Environmental Protection
               Agency                                     December, 1987
4>EPA       Research and
               Development
              HEALTH AND ENVIRONMENTAL  EFFECTS PROFILE
              FOR HEXACHLOROCYCLOHEXANES
               Prepared for
             OFFICE OF SOLID WASTE AND
             EMERGENCY RESPONSE
               Prepared by
              Environmental Criteria and Assessment Office
              Office of Health and Environmental  Assessment
              U.S. Environmental Protection Agency
              Cincinnati,  OH  45268
                         DRAFT: DO NOT CITE OR QUOTE


                                NOTICE

          This document Is a preliminary draft. It has not been formally released
       by the U.S. Environmental Protection Agency  and  should  not at this stage be
       construed to repres nt  Agency policy. It Is being circulated for comments
       on Us technical accuracy and pollry Implications.

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                                      DISCLAIMER



       This  report  Is an  external  draft for  review purposes only and  does  not

   constitute  Agency  policy.   Mention  of   trade  names  or  commercial  products

   does not  constitute endorsement  or  recommendation for  use.
     U.S. Environmental Protection
     Region 5, Library \PL-12J)
     77 West Jackson Boulevard,  12th fkwr
         go,  it  60604-3b90
                                          11
Cl

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                                    PREFACE


    Health and  Environmental  Effects Profiles  (HEEPs)  are prepared  for  the
Office  of  Solid Waste  and Emergency Response  by the  Office  of Health  and
Environmental Assessment.   The  HEEPs  are  Intended  to  support listings  of
hazardous constituents  of  a wide  range  of  waste streams  under  Section  3001
of the  Resource  Conservation  and Recovery Act (RCRA), as  well  as  to provide
health-related limits for  emergency actions under Section  101  of the Compre-
hensive  Environmental   Response,  Compensation  and  Liability  Act  {CERCLA).
Both  published   literature and   Information  obtained  from  Agency  program
office  files are  evaluated  as  they  pertain   to  potential  human  health,
aquatic life and environmental effects of hazardous waste  constituents.   The
literature  searched  and   the  dates  of   the  searches  are  Included  1n  the
section  titled   "Appendix:  Literature   Searched."    The  literature  search
material 1s current through November,  1985.

    Quantitative  estimates  are   presented   provided   sufficient   data   are
available.  For   systemic toxicants, these Include Reference  doses  (RfDs)  for
chronic exposures.   An  RfD 1s defined as the amount  of a chemical  to  which
humans  can  be  exposed  on a  dally  basis over  an  extended  period  of  time
(usually a lifetime) without suffering a  deleterious effect.   In the case of
suspected  carcinogens,  RfDs  are  not  estimated  1n  this  document  series.
Instead, a  carcinogenic potency  factor  of  q-|*  Is  provided.   These  potency
estimates are derived for  both oral and  Inhalation exposures  where  possible.
In addition,  unit  risk estimates  for air  and  drinking water  are  presented
based on Inhalation and oral data, respectively.

    Reportable quantities  (RQs)  based  on both chronic  toxldty  and carclno-
genldty are derived.   The RQ Is  used to determine the  quantity of  a hazard-
ous substance for  which notification 1s  required  In  the event  of  a release
as specified under CERCLA. These two RQs (chronic toxldty  and cardnogen-
1c1ty)  represent two of   six  scores  developed  (the  remaining  four  reflect
1gn1tab1l1ty, reactivity,  aquatic toxldty and acute mammalian toxldty).

    The  first  draft  of  this  document  was  prepared  by  Syracuse  Research
Corporation  under  EPA  Contract  No.  68-03-3228.   The  document was  subse-
quently  revised  after  reviews   by staff within the  Office  of Health  and
Environmental Assessment:  Carcinogen  Assessment Group,  Reproductive  Effects
Assessment Group,  Exposure Assessment Group, and the Environmental Criteria
and Assessment Office In Cincinnati.

    The HEEPs will  become part of the EPA RCRA and CERCLA dockets.
                                      111

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                               EXECUTIVE  SUMMARY

    The  Isomers  of  hexachlorocyclohexane  (HCH)  are  white  or  yellowish
powders  or  flakes,  with  differing  odors  depending  on   the  Isomer.   The
Isomers  are  soluble  to varying  degrees  1n  a  variety  of organic  solvents
Including  ethyl  alcohol,  chloroform,  acetone,  dloxane,   ether  and  others
(Colson,  1979).  HCHs  can  be decomposed  by  alkaline substances  and  are
expected to  undergo  reactions typical of alkyl  halldes  Including hydrolysis
and dehydrohalogenatlon (Morrison and Boyd, 1973).
    Technical  grade  HCH   (T-HCH),  a  65:7:17:4:10 mixture of  a,   B,  Y.  c
and other  Isomers of  HCH,  respectively,  1s produced  by  the photochemically-
Induced  reaction  between  benzene and  chlorine  In  the presence of a  free
radical  Initiator.   A  variety of physical  separation  methods  are used  to
purify  Y-HCH  to  99.9% from T-HCH  for  use  as an  Insecticide  (llndane)
(Colson, 1979).
    y-HCH  1s  used  as  an Insecticide  on  hardwood  logs and  lumber,  a variety
of  seeds,   vegetables  and  fruits,   woody  ornamentals  Including  Christmas
trees,  hardwood forests,  livestock and pets  (external  parasite  control)  and
existing structures  (control  of  woodborlng  beetles  and  termites)  (Federal
Register,  1983).  Pertinent  data  regarding uses  of the  other  Isomers  1n  the
pure  state could  not  be located  1n the  available literature  as  dted  In  the
Appendix.  The  technical product  has  been  used  as an  Insecticide In the past
but Is no longer used as such  (Colson, 1979).
    Half-lives  of Y-HCH 1n  water at 25°C  were  reported  to  be  92, 771  and
648 hours  1n  natural  water samples from a  eutrophlc  pond  In  Texas  (pH 9.3),
a dystrophlc reservoir  1n  Louisiana (pH  7.3)  and an  ollgotrophlc rock  quarry
In Indiana (pH  7.8),  respectively (Saleh et  a!.,  1982).   Hydrolysis experi-
ments In M1111-Q water  at  pH values of  5,  7 and 9 yielded  half-lives of 936,

                                      1v

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4331 and 95 hours, respectively  (Saleh et al.,  1982).   Therefore,  hydrolysis
at  alkaline  pH  values  Is expected  to be  Important In  the  fate of  y-HCH,
while  hydrolysis  at acidic  and neutral  pH values  1s  not.  Pertinent  data
regarding the hydrolysis of the  other  Isomers of  HCH could not  be located In
the available literature; however, all these  Isomers contain  more equatorial
bonds  than  y-HCH,  and  since  these  bonds  are  generally  more stable  than
axial  bonds,  1t  1s expected that  the remaining Isomers will be  more  stable
to hydrolysis than y-HCH.
    First-order  photolysis   half-lives  for  y-HCH   of  169,  1791  and  1540
hours were observed In natural water  samples  from a eutrophlc pond 1n  Texas,
a  dystrophlc  reservoir  In  Louisiana and  an  ollgotrophlc  rock  quarry  1n
Indiana, respectively (Saleh et  al.,  1982).  The  relatively short photolysis
half-life observed In the  Texas  sample  was  attributed  to the  alkaline  pH
that,  H  was concluded,  generated hydrolysis  products more susceptible  to
photolysis  than  y-HCH  (Saleh  et  al.,  1982).    After  50  days exposure  to
sunlight,  the concentrations  of  y- and  a-HCH  1n  purified  water  dropped
from  -9300  to  -7600  vg/mfc  and  from  1480  to  -1130  yg/ma,  respectively
(Malalyandl et al.,  1982).   Pertinent data regarding the  photolysis  of the
other  HCH  Isomers  could  not  be  located  In  the  available  literature  as cited
1n  the  Appendix.   Direct photolysis,  however, 1s not expected  to be a major
fate  process  for any of  the  HCH  Isomers since  they do  not  have conjugated
unsaturated systems.
    Of  the  y-HCH  added  to  unsterlllzed  natural waters  In  capped  bottles,
<30X  remained after  16  weeks  (Sharom  et  al.,  1980).    About  25X  of the
Y-HCH   1n   raw  wastewater   from  Cincinnati  was   removed  during   aerobic
blodegradatlon  In  a  wastewater  treatment  plant  (Petrasek  et  al.,  1983).
Pertinent data regarding  the aqueous  blodegradatlon of  the other HCH  Isomers
could  not be  located In the available  literature as  cited In the Appendix.

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    The  volatilization  half-life  of  y-HCH has  been  estimated  to  be  115
days (Lyman et al., 1982} and  191  days (Mackay  and Lelnonen,  1975),  assuming
a depth of 1 m.   Volatilization  half-lives  of  3.2 and 1.5 days were  observed
for Y-HCH  from still and  stirred water  4.5 cm  deep (Chlou   et  al.,  1980).
The measured  volatilization half-life of  3.2  days  was  used  to  estimate  a
half-life of 692  days  from  water 1 m  deep.  Since  the  half-lives of  115 and
191 days are of  the same order  of magnitude as  the half-life  estimated from
experimental data, the former  values are  considered to  be accurate estimates
of the tendency of q-HCH to  volatilize.   Henry's  Law Constant  values  for the
other Isomers have been estimated and  suggest  that  volatilization of  all HCH
Isomers occurs  at a rate  dependent  upon the  rate of diffusion  through the
air  {Lyman  et  al.,  1982).   Volatilization  of  HCH  Isomers  In water  Is not
expected to be  significant  1n the environment.
    A  mean  K     for  Y-HCH of   1080.9   was  obtained  from  K    determlna-
             oc       T                                        oc
tlons  on  three soils  (Rao   and  Davidson,  1982).   Based on  this K    and  a
low water  solubility  of  7.5  ppm (U.S.  EPA,   1981), Y-HCH  Is  expected  to
leach  slowly   to  groundwater.    K   values  for  the remaining   HCH  Isomers
were estimated  (Lyman et al.,  1982)  and, combined  with  the fairly low water
solubilities of the  Isomers,  suggest  that  they are  expected  to  bind  fairly
tightly to soil and to leach slowly  to groundwater.  Fifteen  years following
the application of technical HCH  to  a  sandy loam soil In Canada, >90X of the
applied  a-,  B-,   y- and  i-HCH  remained  1n   the  upper  20  cm  of   soil,
Indicating minimal leaching  had taken place (Stewart and Chlsholm, 1971).
    BCFs  for  Y-.  «-t  8- and  4-HCH   1n  a   variety  of  species   ranged  from
63-1613  (Matsumura  and  Benezet,  1973;   Ramamoorthy,  1985;  Kanazawa,  1983;
Schlmmel et al.,  1977; Metcalf et  al., 1973; Yamato et  al.,  1983; Suglura et
al., 1979).  No  BCF values  were  available  for  e-HCH, but 1t  Is  expected to
                                      v1

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bloaccumulate  similarly  to  6-HCH,  to  which  H  bears  a  close  structural
similarity.  None of the HCH  Isomers are expected  to  bloconcentrate  signifi-
cantly 1n aquatic organisms.
    Based  on  degradation  data,  the  persistence   half-lives  for  y-HCH  1n
river, lake and groundwater were estimated to be 3-30,  30-300  and >300 days,
respectively (Zoeteman et  al.,  1980).   Pertinent data regarding  the  persis-
tence of the other  Isomers could not be located 1n the  available literature
as cited In the Appendix.
    Anaerobic  soil  preparations   were  found  to   readily   degrade  y-HCH
(Kohnen  et al.,  1975;  Mathur  and Sana,  1975;  Llchtensteln  et al.,  1971;
Sethunathan  and   Yoshlda,  1973;  Haider,  1979).    Degradation  of  a-HCH  by
anaerobic  soils has also been observed  (Castro and Yoshlda, 1974; HacRae  et
al.,  1984;  Haider,  1979).   Doelman  et  al.  (1985)  observed greater  aerobic
than  anaerobic  degradation of  a-HCH 1n polluted  soil.   Anaerobic  degrada-
tion  of  a-, B- and  6-HCH  by  several  organisms has  been  observed  (Haider,
1979).   Pertinent  data  regarding  the  blodegradatlon  of  c-HCH could  not  be
located In the  available  literature as  cited  In  the Appendix.
    After  50  hours,  26 and  100%  of  the surface  applied  y-HCH  remained  on
Hatboro  silt  loam and Norfolk  sandy loam,  respectively (Glotfelty  et  al.,
1984).   The  low  volatility of  the y-HCH  was  attributed  to  the dryness  of
the sandy  loam.   From a moist  soil  surface, the y-HCH  content  decreased  to
50  and  10% of  the  amount  applied  after  6  hours  and 6  days,  respectively,
while  50  hours  after the application  of  y-HCH  to  dry  soil,  88% of  the
applied  compound  remained  (Glotfelty et al., 1984).  Pertinent  data  regard-
Ing the  volatilization of  the other HCH Isomers could not  be  located 1n the
available  literature  as  cited  In  the Appendix.   The estimated  Henry's  Law
constants,  K    and  measured  water  solubility  values  suggest  that  the
             oc

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Isomers will  bind fairly  tightly  to soil and  will  have Uttle  tendency  to
volatilize from dry soils.  Volatilization from moist  soils,  however,  may  be
significant.
    T-HCH  concentrations  of 0.01-0.319  ppb  have  been detected  1n  drinking
water from various rural and urban  areas  (Keith et a!.,  1976; Sandhu et al.,
1978; Bevenue et al., 1972).   Based  on  these  figures  and assuming an average
dally  consumption  of  2   J. of  water,  an  average   dally  y-HCH  Intake  of
0.02-0.638  pg  was   estimated.   A  y-HCH  concentration   of  1.3  ppb  was
detected  1n  Ottawa,  Ontario  (Krayblll,   1977).   The average dally  Intake
based  on  this  figure  1s  2.6  yg,  but   this  figure  1s   considered  to  be
nonrepresentatlve since the monitoring  data  on which  It Is based 1s so high
relative  to  the  other  values.  Surface  water and  precipitation (rain  and
snow)  samples  contained  measurable  concentrations   of  y-HCH  (U.S.  EPA,
1985a;  Oliver  and Charlton,  1984;  Cole  et  al.,   1984;  Saleh et  al.,  1982;
Sandhu  et  al.,  1978;   Bevenue  et  al.,  1972;   Page,  1981;  Strachan  and
Huneault,  1979;  Pankow  et  al.,  1984;  Brooksbank,  1983;  Strachan,  1985).
a-HCH  has been  detected   at  2.7-20.3  and 0.45-9.7  ppt municipal  drinking
water samples collected during the  winter  and  summer,  respectively (Williams
et   al.,   1982)  and  at   17   yg/i  1n  tap   water   from  Ottawa,   Ontario
(Krayb.111,  1977).   An  average dally  Intake  of  a-HCH  of  0.90-40.6  ng  was
estimated,  assuming  an  average dally  consumption of  2  &  of   water  (exclud-
ing  the  Ottawa  result).   Based on  the high a-HCH content  of  the tap water
from  Ottawa,  an  average  dally Intake  of  34  yg  was  estimated.   Because  of
the  relatively  high  value of  a-HCH  1n  the  Ottawa   sample,  this  value  1s
thought to be nonrepresentatlve.  Samples  of  surface  water  and precipitation
(rain  and  snow)  from  a   variety  of  locations contained  a-HCH   (U.S.  EPA,
1985a; Kuntz  and  Warry,  1983;  Page, 1981; Cole  et  al., 1984; Strachan  and

