EPA-540/1-86-040
                                               ice of Emergency and
                                               medial Response
                                             Washington DC 20460
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
                       Superfund
&EPA
                        HEALTH EFFECTS ASSESSMENT
                        FOR CHLOROBENZENE

-------
                                           EPA/540/1-86-040
                                           September 1984
       HEALTH EFFECTS  ASSESSMENT
            FOR  CHLOROBENZENE
    U.S. Environmental  Protection Agency
     Office of Research and  Development
Office of Health  and Environmental Assessment
Environmental Criteria  and Assessment Office
            Cincinnati,  OH  45268
    U.S. Environmental  Protection  Agency
  Office of  Emergency and Remedial Response
Office of Solid Waste and  Emergency Response
            Washington, DC  20460

-------
                                  DISCLAIMER

    This  report  has  been  funded  wholly  or  In  part by  the  United  States
Environmental  Protection  Agency under  Contract  No.  68-03-3112  to  Syracuse
Research Corporation.  It has been  subject  to  the Agency's peer and adminis-
trative review, and  H has  been  approved  for  publication as an EPA document.
Mention of  trade  names or  commercial  products  does  not  constitute  endorse-
ment or recommendation for use.
                                      11

-------
                                    PREFACE


    This  report  summarizes  and evaluates Information  relevant  to a prelimi-
nary  Interim assessment  of  adverse  health effects associated with chloroben-
zene.   All  estimates  of acceptable  Intakes  and carcinogenic  potency pre-
sented  in  this  document should  be  considered  as  preliminary  and  reflect
limited  resources  allocated  to  this  project.   Pertinent  toxlcologlc  and
environmental  data  were located  through  on-line literature  searches  of the
Chemical  Abstracts,   TOXLINE,   CANCERLINE   and  the  CHEMFATE/OATALOG  data
bases.  The basic literature  searched  supporting this  document  1s current up
to September,  1984.   Secondary sources of Information  have also been relied
upon  In  the  preparation of  this  report and  represent  large-scale  health
assessment  efforts  that  entail extensive peer  and Agency  review.   The fol-
lowing  Office  of  Health and  Environmental  Assessment (OHEA)   sources  have
been extensively utilized:


    U.S.  EPA.   1980b.   Ambient  Water  Quality  Criteria for Chlorinated
    Benzenes.   Environmental  Criteria  and  Assessment  Office,  Cincin-
    nati, OH.  EPA 440/5-80-028.  NTIS PB 81-117392.

    U.S.  EPA.   1982a.   Hazard  Profile for  Chlorobenzene.   Prepared  by
    the  Environmental  Criteria and  Assessment  Office,  Cincinnati,  OH,
    OHEA  for  the Office of Solid Waste  and Emergency  Response,  Wash-
    ington, DC.

    U.S.  EPA.   1985.   Health  Assessment  Document  for  Chlorinated  Ben-
    zenes.   Environmental  Criteria and  Assessment  Office,  Cincinnati,
    OH.  EPA 600/8-84-015F.   NTIS PB 85-150332.
    The Intent In these assessments  1s  to  suggest  acceptable exposure levels
whenever sufficient  data  were available.   Values were not  derived  or larger
uncertainty  factors  were  employed  when the  variable data  were limited  In
scope tending  to  generate conservative  (I.e.,  protective)  estimates.  Never-
theless, the  Interim values  presented reflect the  relative  degree  of hazard
associated with exposure or risk to the chemlcal(s) addressed.

    Whenever possible, two categories of values  have  been  estimated for  sys-
temic toxicants (toxicants for which  cancer  Is  not  the endpolnt of  concern).
The  first,  the AIS  or acceptable  Intake  subchronlc, Is  an estimate of  an
exposure  level  that  would not  be  expected  to cause  adverse  effects  when
exposure occurs during a   limited  time  Interval  (I.e., for  an  Interval  that
does  not  constitute a  significant  portion of  the Hfespan).   This  type  of
exposure estimate  has not been  extensively used  or  rigorously  defined,  as
previous  risk  assessment  efforts  have  been  primarily  directed  towards
exposures from toxicants  1n  ambient air or water where  lifetime exposure  1s
assumed.  Animal  data  used   for  AIS estimates  generally  include  exposures
with  durations of  30-90 days.  Subchronlc  human data are  rarely available.
Reported exposures are  usually  from chronic  occupational  exposure situations
or from reports of acute accidental exposure.
                                      111

-------
    The  AIC,  acceptable  Intake  chronic,  1s  similar  In  concept to  the  ADI
(acceptable  dally  Intake).   It   1s  an  estimate  of  an  exposure level  that
would  not  be expected  to cause  adverse  effects  when exposure  occurs  for  a
significant portion  of  the llfespan  [see U.S.  EPA  (1980a)  for  a  discussion
of this  concept].  The  AIC 1s route  specific and  estimates  acceptable expo-
sure  for  a given route with  the Implicit assumption  that exposure  by other
routes 1s  Insignificant.

    Composite  scores  (CSs)   for  noncardnogens  have also  been  calculated
where data  permitted.   These  values  are  used for  ranking  reportable quanti-
ties; the methodology for  their development 1s explained  In U.S.  EPA (1983).

    For compounds for which there  1s  sufficient  evidence  of  cardnogenldty,
AIS  and  AIC values  are not  derived.   For a discussion  of risk  assessment
methodology for  carcinogens  refer to  U.S. EPA  (1980a).   Since  cancer 1s  a
process  that 1s  not  characterized by  a  threshold, any exposure contributes
an Increment of  risk.   Consequently,  derivation of AIS and  AIC  values would
be Inappropriate.  For  carcinogens,   q-j*s have  been  computed  based  on oral
and Inhalation  data 1f available.
                                      1v

-------
                                   ABSTRACT
    In  order  to  place the  risk  assessment  evaluation  1n proper  context,
refer  to  the preface  of  this  document.  The  preface outlines  limitations
applicable to all documents of  this  series as  well  as the appropriate Inter-
pretation and use of the quantitative estimates presented.

    The liver and kidneys  appear to be  target  organs  for chlorobenzene tox-
Iclty.  Three separate subchronlc  oral exposure  studies  (one  In  dogs, two 1n
rats)  define  comparable  NOELs.   The  observed  adverse  effects   Indicated  a
higher sensitivity of  the  dog  to chlorobenzene  than the  rat.   Based on these
findings, the highest  NOEL of  27.3  mg/kg/day  from  the dog study (Monsanto,
1967a) was  considered  appropriate  to  derive an  ADI.   The estimated  AIC  1s
1.9 mg/day, estimated  by applying  an uncertainty factor  of 1000.   This esti-
mate may  be  considered to provide adequate protection against adverse human
health  effects.   Long-term  (lifetime)   animal  exposure   data  are  needed  to
better characterize the toxldty of  this compound.   A CS  of 8 was calculated
for  the  low blood  sugar levels,  vomiting,  diarrhea  and  conjunctivitis
observed In dogs at  55  mg/kg/day.

    Subchronlc  Inhalation  data  from  several   species   are  available,  but
chronic  Inhalation  exposure assessments for chlorobenzene are   lacking.   A
AIC  for  Inhalation  exposure has been  estimated  based upon the  lowest  sub-
chronic LOAEL reported (75 ppm)  (Dllley,  1977).  This AIC, 0.4  mg/day,  may
be conservative.  More experimental  data are needed addressing  lower  concen-
trations  and  longer durations  of exposure  to  more  completely  characterize
chlorobenzene toxldty.

