United States
Environmental Protection
Agency
Office of Water
Regulations and Standards
Criteria and Standards Division
Washington DC 20460
EPA 440/5-80-039
October 1980
'
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AMBIENT WATER QUALITY CRITERIA FOR
DICHLOROBENZENE
Prepared By
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Water Regulations and Standards
Criteria and Standards Division
Washington, D.C.
Office of Research and Development
Environmental Criteria and Assessment Office
Cincinnati, Ohio
Carcinogen Assessment Group
Washington, D.C.
Environmental Research Laboratories
Corvalis, Oregon
Duluth, Minnesota
Gulf Breeze, Florida
Narragansett, Rhode Island
Prctsntipn Agency
-------
DISCLAIMER
This report has been reviewed by the Environmental Criteria and
Assessment Office, U.S. Environmental Protection Agency, and approved
for publication. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
AVAILABILITY NOTICE
This document is available to the public through the National
Technical Information Service, (NTIS), Springfield, Virginia 22161.
11
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FOREWORD
Section 304 (a)(l) of the Clean Water Act of 1977 (P.L. 95-217),
requires the Administrator of the Environmental Protection Agency to
publish criteria for water quality accurately reflecting the latest
scientific knowledge on the kind and extent of all identifiable effects
on health and welfare which may be expected from the presence of
pollutants in any body of water, including ground water. Proposed water
quality criteria for the 65 toxic pollutants listed under section 307
(a)(l) of the Clean Water Act were developed and a notice of their
availability was published for public comment on March 15, 1979 (44 FR
15926), July 25, 1979 (44 FR 43660), and October 1, 1979 (44 FR 56628).
This document is a revision of those proposed criteria based upon a
consideration of comments received from other Federal Agencies, State
agencies, special interest groups, and individual scientists. The
criteria contained in this document replace any previously published EPA
criteria for the 65 pollutants. This criterion document is also
published in satisifaction of paragraph 11 of the Settlement Agreement
in Natural Resources Defense Council, et. al. vs. Train, 8 ERC 2120
(D.D.C. 1976), modified, 12 ERC 1833 (D.D.C. 1979).
The term "water quality criteria" is used in two sections of the
Clean Water Act, section 304 (a)(l) and section 303 (c)(2). The term has
a different program impact in each section. In section 304, the term
represents a non-regulatory, scientific assessment of ecological ef-
fects. The criteria presented in this publication are such scientific
assessments. Such water quality criteria associated with specific
stream uses when adopted as State water quality standards under section
303 become enforceable maximum acceptable levels of a pollutant in
ambient waters. The water quality criteria adopted in the State water
quality standards could have the same numerical limits as the criteria
developed under section 304. However, in many situations States may want
to adjust water quality criteria developed under section 304 to reflect
local environmental conditions and human exposure patterns before
incorporation into water quality standards. It is not until their
adoption as part of the State water quality standards that the criteria
become regulatory.
Guidelines to assist the States in the modification of criteria
presented in this document, in the development of water quality
standards, and in other water-related programs of this Agency, are being
developed by EPA.
STEVEN SCHATZOW
Deputy Assistant Administrator
Office of Water Regulations and Standards
111
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ACKNOWLEDGEMENTS
Aquatic Life Toxicology
William A. Brungs, ERL-Narragansett
U.S. Environmental Protection Agency
David J. Hansen, ERL-Gulf Breeze
U.S. Environmental Protection Agency
Mammalian Toxicology and Human Health Effects
Kirby Campbell (author), HERL
U.S. Environmental Protection Agency
Terence M. Grady (doc. mgr.), ECAO-Cin
U.S. Environmental Protection Agency
Donna Sivulka, ECAO-Cin
U.S. Environmental Protection Agency
Eliot Lomnitz
U.S. Environmental Protection Agency
Myron Men!man
Mobil Oil Corporation
Patrick Durkin
Syracuse Research Corporation
Penelope A. Fenner-Crisp
U.S. Environmental Protection Agency
Si Duk Lee, EPA-Cin
U.S. Environmental Protection Agency
Steven D. Lutkenhoff, ECAO-Cin
U.S. Environmental Protection Agency
Technical Support Services Staff: D.J. Reisman, M.A. Garlough, B.L. Zwayer,
P.A. Daunt, K.S. Edwards, T.A. Scandura, A.T. Pressley, C.A. Cooper,
M.M. Denessen.
Clerical Staff: C.A. Haynes, S.J. Faehr, L.A. Wade, D. Jones, B.J. Bordicks,
B.J. Quesnell, C. Russom, R. Rubinstein.
IV
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TABLE OF CONTENTS
Criteria Summary
Introduction A-l
Aquatic Life Toxicology B-l
Introduction B-l
Effects B-l
Acute Toxicity B-l
Chronic Toxicity B-3
Plant Effects B-4
Residues B-4
Miscellaneous B-5
Summary B-6
Criteria B-7
References B-l4
Mammalian Toxicology and Human Health Effects C-l
Exposure C-l
Ingestion from Water C-l
Ingestion from Food C-9
Pharmacokinetics C-ll
Absorption C-ll
Distribution C-14
Metabolism C-l5
Excretion C-18
Effects C-21
Acute, Subacute, and Chronic Toxicity C-21
Synergism and/or Antagonism C-41
Teratogenicity C-41
Mutagenicity C-48
Carcinogenicity C-49
Criterion Formulation C-55
Existing Guidelines and Standards C-55
Current Levels of Exposure C-60
Special Groups at Risk C-62
Basis and Derivation of Criteria C-63
References C-66
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CRITERIA DOCUMENT
DICHLOROBENZENES
CRITERIA
Aquatic Life
The available data for dichlorobenzenes indicate that acute and chronic
toxicity to freshwater aquatic life occur at concentrations as low as 1,120
and 763 pg/1, respectively, and would occur at lower concentrations among
species that are more sensitive than those tested.
The available data for dichlorobenzenes indicate that acute toxicity to
saltwater aquatic life occurs at concentrations as low as 1,970 v9/l and
would occur at lower concentrations among species that are more sensitive
than those tested. No data are available concerning the chronic toxicity of
dichlorobenzenes to sensitive saltwater aquatic life.
Human Health
For the protection of human health from the toxic properties of dichlo-
robenzene ingested through water and contaminated aquatic organisms, the
ambient water criterion is determined to be 400 pg/1
For the protection of human health from the toxic properties of dichlo-
robenzenes ingested through contaminated aquatic organisms alone, the ambi-
ent water criterion is determined to be 2.6 mg/1.
VI
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INTRODUCTION
The dichlorobenzenes are a class of halogenated aromatic compounds rep-
resented by three structurally similar isomers: 1,2-dichloro-, 1,3-di-
chloro-, and 1,4-dichlorobenzene. Dichlorobenzenes have the molecular for-
mula C6H4C12 and a molecular weight of 147.01 (Weast, et al. 1975).
1,2-Dichlorobenzene (1,2-DCB) and 1,3-dichlorobenzene (1,3-DCB) are
liquids at normal environment temperatures, while 1,4-dichlorobenzene
(1,4-DCB) is a solid. Melting points (MP), boiling points (BP), and densi-
ties for the three isomers are presented in Table 1 (Weast, et al. 1975).
The dichlorobenzenes are soluble in water at concentrations which are
toxic to aquatic organisms. The solubilities in water of the 1,2-, 1,3-,
and 1,4-dichlorobenzene isomers at 25°C are 145,000 ug/1, 123,000 ug/1, and
80,000 ug/1, respectively (Jacobs, 1957). The dichlorobenzenes also are
readily soluble in natural fats or fat soluble substances (Windholz, 1976).
The logs of the octanol/water partition coefficients for 1,3-dichloro- and
1,4-dichlorobenzene are 3.44 and 3.37, respectively (U.S. EPA, 1978). All
three dichlorobenzene isomers are relatively volatile. The vapor pressure
of 1,2-dichlorobenzene at 20"C is 1 mm Hg; the vapor pressure of 1,3-di-
chlorobenzene at 39°C is 5 mm Hg; and the vapor pressure of 1,4-dichloroben-
zene at 25°C is 0.4 mm Hg (Jordan, 1954; Kirk and Othmer, 1963).
The major uses of 1,2-DCB are as a process solvent in the manufacturing
of toluene diisocyanate and as an intermediate in the synthesis of dye-
stuffs, herbicides, and degreasers (West and Ware, 1977). 1,4-Dichloroben-
zene is used primarily as an air deodorant and an insecticide, which account
for 90 percent of the total production of this isomer (West and Ware, 1977).
Information is not available concerning the production and use of 1,3-DCB.
A-l
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TABLE 1
Physical Properties of Dichlorobenzenes*
Compound/ Isomer
1 , 2-Di chl orobenzene
1,3-Di chl orobenzene
1 ,4-Oi chl orobenzene
MP Co
-17.6
-24.2
-53.0
BP CC)
179
172
174
Density (°C)
1.30 g/ml (20)
1.29 g/ml (20)
1.25 g/ml (20)
*Source: Weast, et al. 1975
A-2
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However, it may occur as a contaminant of 1,2- or 1,4-DCB formulations.
Both 1,2-dichloro- and 1,4-dichlorobenzene are produced almost entirely as
by-products during the production of monochlorobenzene. Combined annual
production of these two isomers in the United States approaches 50,000
metric tons (West and Ware, 1977).
A-3
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REFERENCES
Jacobs, S. 1957. The Handbook of Solvents. 0. Van Nostrand Co., Inc., New
York.
Jordan, I.E. 1954. Vapor Pressure of Organic Compounds. Interscience Pub-
lishers, 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.
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. EPA Contract No. 68-01-4646. 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.
West, W.L. and S.A. Ware. 1977. Investigation of selected potential envi-
ronmental contaminants: Halogenated benzenes. U.S. Environ. Prot. Agency,
Washington, D.C.
Windholz, M. (ed.) 1976. The Merck Index. 9th ed. Merck and Co., Rahway,
New Jersey.
A-4
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Aquatic Life Toxicology*
INTRODUCTION
Comparable data for the bluegill, Daphnia magna, and Selenastrum capri-
cornutum (an alga) are available for 1,2-, 1,3-, and 1,4-dichlorobenzene.
Most of these tests were conducted under static conditions and the test con-
centrations were not measured. The alga, based on chlorophyll ai and cell
numbers, has higher 96-hour EC5Q values.
As with the freshwater species, the saltwater data base for the di-
chlorobenzenes is limited to results of acute exposures of fish and inverte-
brate species, predominantly performed with unmeasured concentrations under
static test conditions. The LC5Q and plant values range from 1,970 to
greater than 100,000 yg/1; the mysid shrimp was most sensitive. Although
differences in acute toxicity of the dichlorobenzenes exist among species,
the toxicity of different dichlorobenzenes to individual species is similar
so for practical purposes they may be considered to be equally toxic.
EFFECTS
Acute Toxicity
Daphnia magna and a midge are the only freshwater invertebrate species
for which data for dichlorobenzenes are available (Table 1). The data for
Daphnia magna were obtained using similar methods (U.S. EPA, 1978) and the
48-hour EC5Q values are 2,440, 28,100, and 11,000 yg/1 for 1,2-, 1,3-, and
1,4-dichlorobenzene, respectively. As will be seen, there is no great dif-
ference in sensitivity between the bluegill and Daphnia magna. Comparable
test results (U.S. EPA, 1978) with other chlorinated benzenes and Daphnia
*The reader is referred to the Guidelines for Deriving Water Quality Cri-
teria for the Protection of Aquatic Life and Its Uses in order to better un-
derstand the following discussion and recommendation. The following tables
contain the appropriate data that were found in the literature, and at the
bottom of each table are calculations for deriving various measures of tox-
icity as described in the Guidelines.
B-l
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magna are available. The 48-hour ECgQ values range from 86,000 pg/1 for
chlorobenzene to 5,280 yg/1 for pentachlorobenzene, indicating an increase
in toxicity of the chlorinated benzenes with increasing chlorination. The
midge 48-hour EC5Q values are 11,760 and 13,000 yg/1 for 1,2- and 1,4-di-
chlorobenzene, respectively.
The bluegill has been tested (U.S. EPA, -1978) and the 96-hour LC5Q
values, obtained under static and unmeasured test conditions, are 5,590,
5,020, and 4,280 yg/1 for 1,2-, 1,3-, and 1,4-dichlorobenzene, respectively
(Table 1). These results indicate that the position of the chlorine atoms
on the benzene ring probably does not influence the toxicity of dichloroben-
zenes very much. Dawson, et al. (1977) also tested the bluegill and their
96-hour LC5Q was 27,000 wg/l for 1,2-dichlorobenzene which result is dif-
ferent from that (5,590 ug/1) for the same species by different investiga-
tors (U.S. EPA, .1978). This difference may be due to the fact that Dawson,
et al. (1977) added 1,2-dichlorobenzene to the surface of the test water
without the subsequent mixing usually done for such tests.
Two flow-through measured tests were conducted with the fathead minnow
and the rainbow trout (U.S. EPA, 1980); the 96-hour LC5Q values for
1,3- and 1,4-dichlorobenzene were 7,790 and 4,000 ug/1, respectively. For
the minnow and the rainbow trout the 96-hour LC™ values were 1,580 and
1,120 yg/1 for 1,2- and 1,4-dichlorobenzene, respectively.
When the 96-hour LC^Q values obtained for the bluegill under similar
conditions (U.S. EPA, 1978) for the dichlorobenzenes and a variety of other
chlorinated benzenes (chlorobenzene, trichlorobenzene, tetrachlorobenzene
and pentachlorobenzene) are compared, there is good correlation between the
degree of chlorination and acute toxicity. (See the criterion document for
B-2
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chlorinated, benzenes for details.) These LC5Q values range from 15,900
ug/l for chlorobenzene to 250 ug/l 'for pentachlorobenzene with the dichloro-
benzenes being approximately three times more toxic than chlorobenzene.
The mysid shrimp was more sensitive to the dichlorobenzenes in 96-hour
acute exposures (Table 1) than were the fish; LC5Q values ranged from
1,970 to 2,850 ug/1- As with the freshwater test species, comparable re-
sults (U.S. EPA, 1978) with other chlorinated benzenes and the mysid shrimp
are also available. The IC™ values range from 16,400 ug/l for chloroben-
zene to 160 ug/l for pentachlorobenzene, agaiVi indicating an increase in
toxicity of the chlorinated benzenes with increasing chlorination.
The sheepshead minnow was similarly sensitive to the dichlorobenzenes;
96-hour LCCft values ranged from 7,400 to 9,660 ug/l (Table 1). Toxicity
bO
of these compounds to fishes may be inadequately estimated by these results
since data on only one other fish species are available. The tidewater
silverside (Dawson, et al. 1977) was as sensitive as the sheepshead minnow
with a 96-hour LC™ of 7,300 ug/1-
Comparable data (U.S. EPA, 1978) are available for the sheepshead minnow
and other chlorinated benzenes. (See the criterion document for chlorinated
benzenes for details.) These LC5Q values range from 10,500 ug/l for
chlorobenzene to 830 ug/l for pentachlorobenzene and indicate, again, a good
correlation between the degree of chlorination and acute toxicity.
Chronic Toxicity
An embryo-larval test with fathead minnows and 1,2-dichlorobenzene has
been conducted (U.S. EPA, 1978) and the chronic value for this test is 2,000
ug/1 (Table 2). Embryo-larval tests have also been conducted with the fat-
head minnow and 1,3- and 1,4-dichlorobenzene (ERL-D, 1980) and the acute-
B-3
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chronic ratios for these compounds are both 5.2 (Table 2). No other data on
chronic effects on freshwater or saltwater fish or invertebrate species are
available.
This range of chronic values for the dichlorobenzenes (763 to 2,000
ug/1) and the fathead minnow demonstrate that these chemicals are less
chronically toxic than the more highly chlorinated chemicals. The fathead
minnow chronic values for 1,2,4-trichlorobenzene (two tests) and 1,2,3,4-
tetrachlorobenzene were 287,000, and 318 yg/l, respectively.
Plant Effects
The freshwater alga, Selenastrum capricornutum, has been tested for the
effects of dichlorobenzenes on chlorophyll a. and cell numbers (Table 3).
The EC5Q values range from 91,600 to 179,000 Mg/l for the dichloroben-
zenes, which results indicate little if any relationship to the location of
chlorine atoms on. the benzene ring.