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Huneault, 1979;  Elsenrelch  et al.,  1981;  Pankow et  al.,  1984;  Brooksbank,
1983; Strachan, 1985).  In the Netherlands, B-HCH was found  1n  ng quantities
1n  a  variety  of  locations  (Dulnker  and  Hlllebrand,  1979).    Samples   of
surface water  1n  the United States  contained  a  mean B-HCH  concentration  of
0.1725  yg/i   (U.S.  EPA,  1985a).   Pertinent  monitoring   data   for   i-  or
c-HCH  could  not  be  located  In   the  available  literature  as  dted  1n  the
Appendix.
    A  wide  variety  of  foodstuffs,  Including  dairy products,  meat,  vege-
tables, fruits and seafood,  contain  one  or more HCH  Isomers  (Duggan  et al.,
1983;  Steffey  et  al.,  1984; Podrebarac,  1984;  SchmHt et  al.,   1985; U.S.
EPA,  1985a).   The average  dally  Intake  of  y-HCH  was  estimated  to be 0.27
vg,  based  on   the  y-HCH  content  1n foods   from  1971-1976,  and  that   of
a-HCH  was  estimated  to be  10.5  and  9.1  ng/kg bw/day,  based on 1977  and
1978 data, respectively.  Since monitoring  data  In  foods are available only
for  mixtures   of   the   Isomers,   0-,   4-  and  e-HCH,  It  Is   not  possible   to
estimate the average  dally Intakes of Individual  Isomers.
    The mean  concentration  of y-HCH  In  positive samples  of ambient air  In
the  United  States In  1970-1972  was 0.9  ng/m3 (Kutz  et  al.,  1976).   Based
on  this  value  and assuming an average Intake  of 20 m3 air/day,  the  average
dally  Intake  of  Y-HCH  Is  18  ng.    Monitoring   data   during   the  years
1970-1972  revealed  a  mean  a-HCH  concentration   In  ambient  air  of  1.2
ng/m3  1n  the  positive  samples  collected across the  United  States  (Kutz  et
al.,  1976).   Assuming an average dally  Intake of  20 m3 of  air,  this  figure
1s  equivalent  to  an average dally  Intake of  24  ng.  Pertinent monitoring
data  regarding the other Isomers of HCH could not  be  located  1n the avail-
able literature as cited In the Appendix.
                                      1x

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    A large volume of  Information  Is available concerning effects of HCH  on
aquatic organisms.   Llndane  (y-HCH)  Is generally more  toxic to  freshwater
and  saltwater  fish  and  Invertebrates  than other  HCH  Isomers  or  mixtures
(U.S.  EPA,  1980b).   The  lowest  reported  acutely  toxic concentrations  for
freshwater  species  were  1.7  vg/t  Undane,  which was  a  96-hour  LC5Q  for
brown  trout  (Johnson  and Flnley,  1980) and  1  v9/&  Undane,  which  was  a
96-hour LC5Q  for  stonefHes  (Cope,  1965, Snow,  1958).   The lowest  reported
acutely  toxic   Undane concentrations  for   marine fish  and  Invertebrates,
respectively,  were  7.3  yg/J.,   a  96-hour LC5Q for  striped bass  (Korn  and
Earnest,   1974),   and   0.17  yg/l,   a  96-hour   LC5Q   for   pink   shrimp
(Schlmmel et al., 1977).  Among the freshwater  fishes,  salmonlds appeared  to
be more sensitive  than  other  species.   Crustaceans  other  than cladocerans
were  generally  the most  sensitive  Invertebrate  species  both  In  freshwater
and  saltwater   (U.S.  EPA, 1980b).   Fish and  Invertebrates appeared  to  be
about equally sensitive to HCH.
    In chronic  toxiclty studies, no adverse  effects were  reported  at concen-
trations lower  than the acutely toxic  levels  for  the most sensitive  species;
however, chronic  toxiclty data for  the  most acutely  sensitive  species  were
generally unavailable.
    The available  Information  Indicated  that  aquatic  plants were much  less
sensitive to HCH than fish or Invertebrates.
    HCH accumulates In aquatic biota primarily  In  fatty  tissue;  however,  HCH
Is less I1poph1!1c and less  persistent  than  other  organochloMnes  and  there-
fore 1s not bloaccumulated or blomagnlf led to a great  extent.
    Two  studies provide  direct  evidence  that y-HCH  1s  absorbed  from  the
gastrointestinal tract (Turner and  Shanks,  1980;  Ahdaya et  al., 1981).   The

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appearance of a-HCH  and  B-HCH In  the  blood  and tissues after oral adminis-
tration  1s  also Indicative of gastrointestinal  absorption  {Elchler et al.,
1983; Altmann et al., 1983;  Macholz et  al., 1982a,b).
    In general,  Isomers  of  HCH and  their  metabolites  tend  to accumulate  1n
fatty tissue (Elchler et al., 1983; Chand and Ramachandran, 1980;  Lakshmanan
et al.,  1979; Chadwlck et  al.,  1978a;  Altmann et al., 1983; Baumann et al.,
1980; S1dd1qu1  et  al.,  1981a; Szymczynskl and  Wallszewskl,  1981a,b).   In a
comparative  study  where a-HCH  or  y-HCH  was fed  to  rats  In the diet  for
56 days,  Elchler  et  al.  (1983) found  that a-HCH accumulated  1n  the fat  and
brain  to a  greater  extent  than  did y-HCH.   Furthermore,  the retention  of
a-HCH  In the tissues  (fat, brain,  liver,  kidney) was  12-30  times greater
than  that of  y-HCH.  Tissue  concentrations of y-HCH  declined   to  a much
greater  extent  than  did tissue  levels of a-HCH during  the  15 days follow-
ing termination of exposure.
    The  metabolism  of  HCH   Isomers   primarily  Involves ' dehydrogenatlon,
dehydrochloMnatlon and dechloMnatlon.  Conjugation reactions with sulfurlc
and glucuronlc add are also Important  (Macholz  et al.,  1982a; Engst et al.,
1976,  1979;  Chadwlck et al.,  1975; Grover and  S1ms,  1965;  Freal and  Chad-
wick, 1973;  Chadwlck and Freal.  1972;  Allsup and Walsh,  1982).   In mammals,
Including  humans,  common  metabolites   of  HCH  Include  chlorinated phenols,
chlorinated  benzenes  and   pentachlorocyclohexenes.   These  metabolites  are
usually  excreted  In  conjugated form  (or  a  degradation  product  of a  previ-
ously  conjugated  form)  1n   the urine,  and  have  also been detected  In  blood,
liver, kidney,  spleen, heart and  brain  (Engst et al.,  1976;  Chadwlck et al.,
1975,  1978a;  Freal and  Chadwlck,  1973; Chadwlck and Freal, 1972;  Angerer et
al., 1983; Kujwa et  al., 1977; Grover  and  S1ms,  1965).   A number  of In vitro
studies  have shown that the metabolism of HCHs  In mammals  Is mediated to a
                                      x1

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great  extent  by oxldatlve processes  1n  hepatic mlcrosomes (Gopalaswamy and
Alyar, 1984; Yamamoto et al.,  1983;  FHzloff  et  al.,  1982;  FHzloff  and  Pan,
1984; Baker et al., 1985; Tanaka et al.,  1979; Portlg  et  al.,  1973).
    HCH  Isomers  and  metabolites have been  recovered  In  the urine and  feces
(Ahdaya et al.,  1981; KuMhara  et  al., 1979;  Chadwlck  et al.,  1975,  1978a,b;
Allsup and  Walsh,  1982; Zesch  et  al., 1982;  Angerer  et  al.,  1981;  Stein  et
al.,  1980;  Macholz  et  al.,   1982a,b),  and  trace  amounts (as  14CO )  have
been detected  In expired air  (Ahdaya et  al.,  1981; Chadwlck et  al.,  1978a).
In  comparative studies, KHamura  et al.  (1970) and  Elchler  et al.  (1983)
demonstrated that  the  disappearance of y-HCH  from  the bodies of mice  given
a  single  oral  dose  or  rats  given  repeated oral doses  was more rapid  than
that  of  B-HCH  or  
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    Dietary  B-HCH  has  been  shown  to  cause  Increased Incidences  of  liver
tumors 1n CF1 and  ICR-JCL  mice (Thorpe and Walker, 1973; Goto et al.,  1972)
but not  1n  dd mice  (Ito et  al.,  1973a,b; Hanada  et  al., 1973; Nagasaki  et
al.,  1972a)  or  Wlstar rats (Ito et  al.,  1975;  FHzhugh et al., I960).   The
reproductive  and  teratogenlc   effects  of  B-HCH  have  not  been  Investigated.
Nonneoplastlc and  neoplastlc  hlstologlcal  changes  1n  the   liver  were  not
observed  In  studies  that were  designed  to  Investigate hepatic  carcinogenic
response  (Ito et al.,  1973a,b, 1975);  Increases  In  absolute  and  relative
liver weight  were observed at  dietary  concentrations  >250 ppm.  FHzhugh  et
al.  (1950)  observed   Increases  In  liver  weight  accompanied   by  hlstologlcal
changes In rats  fed  >100 ppm B-HCH; Increased relative liver weight  was  the
only  effect  observed at 10  ppm.    Early mortality was also observed  among
rats  fed  800 ppm.   No tumors  were  observed  1n  this  study, though  It  should
be  noted  that not  all of the  rats  started  on the test were  examined  hlsto-
loglcally-(no criterion for  selection  was given).   No  other  chronic  effects
were reported.
    Dietary  y-HCH  was   shown   to  cause  an  Increased  Incidence   of  liver
tumors 1n male CF1  mice fed 400 ppm  for  110  weeks  (Thorpe and Walker,  1973),
and marginally  In  male  dd  mice fed  600  ppm  for  32 weeks, then  examined  5-6
weeks posttreatment  (Hanada et  al.,  1973),  and  1n male ICR-JCL  mice  fed  600
ppm for  26  weeks (Goto et  al., 1972).   No  liver tumors were observed  1n  dd
mice  fed  up  to  500 ppm for 24  weeks  (Ito et al., 1973a,b; Nagasaki  et al.,
1972a) or In Wlstar  rats fed 500  ppm for up  to  48 weeks  (Ito et al.,  1975).
Significant  compound-related   development of  tumors   of   any type  was  not
observed  In  NMRI mice (Herbst  et al.,  1975;  Welsse and Herbst,  1977), B6C3F1
mice  (NCI,  1977),  Osborne-Mendel  rats  (NCI,  1977) or Wlstar rats  (FHzhugh
et  al.,  1950).   The  study  conducted by  NCI  (1977)  has been criticized  for
-------
poor  survival  of rats,  changes  1n dosing  regimen  and the possibility  that
male  rats  did  not  receive MTOs  (IARC,  1979).   The  negative  findings  of
FHzhugh et  al.  (1950)  are also  Inconclusive since  only  small numbers  of
animals were  examined  hlstologlcally.   The negative  findings  of Ito et  al.
(1973a,b),  Nagasaki et al.  (1972a) and  Ito  et  al.  (1975)  might be  attributed
to  small  numbers of animals  and  short duration.   Notably,  a metabolite  of
Y-HCH,  2,4,6-trlchlorophenol,  Is  carcinogenic 1n  mice and  rabbits  and  1s
considered to be a probable human carcinogen (Group  82).
    Orally-administered  y-HCH  was  not  found  to  be  teratogenlc  or  fetotoxlc
In  Wlstar  rats   (Khera et  al., 1979),  CD  rats (Palmer  et  al., 1978a),  CFY
rats  (Palmer  et  al.,  1978b), New  Zealand White  rabbits   (Palmer  et  al.,
1978b)  or  CD-I  mice (Chernoff and Kavlock,  1983;  Gray and Kavlock,  1984).
In  contrast,  a  study  by  Dzlerzawskl  (1977)   reported  Increased numbers  of
resorbed fetuses  In  hamsters   (40  mg/kg on  day 9  of gestation), rabbits  (40
or  60  mg/kg on  day 9 of  gestation) and rats (40,  50 or 100 mg/kg  on  various
days  of gestation).   Maternal toxldty was not  reported.   These  doses  are
higher  than  any  of  those  tested  1n  the  negative  studies  of y-HCH,  though
Chernoff and  Kavlock (1983)  reported  that  25 mg/kg/day was the  maximum  dose
that was not  toxic to maternal  CD-I mice.
    Palmer  et al.  (1978a)  failed  to observe adverse effects on  reproduction
In  three  generations  of  CD   rats  fed up  to  100  ppm y-HCH  In  the diet.
Dlkshlth and  Datta  (1977) and  DlkshHh  et  al.  (1978),  however, observed
testlcular  atrophy  In ITRC rats  gavaged  with 17.6  mg  Y-HCH/kg  In  peanut
oil  for 90  days,  suggesting  that  y-HCH  might  have  adverse effects  upon
reproduction.
    Long-term oral  studies have  shown targets for HCH  toxldty  to  be  the
liver  (a,  Y,  B)  (Olkshlth et al.,  1978;  FHzhugh et  al.,  1950); Research
and  Consulting  Co., Ltd., 1983;  Oesch et  al.,  1982;  Ito  et  al.,  1973a,
                                     x1v
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Rlvett  et  al., 1978),  kidney  (a, y)  (Fltzhugh  et al.,  1950;  Research and
Consulting  Co.,   Ltd.,   1983).    Hematologlcal  effects  (y)  (Earl  et al.,
1970;  Morgan  et   al.,   1980)  and  neurotoxldty  have  also  been  reported
(FHzhugh et al.,  1950;  Czegledl-Janko and Avar, 1980).  Short-term  studies
suggest  that y-HCH may  cause Imraunosupresslon (Oewan  et al., 1980;  Desl  et
al., 1978).
    Dietary i-HCH  did  not  cause  neoplastlc or nonneoplastlc changes  In the
livers  of male dd mice  (Ito et al.,  1973a; Nagasaki  et al., 1972a)  or male
Wlstar  rats (Ito et al., 1975).   These  studies used small numbers  of  animals
and  were only  conducted  for 24  weeks.  A mixture  of  6-  and  e-HCH  caused
benign  and malignant hepatomas  1n male ICR-JCL mice when fed In the  diet  at
600  ppm for  26 weeks  (Goto et al.,  1972).   Other  pertinent data  regarding
the  teratogenlc,   reproductive  or  chronic  effects  of  6-HCH  could  not   be
located  In the  available literature as cited  In the  Appendix.
    Concerning   the cardnogenlclty  of  e-HCH,  a  mixture   of  5- and  e-HCH
caused  benign  and malignant hepatomas  In  male ICR-JCL. mice when  fed  In the
diet  at 600 ppm   for  26 weeks   (Goto  et  al.,  1972).  Pure  c-HCH was not
evaluated.   Other  pertinent  data  regarding  the health effects  associated
with  exposure  to  e-HCH  could not be  located  1n  the available  literature  as
cited In the Appendix.
    T-HCH  (technical  grade  HCH mixture)  has  been  shown to cause  Increased
Incidences of  liver neoplasms  1n  four strains of mice (Hanada  et  al., 1973;
Goto  et al., 1972; Kashyap  et al., 1979; N1gam et al.,  1984a;  Bhatt  et al.,
1981;  Munlr  et  al.,  1983;  Nagasaki   et  al., 1971,  1972b; Nagasaki,  1973;
Munlr and Bhlde,  1984) but  not  1n Wlstar  rats (Munlr  et al., 1983) or Syrian
golden  hamsters  (Munlr  et  al., 1983).   T-HCH 1s typically  65% a.  Isomer,  7%
B, 17%  y, 4% e and small amounts of 10 other  Isomers Including 6.
                                      xv
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    The  teratogenlc  effects  of T-HCH  have  not  been Investigated.   Nlgam  et
al. (1979) and  ShTvanandappa  and  Krlshnakumarl  (1981,  1983) have  shown  that
orally-administered  T-HCH  causes  testlcular atrophy  1n  rats and  mice  (>800
ppm, rats; 500 ppm, mice).
    Long-term oral  administration  of T-HCH has  been  shown  to  cause adverse
effects on the  liver  (Fltzhugh et al.,  1950;  Barros and  Sallba, 1978; Barros
et  al.,  1982;  Shlvanandappa  and  Krlshnakumarl,  1981; Nlgam  et  al.,  1982,
1984a,b; Munlr  and Bhlde,  1984),  kidney  (Fltzhugh  et  al.,  1950,  Barros  and
Sallba,  1978;  Barros et al.,  1982;  Shlvanandappa  and Krlshnakumarl,  1981),
adrenal cortex  (Shlvanandappa  and Krlshnakumarl,  1981; Shlvanandappa et  al.,
1982) and CNS (Shlvanandappa and Krlshnakumarl,  1981;  Kashyap  et al., 1979).
Kashyap  et  al.  (1979)  also  reported  that  long-term oral exposure  to  T-HCH
was associated with Increased cornea! opacity.
    A large body of  evidence  Indicates  that the  nonneoplastlc  changes In  the
liver associated with exposure to  Vsomers of HCH or to T-HCH  are associated
with neoplastlc development.   The nonneoplastlc  changes support the qualita-
tive estimation of cancer  of  the T-HCH  mixture  and the   Isomers  of  HCH  that
have tested  positive.  A  clear  progression  of hepatic  changes  that  ulti-
mately  lead  to  the  development  of  malignant  tumors  has  been  observed  at
gross,  histologlcal  and ultrastructural  levels  of  examination.   These  non-
neoplastlc changes were proportional  to dose  and duration of  HCH treatment.
These liver effects are reversible only  at  the  stages  before the development
of  nodular hyperplasla.   The exact  stage  at  which  the liver  changes become
Irreversible has not  been  clearly  defined (Ito et  al., 1975,  1976; Schulte-
Hermann  and  Parzefall, 1981;  Munlr  et al.,  1983; Munlr  and  Bhlde,  1984;
Nlgam et al., 1982,  1984a;  Suglhara  et al., 1975).  Although  nodular hyper-
plasla  may appear  to  regress shortly after  HCH  treatment  1s  discontinued,  1f
                                      xvl
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the  observation  period  Is  extended,  the  development  of  hepatocellular
carcinoma becomes apparent  (Suglhara  et  al.,  1975).  Suglhara et  al.  (1975)
postulated that surviving cells from  areas  of  nodular  hyperplasla  ultimately
progress to hepatocellular carcinoma.
    A  q.j*  of  6.34  (mg/kg/day)'1  was  derived  for  a-HCH,  based  on  the
combined Incidences of benign and malignant liver tumors  In  male mice fed 0,
100, 250  and 500  ppm a-HCH  In  the  diet  In  the Ito  et  al.  (1973a)  study.
Corresponding  concentrations  of  a-HCH  1n  water associated with  Increased
cancer  risk  levels  of  10"5,  10"«  and  10~7  are   5.52xlO~5,   5.52xlO"«
and 5.52xlO~7 mg/l.
    A  1/ED-iQ  (F factor)  of  69.5 was  derived  based on  data for  benign  and
malignant liver  tumors  In male mice  fed a-HCH (Ito et al.,  1973a).   This  F
factor  places  a-HCH  1n  potency  Group 3 and,  with  an  EPA classification of
B2,  results  In a  MEDIUM hazard ranking under CERCLA.  A chronic  toxldty-
based  RQ  of  1000 was estimated  for a-HCH,  based on early mortality  of rats
1n a chronic feeding study (FHzhugh  et al., 1950).
    A  q.j*  of  1.8  (mg/kg/day)"1,  originally  derived for  B-HCH  by the U.S.
EPA  (1982a),  Is the  recommended  value for this  Isomer.   This  q,* 1s based
on  the  combined Incidence of  benign  and malignant  liver  tumors  1n male mice
fed  0  or 200  ppm B-HCH  1n  the diet  for  up  to  110 weeks  1n  the study by
Thorpe  and  Walker  (1973).   Corresponding  concentrations  of B-HCH In water
associated  with  Increased  cancer   risk  levels  of  10"5,   10~6   and  10"7
are 1.90xlO~«, 1.90xlO~5 and 1.90x10"* mg/l.
    A  l/EDlfl  (F factor)  of  10.7 was  derived  from  the  data  for  benign  and
malignant liver tumors   In  male  mice  fed  B-HCH  (Thorpe and  Walker,  1973).
                                     xvll
-------
This F factor places B-HCH  In  Potency  Group  2 and with an EPA classification
of  C,  results  In -a LOW  hazard  ranking under  CERCLA.   A chronic  toxlclty-
based RQ  of  1000 was based on early  mortality of rats  In a  chronic  feeding
study with B-HCH (Mtzhugh et al., 1950).
    A  q *  of  1.3  {mg/kg/day)"1,  which  was  derived  for   y-HCH  by  the
U.S. EPA  (1980a),  remains the recommended  value.  This q *  Is  based  on  the
combined  Incidence  of  benign and  malignant  liver tumors In male mice  fed  0
or  400 ppm y-HCH 1n the diet  for  110  weeks  1n a  study  by  Thorpe  and  Walker
(1973).    Corresponding  concentrations   of  y-HCH  'n  water  associated  with
Increased   cancer   risks   of   10~5,   10~6   and   10"7   are   2.64xlO~4,
2.64xlO"s and 2.64x10"' mg/l.
    A 1/EQ-iQ  (F  factor)  of 7.4  was  derived  from  the  data  for benign  and
malignant liver  tumors  1n  male   mice  fed y-HCH  (Thorpe and Walker,  1973).
This F  factor  places y-HCH  In Potency  Group 3 and, with an  EPA classifica-
tion between  82  and C,  results   In  a  MEBIUH  to LOW  hazard ranking  under
CERCLA.    The  chronic  toxldty-based  RQ for  y-HCH,  based  on  degenerative
changes   1n  the  kidneys  of  rats  1n a  subchronlc oral  study (Research  and
Consulting Co.,  Ltd., 1983), Is 100.
    Pertinent data  for  the derivation  of   an  RfD  or   RQ  or for  assessing
carclnogenldty  were not  available  for 6- or  c-HCH.   Both these  Isomers
are given EPA  classifications  of  C.  Since  It  was not  possible to derive  a
potency   estimate,  a  default  potency  group  of  2  1s  assigned.   A Group  C
we1ght-of-ev1dence combined with  a Group 2  potency  results  In  a LOW  hazard
ranking  under CERCLA.
    A q  * of  1.76   (mg/kg/day)'1  was  derived  for  T-HCH  from  the combined
Incidences of benign and  malignant liver tumors  In  male mice  Fed 0,  125  and
250 ppm T-HCH  In the diet from 8-10 weeks  of  age until 15-17 months  of  age
                                    XV111
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(Hunlr et al.,  1983).   Corresponding  concentrations  of T-HCH  In water  asso-
ciated  with  Increased  cancer   risk   levels  of  10~s,  10~6  and  10~7  are
1.99xlO~4, 1.99xlO"5 and 1.99xlO~6 mg/l.
    A 1/ED-iQ  (F  factor) of 8.1  was calculated  from  the data  for  benign  and
malignant liver tumors  1n  male  mice fed T-HCH as noted above  (Munlr  et al.,
1983).   The  animal  evidence  for  T-HCH 1s sufficient,  thus  an EPA Group  82
welght-of-evidence  classification.  A chronic tox1c1ty-based  RQ of  100  was
estimated for  T-HCH on the basis  of  hlstologlcal and  hlstochemlcal  adrenal
changes  Indicative  of  steroldogenlc  Inhibition  1n rats In a  subchronlc oral
study (Shlvanandappa et al., 1982).
                                      xlx
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                              TABLE  OF  CONTENTS

