EPA-540/1-86-053
                    Environmental Protection
                    Agency
     A Emergency and
Remedial 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 HEXACHLOROBUTADIENE
                               Do not remove. This document
                               should be retained in the EPA
                               Region 5 Library Collection.

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                                           EPA/540/1-86-053
                                           September 1984
       HEALTH EFFECTS ASSESSMENT
        FOR  HEXACHLOROBUTADIENE
    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

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                                  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  1t 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

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                                    PREFACE


    This report  summarizes  and evaluates Information relevant  to  a prelimi-
nary   Interim   assessment   of  adverse  health   effects  associated   with
hexachlorobutadlene.   All  estimates of  acceptable Intakes and  carcinogenic
potency presented  1n  this document  should  be considered as  preliminary and
reflect limited  resources  allocated to  this  project.   Pertinent toxlcologlc
and environmental  data were  located  through on-Hne literature  searches  of
the Chemical  Abstracts,  TOXLINE,  CANCERLINE and  the  CHEMFATE/DATALOG  data
bases.  The basic  literature  searched  supporting  this document  1s  current  up
to September,  1984.   Secondary 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  for  Hexachloro-
    butadlene.      Environmental    Criteria    and    Assessment   Office,
    Cincinnati, OH.  EPA-440/5-80-053.   NTIS PB 81-117640.

    U.S. EPA.  1983a.   Review  of  Toxlcologlc  Data  1n  Support  of Evalua-
    tion for  Carcinogenic Potential  of Hexachlorobutadlene.   Prepared
    by  the  Carcinogen  Assessment  Group, OHEA,  Washington,  DC  for the
    Office of Solid Waste and Emergency Response, Washington,  DC.


    The Intent 1n  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  1s  not the  endpolnt of concern).
The first,  the AIS  or acceptable  Intake  subchronlc,  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 llfespan).   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  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

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    The AIC,  acceptable  Intake  chronic,  Is  similar  1n  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 Hfespan [see U.S.  EPA (1980b) for a  discussion
of  this   concept].   The  AIC  1s  route specific  and  estimates   acceptable
exposure  for  a given  route with  the   Implicit  assumption  that exposure  by
other routes is insignificant.

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

    For compounds for which there  is sufficient  evidence  of  cardnogenidty,
AIS  and  AIC values  are not derived.   For  a  discussion  of risk  assessment
methodology  for  carcinogens  refer to  U.S.  EPA  (1980b).   Since cancer  is  a
process that  is  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-|*s  have been computed  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 Inter-
pretation and use of the quantitative estimates presented.

    Hexachlorobutadlene was  treated  as  a  carcinogen  by  U.S.  EPA  (1980a).
Limited data  are  available concerning the carcinogenicity  of  this  compound.
In  the  only  study  available,  oral exposure to  hexachlorobutadlene  resulted
in  Increased  incidence of renal  tumors  in rats  at the highest  dose level.
No human data are available.  U.S.  EPA  (1980a),  using  the data  for  both male
and  female Incidence  of renal  tubular  adenomas  and carcinomas in male rats
derived  a  q-j*  for  oral   exposure of  7.75xlO~2  (mg/kg/day)"1.   This  risk
assessment has been extensively peer reviewed.

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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  Helen Ball  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:

    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
                                      v1

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TABLE OF CONTENTS


1. ENVIRONMENTAL CHEMISTRY AND FATE 	
2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . . .
2.1.
2.2.
ORAL 	
INHALATION 	
3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 	
3.1.


3.2.


3.3.



3.4.
SUBCHRONIC 	
3.1.1. Oral 	
3.1.2. Inhalation 	
CHRONIC 	
3.2.1. Oral 	
3.2.2. Inhalation 	 ,
TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . . ,
3.3.1. Oral 	
3.3.2. Inhalation 	 	
3.3.3. Other 	
TOXICANT INTERACTIONS 	
4. CARCINOGENICITY 	
4.1.


4.2.


4.3.
4.4.
5. REGUL
HUMAN DATA 	
4.1.1. Oral 	
4.1.2. Inhalation 	
BIOASSAYS 	
4.2.1. Oral 	
4.2.2. Inhalation 	
OTHER RELEVANT DATA 	
WEIGHT OF EVIDENCE 	
ATORY STANDARDS AND CRITERIA 	
Page
1
, . 3
, . . 3
3
4
4
, . . 4
4
8
. . . 8
8
8
. . . 8
. . . 9
9
9
10
10
. . . 10
10
10
. . . 10
10
. . . 10
10
. . . 13
        V11

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                           TABLE  OF  CONTENTS  (cont.)

