EPA-540/1-86-001
                    Environmental Protection
                    Agency
^.rice of 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  HEXACHLOROCYCLOPENTADIENE

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                                           EPA/540/1-86-001
                                           September 1984
       HEALTH EFFECTS ASSESSMENT
     FOR HEXACHLOROCYCLOPENTADIENE
    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  1n  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  hexa-
chlorocyclopentadlene.  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  Is 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-
    cyclopentadlene.    Environmental  Criteria  and  Assessment   Office,
    Cincinnati, OH.  EPA 440/5-80-055.   NTIS PB 81-117667.

    U.S.  EPA.   1984.    Health  Assessment Document  for  Hexachlorocyclo-
    pentadlene.   Environmental  Criteria and  Assessment  Office,  Cincin-
    nati,  OH.  EPA 600/8-84-001F.   NTIS PB 85-124915.


    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  1n
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 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

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    The  AIC,  acceptable  Intake  chronic,  Is  similar 1n  concept  to  the  ADI
(acceptable  dally  Intake).   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  (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 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 Is explained  In U.S.  EPA (1983).

    For compounds for which there  Is  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  (1980b).   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-|*s  have been computed  based  on  oral
and Inhalation data 1f available.
                                      1v

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                                   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.

    Subchronlc oral exposure data are  limited.  Ninety  day exposures  of  rats
and mice  Indicated  that rats are more sensitive  to HEX  toxldty  than  mice.
Both species  showed  lesions of  the  forestomach at their respective  LOAELs.
Using the rat data, an  AIS  for  oral  exposure  of 4.9 mg/day  1s  estimated.   In
the absence  of  chronic oral  exposure data,  an AIC of  0.49 mg/day  for  the
oral route  1s  eslmtated by applying  an  additional uncertainty factor of  10
to the AIS.

    Subchronlc Inhalation data are also limited.   Rats  and monkeys  have  been
tested for periods up to 14 weeks.   Using  the monkey  data,  an  Inhalation  AIS
of 0.2 mg/day 1s estimated.

    Chronic   Inhalation  evaluations  of HEX   have  been  conducted   1n  guinea
pigs, rabbits,  rats and mice.   Data are of limited use,  except for the  rat,
because  of   Incomplete  reporting of  results  and  questions concerning  the
purity of the  compound.  However,  the  data  are adequate to raise  questions
concerning  interspecles differences  in sensitivity  to  this  compound.   An
Inhalation AIC  of  0.0046 mg/day 1s  estimated based on  the rat  data of  Clark
et  al.  (1982a).  This  estimate  is  lower  than  an estimate which  could  be
derived  from the  TLV.   Despite questions  concerning  available   data,  the
Incorporation of  uncertainty factors  should  provide  an  adequate  margin  of
safety.   These  estimates  should be  reviewed  when  more complete  data  are
available.  A CS  of  62  was  calculated based  on mortality in mice  exposed  to
1.7 mg/m3, 7 hours/day,  5  days/week, for as many as 150 treatments.

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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.   Or.  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.
2.3.
ORAL 	
INHALATION 	
CONCLUSIONS REGARDING HEX ABSORPTION RATES 	
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 	
TOXICANT INTERACTIONS 	
4. CARCINOGENICITY 	
4.1.
4.2.
4.3.

4.4.
HUMAN DATA 	
BIOASSAYS 	
OTHER RELEVANT DATA 	
4.3.1. MutagenlcHy 	
WEIGHT OF EVIDENCE 	
5. REGULATORY STANDARDS AND CRITERIA 	
5.1.
5.2.
5.3.
5.4.
5.5.
5.6.
5.7.
OCCUPATIONAL STANDARDS 	
TRANSPORTATION REGULATIONS 	
SOLID WASTE REGULATIONS 	
FOOD TOLERANCES 	
WATER REGULATIONS 	
AIR REGULATIONS 	
OTHER REGULATIONS 	
Page
1
8
. . . 8
. . . 8
8
. . . 9
. . . 9
. . . 9
. . . 9
. . 11
. . . 11
11
. . . 12
. . . 12
. . . 13
. . . 13
. . . 15
. . . 15
. . . 15
. . . 15
, , . 15
. . . 17
. . . 19
. . . 19
. . . 19
. . . 19
. . . 20
. . . 20
. . . 20
. . . 20
       V11

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                           TABLE  OF  CONTENTS (cont.)
6. RISK ASSESSMENT 	
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 	
6.1.1. Oral 	
6.1.2. Inhalation 	
6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 	
6.2.1. Oral 	
6.2.2. Inhalation 	
Page
	 22
	 22
	 22
	 22
	 23
	 23
	 23
     6.3.   CARCINOGENIC POTENCY (q-|*)	   25



 7.  REFERENCES	   26



APPENDIX: Summary Table for Hexachlorocyclopentadlene	   35
                                     V111

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                             LIST  OF  ABBREVIATIONS

ADI                     Acceptable dally Intake
AIC                     Acceptable Intake chronic
AIS                     Acceptable Intake subchronlc
BCF                     file-concentration factor
bw                      Body weight
CS                      Composite score
DNA                     Deoxyr1bonucle1c add
PEL                     Frank-effect level
GC/MS                   Gas chromatography/mass spectrometry
105                     Dose lethal to 5% of recipients
LOAEL                   Lowest-observed-adverse-effect level
LOEL                    Lowest-observed-effect level
MED                     Minimum effective dose
NOAEL                   No-observed-adverse-effect level
NOEL                    No-observed-effect level
ppb                     Parts per billion
ppm                     Parts per million
RQ                      Reportable quantity
RVd                     Dose-rating value  
RVe                     Effect-rating value
SMR                     Standardized mortality ratio
STEL                    Short-term exposure limit
TLV                     Threshold limit value
TWA                     Time-weighted average
                                      1x

