TECHNICAL REPORT DATA
                            (Heat retd Inspections on the reverse be fort completing)
 1. REPORT NO.
  EPA/60Q/8-88/057
                              2.
             3. RECIPIENT'S ACCESSION NO.
                   PB88-176367
4. TITLE AND SUBTITLE

  Health  Effects Assessment for  1,2,4-Trichlorobenzene
                                                           5. REPORT DATE
                                                           «. PERFORMING ORGANIZATION CODE
 '. AUTHOR(S)
                                                            I. PERFORMING ORGANIZATION REPORT NO
«. PERFORMING ORGANIZATION NAME AND AOORE5S
                                                           10. PROGRAM ELEMENT NO.
                                                           11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
 Environmental  Criteria and Assessment  Office
 Office of  Research and Development
 U.S. Environmental Protection Agency
 Cincinnati.  OH  45268	
              13. TYPE Of REPORT AND PERIOD COVERED
              14. SPONSORING AGENCY CODE

                EPA/600/22
15. SUPPLEMENTARY NOTES
16. ABSTRACT
   This report  summarizes and evaluates  information relevant to a preliminary interim
 assessment  of  adverse health effects associated with specific chemicals  or compounds.
 The Office  of  Emergency and Remedial Response (Superfund) uses these documents in
 preparing cost-benefit analyses.under Executive Order 32991 for decision-making under
 CERCLA.  All estimates of acceptable intakes  and carcinogenic potency  presented in
 this document  should be considered as preliminary and reflect limited  resources
 allocated to this project.  The intent  in  these assessments is to suggest  acceptable
 exposure levels  whenever sufficient data are  available.   The interim values presented
 reflect the relative degree of hazard associated with exposure or risk to  the
 chemical(s) addressed.  Whenever possible,  two categories of values have been
 estimated for  systemic toxicants (toxicants for which cancer is not the  endpoint of
 concern).   The first, RfD5 or subchronic reference dose, is an estimate  of an exposure
 level that  would not be expected to cause  adverse effects when exposure  occurs during
 a limited time interval.  The RfD is an estimate of an exposure level  that would not
 be expected to cause adverse effects when  exposure occurs for a significant portion
 of the lifespan.   For compounds for which  there is sufficient evidence of
 carcinogenicity,  qj*s have been computed,  if  appropriate, based on oral  and
 inhalation  data  if available.
7.
                                KEY WORDS AND DOCUMENT ANALYSIS
                  DESCRIPTORS
b.lDENTIFIERS/OPEN ENDED TERMS  C. COSATI Field/Group
8. DISTRIBUTION STATEMENT

 Public
19. SECURITY CLASS (ThuReportl

  Unclassified	
21. NO. OF PAGES
                                              20. SECURITY CLASS (Thispagt)
                                                Unclassified
                                                                        22. PRICE
   P«nn 2220-1 (R«». 4-77)   PREVIOUS EDITION i* OBSOLETE

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                                             EPA/600/8-88/057
                                             June,  1987
          HEALTH EFFECTS ASSESSMENT
          FOR  1,2,4-TRICHLOROBENZENE
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
      OFFICE OF RESEARCH AND DEVELOPMENT
    U.S. ENVIRONMENTAL PROTECTION AGENCY
            CINCINNATI, OH 45268

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                                  DISCLAIMER


    This   document  has   been   reviewed   In   accordance   with   the   U.S.
Environmental  Protection Agency's  peer and  administrative review policies
and approved for publication.  Mention  of  trade  names  or  commercial products
does not constitute endorsement or recommendation for use.
                                     11

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                                    PREFACE
    This  report  summarizes and evaluates Information relevant  to  a prelimi-
nary  Interim  assessment  of adverse health effects  associated with  1,2,4-trl-
chlorobenzene.   All  estimates  of  acceptable Intakes  and carcinogenic potency
presented  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
TOXLINE,  CANCERLINE  and the CHEMFATE/OATALOG data bases.  The  basic litera-
ture  searched supporting this  document 1s  current up to  June,  1986.  Secon-
dary  sources  of  Information have  also  been  relied  upon  1n the preparation of
this  report  and  represent large-scale health assessment  efforts  that  entail
extensive  peer  and  Agency  review.   The  following Office of  Health  and
Environmental Assessment  (OHEA) sources have been extensively utilized:

    U.S.  EPA.   1980a.    Ambient  Water  Quality  Criteria  Document  for
    Chlorinated   Benzenes.   Prepared  by  the   Office   of   Health  and
    Environmental  Assessment,  Environmental  Criteria   and   Assessment
    Office,  Cincinnati,  OH  for  the  Office  of Water  Regulations  and
    Standards, Washington, DC.  EPA 440/5-80-028.  NTIS  P881-117392.

    U.S.  EPA.    1980b.    Hazard   Profile  for   1,2.4-Trlchlorobenzene.
    Prepared  by   the Office  of  Health   and  Environmental  Assessment,
    Environmental  Criteria and  Assessment  Office,  Cincinnati, OH  for
    the Office of Solid Waste, Washington, DC.

    U.S.  EPA.   1983a.    Reportable Quantity  Document  for   l,2,4-Tr1-
    chlorobenzene.   Prepared  by  the Office of Health and Environmental
    Assessment,  Environmental  Criteria and Assessment  Office,,  Cincin-
    nati, OH  for the Office of  Emergency and Remedial  Response,  Wash-
    ington, DC.

    U.S.  EPA.   1985a.    Health  Assessment  Document   for   Chlorinated
    Benzenes.  Office of Health and Environmental Assessment,  Environ-
    mental  Criteria  and  Assessment   Office,   Cincinnati,  OH.    EPA
    600/8-84-015F.  NTIS PB85-150332.