                                                                       Page

1.  INTRODUCTION	1-1

    1.1.   STRUCTURE AND CAS NUMBER	1-1
    1.2.   PHYSICAL AND CHEMICAL PROPERTIES 	  1-1
    1.3.   PRODUCTION DATA	1-3
    1.4.   USE DATA	1-5
    1.5.   SUMMARY	1-5

2.  ENVIRONMENTAL FATE AND TRANSPORT PROCESSES	2-1

    2.1.   HATER	2-1

           2.1.1.   Hydrolysis	2-1
           2.1.2.   Oxidation 	  2-1
           2.1.3.   Photolysis	2-2
           2.1.4.   Mlcroblal Degradation 	  2-2
           2.1.5.   Miscellaneous Processes 	  2-3
           2.1.6.   Transport 	  2-3
           2.1.7.   Persistence 	  2-6

    2.2.   AIR	2-6

           2.2.1.   Chemical Removal Processes	2-6
           2.2.2.   Physical Removal Processes	2-7

    2.3.   SOIL	2-7

           2.3.1.   Mlcroblal Degradation 	  2-7
           2.3.2.   Photolysis	2-9
           2.3.3.   Adsorption-Leaching 	  2-9
           2.3.4.   Volatilization	2-10

    2.4.   SUMMARY	2-11

3.  EXPOSURE	3-1

    3.1.   WATER	3-1
    3.2.   FOOD	3-3
    3.3.   AIR	3-5
    3.4.   MISCELLANEOUS EXPOSURE 	  3-5
    3.5.   SUMMARY	3-6

4.  PHARMACOKINETCS	4-1

    4.1.   ABSORPTION	4-1
    4.2.   DISTRIBUTION	4-2
    4.3.   METABOLISM	4-4
    4.4.   EXCRETION	4-5
    4.5.   SUMMARY	4-7
                                     xx
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                         TABLE OF CONTENTS  (cont.)

                                                                       Page

5.  EFFECTS	5-1

    5.1.   CARCINOGENICITY	5-1

           5.1.1.    a-HCH	5-1
           5.1.2.    B-HCH 	   5-1
           5.1.3.    T-HCH 	   5-5
           5.1.4.    i-HCH 	   5-6
           5.1.5.    c-HCH 	   5-6
           5.1.6.    T-HCH 	   5-6
           5.1.7.    General  Comments	5-10

    5.2.   MUTAGENICITY	5-10
    5.3.   TERATOGENICITY	5-14
    5.4.   OTHER REPRODUCTIVE EFFECTS 	   5-19

           5.4.1.    Testlcular Effects	5-19

    5.5.   CHRONIC AND SUBCHRONIC TOXICITY	5-20

           5.5.1.    a-HCH 	   5-20
           5.5.2.    B-HCH 	   5-22
           5.5.3.    T-HCH	   5-24
           5.5.4.    6-HCH 	   5-30
           5.5.5.    c-HCH 	   5-30
           5.5.6.    T-HCH .....  	   5-30

    5.6.   OTHER RELEVANT INFORMATION 	   5-36
    5.7.   SUMMARY	5-36

           5.7.1.    a-HCH 	   5-36
           5.7.2.    B-HCH 	   5-36
           5.7.3.    T-HCH 	   5-38
           5.7.4.    4-HCH 	   5-40
           5.7.5.    c-HCH 	   5-40
           5.7.6.    T-HCH 	   5-40

6.  AQUATIC TOXICITY	6-1

    6.1.   ACUTE	6-1
    6.2.   CHRONIC	6-15
    6.3.   PLANTS	6-15
    6.4.   RESIDUES	6-15
    6.5.   SUMMARY	6-29

7.  EXISTING GUIDELINES AND STANDARDS 	   7-1

    7.1.   HUMAN	7-1
    7.2.   AQUATIC	7-1
                                     xx1
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                           TABLE  OF  CONTENTS  (cont.)
 8.  RISK ASSESSMENT	8-1

     8.1.   a-HCH	8-1
     8.2.   B-HCH	8-5
     8.3.   Y-HCH	8-7
     8.4.   4-HCH	8-12
     8.5.   e-HCH	8-12
     8.6.   T-HCH	8-12

 9.  REPORTABLE QUANTITIES 	   9-1

     9.1.   REPORTABLE  QUANTITY (RQ) RANKING BASED ON CHRONIC
            TOXICITY	9-1

            9.1.1.    a-HCH 	   9-1
            9.1.2.    B-HCH 	   9-3
            9.1.3.    Y-HCH 	   9-6
            9.1.4.    T-HCH 	   9-8

     9.2.   WEIGHT OF EVIDENCE AND POTENCY FACTOR (F=1/ED10)
            FOR CARCINOGENICITY	9-10

            9.2.1.    a-HCH 	   9-10
            9.2.2.    B-HCH 	   9-20
            9.2.3.    Y-HCH 	   9-24
            9.2.4.    6-HCH 	   9-31
            9.2.5.    c-HCH 	   9-31
            9.2.6.    T-HCH 	   9-32