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                     1.   ENVIRONMENTAL CHEMISTRY AND FATE
    Hexachlorocyclopentadlene (HEX)  Is  the most  commonly used name  for  the
compound  that  1s  designated 1,2,3,4,5,5'-hexachloro-l,3-cyclopentad1ene  by
the International Union of Pure and  Applied Chemistry  system (IUPAC).  Table
1-1 cites  the  IUPAC name  and synonyms,  the  Chemical  Abstract  number  and
molecular and structural formulas  for HEX.
    Hexachlorocyclopentadlene 1s a  nonflammable liquid with a characteristic
pungent, musty  odor; the  pure compound  1s  light  lemon-yellow.  Table  1-2
presents the physical properties and constants for HEX.
    Commercial HEX  has  various  purities depending upon  the  route  of synthe-
sis.   HEX  1s a  highly  reactive  dlene that  readily  undergoes  addition  and
substitution reactions  and  also participates  In  01els-Alder  reaction of  HEX
with  a compound  containing  a  nonconjugated  double bond consisting  of  1:1
adducts containing  a hexachloroblcyclo  (2,2,1)  heptene structure;  the monene
derived  part  of  the adduct  1s nearly  always  In the  endo  position.  Figure
1-1  Illustrates  synthetic  pathways  to  various  chlorinated  pesticides  for
which  HEX 1s  a  precursor.   HEX  may be  present 1n  these pesticides as  a
contaminant.
    HEX  1s  released Into the  environment during Its  manufacture  and during
the  manufacture  of  products  requiring  HEX.    Limited monitoring data  from
production  sites  Indicated  that  HEX was  present at 18  mg/8,  1n  the aqueous
discharge from the Memphis pesticide  plant (U.S. EPA,  1984).
    In  May  1977,  HEX was  also detected  at  0.17  mg/8.  1n  the  aqueous  dis-
charge  and at 56  ppb 1n air  samples collected from a waste site 1n Montague,
MI  (U.S.  EPA,  1984).  At a  waste  site In Hardeman  County,  TN,  HEX  has  been
shown  to  be  emitted Into the air,  groundwater,  wastewater and drinking water
(Clark  et al.,  1982b).   Indoor  air  concentrations  of  HEX  In  houses  with
contaminated groundwater supplies ranged  from 0.06-0.10 yg/m3.

                                      -1-

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                                  TABLE  1-1

                    Identity of Hexachlorocyclopentadlene*
  Identifying Characteristic
           Name/Number/Structure
IUPAC Name:

Trade Names:

Synonyms:
CAS Number

CIS Accession Number:

Molecular Formula:

Molecular Structure:
l,2,3,4,5,5'-Hexachloro-l,3-cyclopentad1ene

C56; HRS 1655; Graphlox

Hexachlorocyclopentadlene
Perchlorocyclopentadlene
HEX
HCPD
HCCP
HCCPO
C-56
HRS 1655
Graphlox

77-47-4

7800117
                                                     Cl
                              Cl
                                                     Cl
                              Cl
                                                        Cl  Cl
*Source: Stevens, 1979
                                      -2-

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                                  TABLE 1-2

               Physical  Properties  of  Hexachlorocyclopentadlene
     Property
 Value/Description
          Reference
Molecular Weight:

Physical Form (25C)

Odor:

Electronic Absorption
  Maximum (In 50%
  acetonltr He-water)

Solubility

  Water (mg/l):



  Organic Solvents:

Vapor Density (air =  1)

Vapor Pressure
  (mmHg, C):


Specific Gravity:



Melting Point (C):


Boiling Point (C):
Octanol/Water Partition
  Coefficient (log P)
  (measured):
  (estimated):

Latent Heat of  Vaporiza-
  tion

Henry's Law Constant
  (atm-mVmole)
272.79               Stevens,  1979

Pale yellow liquid   Hawley,  1977; Irish,  1963

Pungent              Hawley,  1977; Irish,  1963
322 nm
2.1 (25C)
0.805 (25C)
1.8 (28C)

Mlsdble (Hexane)

9.4
0.08 (25C)
0.975 (62C)

1.717 (15C)
1.710 (20C)
1.7019 (25C)

 -9.6
-11.34

239 @ 753 mm Hg
234
5.040.04
5.51
176.6 J/g

2.7xlO'2
Wolfe et a!., 1982
Oal Monte and Yu, 1977
Lu et al., 1975
Wolfe et al., 1982

Bell et al., 1978

Verschueren, 1977
Irish, 1963
Stevens, 1979

Hawley, 1977
Stevens, 1979
Weast and Astle, 1980

Hawley, 1977
Stevens, 1979

Hawley, 1977; Stevens, 1979
Irish, 1963
Wolfe et al., 1982
Wolfe et al., 1982
Stevens, 1979

Atallah et al., 1980;
Wolfe et al., 1982
                                     -3-

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                    OlIlMlN
      ei|. M> CM twiin
        MM IN coo ci%
        Ol 1O|C"|  IIN ton
        "
                       Mini
                                   FIGURE  1-1

Synthesis  of  Chlorinated Cyclodlene Pesticides  from Hexachlorocyclopentadlene

                             Source:   U.S. EPA.  1984

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    Published reports,  environmental  releases and physlochemlcal  properties
of HEX  Imply  that  it will be  present  mainly In the aquatic compartment  and
associated with  bottom  sediments  and  organic matter.  Relatively  much  lower
concentrations will  be  found 1n the  soil  and air compartments.   A1r  levels
1n areas  near previous  dump  sites  have been  shown to be  high.   High  concen-
trations  of  HEX have  been  recorded  1n wastewater  and,  1n two  Incidences,
have Increased  the ambient HEX levels Inside treatment facilities above  the
ACGIH TWA.
    Little relevant  Information  Is  available to  predict  the fate of HEX  1n
air.  Its  tropospherlc  residence  time was  estimated by  CupHt  (1980)  to  be
~5 hours  based  upon  rates of reaction  with  hydroxyl  radicals and ozone.   The
respective reaction  rates were  theoretically estimated  to  be  59xlO~12  and
8xlO~18   cm3    molecule'1   sec"1.     Atmospheric   photolysis   of   HEX   was
rated as  probable,  since  HEX  has a  chromophore that absorbs  light  1n  the
solar spectral  and  1s  known  to photolyze  1n aqueous  media.   CupHt  (1980)
listed  the  theoretical  degradation   products   as   CUCO,   dlacylchloMdes,
ketones,  and  free  Cl radical,  all  of  which would  be  likely  to  react with
other elements and  compounds.
    In  the event of  release  Into  shallow or  flowing bodies  of  water,  degra-
datlve  processes such as  photolysis,  hydrolysis and blodegradatlon, as well
as transport  processes  Involving volatlzatlon and other physical  loss mecha-
nisms, are expected to be prominent  1n HEX dissipation.
    Under  a  variety  of  sunlight  conditions, 1n  both  distilled and  natural
waters  of 1-4   cm   depth,  phototransformatlon   half-life  was  <10 minutes.
Addition  of sediments to  distilled water  containing  HEX had  little effect  on
the phototransformatlon  rate  constant of HEX at  this  latitude  on cloudless
                                      -5-