                                                                        Page

 6.  RISK ASSESSMENT	    14

     6.1.   ACCEPTABLE INTAKE SUBCHRONIC (AIS) 	    14
     6.2.   ACCEPTABLE INTAKE CHRONIC (AIC)	    14

            6.2.1.   Inhalation	    14

     6.3.   CARCINOGENIC POTENCY (q^)	    14

            6.3.1.   Oral	    14

 7.  REFERENCES	    16

APPENDIX A: Summary Table for Hexachlorobutadlene	    21

APPENDIX B: Cancer Data Sheet for Derivation of qj*	    22

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                               LIST OF TABLES

No.                               Title                                Page

3-1     Subchronic Oral Toxldty of Hexachlorobutadlene	    5

3-2     Subchronic Inhalation Toxlcity of Hexachlorobutadlene ....    7

4-1     Response to Hexachlorobutadlene Feeding 1n Male and
        Female Rats	   11

6-1     Basis for q-)* for Hexachlorobutadlene	   15
                                     1x

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                             LIST  OF  ABBREVIATIONS

ADI                     Acceptable dally Intake
AIC                     Acceptable Intake chronic
AIS                     Acceptable Intake subchronlc
BCF                     B1oconcentrat1on factor
bw                      Body weight
CAS                     Chemical Abstract Service
CS                      Composite score
ppm                     Parts per million
TLV                     Threshold limit value
TWA                     Time-weighted average

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                     1.   ENVIRONMENTAL CHEMISTRY AND FATE



    The relevant physical  and  chemical properties and environmental  fate  of

hexachlorobutadlene (CAS No.  87-68-3}  are as  follows:
Chemical class:


Molecular weight:

Vapor pressure:

Water solubility:

Log octanol/water
partition coefficient:

BCF:



Half-lives 1n water:
chlorinated aliphatic
hydrocarbon

260.72

0.15 mm Hg at 20°C

2 mg/8. at 20°C

4.78


2.3xl03
29-2300
3-30 days 1n river
3-300 days 1n lakes and
groundwater
Callahan et al., 1979

Callahan et al., 1979

Banerjee et al., 1980
calculated from the
equation of Velth
et al., 1979

U.S. EPA, 1980a
Zoeteman et al., 1980
No data  regarding  the  half-life of this compound  1n  the  atmosphere could be

located  1n the available  literature;  however,  1t  Is  likely that the compound

will  react  with  hydroxyl  radicals  1n  the  atmosphere (Singh et  al.,  1983).

In the absence of  any  rate  constant  data  for  this reaction, 1t Is speculated

that  the half-life of  this  compound  will  be several  weeks 1n the atmosphere,

based on  the estimated residence  times for the  chlorinated  ethylenes  given

by Singh et al. (1981).

    The  half-life  of  hexachlorobutadlene  1n  soils could  not be  located In

the  available literature;   Based on   the  expected  volatility  (Callahan et

al.,  1979)   and  blodegradabUHy  1n  aquatic  media  (Mabey  et  al.,  1981),

significant  volatilization  and  blodegradatlon   may   not   occur   In  soils.
                                      -1-

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The compound may,  however,  be sorbed  significantly  onto soils containing  a
high  content  of   organic  carbon  (U.S.  EPA,   1980a).   In  the  absence  of
significant  loss  processes,  the persistence  of hexachlorobutadiene  in  soil
may allow  some  leaching  of  the compound into groundwater,  particularly  from
sandy soils.
                                     -2-

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           2.  ABSORPTION FACTORS  IN HUMANS AND EXPERIMENTAL ANIMALS
2.1.   ORAL
    Pertinent data  regarding  the  absorption of hexachlorobutadlene  from  the
gastrointestinal  tract  could  not be  located  1n  the available  literature.
The  available  toxldty  data  Indicate  that   some  absorption   does   occur
(Chapter 3) (U.S. EPA,  1980a).
2.2.   INHALATION
    Pertinent data  regarding the  absorption  of Inhaled  hexachlorobutadlene
could not be located 1n the available  literature.
                                     -3-