-------
                               ACKNOWLEDGEMENTS
    The  Initial  draft  of  this  report  was  prepared  by Syracuse  Research
Corporation  under  Contract No.  68-03-3112 for  EPA's  Environmental  Criteria
and  Assessment  Office,  Cincinnati,   OH.   Dr.  Christopher  DeRosa and  Karen
Blackburn were the Technical Project  Monitors  and  Helen Ball  wasithe Project
Officer.  The final documents  1n  this series  were  prepared for the Office of
Emergency and Remedial Response, Washington, DC.

    Scientists from  the  following U.S. EPA offices  provided  review  comments
for this document series:

         Environmental Criteria and Assessment Office, Cincinnati, OH
         Carcinogen Assessment Group
         Office of A1r Quality Planning and Standards
         Office of Solid Waste
         Office of Toxic Substances
         Office of Drinking Water

Editorial review for the document series was provided by:

    Judith Olsen and Erma Durden
    Environmental Criteria and Assessment Office
    Cincinnati,  OH

Technical support services for the document series  was provided by:

    Bette Zwayer, Pat Daunt, Karen Mann'and Jacky Bohanon
    Environmental Criteria and Assessment Office
    Cincinnati,  OH
                                      vl

-------
                               TABLE  OF  CONTENTS

                                                                        Page

 1.  ENVIRONMENTAL CHEMISTRY AND FATE	    1

 2.  ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS 	    2

     2.1.   ORAL	    2
     2.2.   INHALATION	    2

 3.  TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 	    3

     3.1.   SUBCHRONIC	    3

            3.1.1.   Oral	    3
            3.1.2.   Inhalation	    7

     3.2.   CHRONIC	   10

            3.2.1.   Oral	   10
            3.2.2.   Inhalation	   11

     3.3.   TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS	   11
     3.4.   TOXICANT INTERACTIONS	   12

 4.  CARCINOGENICITY	   13

     4.1,   HUMAN DATA	   13
     4.2.   BIOASSAYS	   13
     4.3.   OTHER RELEVANT DATA	   15
     4.4.   WEIGHT OF EVIDENCE	   18

 5.  REGULATORY STANDARDS AND CRITERIA 	   19

 6.  RISK ASSESSMENT	   21

     6.1.   ACCEPTABLE INTAKE SUBCHRONIC (AIS)  	   21

            6.1.1.   Oral	   21
            6.1.2.   Inhalation	   22

     6.2.   ACCEPTABLE INTAKE CHRONIC (AIC)	   22

            6.2.1.   Oral	   22
            6.2.2.   Inhalation	   23

     6.3.   CARCINOGENIC POTENCY (q-|*)	   23

            6.3.1.   Oral	   23
            6.3.2.   Inhalation	   23

 7.  REFERENCES	   24

APPENDIX: Summary Table for Chlorobenzene	   31

-------
LIST OF TABLES
No.
3-1
3-2
4-1
4-2
4-3
5-1
Title
Subchronlc Oral ToxIcHy of Chlorobenzene 1n Experimental
Animals 	
Subchronlc Inhalation ToxIcHy of Chlorobenzene In
Experimental Animals . . 	
Statistical Comparisons of Liver Tumors 1n Male Rats
Treated with Chlorobenzene 	
Pituitary Tumors 1n Rats Treated with Chlorobenzene 	
Mutagenlcity Testing of Chlorobenzene 	
Current Regulatory Standards and Criteria for
Chlorobenzene 	
Page
4
8
14
16
17
20

-------
                             LIST  OF  ABBREVIATIONS
ADI
AIC
AIS
BCF
CAS
CNS
CS
DNA
GGTP
LOAEL
MED
NOAEL
NOEL
ppm
RVd
RVe
SAP
SGOT
SGPT
STEL
TLV
TWA
Acceptable dally Intake
Acceptable Intake chronic
Acceptable Intake subchronlc
B1oconcentrat1on factor
Chemical Abstract Service
Central nervous system
Composite score
Deoxyr1bonucle1c add
y-Glutamyl transpeptldase
Lowest-observed-adverse-effect level
Minimum effective dose
No-observed-adverse-effect level
No-observed-effect level
Parts per million
Dose-rating value
Effect-rating value
Serum alkaline phosphatase
Serum glutamlc oxalacetlc transamlnase
Serum glutamlc pyruvlc transamlnase
Short-term exposure limit
Threshold limit value
Time-weighted average
                                      1x

-------
                     1.   ENVIRONMENTAL CHEMISTRY AND FATE



    The relevant  physical  and  chemical properties and environmental  fate  of

chlorobenzene (CAS No.  108-90-7)  are as follows:
     Chemical class:


     Molecular weight:

     Vapor pressure:


     Water solubility:
     Octanol/water partition
     coefficient:

     Soil mobility
     (predicted as retardation
      factor for soil depth of
      140 cm and organic carbon
      content of 0.087%):

     BCF:
monocycllc  aromatic   (purgeable
aromatic)

112.56

11.7  mm  Hg  at  20°C  (Mabey  et
al., 1981)

466.3  mg/8.  at   20°C   (Horvath,
1982)
692 (Hansch and Leo, 1981)
     Half-lives 1n A1r:
                   Water:
1.9 (Wilson et al., 1981)

45.7   (Rainbow   trout   (muscle);
Salmo galrdnerl) (Branson, 1978)

446.7   (Fathead   minnow;   P1me-
phales  promelas)   (Velth  et  al.,
1979)

3.5 days (Kanno and Nojlma, 1979)
0.3  days  In  river  (Zoeteman  et
al., 1980)
    The  half-life of  chlorobenzene  1n soil  could  not  be  located  1n  the

available literature; however, evaporation  1s  expected  to  be  the  predominant

loss mechanism  from  the  soil  surface  (Wilson  et  al.,  1981).  The  halfUfe

for  soil  evaporation should  be  longer than  Us  evaporation half-life  from

water.   In subsurface soil, a  fraction  of  monochlorobenzene may undergo  bio-

degradation,  and a fraction may leach through the  soil (Wilson et  al.,  1981).
                                      -1-

-------
           2.   ABSORPTION  FACTORS  IN  HUMANS  AND  EXPERIMENTAL  ANIMALS
2.1.   ORAL
    Quantitative studies  regarding  absorption of chlorobenzene  1n  humans  or
laboratory  animals  following  1ngest1on were  not  located  1n the  available
literature.   Reports   of  toxic  effects  1n  humans  following  1ngest1on  or
Inhalation  (Reich,  1934;  Rosenbaum  et  al., 1947;  Tarkhova,  1965)  suggested
absorption  by  these  routes.   Delchmann (1981)  reported that  chlorobenzene
absorption  from  the gastrointestinal tract  was  facilitated by  1ngest1on  of
fats and  oils.   Studies of  the metabolism  of chlorobenzene  in  several  mam-
malian  species  indicated  that absorption  from  the gastrointestinal  tract
occurred readily (Williams,  1959).
2.2.   INHALATION
    No quantitative  studies  regarding  absorption  1n humans  or  experimental
animals following  inhalation exposure  to chlorobenzene  could be located  in
the available  literature.   Delchmann  (1981) stated  that chlorobenzene was
absorbed  rapidly  from  the   lungs.   No  supporting  data  accompanied  this
statement.
                                     -2-