    U.S.  EPA.    1986.    Integrated Risk  Information   System   (IRIS).
    Reference Dose  (RfD) for  Oral  Exposure for  1,2,4-Tr1chlorobenzene.
    Online  (verification  date  2/26/86).   Office of  Health and  Environ-
    mental  Assessment,   Environmental  Criteria   and  Assessment  Office,
    Cincinnati, OH.

    The Intent 1n  these  assessments  1s to suggest  acceptable exposure  levels
for   noncardnogens   and   risk  cancer  potency  estimates   for  carcinogens
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.
Nevertheless,  the Interim  values  presented reflect the  relative  degree  of
hazard or risk associated with exposure to the chemlcal(s) addressed.
                                      111

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    Whenever  possible,  two categories  of  values  have  been  estimated  for
systemic  toxicants  (toxicants  for  which  cancer  Is  not   the endpolnt  of
concern).   The  first, RfD$  (formerly  AIS)  or subchronlc reference  dose,  1s
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  In  ambient  air  or  water  where  lifetime
exposure   Is  assumed.    Animal   data  used  for   RFD$   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.   These
values   are  developed   for   both  Inhalation   (RfOgi)  and   oral   (RfO$o)
exposures.

    The  RfO  (formerly  AIC)  1s  similar  In  concept and addresses  chronic
exposure.   It Is  an estimate of  an exposure level  that  would not be expected
to cause  adverse effects  when  exposure  occurs  for a significant  portion  of
the Hfespan  [see U.S. EPA  (1980c)  for  a  discussion of  this  concept].   The
RfO  1s  route-specific  and  estimates  acceptable  exposure  for either  oral
(RfDrj)  or  Inhalation  (RfDi)  with  the   Implicit   assumption   that  exposure
by other routes 1s  Insignificant.

    Composite  scores  (CSs) for  noncarclnogens  have  also  been  calculated
where  data  permitted.   These  values  are  used  for  Identifying  reportable
quantities  and  the  methodology  for  their  development  1s explained  In  U.S.
EPA (1983b).

    For compounds for which there Is sufficient evidence of cardnogenlclty
RfD$  and  RfO values  are  not derived.   For  a discussion of  risk  assessment
methodology  for  carcinogens refer  to  U.S.  EPA  (1980c).   Since cancer Is  a
process  that  Is  not characterized by  a  threshold,  any exposure  contributes
an Increment  of  risk.  For carcinogens,  q-]*s have been  computed,  1f  appro-
priate, based on  oral and  Inhalation data If available.
                                      1v

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                                   ABSTRACT


    In  order to  place  the  risk  assessment  evaluation  In  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
Interpretation and use of the quantitative estimates presented.

    An  RfD$g of  14  mg/day  and  an RfOg  of  1.4  mg/day  were calculated  for
1,2,4-tMchlorobenzene based on a  NOAEL of 20 mg/kg/day  from a  90-day gavage
study  1n  male rats  (Carlson and  Tardlff,  1976).   Altered enzyme  activities
were  observed at all  treatment  levels  but  Increased  relative Hver  weight
was observed only at  40 mg/kg/day,  the highest  dose  tested.   The U.S.  EPA
(1986)  also  derived  an  RfO  of  1.4 mg/day on the  same basis.   A CS  of  12.4
was calculated  for oral  exposure  to 1,2,4-trlchlorobenzene (U.S.  EPA,  1983a)
based on  Increased adrenal weights 1n rats In a mult1generation  reproduction
study (Robinson et a!., 1981).

    An  RfO$i of  1-75  mg/day and  RfDj  of 0.18 mg/day were  calculated  from
a NOAEL  In  rats exposed to 3 ppm  (22 mg/m3)  for  3 months (Watanabe  et  a"!.,
1978).  Increased urinary uroporphyrln was noted at 10  ppm.

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                               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  John  Helms  (Office  of
Toxic  Substances) was  the 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 Air 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 the following:

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

Technical  support services  for  the document  series  was  provided  by  the
following:

    Bette Zwayer,  Jacky Bohanon and K1m Davidson
    Environmental  Criteria and Assessment Office
    Cincinnati, OH
                                      v1

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TABLE OF CONTENTS

1.
2.


3.










4.








5.
6.




ENVIRONMENTAL CHEMISTRY AND FATE 	
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1. ORAL 	
2.2. INHALATION 	
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 	
3.1. SUBCHRONIC 	
3.1.1. Oral. . . 	
3.1.2. Inhalation 	
3.2. CHRONIC. . . 	 	
3.2.1. Oral. 	
3.2.2. Inhalation 	
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral. . 	
3.3.2. Inhalation 	
3.4. TOXICANT INTERACTIONS 	
CARCINOGENICITY 	
4.1. HUMAN DATA 	
4.1.1. Oral 	
4.1.2. Inhalation 	 „
4.2. BIOASSAYS 	
4.2.1. Oral. 	
4.2.2. Inhalation 	
4.3. OTHER RELEVANT DATA 	
4.4. WEIGHT OF EVIDENCE 	
REGULATORY STANDARDS AND CRITERIA 	
RISK ASSESSMENT 	
6.1. SUBCHRONIC REFERENCE DOSE (RfDs) 	
6.1.1. Oral (RfDso) 	
6.1.2. Inhalation (RfDcr) 	
Page
. . . 1
. . . 3
. . . 3
. . . 3
. . . 4
. . . 4
. . . 4
. . . 5
. . . 5
. . . 5
6
. . . 6
. . . 6
. . . 7
7
. . . 8
. , . 8
. . . 8
8
. . . 8
. . . 8
8
. . . 8
9
, , , 10
11
, , , 11
. . . 11
. . . 11
       V11

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                           TABLE  OF  CONTENTS  (cent.)