     9.3.   SUMMARY OF  ALL HCH CANCER DATA	9-41

10.  REFERENCES	10-1

APPENDIX: LITERATURE SEARCHED	A-l
                                     xx11
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                               LIST OF TABLES
No.              -                Title                               J>aqe
1-1     CAS Numbers and Physical Properties of HCH Isomers	1-2
1-2     Production Data for HCH	1-4
5-1     Summary of Oral Cancer Studies Conducted with a-HCH 	  5-2
5-2     Summary of Oral Cancer Studies Conducted with B-HCH 	  5-4
5-3     Summary of Oral Cancer Studies Conducted with y-HCH
        (Llndane)	5-7
5-4     Summary of Oral Cancer Studies Conducted with 4-HCH 	  5-9
5-5     Summary of Oral Cancer Studies Conducted with T-HCH 	  5-11
5-6     Summary of Mutagenldty Data	5-15
5-7     Oral Toxlclty Summary for a-HCH	5-21
5-8     Oral Toxlclty Summary for B-HCH	5-23
5-9     Oral Toxlclty Summary for y-HCH	5-25
5-10    Oral Toxlclty Summary for 6-HCH	5-31
5-11    Oral Toxlclty Summary for T-HCH	5-32
5-12    Oral LD50 Values for Isomers of HCH	5-37
6-1     Acute Toxlclty of Llndane to Freshwater Vertebrates 	  6-2
6-2     Acute Toxlclty of Other HCH Isomers to Freshwater
        Vertebrates	6-5
6-3     Acute Toxlclty of HCH to Marine Fishes	6-8
6-4     Acute Toxlclty of Llndane to Aquatic Invertebrates	6-11
6-5     Acute Toxlclty of Other HCH Isomers to Aquatic
        Invertebrates  	  6-14
6-6     Chronic Toxlclty of HCH to Aquatic Organisms	6-16
6-7     Effects of HCH on Aquatic Plants	6-17
6-8     HCH Uptake and Elimination by Aquatic Organisms  	  6-19
6-9     HCH Residues In Tissues of Aquatic Organisms	6-24
                                    XX111
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                           LIST OF TABLES (cont.)
No.              "                Title                                Page
6-10    Maximum and Mean Wet Weight and Llpld Weight Residue
        Concentrations of a-HCH and Llndane from Whole F1sh
        Samples Collected from 107 Stations In the United States. . .  6-28
7-1     Ambient Water Quality Criteria for the Protection
        of Human Health	7-2
8-1     Summary of Pertinent Data for q-|* for a-HCH	8-2
8-2     Derivation of a q-j* for a-HCH	8-4
8-3     Derivation of a q-|* for a-HCH	8-6
8-4     Summary of Pertinent Data for q-|* for B-HCH	8-8
8-5     Summary of Pertinent Data for q-j* for y-HCH	8-11
8-6     Summary of Pertinent Data for q-|* for T-HCH .	8-14
8-7     Derivation of a q^* for T-HCH	8-16
8-8     Derivation of the q-|* for T-HCH Recommended as the Best
        Estimate of Cancer Potency for T-HCH	8-17
9-1     Oral Composite Scores for HCH	9-2 .
9-2     a-HCH: Minimum Effective Dose (MED) and Reportable
        Quantity (RQ)	9-4
9-3     B-HCH: Minimum Effective Dose (MED) and Reportable
        Quantity (RQ)	9-5
9-4     f-HCH: Minimum Effective Dose (MED) and Reportable
        Quantity (RQ)	9-9
9-5     T-HCH: Minimum Effective Dose (MED) and Reportable
        Quantity (RQ)	9-11
9-6     Incidence of Liver Neoplasms In Male DDY Mice Fed a-HCH
        (>99X pure) In the Diet	9-12
9-7     Incidence of Hepatic Neoplasms In Mice fed a-HCH
        for 24 Weeks	9-13
9-8     Incidence of Liver Neoplasms 1n Male dd Mice Fed a-HCH
        (>99X pure) In the Diet for 24 weeks	9-15
9-9     Incidence of Liver Neoplasms In Male dd Mice Fed a-HCH
        (>99% pure) In the Diet for 24 weeks	9-16
                                    xxlv
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                           LIST OF  TABLES (cont.)
No.              -                Title                                 Page
9-10    Incidences of Hepatomas In  dd Mice Fed  a-HCH  In  the  Diet
        for 32 Weeks	9-17
9-11    Incidences of Liver Neoplasms In Male Wlstar  Rats  Fed  a-HCH
        (>99% pure) 1n the Diet	9-18
9-12    Incidences of Liver Neoplasms In Female Wlstar Rats
        Exposed to a-HCH (99.5% pure) 	   9-19
9-13    Derivation of Potency Factor  (F) for a-HCH	9-21
9-14    Incidence of Liver Neoplasms  1n  CF1 Mice Fed  B-HCH
        (>99X pure) In the Diet for up to 110 Weeks	9-22
9-15    Derivation of Potency Factor  (F) for B-HCH	9-25
9-16    Incidence of Hepatomas 1n dd  Mice Fed y-HCH  In the Diet
        for 32 Weeks and Examined After  37-38 Weeks  	   9-27
9-17    Incidence of Liver Neoplasms  In  CF1 Mice Fed  y-HCH
        {>99.5% pure) In the Diet for up to 110 Weeks	  .   9-28
9-18    Derivation of the Potency Factor (F) for Y-HCH	9-30
9-19    Incidence of Hepatomas 1n dd  Mice Fed T-HCH  1n the Diet
        for 32 Weeks and Examined After  5-6 Weeks  Posttreatment  .  .  .   9-33
9-20    Incidence of Liver Neoplasms  1n  Male dd Mice  Fed T-HCH
        1n the Diet for 24 weeks	9-34
9-21    Incidence of Tumors In Swiss  Mice Exposed  Orally to  T-HCH
        for 80 Weeks	9-35
9-22    Incidence of Liver Neoplasms  In  Male Swiss  Mice  Fed  T-HCH
        1n the Diet	9-36
9-23    Incidence of Liver Neoplasms  1n  Male Swiss  Mice  Fed  T-HCH
        1n the Diet from 8-10 Weeks of Age up  to 22  Months of  Age  .  .   9-37
9-24    Incidence of Liver Tumors 1n Mice Fed T-HCH  1n the Diet  from
        8-10 Weeks of Exposure up to 20  Months  of Exposure	9-38
9-25    Derivation of Potency Factor (F) for T-HCH	9-40
9-26    Summary of the CardnogenlcHy Evaluation for
        Hexachlorocyclohexanes of Environmental Concern  	   9-42
                                     xxv
-------
                            LIST OF ABBREVIATIONS
AchE  '                  Acetylchollnesterase
ADI                     Acceptable  dally Intake
ATP                     Adenoslne trlphosphate
BCF                     B1oconcentrat1on factor
bw                      Body weight
CAS                     Chemical Abstract Service
CNS                     Central nervous system
CS                      Composite score
DNA                     DeoxyMbonuclelc add
ECso                    Concentration  effective to 50% of recipients
EEG                     Electroencephalogram
PEL                     Frank-effect level
HCH                     Hexachlorocyclohexane
Koc                     Soil sorptlon  coefficient
Kow                     Octanol/water  partition coefficient
LCso                    Concentration  lethal to 50% of recipients
LD5Q                    Dose lethal to SOX of recipients
LOAEL                   Lowest-observed-adverse-effect level
MATC                    Maximum acceptable toxicant concentration
MED                     Minium effective dose
MTD                     Maximum tolerated dose
NOAEL                   No-observed-adverse-effect level
NOEC                    No-observed-effect concentration
                                     xxvl
-------
                        LIST OF ABBREVIATIONS (cont.)
PCB                     PolychloMnated  blphenyls
ppb                     Parts  per  billion
ppm                     Parts  per  million
ppt                     Parts  per  thousand
RBC                     Red blood  cell
RNA                     R1bonucle1c  add
RQ                      Reportable quantity
RVj                     Dose-rating  value
RVe                     Effect-rating value
SDH                     Succlnlc  dehydrogenase
T-HCH                   Technical  grade  HCH
TWA                     Time-weighted average
UDP                     Ur1d1ne dlphosphate
UV                      Ultraviolet
                                     xxvll
-------
                               1.  INTRODUCTION
1.1.   STRUCTURE AND CAS NUMBER
    The structure of HCH 1s depicted below.
                                          Cl
Molecular weight:  290.7
Empirical formula:  C,H,C1,
                     00  0
    The orientations  of  the various  Isomers  discussed In this  document  are
given  below.   The CAS  numbers of  the possible  HCH  Isomers  are listed  1n
Table 1-1.
                            Orientation of
                           Cl Atoms on Ring
            Isomer
Percent of Isomer
1n Technical HCH
AAEEEE
EEEEEE
AAAEEE
AEEEEE
AEEAEE
a
3
Y
(Undane)
6
t
60-70
5-12
10-15
6-10
3-4
1.2.   PHYSICAL AND CHEMICAL PROPERTIES
    The Isomers  of  HCH are white  or  yellowish powders or  flakes,  depending
on  the Isomer.   The  odor  also  depends  on  the  Isomer.  The  Isomers  are
soluble  In  100% alcohol,  chloroform  or  ether   (Hawley,  1981).   Selected
physical properties are listed In Table 1-1.
    HCH Isomers can be decomposed by alkaline  substances  (Hawley,  1981),  and
can  undergo  reactions  typical  of  alkyl halldes.  Including  hydrolysis  and
dehydrohalogenatlon (Morrison and Boyd, 1973).
0816p
1-1
         10/21/86
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0816p
                                   1-2
                                                                    06/27/86
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1.3.   PRODUCTION DATA
    Production  data  from the  1977  TSCA  Inventory  (U.S.  EPA,  1977)  are
presented In Table 1-2.
    T-HCH  (65:7:14:4:10;  a,  8,  Y»  e,  other  Isomers)  1s  produced by  the
action of visible  or  UV light. X-rays or gamma rays  on  a  mixture of benzene
and chlorine  1n  the presence of free radical  Initiators.   Batch or  continu-
ous methods   In  stirred  tank  type  reactors  or  tubular  reactors are  used.
Typically, benzene  1n excess Is chlorinated  at  15-25°C  at 1 atm In a  glass
reactor.  Oxygen  and  substitution catalysts  such as Iron must  be excluded.
Part  of  the  benzene  Is  removed at  ambient  pressure  with  the  remaining
benzene being removed at  reduced  pressure.  The molten product  1s then steam
stripped to remove residual traces of benzene (Colson, 1979).
    Llndane,  which  1s  >99%  y-HCH,  Is  produced  commercially  by  the  super-
saturation  process  or  the  fluid classification process.   After  a-HCH  Is
supersaturated In a  lower  primary alcohol such as methanol,  leaving most of
the Y-HCH undlssolved,  the  alcohol  1s  removed, and  the y-HCH-r1ch  mate-
rial  1s  then  dissolved  1n carbon tetrachlorlde or a  parafflnlc  hydrocarbon.
A  y-HCH  rich  concentrate  Is  precipitated  from  this  preparation.    The
concentrate from  which the  very  pure y-HCH  1s   finally  Isolated  contains  a
number  of Impurities  Including a-,  8- and  
-------
                                  TABLE 1-2
                           Production  Data  for HCH*
Isomer
Y-HCH


a-HCH
B-HCH
4-HCH
c-HCH
Company/Location
Steuber Co. , Inc.
New York, NY
Napp Chemicals, Inc.
Lod1, NJ
Hooker Chemicals i Plastics
Niagara Falls, NY
Hooker Chemicals & Plastics
Niagara Falls, NY
Hooker Chemicals & Plastics
Niagara Falls. NY
Hooker Chemicals & Plastics
Niagara Falls, NY
Hooker Chemicals & Plastics
Niagara Falls, NY
Importer/
Manufacturer
Importer
Importer
manufacturer
manufacturer
manufacturer
manufacturer
manufacturer
Production
(Ibs)
10,000-100
1,000-10,
NR
NR
NR
NR
NR
Range
,000
000





*Source: U.S.  EPA,  1977
NR = Not reported
0816p
1-4
08/07/86
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1.4.   USE DATA
    y-HCH  Is   used  as  an  Insecticide  on  hardwood  logs  and  lumber,  seeds
(such as  wheat,  oats  and rye, corn, sorghum,  lentils,  dry peas),  vegetables
and  fruits  (such as  avocados, pineapples,  curcubHs,  pecans),  woody  orna-
mentals  (such as  Christmas  trees),  hardwood  forests,  livestock  and  pets
(external parasite  control)  and existing structures  (control  for  woodborlng
beetles  and  termites)  (Federal  Register,  1983).   Pertinent data  regarding
uses of  the  remaining  Isomers  1n  a pure state  could  not be located  1n  the
available literature  as cited  1n  the Appendix.   The  technical  form  of  HCH
contains  all  the Isomers,  however,  and  has been  used  as an  Insecticide  In
the past.  It Is no longer used as  such 1n the  United States (Colson,  1979).
1.5.   SUMMARY
    The  Isomers   of   HCH  are  white or  yellowish  powders  or  flakes,  with
differing odors depending on  the Isomer.  The  Isomers  are soluble  to  varying
degrees  In  a variety  of organic  solvents  Including ethyl  alcohol,  chloro-
form, acetone, dloxane,  ether  and  others  (Colson,  1979).   HCHs can  be decom-
posed by  alkaline substances and  are  expected to undergo  reactions  typical
of  alkyl  halldes  Including hydrolysis and  dehydrohalogenatlon (Morrison  and
Boyd, 1973).
    T-HCH,  a  65:7:17:4:10  mixture  of  a,   B, y,  c  and  other  Isomers  of
HCH,  respectively,  1s  produced  by  the  photochem1cally-1nduced   reaction
between benzene and chlorine  In  the  presence of  a  free radical  Initiator.   A
variety  of  physical  separation  methods   are used to  purify y-HCH to  99.9%
from T-HCH for use as an Insecticide (llndane)  (Colson,  1979).
0816p                               1-5                              08/07/86
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    y-HCH 1s  used  as  an Insecticide  on  hardwood logs and lumber, a  variety
of  seeds,   vegetables   and  fruits,  woody  ornamentals  Including Christmas
trees, hardwood  forests, livestock  and pets (external parasite  control)  and
existing structures  (control  of  woodborlng beetles  and termites)  (Federal
Register, 1983).  Pertinent data  regarding  uses  of the  other  Isomers  1n  the
pure state  could not  be located 1n the available  literature as  cited  1n  the
Appendix.  The technical product has been used as  an  Insecticide In  the past
but Is no longer used as such  (Colson, 1979).
 0816p                                1-6                              08/07/86
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                2.  ENVIRONMENTAL FATE AND TRANSPORT PROCESSES
2.1.   WATER
2.1.1.   Hydrolysis.   Hydrolysis   rate  constants  at  25°C  of   7.5xlO"3,
8.99xlO~*  and  l.OTxlO"3  hour'1  were   determined  for   Y-HCH   In  surface
water  samples  from  a  eutrophlc  pond   In  Texas  (pH  9.3),  a  dystrophlc
reservoir  1n  Louisiana (pH 7.3) and  an  ol1gotroph1c rock quarry  In  Indiana
(pH  7.8),  respectively  (Saleh  et  al.,  1982).   The  corresponding  hydrolysis
half-lives  are  92,  771  and   648  hours.   Hydrolysis  rates  of  7.4xlO"«,
1.6xlO"4  and  7.3xlO"3  hour"1   at  pH values  of  5,  7  and 9,  respectively,
were  observed for  y-HCH  1n  M1111-Q water  at  25°C (Saleh  et  al.,  1982).
The  hydrolysis  reactions  followed   first-order  kinetics.    Hydrolysis  1n
addle or  neutral waters  1s  not expected to  be a significant  fate  process
for Y-HCH, although alkaline hydrolysis  may be  Important.
    Pertinent data  regarding  the  rate  of hydrolysis  of  a-HCH  could  not  be
located  1n the available  literature as cited  In  the Appendix.  Hydrolysis  of
Y-HCH  has  been   observed,  however,   and  based   on  the  relatively  greater
stability  of  o-HCH  Imparted by  Its  greater  number of  equatorial  chlorines,
1t may hydrolyze more slowly than Y-HCH.
    Pertinent data  regarding  the hydrolysis of  any of the other  Isomers  of
HCH  could  not  be  located  1n  the   available   literature  as cited   1n  the
Appendix.   6-.   «- and   e-HCH,  however,  have   more   equatorial  chlorines
than  Y-HCH,   and  since  equatorial  bonds  are  generally  more  stable  than
axial  bonds,  H  1s  expected  that these Isomers  will  be  more  resistant  to
hydrolysis than Y-HCH.
2.1.2.   Oxidation.   Pertinent  data  regarding  the oxidation  of any  of the
Isomers  of HCH  could  not be located  1n  the  available  JHerature as cited In
the Appendix.


0817p                               2-1                               06/10/86
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2.1.3.   Photolysis.   First-order  photolysis  of  y-HCH  was  observed   In
direct  sunlight  photolysis  experiments  1n  water  samples  from a  eutrophlc
pond  In Texas, a  dystrophlc  reservoir  In Louisiana and  an  ollgotrophic  rock
quarry  In  Indiana  (Saleh  et  a!.,  1982).   The photolysis  rate  constants  were
4.1xlO~3    (Texas),    3.9xlO"«    (Louisiana)   and    4.5xlO~4    (Indiana)
hour"1, which  correspond  to photolysis  half-lives  of  169,   1791  and  1540
hours,  respectively.   The  relatively  low  half-life  value  observed  1n  the
Texas  water  samples was  attributed  to  the higher pH  since the products  of
hydrolysis, which  were  presumably In equilibrium  with y-HCH,  were  reported
to  be more susceptible  to  photolysis  than y-HCH.  A  dark  control was  used
In  these studies  (Saleh  et  al.,  1982).   After 50  days  exposure to sunlight,
the  concentration  of y-HCH  In  purified  water  dropped  from  -9300 to  -7600
vg/mi,  and  the   concentration   of   a-HCH  dropped   from  -1480   to   -1130
vg/mi   (Mala1yand1   et   al.,  1982).    Since  y-HCH   and   a-HCH  have   no
conjugated  unsaturated  systems,   1t  Is  difficult  to  explain  these  apparent
photolyses.  It  1s  expected, however, that  direct photolysis  will not  be a
predominant fate  mechanism for y-HCH  or  a-HCH 1n  the  environment.
    Pertinent data  regarding the  photolysis  of  any  of  the other  Isomers of
HCH  could   not  be  located  In  the  available  literature  as  cited  1n  the
Appendix.    These  compounds  are  not  expected to  absorb radiation of  wave-
lengths present  In sunlight  since  they do  not  have  conjugated  unsaturated
systems.  They should not, therefore, directly photolyze 1n the environment.
2.1.4.   N1crob1a1  Degradation.   Of   the   y-HCH  added  to  unsterilized
natural waters  1n capped  bottles,  <30X remained  after 16 weeks  (Sharom et
al.,  1980).   The authors  concluded  that blodegradatlon  was  responsible for
this  result, although It  was unclear  to  what extent  hydrolysis may have been
0817p                               2-2                              06/27/86
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Involved.   About  25X  of  y-HCH  In  raw  wastewater   from  Cincinnati  was
removed  during  aerobic  blodegradatlon  In  a  wastewater   treatment   plant
(Petrasek et al.,  1983).  Aqueous  blodegradatlon  data  were  not  available  for
any of the other Isomers of HCH.
2.1.5.   Miscellaneous  Processes.   The  1somer1zat1on  of   y-HCH  to   a-HCH
by  sunlight  has  been  reported  (Mala1yand1  et  al.,  1982).   Only  a  small
amount of  y-HCH 1s  affected  by this  transformation,  however,  so H  Is  not
expected to be a major environmental fate process.
    Deo  et  al.  (1980)  observed  the  formation  of  a-,  y- and  6-HCH  by
the reaction of B-HCH with water  at  25°C.   Only a small  portion (not quanti-
fied)  of  the  B-HCH was  transformed,  however,  so the process 1s  not a  major
fate  process   for  fl-HCH.   Instantaneous dechlorlnatlon  of  B-HCH  was  also
observed (Deo et al., 1980).
2.1.6.   Transport.
    2.1.6.1.    VOLATILIZATION — Assuming a depth  of  1 m, .the  volatiliza-
tion  half-life  of y-HCH  from  water  has   been  estimated  to   be  115  days
(Lyman et al.,  1982)  and  191  days  (Mackay and Lelnonen,  1975).   From a depth
of  4.5 cm,  a volatilization  half-life of 3.2 days was  determined  for  y-HCH
In  still,  pure water  at 24°C,  while with   stirring,  the half-life was  1.5
days  (Chlou et  al.,  1980).   Using an  equation  relating  water depth  to vola-
tilization half-life  (Chlou  et  al.,  1980),  the  experimental volatilization
half-life of 3.2  days was used to calculate a  half-life of 692 days  for a
depth of  1 m.   Since this figure  1s of  the same order of  magnitude  as the
estimated half-lives  of  115  and 191 days for  volatilization from 1  m, these
figures are  considered  to be  valid  estimates of the  tendency  of Undane to
volatilize.
0817p                               2-3                              06/27/86
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    Measured values of the water solubilities and vapor pressures of  the HCH
Isomers  (except  e-HCH)  were used  to estimate  the  Henry's  Law constants of
the Isomers  that  are presented  In  Table  1-1.   Because no experimental data
were  available  for  e-HCH,  the  Henry's  Law constant  for  {-HCH,  the  Isomer
which  most  closely  resembles  e-HCH,  Is given  In  Table 1-1  as an  estimate
of the  c-HCH Henry's Law constant.   Based  on  these values,  all the  Isomers
of HCH  are  expected to  volatilize  from water  at a  rate  dependent upon the
rate of diffusion through the air (Lyman et  al.,  1982).
    2.1.6.2.   ADSORPTION — A    mean   K    of   1080.9  was   obtained  for
                                        oc
Y-HCH  from  K    determinations  on   three  soils  with  an  average  organic
content  of  13X  (Rao and Davidson,  1982).   Based on this moderate  K    value
                                                                     oc
and a  water solubility  of  7.5  ppm  (U.S.  EPA,  1981),  Y-HCH Is expected  to
leach  slowly  to  groundwater.   The   leaching  of  y-HCH  from  Gezlra  soil
(38.8X sand,  34.7X  silt,  26.2X clay and 4.6X  organic  carbon)  from  the Sudan
was slow;  after  45  days,  <50X  of  the  applied y-HCH  had  leached  from  the
soil   (El Belt  et al.,  1981).  The  fate  of  Y-HCH  has  been  studied 1n  a
field  scale  experiment  (01  Toro and  Paquln,  1984).  After 100 days,  75%  of
the applied  Y-HCH was found In  the water  column and  sediment layer  of  the
rock  quarry;  the water  column contained >75X of  this amount.  The  role  of
particle  transport  In the  transfer of  y-HCH  to the  sediment was  found  to
be small  compared with diffusion  (D1  Toro  and Paquln, 1984).  Saleh et  al.
(1982)  determined Freundllch  constants  for  Y-HCH  sorptlon  and  desorptlon
for  four systems:   montmorlllonlte  clay-distilled water,  1258.9  for  both
sorptlon  and desorptlon; Roselawn  Cemetery water-sediment.   354.8  and 4.26;
Cross  Lake   water-sediment,  56.2  and  11,220.2;  and  Indiana  Quarry water-
sediment, 2238.7  and 4.26 for sorptlon  and desorptlorv, respectively.  Saleh
et al.  (1982)  reported that the high  desorptlon constant  for the Cross Lake
system   suggested a  strong   Interaction  between   y-HCH  and  the   organic