-------
                3.  TOXICITY  IN  HUMANS  AND  EXPERIMENTAL  ANIMALS
3.1.   SUBCHRONIC
3.1.1.   Oral.  No reports of  subchronlc  oral exposure of  humans  to chloro-
benzene could be  located  In  the available literature.  Table  3-1  summarizes
pertinent  subchronlc  oral  exposure  data  1n  laboratory  animals.   Most  of
these data  were taken from  summaries  provided  by Delchmann  (1981)  and  U.S.
EPA  (1980b,  1985).   The studies reviewed  by these authors  seemed  to  define
similar NOELs:  Monsanto Company (1967a) found no  effects  In dogs  exposed by
capsule  to  27.3 mg/kg/day.  Following dietary exposure  for 93-99  days,  no
effects  were reported  In  rats at  50 mg/kg/day  (Monsanto  Company,  1967b),
although  slight  and   Inconstant  elevated  liver  and  kidney  weights  were
reported at  this  level  In  the  published  version  of this study (Knapp et  a!.,
1971).   Irish  (1963)  found no  effects  In  rats given 14.4-18.8  mg/kg/day,  5
days/week, for 192 days.
    A  study  by Varshavskaya (1967)  described CNS, liver,  hematopoletlc  and
endocrine effects  1n  groups  of seven  male rats exposed  to 0.01 and  0.1  mg
chlorobenzene/kg/day by gavage.  The U.S.  EPA (1980b) considered the results
of Varshavskaya  (1967)  to  be questionable primarily because  these  data  sug-
gested effects  at dosages  far  lower  than  those Indicated  by  other  Investi-
gators (Table  3-1).   Also, data generated by HolUngsworth  et  al.  (1956)  in
a  similar  study of  the  toxlcity   of  o-d1chlorobenzene   Indicated  similar
effects,  but were associated  with   dosages  >3 orders  of  magnitude  greater
than those reported by Varshavskaya  (1967).
    The NTP  (1983) conducted 13-week range-finding studies  In  groups of  five
male  and  five   female  rats  and  mice with  chlorobenzene  administered  by
gavage.  Both  species were  treated  with 60,  125, 250,  500  or  750  mg/kg  on  5
days/week (transfomed doses  42.9,  89.3, 178.6,  357  and 538  mg/kg  bw/day).
                                      -3-

-------
                               TABLE 3-1

    Subchronlc Oral Toxldty of Chlorobenzene 1n Experimental Animals
Species
Dogs (4M, 4F)


Rats


Rats

Dose
(mg/kg/day)
27.3
54.6
272.5
12.5 or 50
100
250
14.4
144 and 288
Duration
(days)
90
90
90
93-99
93-99
93-99
192
192
Effects Reference
none Monsanto Company,
1967a;
Knapp et al., 1971
diarrhea and vomiting; conjunctivitis
mortality 4/8 1n 3-5 weeks; Increased
Immature leukocytes, SGOT, blUrubln,
cholesterol; decreased blood sugar;
hlstopathologlcal changes In liver,
kidneys, spleen
none Monsanto Company,
1967b
Increased liver and kidney weights
Increased liver and kidney weights;
retarded growth In males
none Irish, 1963
Increased liver, kidney weights,
given 5 days/
week
salivation; partial alopecia

-------
                                                  TABLE  3-1  (cont.)
Species
Rats


House

Dose
(mg/kg/day)
12.5
50 or 100
250
42.9
89.3
Duration
(days)
93-99
93-99
93-99
13 weeks
13 weeks
Effects Reference
none Knapp et al., 1971
Increased liver and kidney weights
Increased liver and kidney weights,
retarded growth In males
one male with hepatic necrosis NTP, 1983
Increased liver weights 1n males;
I
en
I
178.6
                      357
                      538
             one male with hepatic necrosis

13 weeks     >505C reduction 1n weight gain, Increased
             excretion of coproporphyrlns In females,
             Increased liver weights, lesions of the
             liver, kidney, bone marrow,  spleen and
             thymus

13 weeks     100% lethal to males within  1  week,
             reduced body weight gains, polyurla
             In females. Increased liver  weights,
             lesions of the liver, kidney,  bone
             marrow, spleen and thymus

10 weeks     100% lethal to males within  1  week
             and to female mice within 10 weeks,
             lesions of the liver, kidney,
             bone marrow, spleen and thymus at
             death

-------
                                             TABLE 3-1 (cont.)
   Species
   Dose
(mg/kg/day)
Duration
 (days)
Effects
Reference
Rat
 42.9

 89.3

178.6


357
                  538
13 weeks     none                                      NTP,  1983

13 weeks     none

13 weeks     minimal centrolobular hepatocellular
             necrosis

13 weeks     decreased body weight gain,  Increased
             GGTP and alkaline phosphatase In females,
             Increased excretion of porphyrlns,  cen-
             trolobular hepatocellular necrosis,
             nephropathy 1n males, myelold depletion
             of bone marrow

13 weeks     decreased body weight gain and survival
             of animals, hematologlc effects, Increased
             GGTP and alkaline phosphatase In females,
             polyurla In males,  Increased excretion of
             porphyrlns, centrolobular hepatocellular
             necrosis, nephropathy, lymphold depletion
             of thymus and spleen, myelold depletion of
             bone marrow

-------
In mice,  100%  lethality to  males  within  1  week occurred  at >500  mg/kg,
accompanied by hlstopathologlcal lesions  In many  organs.   All  females  1n the
750 mg/kg  group  died by week  10.   A 50% reduction  In body weight  gain and
hlstopathologlcal lesions were noted at  250 mg/kg.   Increased  liver weights
In males were  noted  at  125 mg/kg  and liver  necrosis  was noted  In 1 male In
the 125 and 1  male  In the  60  mg/kg group.  Hale mice appeared to be  affected
more severely than females.
    In  rats,  decreased  body  weight  gain  1n  both sexes, altered  serum bio-
chemistries  1n females   and  hlstopathologlcal  alterations  were observed  at
500 and 750  mg/kg.   Decreased survival  was observed  at  750 mg/kg.   The only
effect  reported at 250 mg/kg  was minimal  centrolobular hepatocellular  necro-
sis.   No effects were observed at the two lowest levels.
3.1.2.   Inhalation.   No studies  regarding   subchronlc  Inhalation  exposure
of humans  to  chlorobenzene  could  be  located  1n  the available  literature.
Because of the potential  for  being  long-term,  reports of  occupational  expo-
sure are discussed In Section 3.2.2.
    Several studies  of  subchronlc  Inhalation  exposure of  laboratory animals
to chlorobenzene  have been  reviewed  by  Delchmann  (1981) and  U.S.  EPA  (1985)
and are summarized   In Table  3-2.    Ollley  (1977)  demonstrated  small,  focal
lesions In the adrenal  cortex and  kidney  tubules  and  decreased SCOT 1n rats
exposed to 75  ppm chlorobenzene 7  hours/day,  5 days/week for  120 days.   This
dosage, corresponding to an  Intake of 53 mg/kg/day,  defined a  LOAEL In rats
from  Inhalation exposure  to  chlorobenzene.   In an earlier  study,  no effects
were seen In rats exposed to 142 mg/kg bw/day for 44 days (Irish, 1963).
    Several reports  from  the  foreign literature Indicate effects  In rats  at
exposures  leading to dosages   far  below  those associated with  no  effects  1n
                                      -7-

-------
                                                                              TABLE 3-2

                                               Subchronlc Inhalation Toxtclty of Chlorobenzene In Experimental Animals
oo
i
Species
Rats