Comparable test procedures (U.S. EPA, 1978) were used for other chlori-
nated benzenes and, as with the fish and invertebrate species, toxicity is
increased with an increase in chlorination.
The saltwater algal species, Skeletonema costatum, has also been tested
(U.S. EPA, 1978) for acute effects of exposure to the dichlorobenzenes
(Table 3). The EC5Q values for cell number or chlorophyll a_ ranged from
44,100 to 59,100 ug/l.
Comparable test procedures (U.S. EPA, 1978) were used for other chlori-
nated benzenes and this saltwater alga, and toxicity generally increases
with an increase in chlorination.
Residues
Bioconcentration by the bluegill (Table 4) has been studied using 14C-
labeled dichlorobenzenes, with thin layer chromatography for verification
(U.S. EPA, 1978). The bioconcentration factors were 89, 66, and 60 for
8-4
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1,2-, 1,3-, and 1,4-dichlorobenzene, respectively. Equilibrium occurred
within 14 days and the half-life for each dichlorobenzene was less than 1
day. These results suggest that the dichlorobenzenes are unlikely to be a
tissue residue problem in the aquatic environment.
Additional comparable data (U.S. EPA, 1978) are available in the chlori-
nated benzenes criterion document for tetrachlorobenzene and pentachloroben-
zene and the bluegill. These compounds are much more lipophilic than the
dichlorobenzenes with bioconcentration factors of 1,800 for tetrachloroben-
zene and 3,400 for pentachlorobenzene. Hexachlorobenzene has been tested
with the fathead minnow and the pinfish and the bioconcentration factors
were 22,000 and 23,000, respectively. In addition, the half-lives of chlor-
inated benzenes increase with chlorination from less than 1 day for the di-
chlorobenzenes, to 2 to 4 days for tetrachlorobenzene, and greater than 7
days for pentachlorobenzene. These results indicate that the environmental
risk due to tissue residues increases with increasing chlorination and
support the conclusion above that dichlorobenzenes will not likely cause a
serious residue problem for aquatic life.
Miscellaneous
Neely, et al. (1974) estimated a steady-state bioconcentration factor
for p-dichlorobenzene (1,4-dichlorobenzene) using a short exposure and de-
puration study with the rainbow trout. This estimated value was 210 (Table
5).
Two polychaete species and clam embryos and larvae were-relatively in-
sensitive to exposures to 1,2- and 1,4-dichlorobenzene (Table 5). The LC5Q
values for 1,2-dichlorobenzene and clam embryos and larvae were greater than
100,000 pg/1 (Davis and Hindu, 1969). Acute exposures to 1,2- and 1,4-di-
B-5
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chlorobenzene at 100,000 ug/1 were responsible for 55-100 percent emergence
of two polychaete species from parasitized oysters (Mackenzie and Shearer,
1959).
Summary
The 48-hour EC5Q values for Daphnia magna and a midge for 1,2-, 1,3-,
and 1,4-dichlorobenzene ranged from 2,440 to 28,100 ug/l with no consistent
difference due to location of the chlorine atoms or sensitivity of the two
species. The range of LC5Q values for three fish species and the same di-
chlorobenzenes was 1,120 to 27,000 ug/l, and the rainbow trout appears to be
a little more sensitive than the two warmwater fish species. Embryo-larval
tests with the fathead minnow and 1,2-, 1,3-, and 1,4-dichlorobenzene have
been conducted and the chronic values ranged from 763 to 2,000 ug/1. The
acute-chronic ratio for both 1,3- and 1,4-dichlorobenzene was 5.2. The
freshwater alga, Selenastrum capricornutum. is less sensitive to the di-
chlorobenzenes with EC5Q values that range from 91,600 to 179,000 ug/1.
The measured steady-state bioconcentration factors for the three dichloro-
benzenes are in the range of 60 to 89 for the bluegill. There appears to be
little if any difference in toxicity to freshwater organisms among the di-
chlorobenzenes.
The saltwater mysid shrimp has been exposed to 1,2-, 1,3-, and 1,4-di-
chlorobenzene and the 96-hour LC5Q values were 1,970, 2,850, and 1,990
ug/1, respectively. For the sheepshead minnow and the same chemicals, the
96-hour LC5Q values were in the range of 7,400 to 9,660 wg/l. No chronic
toxicity data are available for any saltwater species. The 96-hour EC™
ou
for a saltwater alga and 1,2-, 1,3-, and 1,4-dichlorobenzene ranged from
44,100 to 59,100 ug/1. The saltwater data suggest that there is no dif-
ference in toxicity among the three dichlorobenzenes.
8-6
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CRITERIA
The available data for dichlorobenzenes indicate that acute and chronic
toxicity to freshwater aquatic life occur at concentrations as low as 1,120
and 763 ug/1, respectively, and would occur at lower concentrations among
species that are more sensitive than those tested.
The available data for dichlorobenzenes indicate that acute toxicity to
saltwater aquatic life occurs at concentrations as low as 1,970 u9/l and
would occur at lower concentrations among species that are more sensitive
than those tested. No data are available concerning the chronic toxicity of
dichlorobenzenes to sensitive saltwater aquatic life.
3-7
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Table 1. Acute values for dIchlorobenzenes
CO
Species
Cladoceran,
Daphnla magna
C ladoceran,
Daphnla magna
Cladoceran,
Daphnia magna
Midge,
Tanytarsus dissimilis
Midge,
Tanytarsus dissimilis
Rainbow trout,
Sal mo gairdneri
Rainbow trout.
Sal mo gairdneri
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Bluegill,
Lepomis macrochirus
Bluegi 1 1,
Lepomis macrochirus
Bluegi 1 1,
Lepomis macrochirus
Bluegi 1 1,
Lepomis macrochirus
Method*
s.
s.
s,
s,
s,
FT,
FT.
FT,
FT,
s.
s,
s,
s.
U
u
u
M
M
M
M
M
M
U
U
U
U
Chemical
FRESHWATER
1,2-dichloro-
benzene
1,3-dichloro-
benzene
1,4-dlchloro-
benzene
1,2-dichloro-
benzene
1,4-dichloro-
benzene
1,2-dichloro-
benzene
1,4-dlch loro-
benzene
1,3-dichloro-
benzene
1,4-dichloro-
benzene
1,2-dlchloro-
benzene
1,2-dlchloro-
benzene
1,3-dlchloro-
benzene
1,4-dich loro-
benzene
LC50/EC50
(ug/l)
SPECIES
2,440
28,100
11,000
11,760
13,000
1,580
1,120
7,790
4,000
27,000
5,590
5,020
4,280
Species Acute
Value (ug/l)
2,440
28,100
11,000
11,800
13,000
1,580
1,120
7,790
4,000
12,000
5,020
4,280
Reference
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
EPA,
EPA,
EPA,
EPA,
EPA,
EPA,
EPA,
EPA,
EPA,
Dawson, et
U.S. EPA,
U.S. EPA,
U.S. EPA,
1978
1978
1978
1980
1980
1980
1980
1980
1980
al. 1977
1978
1978
1978
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Table 1. (Continued)
w
Spec 1 es
Mysfd shrimp,
Mysidopsls bah I a
Mysld shrimp,
Mysidopsls bah la
Mysid shrimp,
Mysidopsis bah la
Tidewater sllverslde,
Menldla beryl 1 Ina
Sheepshead minnow,
Cyprlnodon varlegatus
Sheepshead minnow,
Cyprlnodon varlegatus
Sheepshead minnow,
Cyprlnodon varlegatus
LC50/EC50 Species Acute
Method* Chemical (ug/l) Value (ug/l) Reference
SALTWATER SPECIES
S, U 1,2-dlchloro- 1,970 1,970 U.S. EPA, 1978
benzene
S, U 1,3-dlchloro- 2,850 2,850 U.S. EPA, 1978
benzene
S, U 1,4-dlchloro- 1,990 1,990 U.S. EPA, 1978
benzene
S, U 1,2-dichloro- 7,300 7,300 Dawson, et al. 1977
benzene
S, U 1,2-dlchloro- 9,660 9,660 U.S. EPA, 1978
benzene
S, U 1,3-dlchloro- 7,770 7,770 U.S. EPA, 1978
benzene
S, U 1,4-dlchloro- 7,400 7,400 U.S. EPA, 1978
benzene
* S = static, FT = flow-through, U = unmeasured, M = measured
No Final Acute Values are calculable since the minimum data base requirements are not met.
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Table 2. Chronic values for dichlorobenzenes
Cfl
h-1
O
Species
Fathead
P i mepha !
Test*
minnow, ELS
les promelas
Fathead minnow, ELS
PI mepha les promelas
Fathead minnow, ELS
PI mepha les promelas
* ELS =
Early 1 ife stage
Species
Fathead minnow,
PI mepha les J>romejas_
Fathead minnow,
PI mepha les promelas
Chemical
FRESHWATER
1,2-dlchloro-
benzene
1,3-dlch loro-.
benzene
1,4-dlch loro-
benzene
Acute-Chron I c
Chemical
1,3-dichloro-
benzene
1,4-dichloro-
benzene
LlMltS
(ug/D
SPECIES
1,600-
2,500
1 ,000-
2,270
560-
1,040
Ratios
Acute
Value
(ug/l)
7,790*»
4,000
Chronic
Value
(wg/i)
2,000
1,510
763
Chronic
Value
(ug/l)
1,510
763
Reference
U.S. EPA, 1978
U.S. EPA, 1980
U.S. EPA, 1980
Ratio
5.2
5.2
**These values were selected to calculate the acute-chronic ratio because tests were conducted In the
same dilution water (Lake Superior).
-------
Table 3. Plant values for dIchIorobenzenes (U.S. EPA, 1978)
Species
Alga,
Selenastrum caprlcornutum
Alga,
Se 1 enastrum caprlcornutum
Alga,
Selenastrum caprlcornutum
Alga,
Selenastrum caprlcornutum
Alga,
Selenastrum caprlcornutum
Alga,
Selenastrum caprlcornutum
Alga,
Skeletonema costatum
Alga,
Skeletonema costatum
Alga,
Skeletonema costatum
Alga,
Skeletonema costatum
Alga,
Skeletonema costatum
Alga,
Skeletonema costatum
Chem 1 ca 1
FRESHWATER SPECIES
1,2-dich loro-
benzene
1,2-dlch loro-
benzene
1 ,3-d Ich loro-
benzene
1, 3-d Ich loro-
benzene
1,4-dlch loro-
benzene
1 ,4-d Ich loro-
benzene
SALTWATER SPECIES
1,2-dlchloro-
benzene
1,2-dlchloro-
benzene
1, 3-d Ich lor o-
benzene
1,3-dlchloro-
benzene
1,4-dlch loro-
benzene
1,4-dich loro-
benzene
Effect
EC50 96- hr
chlorophy 1 1 a
EC50 96-hr
eel 1 number
EC50 96-hr
ch lorophy 1 1 a
EC50 96- hr
eel 1 number
EC50 96- hr
ch lorophy 1 1 a
EC50 96-hr
eel 1 number
EC50 96-hr
ch lorophy 1 1 a
EC50 96-hr
eel 1 number
EC50 96- hr
ch lorophy 1 1 a
EC50 96-hr
eel 1 number
EC50 96-hr
ch lorophy 1 1 a
EC50 96-hr
eel 1 number
Result
(U9/D
91,600
98,000
179,000
149,000
98,100
96, 700
44,200
44,100
52,800
49,600
54,800
59,100
-------
Table 4. Residues for dlchlorobenzenes (U.S. EPA, 1978)
Bloconcentratlon Duration
Species Tissue Chemical Factor (days)
FRESHWATER .SPECIES
Bluegi 1 1,
Lepomis macrochirus
Bluegi 1 1,
Lepomis macrochirus
Bluegil 1,
Lepomis macrochirus
whole body
whole body
whole body
1,2-dlch loro-
benzene
1,3-dich loro-
benzene
1 ,4-d ich loro-
benzene
89
66
60
14
14
14
-------
Table 5. Other data for dlchlorobenzenes
Species
Rainbow trout.
Sal mo gairdneri
Polychaete,
Polydora websterl
Polychaete,
Nerl Is sp.
Clam (embryo),
td Mercenarla mercenarla
i-i
w Clam (larva),
Mercenaria mercenarla
Polychaete,
Polydora websteri
Polychaete,
Nereis sp.
Chemical
1,4-dlchloro-
benzene
1,2-dichloro-
benzene
1,2-dlch loro-
benzene
1,2-dlchloro-
benzene
1,2-dlchloro-
benzene
1,4-dich loro-
benzene
1,4-dlch loro-
benzene
Duration
FRESHWATER
SALTWATER
3 hrs
3 hrs
48 hrs
12 days
3 hrs
3 hrs
Result
Effect (ug/l)
SPECIES
Estimated steady-
state bioconcentra-
tlon factor = 210
SPEC 1 ES
65$ emergence 100,000
from parasitized
oysters
70$ emergence 100,000
from parasitized
oysters
LC50 > 100, 000
LC50 > 100, 000
55$ emergence 100,000
from parasitized
oysters
100$ emergence 100,000
from parasitized
Reference
Neely, et al.
1974
Mackenzie &
Shearer, 1959
Mackenzie &
Shearer, 1959
Davis & Hindu,
1969
Davis & Hindu,
1969
Mackenzie &
Shearer, 1959
Mackenzie &
Shearer, 1959
oysters
-------
REFERENCES
Davis, H.C. and H. Hindu. 1969. Effects of pesticides on embryonic devel-
opment of clams and oysters and on survival and growth of the larvae. U.S.
Fish Wildl. Serv. Fish. Bull. 67: 393.
Dawson, G.W., et al. 1977. The toxicity of 47 industrial chemicals to
fresh and saltwater fishes. Jour. Hazard. Mater. 1: 303.
MacKenzie, C.L., Jr. and L.W. Shearer. 1959. Chemical control of Polydora
websteri and other annelids inhabiting oyster shells. Proc. Natl. Shellfish
Assoc. 50: 105.
Neely, W.B., et'al. 1974. Partition coefficient to measure bioconcentra-
tion potential of organic chemicals in fish. Environ. Science Tech.
8: 1113.
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. 1980. Unpublished laboratory data. Environmental Research
Laboratory - Duluth.
B-14
-------
Mammalian Toxicology and Human Health Effects
EXPOSURE
Ingestion from Water
The production, use, transport, and disposal of dichloro-
benzenes result in widespread dispersal to", and therefore contami-
nation of, environmental media, with resulting opportunity for ex-
posure of the biosphere (including man). Dichlorobenzenes (DCBs)
have been detected or quantified in rivers, ground water, municipal
and industrial discharges, drinking water, air, and soil. They
have also been detected in tissues of lower organisms living in
contaminated waters and in exposed higher animals. Persistence in
the environment varies among compounds and with conditions. The
more highly halogenated benzenes are more generally resistant to
biodegradation and are therefore more persistent.
Table 1 shows detection and concentration of DCBs in raw and
contaminated waters. 1,2-DCB has been reported as entering water
systems at average levels of 2 mg/1 as a result of its use by in-
dustrial wastewater treatment plants for odor control (Ware and
West, 1977). 1,4-DCB enters wastewater systems because of its use
in toilet blocks (Ware and West, 1977). Table 2 summarizes the
data on DCBs in drinking water samples. Reported DCB levels in
drinking water samples have thus far been relatively low (i.e.,
compared to trihalomethanes).
As with halomethanes, new chlorinated organic compounds in-
cluding chlorinated benzenes have been reported from chlorination
of raw and waste waters containing organic precursor material.
C-l
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TABLE 1
Dichlocobenzenes in Raw and Discharge Waters**
O
Medium or Sample
Ground water
Raw water contam. with
municipal waste
Raw water contam. with
municipal waste
Raw water contam. with
indust. discharge
Raw water contam. with
indust. discharge
Industrial discharge
Industrial discharge
Industrial waste
holding
Ground water
Industrial discharge
Submarine outfall, sew.
treatment effluent
Submarine outfall, sew.
treatment effluent
Submarine outfall, sew.
treatment effluent
Submarine outfall, sew.
treatment effluent
Submarine outfall, sew.
treatment effluent
(5 miles)
Location
Miami, Fla.
Philadelphia,
Pa.
Cincinnati ,
Ohio
Cincinnati ,
Ohio
Lawrence, Mass.
