria can speed the degradation rate (U.S.
EPA, 1979a). In general, neither crotonaldehyde nor its
oxidation products are expected to be overly persistent in water
(U.S. EPA, 1977).
In air, aldehydes are expected to photodissociate to RCO and
H atoms rapidly and competitively with their oxidation by HO
radical. The projected half-life is on the order of 2 to 3 hours
(Calvert. and Pitts, 1966). Oxidation of crotonaldehyde by HO
radical should result in addition at the double bond to form a.
keto aldehyde (U.S. EPA, 1977). Crotonaldehyde is a. reactive
component of auto exhaust and may contribute to smog (Dimitriades
and Wesson, 1972).
B. Bioconcentration
Crotonaldehyde is not expected to bioconcentrate (based on
its similarity to acrolein) (U.S. EPA, 1977).
C. Environmental Occurrence
Crotonaldehyde has been detected in finished drinking water,
sewage treatment plant effluents (U.S. EPA, 1976), in wastewater
used for irrigation of potatoes (Dodolina _et_ _al_., 1976), and the
atmosphere (IARC, 1976).
Crotonaldehyde occurs naturally in essential oils extracted
from the wood of oak trees (Egorov, 1976). It has also been
found in the volatiles from cooking mutton (Nixon _et> _al_., 1979)
and in tobacco and tobacco smoke constituents (Pilott, 1975).
-------
III. PHARMACOKINETICS
Although no information was found specifically on the metab-
olism of crotonaldehyde, it is probably oxidized to an acid and
subsequently to CC^ in the same manner as other small aliphatic
aldehydes. Crotonaldehyde is a potential alkylating agent by the
metabolic formation of an activated epoxy derivative at the
double bond and via reaction with amino groups of cellular
macromolecules (NCI, 1978).
IV. HEALTH EFFECTS
A. Carcinogenicity
An increased incidence of malignant neoplasms has been
observed in workers at an aldehyde factory who were exposed to
acetaldehyde, butyraldehyde, crotonaldehyde, aldol, several
alcohols, and longer chain aldehydes. Crotonaldehyde was found
in concentrations of 1-7 mg/m . Of the 220 people employed in
this factory, 150 had been exposed for more than 20 years. Dur-
ing the period 1967 to 1972, tumors were observed in nine males
(all of whom were smokers). The tumor incidences observed in the
workers exceeded incidences of carcinomas of the oral cavity and
bronchogenic lung cancer expected in the general population and,
for the age group 55-59 years, the incidence of all cancers in
chemical plant workers. There is no indication that crotonalde-
hyde was the causative factor in the excess incidence of cancer
(Bittersohl, 1974, 1975).
-------
B. Mutagenicity
Schubert (1972) reported chromosome breakage in human lymph-
ocytes exposed to crotonaldehyde in vitro. When tested in
Salmonella typhimurium (tester strains TA1535, TA1537, TA1538,
TA100, and TA98) both in the presence and absence of a metabolic
activation system, crotonaldehyde was nonmutagenic. It also
failed to increase the incidence of mitotic recombination in
Saccharomyces cerevisiae D3 in the presence and absence of a
metabolic activation system (NCI, 1978).
C. Reproductive Effects
Pathologic change was observed in the testes of mice one
month following a single intraperitoneal injection of crotonalde-
hyde (1 mg/mouse). In a related study, similar changes were
observed in the testes of mice receiving crotonaldehyde in the
drinking water (0.2 g/1) for one month (Auerbach _et_ al. , 1977;
Moutschen-Dahmen et al., 1975; Moutschen-Dahmen et al., 1976).
D. Other Toxicity
Skog (1950) studied the effects of lower aliphatic aldehydes
in rats and mice. When administered subcutaneously or by
inhalation, crotonaldehyde caused lung edema and mild narcosis.
Death was delayed and probably resulted from the lung damage.
With cats, similar effects were seen, with death due to lung
edema or bronchial pneumonia occurring within 24 hours for injec-
tion and between 6 and 48 hours for inhalation studies (Skog,
1950).
»
The oral 1^50 for crotonaldehyde in the rat is 300 mg/kg;
the 30-minute LC5Q in the rat is 4000 mg/kg. The rabbit dermal
LD5Q is 380 mg/kg (NIOSH, 1979).
-------
E. Other Relevant Information
A case of apparent sensitization to crotonaldehyde has been
reported in a laboratory worker who handled "small" amounts of
the material (ACGIH, 1971).
Crotonaldehyde is a strong mucous membrane irritant (NIOSH,
1978).
V. AQUATIC EFFECTS
The 96-hour LC^Q (partial flow-through system) for crotonal-
dehyde in bluegill sunfish is 3.5 ppm; in tidewater silversides
the 96-hour LC5Q is 1.3 ppm (Dawson, 1975/1977).
VI. EXISTING GUIDELINES
The OSHA standard for crotonaldehyde in air is a time
weighted average (TWA) of 2 ppm (39CFR23540).
i
-------
References
ACGIH. American Conference of Governmental and Industrial
Hygienists, Documentation of the threshold limit values,
Cincinnati, Ohio. 1971.
Auerbach, C. _et_ al. Genetic and cytogenetical effects of
formaldehyde and related compounds. Mut. Res. 39, 317-362, 1977.
Bittershol, G. Epidemiological investigations on cancer in
workers exposed to aldol and other aliphatic aldehydes. Arch.
Geschwalstforsch. 43, 172-176, 1964.
Bittersohl, G. Env. Qual. Safety _4, 235-238, 1975. (as. cited in
NCI, 1978).
Calvert, J.G. and J. N. Pitts. Photochemistry. Wiley and Sons,
New York, 899 pp. 1966. (as cited in U.S. EPA, 1977).
Dawson, G. W. _et_ aL. The acute toxicity of 47 industrial chemi-
cals to fresh and salt water fishes. J. Hazardous Materials _1_,
303-318, 1975/1977.
Dimitriades, B. and T. C. Wesson. Reactivities of exhaust
aldehydes. J. Air Poll. Contr. Assoc.. 2(1), 33-38, 1972.
Dodolina, V. T. _et_ _al_. Vestn. S-Kh. Nauki (Moscow) _6_, 110-113,
1976. (as cited in NCI, 1978).
Egorov, I. A. _et_ _al_. Prikl. Biokhim. Mikrobiol. 12(1), 108-112,
1976. (as cited in NCI, 1978).
Hawley, G. G. 1977. Condensed Chemical Dictionary, 9th edition.
Van Nostrand Reinhold Co.
IARC (International Agency for Research on Cancer). IARC mono-
graphs on the evaluation of carcinogenic risk of chemicals to
man. 13, 311, 1976.
Moutschen-Dahmen, J. _et_ _al. Genetical hazards of aldehydes from
mouse experiments. Mut. Res. 29(2), 205, 1975.
Moutschen-Dahmen, J. et^ ^1^. Cytotoxicity and mutagenicity of two
aldehydes: Crotonaldehyde and butyraldehyde in the mouse. Bull.
Soc. R. Sci. , Liege _45_, 58-72, 1976. (as cited in NCI, 1978).
NCI (National Cancer Institute). Chemical Selection Working
Group. September 28, 1978. '
NIOSH (National Institute for Occupational Safety and Health).
Information Profiles on Potential Occupational Hazards-Classes of
Chemical. 1978
-------
NIOSH (National Institute for Occupational Safety and Health).
Registry of Toxic Effects of Chemical Substances. 1979.
Nixon, L. N. _et_ _al_. Nonacidic constituents of volatiles from
cooked mutton. J. Agric. Food Chem. 27(2), 355-359, 1979.
Pilott, A. _et_ _al_. Toxicology _5_, 49-62, 1975. (as cited in NCI,
1978).
Schubert, J. et_ ai. EMS Newsletter _6_, 17, 1972. (as cited in NCI,
1978).
Skog, E. A toxicological investigation of lower aliphatic alde-
hydes I. Toxicity of formaldehyde, acetaldehyde, propionaldehyde,
and butyraldehyde; as well as of acrolein and crotonaldehyde.
Acta Pharmacol. j6, 299-318, 1950. (as cited in NIOSH, 1978).
U.S. EPA. Frequency of organic compounds identified in water.
PB-265 470, 1976.
U.S. EPA. Review of the Environmental Fate of Selected Chemi-
cals. EPA-560/5-77-003, 1977.
U.S. EPA. Oil and Hazardous Materials. Technical Assistance Data
System (OHMTADS DATA BASE), 1979a.
U.S. EPA. Toxic Substances Control Act Chemical Substances Inven-
tory, Produciton Statistics for Chemicals Listed on the Non-
Confidential Initial TSCA Inventory, 1979b.
Sf
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No, 56
Cyanides
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.
-------
CYANIDES
SUMMARY
Cyanide is well-known as an acute, rapidly acting poison
which has caused numerous deaths, primarily in occupational
situations. The mechanism of cyanide intoxication is attrib-
utable to the biochemical inhibition of cellular respiration,
which produces a condition resembling acute hypoxia. De-
spite the considerable potency of cyanide as an acute poison,
repeated sublethal exposures do not result in cumulative ad-
verse effects in animals or man. In a chronic feeding study
in rats, a no observable adverse effect level (NOAEL) was
found to be 12 mg/kg/day. Extrapolation of this value to
humans, using the application of a safety factor of 100,
results in an acceptable daily intake for man (ADI) of 8.4 mg.
Cyanide exists in water in the free form (CN~ and HCN),
which is extremely toxic, or in a form bound to organic
or inorganic moieties which is less toxic. Cyanide is lethal
to freshwater fishes at concentrations near 50 ;ig/l and
has been shown to adversely affect invertebrates and fishes
at concentrations near 10 pq/1. Very few saltwater data
have been generated. Cyanide affects fish and invertebrates
by inhibiting utilization of available oxygen for metabolism
*•
at the cellular level of respiration.
-------
CYANIDES
I. INTRODUCTION
c^
This profile is based primarily upon the Ambient Water
Quality Criteria Document for Cyanides (U.S. EPA, 1979).
The National Institute for Occupational Safety and Health
(NIOSH, 1976) has also prepared a recent comprehensive review
of health hazards associated with hydrogen cyanides (HCN)
and commercially important cyanide salts (NaCN, KCN, and
Ca(CN)2).
The toxicologic effects of cyanides are based upon
their potential for rapid conversion by mammals to HCN.
Cyanide production in the United States is now over 700
million pounds per year and appears to be increasing steadily
(Towill, et al. 1978). The major industrial users of cyanide
in the United States are the producers of steel, plastics,
synthetic fibers and chemicals, and the electroplating and
metallurgical industries (NIOSH, 1976; Towill, et al. 1978).
II. EXPOSURE
A. Water
Cyanide exists in water in the free form (CN~
and HCN), or bound to organic or inorganic moieties. Cya-
nide is not commonly found in United States water supplies.
Among 2,595 water samples tested, the highest cyanide con-
centration found was 8 ppb (Towill, et al. 1978). The vola-
tility of HCN, the predominant form in water, accounts in '
part for the low levels usually measured. The U.S. EPA
(1979) has estimated the bioconcentration factor -of cyanide
at 2.3.
t
-------
. y
B. Food
Except for certain naturally occurring organoni-
triles in plants (e.g., cyanogenic glycosides, such as amyg-
dalin), it is uncommon to find cyanide in foods.
C. Ambient Air
There is insufficient information available to
estimate population exposures to cyanide via ambient air
(U.S. EPA, 1979).
Ill PHARMACOKINETICS
A. Absorption
The common inorganic cyanides are rapidly absorbed
across the skin (Drinker, 1932; Potter, 1950; Tovo, 1955;
Walton and Witherspoon, 1926), stomach and duodenum, and
lungs (Goesselin, et al. 1976). Quantitative estimates
of the rate of penetration by various routes of exposure
are unavailable, however. The rapid absorption of cyanide
is evidenced by the fact that death may be produced within
a matter of minutes following inhalation or ingestion.
B. Distribution
Cyanide is distributed to all organs and tissues
via the blood, where its concentration in red cells is greater
than that in plasma by a factor of two or three. This may
be due, at least in part, to a preferential binding of cya-
nide to methemoglobin (Smith and Olson, 1973.) . Although
quantitative data are lacking, it is predicted that cyanide
may readily cross the placenta.
-------
C. Metabolism
By far, the major pathway for the metabolic detoxi-
fication of cyanide involves its conversion to thiocyanate
via the enzyme rhodanase (deDuve, et al. 1955). A minor
pathway for cyanide metabolism involves nonenzymatic conjuga-
tion with cysteine, a reaction which accounts for no more
than 15 percent of cyanaide metabolism in the rat (Wood
and Cooley, 1956). Very small amounts of cyanide can be
excreted unchanged (as HCN) or converted to carbon dioxide
(Friedberg and Schwarzkopf, 1969).
D. Excretion
Among rats given 30 mg of sodium cyanide intra-
peritoneally over eight days, it was estimated that 80 per-
cent of the total dose was excreted in the urine in the
form of thiocyanate (Wood and Cooley, 1956). Cyanide does
not appear to accumulate significantly in any body compart-
ment with chronic exposures.
IV. EFFECTS
A. Carcinogenicity
Pertinent data confirming the carcinogenicity
of cyanide were not found in the available literature.
B. Mutagenicity
Pertinent data concerning the mutagenicity of
cyanide were not found in the available literature.
C. Teratogenicity
Cyanide is not known to be teratogenic. However,
thiocyanate, the major metabolic product of cyanide in vivo,
-------
has produced developmental abnormalities in the chick (Nowinski
and Pandra, 1946) and ascidian embryo (Ortolani, 1969) at
high concentrations.
D. Other Reproductive Effects
Pertinent information regarding the possible ef-
fect of cyanide on fertility or reproductive success was
not found in the available literature.
E. Chronic Toxicity
Human inhalation of 270 ppra HCN brings almost
immediate death, while 135 ppm is fatal after 30 minutes
of exposure '(Dudley, et al. 1942). The mean lethal dose
of HCN and its alkali metal salts by ingestion in humans
is in the range of 50 to 200 mg (1 to 3 mg/kg), with death
coming in less than one hour (Gosselin, et al. 1976) . In
non-fatal poisonings, recovery is generally rapid and com-
plete. The mechanism of acute cyanide intoxication can
be attributed to the biochemical inhibition of cytochrome
c oxidase, the terminal enzyme complex in the respiratory
electron transport chain of mitochondria (Gosselin, et al.
1976). The major feature of cyanide poisoning resembles
the effects of acute hypoxia, which results in a decreased
utilization of oxygen by the tissues. Cyanide poisoning
differs from other types of hypoxia in that the oxygen ten-
sion in peripheral tissues usually remains normal or may
even be elevated (Brobeck, 1973).
Despite the high lethality of large single doses
or acute inhalation exposures to high vapor concentrations
-------
of cyanide, repeated sublethal doses do not result in cumula-
tive adverse effects (Hertting, et al. 1960; Hayes, 1967;
American Cyanamid, 1959).
F. Other Relevant Information
Since cyanide acts by inhibiting cytochrome c
oxidase, it is reasonable to assume that any other inhibitor
of the same enzyme (e.g. sulfide or azide) would have toxic
effects synergistic with (or additive to) those of cyanide.
This has not been demonstrated experimentally, however.
Cyanide poisoning is specifically antagonized
by any chemical agent capable of rapidly generating methemo-
globin Ln vivo, such as sodium nitrite, or other aromatic
nitro and amino compounds (Smith and Olson, 1973).
V. AQUATIC TOXICITY
A. Acute Toxicity
There have been numerous studies investigating
the toxicity of cyanide in freshwater fish. Free cyanide
concentrations in the range of about 50 to 200 ug/1 have
eventually proven fatal to most species. Certain life stages
and species of fish appear to be more sensitive to cyanide
than others. Eggs, sac fry, and warmwater species tended
to be the most resistant.
Several authors have reported increased cyanide
toxicity with the reduction of dissolved oxygen or with
a rise in water temperature. However, water alkalinity,
hardness, and pH below 8.3 have not been shown to have a
pronounced effect on the acute toxicity of cyanide to fish.
The reported range for LC5Q values for freshwater fish is
-------
from 52 >ig/l, for juvenile brook trout, to 507 jjg/1, for
sac fry brook trout, Salvelinus fontinalis. For the fresh-
water invertebrates, the results from 11 acute tests on
6 species have shown a range of LC^Q values from 83 pg/1
for cladoceran, Daphnia pulex to 760,000 pg/1 for snail,
Goniobasis livescens.
The only saltwater species to be studied is the
oyster. A short, exposure of an oyster to cyanide resulted
in supression of activity after 10 minutes of exposure to
150 ^ug/1 (U.S. EPA, 1979).
B. Chronic Toxicity
Based on long-term tests with bluegills (embryo-
larval) and reproduction by brook trout and fatheads, the
geometric mean of the chronic effect level concentrations
is 9.6 ug/1 (Koenst, et al. 1977; Lind, et al. 1977; Kimball,
et al. 1978). Life cycle tests on the scud, Gammarus pseudo-
limnaeus, and the isopod, Ascellus communis, show the chronic
values to be 18.3 and 34.1 ug/1, respectively (U.S. EPA,
1979). The chronic toxicity of cyanide in marine species
has not been reported.
C. Plant Effects
In the only plant test reported, 90 percent of
the blue-green alga, Microcystis aerusinoss, was killed
when exposed to a free cyanide concentration, of 7,790 /ig/1
(Fitzgerald, et al. 1952).
There was an inhibition of respiration in the
marine alga, Prototheca zopfi, at 3,000 ug/1 and enzyme
-------
inhibition in Chlorella sg. at 30,000 pq/1 (Webster and
Hackett, 1965; Nelson and Tolbert, 1970).
D. Residue
No residue data is available for cyanide toxicity
in either salt or freshwater species. The U.S. EPA (1979)
has estimated the bioconcentration factor of cyanide to
be 2.3.
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 change.
A. Human
The U.S. Public Health Service Drinking Water
Standards of 1962 established 0.2 mg CN~/1 as the acceptable
level for water supplies. A similar criterion has been
adopted by the Canadian government (Health and Welfare Canada,
1977). In addition to defining the 0.2 mg CN~/1 criterion,
the U.S. Public Health Service (1962) has set forth an "objec-
tive" of 0.01 mg CN~/1 in water, "because proper treatment
will reduce cyanide levels to 0.01 mg/1 or less."
The U.S. Occupational Safety and Health Administra-
tion (OSHA) has established a permissible exposure limit
for KCN and NaCN at 5 mg/m as an eight-hour,time-weighted
average. The National Institute for Occupational Safety
and Health (NIOSH) recommends 5 mg/m3 as a ten minute ceil-'
ing for occupational exposure to KCN and NaCN.
-------
The OSHA permissible limit for exposure to HCN
is 10 ppm (11 mg/m ) as an eight-hour time-weighted average.
NIOSH recommends 5 mg/m as a ten minute ceiling level for
exposure to HCN.
Based upon the results of a two year chronic feed-
ing study in rats, the U.-S. EPA (1979) has calculated an
acceptable daily intake (ADI) of cyanide for man to be 8.4
mg/kg. This value was derived from the no observable adverse
effect level (NOAEL) for rats of 12 mg/kg/day and the applica-
tion of a safety factor of 100. The corresponding draft
water quality criterion derived from these data is 4.11
mg/1. However, the U.S. EPA (1979) has recommended that
the U.S. Public Health Service Drinking Water Standard
of 200 jig/1 be retained as a safe level for man.
B. Aquatic
For free cyanide (expressed as CN), the draft
criterion to protect freshwater aquatic life is 1.4 ug/1
as a 24-hour average, and the concentration should not exceed
38 ug/1 at any time (U.S. EPA, 1979).
Draft saltwater criterion is not available for
cyanide toxicity, because of the paucity of valid data (U.S.
EPA, 1979).
-------
CYANIDES
REFERENCES
American Cyanamid Co. 1959. Report on sodium cyanide:
30-day repeated feeding to dogs. Central Med. Dep.
Brobeck, T.R. 1973. Best and Taylor's physiological basis
of medical practice. 9th ed. Williams and Wilkins Co.,
Baltimore.
de Duve, C., et al. 1955. Tissue fractionation studies:
6. Intracellular distribution patterns of enzymes in rat-
liver tissue. Biochem. Jour. 60: 604.
Drinker, P. 1932. Hydrocyanic acid gas poisoning by absorp-
tion through the skin. Jour. Ind. Hyg. 14: 1.
Dudley, H.C.-, et al. 1942. Toxicology of acrylonitrile
(vinyl cyanide): II. Studies of effects of daily inhalation.
Jour. Ind. Hyg. Toxicol. 24: 255.
Fitzgerald, G.P., et al. 1952. Studies on chemicals with
selective toxicity to blue-green algae. Sewage Ind. Wastes
24: 888.
Friedberg, K.D., and H.A. Schwarzkopf. 1969. Blausaureexhala-
tion bei der Cyanidvergiftung (The exhalation of hydrocyanic
acid in cyanide poisoning). Arch Toxicol. 24: 235.
Gosselin, R.E., et al. 1976. Clincial toxicology of com-
merical products. 4th ed. Williams and Wilkins Co., Baltimore.
Hayes, W.T. Jr. 1967. The 90-dose LD5Q and a chronicity
factor as measures of toxicity. Toxicol. Appl. Pharmacol.
11: 327.
Hertting, G., et al. 1960. Untersuchungen uber die Folgen
einer chronischen Verabreichung akut toxicher Dosen von
Natriumcyanid an Hunden. Acta Pharmacol. Toxicol. 17: 27.
Kimball, G., et al. 1978. Chronic toxicity of hydrogen
cyanide to bluegills. Trans. Am. Fish. Soc. 107: 341.
Koenst, W., et al. 1977. Effect of chronic exposure of
brook trout to sublethal concentrations of hydrogen cyanide.
Environ. Sci. Technol. 11: 883.
Lind, D., et al. 1977. Chronic effects of hydrogen cyanide
on the fathead minnow. Jour. Water Pollut. Control Fed.
49: 262.
-------
National Institute for Occupational Safety and Health. 1976.
Criteria for recommended standard occupational exposure
to hydrogen cyanide and cyanide salts (NaCN, KCN and Ca(CN)2).
NIOSH Publ. No. 77-108. Dep. Health Edu. Welfare. U.S. Govefn-
ment Printing Office, Washington, D.C.
Nelson, E.B., and N.E. Tolbert. 1970. Clycolate dihydro-
genase in green algae. Arch. Biochem. Biophys. 141: 102.
Nowinski, W.W., and J. Pandra. 1946. Influence of sodium
thiocyanate on the development of the chick embryo. Nature
157: 414.
Ortolani, G. 1969. The action of sodium thiocyanate (NaSCN)
on the embryonic development of the ascidians. Acta Embryol.
Exp. 27-34.
Potter, A.L. 1950. The successful treatment of two recent
cases of cyanide poisoning. Br. Jour. Ind. Med. 7: 125.
Smith, R.P., and M.V. Olson. 1973. Drug-induced methemo-
globinemia. Semin. Hematol. 10: 253.
Tovo, S. 1955. Poisoning due to KCM absorbed through skin.
Mineria Med. 75: 158.
Towill, L.E., et al. 1978. Reviews of the environmental
effects of pollutants: V. Cyanide. Inf. Div. Oak Ridge
Natl. Lab. Oak Ridge, Tenn.
U.S. EPA. 1979. Cyanides: ambient water quality criteria.
(Draft) EPA PB296792. National Technical Information Ser-
vice, Springfield, VA.
Walton, D.C., and M.G. Witherspoon. 1926. Skin absorption
of certain gases. Jour. Pharmacol. Exp. Ther. 26: 315.
Webster, D.A., and D.P. Hackett. 1965. Respiratory chain
of colorless algae. I. Chlorophyta and Euglenophyta.
Plant Physiol. Lancaster 40': 1091.