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days  (averaged  over  both  light  and dark  periods  for  a  year) that  was  3.9
hour"1,  corresponding  to  a  half-life of  10.7 minutes  (Zepp et  al.,  1979;
Wolfe et al., 1982).
    Studies  of  the hydrolysis  of  HEX Indicate  that at  25-30C  and  In  the
environmental  pH   range  of  5-9,  a  hydrolytlc half-life  of  -3-11   days  Is
observed  (Wolfe et al.,  1982).  Hydrolysis  1s much  slower  than  photolysis,
but may  be a  significant  load-reducing  process  1n waters  where  photolysis
and physical transport processes are not Important  (I.e.,  1n deep,  nonflow-
1ng waters).
    Wolfe et al. (1982)  found  hydrolysis of  HEX  to be Independent of pH over
a  range  of  3-10.    With  a  variation 1n  temperature,  these rates  changed
somewhat.
    HEX  1s  not  expected  to  be oxidized  under ordinary  environmental condi-
tions.   Based  on   an  estimated first order  oxidation rate  constant,  a com-
puter  simulation predicted that HEX would  not be  oxidized  1n the simulated
river, pond or eutrophlc  lake.
    Tabak  et  al.   (1981)  stated  that  HEX 1s blodegraded fairly rapidly 1n  a
static  laboratory  culture.   Upon  release onto soil,  HEX  1s  likely to adsorb
strongly  to  any organic  matter  or  humans  present  (Kenaga  and Goring, 1980;
Weber,  1979).   With  time,  HEX concentrations  should  decrease as  populations
of  soil  microorganisms  better adapted  to  metabolize  HEX  increase  (Rieck,
1977a,b,c; Thuma et al.,  1978).
    The  log octanol/water  partition coefficient  (log  P)  of  HEX has  been
experimentally determined  to be  5.04  (Wolfe  et al., 1982)  and 5.51 (Velth et
al.,  1979),  which  indicates  a  substantial  potential  for  bloconcentration,
bioaccumulation and biomagification.  Actual determinations of bioconcentra-
                                      -6-

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tlon and bloaccumulatlon In several aquatic organisms  Indicate  that  HEX  does
accumulate to  a  great extent  (Podowski  and  Khan,  1979; VeHh  et  al.,  1979;
Spehar et al., 1979).
    VeHh et  al.  (1979)  determined the  BCF for  HEX  to be 29 In  the fathead
minnow,  P^.  promelas.   Spehar  et  al.  (1979)  conducted  a 30-day  early-Hfe
stage,  flowthrough  toxldty  test  at  25C  with  the  fathead  minnow.   HEX
residues  1n  the  fish  after 30  days  of continuous  exposure to  HEX were  <0.1
mg/kg  for  all concentrations  tested  (0.78-9.1  vg/8.  1n  water).   In  two
other  studies  (Velslcol  Chemical  Corporation, 1978;  Bennett, 1982),  HEX was
not detected 1n any of the fish tissue samples analyzed by GC/MS.
    The  fate and  transport of  HEX  1n  the atmosphere are not well  documented,
but available  Information  suggests that  the  compound does not persist.  In
water, HEX  1s  likely  to  dissipate  rapidly by  means of photolysis, hydrolysis
and  blodegradatlon.   B1odegradat1on  may  also  be  a  significant   process  1n
certain  waters,  although the  evidence  1s weak.   HEX  1s  known  to volatilize
from water;  however,  It  1s possible  that volatilization Is limited by diffu-
sion,  particularly  1n waters  that are  not  well  mixed,  and  by  sorptlon  on
sediments.
    The  fate  and transport  of  HEX   1n  soils  are  affected  by   Us  strong
tendency  to adsorb  onto organic  matter.  HEX 1s  predicted  to  be relatively
Immobile  1n soil based  on Us high  log P value.  Volatilization,  which  1s
likely  to occur   primarily at  the soil  surface, Is Inversely  related to the
organic  matter levels and water-holding capacity  of   the  soil.   Leaching  of
HEX  by  groundwater   should  be  very   limited,  and  chemical  hydrolysis and
mlcroblal  metabolism  are  expected to  reduce environmental levels.   HEX  Is
metabolized  by a number of  soil  microorganisms.  HEX  may  be  found  In  areas
where  there was   no HEX  production or  usage,  because  It  may be present  as a
contaminant  In products  made from  It.

                                      -7-

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           2.   ABSORPTION  FACTORS  IN  HUMANS  AND  EXPERIMENTAL  ANIMALS
2.1.   ORAL
    Absorption  rates   have  not  been  calculated  for  HEX.   Dorough  (1979)
studied the  oral  absorption  of  HEX  1n  male and  female  Sprague-Dawley  rats
and mice.  Although absorption was  shown  by the presence of the radlolabeled
compound 1n the feces  (72%)  and urine (14%), the rates were not calculated.
    In a study by Yu and  Atallah  (1981),  male and female Sprague-Dawley rats
(240-350 g) were  given a  single dose  of  3 or  6 mg/kg  14C-HEX  1n  0.5  ms,
corn  oil  by  oral  gavage.   Radioactivity  appeared  1n  the  blood within  30
minutes, reached a  maximum value at  4  hours,  and then gradually decreased.
The excretion levels were near the values of Dorough (1979).
2.2.   INHALATION
    Dorough (1980) studied  the absorption and  fate of  Inhaled  HEX 1n female
Sprague-Dawley  rats   (175-250 g).    Animals   were   exposed   to   vapors  of
14C-HEX  over  a  1-hour   period   to  achieve  doses  of  -24  vg/kg  bw.   The
radlolabel   was  recovered  1n   the  feces  and urine;  however,   no  absorption
rates were calculated.
2.3.   CONCLUSIONS REGARDING HEX ABSORPTION RATES
    From the  data  reviewed 1n  the  pharmacok1net1c studies  of  HEX,  the  fol-
lowing points can be made regarding the fate of HEX 1n biological  systems:
        HEX  reacts  with  biological  tissues  and  macromolecules  at  the
        point of administration  as  Indicated by  the  high concentration
        of HEX equivalents  1n  the  lung  and  trachea following Inhalation
        exposure.
        HEX 1s not  readily  absorbed through  the  gastrointestinal tract
        as  Indicated  by the  following:   the 2- to 3-fold  higher  fecal
        elimination of HEX  equivalents  following oral administration as
        compared with  Intravenous or  Inhalation administration, and  the
        reactivity of  HEX with  the  gastrointestinal   contents  as  Indi-
        cated by  the  fact that  no  unchanged HEX  1s  excreted  following
        oral administration.
                                      -8-