Rats
Rats
Rats

Rats
Rats
Exposure
200 ppm, 7 hours/day.
5 days/week
475 and 1000 ppm,
7 hours/day, 5 days/week
0.75. 1.50 or 2 rag/I
6 hours/day, 5 days/week
0.1 or 1.0 mg/m9 continuous
0.1 mg/rn3 continuous
1.0 mg/m' continuous
0.1. 1.25 or 1.5 rag/lb
0.1 mg/l, 3 hours /day
every other day
Dose3
(ing/kg/day)
142
338 and 713
99. 199 or 265
0.7 or 7.0
0.07
0.7
NO
4.6
Duration
(days)
44
44
87
72-80
60
60
49-98
259
Effects
none
Increasing severity of hepatomegaly,
hlstopathologlcal changes
none
liver necrosis and regenerations;
kidney hyperplasla. encephalopathy,
pneumonia
none
Inhibited chronaxla of antlgonlstlc
muscles at 39 days; Increased blood
chollnesterase
chronaxlmetrlc Inhibition
Inhibition of extensor tlblalls at
7-14 weeks, normal by 20 weeks
Reference
Irish. 1963

Monsanto
Company,
1976
Khanln. 1977
Tarkhova,
1965

Ptslaru,
1960
Gabor and
Raucher,
1960
           Rats                75 or 250 ppm 7 hours/day.       53 or 178
                               5 days/week
           Rabbits             75 or 250 ppm. 7 hours/day,      102 or 340
                               5 days/week

           Rabbits             200 ppm. 7 hours/day,           271
                               5 days/week

           Guinea pigs        , 200 ppm, 7 hours/day,           102
                               5 days/week
120



120


 44


 44
focal lesions In adrenal cortex and         Dllley, 1977
and kidney tubules; congestion of liver
and kidney, decreased SCOT

decreased SGOT                              Dllley. 1977
none                                        Irish, 1963
none                                        Irish, 1963

-------
                                                               TABLE  3-2 (cont.)
Species
Dogs
Exposure
0.75 my/I, 6 hours/day,
5 days/week
Dosed
(mg/kg/day)
15.8
Duration Effects
(days)
87 none
Reference
Honsanto
Company,
1978
                    l.SO mg/i,  6 hours/day,
                    5 days/week

                    200 mg/t,  6 hours/day,
                    5 days/week
31.6


4218
87


87
weight loss, conjunctivitis, moribund
by 31 days

weight loss, hypoactlvlty and conjunctiv-
itis; vacuolated hepatocytes, cytoplasmlc
vacuolation of renal tubules, bilateral
atrophy of seminiferous tubules;  leukocyto-
poenla; elevated SAP, SGOT, SGPT; aplastlc
bone narrow, mortality In 5/8 dogs by
25-29 days
aDose  In  mg/kg was  calculated assuming  the  following inhalation  rates  and  body  weights:  rats  - 0.26 mVday  and 0.35  kg;  rabbits -  1.6
 mVday, 1.13 kg;  guinea pigs - 0.23 mVday, 0.43 kg; dogs - 1.5 mVday, 12.7 kg

^Exposure data insufficient for calculation of dose

ND = Not derived because exposure  data  are insufficient

-------
reports  from the domestic  literature.   For example,  Khanln  (1977)  reported
hlstopathological  lesions  1n  several  organs  at  0.7  mg/kg  bw/day.   Neuro-
muscular dysfunction was  reported  1n  rats  at exposures leading to dosages of
0.7-4.6  mg/kg  bw/day   (Tarkhova,  1965;  Plslaru,  1960;  Gabor and  Raucher,
1960).   In  the absence  of  corroborating  evidence  from the  domestic  liter-
ature, the data are not considered reliable for use 1n risk assessment.
    In  subchronlc  Inhalation  experiments  1n  other  species,  no  adverse
effects  were observed  1n  rabbits  at  102-340 mg/kg  bw/day   (DUley,  1977;
Irish, 1963), 1n  guinea  pigs  at  102  mg/kg bw/day (Irish,  1963) or In dogs at
15.8  mg/kg   bw/day  (Monsanto  Company,  1978).   Dogs  appear  to  be  the  most
sensitive species  tested,  however,  as  weight loss and morlbundlty  occurred
1n  this  species  by  31  days  of  exposure  to 31.6  mg/kg bw/day  (Monsanto
Company, 1978).
3.2.   CHRONIC
3.2.1.   Oral.  No  reports  of  chronic oral exposure of humans  to chloroben-
zene  could  be  located  1n the available  literature.   Minimal  toxldty  data
are available  from  the  103-week  cardnogenlcHy bloassay  1n rats  and  mice
(NTP,   1983).   Groups  of  50  male  and 50  female  B6C3F,  mice were  treated  by
gavage with chlorobenzene In corn  oil at  0,  60 and 120 mg/kg  for  females and
0, 30  and 60 mg/kg  for males.  Groups of  50 male  and  50 female   F344/N  rats
were  treated  with 0,  60  and 120  mg/kg.   Treatments  were  performed 5  days/
week  for  103  weeks.    Both   untreated  and  vehicle-treated  controls  were
maintained.
    Neither  mice  nor  rats had clinical  signs  of toxldty related to  treat-
ment  with  chlorobenzene.   Statistically  significant  reduced  survival   was
observed In  low-dose  male  mice  and high-dose  male  rats.   Increased  body
weights In both treated groups of female  rats were noted  during  the  second
                                     -10-

-------
year  of  the  experiment.   No  histopathologic  evidence  of  toxldty  was  was
observed  In  mice;  however,  rats  had  "equivocal  evidence  for  mild  chloro-
benzene-lnduced hepatocellular necrosis."
3.2.2.   Inhalation.  The  only available reports  of  chronic  human  exposure
to monochlorobenzene were  summaries  by U.S.  EPA  (1985)  and  Delchmann (1981),
from  which  this  discussion was  adapted.   Glrard et al.  (1969)  reported  the
case  of  a 70-year-old  woman  exposed for  6 years  to  a  glue  containing  70%
chlorobenzene.   From the  time  she  began  using the  glue,  she  experienced
headaches and  Irritation  of  the mucosa  of  the  upper  respiratory  tract  and
eyes.  After 6 years, she  had  developed  medullary  aplasia.   No exposure data
were available.
    Rosenbaum et  al.  (1947) examined 28  factory workers, many  of  whom com-
plained of headaches and showed  signs of  somnolescence  and  dyspepsia.  Other
complaints  Included  tingling,  numbness and  stiffness  of the  extremities  (8
workers), hyperesthesia  of the hands (4  workers),  and   spastic  contractions
of  the  finger  muscles  (9 workers)  or  of  the  gastrocnemius  (2  workers).
These  workers  had  reportedly been  exposed for  1-2 years,  but details  of
exposure  were not  specified.   No  neurotoxlc  signs  were   displayed by  26
workers exposed to benzene and/or chlorobenzene fumes for <1  year.
    No  reports  of   chronic  Inhalation  exposure  of  laboratory animals  to
chlorobenzene could be located in the available literature.
3.3.   TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
    No reports of  fetotoxlcity or teratogenlcity In humans  or animals  asso-
ciated with  either  oral  or  Inhalation  exposure  to  chlorobenzene could  be
located in the available literature.
                                     -11-

-------
3.4.   TOXICANT INTERACTIONS



    No pertinent data confirming  the  Interaction  of  chlorobenzene with other



xenoblotlcs could be located  1n  the  available literature.   Generalizing that



the  halogenated  benzenes  appeared  to  Increase  the  activity  of  mlcrosomal



cytochrome  P-450-dependent  enzyme systems,  the  U.S.  EPA  (1980b)  suggested



that  exposure  to chlorobenzene  might  be  expected  to  hasten  metabolism  of



other xenoblotlcs to either more or less toxic metabolites.



    Shelton and Weber (1981)  Investigated  the hepatotoxiclty  of a 1:38 molar



ratio mixture  of  carbon tetrachlorlde  and  chlorobenzene in male  CF-1  mice.