Wood, J.L., and S.L. Cooley. 1956. Detoxication of cyanide
by cystine. Jour. Biol. Chem. 218: 449.
IXi
-------
No. 57
Cyanogen Chloride
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
5-7-1
-------
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.
-------
CYANOGEN CHLORIDE
I. INTRODUCTION
Cyanogen chloride is a colorless gas at room temperature with a molec-
ular weight of 61.48, a melting point of -6.5°c, a boiling point of
13.8°C, and a specific gravity of 1.186. It is soluble in alcohol or
ether, and slightly soluble in water. (Int. Teh. Inf. Inst., 1978).
Cyanogen chloride is used as a fumigant, metal cleaner, in ore refin-
ing, production of synthetic rubber and in chemical synthesis (Arena,
1974). Cyanogen chloride can be used in the military as a poison gas.
II. EXPOSURE -
The major sources of exposure to cyanogen chloride are in the above
mentioned industrial uses. The potentiality of cyanogen chloride as a water
pollutant has not been described in the available literature.
III. PHARMACOKINETICS
The toxicity of cyanogen chloride resides very largely on its pharmaco-
kinetic property of yielding readily to hydrocyanic acid (also called hydro-
gen cyanide or prussic acid) _in vivo. The red cells of whole blood rapidly
convert cyanogen chloride to cyanide, while serum destroys cyanogen chloride
without forming hydrocyanic acid (Aldridge and Evans, 1946).
Reference should be made to the EPA/ECAO Hazard Profile for cyanides
(U.S. EPA, 1979) for a general discussion on absorption, distribution,
metabolism and excretion. Cyanogen chloride, like HCN, is metabolically
converted to thiocyanate (HCNS) (Aldridge and Evans, 1946).
5-7-3
-------
IV. EFFECTS
A. Carcinogenicity, Mutagenicity, Teratogenicity,-and Other
Reproductive Effects
Pertinent information could not be located in the available liter-
ature.
B. Chronic Toxicity
Inhaling small amounts of cyanogen chloride causes dizziness,
weakness, congestion of the lungs, hoarseness, conjunctivitis, loss of appe-
tite, weight'loss, and mental deterioration. These effects are similar to
\
those found from inhalation of cyanide (Dreisbach, 1977). Cyanogen chloride
is an irritant to both eyes.and throat (Int. Tech. Inf. Inst., 1978).
Cyanogen chloride acts as a chenical asphyxiant, releasing cyanide
which causes internal asphyxia by inhibiting cellular respiration. Cyano-
hemoglobin may also be formed slowly, but the toxicity is mainly due to the
inhibition of cytochrome oxidase, an enzyme which utilizes molecular oxygen
for cell respiration (Dreisback, 1977).
C. Acute Toxicity
Ingestion or inhalation of a lethal dose of cyanogen chloride
(LD5Q = 13 mg/kg), as for cyanide or other cyanogenic compounds, causes
dizziness, rapid respiration, vomiting, flushing, headache, drowsiness, drop
in blood pressure, rapid pulse, unconsciousness, convulsions with death oc-
curring within 4 hours (Dreisbach, 1977).
By subcutaneous route, the LDLQ for cyanogen chloride are as
follows: mouse, 39 mg/kg; dog, 5 mg/kg; and rabbit, 20 mg/kg. By inhala-
tion, an |_CLQ in the dog was found to be 79 ppm/8 hours. Also by inhala-
tion, the LC50's in terms of ppm for 30 minute exposures are: rat, 118;
mouse, 177; rabbit, 207; and guinea pig, 207 (Int. Teh. Inf. Inst., 1978).
-------
V. AQUATIC TOXICITY
Pertinent information could not be found in the .available literature
pertaining to the toxic effects of cyanogen chloride to aquatic organisms.
The reader is referred to EPA/ECAO Hazard Profile for cyanides (U.S. EPA,
1979).
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
Threshold limit values .for cyanogen chloride have been set at 0.3
ppm and 0.6 mg/m3 for an 8-hour workday. (ACGIH, 1979).
-------
CYANOGEN CHLORIDE
REFERENCES
Aldridge, W.N. and Evans, C.L, 1946. The physiological effects and fate of
cyanogen chloride. Quart. Jour. Expl. Physiol. 33: 241.
American Conference of Governmental Industrial Hygienists. 1979. Thres-
hold-limit-values for chemical substances and physical agents in the work-
room environment for 1979. Cincinnati, Ohio.
Arena, J.M. 1974. Poisoning. Clark C. Thomas Company. Springfield,
Illinois, p. 210.
Deischmann, W.B. and Gerarde, H.W. 1969. Toxicology of drugs and chem-
icals. Academic Press, New York, p. 641.
Oreisbach, R.H.. 1974. Handbook of Poisoning, IX edition. Lange Medical
Publications, Los Altos, California, p. 221.
International Technical Information Institute. 1978. Toxic and hazardous
chemicals safety manual. Tokyo, Japan, p. 142.
U.S. EPA.. 1979. Environmental Criteria and Assessment Office. Cyanides:
Hazard profile. (Draft).
57-6
-------
No. 58
ODD
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.
-------
Disclaimer Notice
Mention of trade names or commercial products does not constitute
endorsement or recommendation for use.
-------
ODD
Summary
ODD can exist in two forms, the o,p'- or the p,p'-isomers. p,p'-ODD
[l,l-(2,2-dichloroethylidlene)-bis-4-chlorobenzene] is a contaminant
(^0.330 of commerical preparations of DDT [ 1,1 '-(2,2,2-trichloroethyli-
dene)-bis-4-chlorobenzene] as well as being a metabolite of DDT. It has
also been used as an insecticide in its own right under the names TDE or
Rhothane. p,p'-ODO is the first metabolite of p,p'-ODT leading to the even-
tual elimination of p,p'-ODT from the body as p,p'-ODA [2,2-bis(4-chlorophe-
nyl) acetic acid]. The residency time of ODD in the body is relatively
short. There is some evidence that DDD is carcinogenic in mice; however, in
other species, it appears to be non-carcinogenic. p,p'-OOD has been shown
to be mutagenic in Drosophila, but not in yeast or bacteria. In cell cul-
ture, p,p'-ODD causes chromosomal breaks.
The only available p,p'-OOD toxicity data involves saltwater fish and
invertebrates and freshwater invertebrates. The 96-hour LC_Q value for
two invertebrates and three fish range from 1.6 to 42.0 ug/1. p,p'-OOD
appears to be one-fifth to one-seventh as acutely toxic as p,p'-ODT.
-------
ODD
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for DDT (U.S. EPA, 1979a).
ODD is a contaminant of technical p,p'-DDT [l,l'-(2,2,2-trichloroethyl-
idene)-bis-4-chlorobenzene]. It has also been utilized as an insecticide in
its own right under the common names TDE or Rhothane. Its two isomers,
p,p'-ODD [l,l'-(2,2-dichloroethylidene)-bis-4-chlorobenzene] and o,p'-ODD,
make up approximately 0.3 and 0.1 percent, respectively, of technical DDT.
Between 1970 and 1973 (the EPA banned DDT in 1972), a significant drop in
residues of ODD and DDT occurred in the U.S.A., constituting decreases of 89
and 86 percent, respectively.
II. EXPOSURE
Little information is available on exposure to ODD, although the gener-
al exposure pattern probably follows that of DDT, as outlined in DDT: Hazard
Profile (U.S. EPA, I979b). ODD appears to be disappearing from the U.S.
environment at approximately the same rate as DDT as a result of the 1972
ban on DDT (U.S. EPA, 1975). Wessel (1972) calculated the daily intake of
p,p'-DDD to be 0.012 mg/man/day; this was about half the daily intake of
p.p'-OOT.
III. PHARMACOKINETICS
A. Absorption
Pertinent data could not be located in the available literature.
B. • Distribution
The distribution of DOD is the same as that described for DDT in
DDT: Hazard Profile (U.S. EPA, 1979b). The human adipose storage of ODD is
less than that of either DDT or ODE [l,l'-(2,2-dichloroethenylidene)-bis-4-
chlorobenzene].
-------
C. Metabolism
p,p'-ODD is the first metabolite in the multistep pathway of con-
verting p,p'-ODT to p,p'-ODA [ 2,2-bis(4-chlorophenyl) -acetic acid], the
metabolite which is eventually excreted by rats and by man (Peterson and
Robinson (1964). Urinary p,p'-ODA excretion and serum ODD concentrations
showed increases with DOT dosage in man and declined after dosing ended
(Morgan and Roan, 1977). The enzymes for converting p,p'-ODT to p,p'-ODD
are present in all tissues, while the enzymes for further metabolism of ODD
appear to be absent in -brain, heart, pancreas, and muscle of rats (Fang, et
al. 1977).
0. Excretion
Doses of o.p'-OOD yield o,p'-OOA and ring hydroxylation products of
o,p'-QDA in the urine and feces of rats in addition to serine and glycine
conjugates in urine (Reif and Sinsheimer, 1975).
ODD is further metabolized to DOA, which is excreted in the urine
(U.S. EPA, 1979a).
IV. EFFECTS
A. Carcinogenicity
Only two studies have been performed to assess the Carcinogenicity
of p.p'-ODD. In a lifespan study, CF1 mice were fed 37.5 mg/kg/day 000 in
their diet (Tomatis, et al. 1974). DOO-exposed animals showed slight in-
creases in liver tumors in males only, but lung adenomas were markedly in-
creased in both sexes. In a National Cancer Institute study (1978), Osborne-
Mendel rats and B6C3F1 mice were dosed with p.p'-OOQ, for 78 weeks. In rats,
ODD had no carcinogenic effects in the females, (43 or 85 mg/kg/day), but
caused a significant increase of follicular cell adenomas in the low dose
males (82 mg/kg/day). Carcinomas of the thyroid were also observed. Be-
-------
cause of high variation of thyroid lesions in control male rats, these find-
ings are considered only suggestive of a chemical-related effect. In mice,
p,p'-OOD was not carcinogenic.
B. Mutagenicity
p,p'-ODD has been shown to be non-mutagenic in E. coli Pol-A
strains (Fluck, et al. 1976) and Escherichia marcescens (Fahrig, 1974). The
only positive result found in any of the bacterial test systems was reported
by Buselmaier, et al. (1972) upon the administration of p,p'-ODO to mice and
assaying for back mutation of Salmonella typhimurium and E. marcescens fol-
lowing incubation in the peritoneum in the host-mediated assay. Yeast host
mediated assays using Saccharomyces cerevisiae were negative (Fahrig, 1974),
along with an X-linked recessive lethal assay in Drosphila melanogaster
(Vogel, 1972). In mammalian systems, the mutagenic activity of p,p'-ODD is
relatively weak. This is evidenced by the fact that, depending upon the
dose and route of administration and the species sensitivity of the test
organism, reported studies are negative or marginally positive (U.S. EPA,
1979a). Some chromosomal aberrations and inhibition of proliferation have
been observed with p,p'-000 in cell culture (Palmer, et al. 1972; Mahr and
Miltenburger, 1976). The o,p'-isomer is less active with regard to chromo-
some damage (Palmer, et al. 1972).
C. Teratogenicity, Other Reproductive Effects, and Chronic Toxicity
Pertinent data could not be located in the available literature.
0. Other Relevant Information
Since ODD is a metabolite of DDT, as well as a contaminant of com-
mercial preparations of DDT, many of the effects of DDT could be mediated
9
through ODD. Information on DOT is presented in DDT: Hazard Profile (U.S.
EPA, 1979b).
-------
V. AQUATIC TOXICITY
A. Acute Toxicity
The most insensitive freshwater invertebrate was the scud, Gammarus
lacustris. with a 96-hr. LC5Q static value of 0.60 ug/L (Sanders, 1969).
Of the Cladoceran, the Daphnia pulex species was the most, sensitive with a
static LC50 of 3.2 pg/1, while the Simocephalus serrulatus was the least
sensitive with a LC5Q of 5.2 ug/1 (Sanders and Cope, 1966). p,p'-OOD
toxicity has been investigated for several saltwater species. LC-g values
for two invertebrates, the Eastern oyster, Crassostrea virqinica. and the
Korean shrimp, Palaemon macrodactylus (Schoettger, 1970),. are 25 ug/1 and
1.6 jug/1, respectively, in 96-hr flow-through exposures. In flow-through
exposures to three species of saltwater fish, 96-hr LC5Q values range from
2.5 to 42 ug/1 for the stripped bass, Morone saxatilis, Korn and Earnest,
1974). Two species, Morone saxatilis (Korn and Earnest, 1974) and Fundulus
similis (U.S. EPA, 1979a), were exposed to both p,p'-OOD and p,p'-ODT under
similar conditions. A comparison of the results indicates that p,p'-OOD is
one-fifth to one-seventh as acutely toxic to these species as is p,p'-ODT.
However, four to five week old tadpoles of the freshwater toad (Bufo wood-
huusei fowleri) were much more sensitive, having 96-hr. LCg_ values of
160 ug/1 compared with 1,000 pg/1 for p,p'-ODT. The DOT sensitivity in-
creased with age (Sanders, 1970).
B. Chronic Toxicity, Plant Effects and Residues
Pertinent data could not be located in the available literature.
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
In 1972, the U.S. EPA banned the agricultural use of DOT in the
United States. There are no other specific guidelines or standards for ODD.
However, for the protection of human health with respect to ODD, criteria of
0.98, 0.098, and 0.0098 ng/1 have been proposed for DDT corresponding to
risk levels of 10, 10 , and 10" , respectively. If water alone is
consumed, the water concentration should be less than 0.36 pg/1 to keep the
lifetime cancer risk below 10~ .
B. Aquatic
The criteria for DDT and its metabolites are proposed for the pro-
tection of aquatic life from the effects of ODD. The 24-hour average for
the protection of freshwater aquatic life is 0.00023 ug/1, not to exceed
0.41 yg/1 at any time. For saltwater aquatic life, the 24-hour average is
0.0067 pg/l, not to exceed 0.021 jjg/1 at any time.
-------
ODD
REFERENCES
Buselmaier, W., et al. 1972. Comparative investigations on the muta-
genicity of pesticides in mammalian test systems. Eur. Environ. Mutagen
Soc. 2nd Ann. Meet., Ziukovy Castle, 25.
Fahrig, R. 1974. Comparative mutagenicity studies with pesticides. Page
161 In: R. Montesano and L. Tomatis, eds. Chemical carcinogenesis essays,
WHO. IARC Sci. Publ. No. 10..
Fang, S.C., et al. 1977. Maternal transfer of 14C-p,p'-ODT via placenta
and milk and its metabolism in infant rats. Arch. Environ. Contam. Toxicol.
5: 427.
Fluck, E.R., et al. 1976. Evaluation of a ONA polymerase-deficient mutant
of E. coli for the rapid detection of carcinogens. Chem. Biol. Inter-
actions"~l5: 219.
Xorn, S. and Earnest, R. 1974. Acute toxicity of twenty insecticides to
striped bass, Morone saxatilis. Calif. Fish and Game 60: 128.
Mahr, U. and H.G. Miltenburger. 1976. The effect of insecticides on
Chinese hamster cell cultures. Mutat. Res. 40: 107.
Morgan,. O.P. and C.C. Roan. 1977. The metabolism of DOT in man. Essays
Toxicol. 5: 39.
National Cancer Institute. 1978. Bioassays of DOT, TOE and p,p'-OOE for
possible carcinogenicity. Cas No. 50-29-3, 72-54-8, 72-55-9, NCI-CG-TR-131.
U.S. Dept. Health Edu. Welfare.
Palmer, K.A., et al. 1972. Cytogenetic effects of DDT and derivatives of
DDT in a cultured mammalian cell line. Toxicol. Appl. Pharmacol. 22: 355.
Peterson, J.E. and W.H. Robison. 1964. Metabolic products of p,p'-C~DT in
the rat. Toxicol. Appl. Pharmacol. 6: 321.
Reif, V.O. and J.E. Sinsheimer. 1975. Metabolism of 1-10-chloro-
phenyl)-l-(p-chlorophenyl)-2,2-dichloroethane (o.p^-OOD) in rats. Drug.
Metals. Disp. 15.
Sanders, H.O. 1969. Toxicity of Pesticides to the Crustacean gammarus
lacustris. Bur. Sport Fish Wildl. Tech. Paper. 25:, 18.
Sanders, H.O. 1970. Pesticide toxicities to tadpoles of the western chorus
frog. Pseudocris triseriata and Fowler's toad, Bufo woodhousei fowleri.
Copeia No. 2: 246. ~""~~~~
Sanders, H.O. and O.B. Cope. 1966. Toxicities of several pesticides to two
species of cladocerans. Trans. Am. Fish Soc. 95: 165.
58-10
-------
Schoettger, R.A. 1970. Progress in sport fishery research 1970. Research
Publ. NO. 106. U.S. Dept. Interior.
Tomatis, L., et al. 1974. Effect of long-term exposure to 1,1-dichloro-
2,2-bis(p-chlorophenyl) ethylene, to l,l-dichloro-2,2-bis (p-chlorophenyl)
ethane, and to the two chemicals combined on CF-1 mice. Jour. Natl. Cancer
Inst. 52: 883.
U.S. EPA. 1975. Preliminary assessment of suspected carcinogens in drink-
ing water. Interim report to Congress, U.S. Environ. Prot. Agency, Washing-
ton, D.C.
U.S. EPA. 1979a. DDT: Ambient Water Quality Criteria. (Draft).
U.S. EPA. 1979b. Environmental Criteria and Assessment Office. DDT:
Hazard Profile. (Draft).
Vogel, E. 1972. Mutagenitatsuntersuchungen mit DDT und den DDT-metaboliten
DDE, ODD, DOOM and DDA an Drosphila melanogaster. Mutat. Res. 16: 157.
Wessel, J.R. ' 1972. Pesticide residues in foods. Environmental contami-
nants in foods. Spec. rep. No. 9. N.Y. State Agric. Exp. Sta., Geneva.
-------
No. 59
DDE
Health"and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
Sf-l
-------
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 accuracv.
S7-9-
-------
DDE
Summary
DDE exists as two isomers, o,p'- and p,p'-ODE. [l,l'-(2,2-dichloroeth-
enylidene)-bis-4-ehlorobenzene] is the major contaminant (ca. 4 percent) of
commercial preparations of p,p'-ODT [l,l'-(2,2,2-trichloroethylidene)- bis-
4-chlorobenzene], as well as being a metabolite of p,p'-ODT. p,p'-ODE is a
highly lipophilic compound which undergoes no further metabolism. Its resi-
dency time in the body is extremely long. p,pMDOE has been shown to be
carcinogenic in mice but not in rats. In cell culture it causes chromosomal
breaks.
The only aquatic toxicity data available on p,p'-OOE involve acute tox-
ic flow-through exposures to two saltwater invertebrates. The 48-hr. LC-0
for a shrimp is 28 pg/1; the 96-hr. LC-g for the Eastern oyster is 14 jjg/1.
-------
DDE
I. ' INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for DDT and metabolites (U.S. EPA, 1979a).
DDE is a contaminant of technical l,l'-(2,2,2-trichloroethylidene)-bis-
4-chlorobenzene (DDT). Its two isomers, p,p'-ODE [!,!'-(2,2-dichloroetheny-
lidene)-bis-4-chlorobenzene] and o,p'-ODE make up approximately 4.0 and 0.1
percent, respectively, of technical grade DDT. Between 1970 and 1973 (the
EPA banned DDT in 1972), a significant drop in the residues of DDT in the
U.S. occurred, constituting a .decrease of 86 percent. However, during this
time period, residues of DOE decreased only 27 percent. In fact, p,p'-DDE
residues comprise most of the biological residues (ca. 71 percent) arising
from DDT application (U.S. EPA, 1979a; Kveseth, et al. 1979).
II. EXPOSURE
Little information is available on exposure to DDE, although the gener-
al exposure pattern probably follows that of DDT, as outlined in DDT: Haz-
ard Profile (U.S. EPA, 1979b). DDE residues appear to be disappearing from
the environment at a slower rate than DDT following the 1972 ban on DDT
(U.S. EPA, 1975). Wessel (1972) calculated the daily dietary intake of
p,p'-DDE to be 0.018 mg/man/day, as compared with a value of 0.027 mg/man/
day for DDT. A recent study by de Campos and Olszyne-Marzys (1979) based on
studies in Latin American countries still using DDT indicates that human
milk contains more p,p'-OOE than p,p'-DDT (up to 3 pg/1 whole milk) in every
sample taken.
-------
III. PHARMACQKINETICS"
A. Absorption
DDE is absorbed from the gastrointestinal tract with high efficien-
cy characteristic of dietary fat. Maximum lipid solubilities reach 100,000
ppm.
8. Distribution
The distribution of ODE is similar to that described for DDT in the
EPA/ECAO Hazard Profile on DDT (U.S. EPA, 1979b). Serum and adipose concen-
trations of p,p'-ODE rise slower than DDT, with the% peak some months in fol-
lowing termination of dosing. The human adipose storage of p,p'-ODE is
greater than that for DDT, and p,p'-DDE is eliminated from the body very
slowly. This is also true for the Rhesus monkey (Durham, et al. 1963).
Storage loss data predict that, if dietary intake were eliminated, it would
take an entire lifespan to eliminate the average human body burden of p,p'-
DDE. It has been shown that tissue storages of p,p'-ODE in the general pop-
ulation originate almost entirely from dietary p,p'-ODE rather than DOT con-
version (U.S. EPA, 1979a). However, this may not be the case for p,p'-ODE
residues in human milk (de Campos and Olszyne-Marzys, 1979).
C. Metabolism
The end product of the metabolism of DDT which proceeds via reduc-
tive dehydrochlorination is p,p'-DDE. In addition, p,p'-ODE is the major
storage product of DOT in animals [apart from hamsters (Agthe, et al. 1970)]
and humans: The enzymes for metabolizing DDT to p,p'-ODE are present in all
tissues (Fang, et al. 1977).
In humans given p,p'-OOT orally, no more than one-fifth of the
absorbed DDT ultimately undergoes conversion to p,p'-ODE (Morgan and Roan,
1977). p,p'-ODE does not undergo further metabolism to 2,2-bis(4-chloro-
phenyl)-acetic acid (DDA), the urinary excretion product of DDT.
-------
0. Excretion
Excretion of p,p'-ODE has not been demonstrated in man. In mice,
p,p'-ODE is excreted in the urine (Wallcave, et al. 1974). The o,p'-isomer
is more easily excreted than the p,p'-isomer (Morgan and Roan, 1977).
IV. EFFECTS
A. Carcinogenicity
Only two studies have been performed to assess the carcinogenicity
of p,p'-ODE. In a lifespan study, CF-1 mice were fed 37.5 mg/kg/day p,p'-
DDE in their diet (Tomatis, et al. 1974). p,p^-DDE increased liver tumor
incidence from 1 percent in controls to 90 percent in treated female
animals, and. from 34 to 74 percent in male animals. The combination
p,p'-DDE/ODD produced more tumors than either constituent alone at the same
concentration in the combination. In a National Cancer Institute study
(1978), Osborne-Mendel rats and B6C3F1 mice were dosed with p,p'-OOE for 78
weeks. In rats, p,p'- DDE had no carcinogenic effect on either females (22
mg/kg/day) or males (42 mg/kg/ day), although hepatotoxicity was evident.