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                3.  TOXICITY  IN HUMANS AND  EXPERIMENTAL ANIMALS
3.1.   SUBCHRONIC
3.1.1.   Oral.   In  a  range-finding  study,  Litton  B1onet1cs  Inc.  (1978a)
determined the  oral  LD_ of  HEX  1n  Charles River  CD-I  rats to be  76  mg/kg.
However, when  the  LD5 was administered  to rats for 5 consecutive  days,  all
24  animals  died.  In  a comparable range-finding  study  1n Fischer  344  rats
(SRI, 1980b)  no  mortality  was  reported at doses of  25,  50  or  100  mg/kg  when
given 12 doses 1n 16 days.
    The subchronlc toxldty  of  HEX  1s summarized  1n Table  3-1.   In the  oral
dose  studies  (Abdo et  al.,  1984),  dose  levels of  19,  38, 75, 150 and  300
mg/kg  HEX  (94.3-97.4% pure)  in corn  oil were  administered  by   gavage  to
groups  of  10  male and  10  female mice.  Doses  were  administered  5 days/week
for  13  weeks.   At  the highest dose level  (300  mg/kg), all  male mice died by
day  8 and  3 females  died  by  day  14.  In female mice, the liver was enlarged.
Dose  levels  of  >38  mg/kg  HEX. caused  lesions   in  the  forestomach,  including
ulceration in  both  males  and females.  At doses  of  >75  mg/kg,  toxic nephro-
sis  was seen  In  females.   In the rat  portion  of this study, doses of 10,  19,
38,  75  and 150  mg/kg  HEX  were administered.    Mortality  and  toxic nephrosls
were  noted  In both males  and  females  at  doses of >38 mg/kg.   The male  rats
treated at 19  mg/kg  dose level  did  not  show  any highly  abnormal effects,
while  females  exhibited   lesions   of  the  forestomach.    Such  lesions  were
observed  In  male  rats at  the  >38 mg/kg dose levels.    There was a  dose-
related depression  of body weight gain relative  to  the  controls.   The NOAEL
for  rats was  selected  to be  the 10 mg/kg level.
3.1.2.   Inhalation.    Rand  et  al.  (1982)  and  Alexander  et  al.  (1980)
performed  inhalation  studies 1n  rats  and  monkeys.   Groups  of  40  male  and 40
female  Sprague-Dawley  rats  weighing  160-226 g,  or  groups of  12  cynomolgus
                                      -9-

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                                                      TABLE  3-1



                                              Subchronlc Toxlclty of HEX
o
i
Study Species
90-Day rat
Feeding
90-Day mouse
Feeding
14 -Week rat
Inhalation
Toxlclty
14 -Week monkey
Inhalation
Toxlclty
Dose
10, 19, 38, 75,
150 or 300 mg/kg
(by gavage)
19, 38, 75, 150
or 300 mg/kg
(by gavage)
0.01, 0.05 and
0.2 ppm
(5 days/week)
0.01, 0.05 and
0.2 ppm
(5 days/week)
Results
NOAEL
LOEL
NOAEL
LOEL
NOAEL
LOEL
NOAEL
LOEL
- 10 mg/kg
- 19 mg/kg
- 19 mg/kg
- 38 mg/kg
- 0.2 ppm
- NE
- 0.2 ppm
- NE
Effects at LOEL or
Lowest Dose
Lesions of forestomach
In female rats at
19 mg/kg
Lesions of forestomach
In both sexes at
38 mg/kg
No statistically
significant effects
No effects noted
Reference
Abdo et al
1984b
Abdo et al
1984
Rand et al
1982

* t
* 
* t
Alexander
et al., 1980
     NE = Not established

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monkeys weighing 1.5-2.5  kg  (average 2.0 kg), were  exposed  to  HEX,  6 hours/
day, 5  days/week,  for 14 weeks.   Levels  of  exposure were 0, 0.01,  0.05  and
0.20  ppm HEX.   In  monkeys,   there  were  no mortalities,  adverse  clinical
signs, weight gain changes, pulmonary  function  changes,  eye  lesions, hemato-
loglc changes, clinical  chemistry  abnormalities  or  hlstopathologlc abnormal-
ities at any dose level tested.
    Male rats  1n this study  (Rand  et  al., 1982) had  a  transient  appearance
of dark-red eyes at  0.05  and  0.2  ppm HEX.  At 12 weeks,  there were marginal,
but not  statistically  significant,  Increases  1n  hemoglobin concentration  and
erythrocyte count In 0.01 ppm males, 0.05 ppm females  and 0.20 ppm males  and
females.  There  were no  treatment-related abnormalities  1n  gross pathology
or hlstopathology.
3.2.   CHRONIC
3.2.1.   Oral.   The  chronic   oral  toxldty of HEX  has not  been  determined.
The  longest  oral study  to date was  the previously  reviewed work  of Abdo et
al. (1984).
3.2.2.   Inhalation.   Treon   et  al.  (1955)   exposed  guinea  pigs,  rabbits,
rats  and  mice to a  concentration  of 0.33 ppm  for   7  hours/day,  5 days/week
for  25-30  exposures.  Guinea  pigs  survived  30  exposures; however,  rats  and
mice  did  not survive   5  exposures,  and 4/6  rabbits  did  not   survive  30
exposures.  Using a  lower concentration  (0.15 ppm HEX),  guinea  pigs, rabbits
and  rats  survived  150 7-hour  exposure periods.   This  level  was too high  for
a  chronic  level study  1n mice  since  4/5 animals  did not  survive.  Slight
renal  and hepatic  degeneration was  noted  In  all  species;  mice,  rats  and
guinea pigs also developed lesions 1n the  lungs.
                                     -11-