The  dosages  used (not  specified) were  given by  1ntraper1toneal  Injection.



Although  parameters of  hepatotoxiclty  were  not mentioned,   the  U.S.  EPA



(1985) stated  that  the  dose-response did not  deviate  from that predicted  by



addition alone.
                                     -12-

-------
                              4.   CARCINOGENICITY
4.1.   HUMAN DATA
    No  reports  associating  chlorobenzene  with  cancer  1n  humans could  be
located In the available literature.
4.2.   BIOASSAYS
    The NTP  (1983) conducted a  study  of  the cardnogenldty of chlorobenzene
in  rats  and mice.  Based  on data  from  a 13-week dose  range-finding  experi-
ment,  50  rats  of  each  sex were  treated by gavage  with  60 or 120 mg/kg,  5
days/week for  103 weeks.   Both untreated and  vehicle-treated  control  groups
of 50 rats of each sex were maintained.
    Throughout  the  study,  body  weight  of  treated  and  control   animals
remained  comparable.   Survival  rates were  similar   until  about 70 weeks  of
treatment, at which time survival  1n  high-dose group males was significantly
reduced.  Survival at the  end of  2 years was 68,  78, 64 and 52% 1n untreated
control,  vehicle-treated   control,  low-dose  and high-dose  males,   respec-
tively.   Among female  rats,  2-year survival data were 74,  58,  60  and  62% In
untreated control,  vehicle-treated control,  low-dose and  high-dose  groups,
respectively.
    Although  there was  some  disagreement   1n the  Interpretation of  liver
lesions,  pathologists  evaluating  the slides  seemed  to agree  that Inflamma-
tion  and cytoplasmic  basophilla,  manifestations of  hepatic  degeneration,
were  less severe  In chlorobenzene-treated  rats  than in the control  groups.
In male  rats, a  significant  Increase in neoplastlc  nodules  1n  the liver  was
observed  in  the high-dose  group (Table  4-1) as determined  by  both the Inci-
dental  tumor  test (p=0.021) and  the  Cochran-Armitage test  for  dose-related
trend  (p=0.043).   Liver  carcinomas  in  male  rats   were  found only   in  the
vehicle-treated  group  (2/50).    Combining   the  incidences   of   neoplastic
                                     -13-

-------
                                  TABLE 4-1

             Statistical  Comparisons of Liver Tumors 1n Male Rats
                         Treated with  Chlorobenzene*
Tumor Type
Neoplastlc nodule
Incidental tumor test
Cochran-Armltage test
Fisher exact test
Carcinoma
Incidental -tumor test
Cochran-Armltage test
Fisher exact test
Neoplastlc nodule or
carcinoma
Incidental tumor test
Cochran-Armltage test
Fisher exact test
Untreated Vehicle
Control Control
4/50 (8%) 2/50 (4%)
p=0.011
p=0.027
NA
0/50 (0%) 2/50 (4%)
p=0.139
p=0.098
NA

4/50 (8%) 4/50 (8%)
p=0.054
p=0.121
NA
60 mg/kg
4/49 (8%)
p=0.290
NA
p=0.329
0/49 (0%)
p=0.283
NA
p=0.253

4/49 (8%)
p=0.570
NA
p=0.631
120 mg/kg
8/49 (16%)
p=0.021
NA
p=0.043
0/49 (0%)
p=0.331
NA
p=0.253

8/49 (16%)
p=0.083
NA
p=0.168
*Source: NTP, 1983

NA = Not applicable
                                     -14-

-------
nodules  and  carcinomas  failed to create  an  overall  tumor Incidence that was
statistically  significant.   There  was no  evidence  of  neoplastlc  nodule or
liver  tumor  formation 1n female rats.
    The  Incidence  of  pituitary  tumors  (adenoma,  adenocarclnoma   and  car-
cinoma)  In both  male  and  female  rats was  found to be significantly  Inversely
related  to treatment with chlorobenzene (Table 4-2).
    The  carclnogenlclty of  chlorobenzene  has  also been  tested  1n  B6C3F..
mice  (NTP,  1983).   Males were treated with 30 or 60 mg/kg  and females  were
subjected  to 60  or 120  mg/kg,  5 days/week  for  the  2-year  (103-week)  treat-
ment  period.  These  dosages  were  chosen  on  the  basis  of   a  preliminary
13-week  dose range-finding study.   It  appeared that  the doses  chosen for the
chronic  bloassay were  too  low based  on  the  data  generated by  the 13-week
preliminary  study,  and  that  the  accepatable Intake had  not been approached
(U.S.  EPA,  1985).   No  tumors  occurred with frequencies that  differed  sig-
nificantly from those 1n the control groups.
    The  U.S. EPA (1985)  stated that  the data generated  by these studies  were
not  sufficient  to  draw  conclusions  about  the  carclnogenlclty  of  chloro-
benzene.
4.3.   OTHER RELEVANT DATA
    Studies  of  the mutagenlclty  of  chlorobenzene  1n  microorganisms  have
yielded  mixed  results,  with  positive  results  observed  only  in  tests  with
Saccharomyces cerevlslae (Simmon  et  al.,  1979)  and  Streptomyces antlbloticus
(Kesklnova, 1968) (Table 4-3).
    In a sex-Hnked recessive lethal  test  1n DrosophUa melanogaster  (Bio-
assay Systems Corp., 1982), male  flies  were  exposed  to  36,000  or  128,400 ppm
of  chlorobenzene  for 1  hour.   The exposed flies  were mated at   1-3  days
                                     -15-

-------
                                                      TABLE 4-2



                              Pituitary Tumors  In Male Rats Treated with Chlorobenzene*
cr>
i
Untreated
Tumor Type Control
Adenoma 20/49 (4154)
Incidental tumor test
Cochran-Armltage test
Fisher exact test
Adenoma, adenocarclnoma or
carcinoma 20/49 (4154)
Incidental tumor test
Cochran-Armltage test
Fisher exact test
•
Vehicle
Control
10/50 (20%)
p=0.109
p=0.047
NA

12/50 (2454)
p=0.044
p=0.016
NA
60 mg/kg
9/42 (2154)
p=0.532
NA
p=0.534

9/42 (2154)
p=0.462
NA
p=0.484
120 mg/kg
3/47 (654)
p=0.101
NA
p=0.046

3/47 (654)
p=0.044
NA
p=0.015
     *Source:  NTP,  1983


     NA  -- Not  applicable

-------
                                                 TABLE 4-3

                                   Mutagenicity  Testing of  Chlorobenzene*
           Test System
Metabolic
Activation
Concentration
Result
Reference
Asperlqlllus nldulans

Salmonella strains TA1535, TA1537,
TA1538, TA92, TA98, TA100

Salmonella typhirourium strains
*Source: U.S. EPA. 1985

NR = Not reported
               200

               0.1-0.5 pi/plate


               100 yg/plate
                    negative     Prasad, 1970

                    negative     Simmon et al., 1979
                    negative     Merck and Company,
                                 1978
Saccharomyces cerevislao
S. cerevlslae
Mouse lymphoma L5178Y
(forward mutation of TK)
Escherlchla coll
(polAVpolA-)
Bacillus subtilis
(rec~/recf)
Streptomyces antlblotlcus
f 0.05-654
t- 0.01-5 ul/plate
0.001-0.1 til/mi
H 0.0001-0.01 jii/mfc
10^20 pi/plate
10-20 yi/plate
NR
positive
negative
negative
negative
negative
negative
positive
Simmon et al., 1979
Monsanto Company,
1976
Monsanto Company,
1976
Simmon et al., 1979
Simmon et al., 1979
Keskinova. 1968