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               3.  TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1.   SUBCHRONIC
3.1.1.   Oral.   The   subchronlc  oral  toxldty  of   hexachlorobutadlene   are
summarized  In Table  3-1.   Most  of  the  Information  1s  from  the  Russian
literature and 1s available only as abstracts;  therefore,  H  cannot  be fully
evaluated.
    Koclba et al.  (1971)  administered  diets resulting In  doses  of  1,  3,  10,
30, 65  or  100 mg  hexachlorobutadiene/kg  bw/day to  female rats  for  30 days.
The major  hlstopathologlcal  change  observed was degeneration  of  the renal
tubular  epithelium at doses  of  >30 mg/kg  bw/day.    In  the  10  mg/kg  bw/day
group,  there  was  decreased body  weight gain with no  pathologic  alterations.
A marginal change  1n  the  kidney-to-body weight  ratio  was observed at 3 mg/kg
bw/day and no effects were observed at  1  mg/kg bw/day.
    Schwetz et al.  (1977)  administered  diets resulting  1n doses  of  0.2,  2.0
or  20 mg/kg  bw/day to male (groups of 10-12) and female (groups of  24)  rats
for  140 days.   Again,  hlstopathologlcal  lesions  in the -kidneys  were  the
major effects noted,  occurring at doses of >2.0 mg/kg bw/day.
3.1.2.   Inhalation.   The  subchronic  Inhalation toxiclty  of  hexachlorobuta-
dlene 1s  summarized  1n Table 3-2.   Gage  (1970) exposed groups  of  four  male
and  four  female  rats  to  atmospheres containing  5,  10,  25  or  100  ppm  (53,
107,  267  or  1060  mg/m3)  hexachlorobutadlene,  6  hours/day,  for  12-15 days.
A  dose  of 1060 mg/m3  produced  severe  toxiclty and death.  Renal  damage  was
observed  1n  the  two  highest  dose groups, but  the only  effect  observed at an
exposure  of  107  mg/m3   was  a  reduced  weight  gain  in  the   females.   No
effects were  observed at a concentration of 53 mg/m3.
                                      -4-

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                                                                          TABLE  3-1

                                                       Subchronlc Oral Toxlclty of Hexachlorobutadlene*
Route
Oral
(diet)









Oral
(diet)

Species/
Sex
rat/F
rat/F

rat/F

rat/F
rat/F
rat/F



rat/N
rat/F
rat/N
No. of
Animals
4
4

4

4
4
4



12
24
10
% Hexachlorobutadlene
Purity
99
99

99

99
99
99



99
99
99
Dose
1 mg/kg/day
3 mg/kg/day

10 mg/kg/day

30 mg/kg/day
65 mg/kg/day
100 mg/kg/day



0.2 mg/kg/day
0.2 mg/kg/day
2.0 mg/kg/day
Duration
30 days
30 days

30 days

30 days
30 days
30 days



148 days
148 days
148 days
Observations Reference
No effects. Koclba et al.,
Marginal change In kidney-to-body weight 1971
ratio; no pathologic alterations.
Decreased body weight gain; no patho-
logic alterations.
Renal tubular epithelial degeneration,
Individual cell necrosis and regenera-
tion, decreased body weight gain;
Increase In mean kidney-to-body weight
ratio; Increase In hemoglobin concen-
tration.
No effects among adults or neonates. Schwetz et al.,
No effects among adults or neonates. 1977
Kidney "roughened,* mottled cortex;
            rat/N


            rat/N




            rat/F
Oral
Oral
rat/NR

rat/NR

rat/NR

rat/NR
              20


              12




              24
NR

NR

NR

NR
                 99


                 99




                 99
               2.0 mg/kg/day


               20 mg/kg/day




               20 mg/kg/day
NR

NR

NR

NR
0.0005 mg/kg/day

0.004 mg/kg/day

0.02 mg/kg/day

8.4 mg/kg
100 mg/kg
             other kidney changes that normally occur
             appeared to be accentuated.
148 days     Accentuation of normal kidney changes;
             one had renal lesions Identical to those
             on 20 mg/kg/day; no effects on neonates.
148 days     Change In kidney-to-body weight ratio;
             kidney roughened with mottled cortex;
             renal tubular dilation and hypertrophy
             with foci of renal tubular epithelial
             degeneration and regeneration.
148 days     Renal tubular dilation and hypertrophy
             with foci of renal tubular epithelial
             degeneration and regeneration; decreased
             values of body and heart weight, Increased
             values for relative weight of brain and,
             kidney; slight decrease In body weight
             of neonates at time of weaning.