In mice, hepatocellular carcinomas were significantly increased in the
animals fed p,p'-QDE (22 and 39 mg/kg/day for females and males,
respectively). •
B. Mutagenicity
p,p'-DDE has been shown to be nonmutagenic in §_._ coli Pol-A strains
(Fluck, et al. 1976), Escherichia marcescens (Fahrig, 1974), and in the host
mediated assay using Salmonella typhimurium and §_._ marcescens (Buselmaier,
et al. 1972) and Saccharomyces cerevisiae (Fahrig, 1974). Vogel (1972) mea-
*
sured X-linked recessive lethal mutations in Drosophila melanoqaster and
found no activity for p,p'-ODE. In mammalian systems, the mutagenic activi-
ty of p,p'-ODE is relatively weak. This is evidenced by the fact that, de-
-------
pending upon the dose and route of administration4 and the species sensitivi-
ty of the test organism, reported studies are negative or marginally posi-
tive (U.S. EPA, 1979a). Some chromosomal aberrations and inhibition of pro-
liferation have been observed with p,p'-ODE in cell culture (Palmer, et al.
1972; Mahr and Miltenburger, 1976). The o,p'-isomer causes fewer chromosom-
al aberrations (Palmer, et al. 1972).
C. Teratogenicity, Other Reproductive Effects and Chronic Toxicity
Pertinent information could not be located in the available litera-
ture.
D. Other Relevant Information
Since p,p'-ODE is a metabolite of DDT, as well as a contaminant of
commercial preparations of DDT, many of the effects of DDT could be mediated
through p,p'-ODE. Information on DDT is presented in DDT: Hazard Profile
(U.S. EPA, 1979b). Oral acute LD5Q values for p,p'-ODE in rat are 380
mg/kg for males but 1,240 mg/kg for females (Hayes, et al. 1965).
V. AQUATIC TOXICITY
A. Acute Toxicity
The 96-hr. LC5Q value for p,p'-ODE for the comparatively resis-
tant freshwater planarian (Polycelis felina) was 1,050 ;jg/l (Kouyoumjian and
Uglow, 1974). The acute toxicity of p,p'-OOE has also been investigated in
two saltwater invertebrates. The 48-hr. LC,-n for the brown shrimp, Penae-
2U
us aztecus, was 28 Jjg/l; the 96-hr. LC-_ for the Eastern oyster, Crassos-
trea virqinica. was 14 jug/l ('U.S. EPA, 1979a). Both studies were flow-
through exposures.
B. Chronic Toxicity and Plant Effects
Pertinent data could not be located in the available literature.
-------
C. Residues
p,p'-DDE is a major metabolite of DDT in aquatic ecosystems. One
study involving bird eggshells and DDT showed p,p'-DDE to comprise 62 per-
cent of the DDT metabolites (U.S. EPA, 1979a). Average residues in egg-
shells of the great black-backed gull ranged from 14 to 68 ng/g of lipid
(Cooke, 1979). p,p'-ODE in fat and muscle of the white-faced ibis in 1974/
75 were as high as 65 ng/g lipid (Capen and Leiker, 1979). No studies are
available, however, involving p,p'-DDE specifically.
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
In 1972, the U.S. EPA banned the agricultural use of DDT in the
United States. There are no other specific guidelines or standards for
DDE. However, for the protection of human health with respect to DDE,
criteria of 0.98, 0.098 and 0.0098 ng/1 have been proposed for DDT corres-
ponding to risk levels of 10" , 10" , and 10" , respectively. If
water alone is consumed, the water concentration should be less than 0.36
pg/1 to keep the lifetime cancer risk below 10~ .
B. Aquatic
The criteria for DDT and its metabolites are proposed for the
protection of aquatic life from the effects of DDE. The 24-hour average for
the protection of freshwater aquatic life is 0.00023 pg/1, not to exceed
0.41 pg/1 at any time. For saltwater aquatic life, the 24-hour average is
0.0067 |jg/l, not to exceed 0.021 ;jg/l at any time.
-------
DDE
REFERENCES
Agthe, C., et al. 1970. Study of the potential carcinogenicity of DDT in
the Syrian Golden Hamster. Proc. Soc. Biol. Med. 134: 113.
Buselmaier, W., et al. 1972. Comparative investigations on the mutagenici-
ty of pesticides in mammalian test systems. Eur. Environ. Mutagen Soc. 2nd
Ann. Meet., Ziukovy Castle, 25.
de Campos, M. and D.E. Olszyna-Marzys. 1979. Contamination of human milk
with chlorinated pesticides in Guatamala and in El Salvador. Arch. Environ.
Contam. Toxicol. 8: 43.
Capen, O.E. and T.J. Leiker. 1979. DDE residues in blood and other tissues
of white-faced ivis. Environ. Pollut. 19: 163.
Cooke, A.S. . 1979. Eggshell characteristics of gannets (Sula bassoud),
shaps (Phalacrocorax aristotelis) and great black-packed gulls (Larus marin-
us) exposedto DOE and other environmental pollutants. Environ. Pollut.
19: 47.
Durham, W.F., et al. 1963. The effect of various dietary levels of DDT on
liver function, cell morphology and DOT storage in the Rhesus monkey. Arch.
Int. Pharmaccdyn. Ther. 141: 111.
Fahrig, R. 1974. Comparative mutagenicity studies with pesticides. Page
161 In: Montesano and L. Tomatis, (eds). Chemical carcinogenesis essays,
WHO. IARC Sci. Publ. No. 10.
Fang, S.C., et al. 1977. Maternal transfer of 14C-p,p'-DDT via placenta
and milk and its metabolism in infant rats. Arch. Environ. Contam. Toxicol.
5: 427.
Fluck, E.R., et al. 1976. Evaluation of a DNA polymerase-deficient mutant
of E. cqli for the rapid detection of carcinogens. Chem. Biol. Interac-
tions. 15: 219.
Hayes, W.J., Jr., et al. 1965. Chlorinated hydrocarbon pesticides in the
fat of people in New Orleans. Life Sci. 4: 1611.
Kouyoumjian, H.H. and R.F. Uglow. 1974. Some aspects of the toxicity of
p,p!-OOT, p,pl-ODE and p,p!-ODO to the freshwater planarian Polycelis
felina (Tricladida). Environ. Pollut. 7: 103.
Kveseth, N.J., et al. 1979. Residues of DDT in a Norwegian fruit growing
district two and four years after termination of DDT usage. Arch. Environ.
(Contam. Toxicol.). 8: 201.
Mahr, U. and H.G. Miltenburger. 1976. The effect of insecticides on Chi-
nese hamster cell cultures. Mutat. Res. 40: 107.
-------
Morgan, D.P. and C.C. Roan. 1977. The metabolism of DDT in man. Essays
Toxicol. 5: 39.
National Cancer Institute. 1978. Bioassays of DDT, TDE and p,p'-ODE for
possible carcinogenicity. NCI-CG-TR-131. U.S. Dep. Health Edu. Welfare.
Palmer, K.A., et al. 1972. Cytogenetic effects of DDT and derivatives of
DDT in a cultured mammalian cell line. Toxicol. Appl. Fharmacol. 22: 355.
Tomatis, L., et al. 1974. Effect of long-term exposure to 1,1-dichloro-
2,2-bis(p-chlorophenyl) ethylene, to l,l-dichloro-2,2-bis (p-chlorophenyl)
ethane, and to the two chemicals combined on CF-1 mice. Jour. Natl. Cancer
Inst. 52: 883.
U.S. EPA. 1975. DDT. A review of scientific and economic aspects of the
decision to ban its use as a pesticide. EPA52Q/1-75-022. U.S. Environ.
Prot. Agency, Washington, D.C.
U.S. EPA. 1979a. DDT: Ambient Water Quality Criteria. (Draft).
U.S. EPA. 1979b. Environmental Criteria and Assessment Office. DDT: Haz-
ard Profile (Draft).
Vogel, E. 1972. Mutagenitatsuntersuchungen mit DDT und den DDT-metaboliten
DDE, ODD, DOOM and DDA. an Drosohila melanogaster. Mutat. Res. 16: 157.
Wallcave, L., et al.- 1974. Excreted metabolites of l,l,l-trichloro-2,2-bis
(p-chlorophenyl) ethane in the mouse and hamster. Agric. Food Chem.
22: 904.
Wessel, J.R. 1972. Pesticide residues in foods. Environmental contami-
nants in foods. Spec. Rep. NO. 9. N.Y. State Agric. Exp. Sta., Geneva.
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No. 60
DDT
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
60-1
-------
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.
DDT and has found sufficient evidence to indicate that this
compound is carcinogenic.
60-3
-------
DDT
Summary
.The most commonly 'used DDT was a technical formulation and usually con-
sisted of a mixture of p,p'-ODT (77.1 percent), o,p'-DDT (14 percent), p,p'-
DDD (0.3 percent), o,p'-ODD (0.1 percent), p,p'-DDE (4 percent), o,p'-OOE
(0.1 percent and 3.5 percent unidentified compounds. Pure DDT is the p,p'-
isomer [l,l'-(2,2,2-trichloroethylidene)-bis-4-chlorobenzene]. Unless spe-
cifically identified, the term DDT will refer tcr- the pure form. Prior to
being banned in the U.S. in 1972, DDT was used extensively as a pesticide.
Due to the high lipid solubility of DDT, it has a long residency time
in the body. DDT has produced adverse reproductive effects in rodents and
birds, but adverse effects have not been noted in man. The lowest acute
oral to— value was found for the dog (60-75 mg/kg). There is suggestive
evidence that DDT might be a carcinogen, and weak evidence that it might be
a teratogen. Chromosomal breaks have been observed with DDT exposure in
vitro and in_ vivo.
DDT is acutely toxic to freshwater fish at concentrations as low as 0.8
jug/1 and to invertebrates at 0.18;ug/l. Chronic toxicity has been manifest-
ed in the fathead minnow in the range of 0.37 to 1.48 jug/1. A weighted
average bioconcentration factor of 39,000 has been estimated for DDT for
consumed fish and shellfish. For saltwater fish and invertebrates, DDT con-
centrations as low as 0.2 jug/1 and 0.14 /jg/1, respectively, have been re-
ported to be acutely toxic. Chronic toxicity data^ for saltwater organisms
are not available.
-------
DDT
I. INTRODUCTION
This profile is based primarily on the Ambient Water Quality Criteria
Document for DOT (U.S. EPA, 1979a).
DDT has been used extensively world-wide for public health and agricul-
tural programs as a broad spectrum insecticide. It has played a large role
in the world-wide control of the malaria mosquito. In 1972, following an
extensive review of health and environmental hazards of the use of DDT, the
U.S. EPA decided to ban any further use of DDT. .. Prior to this, technical
grade DDT had been widely used in the U.S., with a peak usage in 1959 of 80
million pounds. This amount decreased steadily to less than 12 million
pounds by 1972. Since the 1972 ban, the use of DDT in the U.S. has been ef-
fectively discontinued. However, technical grade DDT is still used in many
other countries and widespread contamination still occurs. Since ODD and
DDE are also metabolites of DDT, it is sometimes difficult to separate con-
tamination from metabolic accumulation. The compounds of DOT are extremely
persistent and are so widespread that levels as high as 15 ppb have been de-
tected in feed for laboratory animals (Coleman and Tardiff, 1979).
II. EXPOSURE
The primary route of human exposure to DDT is from ingestion of small
amounts in the diet. Biological magnification of DDT in the food chains oc-
curs by two routes: (1) direct absorption from contaminated water by aquat-
ic organisms; (2) transfer of residues through sequential predator feeding.
Meats, fish, poultry, and dairy products are the primary sources of DDT
t
residues in the human diet. The U.S. EPA (1979a) has estimated the weighted
average bioconcentration factor of DDT at 39,000 for consumed fish and
shellfish. Due to the banned usage of DDT in the U.S., there has been a
-------
continual decline in the DDT residue in food. These decreases are reflected
in the changing amounts of estimated dietary intake: 1965 - 0.062 mg/man/
day; 1970 - 0.024 mg/man/day; 1973 - 0.008 mg/man/day (U.S. EPA, 1975).
Levels of DDT- found in the air are far below levels that add significantly
to total human intake. Stanley, et al. (1971) sampled air in nine locali-
ties, and found DDT in the ranges of 1 ng/m to 2520 ng/m of air.
Wolfe and Armstrong (1971) showed that industrial workers not wearing respi-
rators could be exposed to significant levels of DDT in the air (up to 34
mg/man/hour), particularly in the formulating plants. Exposure for agricul-
tural spray operators may be as high as 0.2 mg/man/hour (Wolfe, 1967). Der-
mal exposure 'for formulators was estimated to range from 5 to 993 mg/man/
hour (Wolfe and Armstrong, 1971). Little DDT was found in the urine, how-
ever. Dermal absorption of DDT is minimal.
Dermal toxicity in rats occurs at 3,000 mg/kg (U.S. EPA, 1979a). Hayes
(1966) estimated the intake of DDT to be in the following proportions: food
- 0.04 mg/man/day; water - 4.6 x 10~ mg/man/day; and air - 9 x 10~
mg/man/day. The actual dose for the average man is now estimated to be 0.01
mg/man/day (U.S. EPA, 1979a).
III. PHARMACOKINETICS
A. Absorption
DDT is absorbed from the gastrointestinal tract with efficiency ap-
proaching 95 percent when ingested with dietary fat. In humans, Morgan and
Roan (1971) showed that absorption of an oral dose of 20 mg DOT proceeded
faster than transport out of the vascular compartment into tissue storage.
Studies concerning the kinetics of absorption of DOT via inhalation or der-
mal routes were not found in the available literature.
-------
B. Distribution
DDT has been found in virtually all body tissues, approximately in
proportion to respective tissue content of extractable lipid. The adipose/
blood ratios of DDT have been recently estimated to be approximately 280:1
(Morgan and Roan, 1977). DOT concentrations in body tissues were highest
for fat tissue, followed by reproductive organs, the liver and kidney to-
gether, with lowest concentrations found in the brain (Tomatis, et al.
1971). Elimination of very low levels of DOT from storage proceeds much
more slowly than that of the large stores of DDT ^accumulated by occupation-
ally exposed workers or dosed volunteers (Morgan and Roan, 1971). The aver-
age North American adult, with 17 kg of body fat, contains approximately 25
mg of DDT. It is predicted from storage loss data that, if dietary intake
were eliminated, most of the DDT would be lost within one or two decades
(U.S. EPA, 1979a). Trace metals in the diet, particularly cadmium, may af-
fect the mobilization of DDT in tissues' (Ando, 1979).
C. Metabolism
The metabolism of DDT in man appears to be the same as the pathways
reported by Peterson and Robison (1964) for the mouse. Generally, two sepa-
rate reductive pathways produce the primary endpoint metabolites, p,p'-CDE
and p,p'-ODA. The predominant conversion is of DDT to p,p'-ODD via dechlor-
ination. This is the first product in a series which results in metabolites
which are later excreted. The other primary pathway proceeds via reductive
/
dehydrochlorination which results in the formation of p,p'-ODE the major
storage product in animals and humans. Fant, et al. (1977) suggest that
enzymatic activity for the dehydrochlorination and reductive dechlorination
•
reactions transforming DDT to DDO and DDE is present in all tissues, whereas
the enzymes involved in the hydrogenation and hydroxylation steps changing
66-7
-------
ODD to DDA are absent in the brain, heart, pancreas, and muscle of the rat.
Metabolic conversion of DOT to DDA proceeds more rapidly than conversion to
the storage metabolite of DDE. For additional information regarding the DDT
metabolites ODD and DDE, the reader is referred to the Hazard Profile for
those chemicals (U.S. EPA, 1979b,c).
D. Excretion
The excretion of DDT was investigated in human volunteer studies of
Hayes, et al. (1971) and Roan, et al. (1971). Urinary excretion predominat-
».
ed, with 13 to 16 percent of the daily dose being excreted as p,p'-DDA, and
was shown to correlate with exposure levels of individuals working in a for-
mulating plant (Ortelee, 1958). p,p'-DDE and DDT are the predominant com-
pounds excreted and p,p'-DOD and p,p'-DDA are excreted in the least amounts
(Morgan and Roan, 1977). p,p'-DDE was found in slightly higher concentra-
tions in exposed workers versus the general population. Gut microorganisms
have demonstrated a capacity for degradation of DDT to p,p'-DDO and p,p'-ODA.
IV. EFFECTS
A. Carcinogeniity
Lifetime and multigeneration exposures to DDT in the diet of rats,
mice, and fish have produced significant increases in the formation of a
number of tumor types (U.S. EPA, 1979a). The predominant lesion appears to
be hepatoma. Also, Tomatis, et al. (1974) demonstrated that short-term ex-
posure to technical grade DDT (37.5 mg/kg/day for 15 or 30 weeks), using
CF-1 mice, resulted in an increased incidence and early appearance of hepa-
tomas, similar to that caused by lifespan exposure. "'Mice appear much more
susceptible than rats (U.S. EPA, 1979a) and the use of the mouse as an ani-
«
mal model for humans has been criticized (Deichmann, 1972). In these stud-
ies contaminants p,p'-ODD and p,p'-ODE were present, both of which have pro-
-------
duced liver tumors in CF-1 mice (Tomatis, et al. 1974). Also, the combina-
tion of p,p'-ODD/DDE was found to produce more tumors than and equal concen-
tration of either compound alone. Tarjan and Kemeny (1969) noted leukemias
and pulmonary carcinomas in Bald-C mice fed 3 ppm DDT in the diet. Hepato-
mas have been observed in rainbow trout (Halver, et al. 1962).
A number of other studies have shown no significant increase in
tumor formation following DDT exposure. Lifetime feeding studies with Syri-
an Golden Hamsters (Agthe, et al. 1970) and a number of long term feeding
studies with various strains of rats have shown .no significant increase in
tumor incidence (Cameron and Cheng, 1951; Fitzhugh and Nelson, 1947; Radom-
ski, et al. 1965; Deichmann, et al. 1967). In a 78-week National Cancer In-
stitute study (1978), Osborne-Mendel rats given 16 and 32 mg/kg/day (males)
or 11 and 21 mg/kg/day (females) showed no tumors. B6C3F1 mice given 3.3
and 6.6 mg/kg/day (males) or 13 and 26 mg/kg/day (females) also showed no
tumor development. Durham, et al. (1963) found no liver pathology in Rhesus
monkeys fed 100 mg/kg/day or less DDT for up to 7.5 years. At the present
i
time, no evidence of neoplasia has been found in the studies performed in
occupationally exposed or dosed volunteer subjects (U.S. EPA, 1979a).
B. Mutagenicity
DDT has not shown mutagenic activity in any of the bacterial test
systems thus far studied: Salmonella typhimurium (McCann, et al. 1975; Mar-
shall, et al. 1976); §_._ coli Pol-A strains (Fluck, et al. 1976); Bacillus
subtilis (Shirasu, et al. 1976). Tests on eukaryotic yeast cells have been
uniformly negative, with Fahrig (1974) using Saccharomyces cerevisiae and
•* ^^^^^••^^^^^^^^^^
Clark (1974) using Neurospora crassa. Vogel (1972) and Clark (1974) found
positive mutagenic activity in Drosophila melanoqaster by measuring x-»linked
recessive lethal mutations. In mammalian systems, the mutagenic activity of
-------
DDT is relatively weak. This is evidenced by the fact that, depending upon
the dose and route of administration and the species sensitivity of the test
organisms, reported studies are negative or only marginally positive (U.S.
EPA, 1979a). In vivo and in vitro cytogenetic studies seem to indicate that
DDT is a clastogenic (chromosome breaking) substance. The metabolites p,p'-
DDE, p,p'-ODD, p,p'-DDA and p,p'-DDOH were also non-mutagenic except possi-
bly for p,p'-DDD (U.S. EPA, 1979a). Chromosomal aberrations in cell lines
of the kangaroo rat occurred more often with p,p'-isomers than o,p'-isomers
(Palmer, et al. 1972).
C. Teratogenicity
Only •minimal teratogenic effects have been reported following high
dosages of DDT. Sprague-Oawley rats receiving 200 ppm DDT in their diet
showed a significant increase in ring tail, a constriction of the tail fol-
lowed by amputation, in the offspring (Ottoboni, 1969).
D. Other Reproductive Effects
Hart, et al. (1971) showed that DDT has an effect on prematurity
and causes an increase in the number of fetal resorptions in rabbits given
50 mg/kg on days 7, 8, and 9 of gestation. Chronic exposure (less than 200
mg/kg) of rats and mice produced no adverse effects on survival of the off-
spring (Ware and Good, 1967; Ottoboni, 1969). Krause, et al. (1975) noted a
damaging effect on spermatogenesis in rats following acute exposure to DDT
(7,200 mg/kg). Also, DDT has been shown to possess estrogenic activity in
rodents and birds (Welch, et al. 1969; Bittman, et al. 1968).
E. Chronic Toxicity
A number of pathological changes have been noted in rodents; the
most consistent finding in lifetime feeding studies has been an increase in
the size of liver, kidneys, and spleen; extensive degenerative changes in
-------
the liver; and an increased mortality rate .(U.S'. EPA, 1979a). In contrast
'to the rodent models, Rhesus monkeys fed diets with up to 200 ppm DDT did
not show liver histopathology, decrease in weight gain or food consumption,
or clinical signs of illness (Durham, et al. 1963).
F. Other Relevant Information
DDT is a strong inducer of the mixed function oxidase system; this
could potentially enhance the biological effects of other chemicals by acti-
vation, or diminish their activities through detoxification mechanisms (U.S.
EPA, 1979a). Exposure to DOT has caused enhanced €umor incidence in N-fluor-
enacetamide-treated rats (Weisburger and Weisburger, 1968) and decreased
phenobarbital-induced sleeping times (Conney, 1967). Acute oral LD-g val-
ues in rats typically range from 100 to 400 mg/kg and 40 to 60 mg/kg i.v.
The oral LD5Q values in other animals are: 60 to 75 mg/kg (dogs); 250 to
400 mg/kg (rabbits); approximately 200 mg/kg (mice). For p,p'-ODE, the val-
ues are 330 and 1,240 mg/kg in male and female rats, respectively; for p,p'-
ODA in rats, the values are 740 and 600 mg/kg, respectively (U.S. EPA,
1979a). Symptoms of DOT poisoning in humans include the following: convul-
sions, parasthesia of extremities and vomiting (at high doses), convulsions
and nausea (less than 16 mg/kg), dizziness, confusion and most characteris-
tically, tremors (Hayes, 1963). In rats, the liver shows changes at dietary
doses less than 5 ppm (Laug, et al. 1950). No permanent injury to .man from
DDT has been recorded (U.S. EPA, 1979a).
V. AQUATIC TOXICITY
A. Acute Toxicity
The acute toxicity of DDT to freshwater organisms has been well
documented. Data are available for 25 species of fish. The 96-hour LC5Q
values are available for the following freshwater fish: rainbow trout (Sal-
Co//
-------
mo qairdneri), 1.7 to 42 pg/1; fathead minnow (Pimephales promelas), 7.4 to
58 pg/1; channel catfish (Ictalurus punctatus), 16 to 17.5 pg/1; bluegill
(Lepomis macrochirus), 1.2 to 210 pg/1. The most sensitive of fish was the
yellow perch (Perca flavesceus) with a 96-hour LC5Q of 0.6 pg/1 (Marking,
1966). Invertebrate freshwater species are more sensitive than fish. For
Daphnia maqna, 48-hour LC5Q values of 1.48 pg/1 have been reported (Pries-
ter, 1965). One week old crayfish (Orconectus nais) had a 96-hour LC5Q
value of 0.18 pg/1 (Saunders, 1972). LC5Q values for nine saltwater fish
species range from 0.2 to 4.2 pg/1. Saltwater invertebrates were slightly
more sensitive, with LC5Q values ranging from 0.14 to 10.0 pg/1 (U.S. EPA,
1979a).
Concentrations as low as 8 pg/1 elicited hyperactive locomotor re-
sponses in bluegill (Lepomis macrochirus) over 16 days old (Ellgaard, et al.
1977). The acute LD_Q in adult summer frogs (Rana temporaria) was only
7.6 mg/kg. Though adipose tissues contained most of the DOT, the ovaries of
females contained as much of the compound as did bones and spleen (Harri, et
al. 1979).