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    A 30-week  chronic  Inhalation  study of technical  grade  HEX  (96%) 1n rats
was  conducted  by Shell  Toxicology  Laboratory  (Clark  et al.,  1982a).   Four
groups  of  8 male  and  8  female Wlstar  Albino  rats  were  exposed to  HEX  at
nominal  concentrations  of  0,  0.05,  0.1 and 0.5  ppm for  6  hours/day, 5 days/
week, for  30 weeks and  were  observed for a  14-week  recovery period without
HEX  exposure.   At  the  highest  dose  level, 4 males and  2  females  died.   In
males, there was depressed  body weight gain  1n  the 0.5 ppm group relative to
controls  beginning at  7 weeks  of  exposure  and  persisting throughout  the
remainder  of the  study.   Females 1n  the medium  and high dose  groups  had
lower body  weights  at  the  end  of  the  recovery period  as  compared  with
controls.   At  0.5 ppm,  pulmonary degenerative  changes  were noted  1n  both
sexes although  the males  were affected more  severely.   At  the  highest dose,
there were mild  degenerative  changes  1n  the  Hver  and kidneys at 30 weeks  1n
a  few rats and  kidney  weights  were  significantly  Increased  1n the  females.
After 30  weeks  of study,  there was  no  biologically  significant  toxlclty
noted 1n animals exposed  to concentrations of 0.05 or 0.1  ppm  HEX (Clark  et
al., 1982a).
    A chronic  Inhalation study has been  scheduled  by the National Toxicology
Program (Abdo,  1983).
3.3.   TERATOGENICITY AND OTHER REPRODUCTIVE  EFFECTS
3.3.1.   Oral.    The teratogenlc  potential of HEX  was evaluated  In  pregnant
Charles  River CD rats  that  were administered  HEX (98.25%)  by gastric Intuba-
tion 1n  corn oil at  dose levels of 3, 10  and 30 mg/kg/day  from days 6-15  of
gestation.   A control  group received  the  vehicle  (corn oil) at  a dose volume
of  10  ma/kg/day.  Survival  was  100%,  and there  was  no difference  In  mean
maternal body  weight  gain  between dosed groups and controls.   There were  no
differences  1n  the  mean  number  of  Implantations,  corpora   lutea,   live
                                     -12-

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fetuses, mean fetal  body  weights  or male/female sex  ratios  among  any  of the
groups; and  there were  no statistical differences In malformation  or  devel-
opmental variations  compared with  the controls  when external, soft  tissue
and skeletal examinations  were performed (IRDC,  1978).
    Murray et al. (1980)  evaluated  the  teratogenlc potential  of HEX (98%) 1n
CF-1 mice and New  Zealand White rabbits.   Mice were  dosed at 0, 5,  25 or 75
mg/kg/day HEX by gavage from days 6-15 of  gestation, while  rabbits received
the same dose from days 6-18  of  gestation.   The fertility of both  the  treat-
ed  mice and  the  rabbits  was  not  significantly  different  from the  control
groups.  In  the mice,  no evidence of  maternal toxldty, embryotoxldty or
teratogenlc  effects   was   observed.   A  total   of  249-374   fetuses  (22-33
Utters) were examined 1n each dose group.
    In  rabbits, maternal  toxldty  was  noted   at  75  mg/kg/day  (diarrhea,
weight  loss  and mortality), but  there  was  no  evidence of maternal  toxldty
at  the  lower levels.  There  were  no  embryotoxlc effects at  any dose  level.
Although there  was an Increase  1n the  proportion  of  fetuses  with  13 ribs at
75  mg/kg/day  over  controls,  this was  considered a minor  skeletal  variation,
and the authors concluded that HEX was not teratogenlc at the levels tested.
3.3.2.   Inhalation.   Studies  on  the teratogenlc potential  of Inhaled  HEX
were not located 1n the review of the  scientific literature.
    There were  no studies  located 1n  the  literature  that   addressed  other
reproductive effects  from exposure to  HEX.
3.4.   TOXICANT INTERACTIONS
    In  the  review  of available  literature,  HEX  has  not  been shown to  Inter-
act with  other  compounds.   However,   1n  many  experiments  on  absorption of
HEX, some common observations have  been ascertained  regarding HEX  and  living
tissue.  Repeated exposure  of several animal species to  levels of HEX vapor
                                     -13-

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1n  the  0.1-0.2  ppm range  has  been  found  to  cause  pulmonary  degenerative
changes  (Treon  et  a!.,  1955;  Clark  et  al., 1982a).   The  Interaction  of HEX
within  human  tissue has  caused mild  degenerative  changes  In  the  kidneys,
"liver, brain,  heart and  adrenal glands.
    There are Insufficient  data  to Identify clearly the  site  most sensitive
to  prolonged,   repeated  exposure  of  HEX.   However,   researchers  found  1n
comparing routes of  administration over  a wide variety of  doses and  lengths
of exposures that,  regardless of  which  route was used, damage  to  the lungs
occurred  (Lawrence  and  Dorough,  1982).   When  HEX 1s  administered  orally  to
animals, the kidneys may be  the  most  sensitive  site, since subchronlc  dosing
of rats and mice  was found to cause  nephrosls.   Although  the  oral  route may
not  be  significant  In   human exposure,  the  fact  that  the  kidneys  are  a
possible  target  organ   1n   subchronlc   exposure   Indicates  that  low-level,
prolonged systemic exposure from any ambient route may affect the kidneys.
                                     -14-

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                              4.   CARCINOGENICITY
4.1.   HUMAN DATA
    Mortality studies have been conducted  on  workers  Involved  In the produc-
tion  of  HEX or  formulation  of  HEX products.   The Shlndell  and  Associates
(1980) report was  a  cohort study of workers  employed  at  the Velslcol Chemi-
cal Corporation  plant  at Marshall,  IL  between 1946 and  1979.   The analysis
showed no significant differences  1n mortality rates  between these employees
and the United States population.
    Wang and  MacMahon  (1979)  conducted a study  on  a group  of  1403  males
employed In plants producing  or  using HEX.   The  SMR was  used  to compare the
workers with the general population.  The  two highest  SMRs were 134 for lung
cancer and  183  for  cerebrovascular disease,  but  only  the latter was statis-
tically significant.   The authors  noted  that  these effects were unrelated to
exposure because  the deaths  showed  no  consistent  pattern with duration  of
employment or with duration of follow-up.
    Other  studies  (Shlndell  and  Associates,  1981;  Buncher  et  al.,  1980)
showed similar results.  In all of  these studies, no  carcinogenic  effects of
HEX exposure were noted.
4.2.   BIOASSAYS
    There are no animal  bloassay  data  Indicating  that  HEX 1s carcinogenic to
animals by  any  route of exposure.  An  Inhalation  cardnogenesls bloassay 1n
rats and mice 1s being conducted by NTP (Abdo, 1983).
4.3.   OTHER RELEVANT DATA
4.3.1.   Mutagen1c1ty.   Goggelman et  al.  (1978)  found   that  HEX  was  not
mutagenlc before  or  after  liver  mlcrosomal  activation at 2.7xlO~3 M  1n  an
Escherlchla  coll  K,2  back  mutation system.   In  this   test  there was  70%
survival of  bacteria at 72 hours.   HEX was  not  tested at higher  concentra-
tions  because  H  was cytotoxlc  to  E..  coll.   An  earlier  report by  Grelm et