                                                                        Page
     6.2.   REFERENCE DOSE (RfO)	    11

            6.2.1.   Oral (RfD0)	    11
            6.2.2.   Inhalation (RfDj) 	    14

     6.3.   CARCINOGENIC POTENCY (q-|*)	    15

            6.3.1.   Oral	    15
            6.3.2.   Inhalation	    15

 7.  REFERENCES	    16

APPENDIX: Summary Table for 1,2,4-TMchlorobenzene	22

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                             LIST OF ABBREVIATIONS
CS                      Composite score
EPN                     0-ethyl 0-para-n1trophenyl phenylphosphorothloate
LOAEL                   Lowest-observed-adverse-effect  level
MED                     Minimum effective dose
NOAEL                   No-observed-adverse-effect level
ppm                     Parts per million
RfO                     Reference dose
RfDj                    Inhalation  reference dose
RfDrj                    Oral reference dose
RfOs                    Subchronlc  reference dose
RfD$i                   Subchronlc  Inhalation reference dose
RfD$g                   Subchronlc  oral reference dose
RQ                      Reportable  quantity
RVd                     Dose-rating value
RVe                     Effect-rating value
                                       1x

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                      1.   ENVIRONMENTAL CHEMISTRY AND FATE

     Selected  chemical  and  physical   properties  and  environmental   fate  of
 1,2,4-trlchlorobenzene are  presented  In Table 1-1.
     In  the atmosphere,  1,2,4-tMchlorobenzene  1s  expected to exist primarily
 In  the vapor phase  and  would be subject to removal by  reaction with photo-
 chemlcally generated HO   radical.   Based  on  an  observed  reaction  rate
 constant  of  0.532xlO~13 cm3/molecule-sec  at  23°C  (Atkinson,  1985)  and  an
 ambient  HO  radical  concentration  of  8.0x10* molecule/sec.   The  hydroxyl
 reaction half-life  1s -18.8 days.
     In  water, 1,2,4-trlchlorobenzene  should adsorb to  suspended  solids  and
 sediments  and  may  bloaccumulate   1n  some  aquatic organisms.   Significant
 volatilization  from  water  Is  expected,  since  a volatilization  half-life  of
 11-22  days was  determined  during mesocosm  experiments with  aerated  seawater
 (Wakeham   et  al.,   1983);  a  volatilization  half-life  of  6.9  hours  was
 estimated  for a  river   1 m deep flowing at 1  m/sec with  a wlndspeed of  3
 m/sec,  based  on  the method  of  Lyman et  al.   (1982).   The overall  aquatic
 half-lives  for  1,2,4-trlchlorobenzene In rivers, lakes  and  groundwater were
 estimated  to  be  0.3-3,  3-30 and 30-300 days,  respectively  (Zoeteman et al.,
 1980).
     In  soil,  1,2,4-trlchlorobenzene  Is  expected  to  remain strongly  sorbed
 and  therefore will   not  leach  appreciably  Into  the  groundwater;  however,
 1,2,4-trlchlorobenzene has  been  detected  In  some  groundwater  samples  which
 Indicates  that  H can be  transported  In  soils under certain  conditions.   A
 blodegradatlon  study (Marlnucd   and  Bartha,  1979)   suggests   that   this
compound may  blodegrade  slowly  1n  aerobic  soil,  but  1t 1s not expected  to
blodegrade In groundwater (Roberts  et al.,  1980).


0093h                               -1-                              12/03/86

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                                   TABLE  1-1

       Selected Chemical and Physical Properties and Environmental  Fate
                           of 1,2,4-Trlchlorobenzene
        Property
                                  Reference
CAS number:

Chemical class:

Molecular weight:

Vapor pressure:

Water solubility:

Log octanol/water
partition coefficient:

Bloconcentratlon factor:
Soil adsorption
coefficient:
Half-lives In
  Air:
  Surface Water:
  Soil:
120-82-1

haloaromatlc compound

181.46

0.45 mm Hg at 25°C

25-35 mg/l at 25°C


4.12

1200-3200, rainbow trout
(Salmo qalrdnerl)
2800, fathead minnow
{Plmephales proroelas)
182-815, blueglll sunflsh
(Lepomls macrochlrus)


-1000-5000
-19 days (estimated)
0.3-30 days (estimated)
NA
Mackay and Shu1, 1981

Hackay and Shu1, 1981


Hansch and Leo, 1986

Oliver and N11m1, 1983

Ve1th et a!., 1979

Barrows et a!., 1980;
U.S. EPA, 1980a
Frlesel and Stelner,
1984; Chlou et al.,
1983; Wilson et al.,
1981; U.S. EPA, 1985a
Atkinson, 1985
Zoeteman et al., 1980
NA
NA = Not available
009 3 h
         -2-
              12/03/86

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           2.  ABSORPTION FACTORS IN HUMANS AND'EXPERIMENTAL ANIMALS
 2.1.    ORAL
    Male Charles River rats and  female  rhesus  monkeys excreted a mean of 84
 and  40%, respectively, of  the  radioactivity  associated  with an oral dose of
 10  mg  l4C-l,2,4-tr1chlorobenzene/kg  1n  the  urine  In  24 hours  while fecal
 elimination  accounted for  only 11 and 1%, respectively (L1ngg et al., 1982).
 These  results Indicate that this compound  Is absorbed from the gastrointes-
 tinal  tract  of these species to at least 89  and 99% of the  dose In male rats
 and female monkeys,  respectively.
 2.2.    INHALATION
    As   Indicated  by systemic  effects   observed  1n the  Inhalation toxlclty
 study  performed  by  Koclba  et  al.  (1981), 1,2,4-trlchlorobenzene Is absorbed
 by  the  respiratory  tract.   This  study  was not  designed  to give Information
 on absorption  rates;  therefore, no further quantitative data are available.
0093h                               -3-                              12/03/86

