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

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                              DISCLAIMER



      This  report  has been reviewed by  the  Environmental  Criteria and



Assessment Office,  U.S.  Environmental  Protection  Agency,  and approved



for publication.   Mention of trade names or commercial products does not



constitute endorsement or recommendation for use.
                         AVAILABILITY NOTICE



      This  document  is available to  the  public through  the  National



Technical Information Service,  (NTIS),  Springfield,  Virginia  22161.
                                  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

-------
                                                          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

-------
                     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.

-------
                                                      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

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                  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

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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

-------
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

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 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

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     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

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 (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
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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
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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
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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.
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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).
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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
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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

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                                                            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

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                                                             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

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                                                                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

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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

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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

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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

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 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

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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

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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

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     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

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     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

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                                                                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

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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

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(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

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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

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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

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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

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     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.

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 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).
                               C-59

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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.

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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.
                               C-62

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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.
                               C-65

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Kopperman, H.L.,  et al.   1976.   Chlorinated Compounds  Found in
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 Mostafa,  I.Y. and  P.N.  Moza.   1973.   Degradation of gamma-penta-
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Occupational Safety and Health Administration.  1976.  General in-
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Sharma, A.K. and  N.K.  Bhattacharyya.    1956.   Chromosome breakage



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U.S. EPA.  1978c.   In-depth  studies on health and environmental im-
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