0817p                               2-4                               06/10/86
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material  1n  the samples, although  the  organic  contents of  the  two  sediment
samples were similar (Roselawn Cemetery, 1.34X and Cross Lake, 1.33%).
    Using  a  measured   water  solubility  of  2.0  mg/l  (U.S.  EPA,  1981),  a
K    of 6463  was  estimated  for  o-HCH  (Lyman et a!.,  1982).   According  to
Kenaga  (1980),  a K    of >1000  Indicates  such  strong  adsorption  to  organic
matter  In  soil  that the  compound  Is considered  Immobile.   The  K    value of
a-HCH  and  Its  low  water  solubility,  therefore,  suggest  that a-HCH  will
bind tightly to soil and leach slowly to groundwater.
    A  log K    value  of  3.46 was  determined  for  B-HCH  (Schwarzenbach  and
Westall,  1981).  The  water  solubility of  B-HCH  1s   0.24  mg/l  (U.S.  EPA,
1981).  and combined with  the log  K   of  3.46, B-HCH 1s  expected  to  bind
tightly to soil (Kenaga, 1980) and leach slowly to groundwater.
    Using  a  measured  water  solubility of  31.4 mg/j.   (U.S.  EPA, 1981),  a
KQC  of   1394.3  was  estimated   for   a-HCH  (Lyman et  al..  1982).   The
moderate  water  solubility  and  K    of 4-HCH suggest  that  the  Isomer  will
bind  less  tightly  than the  previous   Isomers,   but  still tightly  enough to
prevent rapid Infiltration to groundwater.
    Since  a  measured  water  solubility  for  c-HCH  was  not  available,  the
measured  K    of  i-HCH,  the  Isomer  that  most  resembles  c-HCH, was  used
to  estimate  a  water  solubility of 17.4  mg/l  for c-HCH,  which was  then
used  to  estimate a  K    value of 1950.  The estimated  water  solubility and
KQC  values suggest  that e-HCH  will bind  fairly tightly  to soil  and  will
slowly leach to groundwater.
    2.1.6.3.   BIOACCUMULATION — Direct  Introduction   of  y-HCH  to  water
along  with the primary  food organism  (yeast)  resulted  1n  a BCF  of  183 In
brine  shrimp,  while Introduction  of y-HCH  onto sand Resulted  In a  BCF In
the  shrimp of  95.   Exposure of  northern  brook  sllverslde  fish  to y-HCH
residues .on  sand  resulted  In  a  BCF of 1613  (Matsumura and Benezet,  1973).

0817p                                2-5                              06/10/86
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An average  BCF  of 319 for Y-HCH  was  observed 1n Sal mo qalrdnerl Richardson
fry  (Ramamoorthy,   1985).    BCF   factors   of  1246  1n  topmouth  gudgeons
(Kanazawa, 1983), 560  In  the  fish,  Gambusla afflnls (Schlmmel et al., 1977)
and 456  In  the  snail,  Physa  (Hetcalf  et al., 1973) were observed.  Mean BCF
values   of  84,   218,  63 and  490 were  determined  for  pink  shrimp,  plnflsh,
grass shrimp and sheepshead  minnows,  respectively  (Schlmmel  et al.,  1977).
A  BCF of 697 was observed for  y-HCH  In short-necked  clams  (Yamoto et al.,
1983).
    BCFs of  161  In  short-necked clams  (Yamato et al., 1983), 706 1n  gupples
(Yamato   et  al.,  1983),  216 1n  the golden orfe,  588 In gupples, 330  1n carp
and  605  In  brown trout  {Suglura et  al.,   1979)  were  reported for  a-HCH.
Yamato  et al. (1983) observed BCFs of  1043  and  127  for  B-HCH  and 648  and 272
for 6-HCH 1n gupples  and  short-necked  clams, respectively.
    Pertinent data   regarding  the bloconcentratlon of  e-HCH  could  not  be
located   In  the  available  literature  as   cited   In  the  Appendix.   It   Is
expected,  however,  that   c-HCH  will  bloconcentrate  to a  similar  extent  as
6-HCH  because   the  two   Isomers  are   similar.    Bloconcentratlon   Is  not
expected to be  significant for any of  the Isomers  of HCH.
2.1.7.    Persistence.  Based  on  degradation  data,  the  persistence half-
lives for  y-HCH  In  river,  lake and groundwater  were  estimated to be 3-30,
30-300  and >300  days,  respectively  (Zoeteman et al.,  1980).   Pertinent  data
regarding  the persistence of the other  HCH Isomers could not  be  located  In
the available literature as cited In the Appendix.
2.2.    AIR
2.2.1.    Chemical Removal  Processes.   The   half-life of  the  reaction  of  HCH
(unspecified Isomer) with hydroxyl  radicals  In the atmosphere  was  estimated
to be 1.63 days  (U.S. EPA. 1985a).


0817p                               2-6                              06/27/86
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2.2.2.   Physical  Removal  Processes.   The  removal  rates of  Y-HCH from  the
atmosphere by rainfall and  dry  deposition  are  2.5  and 3.3X per week,  respec-
tively,  and  the estimated  residence  time of  Y-HCH  1n the atmosphere  1s  17
weeks  (Lewis  and  Lee,  1976).   Pertinent  data  regarding the  removal  of  the
other  Isomers  of  HCH  could not  be  located 1n  the  available  literature  as
cited In the Appendix.
2.3.   SOIL
2.3.1.   M1crob1al  Degradation.   As  the  sole  carbon  source,   y-HCH  was
found  to support  the  growth of  71/147 microorganisms  Isolated   from  loamy
sand  (Tu,  1976).   Chloride  Ion  formation  was  noted  In  these  cultures.   The
extent  of   blodegradatlon   In   these  pure  culture  studies  was  not  given.
Metabolites   Isolated   from   13   of    the   71   microorganisms   Included
Y-2,3,4,5,6-pentachloro-l-cyclohexene,     a-,     B-  and     y-3,4,5,6-tetra-
chloro-1-cyclohexene and pentachlorobenzene (Tu, 1976).   From moist  aerated
soil,  62X  of  the  applied  Y-HCH  was  recovered and  3X of  the  applied  14C
was  released after 105 days.   After  140 days, 17.8X of the  applied  14C  was
released from  submerged soil.   The  loss  of  Y-HCH from submerged anaerobic
soil  measured   by  gas-liquid chromatography  was  nearly quantitative,  with
only  45t of  the applied  y-HCH  recoverable (Kohnen  et  al.,  1975).   Mathur
and  Saha (1975)  reported  that  1,2,4-tr1chlorobenzene,  1,2,3,4-tetrachloro-
benzene,    Y-2,3,4,5,6-pentachlorocyclohex-l-ene     and    Y-3,4,5,6-tetra-
chloroclohexane  were  detected  by gas  chromatography  In  the  soil  6  weeks
after  It  was   treated  with Y-HCH  and  submerged.    The  absence of  these
products  from   sterilized  soil  treated  with  Y-HCH  was  cited  as  evidence
that  the  compounds  were  metabolic  products  from  Y-HCH  blodegradatlon.
Incubation of  aerobic and  anaerobic  soil  suspensions .of  Y-HCH  for  3 weeks
resulted  In the  disappearance of  zero  and  63.8X  of  the  applied  Y-HCH,