Law son's Fork
Creek, N.C.
Catawba River
Kentucky
Kentucky
Big Bigby
Creek, Tenn.
Point Loma,
Calif.
Oxnard, Calif.
Joint Wat.
Plant, So.
Calif.
Orange Co.
Sew. Dep.
Hyperion Sew.
Treat. Works,
Los Angeles,
Calif.
1,2-DCB 1,3-DCB 1.4-DCD DCB
l(cce) d(voa) O.S(cce) d(voa) O.S(cce) d(voa)
d(voa) d(voa) d(voa)
d( voa)
d(voa) d(voa)
d( voa)
32,12(fid)
690(fid) 33(fid)
15(ecd) 0.9(ecd)
1.2,71(ecd) 1.2,12(ecd)
40(fid) 58(fid)
<.01,2.2 0.42,1
4-7- 2.3 9.3, 3.1
5.1(ec) 3.3(ms) 7.6(ec) 7.4(ms)
7.3, 12 7.4, 12
1.3(ec) 2.8(ec)
2.4 4.9
1-9. 4 3.4, 5.1
-------
TABLE 1 (Continued)
Medium or Sample
Submarine outfall, sew.
(7 miles) effluent
River, rec. surface
run-off after storm
(4 day period)
Location
Los Angeles
River
Los Angeles
River
1,2-DCB 1,3-DCB
183(ec) 14(ms)
30, 440
0.01
1,4-DCB
90(ec) 7.8(ms)
34, 230
0.05
DCB
Chemical plant waste- Michigan
water (seepage and
cooling)
Textile waste U.S.
effluents
10
detected
w In mg x 10 ; (cce) = carb. chlorof. extract; (voa) = vol. org. anal.; (ecd) = elect, conduct, detect, (fid) = flame
ioniz. det.; (ec) = electron capt.; (ros) = mass spec; (d) = detected.
•Source: Ware & West 1977
-------
TABLE 2
-3,
Dichlorobenzenes in U.S. Drinking Waters, mg x 10/1
1,2-DCB
Highest concentrations 1
reported as of 1975
National Organics Recon-
naisance Survey
Miami, Fl a. 1
Philadelphia, Pa. d*
Cincinnati, Oh. d
Lawrence, Mass.
Q Concentrations reported in Phase
1 U.S. EPA's NOMS study II III
*> during 1976 and 1977
No. pos/no. anal. 0/113 4/110
Mean of pos. analyses,
ug/1 - 2.5
Median, all results,
ug/1 < 0.005 <0.005
1,3-DCB 1,4-DCB Reference
•^3 1 U.S. EPA, 1975
0.5 0.5 U.S. EPA, 1975
d d
d d
d d
Phase Phase
II HI I II III U.S. EPA, 1978a
0/113 2/110 2/111 20/113 29/110
0.10 2.0 0.14 0.07
<0.005
-------
Glaze, et al. (1976) reported the formation of many new chlorinated
organic compounds as a result of chlorine treatment of secondary
municipal wastewater effluents. Total organic-bound (TOC1) levels
in concentrated extracts of effluents increased significantly after
chlorination. Some of the aromatic halides identified were chloro-
benzenes. Kopperman, et al. (1976) reported higher levels of
chlorinated organic compounds (including dichlorobenzenes) in fish
exposed (90 days) to chlorinated wastewater treatment plant ef-
fluent than in those exposed to nondisinfected effluent. They in-
terpreted their data as indicating that even gentle chlorination
conditions cause chlorine to be incorporated into organic mole-
cules. Gaffney (1976) studied removal and formation of organic
compounds at waste treatment plants processing waters containing
effluents from .textile processing plants. His data indicated that
chlorinated components were formed by chlorination in the disinfec-
tion process at the treatment plant. In water purification plant
samples the concentration of DCBs tended to increase in a down-
stream pattern. In two case studies the concentration of DCS in
finished water was higher than in the raw water supply.
Data on air concentrations of DCBs are very limited, but they
suggest the potential for inhalation exposure. Dichlorobenzenes
were measured in aerial fallout and high-volume samples taken at
various locations in the Los Angeles area (Ware and West, 1977).
Fallout samples were obtained at El Segundo, Catalina Island, San
Clemente Island, La Jolla, and Santa Barbara. Levels of 1,2-DCB
2
were reported as less than 8, 27, and less than 53 ng/m
fi 2
(mg x 10 /m ) for Catalina Island, San Clemente, and Santa
C-5
-------
Barbara, respectively. Apparently no 1,4-DCB was detected in fall-
out samples from any of the sites. DDT, Aroclor 1254^, and Aroclor
(R)
1242 ^ were present in samples from all sites and at levels much
greater than for DCB. High-volume air samples were collected at
the El Segundo, Catalina Island, and San Clemente sites. The
1,2-DCB level in air at El Segundo (estimated from reported filter
analytic values at approximately 0.3 x 10 mg/m ) was higher than
that at Catalina Island and at San Clemente (similarly estimated at
approximately 0.04 x 10 mg/m, respectively). 1,2-DCB concentra-
tions were considerably lower than for DDT and Aroclor 1254^at all
sites. Data for 1,4-DCB were inadequate because of high and vari-
able values in the analytical process blanks. The authors con-
cluded that aerial fallout of chlorinated benzenes is less signifi-
cant than that 'of DDT and PCBs because of the higher volatility of
chlorinated benzenes. Gas-phase concentrations of DCBs were not
reported.
Morita and Ohi (1975) have reported "appreciable" levels of
1,4-DCB in the indoor and ambient air of Tokyo. The results of
their survery of air contamination levels are summarized in Table
3. 1,4-DCB concentrations from 2.7 to 4.2 mg x 10 /m (ug/m )
were measured outdoors in central Tokyo. In the outdoor atmosphere
of suburban Tokyo levels from 1.5 to 2.4 mg x 10~ /m were ob-
tained. Considerably higher levels (from 0.105 to 1.7 mg/m ) were
measured in samples of indoor air (bedroom, closet, wardrobe).
1,4-DCB was also measured in human adipose tissue of residents.
Morita and Ohi (1975) collected their airborne 1,4-DCB in the vapor
phase by use of cold solvent traps, whereas Young, et al. (1976)
C-6
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TABLE 3
Atmospheric Concentrations of 1,4-Dichlorobenzene
In and Around Tokyo*
Area
Concentration of 1,4-DCB
(mg x 10"3/m3)
Outdoors
Cental Tokyo
Suburbs
Indoors
a. Residential
b. Busy station square
c. Main street
'a. Quiet Lake, 50 km
west
b. Major highway, 30 km
west
c. Farm 15 km
northwest
a. Inside wardrobe
b. Inside closet
c. Bedroom
4.2
2.7
2.9
1.5
2.4
2.1
1,700
315
105
*Source: Morita and Ohi, 1975
C-7
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collected their DCS from the particulate fraction of air in south-
ern California using filter and fallout samplers. The much higher
airborne concnetrations reported by Morita and Ohi (1975) may re-
flect that their Tokyo downtown and suburban air was more contami-
nated than the air at the California sites and/or that DCB is pre-
sent in ambient air more as vapor than as' a component of suspended
particulates. In New Orleans, although all DCB isomers were de-
tected in human blood samples in the area of New Orleans, no DCBs
were detected in air or drinking water samples (Ware and West,
1977). The source of DCBs in the blood was not determined.
DCB contamination may exist in certain workplace atmospheres
at much higher concentrations than exist in ambient air, presenting
a greater exposure to persons in some occupations than to the gen-
eral public. In workplace atmospheres associated with the manufac-
ture of 1,4-DCB, measurements were made that found 1,4-DCB at air
concentrations averaging 204 mg/m (range: from 42 to 288 mg/m )
near shoveling and centrifuging, and 150 mg/m (range: from 108 to
204 mg/m ) during pulverizing and packaging. No concentrations of
less than 48 mg/m were found (Ware and West, 1977).
In the late 1930's a survey of fulling operations in three
mills of the woolen industry using 1,2-DCB as a solvent, vapor con-
centrations in eight samples of workroom air ranged from 60 to
1,620 mg/m (Hollingsworth, et al. 1958). Concentrations of
1,4-DCB were determined in samples of workplace air associated with
manufacture and/or handling of 1,4-DCB (Hollingsworth, et al.
1956). In the 62 samples of the first survey concentrations of
1,4-DCB ranged from 6 to 3,300 mg/m (average, 510 mg/m ). In the
C-8
-------
second survey 15 samples collected under recurrent, severe,
unpleasant work conditions ranged from 600 to 4,350 mg/m (aver-
age, 630 mg/m ) in 21 samples collected under conditions associated
with worker complaints (eye and nasal irritation). In 25 other
samples, collected under no-complaint conditions, concentrations
ranged from 90 to 510 mg/m (average,. 270' mg/m ).
Novokovskaya, et al. (1976) reported 1,2-DCB as being among
several organic compounds in gaseous emissions from the production
of silicone medical tubing. 2,4-Dichlorobenzene peroxide was an
ingredient of resins used in the manufacture. Emission gases were
said to be below the maximum allowable concentration (MAC). The
recommended MAC for 1,2-DCB in the Soviet Union as of 1970 was 20
mg/m (International Agency for Research on Cancer (IARC), 1974).
Ingestion from-Food
Dichlorobenzenes may be present in food commodities as a re-
sult of direct or indirect contamination from proper or improper
uses or accidents. Schmidt (1971) reported the tainting of pork
(disagreeable odor and taste) as a result of the use in pig stalls
of an odor-control product containing 1,4-DCB. Eggs were tainted
within three days of exposure of hens to 1,4-DCB concentrations
from 20 to 38 mg/m . Neither the hens nor the egg production were
affected (Langner and Hilliger, 1971). Morita, et al. (1975) re-
ported detectable levels of 1,4-DCB in fish of the Japanese coastal
waters. A species of mackerel (Trachurus trachurus) contained 0.05
mg/kg (wet weight). These authors also reported analyzing 1,4-DCB
in human adipose tissue (obtained from central Tokyo hospitals and
medical examiners' offices).
C-9
-------
Dichlorobenzenes may occur in plant tissues as degradation
products of lindane or other chemicals. A DCB was found among
several other polychlorinated benzenes constituting a nonpolar
group of metabolites of lindane used on lettuce and endives (Kohli,
et al. 1976). DCBs were recovered as lindane metabolites in roots
of wheat plants grown from lindane-treated seed (Balba and Saha,
1974). 1,3-DCB was reported to be among several metabolites of
gamma-pentachloro-1-cycylohexane in corn and pea seedlings
(Mostafa and Moza, 1973). There are not enough data to state quan-
titatively the degree of DCB exposure through total diet. Avail-
able evidence indicates that degree of environmental contamination
by DCBs as a result of lindane degradation is probably very small
(Ware and West, 1977). 1,2-DCB and/or 1,4-DCB have also been mea-
sured in soils as products of lindane degradation (Mathur and Saha,
1977).
A bioconcentration factor (BCF) relates the concentration of a
chemical in aquatic animals to the concentration in the water in
which they live. The steady-state BCFs for a lipid-soluble com-
pound in the tissues of various aquatic animals seem to be propor-
tional to the percent lipid in the tissue. Thus the per capita in-
gestion of a lipid-soluble chemical can be estimated from the per
capita consumption of fish and shellfish, the weighted average per-
cent lipids of consumed fish and shellfish, and a steady-state BCF
for the chemical.
Data from a recent survey on fish and shellfish consumption in
the United States were analyzed by SRI International (U.S. EPA,
1980). These data were used to estimate that the per capita
C-10
-------
consumption of freshwater and estuarine fish and shellfish in the
United States is 6.5 g/day (Stephan, 1980). In addition, these
data were used with data on the fat content of the edible portion of
the same species to estimate that the weighted average percent lip-
ids for consumed freshwater and estuarine fish and shellfish is 3.0
percent.
Measured steady-state bioconcentration factors of 89, 66 and
60 were obtained for 1,2-dichlorobenzene, 1,3-dichlorobenzene, and
1,4-dichlorobenzene, respectively, using bluegills (U.S. EPA,
1978b,c). Similar bluegills contained an average of 4.8 percent lip-
ids (Johnson, 1980). An adjustment factor of 3.0/4.8 = 0.625 can
be used to adjust the measured BCF from the 4.8 percent lipids of
the bluegill to the 3.0 percent lipids that is the weighted average
for consumed fish and shellfish. Thus, the weighted average bio-
concentration factors for 1,2-dichlorobenzene, 1,3-dichloro-
benzene, and 1,4-diclorobenzene and the edible portion of all
freshwater and estuarine aquatic organisms consumed by Americans
are calculated to be 55.6, 41.2, and 37.5, respectively.
PHARMACOKINETICS
Absorption
The dichlorobenzenes may be absorbed through the lungs, gas-
trointestinal (GI) tract, and intact skin. Relatively low water
solubility and high lipid solubility of halobenzenes favor their
penetration of most membranes by diffusion, including pulmonary and
GI epithelia, the brain, hepatic parenchyma, renal tubules, and the
placenta (Ware and West, 1977).
C-ll
-------
From their investigation of atmospheric contamination by 1,4-
DCB in the Tokyo area (Table 3), Morita and Ohi (1975) suggested
that inhalation is a major mode of human exposure to environmental
1,4-DCB. The same authors (Morita, et al. 1975) reported finding
1,4-DCB in all samples of human adipose tissue examined. In 32
samples obtained from local hospitals ,and medical examiners, repre-
senting subjects of both sexes and ages of 13 to 80 years, 1,4-DCB
was measured at concentrations of 0.2 to 11.7 mg/kg (mean 2.3).
The mean concentration in adipose tissue was 246 times the mean
concentration (9.3 x 10 mg/1) measured in six samples of whole
blood from males and females aged 21 to 35 years. Although 1,4-DCB
was also measured at 0.05 and 0.012 mg/kg in samples of fish of the
Japanese coastal waters, no concentrations were reported for other
food items or for drinking water, so the relative contribution to
body burden of 1,4-DCB by various exposure sources and routes is
not clear.
Inhalation of DCB vapors was primarily responsible for most
(16 of 22) of a series of clinical cases of poisoning reported in
the literature (Girard, et al. 1969; Sumers, et al. 1952; Weller
and Crellin, 1953; Perrin,1941; Cotter, 1953; Gadrat, et al. 1962;
Petit and Champeix, 1948; Nalbandian and Pierce, 1965; Campbell and
Davidson, 1970; Downing, 1939; Frank and Cohen, 1961; Ware and
West, 1977). 1,2-DCB was the principal or a significant ingredient
in five of these case reports and 1,4-DCB was similarly involved in
eleven. Of these 16 cases, 10 were occupationally related.
There are no data on the quantitative efficiency of absorption
of DCBs via the respiratory route. However, Pagnotto and Walkley
C-12
-------
(1966) have measured urinary excretion of the principal DCB metabo-
lite in occupationally exposed (by inhalation) persons and re-
ported that excretion occurred "soon after exposure...began and
peaked...at the end of the working shift," indicating that respir-
atory absorption during inhalation exposure is rapid.
Dichlorobenzenes, as well as other chlorinated benzene deriva-
tives, may be absorbed through the gastrointestinal (GI) tract.
Lower halobenzenes are more readily and rapidly absorbed by this
route than the higher homologues (Ware and West, 1977; Rimington
and Ziegler, 1963). Three of the 22 cases of human DCB poisoning
mentioned above resulted from accidentally or deliberately ingest-
ing 1,4-DCB (Campbell and Davidson, 1970; Frank and Cohen, 1961;
Hallowell, 1959). These cases clearly indicate significant absorp-
tion by the GI-route. Data on quantitative absorption efficiency
of DCBs are sparse. Azouz, et al. (1955) detected no 1,4-DCB in
feces of rabbits dosed intragastrically with the compound in oil.
This suggests virtually complete absorption at least under those
conditions. Animal experiments indicate that GI absorption of DCBs
occurs and is fairly rapid, since metabolites, various effects, and
excretion have been observed within one day of oral dosing
(Rimington and Ziegler, 1963; Azouz, et al. 1953; Poland, et al.
1971). 1,2-DCB and other components of Rhine River water contam-
ination fed to rats at less than 0.4 to 2 mg/kg/day were absorbed
and accumulated in various tissues indicating significant absorp-
tion by the GI tract even at low levels of ingestion (Jacobs, et al.