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                3.  TOXICITY IN HUMANS AND EXPERIMENTAL  ANIMALS
3.1.   SUBCHRONIC
3.1.1.   Oral.   Carlson and  Tardlff  (1976)  observed  no  effects  on  weight
gain  nor  consistent alteration  In  hemoglobin content  or  packed  cell  volume
1n  male  CD  rats  (6  animals/group)  given  0,  10,  20  or  40  mg/kg/day,
1,2,4-trkhlorobenzene  by  the  oral  route  for  90  days.   At 40  mg/kg/day,
statistically  significant  Increased  (p<0.05)   llver-to-body  weight  ratios
persisting  throughout  a 30-day  recovery period  were  observed.  Altered liver
enzyme activities were  observed 1n all treated groups.
    Groups  of five  female rats  (strain not reported)  received dally  oral
doses of  0, 50,  100  or 200 mg 1,2,4-trlchlorobenzene/kg/day In corn  oil  by
gavage  for   30,  60,  90  or 120  days  (Carlson,  1977).   After   30  days  of
exposure, significant   Increases  1n  liver  porphyrlns were observed at  >100
mg/kg  and  1n  urinary porphyrlns  at  200   mg/kg.   Slight  but  significant
Increases were  also  observed  In liver  weights  at  200  mg/kg.   Only  liver
weights  were Increased when  the  compound was  administered for  60  days.
After 90 days of  exposure,  slight but  significant  Increases  In  "liver  weights
at >50  mg/kg, 1n liver  porphyrlns  at  >100  mg/kg and 1n  urine porphyrlns  at
200  mg/kg   were  observed.   A  significant Increase  In   liver  porphyrlns  was
found after 120  days  of  exposure  at  levels  >50  mg/kg.  Increased  urinary
excretion of  
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3.1.2.    Inhalation.   Koclba  et  al.  (1981)  exposed  20  male  Sprague-Oawley
rats, 4  male New Zealand rabbits and 2 male beagle dogs to concentrations of
0,  30  ppm  (223  mg/m3)  or  100  ppm (742 mg/m3)  1,2,4-tMchlorobenzene  for
7  hours/day,  5  days/week for a total of 30 exposures In 44 days.  No signif-
icant  treatment-related effects  In  any  of the species  tested  were observed
by  gross and comprehensive  hlstologlcal examination.  At  the  100 ppm level,
Increased  liver  weights  were  observed   In  dogs  and   rats.   Additionally,
Increased  kidney  weights were observed In rats.   Rats  exposed  to 1,2,4-trl-
chlorobenzene  at  30  or  100  ppm exhibited   Increased  urinary  excretion  of
porphyrln, which  was  Interpreted as a compound-specific physiological effect
rather  than  a  toxic  effect.   The authors  proposed that  the urinary porphyrln
excretion  was  the result of P-450  Induction  rather  than a result of altera-
tions  In heme destruction or  synthesis.   This hypothesis was  not specific-
ally  tested.   This Interpretation was  supported  by a  follow-up  study.   The
same  team of  Investigators  exposed Sprague-Oawley  rats  of  both  sexes  to
1,2,4-trlchlorobenzene  at 0,  3  or  10 ppm (0, 22 or  74  mg/m3),  6 hours/day,
5  days/week  for  3 months.   As   reported  In  an  abstract  (Hatanabe  et  al.,
1978),   urinary  excretion  of  porphyrlns  was  slightly   Increased  at  74.2
mg/m3  but   returned   to  control  range   2-4  months  postexposure.   Thus,
porphyrln  excretion appeared to  be  the most  sensitive  Indicator  of exposure
In  rats.    Exposure   to  trlchlorobenzene at  22.3  mg/m3   did  not  cause
Increased  porphyrln  excretion;  therefore, 22.3 mg/m3 was considered a  NOEL
for rats.
3.2.   CHRONIC
3.2.1.   Oral.   Pertinent  data   regarding chronic  oral  exposure  to  1,2»
4-trlchlorobenzene could not be located 1n the available literature.
0093h                               -5-                              12/29/86