0817p                               2-7                              06/10/86
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respectively (Uchtensteln et al., 1971), Indicating that anaerobic degrada-
tion  of  y-HCH  Is  more extensive  than  aerobic  degradation.   A Clostrldlum
sp.  Isolated  from y-HCH-amended son was  observed to  degrade  87X of added
Y-HCH  In  24  hours  under  anaerobic  conditions   (Sethunathan  and Yoshlda,
1973).   Blodegradatlon of  y-HCH  In  thick  anaerobic  digested   wastewater
sludge  at  35°C  was  rapid,  with  <1054  of  the  added  10  and  1   ppm y-HCH
remaining after  2  and 4 days,  respectively  (Hill  and McCarty, 1967).  When
y-HCH  was  added  to  an   anaerobic   preparation  of   CUrobacter   Freundll.
Clostrldlum butyrlcum.  Clostrldlum pasteuManum or mixed  soil flora, 91.5,
98.3,  91.0  and  78.OX of  the  organic  3SC1   was   released   as   35C1   1on
(Haider,  1979).   Several  studies  have shown that  anaerobic mlcroblal action
can  transform  y-HCH  Into a-HCH   (Vonk  and  Qu1r1jns,  1979;   Engst  et  al.,
1979).  This conversion Is not  extensive, however, and  1s not  expected to be
of major  Importance In the fate  of  y-HCH.
    After  2  weeks  1n unsterlUzed  submerged  Caslguran  sandy   loam,   the
concentration of  a-HCH declined from -16 to  <1  ppm compared with  a  decline
from  -18  to 15 ppm  In  a  sterilized  preparation (Castro and Yoshlda, 1974).
In another  experiment,  Incubation  of  aerobic and  anaerobic soil  suspensions
of a-HCH  for  3  weeks  resulted  In the  disappearance of 11.0 and 26.2% of
the  added  a-HCH.  respectively  (MacRae et   al.,  1984).   Indicating   that
anaerobic   degradation  Is   more   extensive  than aerobic   blodegradatlon.
Anaerobic pure  cultures,  probably Clostrldlum  sp.,  degraded  suspensions of
a-HCH  1n  flooded  soils,  although  no Information  on  rates  was given  (Ohlsa
and  Yamaguchl,  1978).   When  a-HCH was  added  to an anaerobic  preparation of
C. freund11. C.  butyrlcum.  C.  pasteurlanum  or mixed  soil  flora,  13.9,  97.4,
53.2  and  6.5X  of  the organic   **C1  was   released   ds  "Cl  1on  (Haider,
0817p                               2-8                              06/27/86
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1979).   After  20 weeks of  aerobic  and anaerobic  Incubation of  soil  samples
polluted  with  a-HCH,  55  and  35%  of   the   Initial  amount  of  a-HCH  had
blodegraded (Doelman et al., 1985).
    When  B-HCH  and  5-HCH  were  added  to  an  anaerobic  preparation  of  C.
freundl.1,  C_.  butyrlcum.  C_.  pasteurlanum or  mixed  soil  flora,  15.3,  23.8,
10.1  and 7.434 (B-HCH),  respectively,  and 2.8,  38.5,  5.0 and 1.6% (5-HCH),
respectively,  of  the  organic  3SC1  was  released  as  35C1   Ion  (Haider,
1979).   Pertinent  data regarding" the  blodegradatlon of  c-HCH  could  not  be
located  In the available literature as cited 1n the Appendix.
2.3.2.   Photolysis.   Pertinent   data   regarding   the   photolysis  of   HCH
Isomers  In soil  could  not  be  located 1n  the available literature as dted In
the  Appendix.   Although   some  data  suggest  that y-HCH   1s   subject  to
photolysis In  water (Saleh et  al.,  1982),  because  the  lack of  a  conjugated
unsaturated  system  Indicates   that  little or  no  absorption  of  light  should
occur 1n the environment, soil photolysis Is not expected to be significant.
2.3.3.   Adsorption-Leaching.    A  mean  K     of  1080.9  was  obtained  from
K    determinations  on  three  soils  with an average organic content  of 13%
(Rao  and Davidson,  1982).   Based  on  this  moderate K    value  and  a water
solubility of  7.5  ppm  (U.S.  EPA,  1981), y-HCH 1s  expected to  leach slowly
to  groundwater.   The leaching of  y-HCH  from  Gezlra  soil  (38.8% sand,  26.2%
clay  and 4.6% organic carbon)  from  the  Sudan was  slow;  after 45  days, <50%
of  the   applied  r-HCH  had  leached  from the  soil  (El  Belt et al.,  1981).
Fifteen  years  following  the  application of  technical  HCH  to  a  sandy loam
soil  In Nova  Scotia,  Canada,  4,  44,  10  and  14% of  the  applied  a-. B-,
Y- and  4-HCH  remained  1n  the  soil,  respectively.   Of  this   amount,  -92,
92.1,  94.7  and   95.1% of  the  a-,  B-. Y- and   4-HCH  was  found  within  a
depth of 0-20  cm,  Indicating minimal  leaching of  the Isomers.   The soil was
0817p                               2-9                              06/10/86
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cultivated  yearly  throughout  the  15-year  period,  Increasing the  likelihood
that volatilization may have occurred (Stewart  and  Chlsholm,  1971).
    Using  a  measured  water  solubility  of  2.0  mg/l  (U.S.  EPA,  1981),   a
K    of  6463  was  estimated for  o-HCH  (Lyman  et  al.,  1982).   According  to
Kenaga  (1980),  a  K    of  >1000  Indicates  such  strong adsorption  to  organic
matter  In  soil  that the compound  1s considered Immobile.   The K   value  of
a-HCH  and  Us  low  water   solubility,  therefore,   suggest   that  o-HCH  will
bind tightly to soil and leach slowly to groundwater.
    Schwarzenbach  and  Westall  (1981)  determined  a  log  K   value  of  3.46
for  B-HCH.   Using  the  water  solubility  for  3-HCH of  0.24  mg/l  (U.S.  EPA,
1981) and  the log  KQC  of  3.46.  B-HCH  1s expected  to  bind  tightly  to  soil
(Kenaga, 1980) and leach slowly to groundwater.
    Using  a  measured  water  solubility  of  31.4   mg/l  (U.S. EPA,  1981),  a
K    of   1394.3   was   estimated  for  i-HCH  (Lyman  et   a!.,   1982).   The
moderate  water  solubility  and  K    suggest  that   the  Isomer will bind  less
tightly than  the  previous  Isomers,  but  still  tightly  enough  to  prevent rapid
Infiltration to groundwater.
    Since  a  measured  water  solubility  for  c-HCH  was not  available,  the
measured  K    for  4-HCH,  the  Isomer  that most  resembles  c-HCH, was  used
to  estimate  a  water  solubility  of 17.4  mg/l for  e-HCH,  which was  then
used  to  estimate  a   K     value of  1950.   The   water  solubility  and  K
                        oc                                                  oc
values  suggest  that e-HCH  will  bind fairly tightly  to soil  and  will slowly
leach to groundwater.
2.3.4.   Volatilization.   After 50  hours.  26  and 100%  of  surface  applied
Y-HCH  remained on  Hatboro silt  loam and  Norfolk sandy  loam,  respectively
(Glotfelty  et  al.,  1984).   The  authors  concluded •that  Y-HCH  did  not
volatilize  on the  sandy  loam because  of the  dryness  of  the  soil.   From a
0817p                               2-10                             06/27/86
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moist  soil  surface,   the  y-HCH  content  decreased  to  50  and  10%  of   the
amount applied  after  6 hours  and 6 days,  respectively, while  50 hours after
the  application  of  y-HCH to dry  soil,  88X of the applied  compound  remained
(Glotfelty  et  al.,   1984).   The y-HCH  content of  fallow  soil  1n a mlcro-
agroecosystem chamber  declined  to 12% of  that applied after  11 days  (Nash,
1983).
    Pertinent data  regarding  volatilization of  the  other  HCH  Isomers could
not  be  located   1n  the available literature as  cited  1n  the  Appendix.   The
estimated  Henry's  Law constants, K   s  and measured water  solubilities  (see
Table  1-1) suggest   that  the  Isomers win  bind fairly tightly  to  soil  and
will have  little tendency to volatilize  from  dry  soils.   Volatilization  from
moist soils, however, may be significant.
2.4.   SUMMARY
    Half-lives  of f-HCH In water  at 25°C  were reported  to be 92,  771  and
648  hours  In  natural  water  samples  from a  eutrophlc pond 1n Texas (pH  9.3),
a dystrophlc reservoir  In Louisiana  (pH  7.3)  and  an  ollgotrophlc  rock quarry
In  Indiana  (pH  7.8),  respectively (Saleh et al.,  1982).   Hydrolysis experi-
ments In M1111-Q water  at pH values  of  5,  7 and 9 yielded half-lives of  936,
4331 and 95 hours,  respectively  (Saleh  et  al., 1982).   Therefore,  hydrolysis
at  alkaline pH  values  1s  expected  to  be  Important  In  the  fate  of  y-HCH,
while  hydrolysis  at  acidic  and  neutral  pH values  Is not.   Pertinent  data
regarding  the hydrolysis of the  other  Isomers  of  HCH could not be located In
the  available literature; however, all  these  Isomers contain more equatorial
bonds  than y-HCH,  and  since   these  bonds are generally  more stable  than
axial bonds,  It 1s  expected that  the remaining Isomers  will  be  more stable
to hydrolysis than f-HCH.
0817p                               2-11                             06/10/86
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    First-order  photolysis   half-lives   for  Y-HCH  of  169.  1791   and   1540
hours were observed  In natural water  samples from a eutrophlc  pond  1n Texas,
a  dystrophlc   reservoir  1n   Louisiana and  an   ollgotrophlc  rock  quarry  In
Indiana, respectively (Saleh et al.,  1982).  The relatively  short photolysis
half-life  observed  1n the  Texas  sample  was  attributed  to  the alkaline  pH
that,  H  was   concluded,  generated  hydrolysis   products  more  susceptible  to
photolysis  than  y-HCH  (Saleh  et  al.,  1982).   After  50  days  exposure  to
sunlight,  the concentrations  of  y- and  <*-HCH 1n  purified  water  dropped
from  -9300  to  -7600 yg/mj,  and  from  1480  to  -1130  yg/mi,  respectively
(Mala1yand1 et al.,  1982).   Pertinent data regarding  the photolysis of  the
other HCH  Isomers could  not  be located  1n the  available  literature as  dted
In the  Appendix.  Direct  photolysis,  however.  Is not expected to be a  major
fate  process  for any of  the  HCH  Isomers  since  they  do not have  conjugated
unsaturated systems.
    Of  the Y-HCH added  to  unsterlUzed  natural waters  "1n capped  bottles,
<30X  remained after  16  weeks (Sharom  et al., 1980).   About  25% of  the
Y-HCH   In   raw  wastewater   from  Cincinnati   was  removed  during  aerobic
blodegradatlon  In   a  wastewater  treatment plant  (Petrasek et al.,  1983).
Pertinent  data regarding  the aqueous  blodegradatlon of  the  other HCH Isomers
could not be located  In the  available literature as  dted In the Appendix.
    Mala1yand1  et  al.   (1982)  reported  that  a   small   amount   of  Y-HCH
1somer1zed to  a-HCH upon exposure  to sunlight.  B-HCH reacts with water at
2S°C  to   form  small  amounts  of   a-,   6- and  Y-HCH,   and    Instantaneous
dechlorlnatlon of B-HCH  In water was  observed  to a  small degree (Deo et al.,
1980).  None  of  these processes are  expected to contribute significantly to
the degradation of the HCH Isomers In the environment. '
0817p                               2-12                             06/27/86
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    The  volatilization  half-life  of  y-HCH  has  been  estimated  to  be  115
days  (Lyman et al.,  1982)  and  191  days (Mackay and Lelnonen, 1975),  assuming
a depth of  1  m.   Volatilization  half-lives  of 3.2 and 1.5 days were  observed
for T-HCH  from still  and  stirred water  4.5 cm  deep (Chlou  et  al.,  1980).
The measured  volatilization half-life of  3.2  days  was  used to estimate  a
half-life of  692  days  from water  1 m  deep.   Since  the  half-lives of  115 and
191 days are  of  the same  order  of magnitude as  the half-life estimated from
experimental  data,  the  former  values are  considered to  be accurate  estimates
of the tendency of  q-HCH to  volatilize.   Henry's  Law constant values for the
other Isomers have  been  estimated  and  suggest that  volatilization of all HCH
Isomers occurs  at  a  rate  dependent upon the rate of diffusion  through the
air  (Lyman  et al.,  1982).  Volatilization  of  HCH  Isomers  In water  Is not
expected to be significant In the  environment.
    A  mean  K    for  y-HCH  of   1080.9   was obtained  from  K    determlna-
              oc        '                                       oc
tlons on  three soils  (Rao  and  Davidson,  1982).   Base-d  on  this K    and  a
low water   solubility  of  7.5  ppm  (U.S.  EPA,  1981), y-HCH  Is  expected  to
leach  slowly   to  groundwater.    K   values   for  the  remaining   HCH  Isomers
were  estimated (Lyman  et al.,  1982),  and combined  with  the fairly  low water
solubilities  of  the Isomers suggest   that  they  are  expected  to  bind  fairly
tightly to  soil and  to  leach slowly  to groundwater.  Fifteen years  following
the application of  technical HCH to  a  sandy loam soil 1n Canada, >90% of the
applied  a-,  B-,   ?- and  6-HCH   remained   In  the   upper  20  cm  of   soil,
Indicating minimal leaching had  taken  place  (Stewart  and Chlsholm, 1971).
    BCFs  for  Y-.  «-t  B- and  &-HCH   1n  a  variety  of  species  ranged from
63-1613  (Matsumura   and  Benezet,  1973;   Ramamoorthy,  1985;  Kanazawa,   1983;
Schlmmel et al.,  1977;  Metcalf et  al., 1973; Yamato  et>al., 1983; Suglura et
al.,   1979).   No  BCF  values were  available  for  e-HCH,  but  1s  expected  to
0817p                               2-13                             06/27/86
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bloaccumulate  similarly  to  6-HCH,  to  which  n  bears  a  close  structural
similarity.  None of the HCH  Isomers are expected  to  bloconcentrate  signifi-
cantly In aquatic organisms.
    Based  on  degradation  data,  the  persistence  half-lives  for  y-HCH  In
river, lake and groundwater were estimated to be 3-30,  30-300  and  >300  days,
respectively (Zoeteman et  al.,  1980).   Pertinent data regarding the  persis-
tence of  the other  Isomers could not be located 1n the available  literature
as cited In the Appendix.
    Anaerobic  soil  preparations   were   found   to   readily   degrade   Y-HCH
(Kohnen  et al.,  1975;  Mathur  and Sana,  1975;  L1chtenste1n  et al.,  1971;
Sethunathan  and   Yoshlda,  1973;  Haider,  1979).   Degradation  of  a-HCH  by
anaerobic  soils has also  been observed  (Castro  and Yoshlda, 1974;  MacRae  et
al.,  1984;  Haider,  1979).  Doelman  et  al.  (1985)  observed greater  aerobic
than  anaerobic  degradation of  a-HCH In polluted  soil.  Anaerobic  degrada-
tion  of- a-, B- and  S-HCH by  several  organisms has  been observed  (Haider,
1979).   Pertinent  data  regarding  the  blodegradatlon  of  c-HCH could not  be
located 1n the available  literature as  cited  In  the Appendix.
    After  50  hours, 26  and  100X  of  the surface  applied  y-HCH remained  on
Hatboro  silt  loam and Norfolk  sandy loam,  respectively  (Glotfelty  et  al.,
1984).   The  low  volatility of  the y-HCH  was attributed  to   the  dryness  of
the sandy  loam.   From a moist  soil  surface, the y-HCH content  decreased  to
50  and  10X of  the  amount applied  after 6  hours  and 6  days, respectively.
while  50  hours  after the application  of   y-HCH  to dry  soil,  88X of  the
applied  compound  remained  (Glotfelty et al., 1984).  Pertinent  data regard-
Ing the  volatilization of  the other HCH Isomers could  not  be  located In the
available  literature  as  dted  In  the Appendix.   The 'estimated  Henry's Law
constants,  K    and  measured  water  solubility  values  suggest  that  the
             oc

0817p                               2-14                             06/27/86
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 Isomers  will  bind  fairly  tightly  to soil and  will  have little  tendency  to
 volatilize from dry soils.  Volatilization from moist  soils,  however,  may  be
 s Ignlfleant.
0817p                               2-15                              06/10/86
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                                 3.  EXPOSURE
3.1.   WATER
    Y-HCH  has  been detected  at  0.01 ppb  In  Cincinnati,  OH,  drinking  water
(Keith  et  al.,  1976).   Rural  potable water  samples  1n Hampton County,  SC,
ranged  from  not  detected (<10 ppt)  to  319 ppt, with a median concentration
of  10  ppt, and  1n Chesterfield County,  SC,  from  not  detected to 193  ppt,
with  a  median  concentration  of  10 ppt.  Median y-HCH  concentrations  1n
closed  wells 1n  Chesterfield  and  Hampton  Counties  were  16  and  163  ppt,
respectively, and  In  Hampton County  open  wells,  was  98 ppt  (Sandhu  et  al.,
1978).   Potable water  samples from  Oahu,  HI,  contained 0.06-0.4 ppt  y-HCH,
with a mean concentration of  0.2 ppt (Bevenue  et  al.,  1972).   Tap water  from
Ottawa,   Ontario   contained   1.3   vgA   y-HCH   (Krayblll,    1977).    Using
2 i  as  the  average  amount  of  water   consumed   dally,  the  average  dally
Intake  of  y-HCH  from water  consumption  ranges  from  0.02-0.638  yg,  based
on  the  monitoring  data  (excluding  the data from  Ottawa)  above;  based on the
concentration of  y-HCH   1n  the  Ontario   tap water,  the average  dally  Intake
Is  2.6  pg.   Since the  monitored  value  of  the  y-HCH  concentration  Is  so
high relative to all the other  values,  this  Intake value  Is  considered to be
nonrepresentatlve.   Residues  of  y-HCH  In  whole  samples  of Oregon  river
water  (Includes   dissolved   and  suspended  y-HCH)  ranged  from  <0.001-0.002
yg/l  (U.S.  EPA,   1985a).   Surface  water  from N1agara-on-the-Lake  (Oliver
and  Charlton,  1984). Washington,   DC  and Denver,  CO  (Cole  et al.,  1984),
Virginia (Saleh et  al.,  1982),  South Carolina  (Sandhu  et  al., 1978), Hawaii
(Bevenue  et  al.,  1972)   and  New  Jersey  (Page,  1981)  contained  measurable
quantities  of y-HCH.    Parts  per  trillion   concentrations   of  y-HCH  have
been detected 1n  rain or snow  samples  from the  Great* Lakes  (Canadian side)
0818p                               3-1                              06/10/86
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(Strachan and  Huneault,  1979), Portland,  OR  (Pankow et  al.,  1984), Canada
(12 sites) (Brooksbank, 1983) and two sites In Lake .Superior  (Caribou Island
and Isle Royale) (Strachan,  1985).
    a-HCH  has   been  detected  at  2.7-20.3 and  0.45-9.7  ppt  1n  municipal
drinking  water  samples collected  1n  the  winter  and  summer,  respectively,
from  12 sites  1n  Canada  (Williams  et  al.,  1982)  and  at  17  vq/i  In  tap
water  collected In  Ottawa,  Ontario,  Canada  (KraybUl,  1977).   An average
dally  Intake of a-HCH  of  0.90-40.6  ng  was calculated (excluding the Ottawa
result),  assuming  an average  water  consumption  of  2 I/day.   Based  on  the
high  a-HCH  content of  tap  water from  Ontario,  an average  dally  Intake  of
34  jig was  estimated.   The  relatively  high  value of  a-HCH  In the Ottawa
sample  1s  thought  to be nonrepresentatlve.   Dissolved  residues of a-HCH  1n
water  ranged  from  0.019-0.14  yg/l,  with  a  mean concentration of 0.06025
vg/l  (U.S.   EPA,   1985a).    Surface  water  from  N1agara-on-the-Lake  (Kuntz
and Warry,  1983),  New  Jersey  (Page,  1981),  Washington,  DC  and Denver,  CO
(Cole  et  al.,  1984)  contained  measurable   amounts  of  a-HCH.   Parts  per
trillion concentrations have been detected 1n rain or snow  samples  from the
Great  Lakes  (Canadian  side)  (Strachan and Huneault,  1979).  the Great  Lakes
ecosystem  (Elsenrelch  et  al.,  1981),  Portland,  OR  (Pankow  et al.,  1984),
Canada  (12 sites)  (Brooksbank. 1983) and two  sites  In  Lake Superior  (Caribou
Island and Isle Royale) (Strachan,  1985).
    The  concentration  of   B-HCH   ranged   from  3-50  ng/i,   with  a   mean
concentration of  17.75 ng/i  1n  three  rivers;  from 2-45  ng/i, with a mean
concentration  of   13.3  ng/t  In  freshwater  regions  of  the  Rotterdam;  and
from  1 40 ng/l (no mean  given)  In estuarlne  regions  In   the Netherlands
(Oulnker  and  Hlllebrand,  1979).  Suspended  and  dissolved B-HCH ranged from
0-1.0  and 0.1-0.2  jig/I,  respectively.   The mean  concentrations were 0.75