6 months     Was at threshold level with respect to
             toxlclty.
4 months     Weakly toxic.

2 months     Highly toxic.

NR           Severe necrotlc nephrosls, as well as
NR           abnormal changes In the brain, liver and
             other Internal organs.
                                                                                                                                            Poteryaeva, 1973
                                                                                                                                            Dlmltrlenko and
                                                                                                                                            Vasllos, 1972

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                                                                     TABLE  3-1  (cont.)
Route
Oral




Oral



Oral


Species/ No. of X Hexachlorobutadlene
Sex Animals Purity
dog/NR NR NR




dog/NR NR NR



guinea NR NR
plg/NR

Dose
1 mg/kg/day




0.05 mg/kg/day



0.004-2
mg/kg/day

Duration Observations 1
6 months Administered to puppies from birth to
6 months. Increased secretion of total
N-contalnlng compounds.
Increased vol. and total acidity of the
gastric juice.
45 days Administered 1.5-3 months postnatal;
Increased total vol., acidity, and
amount of HC1 and chloride secreted
by the stomach.
7 months 2 mg dose caused a decrease In -SH
group cone. In blood plasma without
change In blood protein plasma spectrum.
Reference
Boranova,
1974a.b



Kratvltskaya and
Boroanova, 1974


Murzakaev, 1965


'Source: U.S. EPA. 1980a



NR = Not reported

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                                                                   TABLE 3-2
                                             Subchronlc  Inhalation Toxlclty of Hexachlorobutadlene*
Species/
Sex
Rat/NR
Hlce/NR
Rat/NR
Rat/M
Rat/F
Rat/H
Rat/F
Rat/M
Rat/F
No. of
Animals
NR
NR
NR
4
4
4
4
4
4
X Hexachlorobutadlene
Purity
NR
NR
NR
NR
NR
NR
NR
NR
NR
Dose
24 mg/m»-a1r
24 mg/m»-a1r
0.01 imj/m'-alr
25 ppm (267 mg/ra»)
25 ppm (267 mg/ma)
100 ppm (1060 mg/m')
100 ppm (1060 mg/m*)
10 or 5 ppm
(107 or 53 mg/ma)
10 or 5 ppm
(107 or 53 mg/m»)
Duration
7 months
7 months
6 months
(5 hours dally)
15 dally
for 6 hours
12 dally
for 6 hours
15 dally
for 6 hours
Observations Reference
Caused no alterations. Gulko
et al.. 1964
No effects observed Poteryaeva.
1972
Caused respiratory difficulty; Gage, 1970
decreased weight gain and patho-
logic Injury to the tubular
epithelium of the kidneys.
Severe toxlclty Including death.
Caused no toxlclty except for
retarded weight gain In females
at 10 ppm.
*Source: U.S. EPA, 19BOa
NR = Not reported

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 3.2.   CHRONIC
 3.2.1.   Oral.   Koclba  et al.  (1977a,b)  administered  diets   resulting  in
 doses  of  0,  0.2, 2.0 or  20 mg hexachlorobutadiene/kg bw/day to groups of 40
 male  and 40  female rats  for 22-24  months.   In  the high  dose group, body
 weight gain  In  both sexes was depressed.   Both  relative and absolute  kidney
 weights  were  Increased  in  males  and  relative  kidney  weight  In  females.
 Survival  was  decreased  In the males.   Urinary  coproporphyrin  excretion was
 significantly  Increased  1n  male  rats  by  12 months  and  in  females  by  24
 months.    Histologlcal    examination   revealed   significant   abnormalities,
 including neoplasms  (Section 4.2.1.),  in the urinary system.
    The  effects  of  2.0 mg/kg  bw/day  were much  less  severe.  Urinary  copro-
 porphyrin  excretion was  Increased in  females after  14 months,  and   slight
 hlstofoglcal  changes   in  the  kidneys,  possibly  including   renal  tubular
 epithelial hyperplasla, were  observed at necropsy.   No effects were observed
 in animals receiving 0.2 mg/kg bw/day.
 3.2.2.   Inhalation.    Pertinent   data  regarding  the   chronic  inhalation
 toxicity  of  hexachlorobutadlene  could  not   be   located  1n   the  available
 literature.
 3.3.   TERATOGENICITY AND  OTHER REPRODUCTIVE EFFECTS
 3.3.1.   Oral.   Schwetz et al.  (1977) administered diets  resulting  in doses
 of  0.2,   2.0  or 20  mg  hexachlorobutadlene/kg  bw/day  for  90 days   before
mating, 15 days  during  mating, and throughout gestation  and lactation.  The
only effect on the  offspring  was  a slight  decrease in body weight at 21 days
postpartum in the high-dose group.  No gross  malformations  were reported and
neonatal   growth,  survival and   development   were  normal   in   the  low- and
mid-dose groups.
                                      -8-