B. Chronic Toxicity
Only one chronic freshwater fish value is available (Pimephales
promelas). indicating that the chronic toxicity value is 0.74 pg/1 (Jarvi-
nen, et al., 1977). Freshwater invertebrate chronic toxicity data are not
available. Concentration of DDT affecting three saltwater invertebrate spe-
cies in chronic studies are similar in LC5Q values (U.S. EPA, 1979a).
C. Plant Effects
Four species of freshwater algae (Calovella sp.) have evidenced a
wide range of sensitivities, 0.3 to 800 pg/1 (Sodergren, 1968). Wu'rster
(1968) investigated the effects of DDT on four species of marine algae. The
-------
data showed reduced rates of photosynthesis•at 10 /ug/1, indicating that al-
gae are much less sensitive to DOT than are fish and invertebrates.
0. Residues
DOT is bioconcentrated to a very high degree in aquatic organisms.
An average bioconcentration factor (BCF) of 640,000 has been calculated from
31 experimental measurements of bioconcentration done on 26 species of
freshwater fish. Individual BCF's ranged from 490 to 2,236,666. In the
field, BCF factors have been observed which are seven times higher than the
average values derived from laboratory data. This discrepancy may be due to
the many additional trophic levels involved and the possibly higher lipid
content of the organisms in the field. In saltv/ater species, the BCF for
DOT ranges from 800 to 76,300 times for fish and shellfish (U.S. EPA,
1979a). The lowest observed allowable maximum tissue concentration was 0.5
jug/kg for domestic animals in animal feed (U.S. FDA, 1977) and in the brown
pelican (Pelecanus occidentalis) for eggshell thinning (Blus, et al. 1972,
1974).
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived by U.S. EPA
(1979c), 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 existing guidelines and standards for DDT are:
V*
YEAR AGENCY/ORG. STANDARD REMARKS
1971 WHO 0.005 mg/kg Maximum Acceptable Daily
body weight Intake in food
1976 U.S. EPA 0.001 ug/1 Ambient Water Quality
Criteria
-------
1977 Natl. Acad. Sci., - In light of carcinogenic
Natl. Res. Counc. risk projection, suggested
strict criteria for DDT
and DDE in drinking water
1978 Occup. Safety 1 mg/m2 Skin exposure
Health Admin.
1978 U.S. EPA 0.41,ug/l Final acute and chronic
0.00023 ,ug/l values for water quality
criteria for protection of
aquatic life (freshwater)
The U.S. EPA (1979a) is in the process of establishing ambient
«.
water quality criteria. Based on the potential carcinogenicity of DDT, cur-
rent draft criteria are calculated on the estimate that 0.98 jug/man/day
would result in an increased additional lifetime cancer risk of no more than
1/100,000. Since man and the rat appear to be less sensitive than mice,
greater levels may be tolerable.
B. Aquatic
For DDT, the proposed draft criterion to protect freshwater aquatic
life is 0.00023jug/1 as a 24-hour average; the concentration should not ex-
ceed 0.41 yug/1 at any time. For saltwater aquatic species, the concentra-
tion is 0.0067^ug/l as a 24-hour average and should not exceed 0.021yug/l at
any time (U.S. EPA, 1979a).
/
Co-If
-------
DDT
REFERENCES
Agthe, C., et al. 1970. Study of the potential carcinogenicity of DDT in
the Syrian Golden hamster. Proc. Soc. Exp. Biol. Med. 134: 113.
Ando, M. 1978. Transfer of 2,4,5,2',4',5'-hexachlorobiphenyl and 2,2,-bis-
(p-chlorophenyl)-l,l,l-trichloroethane(p,p'-ODT) from maternal to newborn
and suckling rats. Arch. Toxicol. 41: 179.
Bittman, J., et al. 1968. Estrogenic activity of o.,p'-ODT in the mammalian
uterus and avian oviduct. Science 162: 371.
Blus, L.J., et al. 1972. Logarithmic relationship of DOE residues to egg-
shell thinning. Nature 235: 376.
Blus, L.J., et al. 1974. Relations of the brown pelican to certain envi-
ronmental pollutants. Pestic. Monit. Jour. 7: 181.
Cameron, G.R., and K. Cheng. 1951. Failure of oral DDT to induce toxic
changes in rats. Br. Med. Jour. 819.
Clark, J.M. 1974. Mutagenicity of DDT in mice, Drosophila melanoqaster and
Neurospora crssa. Aust. Jour. Biol. Sci. 27: 427.
Coleman, w.E. and R.G. Tardiff. 1979. Contaminant levels in animal feeds
used for toxicity studies. Arch. Environ. Contam. Toxicol. 3: 693.
Conney, A.M. 1967. Pharmacological implications of microsomal enzyme in-
duction. Pharmacol. Rev. 19: 317.
Deichmann, W.8. 1972. The debate on DDT. Arch. Toxicol. 29: 1.
Deichmann, W.B., et al. 1967. Synergism among oral carcinogens. IV. The
simultaneous feeding of four tumorigens to rats. Toxicol. Appl. Pharmacol.
11: 88.
Durham, W.F., et al. 1963. The effect of various dietary levels of DDT on
liver function, cell morphology and DDT storage in the Rhesus monkey. Arch.
Int. Pharmacokyn. Ther. 141: 111.
Ellgaard, E.G., et al. 1977. Locomotor hyperactivity induced in the blue-
gill sunfish, Lepomis macrochirus, by sublethal corrections of DDT. Jour.
Zool. 55: 1077.
Fahrig, R. 1974. Comparative mutagenicity studies with pesticides. Page
161 in R. Montesano and L. Tomatis, eds. Chemical carcinogenesis essays,
WHO. IARC Sci. Publ. No. 10.
»
Fang, S.C., et al. 1977. Maternal transfer of 14C-p-p'-ODT via placenta
and milk and its metabolism in infant rats. Arch. Environ. Contam. Toxicol.
5: 427.
60'
-------
Palmer, K.A. 1972. Cytogenic effects of DDT and derivatives of DDT in a
cultured mammalian cell line. Toxicol. Appl. 'Pharmacol. 22: 355.
Peterson, J.E. and W.H. Robison. 1964. Metabolic products of p,p'-ODT in
the rat. Toxicol. Appl. Pharmacol. 6: 321.
Priester, E.L., Jr. 1965. The accumulation and metabolism of DDT, para-
thion, and endrin by aquatic food-chain organisms. Ph.D. Thesis. Clemson
Univ. Clemson, S.C. 74 p.
Radomski, J.L., et al. 1965. Synergism among oral carcinogens. I. Results
of the simultaneous feeding of four tumorigens to rats. Toxicol. Appl.
Pharmacol. 7: 652.
Roan, C., et al. 1971. Urinary excretion of ODA following ingestion of DDT
and DDT metabolites in man. Arch. Environ. Health 22: 309.
•.
Shirasu, V., et al. 1976. Mutagenicity screening of pesticides in the
microbial system. Mutat. Res. 40: 19.
Sodergren, A. .1968. Uptake and accumulation of C^-DDT by Chlorella sp.
(Chlorophyceae) Oikos 19: 126.
Stanley, C.W., et al. 1971. Measurement of atmospheric levels of pesti-
cides. Environ. Sci. Technol. 5: 430.
Tarjan, R. and T. Kemeny. 1969. Multigeneration studies on DDT in mice.
Food Cosmet. Toxicol. 7: 215.
Tomatis, !_., et al. 1971. Storage levels of DDT metabolites in mouse tis-
sues following long-term exposure to technical DDT. Tumcri 57: 377.
Tomatis, L., et al. 1974. Effect of long-term exposure to l,l-dichlor-2,2-
bis(p-chlorophenyl) ethylene, to l,l-dichloro-2,2-bis (p-chlorophenyl) eth-
ane, and to the two chemicals combined on CF-l mice. Jour. Natl. Cancer
Inst. 52: 883.
U.S. EPA. 1979a. DDT: Ambient Water Quality Criteria. (Draft).
U.S. EPA. 1979b. Environmental Criteria and Assessment Office. DDE: Haz-
ard Profile. (Draft).
U.S. EPA. 1979c. Environmental Criteria and Assessment Office. ODD: Haz-
ard Profile. (Draft)
U.S. FDA. 1977. Administrative Guidelines Manual 7426-04, Attachment E.
Vogel, E. 1972. Mutagenitatsuntersuchungen mit DDT und den DDT-metaboliten
DDE, ODD, DOOM und DDA. an Drosphila melanoqaster. Mutat. Res. 16: 157.
Ware, G.W. and E.E. Good. 1967. Effects of insecticides on reproduction in
the laboratory mouse. II. Mirex, Telodrin and DDT. Toxicol. Appl. Phar-
macol. 10: 54.
-------
Weisburger, J.H. and* E.K. Weisburger. 1968, Food additives and chemical
carcinogens: on the concept of zero tolerance. Food Cosmet. Toxicol.
6: 235.
Welch, R.M., et al. 1969. Estrogenic action of DDT and its analogs. Toxi-
col. Appl. Pharmacol. 14: 358.
Wolfe, H.R. and J.F. Armstrong. 1971. Exposure of formulating plant work-
ers to DDT. Arch. Environ. Health 23: 169.
Wolfe, H.R., et al. 1967. Exposure of workers to pesticides. Arch. Envi-
ron. Hlth. 14: 622.
Wurster, C.F., Jr. 1968. DOT reduces photosynthesis by marine phytoplank-
ton. Science. 159: 1474.
60-/7
-------
No. 61
DibroraochloroTTiethane
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.
-------
DIBRCMOCHLORCMETHANE
SUMMARY
Dibromochlorome thane has been detected in drinking water in
the United States. It is believed to be formed by the haloform
reaction that may occur during water chlorination. Dibromochlo-
romethane can be removed from drinking water via treatment with
activated carbon. There is a potential for dibrcmochlorome thane
to accumulate in the aquatic evironment because of its resistance
to degradation. Volatilization is likely to be an important
means of environmental transport.
Very little toxicity information is available. Dibromochlo-
romethane gave positive results in mutagenicity tests with
Salmonella typhinurium TA100. It is currently under test by the
National Cancer Institute.
I. INTRODUCTION
Dibromochlorome thane (CHBr2Cl, molecular weight 208.29) is a
clear, colorless liquid. It is insoluble in water, but is solu-
ble in a number of organic solvents. Its boiling point is 119-
120°C and its density is 2.45 at 20°C (Weast, 1972). At 10.5°C,
its vapor pressure is 15 torr (Dreisbach, 1952).
A review of the production range (includes importation)
statistics for dibrcmochlorome thane (CAS No.'124-48-1) which is
listed in the initial TSCA Inventory (1979) has shown that
-------
between 0 and 900 pounds of this chemical were produced/imported
in 197 7._y
Dibromochloromethane is used as a chemical intermediate in
the manufacture of fire extinguishing agents, aerosol propel-
lants, refrigerants, and pesticides (Verschueren, 1977).
II. EXPOSURE
A. . Environmental Fate
No information was found pertaining to the rate of oxidation
of dibromochloromethane in either the aquatic or atmospheric
environments. Dibromochlorome thane is probably like other halo-
genated aliphatics in that it is not easily oxidized in aquatic
systems because there are no functional groups which react
strongly with HO radical. A maximum hydrolytic half-life of 274
years has been reported for dibrcmochloronethane at pH 7 and 25°C
(Mabey and Mill, 1978).
The vapor pressure of dibromochlorone thane, while lower than
that for chloroform and other chloroalkanes, is, nonetheless,
sufficient to ensure that volatilization will be an important
means of environmental transport. The concentration of dibromo-
chlorome thane present in water supplies has been reported to
This production range information does no't include any produc-
tion/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).
th*
-------
decrease as a result of volatilization while flowing through open
channels (Rook, 1974).
B. Bio accumulation
The log of the octanol/water partition coefficient (log P)
as calculated by the method of Hansch is 2.09 (Tute, 1971) indi-
cating that dibromochloromethane is somewhat lipophilic. As a
result, dibromochloromethane may exhibit a tendency to bioac-
cumulate in organisms. No experimental data were found to
confirm this.
C. Environmental Occurrence
Dibromochloromethane has been detected in finished drinking
water (Kleoper and Fairless, 1972; U.S. EPA, 1975), in drinking
water supplies (U.S. EPA, 1975), and in wastewater effluents
(Glaze and Henderson, 1975). Dibromochloromethane is hypothe-
sized to be present in water supplies as a result of the haloform
reaction which takes place during the chlorination of such water
(Rook, 1974; U.S. EPA, 1975; Glaze and Henderson 1975).
III. HEALTH EFFECTS
A. Carcinogenicity
Dibromochloromethane is currently under test for
carcinogenicity by the National Cancer Institute. No results are
available.
B. Mutagenicity
Dibromochloromethane was found mutagenic in Salmonella
»
typhimurium TA100 in the absence of metabolic activation (Simmon
1977) .
-------
C. Other Toxicity
A long-term test conducted by administration of high doses
of the chemical by gavage in mice showed a dose-dependent
decrease in the activity of liver and spleen phagocytes (Munson
ejt _al_. , 1978).
The oral LD5Q of dibroraochlororaethane in mice is 800 mg/kg
and 1200 mg/kg for males and females respectively. Sedation and
anesthesia occurred within 30 minutes of administration of the
compound and lasted 4 hours. Necropsies were performed on ani-
mals that died. Hemorrhaging was observed in the adrenals, the
kidneys were pale, and the liver appeared to have fatty infiltra-
tion (Bowman, 1978).
IV. AQUATIC EFFECTS
No information was found.
V. EXISTING GUIDELINES
The Maximum Contaminant Level (MCL) for total trihalometh-
anes (including dibromochloromethane) in drinking water has been
set by the U.S. EPA at 0.10 mg/1 (44 FR 68624). The concentra-
tion of dibromochloromethane produced by chlorination can be
reduced by treatment of drinking water with powdered activated
carbon (Rook, 1974). This is the technology that has been pro-
posed by the EPA to meet this standard.
/
•«
Cl-t
-------
REFERENCES
Bowman, F.J. e_t _al_. The Toxicity of Some Salome thanes in Mice.
Toxicology and Applied Pharmacology 44, 213-215, 1978.
Dreisbach, R.R. Pressure-Volume-Temperature Relationships of
Organic Compounds, Handbook Publishers, Inc. Sandusky, Ohio
1952.
Glaze, W.H. and J.E. Henderson, IV. Formation of Organochlorine
Compounds from the Chlorination of a Municipal Secondary Efflu-
ent. Journal Water Pollution Cont. Fed. 47, 2511-2515, 1975.
Kleopfer, R. D. and B.J. Fairless. Characterization of Organic
Components in a Municipal Water Supply. Environ. Sci. Technol.
6(12), 1036-1037, 1972.
Plabey, W. and T. Mill. Critical Review of Hydrolysis of Organic
Compounds in Water Under Environmental Conditions J. Phys. Chen.
Ref. Data-7, 103, 1978.
Munson, A.Z. a_t _al_. Retoculoendothelial System Function in Mice
Exposed to Four Kaloalkanes: Drinking Water Contaminants.
Toxicology and Applied Pharmacology 45(1), 329-330, 1978.
Rook, J.J. Formation of haloforms during chlorination of natural
watars. Journal of the Society of Water Treatment and Examina-
tion 23(Part 2), 234-243, 1974"
Rook, J.J. Chlorination Reactions of Fulvic Acids in Natural
Waters. Environ. Sci. Technol. 11(5), 473-432, 1977.
Simmon, v.F. Structural Correlations of Carcinogenic and
Mutagenic Alkylhalides, Proc. 2nd FDA Office of Science Summer
Sym. 163-171, 1977.
Tute, M.S. Principles and Practices of Hansch Analysis. A Guide
to Structure-Activity Correlation for the Medicinal Chemist.
Advances in Drug Research 6, 1-77, 1971.
U.S. EPA. Preliminary Assessment of Suspected Carcinogens in
Drinking Water. EPA 560/4-75-003, 1975.
U.S. EPA. Toxic Substances Control Act Chemical Substance
Inventory, Production Statistics for Chemicals on the Non-
Confidential Initial TSCA Inventory, 1979.
.•
Verschueren, K. Handbook of Environmental Data on Organic
Chemicals. Van Nostrand Reinhold Co., New York. 1977.
»
Weast, R. C. , ed. 1972. CRC Handbook of Chemistry and Physics.
CRC Press, Inc., Cleveland, Ohio. '
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No. 62
Di~n-butyl Phthalate
Heal-th and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
a.-'
-------
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.
-------
DI-n-BUTYL PHTHALATE
Summary
Teratogenic effects in rats have been reported in testing of di-
n-butyl phthalate following i.p. administration, but not after oral
administration at high doses (0.600 g/kg/day). Other reproductive
effects in rats following i.p. administration include impaired implantation
and parturition. Rats fed di-n-butyl phthalate or its monoester metabolite
have developed testicular damage and atrophy.
Mutagenic or carcinogenic effects of di-n-butyl phthalate have
not been reported.
One clinical study has indicated that workers exposed primarily,
but not exclusively, to di-n-butyl phthalate showed a higher incidence
of toxic polyneuritis.
The only toxicity data available for review demonstrate that di-
n-butyl phthalate is acutely toxic to freshwater organisms at concentrations
as low as 730 _ug/l.
-------
DI-n-BUTYL PHTHALATE
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Phthalate Esters (U.S. EPA, 1979a).
Di-n-Butyl phthalate (DBP) is a diester of the ortho form of
benzene dicarboxylic acid. The compound has a molecular weight of 278.34,
specific gravity of 1.0465, boiling point of 340°C and a solubility of
0.45 gms per 100 ml of water at 25°C (U.S. EPA, 1979a).
DBP is used as a plasticizer in polyvinyl acetate emulsions and
as an insect repellent.
Current Production: 8.3 x 103 tons/year in 1977 (U.S. SPA, 1979a).
Phthalates have been detected in soil, air, and water samples, in
animal and human tissues, and in certain vegetation. Evidence from in
vitro studies indicates that certain bacterial flora may be capable of
metabolizing DBP to the monoester form (Engelhardt, et al. 1975). For
additional information regarding the phthalate esters in general, the
reader is referred to the EPA/ECAO Hazard Profile on Phthalate Esters
(U.S. EPA, 1979b).
II. EXPOSURE
Phthalate esters appear in all areas of the environment. Environmental
release of phthalates may occur through leaching of the compound from
plastics, volatilization of phthalate from plastics, or the incineration
of plastic items. Sources of human exposure to phthalates include
contaminated foods and fish, dermal application, ,and parenteral administration
by use of plastic blood bags, tubings, and infusion devices (mainly
DEHP release). Relevant factors in the migration of phthalate esteVs
from packaging materials to food and beverages are: temperature, surface
area contact, lipoidal nature of the food and length of contact (U.S.
EPA, 1979a).
-------
Monitoring studies have indicated that most water phthalate concen-
trations are in the ppm range, or 1-2 pg/liter (U.S. EPA, 1979a). Industrial
air monitoring studies have measured air levels of phthalates from 1.7
to 66 mg/m3 (Milkov, et al. 1973). Levels of DBF in foods have ranged
from not detectable to 60 ppm (Tomita, et al. 1977). Cheese, milk,
fish and shellfish present potential sources of high phthalate intake'
(U.S. EPA, 1979a). The U.S. EPA (1979a) has estimated the weighted
average bioconcentration factor for DBP to be 26 for the edible portions
of fish and shellfish consumed by Americans. This estimate was based
on the octanol/water partition coefficient.
III. PHARMACOKINETICS
A. Absorption
A human study in which subjects ate food containing DBP
leached from plastic containers shows significantly higher levels of
DBP found in the blood (Tomita, et al. 1977).
B. Distribution
Pertinent data could not be located in the available literature.
C. Metabolism
Monobutyl phthalate has been identified as a urinary metabolite
in rabbits administered DBP (Ariyoshi, et al. 1976). This metabolite
has also been detected in the urine of rats, hamsters, and guinea pigs,
as well as other metabolites with side chain oxidation, and phthalic
acid (Tanaka, et al. 1978).
*
D. Excretion
Pertinent data could not be located in the available literature.
»
i.
-------
IV. EFFECTS
A. Carcinogenicity
Pertinent data could not be located in the available literature.
B. Mutagenicity
Mutagenic effects of DBF were not observed in the Ames
Salmonella assay (Rubin, et al. 1979) or in a yeast (Saceharomyces)
assay system (Shahin and VonBorstel, 1977).
C. Teratogenicity
Teratogenic effects were not produced by DBF, (0.600 g/kg/day),
following oral administration to pregnant rats (Nikonorow, et al. 1973)
while Singh, et ai. (1972) reported teratogenic effects of DSP following
i.p. injection of pregnant rats.
D. Other Reproductive Effects
Intraperitoneal injection of DBF to pregnant rats showed
that adverse effects prior to gestation day six were primarily on implanta-
tion, while after this day the effect was primarily on parturition
(Peters and Cook 1973).
Testicular damage has been reported in rats fed DBF or its monoester
metabolite (Carter, et al. 1977).
E. Chronic Toxicity
An increase in toxic polyneuritis has been reported by •
Milkov, et al. (1973) in workers exposed primarily to difautyl phthalate.
Lesser levels of exposure to dioctyl, diisooctyl, and benzylbutyl phthalates,
.•
and to tricresyl phosphate were also noted in these workers.
-------
V. AQUATIC TOXICITY
•.
A. Acute Toxicity >
Acute toxicity for di-n-butyl phthalate ranged from a 96-
hour static LC5Q of 730 jug/1 for the bluegill sunfish (Lepomis macrochirus)
to 6,470 ug/1 for the rainbow trout (Saline gairdneri) (Mayer and Sanders,
1973). The freshwater scud (Gammarus pseudolimnaeus) was shown to
provide a 48-hour static LC5Q value of 2,100 ug/1 di-n-butyl phthalate.
Marine data were not available for review.
B. Chronic
Pertinent data could'not be located in the available literature.
C. Plants
Pertinent data could not be located in the available literature.
0. Residues
Bioconcentrat-ion factors ranging from 400 to 1400 have been obtained
for the aquatic invertebrates Daphnia magna and Gammarus pseudolimnaeus.
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 review; therefore.
there is a possibility that these criteria may be changed.
A. Human
Based on "no effect" levels observed in chronic feeding studies
in rats or dogs, the U.S. EPA (1979a) has calculated an acceptable daily
intake (ADI) level of 12.6 mg/day.
The recommended water quality criterion level for protection
of human health is 5 mg/liter for DBP (U.S. EPA, 1979a).
«•
B. Aquatic
The data base for toxic effects in both freshwater and marine
environments was insufficient for the drafting of a water quality criterion
to protect aquatic organisms.
6J.-7
-------
DI-n-BUTYL PHTHALATE
REFERENCES
Ariyoshi, T., et al. 1976. Metabolism of dibutyl phthalate
and the effects of its metabolites on animals. Kyushu Yaku-
gakkai Kaiho 30: 17.
Carter, B.R., et al. 1977. Studies on dibutyl phthalate-
induced testicular atrophy in the rat: Effect on zinc metabo-
lism. Toxicol. Appl. Pharmacol. 41: 609.
Engelhardt, G., et al. 1975. The microbioal metabolism
of di-n-butyl phthalate and related dialkyi phthalates.
Bull. Environ. Contain. Toxicol. 17: 342.
Mayer, F.L., Jr., and H.O. Sanders. 1973. Toxicology of
phthalic acid esters in aquatic organisms. Environ. Health
Perspect. 3: 153.
Milkov, L.E., et al. 1973. Health status of workers exposed
to phthalate plasticizers in th'e manufacture of artificial
leather and films based 'on PVC resins. Environ. Health
Perspect. Jan. 175.
Nikonorow, M., et al. 1973. Effect of orally administered
plasticizers and polyvinyl chloride stabilizers in the rat.
Toxicol. Appl. Pharmacol. 26: 253.