0818p                               3-2                              06/27/86
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and  0.1725  u9/l.  respectively  (U.S.  EPA,  1985a).   Pertinent  monitoring
data  for  5- or  e-HCH  could not  be  located In  the  available  literature as
cited 1n the Appendix.
3.2.   FOOD
    A wide  variety  of  foodstuffs,  Including meats,  dairy products  (except
milk)  and  vegetables  analyzed  from  1971-1976,  contained   y-HCH  at   ppb
concentrations  (Ouggan  et  al.,  1983).   The  average dally  Intake of y-HCH
based on  these  studies  averaged  over  1971-1976  1s  0.27 g.    Market  basket
surveys conducted 1n 1977-1978  revealed  the  presence of  ppb  concentrations
In   lunch   meats,  processed  cheese,  butter,   frankfurters,   pork   chops,
hamburger and  round  steak  (Podrebarac, 1984).   Based on  these  figures,  the
average  dally  Intakes  of  y-HCH  1n  1977  and  1978  were  3.8  and  2.4 ng/kg
bw/day.    Domestic  fish  samples   were  0.7X  positive  for  y-HCH,  with  an
average concentration  of  0.2 ppb, and  Imported samples were  6.4% positive,
with  an  average  concentration  of  1 ppb  In samples  taken from 1969-1976.
Imported shellfish analyzed  In  the same time  period  contained  a mean concen-
tration of  y-HCH of 0.4  ppb In 2.1% of  the  samples (Duggan  et  al.,  1983).
The  concentration  of  y-HCH In  a  variety  of  fish collected  across   the
United  States   contained   <0.01-0.2  ppm   y-HCH  (Schmltt et  al.,   1985).
Residues  of  y-HCH   1n  5026 dried  samples of   shellfish  ranged  from  5-100
ppb, with a mean of 7.703  ppm. and  1n 368 samples of shellfish, ranged  from
0.001-44.0 ppb with  a mean  of 1.347  ppb  (U.S.  EPA, 1985a).  Domestic samples
of milk  were  2.0%  positive for y-HCH, with  a  mean  concentration of 2 ppb
(Ouggan et al., 1983).
    Market  basket surveys  conducted  1n  1977-1978 Indicated  ppb concentra-
tions of  a-HCH  1n  a  variety  of  meats,  cottage  and .processed  cheese.  Ice
cream,  fish   fillets  and  canned  fish,   lunch  meat   and   frankfurters
0818p                               3-3                              06/27/86
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(Podrebarac, 1984).   Based  on these  figures,  the average  dally  Intakes of
a-HCH  In  1977  and  1978  were  10.5 and 9.1  ng/kg  bw/day.   The  concentration
of a-HCH  In a  variety of fish  collected  across  the United States contained
from  <0.01-0.2  ppm  a-HCH  (Schmltt  et a1.,  1985).   Residues  of  a-HCH In
384  shellfish samples  ranged  from 0.005-63.0 ppm  (wet weight), with a  mean
of 1.815 ppm (U.S. EPA, 1985a).
    Residues of  B-HCH  in 375 shellfish samples ranged  from  1.0-38.0  ppm  (wet
weight),  with  a  mean  concentration  of  1.940  ppm,  and  a-HCH  ranged  from
1.0-10.0 ppm. with a mean of 1.408 ppm  1n  375  shellfish samples  (wet weight)
(U.S.  EPA,   1985a).   Specific  data  for  8-,  «- or  e-HCH were  not  located
In  the available  literature.    A variety  of foodstuffs,  Including  meats,
dairy  products    (except  milk)   and  vegetables   analyzed   from   1971-1976,
contained ppb  amounts of a-,  B- and  4-HCH (combined  residues)  (Duggan et
al.,  1983).  Based  on  these  studies,   the  average  dally  Intake  of   the
combined  a-, B-  and   a-HCH  residues  1s   0.67 g.   The  mean  concentrations
of  combined a-,  B- and  a-HCH  Isomers  1n  13.IX  of  domestic  and   33.1% of
Imported fish samples  were  48  and 1  ppb,  respectively.   The  mean  concentra-
tions  of  the Isomers  In 8.1% of  domestic and 22.6%  of  Imported  shellfish
samples were 1  and  66  ppb,  respectively (Ouggan et al.,  1983).   In  a 10-year
study  of  chlorinated  hydrocarbons In  bovine  milk  1n  Illinois, the percent
positive samples for all the Isomers of HCH combined  ranged from 68.6-91.8%,
with average residues  of 0.01-0.02 ppm.   In 1980  and  1981,  only  28.3-31% of
the  samples were positive,  with  average concentrations  of trace (<0.001  ppm)
to 0.01 ppm (Steffey  et  al.,  1984).  Mean concentrations  of combined Isomers
of  HCH  In  a  variety  of   Imported  spices   ranged  from  <0.005-0.51   ppm
(Sullivan,  1980).
0818p                               3-4                              06/27/86
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3.3.   AIR
    Monitoring during  the  years 1970-1972 revealed  a  mean concentration of
Y-HCH  In  ambient  air  of  0.6 ng/m3  for  all  years and  all states combined.
There  were  67.7% positive  samples  with  a  mean concentration  of  0.9 ng/m3
and  a  maximum  value  of  11.7 ng/m3  (Kutz  et  al.,  1976).  Y-HCH  was  also
detected  1n measurable quantities  1n  Jackson,  MS;  Fort Collins, CO (Kutz et
al., 1976); StonevUle, MS  (Arthur  et al.,  1976);  Baltimore,  MD; Iowa CHy,
IA; Salt  Lake CHy,  UT (Stanley et  al.,  1971);  and Miami,  FL (Lewis and Lee,
1976).   Assuming  an average  Intake  of  20 m3  of air/day,  the  average dally
Intake of  y-HCH  by  Inhalation Is 18  ng,  based on  the monitoring data given
above.
    Monitoring during  the  years 1970-1972 revealed  a  mean a-HCH concentra-
tion 1n  ambient  air of  1.2  ng/ma  In 87.37X of the  samples  for all states
and  years combined  (Kutz  et  al.,  1976).   Measurable quantities  of a-HCH
were detected  In  the  air  of the Great  Lakes  ecosystem (Elsenrelch et al.,
1981);  Baltimore,  MD;  Salt Lake CHy, UT, and  Iowa CHy,  IA (Stanley  et al.,
1971).   Assuming  a  normal  dally Intake  of  20 m3 of  air,  the  average dally
Intake  of a-HCH,   based  on  these  monitoring  data,  Is   24  ng.   Pertinent
monitoring data regarding  the other  Isomers  of  HCH  could not  be located  1n
the available literature  as cited  1n the Appendix.
3.4.   MISCELLANEOUS EXPOSURE
    Transfer   of   unspecified  amounts   of   a- and   Y-HCH  to  smoke   from
pesticide-treated  tobacco  has been  observed  (Ceschlnl and Chauchalx, 1980);
Rao-Kovvall et al.  (1980)  reported that  Indian  tobacco contains unspecified
amounts of HCH Isomers.   Occupational exposure to q-HCH occurs  1n  personnel
operating commercial  seed-treating  equipment  (Grey  et, al.,  1983).   The  a-,
B-, Y- and  4 Isomers  of  HCH have been  detected  at  ppb concentrations  In
0818p                               3-5                              06/10/86
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raw wastewater  from  coal  mining,  aluminum forming, foundries and nonferrous
metals  manufacturing   (U.S.   EPA,   1981).    Raw  wastewater  from  organic
chemicals  manufacturing/plastics   Industries  contains  ppb  amounts  of  a-,
Y- and  6-HCH.    The  y- and  
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from  Ottawa,  an average  dally  Intake of  34 pg was  estimated.   Because of
the  relatively  high  value of  a-HCH  In  the Ottawa  sample,  this  value 1s
thought to be nonrepresentatlve.  Samples of  surface water and precipitation
(rain  and snow)  from  a   variety  of  locations  contained a-HCH  (U.S.   EPA,
1985a; Kuntz  and  Warry,  1983;  Page, 1981;  Cole et  al.,  1984; Strachan  and
Huneault,   1979;  Elsenrelch et  al.,  1981;  Pankow  et  al., 1984;  Brooksbank,
1983; Strachan,  1985).  In the  Netherlands, B-HCH  was  found  1n ng quantities
In  a  variety  of  locations  (Dulnker and  Hlllebrand,  1979).   Samples of
surface water In  the United  States  contained a mean  B-HCH  concentration of
0.1725  yg/l  (U.S.   EPA,  1985a).    Pertinent  monitoring   data  for   5- or
e-HCH  could  not  be   located  1n  the available  literature  as dted  1n  the
Appendix.
    A  wide variety  of  foodstuffs,   Including  dairy  products,  meat,  vege-
tables, fruits and seafood,  contain  one  or more HCH  Isomers  (Duggan  et al.,
1983;  Steffey  et al.,  1984; Podrebarac,  1984; Schmltt  et  al.,  19.85;  U.S.
EPA,  1985a).   The average  dally  Intake of  y-HCH  was  estimated  to be  0.27
vg,  based  on   the   y-HCH content   1n  foods  from 1971-1976,  and  that of
a-HCH  was estimated  to  be  10.5 and 9.1  ng/kg  bw/day,  based  on  1977  and
1978 data, respectively.   Since monitoring  data 1n foods are  available only
for  mixtures  of  the  Isomers,  B-,   6-  and   e-HCH,  1t  1s   not  possible  to
estimate the average dally Intakes of Individual Isomers.
    The mean  concentration of  y-HCH 1n  positive  samples of ambient air  1n
the  United  States In  1970-1972 was  0.9  ng/m3 (Kutz  et  al., 1976).   Based
on  this value and assuming an  average Intake of  20 m3 air/day,  the  average
dally  Intake  of  y-HCH   Is  18  ng.   Monitoring  data   during   the  years
1970-1972  revealed  a  mean  a-HCH  concentration  1n« ambient  air  of  1.2
ng/m»  In  the  positive  samples  collected across  the United States  (Kutz et


0818p                                3-7                              06/10/86
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al., 1976).   Assuming  an  average dally Intake of  20  m3  of air, this  figure
1s  equivalent  to an  average dally  Intake  of 24  ng.  Pertinent  monitoring
data regarding  the  other  Isomers of HCH  could not be located  1n  the  avail-
able literature as dted In  the  Appendix.
    There  are  several  miscellaneous  sources of   exposure   to  HCH  Isomers
Including burning of  tobacco (Cesch1n1 and Chauchalx,  1980)  and  the  opera-
tion of  commercial  seed-treatment equipment  (Grey  et al.,  1983).   Isomers
of  HCH were  detected  In  wastewater  from coal   mining,  aluminum  forming,
foundries,  nonferrous  metals  manufacturing, paint   and  Ink   formulation,
petroleum  refining, metal  finishing  and organic chemicals  manufacturing/
plastics Industries  (U.S.  EPA, 1981).
0818p                               3-8                               06/10/86
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                             4.  PHARMACOKINETICS
4.1.   ABSORPTION
    Two  studies  provide  direct  evidence  that  y-HCH  1s  absorbed  from  the
gastrointestinal  tract.  Turner  and  Shanks  (1980)  showed that 29.6-42.6X and
42.3-53.OX  of  0.05   and   0.1   pmol   of  Y-HCH  (dissolved  In  rat  bile),
respectively, were absorbed  Into  the  blood  from Injected Intestinal loops of
male  Wlstar  rats.  Ahdaya et  al.  (1981) administered  radlolabeled  T-HCH (1
mg/kg  In  Emulphor:ethanol:water,  1:1:8)  to  fasted  ICR mice by stomach needle
and monitored  the appearance of  radioactivity  In  the gastrointestinal  tract
(minus contents),  blood,  liver and  carcass  and the  disappearance  of radio-
activity  from the  gastrointestinal  tract contents  for up to 60 minutes after
administration.   Radioactivity  1n  the  gastrointestinal  tract  (minus  con-
tents) reached  a  maximum  of  17X of  the administered dose at -8 minutes after
treatment, then declined  to  9X for  the duration of the study.  The amount of
radioactivity  In  the  blood  reached  a  maximum  of  2.2X of  the administered
dose  within  15  minutes  and   then  declined  slightly  (to  -1.5X)   for  the
remainder of the  study.   Radioactivity  In the  liver  reached a maximum of 8X
within 15 minutes and  declined to  5X by 60  minutes.  By  60  minutes  after
treatment, 70.7X  of the  administered radioactivity was absorbed.   The time
for 50X  absorption was estimated at  14.2±0.6 minutes,  using an unspecified
model that gave the best linearization.
    In a  study  designed to Investigate  the  possibility  of  1somer1zat1on,
Elchler  et  al.  (1983) administered  either  o-HCH (15 mg/kg/day)  or  T-HCH
(15  mg/kg/day   males;  10  mg/kg/day  females)  by  stomach   tube to  male  and
female rats  for  56  days.   The  concentration  of  o-HCH peaked  1n  the blood
within 28 days  of  exposure (13-14 mg/kg  blood) and  remained  at that level
through  56  days  of  treatment.  Peak  levels  of  Y-HCH  were  also  observed


0819p                               4-1                               06/27/86
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within  28  days  of  treatment  (2.1  mg/kg blood),  but  then  declined  to  0.9
mg/kg blood by day 56 of  treatment.  Using methods  with  a  detection  limit of
0.001 mg/kg  blood or  tissue,  Elchler  et  al.  (1983)  found  no  evidence  of
1somer1zat1on of a- or y-HCH.
    The  appearance  of B-HCH  In   the  brain  and  adipose  tissue  of  rats  and
mlnlplgs after  dietary administration  of  this  Isomer   (11  weeks,  rats;  37
weeks,  mlnlplgs)  Indicates  that  0-HCH  1s absorbed by   the  gastrointestinal
tract (Altmann et al., 1983).  No other details  were given.
    Muralldhara  et  al.   (1979)   demonstrated   that  the  acute  tox1c1ty  of
y-HCH  1s  proportional   to  the   solubility  of  y-HCH   In  the  carrier  and
suggested  that  poor  solubility  results  In  reduced  absorption  1n the  small
Intestine.    Herbst  and   Bodensteln  (1972)   suggested   that  I1p1d-med1ated
carriers enhance the rapidity with which y-HCH 1s absorbed.
4.2.   DISTRIBUTION
    In  general,  Isomers   of  HCH  tend  to accumulate 1n  fatty tissue.   In a
comparative study, Elchler  et  al.  (1983) gavaged male   and  female  rats with
either  a-HCH  (15  mg/kg/day)  or   r-HCH  (15  mg/kg/day,  males; 10  mg/kg/day,
females  after  15  days  of  15 mg/kg/day)  for  56  days.   Both  Isomers were
present  In  higher  concentrations  In  the   tissues studied (brain,   liver,
kidney and  fat)  than 1n  the blood;  levels  1n  the  fat were  especially high.
a-HCH  accumulated  1n the  fat   and  brain  to  a  greater   extent  than  did
f-HCH.   Furthermore,  the  retention   of a-HCH  1n the tissues  was  10-20
times   greater   than  that  of   y-HCH.   Tissue   concentrations   of  y-HCH
decreased markedly during  the  15  days  after  the termination of exposure.  In
contrast,  concentrations  of a-HCH  remained  high,  particularly  In  the  fat,
even  15  days posttreatment.   In other  dietary and gavage  studies  In rats.
0819p                               4-2                              06/27/86
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 Isomers  of  HCH were  shown to accumulate  In  fatty tissues (Chand  and  Rama-
 chandran, 1980; Lakshmanan et al., 1979; Chadwlck et  al.,  1978a;  Altmann  et
 al., 1983).
    Chadwlck  et al.  (1978a)  and  Lakshmanan  et al.  (1979)  demonstrated  that
 dietary   factors   can   affect  the  retention  of  y-HCH   In   the  tissues.
 Chadwlck  et  al.  (1978a)  found  that  rats fed  a  high-fiber diet for  28  days
 before  dosing retained a  significantly greater amount  of  radioactivity  from
 i«C-(y-HCH)   In  the  brain,  liver,   kidney,   stomach  and  muscle  than  did
 rats  fed  a  low-fiber  diet.   Retention  was  measured 24  hours  after adminis-
 tration  of  a  single  oral  dose  of 2.87 mg  14C-(Y-HCH).  Lakshmanan et  al.
 (1979)  varied  fat  content  In  the diet of rats and found that  rats  maintained
 on  a  low-fat  diet  had significantly less y-HCH  1n  adipose tissue  than  did
 rats  fed  a  high-fat diet.  y-HCH content of  the brain was not affected  by
 diet.
    Human  studies  have  shown that  y-HCH  and other  Isomers  of HCH  accumu-
 late  In  the  fatty tissues (Baumann  et al.,  1980;  S1dd1qu1  et al.,  1981a;
 Szymczynskl  and  Wallszewskl,  1981a).   Investigators  have also  shown  that
 y-HCH  accumulates  1n  human  milk   and   Is   able  to  cross   the  placenta
 (Slddlqul et al..  1981b;  Poradovsky  et  al.,  1977; Saxena et al., 1981;  Welch
 and  Ftndlay,  1981).   Isomers  of  HCH  (a,  B,  y,  
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4.3.   METABOLISM
    The  metabolism  of  HCH   Isomers  primarily   Involves  dehydrogenat1on,
dehydrochloMnatlon and dechlorlnatlon.  Conjugation reactions with sulfuMc
and  glucuronlc  acid  and  glutathlone  are  also  Important  (Macholz  et  al.,
1982a;  Engst  et al.,  1976,  1979;  Chadwlck et  al., 1975; Grover  and Sims,
1965; Freal and Chadwlck,  1973;  Chadwlck and  Freal, 1972; Allsup and Walsh,
1982; Kurlhara et  al.,  1979).   In  mammals,  Including humans,  common metabo-
lites of  HCHs  Include chlorinated phenols, chlorinated  benzenes  and penta-
chlorocyclohexenes   (Angerer  et al.,   1983;  Kujwa  et  al., 1977;  Grover  and
Sims, 1965;  Freal   and  Chadwlck,  1973; Chadwlck  and Freal,   1972;  Engst  et
al., 1976; Chadwlck et al., 1975, 1978a).   These metabolites are excreted 1n
the urine and have  also been Identified In the  blood, liver, kidney,  spleen,
heart and brain of  rats fed y-HCH {Engst et al.,  1976).
    Chadwlck et al. (1975) demonstrated that  1n  rats y-HCH  Is metabolized
to  hexachlorocyclohexene,  which  1s  then degraded   to 2,3,4,5,6-pentachloro-
2-cyclohexene-l-ol,  two   tetrachlorophenols   and   three  trlchlorophenols.
Macholz  et  al.  (1982a) demonstrated  that  rats  fed  a-HCH  In  the diet for 30
days  excreted  all   Isomers  of  tMchlorophenol  and  tetrachlorophenol  In the
urine.  Similar results  were  obtained when rats were  fed B-HCH In the same
manner  {Macholz et  al.,  1982b).   Pentachlorocyclohexene was also  Identified
as a metabolite of  a-HCH but was  not  excreted  1n the urine.
    A number of In vUro studies have shown  that  the metabolism of  HCHs  In
mammals   Is  probably mediated  to a  great  extent  by  oxldatlve processes  In
hepatic   mlcrosomes  (Gopalaswamy  and  A1yar,  1984;  Yamamoto   et  al.,  1983;
FHzloff et al., 1982; FHzloff and  Pan, 1984;  Baker  et  al.,  1985;  Tanaka  et
al., 1979; Portlg et al., 1973).
0819p                               4-4                              10/27/86
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    Dietary  factors  have  been shown  to  influence  the metabolism and  excre-
tion  of  Y-HCH.   Chadwlck  et  al.  (1978c) pretreated  male  Wlstar rats  with
cadmium  and   then  exposed   them   to   14C-(Y-HCH).    Cadmium-exposed   rats
excreted  less  radioactivity  1n  the  urine  than did  controls.   Exposure  to
cadmium  also  Inhibited  the   dehydrogenatlon  of  y-HCH  to  hexachlorocyclo-
hexene  and  altered  the  distribution  of  neutral  to  polar   metabolites.
Chadwlck et al.  (1978a) also  demonstrated  that  rats fed  high-fiber  diets for
28  days  before  oral  administration  of  y-HCH,  dehydrogenated and  dechlorl-
nated y-HCH to a greater extent than did rats fed a low fiber diet.
    Studies  conducted  by   L1u (1982)  suggested  that  metabolism  of  y-HCH
varies with  the  genetic strain of  the animal  studied.   Long-term administra-
tion  of  y-HCH   resulted   1n lower  levels   of  2,4,6-trlchlorophenol   and
2,3,4,6-tetrachlorophenol   1n  the  blood of DBA/2  mice than  1n C57B1/6  mice.
Subsequently,  however,  levels of  2,3,4,6-tetrachlorophenol  1n DBA/2  mice
exceeded those  In C57B1/6 mice.    DBA/2  mice also  had  higher  concentrations
of 2,4,6-trlchlorophenol 1n the liver, kidney and spleen.
4.4.   EXCRETION
    U.S. EPA  (1980a,  1985a) concluded that even  after  prolonged administra-
tion, y-HCH  and  Us  metabolites  are completely excreted  after application
1s  terminated.   Frawley  and  Fltzhugh  (1949)  demonstrated that y-HCH  con-
centration In  the  fatty  tissue of rats  dropped from 102 ppm to undetectable
levels (sensitivity of method not reported)  within  1  week  after administra-
tion  of  r-NCH  was discontinued.   Lehman (1952a,b)  demonstrated a  similar
reduction  (281  ppm  to  undetectable)  within  2  weeks  of discontinuation  of
exposure.  KHamura  et al.   (1970)  observed  that  after  20 days  of  feeding
Y-HCH at  10 ppm  In  the  diet,  no residues   of y-HCH 'could be  detected  In
the bodies  of  rats  within 1  day  of return  to the control diet.   After  20