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3.3.2.   Inhalation.  Pertinent  data  regarding  the  teratogenlcity or  other
reproductive effects  of  Inhaled  hexachlorobutadlene could not  be  located  1n
the available literature.
3.3.3.   Other.   Female  rats  were  given a  single  20  mg/kg  subcutaneous
Injection  of  hexachlorobutadlene  prior  to  breeding  (Poteryaeva,   1966).
Toxic  effects  reported   1n  the dams  Included  glomerulonephrltis  and  degen-
erative  red blood  cell   changes.   An  Increase  1n neonatal  mortality  and
depressed pup body weights were reported.  A  lack  of  detail  In the reporting
of experimental design and  results,  combined with poor  control  pup survival
(79%)  make  this  study  difficult  to  evaluate.   In addition,  this route  of
administration has limited relevance to the present assessment.
3.4.    TOXICANT INTERACTIONS
    Murzakaev   (1967)  reported   that  treatment  with   hexachlorobutadlene
decreased the  sulfhydryl content  of  blood serum  and  cerebral  cortex  homo-
genate.  Mlzyukova  et al.  (1973)  subsequently  found  that administration  of
thlols  (mercaptlde,  cystelne,  "unlthlol")  20-30  minutes before  a dose  of
hexachlorobutadlene  significantly  reduced  the  resulting  toxic effects,  as
determined by survival rates.
                                     -9-

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                             4.  CARCINOGENICITY
4.1.   HUMAN DATA
4.1.1.   Oral.   Pertinent data  regarding  the oral cardnogenlcHy  of  hexa-
chlorobutadlene 1n humans could  not  be  located  1n  the available  literature.
4.1.2.   Inhalation.    Pertinent  data  regarding   the  cardnogenlcHy  of
Inhaled hexachlorobutadlene 1n  humans  could  not  be located 1n  the  available
literature.
4.2.   BIOASSAYS
4.2.1.   Oral.   Koclba et al.  (1977a,b) fed  diets resulting  1n doses  of 0,
0.2,  2.0 or  20 mg hexachlorobutadiene/kg  bw/day to male and  female Sprague-
Dawley rats  for  2 years  (Table 4-1).  Total tumor Incidences In control  and
treated groups  were  similar;  however,  the Incidence  of  renal  tubular  neo-
plasms was  significantly  Increased  1n  both sexes at the highest dose  level.
No other treatment-related tumors were  found.
4.2.2.   Inhalation.    Pertinent  data  regarding  the  cardnogenlcHy  of
Inhaled hexachlorobutadlene 1n  experimental  animals  could  not  be  located in
the available literature.
4.3.   OTHER RELEVANT DATA
    Taylor  (1978)  tested hexachlorobutadlene for mutagenldty  in  Salmonella
typhimurlum  TA100,   both  with  and   without  metabolic   activation.   The  low
solubility  of  hexachlorobutadlene  limits  the  interpretation of  this  test;
however, hexachlorobutadlene did not appear to  be mutagenlc 1n this system.
4.4.   WEIGHT OF EVIDENCE
    Data are not available regarding  the  cardnogenlcHy  of  hexachlorobuta-
dlene  1n humans.  The cardnogenldty  of  this  compound has been demonstrated
In  animals,  but  only  in  one strain  of  rats.   Hence,  the overall evidence for
the  cardnogenlcHy  In  animals is   best  designated  as  "limited."   Applying
                                     -10-

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                                                 TABLE 4-1



                      Response to Hexachlorobutadlene  Feeding  In  Hale  and  Female  Rats3
Doseb
(mg/kg/day)
20.0
2.0
0.2
Control
Numbers
Hale Rat
9/39
0/40
0/40
1/90
% Response
Hale Rat
23
0
0
1.1
Numbers
Female Rat
3/40
0/40
0/40
1/90
% Response
Female Rat
7.5
0
0
1.1
Observations
renal tubular
adenocarclnomas;
undlfferentlated
carcinoma;
metastasis to the
lung
none
none
nephroblastoma
aSource: Kodba et al., 1977a,b



bDose administered for 669 days of  a  730-day  experimental  period.