Peters, J.W., and R.M. Cook. 1973. Effects of phthalate
esters on reproduction of rats. Environ. Health Perspect.
Jan. 91.
Rubin, R.J., et al. 1979. Ames mutagenic assay of a series
of phthalic acid esters: positive response of the dimethyl
and diethyl esters in TA 100. Abstract. Soc. Toxicol. Annu.
Meet. New Orleans, March 11.
Shahin, M., and R. Von Borstel. 1977. Mutagenic and lethal
effects of a-benzene hexachloride, dibutyl phthalate and
trichloroethylene in Saccharomyces cerevisiae. Mutat. Res.
48: 173.
Singh, A., et al. 1972. Teratogenicity of phthalate esters
in rats. Jour. Pharm. Sci. 61: 51.
Tanaka, A., et al. 1978. Biochemical studies on phthalic
esters. III. Metabolism of dibutyl phthalate (DBP) .in
animals. Toxicology 1: 109.
-------
Toraita, I., et al. 1977. Phthalic acid esters in various
foodstuffs and biological materials. Ecotoxicology and
Environmental Safety. 1: 275.
U.S. EPA. 1979a. Phthalate Esters: Ambient Water Quality
Criteria (Draft).
U.S. EPA. 1979b. Environmental Criteria and Assessment
Office. Phthalate Esters: Hazard Profile (Draft).
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No. 63
Dibenzo(a,h)anthracene
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.
63-3-
-------
SPECIAL NOTATION
U.S. EPA's Carcinogen Assessment Group (GAG) has evaluated
dibenzo(a,h)anthracene and has found sufficient evidence to
indicate that this compound is carcinogenic.
63-4
-------
DIBENZO(a,h)ANTHRACENE
Summary
Dibenzo(a,h)anthracene (DBA) is a member of the polycyclic
aromatic hydrocarbon (PAH) class. DBA was the first pure chemi-
cal shown to produce tumors in animals. It is carcinogenic by
skin application, by injection, and by oral administration to
rodents. Since humans are not exposed to only DBA in the environ-
ment, it is not possible to attribute human cancers solely to
exposure to DBA. Furthermore, it is not known how DBA may inter-
act with other carcinogenic and non-carcinogenic PAH in human
systems.
-------
DIBENZO(a,h)ANTHRACENE
I. INTRODUCTION
This profile is based primarily on the Ambient Water Quality
Criteria Document for Polynuclear Aromatic Hydrocarbons (U.S. EPA,
1979a) and the Multimedia Health Assessment Document for Polycyclic
Organic Matter (U.S. EPA. 1979b).
Dibenzo(a,h)anthracene (DBA; C22H14^ is one of the family of
polycyclic aromatic hydrocarbons (PAH) formed, as a result of incom-
plete combustion of organic material. Other than a reported
melting point of 266-266.5°C (U.S. EPA. 1979b), its physical and
chemical properties have not' been well-characterized.
PAH, including DBA are ubiquitous in the environment, being
found in ambient air, food, water, soils and sediment (U.S. EPA.
1979b). The PAH class contains a number of potent carcinogens
(e.g., benzo(a)pyrene), moderately active carcinogens (e.g.,
benzo(b)fluoranthene), weak carcinogens (benz(a)anthracene), and
cocarcinogens (e.g., fluoranthene), as well as numerous non-carcin-
ogens (U.S. EPA. 1979b).
PAH which contain .more than three rings (such as DBA) are re-
latively stable in the environment, and may be transported in air
and water by adsorption to particulate matter. However, biodegrad-
ation and chemical treatment are effective in eliminating most PAH
in the environment.
II. EXPOSURE
A. Water
Levels of DBA in water have not been reported. However,
the concentration of six representative PAH (benzo(a)pyrene, fluor-
-------
anthene, benzo( j) fluoranthene, benzo(k). fluoranthene, benzo(ghi)-
perylene, indeno(l,2,3-cd-pyrene) in United States drinking water
averaged 13.5 nanograms/liter (Basu and Sacena, 1977, 1978).
B. Food
Based on limited monitoring studies, DBA has been de-
tected in various foods, such as, butter and smoked fish. Al-
though, it is not possible to estimate the human dietary intake
of DBA, it has been concluded (U.S. EPA. 1979b) that the daily
dietary intake of all types of PAH is about 1.6 to 16 ug per
day. The U.S. EPA (1979a) has estimated the weighted average
bioconcentration factor of DBA to be 24,000 for the edible por-
tions of fish and shellfish consumed by Americans. This estimate
is based on the octanol/water partition coefficient for DBA.
C. Inhalation
Levels of DBA have not been monitored in ambient air.
However, it has been estimated that the average total PAH level in
ambient air is about 10.9 nanograms/m (U.S. EPA, 1979a). Thus the
total daily intake of PAH by inhalation of ambient air may be about
207 nanograms, assuming that a human breathes 19 m of air per day.
III. PHAPjyiACOKINETICS
There are no data.available concerning the pharmacokinetics of
DBA, or other PAH, in humans. Nevertheless, it is possible to make
limited assumptions based on the results of animal research con-
ducted with several PAH, particularly benzo(a)pyrene.
A. Absorption
The absorption of DBA in humans or other animals has not
been thoroughly studied. However, it is known (U.S. EPA, 1979a)
that, as a class, PAH are well-absorbed across the respiratory and
t
-------
gastrointestinal epithelia. The high lipid soluoility of compounds
in the PAH class supports this observation.
B. Distribution
Only limited work on distribution of DBA in mammals
has been performed (Heidelberger and Weiss, 1959). However,
it is known (U.S. EPA, 1979a) that other PAH become localized
in a wide variety of body tissues following their aosorption
in experimental rodents. Relative to other tissues, PAH tend
to localize in body fat and fatty tissues (e.g., breast).
C. Metabolism
The-mammalian metabolism of DBA has been well-character-
ized (Sims, 1976). DBA, like other PAH, is metabolized, by the
microsomal mixed function oxidase enzyme system in mammals (U.S.
EPA. 1979b) . Metabolic attack on one or more of the aromatic
rings leads to the formation of phenols, and isomeric dihydro-
diols by the intermediate formation of reactive epoxides. Dihydro-
diols are further metabolized by microsomal mixed function oxi-
dases to yield diol epoxides,- compounds which are known to be
ultimate carcinogens for certain PAH. Removal of activated inter-
mediates by conjugation with glutathione or glucuronic acid,
or Dy further metabolism to tetrahydrotetrols, is a key step
in protecting the organism from toxic interaction with cell macro-
molecules.
D. Excretion
.-
There is no direct information available concerning the
excretion of PAH in man. The excretion of DBA however, by mic"e was
studied by Heidelberger and Weiss (1959). The excretion of DBA was
-------
rapid and occurred mainly via the feces. Elimination in the bile
accounts for a significant percentage of all administered PAH (U.S.
EPA, 1979a). It is unlikely that PAH will accumulate in the body
with chronic low-level exposures.
IV. EFFECTS
A. Carcinogenicity
DBA was the first pure chemical ever shown to produce
tumors in animals. DBA has considerable carcinogenic potency
when applied to the skin of mice (Iball, 19.39; U.S. EPA. 1979b) ,
injected subcutaneously in mice (U.S. EPA. 1979b), injected
into newborn mice (Beuning, et al. 1979), injected into Strain
A mice (Shimkin and Stoner, 1975) or administered orally to mice
(Snell and Stewart, 1962).
B. Mutagenicity
DBA is a mutagenic in the Ames Salmonella assay (Andrews,
et al. 1978; Wood, et al. 1978) in cultured hamster cells (Huberman
and Sacks, 1974) , and is positive in the ir± vivo sister-chroraatid
exchange assay in Chinese hamsters (Roszinsky-Kocher, et al.
1979).
C. Teratogenicity
There are no data available concerning the possible tera-
togenicity of DBA in man. Other related PAH apparently are not
significantly teratogenic in mammals (U.S. EPA, 1979a).
D. Other Reprodutive Effects
Pertinent information could not be located in the avail-
able literature.
63-*
-------
E. Chronic Toxicity
As long ago as 1937, investigators knew that carcinogenic
PAH, including DBA, could inhibit growth in rats and mice (Haddow,
et al. 1937) . In early studies, DBA was administered to mice in
weekly subcutaneous injections for 40 weeks, which produced in-
creased reticulum (stem) cells, dilation of lymph sinuses, and de-
creased spleen weights in comparison to controls (Hoch-Ligeti,
1941) .
A more detailed study of subchronic effects of DBA on
lymph nodes of male rats was reported in 1944 (Lasnitzki and Wood-
house, 1944). Subcutaneous injections given five times weekly for
several weeks caused normal lymph nodes to undergo hemolymphatic
changes.
V. AQUATIC TOXICITY
Pertinent information could not be located in the available
literature.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor aquatic criteria derived by
U.S. EPA (1979a) , which are summarized below, have yet gone
through the process of public review; therefore, there is a possi-
bility that these criteria may be changed.
A. Human
There are no established exposure criteria for DBA. How-
ever, PAH as a class are regulated by several authorities. The
World Health Organization recommends that the concentration of PAH
9
in drinking water (measured as the total of fluoranthene, benzo-
(g,h,i)perylene, benzo(b)fluoranthene, benzo(k)fluoranthene, in
sf
-------
deno(l,2,3-cd)pyrene, and benzo(a)pyrene) not exceed 0.2 ug/1.
Occupational exposure criteria have been established for coke
oven emissions, coal tar products, and coal tar pitch volatiles,
all of which contain large amounts of PAH including DBA (U.S.
EPA, 1979a).
The U.S. EPA (1979a) draft recommended criteria for
PAH in water are based upon the extrapolation of animal carcinogenicity
data for benzo(a)pyrene and DBA. Levels for each compound are de-
rived which will result in specified risk levels of human cancer as
shown in the table below.
BaP
Exposure Assumptions Risk Levels and Corresponding Criteria
(per day) ng/1
0 10"7 10"6 1Q~5
2 liters of drinking water
and consumption of 18.7
grams fish and shellfish 0 0.097 0.97 9.7
Consumption of fish and
shellfish only 0.44 4.45 44.46
DBA
2 liters of drinking water 0 0.43
and consumption of 18.7
grams fish and shellfish
Consumption of fish and 1.96
shellfish only.
4.3 43
19.6 196
B. Aquatic
»
The criterion for freshwater and marine life have not
been derived (U.S. EPA, 1979a) .
C3-/0
-------
DIBENZO(a,h)ANTHRACENE
REFERENCES
Andrews, A.W., et al. 1978. The relationship between carcinogeni-
city and mutagenicity of some polynuclear hydrocarbons. Mutation
Research 51: 311.
Basu and Saxena, 1977, 1978. Polynuclear aromatic hydrocarbons in
selected U.S. drinking waters and their raw water sources.
Environ. Sci. Technol. 12: 795.
Beuning, M.K., et al. 1979. Tumorigenicity of the dihydrodiols of
dibenzo(a,h)anthracene on mouse skin and in newborn mice. Cancer
Res. 39: 1310.
%
Haddow, A., et al. 1937. The influence of certain carcinogenic
and other hydrocarbons on body growth in the rat. Proc. Royal Soc.
B. 122: 477.
Heidelberger, C., and S.M. Weiss. 1959. The distribution of
radioactivity in mice following administration of 3,4-benzopyrene-
5C and 1,2,5,6-dibenzanthracene-9, IOC . Cancer Res. 11: 885.
Hoch-Ligeti, C. 1941. Studies on the changes in the lymphoid
tissues of mice treated with carcinogenic and non-carcinogenic
hydrocarbons. Cancer Res. 1: 484.
Huberman, E. , and L. Sachs.. 1974. Cell-mediated mutagenesis of
mammalian cells with chemical carcinogens. Int. Jour. Cancer.
13: 326.
Iball, J. 1939. The relative potency of carcinogenic compounds.
Am. Jour. Cancer. 35: 188.
Lasnitzki, A., and Woodhouse, D.C. 1944. The Effect of 1:2:5:6-
Dibenzanthracene on the lymph-nodes of the rat. J. Anat. 78: 121.
Roszinsky - Kocker, et al. 1979. Mutagenicity of PAH's. Induc-
tion of sister-chromatid exchanges in vivo. Mutation Research.
66: 65.
Shimkin, M.B., and G.D. Stoner. 1975. Lung tumors in mice: appli-
cation to carcinogenesis bioassay. In; G. Klein and S. Wein-
house, (eds.) Advances in Cancer Research, Vol. 12 Raven Press,
New York.
Sims, P. 1976. The metabolism of polycyclic hydrocarbons to di-
hydrodiols and diol epoxides by human and animal tissues. Pages
211-224 in R. Montesano, et al. eds. screening tests in chemical
carcinogenesis. IARC Publ. No. 12. Lyon, France.
6 3-II
-------
Snell, K.C., and H.L. Stewart. 1962. Induction of pulmonary
adenomatosis in DBA/2 mice by the oral administration of dibenzo-
(a,h)anthracene. Acta. Vn. Int. Cone. 19: 692.
U.S. EPA. 1979a. Polynuclear aromatic hydrocarbons: ambient
water quality criteria. (Draft).
U.S. EPA. 1979b. Health Effects Research Laboratory, Environment-
al Criteria and Assessment Office Research Triangle Park, N.C.
Wood, A.W., et al. 1978. Metabolic activation of dibenzo(a,h)-
anthracene and its dibydiodiols to bacterial rautagens. Cancer
Res. 38: 1967.
World Health Organization. 1970. European Standards for drinking
water, 2nd ed. Geneva.
-------
No. 64
1,2-Dichlorbenzene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, B.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"!imitations 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-DICHLOROBENZENE
SUMMARY
1,2-Dichlorobenzene is a lipophilic compound which
upon absorption into the body, deposits in the fatty tissues.
This compound is detoxified by the liver microsomal enzymes.
On chronic exposure to 0.1 mg 1,2-dichlorobenzene/kg, rats
developed anemia, liver damage, and central nervous system
depression. There have not been studies available to deter-
mine the carcinogenic or teratogenic potential of 1,2-di-
chlorobenzene. 1,2-Dichlorobenzene was mutagenic when tested
with the mold Aspergillis nidulans and negative when tested
with the bacteria Salmonella typhimurium in the Ames assay.
The toxicity of 1,2-dichlorobenzene appears to be simi-
lar for freshwater and marine organisms with reported LC5Q
values ranging between 1,970 and 27,000 ug/1.
X
-------
1,2-DICHLOROBENZENE
I. INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria Document for Dichlorobenzenes (U.S. EPA, 1979a).
1,2-Dichlorobenzene (1,2-DCB or ODCB; CgH4Cl2; molecular
weight 147.01) is a liquid at normal environmental tempera-
tures. 1,2-Dichlorobenzene has a melting point of -17.6°C,
a boiling point of 179°C, a density of 1.30 g/ml at 20°c,
a water solubility of 145,000 ug/1 at 25°C,'- and a vapor
pressure of 1 mm Hg at 20°C (Weast, 1975). The major uses
of 1,2-dichlorobenzene are as a process solvent in the manu-
facturing of toluene diisocyanate and as an intermediate
*
in the synthesis of dyestuffs, herbicides, and degreasers
(West and Ware, 1977) .
II. EXPOSURE
A. Water
1,2-Dichlorobenzene has been detected in rivers,
groundwater, municipal and industrial discharges, and drink-
ing water. 1,2-Dichlorobenzene has been reported entering
water systems at average levels of 2 mg/1 as a result of
its use by industrial wastewater treatment plants for odor
control (Ware and West, 1977). In 4 out of 110 drinking
waters, 1,2-dichlorobenzene was detected at an average con-
centration of 2.5 pg/1 (U.S. EPA, 1979a). Also, 1,2-dichloro-
benzene may be formed during chlorination of water contain-
#
ing organic precursor material (Glaze, et al. 1976).
-------
B. Food
There are not enough data to state quantitatively
the degree of 1,2-dichlorobenzene exposure through total
diet (U.S. EPA, 1979a). The U.S. EPA (1979a) has estimated
the weighted average bioconcentration factor of 1,2-dichloro-
benzene to be 200 for the edible portion of aquatic organisms
consumed by Americans. This estimate is based on measured
steady-state bioconcentration studies in bluegill.
C. Inhalation
1,2-Dichlorobenzene has been detected on airborne
particulate 'matter in California at concentrations between
8 and 53 ng/m (Ware and West, 1977). There is no other
available information on the concentration of this compound
in ambient air (U.S. EPA, 1979a) .
III. PHARMACOKINETICS
A. Absorption
There is little information provided in U.S. EPA
(1979a) on the absorption specifically of 1,2-dichloroben-
zene. General information on the absorption of dichloro-
benzenes can be found in the Hazard Profile for Dichloro-
benzenes (U.S. EPA, 1979b). Reidel (1941) has reported
absorption of 1,2-dichlorobenzene through the skin of rats
in lethal amounts after five dermal applications under severe
test conditions (painting twice daily directly on a 10 cm
area of abdominal skin). Also, 1,2-dichlorobenzene fed to
rats at less than 0.4 to 2 mg/kg/day was absorbed and accu-
-------
raulated in various tissues indicating significant absorption
by the gastrointestinal tract even at low levels of exposure
(Jacobs, et al. 1974a,b).
B. Distribution
After feeding rats low levels of 1,2-dichloroben-
zene, in combination with other trace pollutants found in
the Rhine River, tissue accumulation was greater in fat
than in the liver, kidney, heart, and blood (Jacobs, et
al. 1974a).
C. Metabolism
The metabolism of 1,2-dichlorobenzene was studied
by Azouz, et al. (1955) in rabbits. 1,2-Dichlorobenzene
was mainly metabolized by oxidation to 3,4-dichlorophenol
followed by the formation of conjugates with glucuronic
and sulfuric acids. Minor oxidative metabolites and their
conjugates were also detected.
D. Excretion
Excretion of the metabolic products of 1,2-dichloro-
benzene in the rabbit was mainly through the urine (Azouz,
et al. 1955).
IV. EFFECTS
A. Carcinogenicity
Specific positive evidence of the carcinogenicity
of DCB's is lacking. However, a sufficient collection of
varied data exist to suggest prudent regard of DCS as a
potential carcinogen (U.S. EPA, 1979a).
-------
B. Mutagenicity
Treatment of the soil mold Asper_gj.llus nidulans
for one hour in an ether solution of 1,2-dichlorobenzene
increased the frequency of back-mutations (Prasad, 1970).
In the Ames assay, 1,2-dichlorobenzene did not increase
the mutational rate of the histidine-requiring strains of
Salmonella typhimurium (Andersen, et al. 1972).
C. Teratogenicity
Studies of the teratogenicity of '•!, 2-dichloroben-
zene could not be located in the available literature.
D. Other Reproductive Effects
Information is not available.
E. Chronic Toxicity
In an inhalation study, Hollingsworth, et al.
(1958) exposed groups of 20 rats, 8 guinea pigs, 4 rabbits,
and 2 monkeys to the vapor of 1,2-dichlorobenzene seven
hours per day, five days per week for six to seven months
at an average concentration of 560 mg/m . No adverse effects
were noted in behavior, growth, organ weights, hematology,
or upon gross and microscopic examination of tissues. In
a nine month chronic toxicity study, Varshavskaya (1967)
gave rats 1,2-dichlorobenzene at daily doses of 0.001, 0.01,
and 0.1 mg/kg. The toxicological observations in the highest
dose group were anemia and other blood change-s, liver damage,
and central nervous system depression. The highest no-observ-
able-adverse-effect level for 1,2-dichlorobenzene by Var-
shavskaya (1967) was 0.001 mg/kg/day, whereas the compar-
-------
able level in the rat study by Hollingsworth, et al. (1953)
was 18.8 mg/kg/day.
F. Other Relevant Information
1,2-Dichlorobenzene can induce microsomal drug
metabolizing enzymes (Ware and West, 1977).
V. AQUATIC TOXICITY
A. Acute Toxicity
For freshwater fish, two 96-hour static bioassays
have produced LCc* values of 5,590 and 27,0-00 ug/1 for the
bluegill (Lepomis macrochirus) (U.S. EPA, 1978; Dawson,
et al. 1977). A single 96-hour static assay for the fresh-
water invertebrate Daphnia magna provided an LCcQ value
of 2,440 ug/1. In marine fish, LCg0 values reported were
7,300 ug/1 for the tidewater silverside (Menidia beryllina)
and 9,560 ug/1 for the sheepshead minnow (Cypringdon. yariega-
tus) (U.S. EPA, 1978). An adjusted LC5Q value of 1,970
ug/1 was obtained for the marine invertebrate (Mysidopsis
bahia).
B. Chronic
The only freshwater, organisms tested were embryo-
larval stages of the fathead minnow (Pimephales pcomelas),
which produced a chronic value of 1,000 ug/1 for 1,2-dichloro-
.benzene. No chronic data for marine organisms were avail-
able for evaluation.
C. Plants
The freshwater algae Selenastrum capricornutum
has been tested for the effects of 1,2-dichlorobenzene on
-------
chlorophyll a and cell numbers. The EC^Q values were 91,600
and 98,000 pg/1, respectively, while comparable values of
44,200 to 44,100 pg/1 were reported for the marine algae
Skeletonema costatum (U.S. EPA, 1978).
D. Residues
A bioconcentration of 89 was obtained for the
bluegill.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The Occupational Safety and Health Administration
(OSHA, 1976) , and the American Conference of Governmental
Industrial Hygienists (ACGIH, 1977) threshold limit value
is 300 mg/m for 1,2-dichlorobenzene. The U.S. EPA (1979a)
draft water quality criterion for total dichlorobenzene
(all three isomers) is 160 ug/1.
B. Aquatic
Criteria have been drafted for freshwater organisms
as 44 ug/1 for the 24-hour average concentration, not to
exceed 99 pg/1. The marine draft criterion is 15 pg/1 not
to exceed 34 pg/1 (U.S. EPA, 1979a).
-------
1,2-OICHLORQBENZENE
REFERENCES
American Conference of Governmental Industrial Hygienists. 1977. Documen-
tation of the threshold limit values for substances in workroom air (with
supplements for those substances added or changed since 1971). 3rd ed.
Cincinnati, Ohio.
>.
Andersen, K.J., et al. 1972. Evaluation of herbicides for possible muta-
genic properties. Jour. Agric. Food Chem. 20: 649.
Azouz, W.M., et al. 1955. Studies in detoxication, 62: The metabolism of
halogenobenzenes. Orthoand paradichlorobenzenes. Siochem. Jour. 59: 410.
Oawson, G.W., et al. 1977. The toxicity of 47. industrial chemicals to
fresh and saltwater fishes. Jour. Hazard Mater. 1: 303.
Glaze, W.H., et al. 1976. Analysis of new chlorinated organic compounds
formed by chlorination of municipal wastewater. In: Proc. Conf. Environ.
Impact Water Chlorination. Iss. Ccnf.-751096, pages 153-75. (Abstract)
Hollingsworth, R.L., et al. 1958. Toxicity of o-dichlorobenzene. Studies
on animals and industrial experience. AMA Arch. Ind. health 17: 180.
Jacobs, A., et al. 1974a. Accumulation of noxious chlorinated substances
from Rhine River water in the fatty tissue of rats. Vom Wasser (German')
43: 259. (Abstract)
Jacobs, A., et al. 1974b. Accumulation of organic compounds, identified as
harmful substances in Rhine water, in the fatty tissues of rats. Kern-
forschungszentrum Karlsruhe (Ber.). KFK 1969 UF, pp. 1. (Abstract)
National Academy of Sciences. 1977. Drinking water and health. U.S. EPA
Contract No. 68-01-3169. Washington, D.C.
Occupational Safety and Health Administration. 1976. General industry
standards. 29 CFR 1910, July 1, 1975; OSHA 2206, revised Jan. 1976. U.S.
Dep. Labor, Washington, O.C.