                                     -15-

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al.  (1977)  from the  same  laboratory Indicated  that  HEX was also  not  muta-
genlc 1n  Salmonella  typhlmurlum strains TA1535  (base-pair  mutant)  or TA1538
(frame shift  mutant)  after  liver mlcrosomal activation;  however,  no details
of  the  concentrations  tested were  given.  Although  tetrachlorocyclopenta-
dlene Is  mutagenlc  1n  these  systems,  probably  through  metabolic  conversion
to  the  dlenone,  1t  appears  that the chlorine atoms  at  the C-l  position  of
HEX  hindered  metabolic oxidation  to  the  corresponding  acylatlng  dlenone
(Grelm et al., 1977).
    A study  conducted  by Industrial  B1o-Test  Laboratories  (IBT,  1977)  also
suggests  that  HEX 1s  not mutagenlc  In S.  typhlmurlum.   Both  HEX  and  Us
vapors were  tested  with  and  without metabolic  activation.   The  vapor  test
was done  In  desiccators with  only  the  TA100 strain of J>. typhlmurlum.  It  1s
not clear from the presented  data  of  the  vapors  test that sufficient amounts
of HEX or adequate times  of  exposure  were  used.   Exposure times of 30,  60  or
120  minutes  were  'studied.    Longer  exposures  1n  the  presence  of  the  HEX
vapors may  be necessary  for  observation  of a  potential mutagenlc  effect.
The  statement  1n  the  text that  testing was conducted 1n  the toxic range  1s
not supported convincingly by the Investigators'  results.
    At concentrations  of up  to 1.25xlO~3  yg/ms. In  the  presence  of an  S-9
Hver activating  system,  HEX was  not  mutagenlc  1n  the  mouse  lymphoma  muta-
tion  assay.   Mutagenldty could not be  evaluated at higher  concentrations
because of  the cytotoxldty  of  HEX  (Litton  B1onet1cs,  Inc.,  1978b).   This
assay uses  L5178Y  cells that  are  heterozygous  for  thymldlne klnase (TK+/-)
and  are  bromodeoxyuMdine   (BUdR)  sensitive.   The  mutation   1s   scored  by
cloning with BUdR 1n  the  absence of  thymldlne.   HEX 1s  highly toxic to  these
cells,  particularly   1n  the  absence  of   an activating  system  (at  4xlO~5
yfc/ms.);    a    positive   control,   dimethylnitrosamine,   was   mutagenlc   at
0.5 yl/ms..

                                     -16-

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    Williams  (1978)   found  that  HEX  (10 6 M)  was   Inactive  1n  the  Hver
epithelial  culture  hypoxanthlne-guanlne-phosphorlbosyl  transferase  locus/
mutation assay.   At  10~s M HEX also  failed to  stimulate  DNA  repair synthe-
sis in  hepatocyte  primary  cultures.   Negative results  were  also  obtained in
an additional unscheduled DNA synthesis assay (Brat,  1983).
    Two  recent studies  provided  by  NTP   (Juodeika,  1983)  also  failed  to
demonstrate the mutagenidty of HEX.   In  S.  typhimurium strains  TA98, TA100,
TA1535  and  TA1537,  levels of  up  to  3.3 yg/plate were  not mutagenic without
activation  and levels  of  up   to  100.0  vg/plate  were  not  mutagenic  after
mlcrosomal activation.   Higher  levels  could not be  tested because  of exces-
sive  bacterial mortality.   In  the  Drosophila  sex-linked  recessive  lethal
test,  HEX  was  not mutagenic.   The  doses  used  1n  this  study were  40 ppm by
feeding for 3 days or by a single injection of 2000 ppm.
    HEX has also  been assayed  1n  the mouse dominant  lethal test (Litton Bio-
netlcs, Inc.,  1978a).   In  this  assay,  0.1,  0.3 or  1.0 mg/kg HEX was adminis-
tered  by  gavage  to  10  male CD-I  mice for 5  days  and these mice  were then
mated  throughout  spermatogenesls  (7 weeks).   This  test  determines whether
the  compound  induces   lethal  genetic  damage  to  the  germ  cells  of  males.
There  was  no evidence  of  dominant  lethal  activity at  any dose  level  by any
parameter;  e.g.,  fertility  Index,   implantations/pregnancy, average resorp-
tions/pregnancy.   In  this study, the  highest  dose  used was  the  LD,., deter-
mined  by a 5-day mortality study in male CD-I mice.
4.4.    WEIGHT OF EVIDENCE
    No  reports of carclnogenicity  of HEX  have  been found  1n  the  available
literature.  The  data base is  neither extensive nor  adequate  for  assessing
the  carcinogenicity  of  HEX.   The National Toxicology Program  has recently
completed  a  subchronlc animal  study  and  Is  conducting  a chronic  animal
                                     -17-

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Inhalation  bloassay  using both  rats and  mice  (Abdo,  1984).   Applying  the
criteria  proposed  by   the   Carcinogen  Assessment  Group  of  the  U.S.   EPA
(Federal Register, 1984)  for  evaluating  the overall weight  of  evidence,  HEX
1s most appropriately considered a Group  D - Not Classified chemical.
                                     -18-

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                     5.   REGULATORY STANDARDS AND CRITERIA
5.1.   OCCUPATIONAL STANDARDS
    There 1s no current  Occupational  Safety and  Health Administration (OSHA)
standard  for  HEX  levels  1n  the  workplace.   However,  the AC6IH  (1982)  has
adopted  a TLV,  expressed  as an  8-hour  TWA  of  0.1  mg/m3  (0.01  ppm).   A
STEL,  the maximum  allowable concentration  1n  a  !5-m1nute  period,  of  0.3
mg/m3  (0.03  ppm)  for  HEX has also  been  adopted  (ACGIH,  1982).   The levels
are based on Treon et al. (1955).
    NIOSH  (1978)   classlfed   HEX  as   a  Group  II  pesticide  and  recommended
criteria  for standards for  occupations  1n pesticide  manufacturing and formu-
lating.   These  standards  rely  on engineering  controls, work  practices  and
medical  surveillance  programs,  rather than workplace  air  limits,  to  protect
workers  from the  adverse effects of  pesticide exposure  1n manufacturing and
formulating (NIOSH, 1978).
5.2.   TRANSPORTATION REGULATIONS
    The  Hazardous  Materials  Transportation  Act  specifies the requirements to
be  observed 1n  the  preparation  for shipment  and  transport  of  hazardous
materials.   The  transport  of HEX  by air,  land  and  water  1s regulated by
these  statutes, and  the  Department  of Transportation has designated HEX as a
"hazardous  material,"  a  "corrosive  material"  and a "hazardous substance."
The  maximum net  quantity  for  transport  by  passenger-carrying  aircraft or
rallcar  has  been  set at  10  gallons  per  package.   Transport  on  deck or below
deck by  cargo vessel 1s also  permitted.
5.3.   SOLID WASTE REGULATIONS
    Under  the  Resource  Conservation  and Recovery Act  (RCRA),  the  U.S.  EPA
has  designated  HEX  as  a hazardous  toxic waste,  Hazardous  Waste  No. U  130,
subject  to disposal and  permit regulations (40 CFR 262-265 and  122-124).
                                     -19-