-------
(to  sample  effects on  spermatozoa),  4-5  days  (to  sample  effects on  sper-
matlds) and  6-7  days  (to measure  effects  on spermatocytes) after  exposure.
No  evidence  of mutagenldty  was  found  1n  11,543  chromosomes  from  treated
flies compared to 9430 chromosomes  from control  flies.
    A  positive  response was  obtained  1n  a  test  for  1j\  vitro  Induction  of
chromosomal   aberrations  1n  Chinese  hamster  ovary  cells  (U.S.  EPA,  1982b).
Concentrations  of  444,  266   and   178  yg/ms,   were  tested  1n   assays   not
Incorporating a metabolic activating  system  and concentrations  of  493,  296,
197  and  99   yg/mj.  were  assayed  with  an S-9 activating  system.   A  positive
response was  observed 1n the  S-9  activated system after a 4-hour  exposure
but not after a 2-hour exposure.
4.4.   WEIGHT OF EVIDENCE
    No evidence of cardnogenldty associated with  exposure to chlorobenzene
In humans could be located  1n  the  available  literature.   The NTP  (1983)  bio-
assay failed  to confirm  or  deny  the cardnogenldty of chlorobenzene  1n  rats
or mice.  IARC  has  not  evaluated the risk to humans associated with  oral  or
Inhalation exposure to  chlorobenzene.   By applying the criteria  proposed  by
the  Carcinogen  Assessment  Group  of the  U.S. EPA for  evaluating  the  overall
weight of evidence for cardnogenldty  to  humans  (Federal Register,  1984),  a
designation   of  chlorobenzene  as  a  Group  D  -  Not Classified chemical  seems
most appropriate.
                                     -18-

-------
                     5.   REGULATORY  STANDARDS AND  CRITERIA

    A  summary  of  regulatory  standards  and  criteria  for  chlorobenzene  1s
presented in Table 5-1.  Both  the ACGIH  (1980)  and  NIOSH (1982) have set the
TWA for chlorobenzene at 75 ppm.   No STEL has  been set.
    The U.S. EPA (1980b) has suggested an  ambient water  quality criterion of
488  yg/a.  to protect  human  health.   This  criterion  Is  based  on  an ADI  of
1.008  mg/day,  assumes  consumption  of   2  i  water/day  and  takes  Into  con-
sideration consumption by fish  and shellfish.
                                     -19-

-------
                                   TABLE  5-1
          Current  Regulatory Standards  and  Criteria  for  Chlorobenzene
     Standard or Criterion
       Value
  Reference
TLV
TWA
Ambient water quality criteria:
  Freshwater aquatic life
    Acute toxlclty
  Saltwater aquatic life
    Acute toxldty
    Chronic toxlclty
  Ambient water quality criterion:
    Human life
    Organoleptlc
75 ppm (-350 mg/m3)
75 ppm


250 pg/8,
160
129
488 vg/l
20
AC6IH, 1980
U.S. EPA, 1985
U.S. EPA, 1985
U.S. EPA, 1985
U.S. EPA, 1985
U.S. EPA, 1985
U.S. EPA, 1985
                                     -20-

-------
                              6.   RISK  ASSESSMENT
6.1.   ACCEPTABLE INTAKE SUBCHRONIC (AIS)
6.1.1.   Oral.  NOAELs  from subchronlc oral  studies  Include 14.4  mg/kg/day
In rats  (Irish,  1963),  50 mg/kg/day in  rats  (Monsanto  Company,  1967b), 89.3
mg/kg/day  1n  rats (125  mg/kg,  5  days/week)  (NTP,  1983), 12.5  mg/kg/day  In
rats  (Knapp  et  a!.,  1971)  and  27.3  mg/kg/day  In  dogs  (Monsanto  Company,
1967a; Knapp  et  al..  1971).  The  Irish  (1963)  study  reported a  NOEL of 14.4
mg/kg/day and LOAEL of  144.4  mg/kg/day,  however,  Intermediate doses  were not
evaluated.  The Monsanto  (1967a,b)  study  defined  a  NOAEL of  50  mg/kg/day and
LOAEL  of  100  mg/kg/day  In  the  rat.   In  contrast,  a  NOEL of 27.3  mg/kg/day
and a  LOAEL of  55 mg/kg/day were  defined  for  the dog.   The  observed adverse
effects  Indicated a higher  sensitivity of the  dog  to  chlorobenzene  than the
rat.   Based on  these  findings  the highest dog NOEL of  27.3 mg/kg/day  (Mon-
santo,  1967b) was considered  appropriate  to  derive  an ADI for  subchronlc
exposure.   An uncertainty  factor  of  100 1s  applied,   a  factor  of   10  to
account for Interspecles  extrapolation and a  factor of  10 to provide greater
protection  for especially sensitive populations.   Assuming a body weight  1n
man of 70 kg,  an AIS for man can be calculated as  follows:

                  AIS = (27.3 mg/kg/day  days  x  70 kg) f  100
                    (the uncertainty factor derived above)
                              AIS =19.1  mg/day

    In dogs  Immature  leukocytes,  low  blood sugar, conjunctivitis,  vomiting
and  diarrhea  were  reported  at  55 mg/kg/day,  whereas  higher  doses  caused
mortality  and histopathologlcal   lesions  In  liver  and kidneys  (Monsanto,
1967a).  A  human  MED  was calculated by  multiplying  the dog MED by  the cube
root of  the ratio of  the body weight  of  dogs (assumed:   12.7 kg) to that  of
humans  (assumed:   70  kg)  and  dividing  the result  by  10,  an  uncertainty
                                     -21-

-------
factor  chosen to  reflect  the  unknowns  1n  extrapolating from  a  subchronlc
study  to chronic application.   The  result,  3.1 mg/kg/day,  1s  multiplied by
70,  resulting  in  an  MED of 218 mg/day for a 70 kg man.  This MED corresponds
to  an  RVd  of  2.0;  the  effects of  vomiting,  diarrhea,  conjunctivitis and
Immature  luekocytes  rate  an  RV  of  4.   A CS  of  8,  the product  of  RV. and
RVe, 1s calculated.
6.1.2.   Inhalation.  No  pertinent  data regarding the  effects  of subchronlc
Inhalation  exposure of  humans  to  chlorobenzene  could  be  located   1n the
available literature.   Studies by Irish  (1963) defined NOELs  in  rats,  rab-
bits and  guinea  pigs  of   142,  271  and 102 mg/kg/day,  respectively.   Dilley
(1977)  found  small  focal   lesions  1n the adrenal  cortex  and kidney tubules,
congestion of  the liver and kidney,  and decreased  SGOT in rats exposed  to 75
ppm  chlorobenzene  for  7  hours/day,  5 days/week for  120  days.   This  concen-
tration  resulted in  an  intake  of  53 mg/kg/day  (applying  the  assumptions
stated  in  Table  3-2),  which  was designated  as a  LOAEL  in  this  study.  An
interim AIS  can  be calculated  from  these data  by assuming  a  body  weight  of
man  of  70 kg  and using  an uncertainty  factor  of 1000;  a  factor  of 10  to
account for  interspecies  conversion, another  factor of 10  to  convert  from a
LOAEL  to  a  NOEL  and  a final  factor of  10  to  afford  greater  protection  to
unusually sensitive populations.  The resultant  interim AIS is 3.7 mg/day.
6.2.   ACCEPTABLE INTAKE CHRONIC (AIC)
6.2.1.    Oral.  No reports  of  chronic  oral exposure  of humans or animals  to
chlorobenzene could be  located 1n  the available literature.  An  Interim AIC
for chronic  oral exposure  can  be derived  from the  subchronic AIC  by applying
an additional uncertainty  factor of  10  to convert  from a  subchronic study  to
chronic  exposure;  this  results  1n   an  overall  uncertainty  factor  of 1000.
The resultant AIC is 1.9 mg/day.
                                     -22-