Prasad, I. 1970. Mutagenic effects of the herbicide 3',4'-dichloropropio-
nanilide and its degradation products. Can. Jour. Microbiol. 16: 369.
Riedel, H. 1941. Einige beobachtungen uber orrhodichlorbenzol. Arch.
Gewerbepath. u Gewerbehyg. 10: 546. (German)
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. Dichlorobenzenes: Ambient Water Quality Criteria.
(Draft).
-------
U.S. EPA. 1979b. Environmental Criteria and .Assessment Office. Dichloro-
benzenes: Hazard Profile. (Draft)
Varshavskaya, S.P. 1967. Comparative toxicological characteristics of
chlorobenzene and dichlorobenzene (ortho- and para-isomers) in relation to
the sanitary protection of water bodies. Gig. Sanit. (Russian) 33: 17.
Ware, S., and W.L. West. 1977. Investigation of selected potential envi-
ronmental contaminants: halogenated benzenes. EPA-56072-77-004. Rep. EPA
Contract No. 68-01-4183. Off. Toxic Subst. U.S. Environ. Prot. Agency,
Washington, O.C.
Weast, R.C., et al. 1975. Handbook of chemistry and physics. 56th ed.
CRC Press, Cleveland, Ohio.
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No. 65
1,3-Dichlorobenzar.e
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 accuracv.
-------
1.3-OICHLOROBENZENE
Summary
1,3-Oichlorobenzene is not used commercially and is produced only as a
by-product in the manufacture of chlorinated benzenes. This compound is
metabolized by the liver mixed function oxidase system. Little is known of
the toxicological, teratogenic, or carcinogenic properties of this compound.
1,3-Oichlorobenzene has been shown to be mutagenic to the soil mold Asper-
qillus nidulans. Since 1,3-dichlorobenzene may be a contaminant of the
other dichlorobenzenes, some of the toxicologic ptoperties ascribed to these
isomers may be due to the 1,3-isomer.
For freshwater and marine fish and invertebrates, acute toxicity values
ranged from 2,414 to 4,248 pg/1, but the freshwater invertebrate, Daphnia
magna, was more resistant to 1,3-dichlorobenzene with an acute value of
23,800 pg/1.
-------
1,3-DICHLORQBENZENE
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Dichlorobenzenes (U.S. EPA, 1979a).
1,3-Dichlorobenzene (1,3-DCB; MDCB; C6H4C12; molecular weight
147.01) is a liquid at normal environmental temperatures, has a melting
point of -24.2°C, a boiling point of 172°C, a density of 1.29 g/ml at
20°C, a water solubility of 123,000 ^ig/1 at 25°C, and a vapor pressure
of 5 mm Hg at 39°C (Weast, 1975). 1,3-Dichlorobenzene may occur as a con-
taminant of 1,2- or 1,4-dichlorobenzene formulations (U.S. EPA, 1979a).
II. EXPOSURE
A. Water
1,3-Dichlorobenzene has been detected or quantified in groundwater,
raw water, and drinking water. In two of 11C drinking water samples, 1,3-
dichlorcbsnzene was detected at an average concentration of 0.1 pg/1 (U.S.
EPA, 1979a). Also, 1,3-dichlorobenzene may be formed during chlorination of
raw and waste water containing organic precursor material (Glaze, et al.
1576).
8. Food
The data are' insufficient to state quantitatively the degree of
1,3-dichlorobenzene exposure through total diet (U.S. EPA, 1979a). 1,3-Oi-
chlorobenzene is reported to be among several metabolites of gamma-penta-
chloro-1-cyclohexane found in corn and pea seedlings (Mostafa and Moza,
1973). The U.S. EPA (1979a) has estimated" the weighted average
bioconcentration factor to be 150 for 1,3-dichlorobenzene for the edible
»
portions of fish and shellfish consumed by Americans. This estimate is
based on measured steady- state bioconcentration studies in bluegill.
-------
C. .Inhalation
Pertinent data could not be located in the available literature.
III. PHARMACOKINETICS
A. Absorption
Specific information on the absorption of 1,3-dichlorobenzene was
not found in the available literature. General information on the absorp-
tion of the dichlorobenzenes can be found in the Hazard Profile for Dichlor-
obenzenes (U.S. EPA, 1979b). .
8. Distribution
Specific information on the distribution of 1,3-dichlorobenzene was
not found in the available literature. Reference may be made to the Hazard
Profile for Dichlorobenzene (U.S. EPA, 1979b) and the 1,2-iscmer (U.S. EPA,
1979c).
C. Metabolism
The metabolism of 1,3-dichlorobenzene in rabbits was studied by
Parke and Williams (1955). 1,3-Oichlorcbenzer.e was mainly metabolized by
oxidation to 2,4-dichlorophenol followed by the formation of the glucuro-
nides and ethereal sulfates. Minor oxidative metabolites and their conju-
gates were also detected.
0. Excretion
Excretion of the metabolic products of 1,3-dichlorobenzene in the
rabbit is mainly through the urine with excretion being essentially complete
within five days (Parke and Williams, 1955).
IV. EFFECTS
A. Carcinogenicity
*
Reports of specific Carcinogenicity tests of 1,3-dichlorobenzene in
animals or of pertinent epidemiologic studies in humans were not found in
the available literature (U.S. EPA, 1979a).
-------
8. Mutagenicity
Treatment of the soil mold Asoeraillus nidulans for one hour in an
ether solution of 1,3-dichlorobenzene increased the frequency of back muta-
tions (Prasad, 1970).
C. Teratogenicity and Other Reproductive Effects
Studies of the teratogenicity and other reproductive effects of
1 ,'3-dichlorobe'nzene were not found in the available literature.
0. Chronic Toxicity
... s
Specific information on the chronic toxiclty of 1,3-dichlorobenzene
was not found in the available literature. However, 1,3-dichlorobenzene may
have been a contaminant of the 1,2- and l,i-dichlorobenzenes used in toxico-
Icgical studies. For further information on the general toxicologic proper-
ties of the dichlorobenzenes, refer to the Hazard Profile for Oichloroben-
zenas (U.S. EFA, I579b).
E. Other Relevant Information
1,3-Dichlorobenzene can induce microscmal drug metabolizing en-
zymes. Changes in the levels of microsomal enzymes can affect the metabo-
lism and biological activity of a wide variety of xenobiotics (Ware and
West, 1977).
V. AQUATIC TOXICITY
A. Acute Toxicity
For the bluegill (Lepomis macrochirus), a 96-hour static LC-Q of
5,020 jjg/1 has been obtained. The freshwater invertebrate, Daohnia maqna,
has a much higher LC50 of 28,100 ug/1 for a 48-hour'static assay. For the
sheepshead minnow, an acute LCcg of 7,770 ug/1 has been obtained. A ^value
of 2,850 pg/1 has been obtained for the marine mysid shrimp (Mysidopsis
bahia) (U.S. EPA, 1978).
-------
B. Chronic
Chronic studies with either freshwater or marine species are not
available.
C. Plant Effects
The freshwater alga Selenastrum caoricornutum was tested for the
effects of 1,3-dichlorobenzene on chlorophyll a and cell numbers. The
EC50 values ranged from 149,000-179,000 ug/1. For the marine alga Skele-
tonema costatum, the EC5Q values for cell number and chlorphyll a ranged
from 49,600-52,800 pg/1 (U.S. EPA, 1979a).
D. Residues
A bioconcentration factor of 66 was obtained for the bluegill (U.S.
EPA, 1979a).
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
There are no existing standards for 1,3-dichlorobenzene. The U.S.
EPA (1979a) draft water quality criterion for total dichlorobenzene (all
three isomers) is 160 ug/1.
8. Aquatic
A criterion for the protection of freshwater organisms has been
drafted as 310 ug/1 for a 24-hour average concentration not to exceed 700
jjg/1. For marine life, the criterion has been proposed as 22 ug/1 for 24-
hour average not to exceed 49 ug/1.
-------
1,3-DICHLOROBENZENE
REFERENCES
Glaze, W.H., et al. 1976. Analysis of new chlorinated organic compounds
formed by chlorination of municipal wastewater. _In Proc. Conf. Environ.
Impact Water Chlorination. Iss. Conf.-751096, pages 153-75. (Abstract)
Mostafa, I.Y. and P.N. Moza. 1973. Degradation of gamma-pentachloro-1-
cyclohexane (gamma-PCCH) in corn and pea seedlings. Egypt. Jour. Chem. Iss.
Spec.: 235. (Abstract)
Parke, D.V. and R.f. Williams. 1955. Studies in detoxication: The metabo-
lism of halogenobenzenes. (a) Metadichlorobenzene (b) Further observations
on the metabolism of chlorobenzenev Biochem. Jour. 59: 415.
Prasad, I. 1970. Mutagenic effects of the herbicide 3',4'-dichloropropio-
nanilide and its degradation products. Can. Jour. Microbiol. 16: 369.
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. Contract No. 68-01-4646. U.S. Environ. Prat.
Agency.
U.S. EPA. 1979a. Oichlorobenzenes: Ambient Water Quality Criteria Docu-
ment. (Draft)
U.S. EPA. 1979b. Environmental Criteria and Assessment Office. Dichloro-
benzenes: Hazard Profile. (Draft)
U.S. EPA. 1979c. Environmental Criteria and Assessment Office. 1,2-Di-
chlorobenzene: Hazard Profile. (Draft)
Ware, S. and W. L. West. 1977. Investigation of selected potential envi-
ronmental contaminants: halogenated benzenes. EPA 560/2-77-004. Rep. EPA
Contract NO. 68-01-4183. Off. Toxic Subst. U.S. Environ. Prot. Agency,
Washington, D.C.
Weast, R.C., et al. 1975. Handbook of chemistry and physics. 56th ed.
CRC Press, Cleveland, Ohio.
C5-?
-------
No. 66
1,4-Dichlorobenzane
Health and Environmental Effect3
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, B.C. 20A60
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 accuracv.
-------
1,4-DICHLOROBENZENE
SUMMARY
1,4-Dichlorobenzene is a lipophilic compound which, upon
absorption into the body, deposits in the fatty tissues.
This compound is detoxified by the liver microsomal enzymes.
Chronic intoxication produces increased liver and kidney
weights' and abnormal liver pathology. Studies to determine
the carcinogenic or teratogenic potential of 1,4-dichloroben-
zene could not be located in the available literature. 1,4-
Dichlorobenzene produces chromosomal aberrations in root tips
and has been shown to increase the mutation rate in the mold
Aspergillus nidulans.
Acute values for freshwater and marine organisms ranged
from 1,990 to 11,000 ug/1 for 1,4-dichlorobenzene. Marine in
vertebrates were most sensitive and freshwater invertebrates
were most resistant to the effects of 1,4-dichlarcbenzer.e.
t
-------
1,4-DICHLOROBEN ZENE
I. INTRODUCTION
This profile is based on the Ambient Water Quality Cri-
teria Document for Dichlorobenzene (U.S. EPA, 1979a).
1,4-Dichlorobenzene (CgH^C^; molecular weight 147.01)
is a solid at normal environmental temperatures. 1,4-Di-
chlorobenzene has a melting point of 53.0°C, a boiling point
of 174°C, a density of 1.25 g/ml at 20°C, a water solubility
of.80/000 u.g/1 at 25°C, and a vapor pressure of 0.4 mm Hg at
25°C (Weast, et al. 1975). The primary use of 1,4-dichloro-
benzene is 'as an air deodorant and insecticide. This com-
pound is produced almost entirely as a byproduct during the
manufacture of monochlorobenzene (Ware and West, 1977).
For a more general discussion of dichlorobenzene, the
reader is referred co the Hazard Profile for Dichlcrobenzene
(U.S. EPA, 1979b).
II. EXPOSURE
A. Water
1,4-Dichlorobenzene has been detected or quantified
in rivers, groundwater, municipal and industrial discharge,
and drinking water. 1,4-Dichlorobenzene enters wastewater
systems because of its use in toilet blocks (Ware and West,
1977). 1,4-Dichlorobenzene may also be formed during chlori-
nation of raw and waste water containing organic percursor
material (Glaze, et al. 1976). In 20 of 113 drinking water
samples, 1,4-dichlorobenzene was detected at an average con-
centration of 0.14 ug/1 (U.S. EPA, 1979a) .
-------
B. Food
There are not enough data available to quantita-
tively state the degree of 1,4-dichlorobenzene exposure
through total diet (U.S. EPA, 1979a). Schmidt (1971) report-
ed the tainting of pork as a result of the use of an odor
control agent-containing 1,4-dichlorobenzene in pig stalls.
Also, Morita, et al. (1975) reported 0.05 mg/kg 1,4-dichloro-
benzene in fish from Japanese coastal waters. The U.S EPA
(1979a) has estimated the weighted bioconcentration factor of
1,4-dichlorobenzene to be 140 for the edible portion of fish
and" shellfish consumed by Americans. This estimate is based
on measured steady-state bioconcentration studies in blue-
gills.
C. Inhalation
Merita and Chi (1975) measured 1,4-dichlorcbenzene
in the vapor phase, in and around Tokyo, by use of a cold
solvent trap. Urban levels were found to range from 2.7 to
4.2 ug/m3, while suburban levels were lower, ranging from
1.5 to 2.4 ug/m^; indoor levels were considerably higher,
ranging 0.105 to 1.7 mg/m^. No other information was found
regarding the concentration of this compound in ambient air
(U.S. EPA, 1979a) .
III. PHARMAKINETICS
A. Absorption
In humans, toxic effects following accidentally or
»
deliberately ingested 1,4-dichlorobenzene clearly indicate
significant absorption by the gastrointestinal route (Camp-
bell and Davidson, 1970; Frank and Cohen, 1961; Hallowell,
-------
1959). Also, Azouz, et al. (1955) detected no 1,4-dichloro-
benzene in the feces of rabbits dosed intragastrically with
the compound in oil. This suggests virtually complete ab-
sorption under these conditions.
B. Distribution
The studies of Morita and Ohi (1975) and Morita, et
al. (1975) have shown 1,4-dichlorobenzene in adipose tissue
(mean about 2 mg/kg) and blood (about 0.01 ng/1) of humans
exposed to ambient pollution levels in the Tokyo area.
C. Metabolism
The metabolism of 1,4-dichlorobenzene in rabbits
was studied by Azouz, et al. (1955). 1,4-Dichlorobenzene was
primarily metabolized by oxidation to 2,5-dichlorophenol,
followed by the formation of the glucuronides and ethereal
sulfates. Minor oxidative metabolites and their conjugates
were also detected. Pagnatto and Walkley (1966) indicated
that 2,5-dichlorophenol was also the principal metabolite of
1,4- dichlorobenzene in humans.
D.' Excretion
Excretion of the metabolic products of 1,4-di-
chlorobenzene in the rabbit occurs mainly through the urine
(Azouz, et al. 1955), with no mention made of fecal excre-
tion.
IV. EFFECTS
A. Carcinogenicity
»
Mo reports of specific carcinogenicity tests of
1,4-dichlorobenzene in animals or of pertinent epidemiologic
studies in humans were available. ' A few inconclusive experi-
-------
ments which indicate further investigation of the carcino-
genic potential of 1,4-dichlorobenzene is warranted are re-
viewed in. U.S EPA (1979a).
B. Mutagenicity
Various mitotic anomalies were observed in cells
and somatic chromosomes of 1,4-dichlorobenzene treated root
tips (Carey and McDonough, 1943; Sharma and Sarkar, 1957;
Srivastava, 1966). Treatment of Aspergillus nidulans (a soil
mold organism) for one hour in an ether solution of 1,4-di-
chlorobenzene increased the frequency of back-mutations
(Prasad, 1970).
C. Teratogenicity and Other Reproductive Effects
Pertinent data could not be located in the avail-
able literature.
D. Chronic Toxicity
Effects observed in racs and guinea pigs exposed to
a concentration of 2,050 mg/m3 1,4-dichlorobenzene for six
months included: growth depression (guinea pigs); increased
liver and kidney weights (rats); abnormal liver pathology
(cloudy swelling, fatty degeneration, focal necrosis, cirrho-
sis) (Hollingsworth, et al. 1956). In animals exposed to
4,800 mg/m^ 1,4-dichlorobenzene, up to 25 percent deaths
were noted; and in survivors, symptoms were noted that were
similar to those observed at the lower dose. Similar pathol-
ogy was also observed in female rats, who received 376 mg/kg
»
dose of 1,4-dichlorobenzene by stomach tube 5 days a week for
a total of 138 doses.
6 -7
-------
E. Other Relevant Information
1,4-Dichlorobenzene can induce microsoraal drug-
metabolizing enzymes. Changes in the levels of microsomal
enzymes can affect the metabolism and biological activity of
a wide variety of xenobiotics (Ware and West, 1977).
V. AQUATIC TOXICITY
A. Acute Toxicity
Acute 96-hour LC^Q values for all aquatic species
tested were relatively similar. For the freshwater fish, the
bluegill (Lepomis macrochirus), a LC50 of 4,280 ug/1 was
obtained, while the freshwater invertebrate Daphnia magna was
more resistant, with a LC50 value of 11,000. An LC50
value of 7,400 ug/1 was obtained for the marine fish, the
sheepshead minnow (Cyprinodon variegatus); and the myrid
shrimp (Mysidopsis bahia) had an LC50 valua of 1,990 ug/1
(U.S. EPA,1973).
B. Chronic
Pertinent data could not be located in the avail-
able literature.
C. Plants
The freshwater alga, Selenastrum capricornutum,
when tested for the effects of 1,4-dichlorobenzene on chloro-
phyll _a and cell numbers, was shown to have had a range of
effective concentration of 96,700 to 98 ,100''ug/1, while the
marine alga Skeletonema costatum was more sensitive, with an
»
effective concentration range of 54,800 to 59,100 ug/1.
66-1
-------
D. Residues
A bioconcentration factor of 60 was obtained for
the freshwater bluegill.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human\
The Occupational Safety and Health Administration
Standard (OSHA, 1976), and the American Conference of Govern-
mental Industrial Hygienists (ACGIH, 1977) threshold limit
value are 450 mg/m^ for 1,4-dichlorobenzene. The
acceptable daily intake (ADI) of 1,4-dichlorobenzene is 0.94
mg/day (Natl. Acad. Sci., 1977). The U.S. EPA (1979a) draft
' water quality criterion for total dichlorobenzene (all three
isomers) is 0.16 mg/1.
B. Aquatic
A criterion for the protection of freshwater aqua-
tic life has been drafted as a 190 ug/1 24-hour average con-
centration, not to exceed 440 ug/1 at any time. For the pro-
tection of marine life, the criterion is 15 ug/1 as a 24-hour
average, not to exceed 34 ug/1 at any time.
-------
1 , 4-DICHLOROBEN ZEN E
REFERENCES
American Conference of Governmental Industrial Hygienists.
1977. Documentation of the threshold limit values for sub-
stances in workroom air (with supplements for those sub-
stances added or changed since 1971). 3rd ed. Cincinnati,
Ohio.
Azouz, W.M., et al. 1955. Studies in detox ication, 62: The
metabolism of halogenobenzenes. Ortho- and paradichloro-
benzenes. Biochem. Jour. 59: 410.
Campbell, D.M., and R.J.L. Davidson. 1970. Toxic haemolytic
anaemia in pregnancy due to a pica for paradichlorobenzene.
Jour. Obstet. Gynaec. Br. Cmnwlth. 77: 657.
Carey, M.A. , and E.S. McDonough. 1943. On the production of
polyploidy .in Allium with paradichlorobenzene.
Frank, S.B., and H.J. Cohen. 1961. Fixed drug eruption due
to paradichlorobenzene. N.Y. Jour. iMed. 61: 4079.
Glaze, W.H., et al. 1976. Analysis of new chlorinated
organic compounds formed by chlorination of municipal waste-
water. In: Proc. Conf. Environ. Impact Water Chlorination.
Iss. Conf .-751096, pages 143-75. (Abstract).
Hallowell, M. 1959. Acute haemolytic anemia following the
ingestion of paradichlorobenzene. Arch. Dis. Child. 34:
~
Hollingsworth, R.L., et al. 1956. Toxicity of paradichloro-
benzene. Determinations on experimental animals and human
subjects. AMA Arch. Ind. Health 14: 138.
Morita, M., et al. . 1975. A systematic determination of
chlorinated benzenes in human adipose tissue. Environ.
Pollut. 9: 175 (Abstract).
Morita, M. , and G. Ohi. 1975. Para-dichlorobenzene in human
tissue and atmosphere in Tokyo metropolitan area. Environ.
Pollut. 3: 269.
National Academy of Sciences. 1977. Drinking water and
health. U.S. EPA Contract No. 68-01-3169. "Washington, D.C.
Occupational Safety and Health Administration. 1976. Gener-
al industry standards. 29 CFR 1910, July 1, 1975; OSHA 2206,
revised Jan. 1976. U.S. Dep. Labor, Washington, D.C.
-------
Pagnotto, L.D. , and J.E. Walkley. 1966. Urinary dichloro-
phenol as an index of paradichlorobenzene exposure. Ind.
Hyg. Assoc. Jour. 26: 137. (Rev. in Food Cosmet. Toxicol.
4: 109. (Abstract).
Prasad, I. 1970. Mutagenic effects of the herbicide 3',4'-
dichloropropionanilide andd its degradation products. Can.
Jour. Microbiol. 16: 369.
Schmidt, G.E. 1971. Abnormal odor and taste due to p-di-
chlorobenzene. Arch. Lebensmittelhyg. (German) 22: 43.
(Abstract)'.
Sharma, A..K., and S.K. Sarkar. 1957. A study on the compar-
ative effect of chemicals on chromosomes of roots, pollen
mother cells and pollen grains. Proc. Indian Acad. Sci.
Sect. B. 45: 288.
Srivastava, L.M. 1966. Induction of mitotic abnormalities
in certain genera of tribe Vicieae by paradichlorobenzene.
Cytologia 31: 166.
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, 1979a. Dichlorobenzenes: Ambient Water Quality
Criteria. (Draft).
U.S. EPA. 1979b. Environmental Criteria Assessment Office.
Dichlorobenzene: Hazard Profile (Draft).
Ware, S.A., and W.L. West. 1977. Investigation of selected
potential environmental contaminants: halogenated benzenes.
EPA 560/2-77-004. Rep. EPA Contract No. 63-01-4183. Off.
Toxic Subst. U.S. Environ. Prot. Agency, Washington, D.C.
Weast, R.C., et al. 1975. Handbook of chemistry and
physics. 56th ed. CRC Press, Cleveland, Ohio.
-------
No. 67
Dichlorobanzenes
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
£7--I
-------
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.
-------
DICHLOROBENZENES
Summary
Dichlorobenzenes are lipophilic compounds which, upon absorption into
the body, deposit in the fatty tissues. These compounds are metabolized by
the liver microsomal enzyme system to water soluble compounds. Chronic ex-
posure to any of the "three isomers produces effects on the liver, blood,
central nervous system and respiratory^tract. Studies to determine the car-
cinogenic or teratogenic potential of the dichlorobenzenes were not located
in the available literature. In one study these compounds have increased
the mutational rate of soil mold.
The position of the chlorine atoms on the benzene ring appears to have
little significant effect on the toxicity of the 1,2-, 1,3-, or
Iji-dichlorobsnzsne isomsrs 'to fish and invertebrates, sxcept for the appar-
ent resistance of the freshwater invertebrate Daonnia maena to 1,3-chloro-
benzene. Marine fish tend -to be slightly mere resistant thar. freshwater
fish, although the inverse is true for freshwater and marine invertebrates.
-------
DICHLOROBENZENES
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Dichlorobenzenes (U.S. EPA, 1979).