1974a,b).
C-13
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Evidence in the literature indicates the DCBs are also absorbed
via the skin (Ware and West, 1977). Three of the 22 clinical case
reports mentioned previously involved dermal exposure and conse-
quent toxicosis (Girard, et al. 1969; Downing, 1939; Nalbandian
and Pierce, 1965). Riedel (1941) reported absorption of 1,2-DCB
through the skin of rats in lethal amounts'after five dermal appli-
cations under severe test conditions (painting twice daily directly
on a 10 cm2 area of abdominal skin) (Ware and West, 1977). There
were no available data on the quantitative efficiency of absorption
by the dermal route in man or animals.
Distribution
As noted previously, the relative insolubility in water and
high lipid solubility of DCBs render them able to cross barrier
membranes (Ware and West, 1977). This indicates that they (DCBs)
would be widely distributed to various tissues. Clinical and ex-
perimental data also indicate wide distribution to various tissues.
Lipid soluble halobenzenes tend to accumulate in the body, may
reach toxic levels, and may recirculate for long periods (Ware and
West, 1977).
Cases of human poisonings and animal testing demonstrating
changes in blood, blood chemistry, neuromuscular function, liver
and kidney structure and function, and bone marrow elements indi-
cate distribution of absorbed DCBs in and by blood to at least the
brain, heart, liver, kidney, and bone marrow in multiple mammalian
species (references noted: Hollingsworth, et al. 1956, 1958; Ito,
et al. 1973; Totaro and Licari, 1964; Totaro, 1961; Salamone and
Coppola, 1960; Coppola, et al. 1963; Rimington and Ziegler, 1963;
C-14
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Azouz, et al. 1953, 1955; Poland, et al. 1971; Girard, et al. 1969;
Sumers, et al. 1952; Cotter, 1953; Campbell and Davidson, 1970;
Frank and Cohen, 1961; Petit and Champeix, 1948).
In a study by Jacobs, et al. (1974a) 1,2-DCB and other chemi-
cals known to be contaminants in Rhine River water were fed daily
in a mixture to rats at 2 mg/kg (each .component). Tissue accumula-
tion was greater in fat than in the liver, kidney, heart, and
blood. The same investigators (Jacobs, et al. 1974b) fed such a
contaminant mixture to rats at two lower dose levels (0.4 and 0.8
mg/day) for 4 to 12 weeks. A dose-related accumulation of all com-
pounds (including 1,2-DCB) in abdominal and renal adipose tissue
occurred, and there was no evidence of saturation. The studies of
Morita and Ohi (1975) have shown 1,4-DCB in adipose tissue (mean
about 1 mg/kg) and blood (mean about 0. 01 mg/1) of humans exposed to am-
bient pollution levels in the Tokyo area.
Injection of DCB intramuscularly into hens at about 50 mg/kg
resulted in recovery of 0.4 to 0.6 percent of the dose from yolks of
eggs. The egg white contained negligible amounts. An increase in
the chlorine content of chlorinated benzenes increased the period
from injection to accumulation of residue in the yolk (Kazama, et
al. 1972). DCB, as a metabolic residue of DDT injected intraperi-
toneally into mice during pregnancy, was found in fetal and mater-
nal blood, brain, liver, and fat (Schmidt and Dedek, 1972).
Metabolism
Metabolism of the 1,2-DCBs was studied by Azouz, et al. (1955)
in chinchilla rabbits. Single doses of 500 mg compound/kg body
weight were given by stomach tube, the 1,2-DCB suspended in water
C-15
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and the 1,4-DCB dissolved in olive oil at 25 percent (w/v). Their
results showed 1,2-DCB to be mainly metabolized by oxidation to
3,4-dichlorophenol and excreted (primarily in urine) as conjugates
of glucuronic and sulphuric acids. Peak excretion of these oc-
curred on the first day after dosing. Minor metabolites also
formed and excreted as conjugates included- 2,3-dichlorophenol (peak
excretion on second day), 4,5-dichlorocatechol, 3,4-dichloro-
catechol, and 3,4-dichlorophenylmercapturic acid. Metabolism and
urinary excretion of 1,2-DCB was considered relatively slow, being
essentially complete five to six days after dosing. During this
period an average of 76 percent of the dose was excreted as "total
conjugates," of which identified components were 48 percent glucu-
ronide, 21 percent ethereal sulfate, and 5 percent mercapturic
acid. 1,4-DCB was metabolized mainly by oxidation to 2,5-dichloro-
phenol and excreted as only glucuronides and ethereal sulfates.
Peak excretions occurred on the second day after dosing, possibly
reflecting a slower absorption (however, no 1,4-DCB was detected in
the feces during the 6-day test period, indicating that absorp-
tion was essentially complete). 2,5-Dichloroquinol was also formed
as minor metabolite (about 6 percent of the dose), but in con-
trast to the case with 1,2-DCB, no mercapturic acid or dichloro-
catechol was formed from 1,4-DCB. Total conjugates (64 percent of
dose) during the 6-day period after dosing were comprised essen-
tially of glucuronide (36 percent) and ethereal sulfate (27 per-
cent), but excretion of metabolites was not considered complete af-
ter six days. Pagnotto and Walkley (1966) indicated that 2,5-di-
chlorophenol was also the principal metabolite of 1,4-DCB in
C-16
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humans, and that levels excreted in urine were useful in assessing
occupational exposure by inhalation.
Parke and Williams (1955) studied the metabolism and excretion
of 1,3-DCB using the rabbit and methods as described by Azouz, et
al. (1955), discussed previously. An average of 54 percent of the
administered dose of 1,3-DCB was measured as urinary conjugates of
the metabolites, primarily glucuronides (36 percent) and ethereal
sulfates (7 percent) which reach peak excretion on the first day
after dosing. The major metabolite of 1,3-DCB was shown to be 2,3-
dichlorophenol (2,3-DCP), accounting for at least 20 percent of the
dose. 3,5-Dichlorophenol, 2,4-dichlorophenylmercapturic acid, and
3,5-dichlorocatechol were additional, minor metabolites. Excre-
tion of 1,3-DCB was considered to be relatively slow, as with 1,2-
and 1,4-DCB. Metabolites in measurable quantities were not excret-
ed after five days from dosing, at which time about half of the dose
was accounted for as total conjugates.
The detailed analytic and metabolic chemistries involved in
the above studies are omitted here but are discussed in the origi-
nal reports (Azouz, et al. 1955; Parke and Williams, 1955).
Daily dosing of rats with DCBs at doses from 450 to 1,000
mg/kg has induced delta-aminolevulinic acid (ALA) synthetase ac-
tivity in liver and has produced hepatic porphyria characterized by
increased levels of porphyrins and porphyrin precursors in liver
and urine (Rimington and Ziegler, 1963; Poland, et al. 1971).
Dosing with 1,3-DCB at 1,000 mg/kg was prophyrogenic, but at 800
mg/kg a biphasic influence on hepatic metabolic activity was noted.
There was an initial stimulation of ALA synthetase activity and
C-17
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increased urinary excretion of coproporphyrin, peaking at one and
three days, respectively, and then declining. There was also a
stimulation of drug metabolism by the hepatic microsomal system
that peaked at five days. The investigators (Poland, et al. 1971)
emphasize that in some cases porphyria could be caused by the
1,3-DCB or its metabolites (primarily 2,4-dichlorophenol in rab-
bits). However, since 2,3-DCP was not found in significant quan-
tity in the experimental rats, it was concluded that the 1,3-DCB
was responsible for the porphyria shown in this experiment. The
authors interpreted their decline in porphyria as being a result of
1,3-DCB stimulating its own metabolism. A similar biphasic pattern
of coproporphyrin excretion was observed in rats dosed with 2,4-DCP
(the major metabolite of 1,3-DCB) and 1,4-DCB at 900 mg/kg/day.
Carlson and Tardiff (1976) also reported on the induction of hepa-
tic microsomal xenobiotic metabolism systems by DCB and other chlo-
rinated benzenes. Chronic dosing of 1,4-DCB at low levels (10 to
40 mg/kg/day) in male rats increased detoxication of EPN (o-ethyl
o-p-nitrophenyl phenylphosphonothiolate) benzpyrene hydroxylation
and azoreductase activity (Ware and West, 1977). Effects persisted
for at least 30 days after termination of exposure. The ability of
halogenated aromatic compounds such as DCBs to induce enzyme sys-
tems associated with the metabolism of foreign compounds may in-
fluence the metabolism and effects of endogenous steroids, drugs,
and other environmental contaminants (Ware and West, 1977).
Excretion
As noted above, excretion of the metabolic products of the
DCBs, primarily through the urine, is rather slow. Five to six
C-18
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days were required to metabolize and eliminate the metabolites of a
single intragastric dose (500 mg/kg) of 1,2-DCB or 1,3-DCB. Elim-
ination of the metabolites of 1,4-DCB (similar dose) were not com-
plete at six days after dosing (Parke and Williams, 1955), although
this may have been influenced by a slower or delayed absorption.
The excretion of DCS metabolites in rabbits dosed (single, intra-
gastic) at 500 mg/kg body weight, as reported by Parke and Williams
(1955) is summarized in Table 4. Peak excretion for some of the
metabolites occurred on the first day after dosing and for others,
later. Measurements by Pagnotto and Walkley (1966) of urinary di-
chlorophenol in workers exposed to 1,4-DCB indicated that excretion
of metabolites began within the workshift "soon after exposure
began," peaked at the end of the working shift, then decreased rap-
idly at first and then more slowly, continuing for several days.
Ware and West (1977) stated that the portion of halogenated
benzenes that escape biotransformation "may be excreted in part un-
changed in the urine, feces, or expired air." No information was
available to quantify these phenomena. These authors also indi-
cated that halobenzenes which are not extensively metabolized: (1)
may be hazardous if they form an arene oxide intermediate; (2) not
only tend to accumulate in the body reaching toxic levels but may
recirculate for long periods; and (3) may cause repeated tissue
insults and increase the likelihood of cellular damage from toxic
intermediates (e.g., arene oxides, phenols). Azouz, et al. (1955)
and Parke and Williams (1955) did not report any excretion by way
of the feces, nor did they report the fate of that portion of admin-
istered DCBs unaccounted for in urinary metabolites. Available data
C-19
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TABLE 4
Excretion of DCB Metabolites by Rabbits*
Metabolite
Glucuronide
Ethereal sulfate
Mercapturic acid
Total conjugates
Monophenols
Catechols
Q u i no 1 s
Period of excretion, days
1,2-DCB
48
21
5
74
39
4
0
6+
1,3 -DCB
36
7
11
51
25
3
0
5+
1,4-DCB
36
27
0
63
35
0
6
6++
Data expressed as percent of dose fed (500 mg/kg).
Excretion apparently complete.
Excretion not complete.
*Source: Parke and Williams, 1955.
C-20
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also did not provide information on the efficiency of detoxication
and elimination of the DCBs in humans at lower, more "realistic"
environmental levels.
As noted previously, nonmetabolized DCBs accumulate in tis-
sues. Bioconcentration factors in fish (bluegill sunfish) were re-
ported as 89, 66, and 60 for 1,2-, 1,.3-, and 1,4-DCB, respectively
(U.S. EPA, 1978c). Morita and Ohi (1975) reported levels averaging
about 2 mg/kg in adipose tissues of residents of the Tokyo area
compared with blood levels averaging only 0.0095 mg/1. When sev-
eral Rhine River contaminants including 1,2-DCB were fed to rats,
tissue accumulation was greater in fat tissue than in liver, kid-
ney, heart, and blood, and there was no evidence of saturation (at
dose levels of less than 1 mg/day) (Jacobs, et al. 1974a,b). Resi-
due of DCB in eggs of injected (intramuscularly) hens was measured
at much higher levels in the yolk sac than in white (about 0.5 per-
cent of dose vs. virtually none) (Lunde and Ofstad, 1976). Eggs of
hens exposed to 1,4-DCB in air at 20 or 38 mg/m3 developed an un-
pleasant taste within three days, and two metabolites were detected
in the yolks (Langner and Hilliger, 1971). Undesirable odor and
taste of pork meat from swine exposed to vapor of 1,4-DCB used for
odor control in the stalls were reported by Schmidt (1971).
EFFECTS
Acute, Subacute, and Chronic Toxicity
Prior to the 1940's very little had been reported concerning
any harmful properties of DCBs, which had become industrially im-
portant in recent years. DCBs were generally regarded as having
very low or no toxicity for man (Downing, 1939; Perrin, 1941).
C-21
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However, clinical data reported beginning in 1939 have substantiat-
ed the conclusion that DCBs should no longer be considered harmless
(Perrin, 1941).
Most reported cases (16 of 22) of human poisoning by DCBs
since 1939 have resulted from long term exposure primarily by in-
halation of vapors/ but some have also resulted from exposure by
ingestion (3 of 22) and skin absorption (3 of 22). Toxic exposures
have been occupational in nature in most cases, but have also in-
volved the use or misuse of DCS products in the home. Most case
reports (15 of 22) have involved exposure to agents containing pri-
marily 1,4-DCB, and the remainder involved primarily 1,2-DCB. In
some of these, DCB mixtures including 1,3-DCB were involved. Tar-
get systems or tissues have involved one or more of the following:
liver, blood (or reticuloendothelial system, including bone marrow
and/or immune components), central nervous system (CNS), respira-
tory tract, and integument (references noted: Dupont, 1938; Girard,
et al 1969; Gadrat, et al. 1962; Downing, 1939; Sinners, et al.
1952; Cotter, 1953; Petit and Champeix, 1948; Perrin, 1941; Weller
and Crellin, 1953; Hallowell, 1959; Campbell and Davidson, 1970;
Frank and Cohen, 1961; Nalbandian and Pierce, 1965; Ware and West,
1977). Clinical findings in these reports, which are summarized in
Table 5, imply broad toxicologic propensities for the DCBs in terms
of biological systems and tissues affected.
Riedel (1941) reported that a burning sensation was produced
when 1,2-DCB was applied for 15 minutes to the skin of human sub-
jects. The response intensified with continued exposure up to one
hour and abated when the liquid was removed. However, hyperemia
C-22
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TABLE 5
Human Poisoning by Dichlorobenzene
Compound
Subject and Exposure
Effects
Reference
O
I
NJ
1,2-DCB (vapor)
1,2-DCB solvent
mixtures:
80% 1,2-DCB;
15% 1,4-DCB;
2% 1,3-DCB
1,2-DCB solvent
mixture:
95% 1,2-DCB;
5% 1,4-DCB
1,2-DCB and
other chloro-
benzene
1,2-DCB included
in mixture
1,2-DCB (37% in
commerc. soln.)
Sewage workers; occupational; inhalation;
effluent from dry cleaning establishment.
Male, 40 yrs; occupational; use of solvent
to clean equipment; chronic daily exposure
probably inhalation of vapor, and perhaps
dermal absorption from clothing.
Female, 18 yrs; occupational; chronic daily
inhalation exposure to vapors as pressing-
ironing worker.
Male, 60 yrs; occupational; filling barrels
with 1,2-DCB and other chlor. benzenes
(mono-, tri-); chronic inhalation of vapors
(last 3 yrs.), perhaps also skin contact.
Male, 47 yrs; occupational; handling window
sashes dipped in solution; chronic skin
contact (also inhalation).
Female, 15 yrs; non-occupational; chronic
repeated dermal contact from compulsive
use of cleaning solution on clothing (in
place).
1,2-DCB 80% (in Female, 55 yrs; non-occupational; chronic
solvent mixtue repeated inhal. exposure to vapors from
with 1,4-DCB, 15% use of solution to clean clothes; 1 to 2
and 1,3-DCB, 2%) 1/yr.
Eye and upper respiratory
tract irritation, vomiting.
'Weakness, fatigue; peripheral
lymphadenopathy; chronic lym-
phoid leukemia.
Severe acute hemolytic anemia;
leukocytosis; polynucleosis;
fatigue, nausea, headache;
icterus; bone marrow hyper-
plasia; possible inherent pre-
disposing factor.
Anemia, requiring transfer to
other work.
Contact eczematoid dermatitis
(itch, eruption) on hands, arms,
face, erythema, edema, bullae 'in
response to skin test.
Acute myeloblastic leukemia
progressing to 100% leukoblas-
tosis, hemorrhage, death.
Acute myeloblastic leukemia.