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3.2.2.   Inhalation.   Pertinent  chronic Inhalation  toxldty  data could  not
be located  1n the available literature.
3.3.   TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1.   Oral.  KHchln and Ebron  (1983) gave  oral  doses  of 0, 36, 120,  360
and  1200  mg/kg/  1,24-trlchlorobenzene  dissolved   In  corn oil  to  pregnant
Sprague-Dawley  (CD  strain)   rats   (>6/group)  on  days  9-13  of  gestation.
Mortality  Increased to 100  and 22%  In the  120 and  360 mg/kg/day  groups,
respectively.   Body weight  gains  were greatly  reduced  at  360  mg/kg/day.
Signs of maternal hepatotoxldty,  reflected by a slight and moderate  hepato-
cellular  hypertrophy,  were  observed   In  1/9  and  7/8 rats  at  120  and  360
mg/kg/day,  respectively,   but  not  at  36 mg/kg/day.    These  hlstologlcal
lesions  were not  accompanied by  changes   In  maternal  I1ver-to-body  weight
ratios or  hepatic  mlcrosomal  protein content.  1,2,4-Trlchlorobenzene was  a
strong Inducer of hepatic enzymes  at  120 and  360 mg/kg/day.   Only fetuses In
the  0 and  360 mg/kg/day  groups  were  examined  for  1,2,4-trlchlorobenzene-
Induced  embryonic   effects.    No  statistically  significant  differences   In
resorptlons,  embryolethaHty  or abnormalities were  reported; however, 3/12
treated  litters exhibited  embryolethalHy  as  compared   with  0/12  1n  the
control  Utters.  Several embryonic parameters were  significantly  decreased^
Including  embryonic  head  length, crown-rump length, somite number and  total
embryo protein content (reduced 23%).
    Robinson  et  al.  (1981)  gave  male  and female  Charles  River rats  (each
treatment  group contained  17-23 Utters) 0,  25, 100 or  400 ppm  In  drinking
water  1n  a 3-generatlon reproductlve-teratogenlc effect  study.  The  authors
estimated  that  at   83  days  of  age the  FQ rats had received approximately
the  following  doses:  males  2.5,  8.9  and  33  mg/kg/day for  the  25,  100  and
400 ppm  groups,  respectively, and  females  3.7,  14.8 and 53.6 mg/kg/day  for


0093h                               -6-                              12/29/86

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 the same  respective  nominal exposure concentrations.   At  400 ppm, signifi-
 cantly  enlarged adrenals  were  observed  at 95  days  of  age  (p<0.006) In both
 sexes  of  the  FQ and  F,  generations.   There  were no  effects on  fertility,
 survival,  growth,  locomotor  activity  or  blood  chemistries.
 3.3.2.    Inhalation.    Inhalation  data   concerning   the  teratogenlclty  of
 1,2,4-trlchlorobenzene  were  not  available.
 3.4.   TOXICANT INTERACTIONS
    Townsend  and Carlson  (1981)  demonstrated  that a dose  of  181.5 mg/kg (1
 mmol/kg)  of 1,2,4-trlchlorobenzene given to Swiss mice for 7  days protected
 them from  the  toxic effects  of malathlon, malaoxon, parathlon  and paraoxon.
0093H                               -7-                              12/03/86

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                              4.  CARCINOGENICITY
4.1.   HUMAN  DATA
4.1.1.   Oral.   Human  oral  carc1nogen1dty  data could not be  located  In  the
available  literature.
4.1.2.   Inhalation.   Human  Inhalation  cardnogenlcUy  data  could  not  be
located  1n the available literature.
4.2.   BIOASSAYS
4.2.1.   Oral.   Oral  bloassays  could  not  be  located  In  the  available
literature.
4.2.2.   Inhalation.   Inhalation  bloassays  could  not  be  located  In  the
available  literature.   The  NTP  (1986)  has  not  scheduled  1,2,,4-tMchloro-
benzene  for carclnogenlclty testing.
4.3.   OTHER RELEVANT DATA
    Yamamoto  et  al.  (1957)  applied 0.03  ml/application of  a   30 and 60%
solution of 1,2,4-tr1chlorobenzene  1n acetone to the  skin  of male and  female
mice  twice  weekly  for  2  years.   Mean  survival  days  were  significantly
reduced  In  treated mice of both  sexes  at 60%  and  In females  at  30%.  Nine
different  tumors  were  found  In the high-dose  males  as  compared with  three
and  eight  tumors  found  1n the low-dose  and control groups,  respectively.
The  English  translation of this  Japanese study did  not provide  sufficient
detail of  expressed Incidence  data as  the number of  animals with  tumors/
animals examined.
    Negative  results were  obtained 1n  the  Salmonella  typhlmurlum  reverse
mutation assay  1n  strains  TA98, TA100,  TA1535,  TA1537 and TA1538 with  or
without  rat liver  S-9  metabolic activation  (Schoeny et al., 1979;  Lawlor  et
al.,  1979).   In  general,  this  test system  1s Insensitive  to   chlorinated
compounds (Rlnkus and Legator, 1980).


0093h                               -8-                              09/20/86

-------
 4.4.    HEIGHT OF  EVIDENCE
     Only qualitative evidence concerning the possible carcinogenic effect of
 1,2,4-trlchlorobenzene was  available.   Yamamoto  et  al.  (1957)  observed a
 tumorlgenlc   effect  of  1,2,4-trlchlorobenzene  In a  skin-painting  test 1n
 mice.   These data are Inadequate for determining carcinogenic risk 1n humans
 (U.S.  EPA,  1985a).  According to  the guidelines  proposed  by EPA for evalua-
 tion  of carcinogenic potential to humans (U.S. EPA, 1986a), 1,2,4-trlchloro-
 benzene  Is  an EPA  Group  D  -  Not  Classified  and IARC  Group  3  chemical,
 meaning that  available data  are  Inadequate  for assessment.
0093h                               -9-                              12/03/86

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                     5.   REGULATORY STANDARDS AND  CRITERIA

    An  ambient water  quality  criteria  for  the  trlchlorobenzenes  was  not
derived by  the U.S.  EPA (1980a).  ACGIH  (1986) adopted a  celling  limit  of  5
ppm  (-40  mg/m3) for 1,2,4-tr1chlorobenzene.  An  RfO of 1.4 mg/day  for  a 70
kg man  (0.02 mg/kg/day)  has  been verified (U.S.  EPA, 1986b).   This value was
obtained  by applying  an  uncertainty  factor  of  1000 to the  NOAEL  of  20
mg/kg/day 1n the Carlson and Tardlff (1976) 90-day study In male CD rats.
0093h                               -10-                             12/03/86