The dichlorobenzenes (CgH4Cl2; molecular weight 147.01) are a
class of halogenated aromatic compounds represented by three structurally
similar isomers: 1,2-dichloro-, 1,3-dichloro-, and 1,4-dichlorobenzenes
(Weast, et al. 1975). 1,2-Oichloro- and 1,3-dichlorobenzene are liquids at
normal environmental temperatures while 1,4-dichlorobenzene is a solid. All
the dichlorobenzenes boil at approximately 175°C and have a density close
to 1.28 a/ml. The solubilities in water of the 1,2-, 1,3-, and
1,,4-dichlorobenzene iscmers at 25°C are 145,000 pg/1, 123,000 pg/1, and
80,000 pg/1, respectively (Jacobs, 1957). The vapor pressure of
1,2-dichlorobenzene at 20°C is 1 mm Hg; the vapcr pressure of
1,3-dichlorobenzene at 39°C is 3 mm Kg; and the vapor pressure of
1,4-dichlorobenzsns at 25°C is 0.4 mm Hg (Jordan, 1954; Kirk and Othrr.er,
1963).
The major uses of 1,2-dichlorobenzene are as a process solvent in the
manufacturing of toluene diisocyanate and as an intermediate in the syn-
thesis of dyestuffs, ' herbicides, and degreasers. 1,4-Oichlorobenzer.e is
used as an air deodorant and an insecticide. 1,3-Oichlorobenzene is found
as a contaminant of the other two isomers. The combined annual production
of 1,2-, and 1,4-dichlorobenzene in the United States approaches 50,000
metric tons (Ware and West, 1977).
-------
II. EXPOSURE
A. Water
Dichlorobenzenes have been detected or quantified in rivers, ground
water, municipal and industrial discharges, and drinking water. Dichloro-
benzenes enter the water systems from the use of 1,2-dichlorobenzene as a
deodorant in industrial wastewater treatment and from the use of
1,4-dichlorobenzene toilet blocks (Ware "and" West, "1977). "Chlorinated ben-
zenes may also be formed during chlorination of raw and wastewater con-
taining organic precursor material (Glaze, efc al. 1976). In two case
studies the concentration of dichlorobenzene in finished water was higher
than in the raw water supply (Gaffney, 1976).
8. Food
There are not enough data to state quantitatively the degree of
dichlcrcbenzer.e exposure through total diet. Tainting of cork has been
reported due to the use of an odor control product containing 1,4-dichloro-
benzene in pig stalls (Schmidt, 1971). Also, low .levels of contamination of
plant products have been noted from the metabolism of lir.dane and garcma-
pentachlor-1-cyclohexane (Balba and Sana, 1974; Niostafa and Moza, 1973).
Morita, et ai. (1975) reported detectable levels of 1,4-dichlorobenzene in
fisn of the Japanese coastal waters; the concentration was Q.Q5 mg/kg. The
U.S. EPA (1979) has estimated the weighted average bioconcentration factors
for the edible portion of fish and shellfish consumed by Americans for 1,2-
dichloro-, 1,3-dichloro-, and 1,4-dichlorobenzene to be 200, 150, and 140,
respectively. These estimates are based on measured steady-state biocon-
centration studies in bluegills.
47-
-------
C. Inhalation
1,2-Oichlorobenzene has been detected in airborne participate
matter in' California at concentrations between 8 and 53 ng/m (Ware and
West, 1977). Merita and Ohi (1975) measured 1,4-dichlorobenzene in the
vapor phase, by the use of a cold solvent trap, in and around Tokyo. Urban
levels were 2.7 to 4.2 /jg/nr5; suburban levels were lower at 1.5 to 2.4
pg/m ; however, indoor levels were considerably higher at 0.105 to 1.7
mg/m .
III. PHARMACOKINETICS
A. Absorption
The (jichicrcbenzsnss may be absorbed through the lungs, gastro-
intestinal tract, and intact skin (Ware and West, 1977). There is no data
on the quantitative efficiency of absorption of dichlorobenzenes; however,
as indicated from the appearance of metabolites in the urine, respiratory
absorption during inhalation exocsure is rapid (Pagnatto and Walkley.
1966). In humans, toxic effects following accidentally or deliberately in-
gested 1,4-dichlorobenzene clearly indicate significant absorption by the
gastrointestinal route (Campbell and Davidson, 1970; Frank and Cohen, 1961;
Hallowell, 1959). Also, 1,2-dichlorobenzene fed to rats at less than 0.4 to
2 mg/kg/day was absorbed and accumulated in various tissues, indicating
significant absorption by the gastrointestinal tract even at low levels of
exposure by ingesticn (Jacobs, et al. 1974a,b).
B. Distribution
After feeding rats low levels of 1,2-dichlorobenzene in combination
with other trace pollutants found in the Rhine River, tissue accumulation
was greater in fat than in the liver, kidney, heart, and blood (Jacobs, et
al. 1974a). Studies of Morita and Ohi (1975) and Morita, et al. (1975) have
-------
shown 1,4-dichlorobenzene in adipose tissue (mean about 2 mg/kg) and blood
(about 0.01 mg/1) of humans exposed to ambient pollution levels in the Tokyo
area.
C. Metabolism
Metabolism of the 1,2- and 1,4-dichlcrobenzenes was studied by
Azouz, et al. (1955), and 1,3-dichlorobenzene was studied by Parke and
Williams (1955) in rabbits. These compounds are mainly metabolized by.oxi-
dation to 3,4-dichlorophenol, 2,5-dichlorophenol, and 2,4-dichlorophenol
respectively, which are subsequently conjugated. Other oxidation products
are formed to a lesser extent, followed again by conjugation. Pagnatto and
Walkley (1966) indicated that 2,5-dichlorophenol was also the principal
metabolite of 1,4-dichlorobenzene in humans.
0. Excretion
In studies of rabbits, Azouz, et al. (1955) and Parks and wUliams
(1955) reported the excretion of metabolic products of the dichiorobenzenes
in the urine.
IV. EFFECTS
A. Carcinogenicity
NO reports of carcinogenicity testing of specific dichlorcbenzenes
cculd be located in .the available literature. Inconclusive experiments
reviewed in U.S. EPA (1979) indicate that further investigation of the car-
cinogenic potential of the dichiorobenzenes is warranted.
8. Mutagenicity
Various mitotic anomalies were observed in cells and somatic
chromosomes of 1,4-dichlorobenzene-treated root tips (Srivastava, 1966;
Sharma and Sarkar, 1957; Carey and McDonough, 1943). Treatment of
Aspergillus nidulans (a soil mold organism) for one hour in an ether
67-7
-------
solution of any of the three isomers of dichlorobenzene increased the
frequency of back-mutations (Prasad, 1970). -In the Ames assay,
1,2-dichlorobenzer.e did not increase the mutational rate of the
histidine-requiring strains of Salmonella tvchircurium (Andersen, et al.
1972).
C. Teratogenicity and Other Reproductive Effects
Pertinent data could not be located in the available literature.
Campbell and Davidson (1970) reported the history of a woman who
was eating p-OCS during her pregnancy, and which had no apparent effect on
the offspring.
0. Chronic Toxicity
In humans, chronic occupational exposure by inhalation has occurred
mainly from 1,4-dichlorobenzene and to a lesser extent 1,2-dichlorobenzene.
Toxicity has involved the following organs and tissues: liver, blood (or
reticulcsndothelial system, including bone marrow and/or immune components),
central nervous system, respiratory tract, and integument (U.S. EPA, 1979).
In an inhalation study, Hollingsworth, et al. (1958) exposed groups of 20
rats, eight guinea pigs, four rabbits, and two monkeys to vapor of
1,2-dichlorcbenzene for seven hours per day, five days per week for six to
seven months at an average concentration of 560 mg/m . NO adverse effects
were noted in behavior, growth, organ weights, hematology, or gross and
microscopic examination of tissues. In a nine-month chronic toxicity study
Varshavskaya (1967), gave rats 1,2-dichlorobenzene at daily doses of 0.001,
0.01, and 0.1 mg/kg. The toxicological observations in the highest dose
group was anemia and other blood changes, liver damage, and central nervous
system depression. Liver carnage has also been observed with rats and guinea
pigs exposed to 1,4-dichlorobenzene at a concentration of 2,050 mg/m for
-------
six months (Hollingsworth, et al. 1956)'. There have been no specific
studies on the chronic effects of 1,3-dichlorobenzene, although this com-
pound may 'have been a contaminant in the preparations of the other two iso-
mers used for toxicological testing (U.S. EPA, 1979).
E. Other Relevant Information
Dichlorobenzenes can induce the microsomal drug metabolizing en-
zymes. Changes in the levels of microsomal enzymes can affect the metab-
olism and biological activity of a wide variety of xenobiotics (Ware and
West, 1977).
V. AQUATIC ' TOXICITY
A. Acute Toxicity
Acute studies have indicated that the position of the chlorine
atoms on the benzene ring do not dramatically influence the toxicity of
dichlorcbanzenes for freshwater fish. In 56-hour static bioassays with
bluegills, Leocrnis ~acrohirus, >-^=o values were 4,280, 5,590 and 5,020
,ug/l for 1,4-, 1,2, and 1,3-dichlorobenzene, respectively (U.S. EPA, 1973).
However, Dawson, et al. (1977) has provided a 96-hour static LCSg value of
27,000 pg/1 for 1,2-dichlorobenzene for the same species. A greater range
Oi toxicmiss was obw2i,n.sc rcr the \ resnwatcr invsrteGrace C5G~riia iTiacna
tested in 96-hour static bioassays. LC5Q values were: 2,440; 11,000; and
28,100 /jg/1 for the 1,2-, 1,4-, and 1,3-dichlorobenzene isomers, respec-
tively (U.S. EPA, 1978). Marine fish were slightly more resistant than
freshwater fish in 96-hour static assays with L.CCQ values ranging from
17,400 to 9,660 ug/1 for 1,4- and 1,2-dichlorobenzene, respectively, for the
sheepshead minnow. Marine invertebrates were the most sensitive organisms
-------
tested with LC5Q values of 1,970, 1,990, and 2,850 jug/1 obtained for 1,2-,
1,4-, and 1,3- dichlorobenzenes respectively in mysid shrimp (Mysidoosis
bahia) (U.S. EPA, 1978).
8. Chronic Toxicity
The only chronic study performed was an embryo-larval test of the
freshwater fish, the fathead minnow (Pimeohales promelas), that produced a
chronic value of 1,000 ug/1. No other chronic studies were available.
C. Plant Effects
The freshwater algae Selenastrum capricfarnutum, when tested for the
effects of dichlorobenzenes on chlorophyll a and cell numbers, had effective
concentrations ranging from 91,500 to 98,000; 149,000 to 179,000; and 96,700
to 98,100 ug/1 for 1,2-, 1,3-, and 1,4-dichlorobenzene, respectively.
Similar studies in the marine algae Skeletonema costatum revealed effective
concentrations of 44,100 to 44,200; 49,500 to 52,300; and 54,300 tc 59,ICQ
for 1,2-, 1,3-, and 1,4-dichlorobenzenes.
0. Residues
Bioconcentraticn factors of 89, 66, and £0 were obtained for 1,2-,
1,3-, and 1,4-dichlorobenzenes in the bluegill. Data on marine biccon-
centration factors are not available.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The Occupational Safety and Health Administration, (OSHA, 1976),
and the American Conference of Governmental Industrial Hygienists (ACGIH,
1977) threshold limit value is 300 mg/m for 1,2-dichlorobenzene and 450
mg/m for 1,4-dichlorobenzene. The acceptable daily intake (ADI) of 1,2-
»
or 1,4-dichlorobenzene is 1.316 mg/day (Natl. Acad. Sci., 1977). There are
-------
no standards for 1,3-dichlorobenzene. The U.S. EPA (1979) draft water
quality criterion for total dichlorobenzene (all three isomers) is 0.16 mg/1.
B. Aquatic
The draft criteria for the protection of freshwater organisms are
44 pg/1 not to exceed 99 pg/1 for 1,2-dichlorobenzene; 310 pg/1 not to ex-
ceed 700 ug/1 for 1,3-dichlorobenzene; and 190 pg/1 not to exceed 440 pg/1
for 1,4-dichlorobenzene. For marine organisms criteria have been drafted as
15 pg/1 not to exceed 34 pg/1 for 1,2-dichlorobenzene; 22 pg/1 not to exceed
49 ug/1 for 1,3-dichlorobenzene; and 15 pg/1 '"not to exceed 34 pg/1 for
1,4-dichlorobenzene.
-------
DICHLOROBENZENE5
References
American Conference of Governmental Industrial Hygienists. 1977. Docu-
mentation of the threshold limit values for substances in workroom air (with
supplements for those substances added or changed since 1971). 3rd ed.
Cincinnati, Ohio.
Anderson, K.J., et al. 1972. Evaluation of herbicides for possible muta-
genic properties. Jour. Agric. Food Chem. 20: 649.
Azouz, W.M., et al. 1955. Studies in detoxication, 62: The metabolism of
halogenobenzenes. Orthoand paradichlorobenzenes. Biochem. Jour. 59: 410.
Balba, M.H. and J.G. Sana. 1974. Metabolism'• of lindane-1^ by wheat
plants frown from treated seed. Environ. Latt. 7: 181 (Abstract).
Campbell, O.M; and R.J.L. Davidson. 1970. Toxic haemolytic anaemia in
pregnancy due to a pica for paradichlorcfcenzene. Jour. Obstet. Gynaec. 3r.
Cmnwlth. 77: 657.
Carey, M.A. and E.S. McDonougn. 1S43. On the production of polyploicly in
Allium with paradichlorobenzene.
Qav.'son, G.W., et al. 1977. The toxicity of 47 industrial chemicals to
fresh and saltwater fishes. Jour. Hazard. Mater. 1: 3C3.
"rank, S.S. and H.J. Cchsn. 1961. Fixed drug eruption due to pars-
c'ichiorobenzene. N.Y. Jour. Wed. 61: 4075.
Gaffney, P.E. 1976. Carpet and rug industry case study. I. Water and
wastewater treatment plant operation. Jour. Water Poliut. Control Fed.
48: 2590.
Glaze, W.H., et al. 1976. Analysis of new chlorinated organic compounas
formed by chlorination of municipal wastewater. In: ?roc. Con.f. Environ.
Impact Water Chlorination. Iss. Conf.-751096, pages~l53-75. (Abstract).
Hallowell, M. 1959. Acute haemolytic anemia following the ingestion of
paradichlorobenzene. Arch. Dis. Child. 34: 74.
Hollingsworth, R.L., et al. 1956. Toxicity of paradichlorobenzene. Deter-
minations on experimental animals and human subjects. AMA Arch. Ind.
Health 14: 133.
«•
Hollingsworth, R.L., et al. 1958. Toxicity of o-dichlorobenzene. Studies
on animals and industrial experience. AMA Arch. Ind. Health 17: 180.
»
Jacobs, S. 1957. The handbook of solvents. 0. Van Nostrand Co., Inc., New
York.
-------
Jacobs, A., et al. 1974a. Accumulation of noxious chlorinated substances
from Rhine River water in the fatty tissue of rats. Vom Wasser (German)
43: 259. (Abstract).
Jacobs, A., et al. 1974b. Accumulation of organic compounds, identified as
harmful substances in Rhine water, in the fatty tissues of rats.
Kernfcrschungszsntrum Karlsruhe (Ser.) KFK 1969 UF, pp. 1 (Abstract).
Jordan, I.E., 1954. Vapor pressure of organic compounds. Interscience
Publishers, Inc., New York.
Kirk, R.E. and D.E. Othmer. 1963. Kirk-Othmer encyclopedia of chemical
technology. 8th ed. John Wiley and Sons, Inc. New York.
Morita, M., et al. 1975. A systematic determination of chlorinated ben-
zenes in human adipose tissue. Environ. Pollut. 9:.175. (Abstract).
Morita, M. and G. Ohi. 1975. Para-dichlorobenzene in human tissue and
atmosphere in Tokyo metropolitan area. Environ. Pollut. 8: 269.
Mostafa, I.Y. and P.M. Moza. 1973. Degradation of camma-oenta-
chloro-1-cyclohexane (garnma-PCCH) in corn and pea seedlings. Egypt. Jour.
Cnem. Iss. Spec.: 235. (Abstract).
National Academy of Sciences. 1977. Drinking water and health. U.S. EPA
Contract No. 68-01-3169. Washington, O.C.
Occupational Safety and Health Administration. 1576. General industry
standards. 19 CFR 1=10. July 1. 1975; OSEA 22Cc", revised Jan. 1976. U.S.
Dep. Labor. Washington, D.C.
Pagn.otto, L.D. and J.E. Walkley. 1966. Urinary dichlcrcpher.ol as an index
of paradichlorobenzene exposure. Ind. Eyg. Assoc. Jour. 26: 137. (Rev. in
Food Cosmet. Toxicol. 4: 109. (Abstract)".
Parke, D.V. and R.T. Williams. 1955. Studies in detoxication: The
metabolism of halogenobenzenes. (a) Metadichlorobenzene (b) Further obser-
vation on the metabolism of chlorobsnzene. Biochem. Jour. 59: '415.
Prasad, I. 1970. Mutagenic effects of the herbicide 3',4'-dichlorcpropio-
nanilide and its degradation products. Can. Jour. Microbiol. 16: 369.
Schmidt, G.E. 1971. Abnormal odor and taste due to p-dichlorobenzene.
Arch. Lebensmittelhyg. (German) 22: 43. (Abstract).
Snarma, A.K.>and S.K. Sarkar. 1957. A study on the comparative effect of
chemicals on chromosomes of roots, pollen mother cells and pollen grains.
Proc. Indian Acad. Sci. Sect. B. 45: 288.
Srivastava, L.M. 1966. Induction of mitotic abnormalities in certain
genera of tribe Vicieae by paradichlorobenzene. Cytologia 31: 166.
-------
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. ' 1979. Dichlorobenzenes: Ambient Water Quality Criteria.
(Draft).
Varshavskaya, S.P. 1967. Comparative toxicological characteristics of
chlorobenzene and dichlorabenzene (orthoand para-isomers) in relation to the
sanitary protection of water bodies. Gig. Sanit. (Russian) 33: 17.
Ware, S.A. and W.L. West. 1977. Investigation of selected potential envi-
ronmmental contaminants: halogenated benzenes. U.S. Environ. Prot. Agency,
Washington, O.C.
Weast, R.C., et al. 1975. Handbook of chemistry and physics. 56th ed.
CRC Press, Cleveland, Ohio.
-------
No. 68
3,3'-Dichlorobenzidine
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. EPA1s Carcinogen Assessment Group (GAG) has evaluated
3,3'-dichlorobenzidine and has found sufficient evidence to
indicate that this compound is carcinogenic.
-------
3,3'-PICHLOROBEN 2IDINE
SUMMARY
The adverse health effects associated with 3 ,3'-dichloro-
benzidine include the elevated risk of carcinogenicity based
upon data from several experimental bioassays. Animals ex-
posed to dust containing dichlorobenzidine were found to have
a slight to moderate pulmonary congestion.
• One aquatic toxicity test has been performed for di-
/•
chlorobenzidine, yielding results indicating that concentra-
tions of 0.5 ug/1 were acutely toxic to a freshwater fish
species.
-------
3,3'-DICHLOROBEN ZIDINE
I. INTRODUCTION
This profile is based primarily on the Ambient Water
Quality Criteria Document for Dichlorobenzidine (U.S. EPA,
1979). The molecular formula of 3,3'-dichlorobenzidine
(4,4'-diamino-3,3'-dichlorobiphenyl) is C^H^gC^^/
and has a molecular weight of 253.13. The chemical is spar-
ingly soluble in water (0.7 g/1 at 15°C), but readily soluble
in organic solvents. Because of the fact that 3,3'-dichloro-
benzidine is an organic base, it may be fairly tightly bound
to humic materials, causing long-term storage in soils.
3,3'-Dichlorobenzidine has been demonstrated to be a
carcinogen in experimental animals. Various types of sar-
comas and adenocarcinomas have been induced at injection
sites, and in specific organ systems upon dosage by gavage.
No evidence is available implicating 3,3'-dichlorobenzidine
as a human carcinogen.
II. EXPOSURE
A. Water
3,3'-Dichlorodibenzidine has been detected in water
near a waste disposal lagoon ranging from 0.13 to 0.27 mg/1,
as have benzidine concentrations up to 2.5 mg/1 (Sikka, et
al. 1978). In water of the Sumida River in Tokyo receiving
effluents of dye and pigment factories (Takemura, et al.
»•
1965) total aromatic amines including 3,3'-dichlorobenzidine
were reported as high as 0.562 mg/1. The literature tends, to
support the possibility that the use of storage lagoons to
handle 3,3'-dichlorobenzidine wastes may pose a threat to
persons relying on nearby wells for drinking water.
-------
B. Food
Data quantifying levels of 3,3'-dichlorobenzidine
in foods have not been reported. It was suggested that con-
sumption 'Of fish would serve as the major dietary intake of
3,3'-dichlorobenzidine. No measurable levels of 3,3'-dichloro-
benzidine were detected (<10 ug/D in fish sampled near a
contaminated waste-lagoon (Diachenko, 1978).
The U.S. EPA (1979) has estimated the weighted
•
average bioconcentration factor to be 1,150 for 3,3'-dichloro-
benzidine for the edible portions of fish and shellfish con-
sumed by Americans. This estimate is based on the octanol/
water partition coefficient.
C. Inhalation
The low volatility and large crystal structure of
3,3'-d ichlorobenzidine would tend to minimize the risk of .ex-
posure to the chemical Ln ambient air. However, inhalation
may be a major source of exposure to those individuals occu-
pationally exposed to 3,3'-dichlorobenzidine. Concentrations
as high as 2.5 mg/100 m-^ have been reported in one Japanese
pigment factory (Akiyama, 1970).
D. Dermal
Under specific conditions of moist skin and high
atmospheric humidity and temperature dermal absorption of
3,3'-dichlorobenzidine may be possible.
••
III. PHARMACOKINETICS
A. Absorption .
Data concerning the rates and degree of absorption
of dichlorobenzidine have not be quantitated.
-------
B. Distribution
One study administering (14C}-3,3'-dichloroben-
zidine at doses of 0.2 mg/kg intravenously in rats, monkeys,
and dogs revealed a general distribution of radioactivity
after 14 days. The highest (14c)-3,3'-dichlorobenzidine
levels were found in the livers of all three species, in the
bile of monkeys and in lungs of dogs (Kellner, et al. 1973).
C. Metabolism
Following the intravenous injection of 0.2 mg/kg
(^*c)-3,3'-dichlorobenzidine, the total urinary radioac-
tivity was recovered as one-third unchanged (^C)-3,3'-
dichlorobenzidine, one-third as the mono-N-acetyl derivative
of the parent compound, and the remainder not recoverable
(Kellner, et al., 1973). Chronic ingestion of small doses of
3 , 3'-dichlorobenzidine lead to the appearance of four meta-
bolic products including benzidine (U.S. EPA, 1979), however,
the results may be questionable due to the analytical methods
employed in the study. No metabolites of 3,3'-dichlorobenzi-
dine have been detected in the excreta of dogs experimentally
administered the parent compound (U.S. EPA, 1979), nor the
urine of human subjects experimentally administered the chem-
ical (Gerarde and Gerarde, 1974).
E. Excretion
Several studies have indicated that fecal elimina-
tion may be a major route of excretion in animals and humans
(U.S. EPA, 1979). One study (Meigs, et al. 1954) detected'
unspecified amounts of 3,3'-dichlorobenzidine in the urine of
occupationally exposed workers.
-------
IV. EFFECTS ON MAMMALS
A. Carcinogenicity
A number of investigations have reported the car-
cinogenic potential of 3,3'-dichlorobenzidine. Dietary 3,3'-
dichlorobenzidine at 1,000 mg/kg have been associated with
the significant occurrence of mammary adenocarcinomas, granu-
locytic leukemia, and zymbal gland carcinomas in male rats
and mammary adenocarcinomas in female ra-ts (Stula, et al.