Dupont, 1938
Girard, et al. 1969
Gadrat, et al. 1962
Girard, et al. 1969
Downing, 1939
Girard, et al. 1969
Girard, et al. 1969
-------
TABLE 5 (continued)
Compound
Subject and Exposure
Effects
Reference
n
I
NJ
1,4-DCB
pr imar ily
1,4-DCB
pr imar ily
1,4-DCB
1,4-DCB
pr imar ily
1,4-DCB
1,4-DCB
1,4-DCB
Female, 30 yrs; occupational; for two years
selling mothballs and insecticide products
containing 1,4-DCB chiefly; chronic inhala-
tion, perhaps some dermal component.
Female, 34 yrs; occupational; demonstrating
1,4-DCB products in booth in department
store; odor strong in area;chronic inhala-
sure to vapors.
Male, 52 yrs; occupational; used 2 years in
fur warehouse (formerly used naphthalene);
chronic inhalation exposure to high vapor
levels.
Female, 19 yrs; occupational; crushing,
pouring, seiving, filling containers; poor
ventilation; chronic inhalation of vapors.
Female, occupational; casting 1,4-DCB in
molds; chronic inhalation (skin contri-
bution unknown, if any).
Male, 20 yrs. and workmates; occupational;
1,4-DCB manufacturing activities; 1 to 7
months exposure; inhalation (presumably).
Male, 62 yrs; non-occupational; used "moth
killer" product in bathroom at home,
chronic inhalation of vapors, and wearing
of impregnated clothing (possible skin ex-
posure) .
Weakness, nausea, splenomegaly;
"severe hepatocellular derange-
ment and ensuing portal hyper-
tension" with esophageal varices.
Malaise, then acute nausea, vom-
iting, headache, Icterus, hepa-
tomegaly, splenomegaly, esopha-
geal vac ices and hemorrhoids;
subacute yellow atrophy and cir-
rhosis of liver.
Weakness, nausea, hematemesis,
jaundice, emaciation, petech,
hemorrhages; hepatomegaly,
splenomegaly, hemorrhoids; pro-
teinuria, biliribinuria; hema-
turia; anemia, leukopenia; sub-
acute yellow atrophy of liver.
Marked asthenia, dizziness,
weight loss; anemia and re-
actional leucocytosis.
Severe anemia.
Weight loss, exhaustion, de-
creased appetite; methemo-
globinemia and other blood
pathologies.
Asthenia, dizziness; anemia,
hypogranulocytosis. Similar
to cases of intoxication by
benzene.
Sumers, et al. 1952
Cotter, 1953
Cotter, 1953
Petit and Champeix,
1948
Perrin, 1941
Ware and West,
1977
Perrin, 1941
-------
TABLE 5 (continued)
Compound
1,4-DCB
1,4-DCB
1,4-DCB
n
NJ
cn
1,4-DCB
1,4-DCB
Subject and Exposure
Female, 36 yrs; non-occupational; use of
commericial moth killer in home (presum-
ably inhalation of vapors).
Male, 60 yrs; non-occupational; 3 to 4
month exposure to "moth gas vapor" in
home.
Female, wife of above, non-occupational;
prolonged severe exposure to "moth gas
vapor."
Female, 53 yrs; non-occupational; used moth
eradicator product heavily in home for 12
to 15 years, odor always apparent; chronic
inhalation of vapor.
Male, 3 yrs; non-occupational; played with
canister of de-mothing crystals, spreading
on floor, handling; ingestion, likely
acute.
Effects
Reference
Acute illness with intense
headache, profuse rhinitis,
periorbital swelling.
Headache, weight loss, diarrhea
numbness, clumsiness, icterus,
enlarged liver, anemia, neutro-
penia; developed ascites, died;
acute yellow atrophy of liver.
Gradual loss of strength and
weight, then abdominal swelling
and jaundice before acute ill-
ness; elevated temperature and
pulse, dilated vessels, swollen
liver, toxic granulocytosis;
died 1 year later; acute yellow
atrophy (liver), Laennec's cir-
rhosis, splenomegaly.
Chronic progressive cough and dys-
pnea with mucoid sputum, wheezing,
fatigue, diminished breath sounds
and rales; abnormal lung field on
x-ray; fibrotic, rubbery lung with
architecture changes on histology
of biopsy; diagnosis: pulmonary
granulomatosis.
Listlessness, jaundice, oliguria,
methemoglobinuria and other urine
abnormalities, anemia, hypother-
mia; diagnosis: acute hemolytic
anemia.
Cotter, 1953
Cotter, 1953
Cotter, 1953
Weller and Crellin,
1953
Hallowell, 1959
-------
TABLE 5 (Continued)
Compound
Subject and Exposure
Effects
Reference
1,4-DCB
1,4-DCB
Female, 21 yrs; non-occupational; ingestion
during pregnancy of toilet air freshner
blocks (pica) at rate of 1 to 2 each week.
Female, 19 yrs; non-occupational; ingestion
(pica), 4 to 5 moth pellets daily for 2h
years.
n
1,4-DCB
Male, 69 yrs; non-occupational; dermal ex-
posure, presumably interrupted; episode pre-
cipitated by use of chair treated with 1,4-
DCB.
Fatigue, anorexia, dizziness,
edema of ankles; hypochromic
microcytic anemia; bone marrow
normoblastic hyperplasia; diag-
nosis: toxic hemolytic anemia.
Recovery complete.
Increased skin pigmentation in
areas 3 to 7 cm. diameter on
limbs; mental sluggishness, tre-
mor, unsteady gait upon with-
drawl, along with decrease in
pigmentation; 1 diagnosis: fixed
drug eruption, conversion hyste-
ria.
Dyspnea followed by stiff neck;
"tightness" in chest, "gas pains"
in abdomen; symmetrical petechia
and purpura on extremitities, swell-
ing discomfort; stool occult "blood
positive, blood cells in urine, and
incr. BUN; basophil degranul. test
positive for 1,4-DCB; diagnosis:
allergic (anaphylactoid) purpura
acute glomerulonephritis.
Campbell and
Davidson, 1970
Frank and Cohen,
1961
Nalbandian and
Pierce, 1965
-------
and blisters developed afterward at the site of application and
were followed by a brown pigmentation that persisted at least three
months (Hollingsworth, et al. 1958). Analyses of workroom air
associated with 1,2-DCB manufacture and handling operations at the
Dow Chemical Company were reported by Hollingsworth, et al. (1958)
as ranging from 6 to 264 mg/m , with a' 40-sample average of 90
mg/m . Medical examinations of workers from time to time, includ-
ing hemograms and urinalyses, revealed no evidence of organic in-
jury or adverse hematologic effects attributable to 1,2-DCB expo-
sure. Although Patty (1963) and Hollingsworth, et al. (1958) stat-
ed that eye and nose irritation are not noticeable at the concen-
tration in air detectable by the average person (300 mg/m ), the
American Conference of Governmental Industrial Hygienists (ACGIH,
1977) mentions- that a ceiling limit of 300 mg/m should prevent
serious but not all eye and nose irritation. Elkins (1959) report-
ed concentrations approaching 600 mg/m to be irritating but with-
out other effects (ACGIH, 1977).
Hollingsworth, et al. (1956) have reported on surveys of plant
conditions associated with the manufacture of 1,4-DCB. Workroom
air contamination levels were previously summarized in the section
on Exposure. Workers were monitored also under the various condi-
tions of air contamination in the surveys. These data indicated
that concentrations of 1,4-DCB greater than 960 mg/m were ir-
respirable (intolerable) for unacclimated persons, i.e., painful
irritation of the eyes and nose occurred at levels of 480 to 960
mg/m3, odor was strong at 180 to 360 mg/m , and a faint odor was
noticeable at 90 to 180 mg/m . Workers complained under conditions
C-27
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yielding air sample concentrations ranging from 800 to 1,020 mg/ra ,
but conditions yielding samples with concentrations of 90 to 510
mg/m did not elicit complaints. In the data of periodic medical
examinations on the workers no evidence was found of organic injury
or adverse changes in hematology or eye lenses attributable to
1,4-DCB exposure (Hollingsworth, et al. 1956). Solid particles of
1,4-DCB and heavy vapor or fumes (such as when heated and volatil-
ized in poorly ventilated spaces) are painful to the eyes and nose.
The painful effect of vapor is evident to most people at 300 to 480
mg/m and is severe at 960 mg/m or more. Tolerance or acclimati-
zation may occur with repeated exposure, so sensory warning proper-
ties may be less protective of more generalized toxicity in these
persons (Hollingsworth, et al. 1956).
Solid 1,4-DCB is not regarded as significantly irritating to
intact skin unless held in close contact for some time, when it may
produce a burning sensation. Warm fumes or strong solutions may be
irritating to skin on prolonged and repeated contact, but 1,4-DCB
is said to produce no significant hazard from skin irritation or
absorption except under extreme conditions (Hollingsworth, et al.
1956).
Although Berliner (1939) reported two cases of human cataracts
that he believed to be due to chronic exposure to a 1,4-DCB-con-
taining moth or deodorant product, Hollingsworth, et al. (1956) has
interpreted considerable subsequent human data as indicating that
1,4-DCB does not produce human cataracts.
Varshavskaya (1967a) reported that odor and taste thresholds
for 1,2-DCB in water were determined to be 0.002 and 0.0001 mg/1,
C-28
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and for 1,4-DCB, 0.002 and 0.006 mg/1, respectively. The olfactory
and gustatory thresholds for DCBs were also separately reported as
0.001 to 0.002 mg/1 (Varshavskaya, 1967b). These organoleptic
properties have been considered in establishing Russian tolerance
levels of 1,2- and 1,4-DCB in drinking water (Stofen, 1973).
The 1,2- and 1,4-DCBs are extensively metabolized. One theory
for the mechanism of toxicity of DCBs (i.e., cellular damage) is
that reactive metabolites such as arene oxides or epoxides are
formed in the process of metabolic transformation of the parent
foreign compound through the action of hepatic microsomal enzyme
systems involving cytochrome P-450. The enzymes concerned with
foreign compounds (including drugs), often referred to as mixed
function oxidases (MFO), are located in the endoplasmic reticulum
(ER) of liver cells and require nicotinamide adenine dinucleotide
phosphate (NADPI^), molecular oxygen, and P-450 (a cytochrome).
Biotransformation of drugs and other xenobiotic chemicals occurs in
two phases: (1) oxidation, reduction, and hydrolysis reactions,
and (2) syntheses or conjugations. Biotransformation enzymes and
reactions vary among species and tissues and are influenced by
steroids, various intermediate and metabolic byproducts and xeno-
biotics. P-450 content and the ability to form toxic intermediate
metabolites also vary with species. Other factors affecting bio-
transformation and xenobiotic toxicity are the quantity of enzymes
catalyzing conjugation with glutathione, an important detoxifica-
tion mechanism (glutathione depletion by such a process is associ-
ated with toxicity and cellular damage), subsequent formation of
mercapturic acids, and the concentration of the enzyme epoxide
hydrase (Ware and West, 1977).
C-29
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Hepatic damage in rats is enhanced when biotransformation of
bromobenzenes (a prototype hepatotoxic chemical relative of DCB) is
stimulated by pretreatment with phenobarbital (an MFO-inducer or
stimulant). Conversely, blocking metabolism of the bromobenzene by
use of SKF-525A or piperonyl butoxide (metabolic inhibitors) les-
sens the toxicity. Studies of halobenzertes have shown that tox-
icity such as reflected by hepatic necrosis is a result of their
conversion to reactive toxic intermediate metabolites (Ware and
West, 1977). In the case of bromobenzene, hepatic necrosis results
from the reaction of the toxic intermediate, arene oxide, with cel-
lular macromolecules. Severity of hepatic necrosis correlates well
with the extent of covalent binding and with the depletion of
glutathione from conjugation with toxic metabolites (Ware and West,
1977).
Bromobenzene and 1,2-DCB caused hepatic necrosis in rats, sig-
nificant covalent binding, mercapturic acid excretion, and gluta-
thione depletion (Ware and West, 1977).
In 1937, Cameron, et al. report early toxicity tests of
1,2-DCB. In the work a mixture containing only 48.8 percent
1,2-DCB was used, so conclusions as to specific toxicity of the
pure compound may be questionable. Later, Hollingsworth, et al.
(1958) exhaustively investigated the toxicity of 1,2-DCB using
inhalation, gastric intubation, and ocular exposure techniques in
several species of experimental animals over a range of lower dose
levels. In the inhalation studies, groups of 20 rats, eight guinea
pigs, four rabbits, and two monkeys were exposed to vapor seven
hours per day, five days per week for six to seven months at an
C-30
-------
average concentration of 560 mg/m . On the basis of the following
criteria, none of the following effects were noted in any of the
species: gross appearance, behavior, growth, organ weights, hema-
tology (rabbits, monkeys), urinalysis (qualitative, for blood,
sugar, albumin, sediment), blood urea nitrogen, gross and micro-
scopic examination of tissues and mor.tality. A similar test using
20 rats, 16 guinea pigs, and 10 mice exposed to 290 mg/m in the
same pattern for six and one-half months was also negative.
Hollingsworth, et al. (1958) conducted single and repeated-
oral-dose studies of 1,2-DCB. Intubation of 10 guinea pigs with
1,2-DCB (50 percent in olive oil) in single oral doses of 800 mg/kg
resulted in loss of body weight, but was survived by all subjects,
whereas 2,000 mg/kg doses were fatal to all subjects. In a test of
repeated doses, of 1,2-DCB in olive oil emulsified with acacia,
groups of white rats were dosed by stomach tube five days a week for
a total of 138 days in 192 days at dose levels of 18.8, 188, and 386
mg/kg. Positive toxicologic findings in the high-dose subjects
included: increased liver and kidney weights, decreased spleen
weight, and slight to moderate cloudy swelling on microscopic exam-
ination of the liver. In the intermediate-dose group, liver and
kidney weights were slightly increased. No adverse effects were
noted at the low-dose level. Two drops of undiluted 1,2-DCB in the
rabbits' eyes caused pain and conjuctival irritation which cleared
completely within one week. Prompt washing with water reduced pain
and irritation.
Varshavskaya (1967a) reported on the hygienic evaluation
of dichlorobenzenes in reservoir waters. Median lethal dose
C-31
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Q) values for DCBs given to four animal species in single doses
in oil by stomach tube are as follows (in mg/kg body weight):
Species 1,2-DCB 1,4-DCB
White mice 2,000 3,220
White rats 2,138 2,512
Rabbits 1,875 2,812
Guinea pigs 3,375 7,593
The acute poisoning manifestations were similar between compounds
and among species which included: hyperemia of mucous membranes;
increased lacrimation and salivation; excitation followed by sleep-
iness, adynamia, ataxia, paraparesis, paraplegia, and dyspnea
developing into Kuss-Maul breathing; death from central respiratory
paralysis, usually within three days; autopsy findings of a ple-
thora of parenchymatous organs; enlarged liver with necrotic areas;
submucosal hemorrhages in stomach; brain edema; histological find-
ings of vascular and necrotic changes in the liver, stomach mucosa,
kidneys, and brain edema. In a later experiment, rats were given
DCBs at a daily dose level of one-fifth of the LDgo dose. 1,2-DCB,
in contrast to 1,4-DCB, was concluded to be a cumulative toxin
since half of the animals died when they had received a total dose
equal to the single LD dose. 1,4-DCB was, again, less toxic than
1,2-DCB.
In a chronic toxicity test, rats were given 1,2-DCB at daily
doses of 0.001, 0.01, and 0.1 mg/kg. Toxicity was evaluated on the
basis of multiple criteria, including: weight, serum enzymes and
protein fractions, prothrombin index, leukocyte phagocytosis,
sulfhydryl groups in blood, urinary 17-ketosteroids, conditioned
C-32
-------
reflex activity. Preliminary results reported as of five months
into the experiment indicated that 1,2-DCB was toxic and exerted a
predominant effect on the hematopoietic system. Effects included:
reduced hemoglobin, erythrocytes, and thrombocytes; increased
leukocytes and reticulocytes (an apparent shift of the blood formu-
la to the left); increased prothrombin time and activity of alka-
line phosphatase and transaminases; altered liver and central ner-
vous system function; altered conditioned reflex activity
(Varshavskaya, 1967a).