-------
                              6.  RISK ASSESSMENT
6.1.   SUBCHRONIC REFERENCE DOSE  (RfD$)
6.1.1.   Oral  (RfDSQ).   U.S.  EPA  (1986b)  derived an  RfO  of 1.4 mg/day  for
a  70 kg man based  on  an oral subchronlc NOAEL  of  20  mg/kg/day (Carlson  and
Tardlff,  1976)  (Section 6.2.1.).   An uncertainty  factor  of  1000  (10  for
Interspecles extrapolation, 10  for  Intraspedes  variation  and 10 for the  use
of  subchronlc  data) was used.   An  RfD~0  of 0.2  mg/kg/day or  14  mg/day  1s
calculated  based on  the  same  NOAEL  but  omitting  the  factor  of  10 for  a
subchronlc study.
6.1.2.   Inhalation  (RfD$I).    In  the study  by  Watanabe  et  al.   (1978),
rats  were  exposed  to  0,  3 or  10 ppm  (0,  22.3  or  74.2  mg/m3)  1,2,4-trl-
chlorobenzene  for 6 hours/day,  5 days/week  for  3  months.   Increased urinary
porphyrln  excretion was  observed  at  74.2 mg/m3  but  not  at 22.3  mg/m3.
Thus,  a  NOEL  of  2.5  mg/kg/day  [transformed  dose  was  calculated  using
exposure data  provided  by the authors and  by  assuming an  Inhalation rate  of
0.223  mVday  (U.S.  EPA,  1980b)  and  a  body weight  of  0.35  kg (U.S. EPA,
1985b)  for  the  rat]  was defined  (U.S.  EPA, 1985a).  Koclba et al.  (1981)
provided  further support  for  this  estimate by  reporting a  rat  Inhalation
LOAEL  of  30 ppm (223  mg/m3),  5  days/week  for  -6  weeks,  based on  the same
endpolnt.   An  RfD$I 1s  calculated  by dividing  the  NOAEL of  2.5  mg/kg/day
by  an  uncertainty  factor  of  100  (10  for  Interspecles extrapolation  and  10
for  Intraspedes variation)  to  yield 0.025 mg/kg/day  or  an  RfDST  of  1.8
mg/day for a 70 kg man.
6.2.   REFERENCE DOSE (RfD)
6.2.1.   Oral  (RfDQ).    U.S.   EPA  (1986b)  based  the  RfD  for 1,2,4-trl-
chlorobenzene of  1.4 mg/day on  a 90-day study by  Carlson  and  Tardlff  (1976)
In which male  CO rats  were given oral doses of  0,  10, 20  and  40 mg/kg/day.
0093h                               -11-                             06/17/87

-------
Induction  of  the  enzymes  of  xenoblotlc  metabolism  and  Increased  Hver-
to-body  weight  ratio,  which persisted  for  30 days,  was  observed  at  40
mg/kg/day.   Enzyme Induction,  but not  altered  llver-to-body weight  ratio,
was  observed at  20 mg/kg/day.   Although enzyme  Induction  was   a  sensitive
endpolnt,  1t  was  not  necessarily an adverse  effect;  therefore,  20  mg/kg/day
was  considered  a  NOAEL.  This NOAEL was  divided by an uncertainty  factor of
1000  (10 for  Interspedes  extrapolation, 10 for  Intraspecles variation  and
10  for  a subchronlc study)  to  yield  an RfO of  0.02 mg/kg/day or 1.4  mg/day
for  a  70 kg man.   The  NOAEL  defined  1n the  Carlson and Tardlff  (1976) study
was  supported  by  a  range of  values  defined 1n  other  subchronlc  studies.
NOAELs  of  14.8 and 8.9  mg/kg/day for  female and male  rats,  respectively,
were  reported 1n  the multlgeneratlon  reproduction  study by  Robinson  et  al.
(1981),  and  a 120-day  LOAEL  of  50  mg/kg/day based  on  the   endpolnt  of
Increased liver porphyMn  In rats was observed as well (Carlson,  1977).
    An  oral   CS of  12.4  (Table  6-1)  based  on  a LOAEL  defined  by a  multi-
generation reproduction  study (Robinson et al.,  1981)  In  which  rats  exposed
to  400  ppm of  1,2,4-trlchlorobenzene  1n drinking  water  exhibited  Increased
adrenal  weight  In  the  first two generations, but  not  the third,  was  derived
by  U.S.  EPA  (1983a).    No  effect  on adrenal  weight was observed  at 100  ppm.
Doses expressed as  mg/kg/day based on  water consumption  data were provided
by  the  Investigators;   however,  these  were not  used  by U.S. HPA (1983a)  to
calculate  the MED.   The  preferred  approach  1s to  use  the  experimentally
determined  values  rather  than  reference  values;   however,  the  difference
between  the  resulting  MED values  1s  trivial (33.5 and  37.2  mg/day,  respec-
tively).  The CS of 12.4 calculated by  U.S.  EPA  (1983a) 1s adopted  as  the CS
for  oral  exposure  to  1,2,4-trlchlorobenzene  for  the  purposes  of  this
document.
0093h                               -12-                             06/17/87