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the criteria for evaluating  the  overall  weight of evidence for the  cardno-
genldty to humans  proposed  by the Carcinogen  Assessment  Group of  the U.S.
EPA  (Federal   Register,  1984),  hexachlorobutadlene  1s  most   appropriately
designated  a Group  C chemical  - Possible  Human  Carcinogen.
                                    -12-

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                     5.   REGULATORY  STANDARDS  AND  CRITERIA







    The  ACGIH  (1980)  has  recommended  a TLV  of  0.02 ppm (-0.24  mg/m3),



based on  the  2-year  feeding study by Koclba  et al.  (1977a,b).   The U.S.  EPA



(1980a)  estimated  that   a   concentration of  4.47  yg/8.  In  ambient  water



would result 1n an Increased cancer  risk of 10~5.
                                     -13-

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                              6.   RISK  ASSESSMENT
6.1.   ACCEPTABLE INTAKE SUBCHRONIC (AIS)
    Hexachlorobutadlene is a  chemical  shown  to be carcinogenic  1n  male rats
and for  which a  q  *  has been  calculated.   It Is  Inappropriate,  therefore,
to calculate an AIS for this  chemical.
6.2.   ACCEPTABLE INTAKE CHRONIC (AIC)
    Hexachlorobutadlene 1s a  chemical  shown  to be carcinogenic  1n  male rats
and for  which a  q  *  has been  calculated.   It Is  Inappropriate,  therefore,
to calculate an AIC for this  chemical.
6.2.1.   Inhalation.   Pertinent   data  regarding  the   chronic   inhalation
toxicity  of  hexachlorobutadlene  could   not   be  located  in  the  available
literature.
6.3.   CARCINOGENIC POTENCY (q^)
6.3.1.   Oral.  Koclba et al.  (1977a,b)  demonstrated the  Induction of renal
tubular  adenomas  and  carcinomas  in  rats.  The  U.S.  EPA  (1980a),  using the
tumor   incidence  in  male  rats  and a linearized multistage model  (Table 6-1),
has derived a human q  * of 7.75xlO~2 (mg/kg bw/day)"1.
                                     -14-

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                                   TABLE  6-1

                    Basis for q-j* for Hexachlorobutadlene*
              Dose
         (mg/kg bw/day)
         Incidence
(No.  Responding/No.  Tested)
               0.0

               0.2

               2.0

              20.0

Duration of Experiment = 730 days

Length of Treatment = 669 days

Llfespan of Animals = 730 days

Average Weight = 0.610 kg
           1/90

           0/40

           0/40

           9/39
^Source: U.S. EPA, 1980a
                                     -15-

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                                7.   REFERENCES

AC6IH  (American  Conference  on  Governmental  Industrial  Hyg1en1sts).   1980.
Documentation  of  the  Threshold Limit  Values.   4th  ed.    (Includes  Supple-
mental Documentation, 1981, 1982,  1983).   Cincinnati,  OH.

Banerjee, S.,  S.H.  Yalkowsky and S.C. Valvan.   1980.  Water  solubility  and
octanol/water  partition  coefficient of  organlcs.   Limitations  of the  sol-
ubility-partition  coefficient  correlation.   Environ.   Sc1.   Techno!.    14:
1227-1229.