According to Varshavskaya (1967b), at the completion of the
chronic testing, results were interpreted as follows: at the 0.1
mg/kg dose level, 1,2-DCB disturbed higher cortical function in the
central nervous system; at the 0.01 mg/kg dose level was "liminal,"
and at the low .dose level (O.OOlmg/kg) was "subliminal." The high-
est dose level (0.1 mg/kg) caused inhibition of erythropoiesis
(decreased hemoglobin and erythrocytes, anisocytosis, poikilo-
cytosis, increased reticulocytes), thrombocytes, neutropenia, and
inhibited bone marrow mitotic activity. Similar, but less pro-
nounced effects were noted at the intermediate level, and the low
dose level showed no such effects. At the high dose level, there
was a marked increase in urinary 17-ketosteroids with an increase
in adrenal weight coefficient and a decrease in adrenal ascorbic
acid content. The high level resulted in increased alkaline phos-
phatase and serum transaminase activity, and decreased glutathione
(SH groups) in the blood. Reduced alkaline phosphatase and in-
creased acid phosphatase, and decreased di- and triphosphopyridine-
nucleotides occurred in the liver and kidneys; decreased succinate
C-33
-------
dehyrogenase, glucose-6-phosphatase, and ^-glycerophosphate also
occured in liver and kidney. The intermediate exposure had similar
effects on blood enzymes and less effect on other enzyme activi-
ties. Enzyme-system effects were not noted in the low-dose sub-
jects. Although the 0.1 and 0.01 mg/kg regimens caused decreased
alkaline phosphatase, there was no microscopic or histologic evi-
dence of carcinogenic activity. The maximal innocuous concentra-
tion of 1,2-DCB in water by toxicological criteria was considered
to be 0.02 mg/1 (extrapolated from 0.001 mg/kg/day), and 0.2 mg/1
by water sanitation criteria; but since the liminal concentration
by organoleptic criteria was 0.002 mg/1, the recommended maximum
permissible water concentration was set at 0.002 mg/1. Although
toxicity of 1,4-DCB was regarded as less than 1,2-DCB, its organo-
leptic and sanitary properties were similar to those of 1,2-DCB, so
its recommended maximum permissible concentration was set at 0.002
mg/1 (as for 1,2-DCB) on the organoleptic basis (Varshavskaya,
1967b).
The toxicological observations of Varshavskaya (1967a,b) are
in qualitative agreement with the clinical toxicity of DCBs dis-
cussed earlier (e.g., anemia and other blood changes, liver damage,
central nervous system depression), and with some aspects of other
reported animal toxicology, but indicate that adverse effects occur
at considerably lower exposure levels than indicated by the other
data presented.
The highest no-detected-adverse-effect level for 1,2-DCB re-
ported by Varshavskaya (1967b) was 0.001 mg/kg/day, whereas the
comparable subliminal level in the long-term rat study by
C-34
-------
Hollingsworth, et al. (1958) was 18.8 mg/kg/day. The reason for
this discrepancy of several thousandfold is not clear.
Acute and subacute toxicity of 1,4-DCB was investigated by
Ito, et al. (1973) using subcutaneous injections and inhalation
test methods. Male mice (22 to 26 g) were injected subcutaneously
with 1,4-DCB in olive oil at doses ranging from 3,500 to 7,258
mg/kg and observed for one week. The calculated LD,-g dose for
1,4-DCB was reported as 5,145 mg/kg (4,760 to 5,530). Tremors
occurred within two to three hours and continued over three days.
Naphthalene was more potent (LD5Q = 969 mg/kg), but both were re-
garded as neurotoxins and death was attributed to respiratory
paralysis. Mice were exposed to atmospheres containing 1,4-DCB
vapor for one 8-hour period and for two weeks at eight hours per
day. The 8-hour exposure caused "inertia" (probably lassitude,
weakness, or listnessness) and an increased breathing rate. The
repeated subacute exposure resulted in liver damage and a 1,4-DCB
concentration in blood of 64.5 mg/1. Vapor concentrations were not
clearly identified in the translated report.
Hollingsworth, et al. (1956) reviewed some of the literature
concerning toxicity of 1,4-DCB. The report of Landsteiner and
Jacobs (1936) stating that the material did not sensitize guinea pig
skin should be interpreted with caution in view of the clinical
report of allergic purpura by Nalbandian and Pierce (1965).
Berliner's report in 1939 of lenticular cataracts in humans exposed
to vapors containing 1,4-DCB was not substantiated in subsequent
studies with better characterization of vapor or more controlled
experimental conditions (Hollingsworth, et al. 1956). Further,
C-35
-------
1,4-DCB does not produce mercapturic acid and interfere with lens
metabolism (by virtue of inhibition and/or depletion of gluta-
thione, cyteine, and protein), as does napthalene, which is catar-
actogenic.
Several species of laboratory animals were exposed to 1,4-DCB
vapor at each of five concentrations for seven hours per day (eight
for the highest dose group), five days per week (Hollingsworth, et
al. 1956). Effects in animals (rats, guinea pigs, rabbits) exposed
to 4,800 mg/m for up to 69 exposures included: some deaths (up to
25 percent), marked tremors, weakness, collapse, eye irritation,
and reversible eyeground changes in rabbits, but no lens changes,
weight loss, liver degeneration, and necrosis, cloudy swelling of
renal tubular epithelium (rats), lung congestion, and emphysema
(rabbits). Effects in rats and guinea pigs exposed at 2,050 mg/m
for six months included: growth depression (guinea pigs); in-
creased liver and kidney weights (rats); liver pathology (cloudy
swelling, fatty degeneration, focal necrosis, cirrhosis). Effects
in animals exposed for as high as 139 exposures over 199 days at
1,040 mg/m were: increased liver, spleen, and kidney weights
(guinea pigs); pulmonary edema, congestion, hemorrhage; hepatic
centrolobular congestion, and granular degeneration (rats). Ef-
fects in animals exposed to 950 mg/m for 157 to 219 days included:
growth depression (guinea pigs); increased liver weights (rats,
guinea pigs) and increased kidney weights (rats); centrolobular
hepatocellular cloudy swelling or granular degeneration (rats). No
adverse effects were observed in rats, guinea pigs, rabbits, mice,
or a monkey exposed at 580 mg/m for six to seven months.
C-36
-------
Results from acute, single high-level exposures to 1,4-DCB in
oil by stomach tube are summarized as follows:
Species No Deaths 100% Killed
Rats 1,000 mg/kg 4,000 mg/kg
Guinea pigs 1,600 mg/kg 2,800 mg/kg
1,4-DCB was dissolved in oil and given to male adult rats at
10, 100, or 500 mg/kg/dose five days per week for four weeks.
Centrolobular hepatic necrosis and marked cloudy swelling of renal
tubular epithelium with cast formation occurred in animals given
500 mg/kg. No effects were observed at the lower dose levels
(Hollingsworth, et al. 1956).
White female rats were fed, 1,4-DCB in oil (emulsified with
acacia) by stomach tube five days a week for a total of 138 doses in
192 days (Hollingsworth, et al. 1956). At the high dosage level of
376 mg/kg/dose, increased liver and kidney weights, and hepatic
cirrhosis and focal necrosis were observed. No adverse effects
were noted at the low dose level (18.8 mg/kg). No cataracts were
observed in these exposures. The same investigators fed rabbits
with 1,4-DCB in oil by intubation for up to 92 doses in 219 days at
a level of 1,000 mg/kg/dose. Another group received a dose level
of 500 mg/kg/dose five days a week for a total of 263 doses in 367
days. Effects at the high dose level (1,000 mg/kg) included:
weight loss, tremors, weakness, hepatic cloudy swelling and focal
necrosis, and deaths. Similar changes, but no deaths, were noted
in rabbits on the lower dose regimen. No cataracts were observed.
Peking ducks fed 1,4-DCB in their diet at 0.5 percent (5,000 mg/kg
diet) for 35 days experienced retarded growth and 30 percent
C-37
-------
mortality in 28 days, but no cataracts were observed
(Hollingsworth, et al. 1956).
Coppola, et al. (1963) reported an effect on blood coagulation
(increase in thromboelastrogram reaction and clotting formation
times) in guinea pigs injected intramuscularly with daily doses of
124 mg 1,4-DCB in oil for three weeks. Totaro (1961) reported
weight loss and increased serum transaminases in guinea pigs in-
jected intramuscularly with 1,4-DCB (50 percent in oil) for 11 and
20 days at 125 mg per day. The increase in the serum glutamic-
oxalacetic transaminase (SCOT) level was greater than the increase
in serum glutamic-pyruvic transaminase (SGPT). The level of serum
aldolase was not altered. The effect of lipotropic factors on
transaminase and weight loss effects of injected 1,4-DCB were later
studied by Totaro and Licari (1964). Groups of guinea pigs were
injected intramuscularly daily for 20 days with 125 mg 1,4-DCB in
oil (group 2), with a mixture of betaine chloride 70 mg:choline
chloride 75 mg:vitamin B.^ 1 mg:vitamin B12 0.5 ug (group 3), or
with 125 mg 1,4-DCB together with the lipotropic mixture (group 4).
The control group received no treatment. Weight losses in groups 2
and 4 were 11.4 and 5.5 percent, respectively. SCOT and SGPT in-
creases in group 2 were 312 and 149 percent, respectively, and in
group 4 they were 187 and 124 percent, respectively. The authors
concluded that the lipotropic factors exerted a protective action
on the enzymatic modifications induced by 1,4-DCB. A similar pro-
tection action by lipotropic factors against the lowering of clot-
ting factors ascribed to liver damage by 1,4-DCB was demonstrated
C-38
-------
by Salamone and Coppola (1960) in an experiment similar to that
just described for the transaminases.
Hepatic prophyria was induced in rats fed 1,2- and 1,4-DCB in
liquid paraffin by stomach tube at levels increasing over several
days to 455 and 770 mg/kg, respectively (Rimington and Ziegler,
1963). The first sign of intoxication was a markedly increased
urinary excretion of urinary coproporphyrin III. Urinary excretion
of uroporphyrin, porphobilinogen (PEG), and delta-aminolevulinic
acid (ALA) increased. Liver content of protoporphyrin and uropor-
phyrin was also increased. Liver catalase was increased in sub-
jects with necrotic liver changes, which occurred with 1,2-DCB.
Clinical observations included: anorexia and weight loss, hemi-
paresis (one rat on 1,4-DCB), weakness, ataxia, clonic contrac-
tions, hepatomegaly, severe liver damage with intense necrosis and
fatty change (1,2-DCB) or degeneration and focal necrosis (1,4-DCB)
or degeneration and focal necrosis (1,4-DCB). No skin lesions were
observed after testing for light sensitivity. 1,4-DCB was more
porphyrogenic than 1,3-DCB. Of several chlorinated benzenes test-
ed, those with para-positioning of chlorine atoms were the more
porphyrogenic. The authors point out that mechanisms producing
porphyrin derangements are different from those leading to hepatic
necrosis. Of the two DCBs considered, 1,2-DCB was the more acutely
toxic and liver-damaging, apparently reflecting the metabolism and
formation of mercapturic acid, a process which depletes resources
of sulfur compounds (e.g., glutathione) (Rimington and Ziegler,
1963).
As noted previously, 1,3-DCB also induced hepatic porphyria in
rats fed the compound daily by intubation at 800 mg/kg or 900 to
C-39
-------
1,000 mg/kg (Poland, et al. 1971). The higher dose level produced
porhyria similar to that reported by Rimington and Ziegler (1963),
but the lower dose produced an initial porphyric response which
then abated, probably as a result of the accompanying stimulation
of liver microsomal drug metabolizing mechanisms.
Carlson and Tardiff (1976) studied' the ability of several
halogenated benzenes to induce enzyme systems associated with the
metabolism of foreign compounds. Rats were given daily oral doses
of from 10 to 40 mg/kg for 14 days. In this regimen, 1,4-DCB and
other benzene derivatives decreased hexabarbital sleeping time dur-
ing exposure and the effect persisted at least two weeks after
treatment. Cytochrome c_ reductase, cytochrome P-450 content,
glucuronyl transferase, benzpyrene hyroxylase, azoreductase, and
detoxication of-o-ethyl-o-nitrophenyl-phenylphosphonothiolate (EPN)
were increased (most of them at the 20 and 40 mg/kg dose levels)
(Ware and West, 1977).
Ariyoshi, et al. (1975) and others have reported the induction
of liver drug metabolizing enzyme systems in rats acutely fed
chlorinated benzenes at 250 mg/kg. The three DCB isomers were
highly metabolized, increased ALA synthetase, and were considered a
possible producer of epoxide intermediates (Ware and West, 1977).
Rats injected intraperitoneally with 1,2-DCB at 735 mg/kg (5
mmol/kg) showed an increase in bile duct pancreatic flow (Yang and
Peterson, 1977). Injection of 1,2-DCB and 1,4-DCB caused a reduc-
tion of protein concentration in bile duct pancreatic flow and in-
creased hepatic bile flow.
C-40
-------
Selected toxicity data for 1,2- and 1,4-DCB are summarized in
Tables 6, 7, 8, and 9.
Synergism and/or Antagonism
There would appear to be many possibilities for synergistic
and/or antagonistic actions among halogenated benzene compounds and
between them and other compounds or conditions (Ware and West,
1977). DCBs have been shown to induce hepatic xenobiotic drug-
metabolism systems and components (Ariyoshi, et al. 1975; Carlson
and Tardiff, 1976), and the effects of DCBs have been shown to be
modified by other chemical or biological factors (Salamone and
Coppola, 1960; Totaro and Licari, 1964; Gadrat, et al. 1962). For
example, an individual, with existing liver damage or under the
influence of another chemical (or hormone) which enhanced the meta-
bolism of 1,2-DCB into reactive hepatotoxic intermediates would be
expected to be more susceptible to DCB toxicity (Thompson, 1955).
Conversely, a condition or other chemical, that reduced conversion
of DCB to hepatotoxic metabolites or provided essential materials
to protect against harmful depletions (e.g., glutathione, lipo-
tropic factors), would tend to ameliorate the direct cellular tox-
icity of absorbed DCB.
Teratogenicity
Embryotoxicity and teratogenicity of DCBs apparently have not
been studied and reported. A pregnant woman who developed mild,
chronic erythrotoxic anemia from ingestion of toilet air freshner
blocks containing 1,4-DCB recovered after withdrawal and treatment
and delivered an infant free of congenital abnormality (Campbell
and Davidson, 1970). The potential for transplacental toxicosis or
C-41
-------
TABLE 6
Acute Toxicity of 1,2-DCB
O
I
>u
K)
Route
I nhalation
Oral
Intravenous
Subcutaneous
Dermal
Eye
Nose
Cone, or Dose
5,872 mg/m3
4,808 mg/m3
4,808 mg/m
4,249 mg/m
3,239 mg/m3
300-4,808 mg/m
2,000 mg/kg
1,875 mg/kg
800 mg/kg
428 mg/kg
324-649 mg/kg
250 mg/kg
520 mg/kg
330 mg/kg
Unspecified
Undil.
Unspecif led
Undil. , 2 drops
600 mg/m
300 mg/m3
Regimen
7 hrs
24 hrs
11-50 hrs
7 hrs
7 hrs
Few hrs
Single
(oil)
n
n
Daily,
3 days
Single
Daily
Single
Single
Appl. to skin
1/4 - 1 hr
Skin appl. 2x/d
x 5 applic.
Single
Single
Single
Subject
Rat
G. pig
Rat
Rat
Rat
Animals
G. pig
Rabbit
G. pig
Rat
Rabbit
Rat
Mouse
Rabbit
Human
Rat
Rabbit
Human
Human
Effect
Lethal in 4/5
LCr
Lo
Irritation, eyes, nose; coma;
death in 1/10; liver necrosis
LCLO
Eye irrit.; CNS depress.;
liver, kidney damage
Liver damage
Lethal to 100%
Lethal to 50% (LD5Q)
Survival, but weight loss.
Cumulative lethal toxicity;
1/5 LD5Q
Lethal within 24 hrs.
Increased liver metab. enzym.
syst.
LDLo
LDr
Lo
Localized edema and necrosis
Irritation, abnorm. pigmenta-
tion afterward lasting 3 mos.