-------





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-13-
09/20/86

-------
6.2.2.   Inhalation   (RfDj).    No    Information   concerning   the   chronic
Inhalation  toxldty of  1,2,4-tMchlorobenzene  was  available;  however,  the
RfOSI  of  0.025 mg/kg/day  (see Section 6.1.2.)  based  on a  subchronlc  NOAEL
of urinary  porphyrln  excretion (Watanabe  et al., 1978) may  be  divided  by an
additional  factor  of  10  to  approximate  chronic exposure.   This  yields  an
RfOj of 2.5xlO~3 mg/kg/day or 0.18 mg/day  for a  70 kg man.
    U.S. EPA  (1983a) derived  an  Inhalation  CS (see  Table  6-1)  for  1,2,4-tM-
chlorobenzene  based  on   an   Inhalation  LOAEL  defined  by  Watanabe  et  al.
(1978).   In that  study,  rats exposed  to  10 ppm  (74  mg/ma)  of  l,2,4-tr1-
chlorobenzene, 6 hours/day,  5 days/week  for 3 months exhibited a  reversible
Increase 1n uroporphyrln.   No effect  on  uroporphyrln levels was observed  at
22.3  mg/m3  with the  same  exposure  schedule.   A  few  discrepancies  between
current and previous  methodology  for deriving  a CS were  noted.   U.S.  EPA
(1983a) calculated  a  transformed dose assuming  continuous exposure,  a  human
Inhalation  rate  of  20  mVday and  an absorption  coefficient  of  0.5;  the
transformed dose was  divided by  a factor  of 10  to  expand from  subchronlc  to
chronic exposure.   Using current methodology,  a  transformed dose 1s calcu-
lated  by  assuming  continuous  exposure, an   Inhalation   rate  of  0.223 mVday
for the rat  (U.S.  EPA, 1980b) and a body weight of  35  kg (U.S. EPA,  1985b).
When  the  transformed  dose was divided by 10 for a  subchronlc  study, multi-
plied by the cubed  root of  the animal  body  weight  to human  body weight  ratio
and multiplied by 70 kg,  a  human  MED  of 10.15 mg/day was  obtained, which  was
substantially  similar  to  the MED  of  13.2 mg/day reported  1n  U.S.  EPA
(1983a). The  Impact of  this  discrepancy  on the RV.  was minimal, yielding
4.0  by current  methodology  and  3.8 by  previous  methodology.    U.S.  EPA
(1983a) assigned an  effect  ranking  of 1   to  Increased uroporphyrln.   The  CSs
calculated  by previous  and  current  methodologies  would  be  3.8  and   4.1,


0093h   ;                            -14-                             06/17/87

-------
 respectively.   Since this CS Is  lower  than  that  based on oral exposure,  the
 oral  CS of  12.4 1s chosen  to  represent the chronic  toxlclty of 1,2,4-tM-
 chlorobenzene.
 6.3.    CARCINOGENIC  POTENCY  (q^)
 6.3.1.   Oral.   The  lack of  data  regarding  the  cardnogenlclty  of  Ingested
 1,2,4-trlchlorobenzene precluded assessment of carcinogenic risk.
 6.3.2.   Inhalation.   The  lack  of  data  regarding  the  cardnogenlclty   of
 1,2,4-trlchlorobenzene  by  Inhalation  precluded  assessment of  carcinogenic
 risk.
0093h                               -15-                            12/03/86

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                                7.  REFERENCES

ACGIH  (American Conference  of Governmental  Industrial Hyglenlsts).   1986.
Documentation  of  the  Threshold   Limit  Values,  5th  ed.   Cincinnati,  OH.
p. 593.

Atkinson,  R.   1985.   Kinetics and mechanisms  of  the gas-phase  reactions  of
the  hydroxyl  radical  with  organic compounds  under atmospheric  conditions.
Chem. Rev.  85: 170.

Barrows, M.E., S.R. PetrocelH, K.J. Hacek and  J.J.  Carroll.   1980.   Blocon-
centratlon and  elimination  of selected water pollutants by blueglll  sunflsh
(Lepomls  macrochlrus).   In;   Dynamics,  Exposure  and  Hazard  Assessment  of
Toxic  Chemicals,  R.  Hague,  Ed.   Ann   Arbor  Science  Publ.,   Arbor,   HI.
p. 379-392.

Carlson,  G.P.   1977.   Chlorinated  benzene  Induction  of hepatic  porphyrla.
ExpeMentla.   33(12): 1627-1629.

Carlson,  G.P.  and  R.G.  Tardlff.   1976.   Effect  of  chlorinated benzenes  on
the metabolism of  foreign organic  compounds.   Toxlcol.  Appl.  Pharmacol.   36:
383-394.

Chlou,  C.T.,  P.E.  Porter and  D.W.  Schmeddlng.  1983.   Partition  equilibria
of  nonlonlc  organic  compounds   between  soil  organic  matter   and   water.
Environ. Sc1. Techno!.  17:  227-231.
0093h                               -16-                             12/03/86

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 Frlesel,  P.M.  and B.  Stelner.    1984.   Interactions of  halogenated  hydro-
 carbons with  soils.   Fresenlus Z.  Anal. Chem.  319: 160-164.

 Goto,  M.,  M.  Hattorl,  T.  Mlyagawa and  M.  Enomoto.   1972.   Be1tra"ge  zur
 okologlschen  chemle.   II. Hepatoma-blldung  In ma'usen nach verabrelchung von
 HCH-1someren  1n hohen  dosen.   Chemosphere.   6:   279-282.   (Ger.)   (CHed In
 U.S. EPA, 1985a)

 Hansch,  C.  and  A.J.  Leo.   1986.   MedChem  Project.   Issue  No.  26.   Pomona
 College, Claremont, CA.

 Kltchln, K.T. and  M.T.  Ebron.   1983.   Maternal hepatic and embryonic  effects
 of 1,2,4-trlchlorobenzene 1n the rat.  Environ. Res.  31: 362-373.