-------
6.2.2.   Inhalation.  No  reports  of  chronic  exposure of  humans  to  chloro-
benzene  that  were satisfactory for  risk assessment,  or  studies  of  chronic
animal exposure could be  located  In the available  literature.  The  study  by
Dllley  (1977),  used to  derive an  AIS, can  be used  to  derive  an  AIC  for
Inhalation exposure.  An  additional  uncertainty factor of 10 to  account  for
derivation of  an  AIC from subchronlc  data  results  1n an  AIC of  0.4  mg/day,
starting with the AIS of 3.7  mg/day (see Section 6.1.2).
6.3.   CARCINOGENIC POTENCY (q^)
6.3.1.   Oral.  The  NTP  (1983) bloassay failed  to  demonstrate conclusively
the  cardnogenldty,  or  lack  of  cardnogenldty,   of chlorobenzene  admin-
istered  to rats and  mice  by  gavage.  No other  reports of  cardnogenldty  1n
humans  or  animals  resulting  from oral  exposure to  chlorobenzene  could  be
located  1n  the  available  literature.   Therefore,   Insufficient  data  are
available from which to  estimate carcinogenic  potency.
6.3.2.   Inhalation.  No  reports   of  cardnogenldty  1n  humans  or  animals
associated with Inhalation exposure to  chlorobenzene could be located  1n  the
available literature; hence,  no estimation  of carcinogenic postency has been
made.
                                     -23-

-------
                                8.  REFERENCES

ACGIH  (American Conference  of Governmental  Industrial  Hyg1en1sts).   1980.
Documentation of the  Threshold Limit Values for Substances  In  Workroom A1r,
4th ed.  Cincinnati, OH.  p. 84-85.  (Cited In U.S. EPA, 1982a)

Bloassay Systems Corp.   1982.   DrosophHla sex-linked  recessive  lethal test
on monochlorobenzene.   U.S.  EPA,  Office of Pesticides  and  Toxic  Substances,
Washington, DC.   TSCA Section 8(d) submission.   (Cited 1n U.S. EPA, 1985)

Branson,  D.R.    1978.   Predicting  the  fate  of   chemicals   In  the  aquatic
environment  from  laboratory   data.   ASTM  STP 657.    American  Society  for
Testing and Materials, Philadelphia, PA.  p. 55-76.

Delchmann,   W.B.   1981.   Halogenated Cyclic  Hydrocarbons.    In_:  Toxicology.
Patty's Industrial  Hygiene and Toxicology,  3rd ed..  Vol.  2B,  G.O.  Clayton
and E.E. Clayton, Ed.   John Wiley  and Sons,  Inc.,  NY.   p. 3605-3611.   (Cited
In U.S. EPA, 1982a)

DUley,  J.V.    1977.    Toxic  Evaluation  of Inhaled  Chlorobenzene.   NIOSH,
DHEW,  Cincinnati, OH.   Contract 210-76-0126.  (Cited In U.S.  EPA,  1985)

Federal Register.   1984.   Environmental Protection Agency.   Proposed  guide-
lines  for  carcinogenic risk assessment.   49 FR  46294-46299.
                                     -24-

-------
Gabor,  S.  and  K.   Raucher.   1960.   Studlen  zur  Bestlmmung der  zulasslgne
benzol   und   monochorbenzol   grenzkonzentratlonen.    J.    Hyg.   Epidemic!.
Mlcrobiol. Immunol.  4: 223-231.  (Ger.)  (CHed In U.S. EPA, 1985)

Glrard,  R.,  F.  Tolot, P.  Martin  and J. Bourret.   1969.   Serious  blood dis-
orders  and  exposure  to  chlorine  derivatives   of  benzene  (A   report  of  7
cases).  J. Med. Lyon.  50: 771-773.  (CHed 1n U.S. EPA, 1985)

Hansch,  C.  and  A.J.  Leo.   1981.   Medchem Project.   Issue No. 19.   Pomona
College, Claremont, CA.

Holllngsworth, R.L., V.K.  Rowe, F.  Oyen,  H.R.  Hoyle and H.C. Spencer.   1956.
Toxldty  of  paradlchlorobenzene:  Determination  on  experimental animals  and
human  subjects.  AMA Arch. Ind.  Health.   14:  138-147.  (Cited  In  U.S.  EPA,
1980b)

Horvath, A.L.   1982.  Halogenated  Hydrocarbons:  Solub1lity-H1sc1b1l1ty  with
Water.  Marcel Dekker, Inc., New York, NY.  p.  889.

Irish,  D.D.   1963.   Halogenated  Hydrocarbons:   II.  Cyclic.  ITK  Industrial
Hygiene and Toxicology, Vol. II,  2nd  ed.,  F.A.  Patty,  Ed.   Intersclence,  NY.
p. 1333-1361.  (Cited 1n U.S. EPA, 1980b)

Kanno,  S.  and  K.   Nojima.  1979.   Studies  on  photochemistry  of  aromatic
hydrocarbons.   V.   Photochemical   reaction  of  chlorobenzene  with  nitrogen
oxides In air.  Chemosphere.  8: 225-232.
                                     -25-

-------
Keskinova,  D.V.   1968.   The  effect of  d1methylcyclod1azomethane  In chloro-
benzene  solution  on mutagenesls  In  Actlnomyces  antlbiotlcus 400.   Genetlka.
4(8): 121-125.  (Cited  In U.S. EPA,  1985)

Khanln,  A.6.   1977.   Pathological changes In  the  general  nervous  system and
Internal  organs  of experimental  animals  after chronic continuous  Inhalation
of toxic  substances.  Chem. Abstr.   74: 97-106.  (Cited In U.S. EPA, 1985)

Knapp, W.K.,  Jr.,  W.M.  Busey  and  W.  Kundzlns.   1971.  Subacute oral toxldty
of monochlorobenzene  1n dogs  and rats.   Toxlcol.  Appl.  Pharmacol.   19:  393.
(Abstr.)  (Cited In U.S. EPA, 1980b)

Mabey, W.R.,  J.H.  Smith and R.T. Podoll.    1981.   Aquatic  Fate Process  Data
for  Organic  Priority  Pollutants.   Monitoring  and  Data  Support  Division,
Office of Water Regulations and Standards, Washington, DC.   EPA 440/4-81-014.