Absorption of lethal amount
Moderate pain; conjunct. , ir-
ritation, clearing in 7 days
Strong odor; nasal and ocul. ir-
ritation; possible adaptation
Odor detectable; no irritation
Reference*
e
f
e cit. g
f
e
c cit. g
e
1
e
1
b cit. g
b cit. p
f
f
b cit. h
e cit. h
e cit. h
e
a,e cit. n
a, e
*References listed after Table 9.
-------
o
I
ife.
to
TABLE 7
Long-term Toxicity of 1,2-DCB
Route
Inhal at ion
Oral
Dermal
Subcut.
Cone, or Dose
S60 mg/m3
290 mg/m
6-264 mg/m3
(av. 90)
455 mg/m3 (tube)
376 rag/kg (tube)
188 mg/kg (tube)
18.8 mg/kg (tube)
0.01-0.1 mg/kg/day
Expos, to liquid
mixture
Unspecified
Regimen
7 h/d, 5d/wk,
6-7 mos.
7 h/d, 5d/wk,
6.5 mos.
Plant expos. ,
daily
Daily up to 15
days
5d/wk, 138
doses
5d/wk. 138
doses
5d/wk, 138
doses
5 mos.
Repeated
Repeated
Subject
Rat, g. pig,
rabbit
Rat, g. pig,
Human
Rat
Rat
Rat
Rat
Rat
Human
Rabbit
Effect Reference*
No effect on several param.
No effect on several param.
No evidence of organic or he-
roatol. effect on din. exam.
Hepatic porphyria
Liver, kidney weight increase;
cloudy swelling in liver
Increase in liver and kidney
weight
No effects noted
Hematopoietic syst; altered cond.
reflexes; increased prothromb time
and altered enzyme activities
Sensi tization, dermatitis (case
report)
Blood dyscrasias, (agcanulo-
cytosis)
e
e
e
r
e
e
e
4.
e
b
Note: See also TABLE 5 pertaining to human poisoning.
'References listed after Table 9.
-------
O
I
TABLE 8
Acute Toxicology of 1,4-DCB
Route
Inhalation
Oral
Intraper itoneal
Subcutaneous
Skin
Eye
Injection
Cone, or Dose
10 5 mg/m3
10^ mg/ra3
10 mg/m
300-480 mg/m
90-180 mg/m3
4,000 mg/kg
2,950 mg/kg
2,812 mg/kg
2,800 mg/kg
1,600 mg/kg
500 mg/kg
300 mg/kg
2,562 mg/kg
5,145 mg/1
Contact with
solid
Strong fumes
Solid particles,
vapor, fumes
5 mg
Regimen
30 min. , daily
30 min. , daily
30 min. , daily
Acute
Single
Single, 20 or
50% solution
Single
Single (oil)
Single, 50%
solution
Single, 50%
solution
Single
Single
Single
Single
Single
. Single or
repeated
Single
Single
Subject
Rabbit
Rat
G. pig
Human
Human
Rat
Mouse
Rabbit
G. pig
G. pig
Rat
Human
Rat
Mouse
Human
Human
Human
Rat
Effect
CNS depression; ocul. and nasal
irrit.
Irritation, narcosis
Irritation, CNS depression, deaths
Painful irrit. to eyes and nose;
acclimatization can occur.
Odor detection (strong odor at
180-360)
LD100
LD5Q
LD50
100% lethal
100% survival
LD50
Toxic dose
LD50
LD50
Somewhat irritating. Burning
sensation if contact is direct
and prolonged. No apprec. abs.
through skin
May irritate in severe expos.
conditions; no problem normally
Painful (also vapor at 300-480
•i 3
mg/m and severe at 960 mg/m )
Occasionally, slight liver
necrosis
Reference*
c cit.
c cit.
c cit.
a
3
j
c cit.
1
3
3
f
£
c cit.
b cit.
a, 3
3
L
c cit.
k
k
k
k
i
m
9
*References iTsted after Table 9.
-------
O
I
*»
Ul
TABLE 9
Long-term Toxicity of 1,4-DCB
Route Cone, or Dose
Inhalation 105 mg/m3
4,800 mg/m
4,600^4,800
mg/m
2,050 mg/m
1,040 mg/m
950 mg/m
300-1,020 mg/m3
(avg. 630)
900 mg/m
576 mg/m3
480-960 mg/m
180-360 mg/m3
(avg. 270)
90-510 mg/m3
Regimen
0.5 h/d, 5-9
days
8h/d, 5d/wk.,
up to 69 expos.
8h/d, 5d/wk
7h/d, 5d/wk,
6 mos.
7 h/d, 5d/wk,
16 days
7 h/d, 5d/wk,
157-219 days
8/h/d, 5d/wk,
chron.
8h/d, 2 wks
7 h/d, 5d/wk,
6-7 mos.
Daily, occu-
pational
Daily expos.
Daily occu-
pational
Subject
Rabbit
Rat, G. pig,
rabbit
Rabbit
Rat, G. pig
Rat, G. pig
Rat, G. pig
rabbit.
mouse, mon-
key
Human
Mouse
Rat, G. pig,
mice, rabbit,
monkey
Human
Human
Human
Effect
Granulocytopenia; irrit.; CNS
and lung tox. ; death (12/18)
Severe irrit,; CNS depress. &
collapse; liver, kidney, lung
pathol. ; deaths
Tremors, weakness, nystagmus;
some deaths
Growth depression, incr. liver,
kidney wt. ; liver pathol. (ne-
crosis, fatty degen. , swelling,
fibrosis)
Incr. liver, kidney wt. (rat);
lung, liver pathol.
Growth depress, (g.p. ); incr.
liver, kidney weight; histol.
liver changes (cloudy .swelling,
granular degen. ) in rats
Eye, nose irritation
Respir. excitation; liver
pathol., deaths; at serum cone.
39 mg/1
No adverse effects on several
parameters
Painful irrit. of eyes, nose.
Intolerable at more than 960
mg/m
Strong odor
No complaints or evidence of
injury
Reference*
b cit. i
j
j ci t. o
j
j
j
j
m
j
j
j
J__
*References listed after Table 9.
-------
TABLE 9 (Continued)
O
I
£*
CTi
Route Cone, or Dose
Oral 1,000 rag/kg per
dose (tube)
770 rag/kg/day
500 mg/kg/day
(tube)
5,000 mg/kg dose
500 mg/kg/day
(tube)
376 mg/kg/day
250 mg/kg/day
188 mg/kg/day
20-40 mg/kg/day
18.8 mg/kg/day
Regimen
92 doses in
219 days
Up to 5 days
5d/wk, 20
doses
Up to 35 days
5d/wk 263
doses in 367
days
5d/wk 138
doses in 192
days
3 days
5d/wk 138
doses in 192
days
2 weeks
5d/wk 138
doses in 192
days
Subject
Rabbit
Rat
Rat
Peking
duck
Rabbit
Rat
Rat
Rat
Rat
Rat
Effect
CNS depression; wt. loss; liver
degen. and necrosis; deaths
Hepatic porphyria
Hepatic centrolobular necrosis;
cloudy swelling, renal tubul.
epith. , and casts
Death in 3/10. Retarded growth
CNS depress.; wt. loss; liver
pathol.
Incr. liver and kidney wt.; liver
cirrhosis and focal necrosis
Induced liver me tab. enzyme syst.
Incr. liver and kidney- wt.
Induced liver me tab. enzyme syst.
no adverse effects detected
Reference*
j
r
j
j
j
3
b cit. p
j
b. cit. q
3
Note: See also TABLE 5 pertaining
*References follow this page.
to human poisoning.
-------
Previous references used in Tables 6, 7, 8, & 9
a. Patty, 1963
b. Ware and West, 1977
c. Am. Conf. Gov. Ind. Hyg., 1977
d. Occup. Safety Health Admin., 1976
e. Hollingsworth, et al. 1958
f. Christenson and Fairchild, 1976
g. Cameron, et al. 1937
h. Riedel, 1941
i. Zupko and Edwards, 1949
j. Hollingsworth, et al. 1956
k. Domenjoz, 1946
1. Varshavskaya, 1967a
m. Irie, et al. 1973
n. Elkins, 1959
o. Pike, 1944
p. Ariyoshi, et al. 1975
q. Carlson and Tardiff, 1976
r. Rimington and Ziegler, 1963
C-47
-------
developmental effects may be inferred from evidence that lower
chlorinated benzenes pass membrane barriers (including egg and
placenta) and affect hormone-metabolizing systems (Ware and West,
1977).
Mutagenicity
The formation of a metabolic arene oxide intermediate has been
associated with mutagenesis and carcinogenesis, and halobenzenes
have been shown to form reactive intermediates (Ware and West,
1977). Chromosomal and other nuclear derangements in roots of
Aliiurn exposed for four hours to 1,4-DCB vapor (resulting from
placing 0.5 to 1.5 g in a petri dish) were reported by Carey and
McDonough (1943). Abnormal chromosome numbers were found in divid-
ing nuclei; polyploidy was especially apparent in metaphase stages;
and lagging chromosomes and dumbbell-shaped nuclei were occasional-
ly noted. The authors warned of the possibility of varietal in-
stability if 1,4-DCB products were allowed to come in contact with
buds.
Sharma and Bhattacharyya (1956) reported their experience with
the use of 1,4-DCB solution in processing plant tissues for chromo-
some analyses. They indicated the potential of aqueous solutions
causing chromosomal breakage and persistence of fragment-contain-
ing cells for several cell generations after treatment. Sharma and
Sarkar (1957) reported on effects of 1,4-DCB solution on chromo-
somes of root tips, flower buds, and pollen grains of Nothoscordum
fragans. Saturated aqueous solution caused meta- and ana-
phase chromosome fragmentation in root tip cells, chromosomal
C-48
-------
"stickiness" and non-disjunction in meiotic cells of flower buds,
but no irregularities in pollen grain chromosomes.
Various mitotic anomalies were observed in cells and somatic
chromosomes of 1,4-DCB-treated root tips of Vicia faba, V. narbo-
nesis, V. hirsuta, Pisum arvense, and Lathyrus sativus (Srivastava,
1966). These deviations from normal mitosis included: shortening
and thickening of chromosomes, precocious separation of chromatids,
tetraploid cells, binucleate cells, chromosome bridges, and chromo-
some breakage (generally at heterochromatic regions). The author
emphasized the potential of 1,4-DCB as a mutagenic substance.
Treatment of Aspergillus nidulans (a soil mold organism) for
one hour in an ether solution of 1,2-, 1,3-, and 1,4-DCB isomers
increased the frequency of back-mutations (Prasad, 1970). Chlor-
ination in the para- position appeared to have special genetic sig-
nificance.
Anderson, et al. (1972) found 1,2-DCB not to be mutagenic in
an in vitro point mutation test system using several strains of
histidine-requiring mutants of Salmonella typhimurium. Several
compounds chemically similar to DCBs were also reported as negative
in Salmonella mutagenicity tester strains (Simmon, et al. 1977).
These were benzene, bromobenzene, 1,3- and 1,4-bromochlorobenzene,
and parachlorotoluene.
Carcinogenicity
DCB (isomer not specified) gave negative results in a skin
test of carcinogenicity in mice (Guerin and Cuzin, 1961; Guerin, et
al. 1971). Three- to four-month old Swiss mice in lots of four to
eight (male and female) were treated topically three times with
C-49
-------
0.1 ml of a solution of 104 mg DCB/1 acetone. After 10 days the
mice were euthanized and the treated skin area was examined for
atrophy of sebaceous glands and for epithelial hyperplasia. On a
scale of 0 to 4 (negative to very strongly positive) DCB was rated
0.9 and 0.7 on the sebaceous gland and hyperplasia criteria,
respectively. This was interpreted as a negative result (not car-
cinogenic) .
In a later investigation using an rn vitro carcinogenicity
test system, Guerin, et al. (1971) reported DCB as being negative
again. This test involved treating a culture of rat pulmonary
cells with test material and evaluating the inhibition of mitoses
in cells fixed on slides after eight days. The test had been demon-
strated as being able to detect known carcinogens, the correspond-
ence between test results on mitotic inhibition and carcinogenic
versus noncarcinogenic chemicals being significant at the one per-
cent level. The authors also reported a correlation between re-
sults of the lung cell mitosis inhibition test and those of the
cutaneous test (sebaceous gland atrophy and epithelial hyperplasia)
for various chemicals.
Ware and West (1977) have summarized a series of toxicity
experiments by Hollingsworth, et al. (1956, 1958) in which tox-
icities of 1,2- and 1,4-DCB were studied in several animal species
exposed by inhalation and gastric intubation at various dose levels
over various periods of time. No tumors were reported in combined
totals of 146 animals exposed to 1,2-DCB or 189 exposed to 1,4-DCB.
These were regarded as negative carcinogenicity results, but it
should be pointed out that these studies were toxicity tests and
were not designed to assess carcinogenicity. Small group sizes and
C-50
-------
relatively short durations render the data from these studies
inconclusive and inadequate for the assessment of carcinogenic
properties of the DCBs. Further details of these experiments were
discussed in the toxicity section.
Varshavskaya (1967b) reported macroscopic, histolgic, and
histochemical data in rats exposed for nine months to 1,2-DCB (in
oil, by tube) at daily dose levels of 0.1, 0.01, and 0.001 mg/kg.
No evidence of carcinogenic activity was revealed. Again, this
experiment (previously summarized in greater detail) was clearly
not designed for the assessment of carcinogenicity. Although the
exposure duration may be sufficient for some test models, the expo-
sure levels were quite low and the group sizes (numbers of animals)
were too small for valid detection and quantification of carcino-
genesis.
Murphy and Sturm (1943) reported that repeated exposures to a
relatively high concentrations of 1,4-DCB vapor caused a reduction
in the induced resistance to transplanted leukemia in rats. They
tested four toxic agents (including 1,4-DCB) which they character-
ized as having been found to increase the leukemia rate in a strain
of mice having a natural leukemia tendency (but no reference or
details for this characterization were given). All four compounds,
1,4-DCB, L.C. sodium pentobarbital, Sovasol (a purified naphtha),
and amyl acetate, were positive in the leukemia resistance reduc-
tion test. Two other carcinogenic agents, x-ray and coal tar,
had been shown to modify induced resistance to transplantable
tumors in mice (Murphy and Sturm, 1943). Eighty-four percent of
the activity control group (non-immunized) responded with leukemia
C-51
-------
(takes) to the injected leukemia cells. Only 20 percent occurred
in the immunized but untreated group. The immunized and treated
(1,4-DCB vapor-exposed) group had 68 percent takes. About 40 young
rats were used in each group. The toxic mechanism of the effect and
its general applicability to distinguishing carcinogenic versus
noncarcinogenic chemicals had not been determined.
Parsons (1942) reported that injections of 1,4-DCB (commer-
cial, in sesame oil) along with injection of silica have induced
early tumor formation in mice. In six irradiated mice a single
dose of 0.2 ml of a 0.2 percent solution of 1,4-DCB (2,000 mg/1) in
oil was injected subcutaneously, and 0.2 ml of silica in suspension
was introduced at the injection site on the fourth day. One ir-
radiated mouse received its injection intraperitoneally. On the
tenth day the intraperitoneally treated mouse had ascites, and when
euthanized was found to have "widespread sarcomatous growth"
throughout the peritoneum. This tumor gave 100 percent takes when
grafted. Three of the irradiated mice died by the tenth day. Ten
nonirradiated mice were injected subcutaneously with similar
1,4-DCB preparations for nine doses over two months, receiving also
silica at two week intervals. Four of these died within 30 days.
In one of the survivors a large sarcoma had developed (by the 77th
day), with secondary growths in the lymph glands and peritoneum.
Small group sizes and lack of further detail, especially concerning
control groups, limit the usefulness of this data in assessing
1,4-DCB carcinogenicity.
Of the seven case reports of human poisoning by 1,2-DCB or
products containing primarily 1,2-DCB (Table 5) three involved
C-52
-------
diagnoses of neoplastic disease (leukemia: two acute rayeloblastic,
one chronic lymphoid). Although these data suggest the posibility
of cancer-related hazard with exposure to 1,2-DCB, they fall very
short of proving a cause-effect relationship and do not permit a
quantitative risk assessment applicable to the general population.