 Kodba, R.J., B.K. Leong  and  R.E.  Hefner,  Or.   1981.   Subchronlc  toxlclty
 study  of  1,2,4-trlchlorobenzene  1n  the  rat,  rabbit  and  beagle dog.   Drug
 Chem. Toxlcol.  4(3): 229-249.

 Lawlor, T.,  S.R.   Haworth  and  P.  Voytek.   1979.   Evaluation of  the  genetic
 activity of  nine  chlorinated phenols, seven chlorinated  benzenes,  and  three
 chlorinated hexanes.  Environ.  Mutagen.  1: 143.   (Abstract)

 L1ngg, R.D.,  W.H.  Kaylor, S.M.  Pyle,  et  al.  1982.   Comparative  metabolism
 of  1,2,4-trlchlorobenzene  1n  the  rat  and  rhesus   monkey.   Drug Metabol.
 Olspos.  10(2):  134-141.
0093h                               -17-                             09/20/86

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Lyroan,  J.W.,  W.F. Reehl  and O.H.  Rosenblatt.   1982.   Handbook of  Chemical
Property  Estimation   Methods.   McGraw-Hill  Book  Co.,  New York.   p.  15-13,
15-21.

Mackay, D. and W.Y.  Sh1u.   1981.   A critical  review of Henry's Law constants
for  chemicals  of  environmental  Interest.   J.  Phys.  Chem.  Ref.  Data.   19:
1175-1199.

Harlnucd,  A.C.   and  R.  Bartha.   1979.   Blodegradatlon   of   1,2.3-  and
1,2,4-trlchlorobenzene  In   soil   and  liquid  enrichment  culture.    Appl.
Environ. Mlcroblol.  38: 811-817.

NTP   {National   Toxicology   Program).   1986.   Management  Status  Report.
6/10/86.  NTP,  RTP, NC.

Oliver, B.G. and  A.J.  N11m1.  1983.   Bloconcentratlon  of  chlorobenzenes from
water  by  rainbow   trout:   Correlations   with  partition   coefficients   and
environmental  residues.  Environ.  Sc1. Technol.   17: 287-291.

Rlnkus, S.J. and M.S.  Legator.   1980.   The  need  for both In vitro and  U^
vivo  systems In  mutagenlclty screening.   In: Chemical  Mutagens,  Vol.  6,  A.
Hollander, Ed.   Plenum Press, New York.   p. 365-473.   (Cited 'in  U.S. EPA,
1985a)

Roberts, P.V., P.L.  McCarty, M.  Relnhard  and J.  Schrelner.   1980.  Organic
contaminant behavior  during  groundwater recharge.   J. Hater Pollut. Control
Fed.  52:  161-171.
0093h                               -18-                             09/20/86

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 Robinson,  K.S.,  R.J.  Kavlock,  N.  Chernoff  and I.E.  Gray.   1981.   Multi-
 generation  study of  1,2,4-trlchlorobenzene  1n  rats.   J. Toxlcol.  Environ.
 Health. 8(3): 489-500.

 Schoeny,  R.S.,  C.C.   Smith  and  J.C.  Loper.    1979.   Non-mutagen1c1ty  for
 Salmonella  of  the  chlorinated hydrocarbons  Arochlor  1254,  1,2,4-tMchloro-
 benzene, mlrex  and  kepone.  Mutat. Res.  68(2): 125-132.

 Townsend,  B.A.  and G.P.  Carlson.   1981.   Effect of halogenated  benzenes  on
 the  toxldty  and metabolism  of  malathlon,  malaoxon, parathlon and  paraoxon
 1n mice.  Toxlcol.  Appl.  Pharmacol.  60(1):  52-61.

 U.S.  EPA.   1980a.  Ambient Water  Quality Criteria  Document  for  Chlorinated
 Benzenes.   Prepared by  the Office of  Health  and  Environmental  Assessment,
 Environmental Criteria  and Assessment Office,  Cincinnati, OH for  the  Office
 of Water Regulations and  Standards, Washington,  DC.   EPA  440/5-80-028.   NTIS
 PB81-117392.

 U.S.  EPA.   1980b.  Hazard  Profile  for 1,2,4-TMchlorobenzene.   Prepared  by
 the  Office  of  Health  and  Environmental  Assessment, Environmental  Criteria
 and  Assessment  Office,  Cincinnati,   OH  for  the  Office  of  Solid  Waste,
Washington, DC.

U.S.  EPA.   1980c.  Guidelines  and Methodology  Used In  the  Preparation  of
Health  Effect  Assessment  Chapters  of  the  Consent Decree  Water  Criteria
 Documents.   Federal Register.   45(231): 49347-49357.
0093h                               -19-                            06/17/87

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U.S.  EPA.   1983a.  Reportable Quantity  Document  for 1,2,4-Tr1chlorobenzene.
Prepared by  the  Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office,  Cincinnati,  OH  for the  Office  of Emergency
and Remedial Response, Washington, DC.

U.S.  EPA.  1983b.   Methodology and  Guidelines for  Reportable Quantity Deter-
minations  Based  on  Chronic Toxldty Data.  Prepared by  the  Office of Health
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U.S.  EPA.    1985a.    Health  Assessment  Document   for  Chlorinated  Benzenes.
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U.S.  EPA.   1985b.  Reference Values  for Risk  Assessment.   Prepared  by  the
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tion date  2/26/86;.   Office  of Health and Environmental  Assessment,  Environ-
mental Criteria and Assessment  Office, Cincinnati,  OH.


0093h                               -20-                             02/09/87

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 Velth,  G.D.,  D.L. Oelore and 8.V.  Bergstedt.   1979.   Measuring and estimat-
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0093h                               -21-                             02/09/87

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