Boranova, T.I.  1974a.   Nitrogen  releasing  function of the stomach  1n  onco-
genesls  under  the  effect of hexachlorobutadlene.  Eksp. Issled.  Khlm.  B1ol.
(no vol.):  198.   (Cited 1n U.S. EPA, 1980a)

Boranova, T.I.  1974b.   Effect  of hexachlorobutadlene on the  secretory  func-
tion of  the  stomach  of puppies  of various ages.   Protsessy Obmena Veshchestv
S-kh.  Zhlvotn.  Uslovlyakh  Normy Vozdelstv.  Vysokochast.   Elektromagn.  Pol.
(no vol.):  83.  (Cited 1n U.S.  EPA, 1980a)

Callahan,  M.A.,   M.W.   Sllmak,  N.W.  Gabel,  et  al.   1979.    Water-Related
Environmental  Fate  of  129 Priority  Pollutants.   Vol.  II.   U.S.  EPA,  Office
of  Water Planning  and  Standards,   Office  of  Water  and  Waste  Management,
Washington,  DC.  EPA-440/4-79-029b.
                                     -16-

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D1m1tr1enko,  V.D.  and  A.F.  Vasllos.   1972.   Kidney  damage  during  experi-
mental  acute  poisoning  with  hexachlorobutadlene.   Zdravookhranenle  15-11.
(CHed in U.S. EPA,  1980a)

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

Gage, J.C.  1970.   The  subacute  Inhalation  toxldty of 109 Industrial  chem-
icals.  Br.  J.  Ind. Med.   27:  1.   (CHed 1n U.S.  EPA,  1980a)

Gulko, A.G., N.I. Zlmlna and 1.6. ShroH.   1964.   lexicological  study  of  the
Insecticide hexachlorobutadlene.   Vopr.  G1g1eny  1. Sanlt. Ozderovl.  Uneshn.
Sredy, Kishinev, Sb.  (no vol.):  128.  (CHed  1n  U.S.  EPA,  1980a)

Koclba, R.J., P.J.  Gehrlng,  C.G.  Humlston  and  G.L. Sparschu.   1971.   Tox1-
cologlc study of female rats administered hexachlorobutadlene  or  hexachloro-
benzene for  30  days.   Dow Chemical  Company,  Midland,  Michigan.    (CHed  In
U.S. EPA, 1980a)

Koclba, R.J.,  D.G.  Keyes,  G.C.  Jersey, et al.  1977a.   Results  of a two-year
chronic  toxlclty  study  with  hexachlorobutadlene   In  rats.   Am.  Ind. Hyg.
Assoc.  38: 589.  (CHed 1n U.S.  EPA, 1980a)

Koclba, R.J.,  B.A.  Schwetz, D.G.  Keyes,  et  al.   1977b.  Chronic  toxlclty  and
reproduction  studies  of  hexachlorobutadlene   1n  rats.   Environ.   Health
Perspect.   21: 49-53.  (CHed In  U.S. EPA, 1980a)
                                     -17-

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KratvHskaya,  P.A.  and  T.I.  Boroanova.   1974.   Secretory  function  of  the
stomach  in  pups from  1.5-3 months of  age under  the  effect of  hexachloro-
butadlene.  Eksp.  Issled.  Kh1m.  Blol.   (no vol.): 207.   (Cited  In  U.S.  EPA,
1980a)

Mlzyukova, I.G., et al.   1973.   Relation between the  structure  of  detoxify-
ing action  of several thlols and  amines during  hexachlorobutadlene  poison-
Ing.  Fizlol. Aktlv.   Veshchestva.   5:  22.   (Cited In U.S. EPA,  1980a)

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

Murzakaev, F.G.   1965.  Effect  of small  hexachlorobutadlene  doses on  some
biochemical  and 1mmunob1olog1cal  Indexes.   G1g.  Tr.  Prog. Zabol.   9:  50-53.
(Cited In U.S. EPA,  1980a)

Murzakaev,  F.G.   1967.   Effect  of  small  doses  of hexachlorobutadlene  on
activity  of   the  central   nervous  system and  morphological  changes  1n  the
organism of animals Intoxicated  with  It.   Gig.  Tr.  Prog.  Zabol.   11:  23-28.
(Translation)  (Cited  1n  U.S.  EPA,  1980a)

Poteryaeva,  G.E.  1966.   Effect of hexachlorobutadlene  on the  offspring  of
Albino rats.   Gig. SanH.   31:  33.   (Cited  1n  U.S. EPA, 1980a)
                                     -18-

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Poteryaeva, G.E.   1972.   Substantiating  the  maximum permissible  concentra-
tion of hexachlorobutadlene  1n  the  air of Industrial premises.   61g.  SanH.
37: 32-36.  (Cited 1n U.S.  EPA,  1980a)