Veljkovi'c and Lalovi'c (1977) examined the correlation be-
tween the quasi-valence number (2*) and the known carcinogenic
activity of a number of chemical compounds tested in animals and
evaluated by IARC criteria. The Z* is a derived parameter recog-
nizing valence electrons, atoms, and elements in the compound for-
mula. The authors reported a strong correlation in the array of
values examined, those with Z* below 3.20 corresponding to poten-
tial carcinogens and those above noncarcinogens. DCS was evaluated
as being in the potential carcinogen class with a Z* = 2.50.
No reports of specific carcinogenicity tests of DCBs in ani-
mals or of pertinent epidemiologic studies in humans were avail-
able.
Although strong direct evidence of carcinogenicity of DCBs is
not at hand, there seems to be a sufficient collection of varied
data to suggest a prudent regard of the DCBs as suspected carcino-
gens, pending the availability of better data. Apparently on the
basis of the limited sarcoma induction data of Parsons (1942),
1,4-DCB was listed in the National Institute for Occupational Safe-
ty and Health Subfile of Suspected Carcinogens (Christensen and
Luginbyhl, 1975). The National Academy of Sciences (NAS, 1977)
found the lack of information "disturbing, in view of the suspected
role of DCB in human leukemia and its apparent ability to undergo
C-53
-------
metabolic activation and covalent binding to tissue constitutents. "
The International Agency for Research on Cancer (IARC, 1974) re-
garded the data on DCBs as of 1974, i.e., primarily those of
Hollingsworth, Parsons, and Girard, as insufficient for assessing
carcinogenic risk. Clearly, additional data is needed for a DCB
carcinogenic risk evaluation, especially studies involving humans
in pertinent exposure categories and animal studies under well-
designed protocols. 1,2- and 1,4-DCB have been selected for test-
ing in the bioassay program of the National Cancer Institute (NCI,
1978), and as of January 1978, a study of 1,4-DCB in mice was in
progress at the Nagoya City University Medical School in Japan
(IARC, 1978).
C-54
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CRITERION FORMULATION
Existing Guidelines and Standards
The known current standards and guidelines for DCBs in air and
water are summarized in Table 10. For air the only official fed-
erally regulated limits are by the Occupational Safety and Health
Administration (OSHA) (29 CFR 1910) for 1,2-DCB and 1,4-DCB in
workroom air at 300 mg/m (ceiling) and 450 mg/m (time-weighted
average), respectively. The threshold limit value (TLV) guidelines
of the American Conference of Governmental Industrial Hygienists
(ACGIH, 1977) are virtually the same as the OSHA standards. These
may need downward revision in view of human sensory responses in
unacclimated persons. The Russian maximal allowable concentration
(MAC) value for both 1,2-DCB and 1,4-DCB is 20 mg/m3 (IARC, 1974),
much lower than U.S. standards. The U.S. EPA (1977) has published
multimedia environmental goals (MEGs) for health related Estimated
Permissible Concentrations in air (EPC-AH): 1,2-DCB, 0.714 mg/m
(0.12 ppm) and 1,4-DCB, 1.07 mg/m (0.18 ppm). The Russian and MEG
limits appear to recognize the following detection limits more
closely than the OSHA and ACGIH values: 1,2-DCB, 12 to 24 mg/m ,
odor threshold; 60 to 90 mg/m , very noticeable odor; 150 to 180
mg/m , unpleasant odor and eye irritation; 360 to 600 mg/m , pain-
ful mucosal irritation; and 960 mg/m , painful irritation (Am. Ind.
Hyg. Assoc., 1964).
1,4-DCB is listed for inclusion among chemicals to be moni-
tored by the U.S. EPA under the Safe Drinking Water Act (40 CFR 141,
Subpart E, PL 93-523).
C-55
-------
o
I
TABLE 10
Standard, Criteria, or Goal Limits of Contamination for Dichlorobenzenes
Med i urn
Air
Water
Standard, criterion, etc.
OSHA Standard for worker exposure
ACGIH recommended TLV
EPA, MEG: EPC-AHld
Russian MAC (max. allow, cone.)
EPA, MEG: EPC-WHlf
WH2
Russian MPC9
1,2-DCB
50 ppm (300 mg/m )
(ceiling)
50 ppm (300 mg/m3)
(ceiling)
0.12 ppm ,
(0.714 mg/m3)
3.3 ppm (20 mg/m3)
10.7 mg/1
4.4 mg/1
0.002 mg/1
1,4-DCB
75 ppm (450 mg/m3) (TWA)b
(Car)c
75 ppm (450 mg/m3) (limit)
0.18 ppm (2.07 mg/m3)
3.3 ppm (20 mg/m3)
16.1 mg/1
6.21 mg/1
0.002 mg/1
Reference
A,B
C
D
E
D
D
F
A: Occup. Safety Health Admin. 1976. B: Christensen and Luginbyhl, 1975. C: ACGIH, 1977. D: U.S. EPA, 1977.
E: IARC, 1974. F: Stofen, 1973
aCurrent, based on available information. Note: No known regulatory standards exist in U.S. for any l)CB isomers
(1,2-, 1,3-, or 1,4-DCB) in ambient air or waterj 1,3-DCB apparently omitted altogether
Time weighted average, 8 hours
GCarcinogenicity notation in ref. B; care, determination indefinite in A
dEstimated permissible concentration in air based on a model utilizing TLV
eEstim. permiss. cone, in water derived from EPC-ALL extrapolated to water intake
£Estim. permiss. cone, in water based on max. safe body cone, and biol. half-life considerations
^Maximum permissible concentration recognizing organoleptic effect
-------
The U.S. EPA (1977) has published MEGs for health-related EPCs
in water based on different approaches (Table 11): (1) derived
from the air-health EPC, extrapolated to water intake assuming the
following daily intake and absorption efficiency values: EPC-WH1,
10.7 mg 1,2-DCB/l and 16.1 mg 1,4-DCB/l; (2) based on considera-
tions of maximum safe body concentration and biological half-life
data: EPC-WH2, 4.4 mg 1,2-DCB/l and 6.21 mg 1,4-DCB/l. The re-
ported maximum permissible concentrations (MPCs) in Russia, recog-
nizing that organoleptic factors (odor, taste) are much more
conservative, are: 0.002 mg/1 for both 1,2-DCB and 1,4-DCB
(Varshavskaya, 1968; Stofen, 1973).
Apparently 1,3-DCB has been omitted from regulations or guide-
lines for media contamination, undoubtedly reflecting its insig-
nificant environmental contamination level and potential at this
time. Practically speaking, it would seem reasonable to assume
that efforts to control the 1,2- and 1,4- isomers of DCB would also
effectively control the 1,3-DCB as well, since it generally would
accompany its isomers in total DCB contamination and would not have
a significant contamination mode of its own.
Under the Federal Food, Drug and Cosmetic Act certain uses of
both monochlorobenzene (MCB) and 1,4-DCB are regulated. MCB is a
solvent in the manufacture of resins for food contact articles; res-
idues in such resin products must not exceed 500 mg/kg. 1,4-DCB
is an intermediate in the manufacture of other resins for coating
products in food contact use; in such products 1,4-DCB residues are
limited to 0.8 mg/kg (32 FR 14324, Oct. 17, 1967; 34 FR 17332, Oct.
C-57
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TABLE 11
Estimated Dichlorobenzene Exposure from
Drinking Water*
Exposure Level Exposure, mg
Daily uptake Annual uptake
Per person Per kg Per person Per kg
"Minimal" case;
Median level in 6 x 10~6 0.086 x 10~6 2.2 x 10~3 0.031 x 10~3
drinking water of
0.000005 mg/1 (assume 3).
o
m "Moderate" case:
oo
Assume level of 200 x 10~6 2.86 x 10~6 73 x 10~3 .1.04 x 10~3
10~4 mg/1 (33 x
minimal, 1/33 x
maximal).
"Maximal" case;
Maximal reported 6,000 x 10~6 86 x 10~6 2,190 x 10~3 31.3 x 10-3
level in drinking
water of 0.003 mg/1.
*Assuming human water consumption of 2 I/day, absorption efficiency of 100 percent, and body
weight of 70 kg. Values are about equally applicable to any single isomer, but not total
of all. See exposure section for data base.
-------
25, 1969; 37 FR 22374, Oct. 19, 1972). No information on regula-
tion of residues or levels in food commodities was available.
The U.S. EPA has regulatory authority over some uses of DCBs
under the Federal Environmental Pesticide Control Act of 1972.
Registered under this act are 43 uses of 1,2-DCB and 304 uses of
1,4-DCB. The chlorinated benzene pesticides are categorized as
Class III toxins (oral LD5Q values ranging from 500 to 5,000 mg/kg
and LC5Q values ranging from 200 to 20,000 mg/m ) and as such, have a
hazard signal ("caution") and precautionary labeling requirement:
"Harmful if swallowed, inhaled or absorbed through skin. Avoid
breathing vapors (dust or spray mist). Avoid contact with skin
(eyes or clothing). In case of contact immediately flush eyes or
skin with plenty of water. Get medical attention if irritation
persists" (40 FR 28242, July 3, 1975).
The Department of Transportation (DOT) regulates interstate
transport, and there are specific requirements in regard to hand-
ling DCBs as combustible materials (for which they are classified
due to their toxic and flashpoint properties). The Coast Guard has
regulatory authority for overseas transportation and has recognized
toxic, aquatic life hazard, and combustible properties of DCBs by
requiring notification of health, pollution, and fire authorities
in the event of spills. DCBs have been determined to be hazardous
to aquatic life in very low concentrations (Ware and West, 1977).
Several states have or intend legislation regulating manufac-
ture, use, disposal, handling, and/or registration and inventory of
toxic/hazardous chemicals, often mirroring Federal legislation and
promulgations (Ware and West, 1977).
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Current Levels of Exposure
Generally, there is a paucity of environmental data on di-
chlorobenzenes. In the few samples of relatively uncontaminated
ground water and of drinking water, the reported DCS levels ranged
from on the order of less than 0.001 to 0.003 mg/1. In the National
Organics Monitoring Survey (U.S. EPA,, 1978a) median concentrations
and frequency of positive samples in drinking water were low, com-
pared to halomethanes. This data by itself would suggest a rela-
tively low exposure level for the general public from drinking mu-
nicipally treated water.
An attempt to estimate human DCB exposure doses by using
available survey contaminant-level data and certain assumptions for
water consumption and absorption efficiency is shown in Table 11.
A spread of about 1,000 times between "minimal" and "maximal" case
exposures resulted. Even so, less than "minimal" exposures may ap-
ply for some of the population (e.g., very pure water supply) and
more than "maximal" exposure for others (e.g., highly contaminated
supplies). Meaningful representative or typical values and limits
defy precise definition at this time.
Specific data on ambient air contamination by DCBs was meager.
Based on the data of Morita and Ohi (1975) an attempt is made to
estimate levels of human exposure via air contamination (Table 12).
The extent of the population that may be represented by the table
values is simply unknown. Some segments may be subject to less ex-
posure (e.g., remote rural dwelling), and some to more (e.g., highly
contaminated urban or industrial area air, especially contaminated
air associated with some occupations or perhaps indoor air where
C-60
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TABLE 12
Estimated Dichlorobenzene Exposure
from Air Contamination*
Exposure Level
Per person
Estimated Exposure, mg
Daily uptake . Annual uptake
Per kg
Per person
Per kg
"Minimal" case;
1.5 x 10~3 mg/m3
(lowest suburban
concentration
reported)
n "Moderate" case;
M 0.24 mg/m3
(mean of all values
reported from urban,
suburban, and
indoor air)
"Maximal" case:
1.7 mg/m3
(Reported in wardrobe air
due to use of 1,4-DCB)
0.01725
2.76
19.55
0.000246
.0394
0.28
0.63
1,007
7,136
0.09
14
102
Based on assumptions as follows: daily inspired volume for reference adult male, 23m3
(NAS, 1978); human body weight, 70 kg (NAS, 1978); absorption efficiency by inhalation,
50 percent.
*Based on data of Morita and Ohi (1975) for 1,4-DCB.
-------
DCB products are used). Comparison of Tables 11 and 12 suggest
greater intake doses via air than via water.
No data are available by which specific exposure to DCBs by
consumption of food could be estimated. Reports of detectable,
even significant levels in fish, meat, eggs, and grains represent-
ing direct-contamination residues or products of degradation of
other chemicals would suggest the likelihood of at least some in-
take by ingestion of food (probably mostly from food of lipid na-
ture because of food-chain lipophilic bioaccumulation processes).
Data indicate the possibility of dermal absorption from un-
usually high-level exposure to vapors or perhaps liquids, but this
would likely be significant only in special individual circum-
stances. There are no data on the level or importance of dermal
exposure for the general public, but it seems reasonable to specu-
late that it would be insignificant in relation to other exposure
routes.
Special Groups at Risk
Persons with pre-existing pathology (hepatic, renal, central
nervous system, blood) or metabolic disorders, who are taking cer-
tain drugs (hormones or otherwise metabolically active), or who are
otherwise exposed to DCBs or related (chemically or biologically)
chemicals by such means as occupation, or domestic use or abuse
(e.g., pica or "sniffing") of DCB products, might well be con-
sidered at increased risk from exposure to DCBs.
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Basis and Derivation of Criteria
There is not a sufficient weight of evidence from human or
animal tests to qualitatively suggest that DCBs are carcinogenic or
mutagenic in mammals or to derive a quantitative estimate of ac-
ceptable daily intake using cancer risk extrapolation methods. In
addition, there are no human data to allow an estimation of the
maximum daily oral dose producing no detected adverse effect.
Hollingsworth's data were chosen over the Varsharskaya study
for several reasons. Although Varsharskaya reported lower effect
levels, the endpoints of this study were not clearly pathologic,
nor were sufficient data provided on which to substantiate the
author's claims. The acute data from both studies were in agree-
ment while a significant difference was seen in the chronic tox-
icity data. I-t is possible that had Hollingsworth been studying
chemical endpoints, he might have seen effects at lower levels than
he did. However, it is very difficult to make comparisons between
data with different endpoints. The Varsharskaya data do provide an
organoleptic value but this cannot be used to recommend a criterion
for the protection of health.
Therefore, the most usable controlled experimental data on
chronic enteric exposure in multiple animal species is that of Hol-
lingsworth, et al. (1956, 1958). The maximum tested dose level
producing no detectable adverse effects in these tests was 13.42
mg/kg/day (18.8 x 5/7) over a period of six to seven months, for
both 1,2-DCB and 1,4-DCB. Assuming the average weight of adult
humans to be 70 kg, and applying an uncertainty factor of 1,000
C-63
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(NAS, 1977), the acceptable daily intake (ADI) of 1,2- or 1,4-DCB
in man is calculated as follows:
._.,. 18.8 x 5/7 x 70 n n. /,
ADI = rsfr?5 = 0.94 mg/day.
1000
The water quality criterion can be calculated from the ADI as
follows:
Criterion = 2 '(O.OOex 55.6)' = °'398 "9/1 or 40°
where:
0.94 mg/day = ADI
2 = liters of drinking water consumed daily
0.0065 = kg of fish consumed daily
55.6 = bioconcentration factor.
The similarity of toxicities among the DCB isomers indicates the
applicability of this value to 1,3-DCB as well.
This calculation assumes that 100 percent of man's exposure is
assigned to the ambient water pathway. The only environmental mon-
itoring data available on the DCBs, inadequate as they are, suggest
that man's exposure by inhalation of the material in air may be
3,000 to 15,000 times his exposure from water. Although it is
desirable to arrive at a criterion level for water based on total
exposure analysis, the data base for exposure pathways other than
water is not sufficient to support a factoring of the ADI level
calculated from ambient water assumptions.
The calculated level of 0.40 mg/1, or 400 ug/1 for any DCB
isomer should be considered a total, i.e., the total contamination
by DCB isomers whether occurring singly or in combination should
not exceed the criterion level. Pending the availability of better
data on relative exposure by various routes and on carcinogenic
C-64
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risk, this level should be adequate to prevent adverse health ef-
fects from long-term ambient water exposures.
In summary, based upon the use of chronic toxicologic test data
in animals, and an uncertainty factor of 1,000, the criterion level
for DCBs (total) corresponding to the calculated total acceptable
daily intake of 0.94 mg/day is 400 ug/1. Drinking water contrib-
utes 85 percent of the assumed exposure, while eating contaminated
fish products accounts for 15 percent.
The criterion level for DCB can alternatively be expressed as
2.6 mg/1 if exposure is assumed to be from the consumption of fish
and shellfish products alone.
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