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5.4.   FOOD TOLERANCES
    Under  the  Federal  Insecticide  Fumlgant and  Rodentldde Act  (FIFRA),  a
tolerance of 0.3  ppm  has  been established  for  chlordane  residues,  which are
not to contain >1% of  HEX (40 CFR 180.122).
5.5.   WATER REGULATIONS
    Under Section  311  of  the  Federal  Water Pollution Control  Act,  the U.S.
EPA designated HEX as a hazardous  substance and established an RQ of 1  pound
(0.454 kg) for HEX.   Discharges  equal  to  or greater  than  the RQ Into or upon
United States  waters  are  prohibited  unless the  discharge  1s  In  compliance
with applicable permit programs.
    Under  the  Clean  Water Act,  the  U.S.  EPA  has  designated HEX as  a  toxic
pollutant  (I.e.,  priority pollutant).   Effluent  limitations guidelines, new
source performance standards,  and  pretreatment standards  have been developed
or will be developed for the priority pollutants for  21 major Industries.
    Under the Clean Water Act, Ambient  Water  Quality Criteria (AWQC) for HEX
were also developed (U.S. EPA, 1980a).  Based  on  available toxldty data for
the protection of public health,  the level derived was 206 yg/l.
    Using  organoleptlc  data  for  controlling  undesirable  taste and  odor  of
ambient water, the estimated level was  1 yg/8,  (U.S. EPA,  1980a).
5.6.   AIR REGULATIONS
    HEX 1s not regulated under the Clean A1r Act.
5.7.   OTHER REGULATIONS
    Pursuant to  rules under sections  8{a)  and 8(d)   of the Toxic  Substances
Control  Act,  all  manufacturers   of  HEX  are  required to  report  health and
safety Information on HEX to  EPA's  Office of Toxic Substances.  The deadline
for  submission  of Preliminary  Assessment  Information Manufacturer's  Report
on HEX was November 19, 1982.
                                     -20-

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    In  1979,   the  Interagency  Testing  Committee  recommended  that  HEX  be

considered for  health and  environmental  effects  testing under  Section  4{a)

of  the  TSCA  (44  FR   31866).  This  recommendation  was based  on evidence  of

potential human  exposure and a  potential for environmental  persistence  and

bloaccumulatlon.  The U.S.  EPA  (1982)  responded  1n  the  Federal  Register.

The following 1s the  statement from that notice:


    EPA  has  decided  not  to Initiate rulemaklng  to require  testing  of
    HEX under section 4  of  TSCA  because  EPA  does  not believe that  there
    Is a  sufficient  basis  to  find that  current  manufacture,  distribu-
    tion 1n commerce, processing,  use or  disposal  of HEX may present  an
    unreasonable risk of  Injury  to the environment  or of mutagenlc  and
    teratogenlc  health   effects.   Neither has  the  EPA  found  evidence
    that there  1s  substantial  or  significant environmental  release  of
    HEX.  In  addition,  certain  new studies have  become  available  since
    the  ITC's  report  or are  underway,  making  additional   testing  for
    chronic and oncogenlc effects unnecessary.
                                     -21-

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                             6.  RISK ASSESSMENT
    Pertinent risk  assessment  data are  summarized In  the  Appendix of  this
report.
6.1.   ACCEPTABLE INTAKE SUBCHRONIC (AIS)
6.1.1.   Oral.   Short-term  studies by  IROC  (1978)  and Abdo  et al.  (1984)
provide  Information  on  oral toxldty  to rats  and mice; however,  the  study
sizes were  small  (5 and  10  animals/dose group, respectively).   The  studies
by  Abdo  et  al.   (1984)  are  the only short-term studies  yielding no-adverse-
effect  levels.  Based  upon   the  rat and  mouse data,  these short-term  oral
studies  Indicate  a  lowest-effect  level  for dally exposure  to be 19 and  38
mg/kg,  respectively.   Multiplying  by 5/7  to estimate a continuous  exposure
expanded  from treatment  on 5  days/week results  In estimates  of  13.6  and
27.14 mg/kg/day,  respectively.  The NOAELs  estimated  for continuous  exposure
for  the  rat  and  mouse were 7  and  14 mg/kg/day, respectively.   Using  the rat
NOAEL of  7  mg/kg/day  an AIS can be calculated.  For a 70 kg man, an  AIS for
HEX  by  oral  exposure  would  be 7  mg/kg/day  x  70 kg  * 100  =  4.9  mg/day.
Division  by  100  represents an uncertainty  factor  of 10,   Introduced  for
Interspedes  extrapolation,  combined  with  another uncertainty  factor of  10
1n an attempt to protect unusually sensitive populations.
6.1.2.   Inhalation.  In  14-week  Inhalation studies a  NOAEL  for cynomolgus
monkeys  of  0.2  ppm  HEX was established when  exposures  were  6  hours/day,  5
days/week.   This  same  concentration was  determined to  be  a  NOAEL for  rats
using the same exposure regimen.
    Using  a  monkey  respiratory  volume  of  1.4   mVday,  a  dally  exposure
estimate  can  be  calculated  as  follows:    2.27  mg/m3  (0.2  ppm)   x   1.4
mVday  x 6/24  x 5/7 = 0.568   mg/day.   Dividing   this  exposure  estimate  by
2.0  kg,  the  average  body  weight  of the  monkeys used  1n   this  experiment,
                                     -22-