1975). In dogs, oral doses of 100 mg/kg were associated with
the significant occurrence of hepatic and urinary bladder
carcinomas (Stula, et al. 1975). Levels of 0.5 and 1.0 mis
of a 4.4 percent suspension of 3,3'-dichlorobenzidine in rat
feed, resulting in a 4.53 g total dose of the chemical, pro-
duced an increase of cancers of the mammary gland, Zymbal
gland, urinary bladder, skin, sraall intestine, liver, thyroid
gland, kidney, hematopoietic system and salivary glands
(Pliss, 1959). Hepatic tumors and sebaceous gland carcinoma
were observed in mice exposed to a total dose of 127.5 to 135
mg over a ten month period of time (Pliss, 1959). 3,3'-Di-
chlorobenzidine was administered at levels of 30 mg every 3
days for 30 days by gavage. Observations over nine months
demonstrated that DCB is ineffective as a mammary carcinogen
(Griswold, et al. 1968). A diet of 0.3 percent 3,3'-dichloro-
benzidine was marginally carcinogenetic and tumorigenic to
hamsters (U.S. EPA, 1979). 3,3'-Dichlorobenzidine has also
found to produce transformation in cultured rat embryo celis
(Freeman, et al. 1973). Epidemiology studies in the United
States, Great Britian, and Japan have not provided evidence
-------
that 3,3'-dichlorobenzidine by itself induces bladder cancer
in workers occupationally exposed to the chemical. For some
studies, though, the latent period for tumor formation might
not have elapsed.
B. Mutagenicity
3,3'-Dichlorobenzidine has been shown to induce
frame shift mutations in Salmonella typhimurium tester strain
TA1598 in the presence of the S9 NADPH-fortified rat liver
enzyme preparation (Garner, et al. 1975). Similar results
with tester strain TA98 indicating frame shift mutations and
tester strain 1000 indicating base-pair substitutions were
observed by prior metabolic activation with a male mouse
enzyme system (Lazear and Louis, 1977).
C. Teratogenicity
Information relative to the teratogenic effects of
3,3'-dichlorobenzidine was not found in the available
literature. Document (U.S. EPA, 1979). The chemical has
been shown to cross the placental barrier and increase the
incidence of leukemia in the offspring of pregnant mice given
doses of 8-10 mg of 3 , 3'-dichlorobenzidine subcutaneously
during the last week of pregnancy, but these results may
represent toxic effects on neonates through suckling milk
from dosed mothers (Golub, et al. 1969, 1974). Altered
growth and morphology of cultured kidney tissue obtained from
prenatally exposed mouse embryos has been observed (Shabad,
»
et al. 1972; Golub, et al. 1969).
-------
D. Toxicity
An acute oral LD^Q for DCS in mice, given to
mice for seven consecutive days was 352 mg/kg/day for females
and 386 mgAg/day for males. Single-dose LD50 values
were reported as 488 and 676 mg/kg for female and male mice,
respectively. Rats exposed to atmospheric dust containing
unspecified amounts of 3,3'-dichlorobenzidine for 14 days
showed no increased mortalities. Upon autopsy slight to*
moderate pulmonary congestion and one pulmonary abcess were
observed.
V. AQUATIC TOXICITY
The only aquatic species tested for the toxic effects of
3,3'-dichlorobenzidine was the bluegill, Lepomis macrochirus.
It was found to be acutely toxic at concentrations of 0.5
mg/1 or greater (Sikka, et al. 1978).
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 possibil-
ity that these criteria will be changed.
A. Human
The American Conference of Governmental Industrial
Hygienists has recommended that exposure to 3,3'-dichloroben-
zidine be reduced to zero, based on the demonstrated carcino-
genicity of the chemical in experimental animals. Occupa-
tional standards have not been placed on 3,3'-dichlorobenzl-
dine and standards regulating levels of the chemical in the
environment or in food have not been proposed.
-------
A recommended draft criterion of 1.69 x 10~2 ug/i
has been established, corresponding to a lifetime cancer risk
of lO""^. This value was derived from data relating 3,3'-
dichlorobenzidine to the daily consumption of two liters of
water and 18.7 g of fish and shellfish.
B. Aquatic
Data were insufficient to draft criteria for either
freshwater or marine life.
-------
3,3'-DICHLOROBEN ZIDINE
REFERENCES
Akiyama, T. 1970. The investigation on the manufacturing
plant of organic pigment. Jikei. Med. Jour. 17: 1.
Diachenko, G. 1978. Personal communication, U.S. Food and
Drug Administration.
Freeman, A.E., et al. 1973. Transformation of cell cultures
as an indication of the carcinogenic potential of chemicals.
Jour. Natl. Cancer Inst. 51: 799.
Garner, R.C., et al. 1975. Testing of some benzidine ana-
logues for raicrosomal activation to bacterial mutagens.
Cancer Lett. 1: 39.
Gerarde, H.W., and D.F. Gerarde. 1974. Industrial experi-
ence with 3,3'-dichlorobenzidine: an epidemiological study of
a chemical manufacturing plant. Jour. Occup. Med. 16: 322.
Golub, N.I. 1969. Transplacental action of 3,3'-dichloro-
benzidine and orthotolidine on organ cultures of embryonic
mouse kidney tissue. Bull. Exp. BipJL. Med. (U.S.S.R.) 68:
1280.
Golub, N.I., et al. 1974. Oncogenic action of some nitrogen
compounds on the progeny of experimental mice. Bull. Exp. •
Biol. Med. (U.S.S.R.) 78: 62.
Griswold, D.P., et al. 1968. The carcincgenicity of multi-
ple intragastric doses of aromatic and heterocyclic nitro or
amino derivatives in young female Sprague-Dawley rats.
Cancer Res. 28: 924.
Kellner, H.M., et al. 1973. Animal studies on the kinetics
of bensidine and 3 , 3'-dichlorobenzidine. Arch. Toxicol. 31:
61.
Lazear, E.J., and S.C. Louis. 1977. Mutagenicity of some
congeners of benzidine in the Salmonella typhimurium assay
system. Cancer Lett. 4: 21.
Meigs, J.W., et al. 1954. Skin penetration by diamines of
the benzidine group. Arch. Ind. Hyg. Occup. Med. 9: 122.
Pliss, G.B. 1959. Dichlorobenzidine as a blastomogenic
agent. Vopr. Onkol. 5: 524.
6 ?--
-------
Shabad, L.M., et al. 1972. Transplacental effects of some
chemical compounds on organ cultures of embryonic kidney
tissue. Cancer Res. 32: 617.
Sikka, H.C., et al. 1978. Fate of 3,3'-dichlorobenzidine in
aquatic environments. U.S.-•"Environ. Prot. Agency 600/3-8-
068.
Stula, E.F., et al. 1975. Experimental neoplasia in rats
from oral administration of 3,3'-dichlorobenzidine , 4,4'-
methylene-bis(2-chloroaniline), and 4,4'-methylene-bis(2-
methylaniline). Toxicol. Appl. Pharmacol. 31: 159.
Takemura, N., et al. 1965. A survey of the pollution of the
Sumida River, especially on the aromatic, amines in the water.
Internat. Jour. Air Water Pollut. 9: 665.
U.S. EPA. 1979. Dichlorobenzidine: Ambient Water Quality
Criteria. (Draft).'
-------
No. 69
1,1-Dichloroethane
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENC7
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.
-------
1.1-OICHLDROETHANE
Summary
There i's no available evidence to indicate that 1,1-dichloroethane pro-
duces carcinogenic or mutagenic effects. A single study in rats failed to
show teratogenic effects following inhalation exposure.
Symptoms produced by human poisoning include respiratory tract irrita-
tion, central nervous system depression, and marked cardiac excitation. An-
imal studies indicate that 1,1-dichloroethane may produce liver damage.
Sufficient toxicological data are not available to calculate aquatic
exposure criteria.
£7-3
-------
1,1-OICHLOROETHANE
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 have been replaced by chlorine atoms. Water solubility and vapor
pressure decrease with increasing chlorination, while density and melting
point increase. 1,1-Oichloroethane (ethylidene dichloride; ethylidene
chloride; molecular weight 98.96) is a liquid at room temperature with a
boiling point of 57.3°C, a melting point of -98°C, a specific gravity of
1.1776, and a solubility in water of 5 g/liter (U.S. EPA, 1979a).
The chloroethanes are used as solvents, cleaning and degreasing agents,
and in the chemical synthesis of a number of compounds. No commercial pro-
duction of 1,1-dichloroethane has been reported in the United States (NIOSH,
1973).
The chlorinated ethanes form azeotropes with water (Kirk and Othmer,
1963). All are very soluble in organic solvents (Lange, 1936). 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 due primarily
to industrial discharges. Small amounts of the chlqxoethanes may be formed
by chlorination of drinking water or treatment of sewage. Air levels of
these volatile compounds are produced by evaporation during use as degreas-
ing agents and in dry-cleaning operations (U.S. EPA, 1979a).
t-f-1
-------
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).
No information on levels of 1,1-dichloroethane in foods was found in
the available literature. Sufficient data is not available to estimate a
steady-state bioconcentration factor for 1,1-dichloroethane.
III. PHARMACOKINETICS
Pertinent data could not be located in the available literature on
1,1-dichloroethane for absorption, distribution, metabolism and excretion.
However, the reader is referred to a more general treatment of chloroethanes
(U.S. EPA, 1979b) which indicates rapid absorption of chloroethanes follow-
ing oral or inhalation exposure; widespread distribution of the chloroeth-
anes throughout the body; enzymatic dechlorination and oxidation to the al-
cohol and ester forms; and excretion of the chloroethanes primarily in the
urine and in expired air.
Additionally, it has been indicated that the absorption of 1,1-dichlcr-
oethane is most similar to that of the 1,2-isomer (indicating significant
dermal absorption as well as rapid oral or inhalation absorption).
IV. EFFECTS
A. Carcinogsnicity and Mutagenicity
Pertinent data could not be located in the available literature.
8. Teratogenicity
An inhalation study in rats has indicated no major teratogenic ef-
fects of 1,1-dichloroethane (Schwetz, et al. 1974).
C. Other Reproductive Effects
Inhalation of 1,1-dichloroethane by pregnant rats produced delayed
ossification of sternebrae in fetuses, indicating an effect of the compound
in retarding fetal development (Schwetz, et al. 1974).
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D. Chronic Toxicity
Use of 1,1-dichloroethane as an anesthetic was discontinued because
of marked excitation of the heart (Browning, 1965). Poisoning cases have
shown respiratory tract irritation and central nervous system depression
(U.S. EPA, 1979a). Animal studies indicate that inhalation of 1,1-dichloro-
ethane may produce liver damage (Sax, 1975).
V: AQUATIC TOXICITY
Pertinent aquatic toxicity data could not be located in the available
literature.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The current promulgated Occupational Safety and Health Administra-
tion exposure standard for 1,1-dichloroethane is 100 ppm, time-weighted
average for up to a 10-hour work day, 40-hcur work week.
Sufficient data are not available to derive a criterion to protect
human health from exposure to 1,1-dichloroethane from ambient water.
8. Aquatic
Sufficient toxicologic data are not available to calculate aquatic
exposure criteria.
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1,1-OICHLQROETHANE
REFERENCES
Browning, E. 1965. Toxicity and metabolism of industrial solvents.
Elsevier Publishing Co., Amsterdam.
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.
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 Publishers,
Inc. Sandusky, Ohio.
National Institute for Occupational Safety and Health. 1978. Ethylene
dichloride (1,2-dichloroethane). Current Intelligence Bull. 25. OHEVJ
(NIOSH) Publ. NO. 78-149.
Sax, N.I., ed. 1975. Dangerous properties of industrial materials. 4th
ed. Reinhold Publishing Corp. New York.
Schv/etz, 3.A., at al. 1974. Embryo and fetotoxicity of inhaled carbon
tetrachloride, 1,1-dichloroethane, and methyl ethyl ketone in rats.
Toxicolo. Appl. Pharrnacol. 28: 452.
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).
61-7
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No. 70
I,2-Dichloroethane
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.
70-1
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SPECIAL NOTATION
U.S. EPA1s Carcinogen Assessment Group (GAG) has evaluated
1,2-dichioroethane and has found sufficient evidence to
indicate that this compound is carcinogenic.
70-3
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1,2-OICHLOROETHANE
Summary
Results of an NCI carcinogenesis bioassay in rats and mice have shown
that 1,2-dichloroethane may produce a wide variety of tumors, including
squamous cell carcinomas, hemangiosarcomas, mammary adenocarcincmas, and
hepatocellular carcinomas. Mutagenic effects have been shown in the Ames
Salmonella system and in E. coli; metabolites of 1,2-dichloroethane have
also shown rnutagenic effects in the Ames assay. v
One study has failed to indicate teratogenic effects following inhala-
tion exposure to 1,2-dichloroethane although reproductive toxicity was
demonstrated. Chronic human exposure to 1,2-dichloroethane has produced
neurological symptoms and liver and kidney damage. Poisoning victims have
shown diffuse dystrcphic changes in the brain and spinal cord.
Acute toxicity values for freshwater organisms ranged from 431,QCO to
530,GOO jjg/1. • Marine invertebrates appeared to be somewhat more sensitive
to 1,2-dichlorcethane with an LC^ value of 113,GCC jjg/1 reported.
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1,2-OICHLOROETHANE
I. INTRODUCTION
This profile is based on the draft Ambient Water Quality Criteria Docu-
ment 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 density and melting
point increase. 1,2-Dichloroethane (molecular weight 98.96) is a liquid at
room temperature with a boiling point of 83.4 C, a melting point of
-35.4°C, a specific gravity of 1.253, and a solubility of 8.1 g/1 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. A large portion of
1,2-dichloroethane is used in the production of vinyl chloride and chlori-
nated chemicals, and 33 an ingredient, along with tetraethyl lead, in anti-
knock mixtures (U.S. EPA, 1979a).
1,2-Oichloroethane production in 1976 was 4.000 x 103 tons (U.S. EPA,
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 teen demonstrated (U.S. E?a,
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
•70-r
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by chlorination of drinking water or treatment of sewage. Of 80 water
samples tested, 27 contained 1,2-dichloroethane at concentrations of 0.2 to
3pg/l (U.S. EPA, 1974).
Sources of human exposure to chloroethanes not only include water, but
also air, contaminated foods and fish, and dermal absorption. For example,
1,2-dichloroethane has been detected in 11 of 17 spices in concentrations
ranging from 2 to 23 jug/g of spice (Page and Kennedy, 1975). In fish and
shellfish, levels of chloroethanes in the nanogram range have been found
(Oickson and Riley, 1576).
The U.S. EPA (1979a) has estimated the weighted average bioconcen-
tration factor for 1,2-dichloroethane to be 4.6 for the edible portions of
fish and shellfish consumed by Americans. This estimate was based on the
measured steady-state bioconcentration studies in bluegills.
III. PHARMACQKINETICS
A. Absorption
The chloroethanes are acsorbed rapidly following oral or inhalation
routes of exposure (U.S. EPA, 1979a). Animal studies indicate that signif-
icant absorption of 1,2-dichloroethane may occur following dermal apcli-
cation (Smyth, et al. 1969).
3. Cistrioution
Pertinent information could not be located in the available litera-
ture on 1,2-dichloroethane. The reader is referred to more general treat-
ment of the chloroethanes (U.S. EPA, 1979b) which indicates a widespread
distribution of chloroethanes through the body.
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C. Metabolism
In general, the metabolism of chloroethanes involves both enzymatic
dechlorination and hydroxylation to corresponding alcohols (U.S. EPA,
1979a). Metabolism of 1,2-dichloroethane produces a variety of metabolites
in the urine. The main two are: s-carboxymethylcysteine and thiodiacetic
acid (Yllner, 1971a,b,c,d). Yllner (1971a,b,c,d) also stated that the
percentage of 1, 2-dichloroethane metabolized decreased with increasing
dose, suggesting saturation of metabolic pathways.
D. Excretion
The chloroethanes are excreted primarily in the urine and in ex-
pired air (U.S. EPA, 1979a). Animal studies conducted by Yllner (1971a,b,
c,d) indicate that large amounts of chlorinated ethanes administered by i.p.
injection are excreted in the urine, with very little excretion in the
feces. Excretion appears tc be rapid, since 90 percent of an i.p. adminis-
tered dose o:~ 1,2-dichlcrosthane was eliminated in the first 24 hours (U.S.
EPA, 1979a).
IV. EFFECTS
A. Carcinogenicity
Results of the NCI bioassay for carcinogenicity (NCI, 1978) have
indicated that 1,2-dichloroethane e.c~inistratiQn produced an incrsase in
several types of tumors. Squamous cell carcinomas and hemangiosarcomas were
produced in male rats, and mammary adenocarcinomas in female rats, following
feeding of 1,2-dichloroethane. In mice, hepatocellular carcinomas in males
and mammary adenocarcinomas in females were both increased after oral treat-
ment with 1,2-dichloroethane.
70-7
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8. Mutagenicity
Testing of 1,2-dichloroethane in the Ames "Salmonella assay and an
E. coli assay system have indicated mutagenic activity of this compound
(8rem, et al. 1974). Metabolites of 1,2-dichloroethane (S-chloroethyl
cysteine, chloroethanol, and chloroacetaldehyde) have shown positive muta-
genic effects in the Ames system (U.S. EPA, 1979a). 1,2-Oichloroethane has
also been reported to increase mutation frequencies in pea plants
(Kiricheck, 1974) and Drosophila (Nylander, et al. 1978).
C. Teratogenicity "
Inhalation studies with 1,2-dichloroethane in pregnant rats did not
indicate teratogenic effects (Vozovaya, 1974).
0. Other Reproductive Effects
Rats exposed' to 1,2-dichloroethane by inhalation showed reduced
litter sizes, decreased live births, and decreased fatal weights (Vczovaya,
1974).
E. Chronic Toxicity
Patients suffering from 1,2-dichlorcethane poisoning have shown
diffuse dystrophic changes in the brain and spinal cord (Akimov, et al.
1973). Chronic exposures have produced neurologic changes and liver and
kidney impairment (NIOSH, 197Sa).
Animal studies with 1,2-dichloroethane toxicity have shown liver
and kidney damage and fatty infiltration, and some bone marrow effects (U.S.
EPA, 1979a).
F. Acute Toxicity
Oral human LD. (lowest dose which has caused death) values have
»
been estimated at 500 and 810 mg/kg in two studies (NIOSH, 1978b). Other
species show a similar sensitivity to 1,2-dichloroethane, except for the
70-%
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rat. An LD^- value for this species has been estimated to be 12 jjg/kg
(NIOSH, 1978b).
V. AQUATIC TOXICITY
A. Acute Toxicity
Acute 96-hour static LC5Q values ranged from 431,000 to 550,000
ug/1 for the bluegill (Lepomis macrochirus), while a single 48- hour static
LC5Q value of 218,000 ug/1 was obtained for the freshwater cladoceran
Daphnia magna (U.S. EPA, 1978). A single acute marine invertebrate study
was available, reporting a 96-hour static LCco value of 113,000 jjg/1 for
the mysid shrimp (Mysidopsis bahia) (U.S. EPA, 1978).
B. Chronic Toxicity and Plant Effects
Pertinent information could not be located in the available litera-
ture on chronic toxicity and plant effects.
C. Residues
A bicconcentraticn factor of 2 has been reported fcr the bluecill
(U.S. EPA, 1979a).
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
Based on the NCI carcinogenesis bioassay data, and using a linear,
nonthreshold model, the 'U.S. EPA (1979a) has' estimated a level of
1,2-dichloroethane in ambient water that will result in an additional cancer
»
risk of 10"5 to be 7 ug/1.
70-7
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The 8-hour TV/A exposure standard developed by QSHA for
1,2-dichloroethane is 5Q ppm.
3. Aquatic
In freshwater environment a criterion has been drafted for
1,2-dichloroethane as 3,900 jug/1 as a 24-hour average, not to exceed 8800
jug/1. For marine life, the criterion has been drafted as 880 ug/1, not to
exceed 2000 >jg/l.
70-10
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1,2-DICHLOROETHAHE
REFERENCES
Akimov, G.A., et al. 1978. Neurologic disorders in acute
dichloroethane poisoning. Zh. Nerropatol. Psikhiatr. 78:
687.
Brem, S.L., et al. 1974. The mutagenicity and DNA-tMod ifying
effect of haloalkanes. Cancer Res. 34: 2576.
Dickson, A.G., and J.P. Riley. 1976. The distribution of
short-chain halogenated aliphatic hydrocarbons in some marine
organisms. Mar. Pollut. Bull. 79: 157.
Kirk, R., and D. Othmer. 1963. Encyclopedia of chemical
technology. 2nd ed. John Wiley and Sons,"'Inc., New York.
Kiricheck, Y.F. 1974. Effect of 1,2-dichloroethane on muta-
tions in peas. Usp. Khim. Mutageneza' Se. 232.
Lange, N. (ed.) 1956. Handbook of chemistry. 9th ed.
Handbook Publishers, Inc., Sandusky, Ohio.
National Cancer Institute. 1978. Bioassay of 1,2-dichloro-
ethane for possible carcinogenicity. Natl. Inst. Health,
Ilatl. Cancer Ins-. Carcinogenesis Testing -Program. DHEW
Publ. Ho. (NIH) 75-1205. Pub. Health Sec". U.S. Dep. Health
Sdu. Welfare.
National Institute for Occupational Safety and Health. I973a.
Ethylene dichloride (1,2-dichloroethane). Current Intelli-
gence Bull. 25. DHEW (NIOSH) Publ. No. 78-149.
National Institute for Occupational Safety and Health. 1978b.
Registry of toxic effects of chemical substances, DHEW (NIOSH)
Publ. No. 79-100.
Nylander, P.O.., et al. 1978. Mutagenic effects of petrol in
Drosophila melanoaaster. I. Effects of benzene of and 1,2-
dichloroethane. Mutat. Res. 57: 163.
Page, B.D., and B.P.C. Kennedy. 1975. Determination of
methylene chloride, ethylene dichloride, and trichloroethy-
lene as solvent residues in spice oleoresins, using vacuum
distillation and electron-capture gas chromatography. Jour.
Assoc. Off. Anal. Chem. 58: 1062.
Smyth, H.F. Jr., et al. 1969. Range-finding toxicity data:
List VII. Am. Ind. Hyg. Assoc. Jour. 30: 470.
U.S. EPA. 1974. "Draft analytical report-Mew Orleans area
water supply study," EPA 906/10-74-002. Lower Mississippi
River Facility, Slidell, La., Surveill. Anal. Div. Region VI,
Dallas, Tex.
70-11
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U.S. EPA. 1978. In-depth studies on health and environmen-
tal impacts of selected water pollutants. U.S. Environ.
Prot. Agency. Contract No. 68-01-4646.
U.S. EPA. 1979a. Chlorinated Ethanes: Ambient Water Quality
Criteria. (Draft) .
U.S. EPA. 1979b. Environmental Criteria and Assessment Of-
fice. Chlorinated Ethanes: Hazard Profile (Draft).
Van Dyke, R.A., and C.G. Wineman. 1971. Enzymatic
dechlorination: Dechlorination of chloroethanes and propanes
in vitro. Biochem. Pharmacol. 20: 463.
Vozovaya, M.A. 1974. Development of progeny of two genera-
tions obtained from female rats subjected to the action of
dichloroe thane. , Gig. Sanit. 7: 25.
Yllner, S. 1971a. Metabolism of 1 ,2-dichloroethane -14c
in the mouse. Acta. Pharmacol. Toxicol. 30: 257.
Yllner, S. 1971b. Metabolism of 1, 1, 2-trichloroethane-l-2-
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 1 , 1 , 2 ,2-tetrachloroethar.e-
-•^C in the mouse. Acta. Pharmacol. Toxicol. 29: 499.
70 -
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