Poteryaeva, G.E.   1973.   Toxldty  of  hexachlorobutadlene during  entry  Into
the  organism   through  the  gastrointestinal   tract.   G1g.  Tr.   9:  98-100.
(Cited 1n U.S. EPA, 1980a)

Schwetz, B.A., F.A. Smith, C.G. Humlston, J.F.  Quast  and  R.J.  Kociba.   1977.
Results of a  reproduction study in  rats  fed diets  containing  hexachlorobuta-
dlene.  Toxlcol.  Appl.  Pharmacol.   42:  387-398.   (Cited  1n U.S.  EPA, 1980a)

Singh, H.B.,  L.J.  Salas,  A.J. Smith and H.  Sh1ge1sh1.    1981.   Measurements
of  some  potentially  hazardous   organic  chemicals   in  urban  environments.
Atmos. Environ.  15:  601-612. -

Singh, H.8., L.J. Sales, R.  Stiles  and  H. Shigaishi.  1983.   Measurements  of
hazardous  chemicals  in  the  ambient  atmosphere.    Prepared  by  SRI  Inter-
national, Menlo Park, CA.   EPA 600/3-83-002.   NTIS  PB 83-156935.

Taylor,  G.   1978.   Personal  communication.    Natl.  Inst.   Occup.   Safety
Health.  (Cited in U.S. EPA,  1980a)

U.S.  EPA.   1980a.   Ambient  Water  Quality Criteria  for  Hexachlorobutadlene.
Environmental   Criteria  and  Assessment  Office,  Cincinnati,  OH.   EPA-440/5-
80-053.  NTIS  PB  81-117640.
                                     -19-

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U.S.  EPA.   19805.   Guidelines  and Methodology  Used  1n  the Preparation  of
Health  Effects  Assessment  Chapters  of  the  Consent  Decree  Water  Quality
Criteria.  Federal Register.  45: 79347-79357.

U.S.  EPA.   1983a.   Review of Toxlcologlc  Data 1n Support  of  Evaluation for
Carcinogenic  Potential  of:  Hexachlorobutadlene.   Prepared  by  Carcinogen
Assessment  Group,  OHEA,  Washington,  DC for  the Office  of Solid  Waste and
Emergency Response, Washington,  DC.

U.S.  EPA.   1983b.  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.

Velth, G.D., D.L. DeFoe and 8.V.  Bergstedt.   1979.   Measuring  and estimating
the bloconcentratlon factor of  chemicals In fish.   J.  F1sh.  Res. Board Can.
36: 1040-1048.

Zoeteman, B.C.J., K. Harmsen,  J.B.H.J.  Llnders,  C.F.H. Morra and W.  Slooff.
1980.  Persistent  organic pollutants  1n river water and groundwater  of The
Netherlands.  Chemosphere.  9:  231-249.
                                     -20-

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                                                      APPENDIX A

                                        Summary Table  for Hexachlorobutadlene
Carcinogenic
Potency
Species
Experimental Effect qi*
Dose/Exposure
Reference
^     Inhalation                                                                  ND
i
      Oral               rat        0, 0.2, 2.0 or       renal tumors       7.75x10 2            Koclba et al.,
                                    20 mg/kg bw/day                        (mg/kg but/day)'1      1971; U.S. EPA,
                                                                                                 1980a


     ND = Not derived

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                                  APPENDIX B

                    Cancer Data Sheet for Derivation of q-|*


Compound:  hexachlorobutadlene

Reference:  Koclba et al., 1977a,b

Species, Strain, Sex:  rat, Sprague-Dawley, male

Body weight:  0.610 kg (measured)

Length of exposure (le) = 669 days

Length of experiment (Le) = 730 days

Llfespan of animal (L) = 730 days

Tumor site and type:  kidney tubules, adenomas and carcinomas

Route, vehicle:  oral, diet
                                       	Incidence	
             Transformed Dose*
               (mg/kg/day)             No. Responding/No. Tested
                                              or Examined
                   0                             1/90
                   0.18                          0/40
                   1.83                          0/40
                  18.33                          9/39


transformed  dose  expanded  for  treatment  on  669  of  730-day  experimental
 period.

Unadjusted q-|* from study = 1.598xlO~2 (mg/kg/day)"1

Human q-j* = 7.75xlO~2 (mg/kg/day)'1
                                     -22-

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