-------
applying an  uncertainty  factor  of TOO and multiplying  by  70 kg,  the assumed
body weight  of  an average  human,  results in an AIS  for  Inhalation exposure
of 0.2 mg/day for a  human.   This  AIS assumes that  exposure will be uniformly
distributed over the day.
    An RQ has been calculated for  the effect of mortality  In mice exposed by
Inhalation to 0.15  ppm  (1.7 mg/m3)  HEX,  7 hours/day, 5 days/week  for  up to
150 exposures (Treon et  al., 1955).   A human MED was  calculated by expanding
to continuous  exposure,  assuming  a  human Inhalation  rate of  20  mVday  and
an  Inhalation  absorption  coefficient of  0.5,   and  applying an  uncertainty
factor of 10 to extrapolate  from  subchronlc  to  chronic  data.  A human MED of
0.35 mg/day  was  calculated, which corresponds  to  an RV.  of 6.2.   Mortality
1s assigned  an RV   of  10.   The  CS of  62  was obtained  as the  product  of
RV . and RV .
  d       e
6.2.    ACCEPTABLE  INTAKE  CHRONIC (AIC)
6.2.1.   Oral.   No  chronic  oral  toxlcity evaluations  of   HEX  were  located
which could  be  used  for  risk assessment  purposes.  Based  on subchronlc oral
data  (Abdo  et   al.,  1984)  an  AIC of  0.49  mg/man/day  for oral exposure  is
estimated by application  of an  additional  uncertainty factor of  10.
6.2.2.   Inhalation.    Treon  et  al.  (1955)   exposed   rats,   guinea  pigs,
rabbits  and  mice  to 0.15  ppm HEX  7  hours/day,  5  days/week  for  up to  7
months.  No  effects  were  seen  in any species   except  mice:  4/5  mice died
before  the  end  of  the  exposure  period.   The dose-response  relationship
appears  to be  very  steep  in an earlier  segment of  the Treon  et  al.  (1955)
report.  Exposure  to  0.33  ppm HEX  resulted  1n  the death  of 4/6  rabbits
before  25  exposure  sessions were  completed;  no  rats  or  mice survived  20
exposure periods and  guinea pigs survived  the planned  series of  30  exposures.
                                     -23-

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    Clark et  al.  (1982a) exposed groups  of  Wlstar rats  (8/sex/dose)  to HEX
concentrations of  0,  0.05,  0.1  or  0.5 ppm 6  hours/day,  5 days/week  for  30
weeks followed by a 14-week recovery  period.   At  the  0.5  ppm exposure level,
4 males  and 2 females  did  not  survive and body  weights were  depressed  1n
both  sexes;  pulmonary   degenerative  changes  were  noted,  with  males  more
severely affected.   M1ld degenerative  changes  were  seen  1n  the  Hvers  and
kidneys, and  kidney weights  were  elevated  1n females.   At  0.1  ppm  female
body weights were depressed.  No effects were noted at 0.05 ppm.
    The reason for  the  discrepancy  between these  studies  Is  unclear.   Treon
et  al.  (1955) reported  100%  mortality In  rats exposed  to  0.33  ppm  for  20
6-hour  exposure  sessions.   In  contrast,  Clark et  al.  (1982a)  exposed  rats
for 0.5 ppm for  30 weeks and noted 50% mortality  1n  males  and 25% mortality
1n  females.  Some  differences  may  be attributable  to  the  purity  of  the
compound.   Clark  et al.  (1982a) reported  that the  compound was  96% pure,
with  hexachloro-1,3-d1ene   and  octachlorocyclopentene  as Impurities,  while
Treon et al.  (1955)  reported  89.5% purity with contaminants  not Identified.
It would be helpful  to  have another study 1n  mice with a  compound of similar
purity  to  that  used by Clark  et  al.  (1982a)  1n  order  to  evaluate whether
mice are, 1n fact, more sensitive to HEX.
    Using the Clark  et  al.  (1982a)  data which  defined  a  NOEL for  the rat  of
0.05  ppm (0.5  mg/m3),   an  exposure  dose of  0.066  mg/kg/day  can  be esti-
mated  by  assuming a  rat ventllatory  volume  of 0.26 mVday, a  body  weight
of  0.35  mg  and 100% absorption,  and multiplying  by  6 hours/24 hours  and  5
days/7 days to estimate continuous  exposure.   Applying an uncertainty factor
of  1000  (10  for   Interspedes  conversion,   10   to  reflect  concern  about
discrepancies 1n  the available data  and  10 to protect especially sensitive
members  of  the  population)  and  multiplying  by  70  kg,  an  assumed  average
                                     -24-

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human  body  weight, results  In an  Inhalation AIC  of  0.00462 mg/day.   This
corresponds closely  to that  estimated  from the TLV of  0.1 mg/m3.   Using  a
human  8-hour  ventHatory  volume of 10  m3/8 hour workday and  multiplying  by
5 days/7  days and dividing  by  an uncertainty factor  of  100  (10  to  protect
potentially more sensitive segments of  the  general  population,  10  to  reflect
deficiencies  1n the available data  base) would  result 1n an estimated  dally
Intake  of  0.0071   mg/day  based on  the  TLV.   The  AIC,  1n  units  of  mg/day,
makes  an  Implicit  assumption  that  exposure will  be  uniformly  distributed
over the day.
6.3.   CARCINOGENIC POTENCY (q.,*)
    There are no available data on  the  long-term effects  of exposure  to HEX.
Because the NTP 1s testing HEX In a  chronic  bloassay, the  U.S.  EPA Carcino-
gen Assessment  Group  will defer  any  decision on the  carclnogenlcity of  HEX
until the completion of the bloassay.
                                     -25-

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                                7.  REFERENCES







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                                     -26-

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                                     -30-

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                                     -31-

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                                     -34-

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                                                       APPENDIX


                                     Summary Table for Hexachlorocyclopentadlene
GO
tn
i
Species
Inhalation
AIS monkey
AIC rat
Maximum mice
composite
score
Oral
AIS mouse
AIC
Experimental
Dose/Exposure

2 mg/m3 for 14 weeks
0.5 mg/m3 for 30 weeks
0.15 ppm (1.7 mg/m3)
7 hours/day,
5 days/week for up
to 150 exposures
RVd=6.2)

27.1 mg/kg/day for
13 weeks

Effect Acceptable Intake Reference
(AIS or AIC)

NOEL 0.2 mg/day Rand et al.,
1982
NOEL 0.0046 mg/day Clark et al.,
1982a
mortality 62 Treon et al.,
(RVe=10) 1955

forestomach 4.9 mg/man/day SRI, 1981a
hyperplasla
ND
     ND =  Not  determined

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