Merck and Company.   1978.   Summary of  Monochlorobenzene Bacterial  Mutagen
Test  (Ames  Test).   Office of  Pesticides and Toxic  Substances,  U.S.  EPA,
Washington,  DC.   TSCA  Sec  8(d)  submission  8DHQ-1078-0302.   (Cited  1n  U.S.
EPA, 1985)

Monsanto  Company.   1967a.   13-Week  oral  administration - dogs, monochloro-
benzene.    U.S.  EPA,   OPTS,  Washington.  DC.   TSCA  Sec   8(d)   submission
8DHQ-1078-0202(2).   (Cited 1n U.S. EPA, 1985)
                                     -26-

-------
Monsanto Company.   1967b.   3-Month subacute oral study  of  monochlorobenzene
in   rats.     U.S.   EPA,   Washington.   DC.    TSCA   Sec   8(d)   submission
8DHQ-1078-Q212(3).   (Cited 1n U.S.  EPA,  1985)

Monsanto  Company.    1976.    Litton   Blonetlcs   mutagenldty   evaluation   of
B10-76-86-CP  5535  (WGK):  Monochlorobenzene.  Office of  Pesticides  and  Toxic
Substances,  U.S. EPA,  Washington,  DC.   TSCA  Sec 8(d) submission  8DHQ-1078-
0214(1).  (Cited 1n U.S. EPA, 1985)

Monsanto  Company.    1978.    Industrial   Bio-Test  draft report   of   90-day
subacute vapor  Inhalation  toxldty  study  with  monochlorobenzene   In  beagle
dogs  and albino   rats.   U.S.  EPA,   OPTS,  Washington,   DC.    TSCA  Sec  8{d)
submission 8DHQ-1078-0202(1).  (Cited In U.S.  EPA,  1985)

NIOSH  (National  Institute for  Occupational Safety  and   Health).   1972.   The
1982 Registry of Toxic Effects of  Chemical Substances,  R.L.  Lewis and  R.L.
Tatken, Ed.   Cincinnati, OH.  (Cited 1n  U.S. EPA, 1985)

NTP  (National Toxicology  Program).   1983.   Cardnogenesls studies  of  chloro-
benzene  (CAS  No. 108-99-7)  In F344/N rats  and  B6C3F1 mice  (gavage studies).
NTP-82-90.   NIH Publ.  83-2517.  (Draft)

Plslaru,  V.   1960.   Modlflcarl  cronaxlmetrlce  In   1ntox1cat1a  cronlca  cu
benzen s1 monochlorobenzen.   Iglena.   9: 127-135.  (Cited In U.S. EPA,  1985)
                                     -27-

-------
Prasad, I.   1970.   Mutagenlc  effects of  the  herbicide  3',4'-d1chloroprop1o-
anHlde and   Its  degradation  products.   Can.  J.  M1crob1ol.   16:  369-372.
(CHed 1n  U.S. EPA, 1985)

Reich, H.   1934.   Puran  (Monochlorobenzol)-Verg1ftung bel  elnem zweljahrlgen
K1nde.  Verglftungsfalle.  5:  193-194.   (Ger.)  (CHed  In U.S.  EPA,  1985)

Rosenbaum,  N.D.,   R.S.   Block,   S.N.   Kremneva,  S.L.   Glnzburg   and   I.V.
PozhaMskll.   1947.  The use of chlorobenzene as  a  solvent  from the point  of
view of industrial  hygiene.  G1g. Sanlt.  12(1):  21-24.   (Cited In  U.S.  EPA,
1985)

Shelton, D.W. and  L.J. Weber.  1981.  Quantification of  the  joint  effects  of
mixtures  of  hepatotoxlc agents:  Evaluation  of  a  threshold  model   In mice.
Environ. Res.  26: 33-41.  (CHed 1n U.S.  EPA, 1985)

Simmon, V.F.,  E.S Rlccio and  M.V.  Pelrce.   1979.  In.  vitro  microbiological
genotoxiclty  assays of  chlorobenzene,  m-d1chlorobenzene,  o-dlchlorobenzene
and p-d1chlorobenzene.   Contract No. 68-02-2947.  U.S.  EPA,  ORD,  Washington,
DC.  (CHed In U.S. EPA, 1985)

Tarkhova,  L.P.   1965.   Maximum permissible  concentration of  chlorobenzene  In
the atmosphere.  G1g. Sanlt.  30:  8.  (CHed 1n  U.S. EPA, 1985)

U.S.  EPA.   1980a.   Guidelines  and   Methodology  Used In  the  Preparation  of
Health  Effects  Assessment  Chapters  of  the Consent   Decree  Water  Quality
Criteria.   Federal Register.  45:79347-79357.
                                     -28-

-------
U.S. EPA.   19805.   Ambient Water Quality Criteria  for  Chlorinated Benzenes.



Environmental   Criteria   and   Assessment   Office,   Cincinnati,  OH.    EPA



440/5-80-028.  NTIS PB 81-117392.







U.S.  EPA.    1982a.    Hazard   Profile   for  Chlorobenzene.   Prepared  by  the



Environmental Criteria  and Assessment Office,  Cincinnati,  OH,  OHEA  for  the



Office of Solid Waste and Emergency Response,  Washington, DC.







U.S. EPA.  1982b.  Effects of Monochlorobenzene  on  the  In  vitro Induction of



Chromosomal  Aberrations  1n Chinese Hamster  Ovary Cells.  Prepared  for  U.S.



EPA by Bloassay Systems Corp.   (Cited  In  U.S.  EPA, 1985)







U.S. EPA.   1983.   Methodology and Guidelines for Reportable  Quantity Deter-



minations  Based on  Chronic   Toxldty  Data.   Prepared  by  the  Environmental



Criteria and Assessment Office;  Cincinnati, OH,  OHEA  for the  Office  of Solid



Waste and Emergency Response,  Washington, DC.







U.S.  EPA.    1985.    Health Assessment   Document  for  Chlorinated  Benzenes.



Environmental   Criteria   and   Assessment   Office,   Cincinnati,  OH.    EPA



600/8-84-015F.   NTIS PB 85-150332.







Varshavskaya,  S.P.    1967.   Comparative  toxlcologlcal characteristics   of



Chlorobenzene and  dlchlorobenzene (ortho- and  para-1somers)  1n relation  to



the sanitary protection  of water bodies.  (Rus.  trans.)  Hyg.  San.   33(10):



17-23.   (Cited  In U.S. EPA, 1980b)
                                     -29-

-------
- -I
           Velth,  G.D.,  D.L.  DeFoe and B.V. Bergstedt.  1979.  Measuring and  estimating
           the  bloconcentratlon factor of  chemicals  1n fish.   J.  Fish Res.  Board  Can.
           36:  1040-1048.

           Williams,  R.T.   1959.  The  Metabolism of  Halogenated Aromatic Hydrocarbons.
           Detox1cat1on  of  Mechanisms,  2nd ed.  John  WHey and Sons, Inc.,  NY.  p.  237.
           (Cited  In  U.S. EPA,  1985)

           Wilson,  J.T., C.G.  Enfleld, W.J.  Dunlap,  R.L. Cosby,  D.A.  Foster and  L.B.
           Baskln.   1981.   Transport  and  fate of selected organic  pollutants  In a sandy
           soil.   J.  Environ.  Qual.   10:  501-506.

           Zoeteman,  B.C.J.,  K. Harmsen,   J.B.H.J.  Unders,  C.F.H.  Morra and W. Slooff.
           1980.-  Persistent  organic pollutants  1n river water  and  groundwater  of The
           Netherlands.  Chemosphere.   9:  231-249.
                                               -30-

-------
                                                  APPENDIX



                                      Summary Table for Chlorobenzene
Species
Inhalation
AIS rat
AIC rat
Oral
AIS dog
AIC dog
Maximum dog
composite
score
Experimental
Dose/Exposure

53 mg/kg/day
53 mg/kg/day

27.3 mg/kg/day
for 90 days
27.3 mg/kg/day
for 90 days
55 mg/kg/day
for 90 days
(RVd = 2.0)
Acceptable Intake
Effect (AIS or AIC)

focal lesions In liver, 3.7 mg/day
kidney tubules; hepatic
and renal congestion;
decreased SGOT
focal lesions In liver. 0.4 mg/day
kidney tubules; hepatic
and renal congestion;
decreased SGOT

none 19.1 mg/day
none 1.9 mg/day
Immature leukocytes, con- 8
junctlvltls, vomiting and
diarrhea (RVe=4)
Reference

Dllley, 1977
Dllley, 1977

Monsanto, 1967a
Monsanto. 1967a
Monsanto, 1967a
ND = Not derived

-------