0819p                               4-5                              06/27/86
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days  of  feeding  a-HCH   at  100  ppm  1n  the  diet,  residues  In  the  body
declined to 0.1  ppm  by 3 days  after return to the control diet  (KHamura et
al., 1970).
    In  a  comparative  study, KHamura  et  al.  (1970)  demonstrated  that  the
disappearance  of  y-HCH  from  the bodies  of  mice  given  a  single oral  dose
(500  yg)  was  more  rapid  than   that of  B-HCH under  Identical  experimental
conditions.
    Y-HCH  was  eliminated  more   rapidly  from  fat   than  was   a-HCH   1n  a
longer-term  oral  study   (Elchler  et  al.,  1983).   In   this  study,   Y-HCH
levels  In  fat  declined from a maximum  of 385  to  15 ppm by 15 days  after  the
termination of  56 days  of  oral  administration  of  10-15  mg/kg/day of  y-HCH
to  rats.   In  contrast,  a-HCH accumulated to  a  maximum  of  4255 ppm In  fat
and then declined  to 1947 ppm by  15  days after the termination  of 56 days of
oral administration of  15 mg/kg/day  of  a-HCH  to rats.
    The principle  route  of  excretion  for  Y-HCH  and  metabolites  1s urinary.
When  U-14C-(Y-HCH)  was  administered  orally  to  rats  or  IntrapeMtoneally
to mice, radioactivity was excreted  primarily  In the  urine  (Chadwlck et al.,
1978a;   Engst   et   al.,   1979).     Following    oral    administration  of
U-14C-[Y-HCH]   to  rats,   lesser  amounts  of  radioactivity  appeared  1n  the
feces  than In  the  urine  (Chadwlck et  al.,   1978a)  and  trace  amounts  (as
14CO?)  appeared  1n  the expired  air   (Adhaya  et al.,  1981;  Chadwlck  et
al., 1978a).
    Very little  Y-HCH  Is excreted  unaltered   according  to  U.S.  EPA  (1980a,
1985a).  Laug  (1948)  recovered  only  4% of  the administered dose of  Y-HCH
(not  specified)  as  parent  compound  In  the urine  of  rats fed  Y-HCH.   Egnst
et  al.  (1976),  however, reported  that  substantial  amounts  of  free  Y-HCH
were  excreted  In  the  urine of  rats  administered 8 mg/kg/day  of Y-HCH  1n


0819p                               4-6                              10/27/86
-------
sunflower  oil  by gavage  for  19  days.   Metabolites  were also  found  In  the
urine.   In  the  feces,  only  unaltered  y-HCH  was  detected.   Excretion of
urinary  metabolites  of  Y-HCH,   primarily   1n  conjugated  forms,  has   been
reported by  Kurlhara  et al.  (1979), Chadwlck et al.  (1975,  1978a,b), Allsup
and Walsh  (1982),  Zesch et al.  (1982),  Angerer et al.  (1981)  and Stein et
al.   (1980).   Urinary  excretion   of  a-HCH metabolites  was   reported by
Macholz et al. (1982a).
    In  feeding  studies, Chadwlck  et al.  (1978a)  demonstrated  that  dietary
fiber  can  Influence  the metabolism and  excretion of  Y-HCH  In rats  given  a
single oral dose of 2.87 mg of U-14C-(Y-HCH).
    The  feeding  of  high  fiber  diets (Purina  Lab  Chow or  a low  fiber  diet
supplemented  with  pectin) for  28  days  before administration  of y-HCH  was
shown  to cause significant Increases  1n  the excretion  of  radioactivity  (as  X
of  dose)  1n the urine  (9.70-13.00X for  high fiber diets  vs. 7.85%  for low
fiber  diet)  and feces  (3.55-4.12X for  high fiber  diets vs.  0.72X  for  low
fiber  diet)  and  significant  Increases In  the amounts of conjugated  chloro-
phenols and polar metabolites  excreted In the urine.
    Isomers  of HCH  are excreted 1n human milk  (Herbst and  Bodensteln,  1972;
Welch  and  Flndlay,  1981)  and  semen (Szymczynskl and  Wallszewskl,  1981a,b).
8-HCH  accounts   for  9OX  of  the   HCH  found  1n human  milk,  while  a- and
Y-HCH  accounts  for  the remaining  10X.   All five Isomers have  been  found In
human  semen.
4.5.   SUMMARY
    Two  studies  provide  direct  evidence   that  y-HCH  1s absorbed from the
gastrointestinal tract  (Turner  and Shanks,   1980; Ahdaya et  al.,  1981).  The
appearance of a-HCH and 8-HCH  In the blood and tissues after  oral  adminis-
tration  Is  also Indicative of  gastrointestinal absorption  (Elchler  et al.,
1983; Altmann et al., 1983; Macholz et al.,  1982a,b).

0819p                               4-7                              08/07/86
-------
    In general,  Isomers  of  HCH and  their  metabolites  tend  to accumulate In
fatty tissue (Elchler et al., 1983;  Chand and Ramachandran,  1980; Lakshmanan
et al.,  1979;  Chadwlck  et  al.,  1978a;  Altmann et al., 1983; Baumann et al.,
1980; S1dd1qu1  et  al.,  I981a; Szymczynsk! and  Wallszewskl,  1981a,b).   In a
comparative  study  where a-HCH  or  y-HCH  was fed  to  rats  In the  diet  for
56 days,  Elchler  et  al. (1983) found  that a-HCH  accumulated  In  the fat  and
brain  to a  greater  extent   than  did y-HCH.   Furthermore,  the  retention of
a-HCH  In the  tissues  (fat,  brain,  liver,  kidney) was  10-20  times greater
than  that of  y-HCH.   Tissue  concentrations of  y-HCH  declined  to  a much
greater  extent  than  did tissue  levels of a-HCH during  the 15  days follow-
ing termination of exposure.
    The  metabolism  of  HCH   Isomers   primarily   Involves  dehydrogenatlon,
dehydrochloMnatlon and dechlorlnatlon.  Conjugation  reactions with  sulfurlc
and glucuronlc add are also  Important  (Macholz et al.,  1982a; Engst et al.,
1976, 1979;  Chadwlck et al.,  1975;  Grover and Sims,  1965; Freal and  Chad-
wick, 1973;  Chadwlck and Freal,  1972;  Allsup and Walsh,  1982).   In  mammals,
Including  humans,  common  metabolites   of  HCH  Include chlorinated  phenols,
chlorinated  benzenes  and  pentachlorocyclohexenes.   These   metabolites  are
usually  excreted  In  conjugated form (or  a  degradation  product  of a  previ-
ously conjugated  form)  In  the urine,  and  have  also been detected  In  blood,
liver, kidney, spleen, heart and  brain  (Engst et  al.,  1976; Chadwlck et al.,
1975, 1978a; Freal and  Chadwlck,  1973; Chadwlck and  Freal,  1972;  Angerer et
al., 1983; Kujwa et  al., 1977; Grover  and  Sims, 1965).  A number  of 1n vitro
studies  have  shown that the metabolism of HCHs In mammals  Is mediated to  a
great extent  by oxldatlve processes 1n hepatic mlcrosomes  (Gopalaswamy  and
Alyar, 1984; Yamamoto et al.,  1983;  FHzloff  et al.,  >982;  FHzloff and Pan.
1984; Baker et al., 1985; Tanaka et al., 1979; Portlg et al.,  1973).


0819p                               4-8                              08/07/86
-------
    HCH  Isomers  and  metabolites have  been  recovered  1n the urine and  feces
(Ahdaya  et al.,  1981;  KuMhara  et  al.,  1979;  Chadwlck  et  al.,  1975,  1978a,b;
Allsup and  Walsh,  1982; Zesch  et  al.,  1982;  Angerer  et al.,  1981;  Stein  et
al.,  1980;   Macholz  et  al.,  1982a,b),  and  trace  amounts  (as  14CO_)  have
been detected  In expired air  (Ahdaya et al.,  1981; Chadwlck et  al.,  1978a).
In  comparative  studies, KHamura  et  al.  (1970) and  Elchler  et al.  (1983)
demonstrated  that  the  disappearance of y-HCH  from  the bodies of mice  given
a  single oral dose  or rats given  repeated oral doses  was more rapid  than
that  of  B-HCH or  «-HCH administered  1n the  same  manner.   Isomers of  HCH
are known  to be  excreted  1n  human milk (Herbst and Bodensteln,  1972;  Welch
and Flndlay, 1981) and semen (Szymczynskl  and Wallszewskl,  1981a,b).
    Chadwlck et  al.  (1978a,c) and  lakshmanan  et  al.  (1979) have  demonstrated
that  dietary  factors  (cadmium,  fiber and  fat)  can   alter   the  retention,
metabolism  and  excretion   of   y-HCH.   Herbst  and  Bodensteln  (1972)  have
suggested  that  I1p1d-med1ated   carriers  enhance  the   absorption  of  y-HCH.
L1u  (1982)   suggested   that  the  metabolism  of  y-HCH  might  vary  with  the
strain of animal  used  1n the study.
0819p                               4-9                              08/07/86
-------
                               .   5.   EFFECTS
5.1.   CARCINOGENICITY
5.1.1.   a-HCH.    Dietary  a-HCH   has   been   shown   to  cause   Increased
Incidences  of liver  tumors  In  five  strains of mice  (Ito et  al.,  1973a,b,
1976;  Nagasaki et  al.,  1972a,  1975; Hanada  et  al.,  1973;  Goto  et  al.,  1972)
and  In Wlstar rats  (Ito  et  al., 1975;  Schulte-Hermann  and  Parzefall,  1981)
(Table 5-1).   None  of  the   tests   In  mice were  negative.   However,  the
cardnogenlclty  In  Wlstar  rats  In  these   studies  was  either  marginal  or
negative, Indicating a greater sensitivity of the mouse to this  compound.
    Goto  et al.   (1972)  reported that  when  control  diet  or  diet  containing
600  ppm  of  T-HCH,  a-HCH,   B-HCH,   y-HCH   or  a  mixture  of  4- and  c-HCH
or  300 ppm Y-HCH  was  fed to  ICR-JCL  mice  for  26 weeks,  grossly  observable
hepatic  nodules  occurred 1n all  mice fed T-HCH or  a-HCH, In  5/10  mice fed
Y-HCH  and  In 10/10 mice  fed  4-  and  e-HCH.   By  Implication,  no  grossly
observable .hepatic  nodules were  seen  1n mice treated  with 600 ppm B-HCH, 300
ppm y-HCH  or control  diet.   The report,  written  1n  German,  Indicates that
hlstologlcal  examination revealed  benign  hepatomas   1n  all  groups  treated
with 600 ppm  HCH  as above and  that  malignant hepatomas were frequently found
In  the groups  treated  with  a-HCH  or  6- and  e-HCH.    The  report  does  not
explicitly  state   the  Incidences  of  hlstologlcally  confirmed  benign  or
malignant hepatomas  1n any group.
5.1.2.   B-HCH.   Table  5-2  summarizes  the  available  oral  cardnogenlclty
studies  on  B-HCH.   Dietary  B-HCH  has been  shown  to cause  Increased  Inci-
dences of  liver  tumors only  1n  CF1  mice with  marginal  Increases  In ICR-JCL
mice (Thorpe and Walker,  1973; Goto  et al.,  1972)  but no  Increased Incidence
1n  dd  mice  (Ito  et al., 1973a,b;  Hanada  et  al.,   1973; Nagasaki  et al.,
1972a) or In Wlstar  rats (Ito et al.,  1975;  FHzhugh et al.. 1950).


0820p                               5-1                              10/27/86
-------
































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    The  studies  with  negative  results,  however,  were of  short Duration
 (Hanada  et al.,  1973;  Ito et  al.,  1973a,b; Nagasaki  et  al., 1972a),  used
 small  numbers of  animals  [except Thorpe  and Walker  (1973)],  or  failed  to
 examine  all   the  experimental  animals  (Fltzhugh  et al.,  1950;  Nagasaki  et
 al.,  1972a;  Hanada et  al.,  1973).  These  studies  that were observed  to  be
 negative  for  B-HCH  might  have  been  expected   to yield  negative  results
 because  of  study  design  limitations  and,  therefore,  are  only  of  limited
 utility.
 5.1.3.   f-HCH.    Dietary  f-HCH   was   shown  In   one   study   to  cause  an
 Increased  Incidence of liver  tumors  1n male  CF1  mice  fed  400  ppm  for  110
 weeks  (Thorpe and  Walker,  1973).  Marginal  results were  observed  In  male
 ICR-JCL  mice  fed 600 ppm for  26  weeks  (Goto et   al., 1972).   The Thorpe and
 Walker  (1973) study  was  the only full-term study  In  mice  since  the  other
 studies  1n  mice were terminated  at  shorter than  lifetime testing  durations
 (24,  24,  32.  26  and 24  weeks).   Only  the most  potent carcinogens  would
 display  clear results  In  these  shorter duration studies.   For  example,  no
 liver tumors  were  observed 1n  dd  mice  fed  up to  500 ppm for  24 weeks (Ito et
 al.,  1973a.b;  Nagasaki  et  al.. 1972a)  or  1n Wlstar rats fed 500 ppm for  up
 to 48 weeks  (Ito  et al., 1975).   Significant compound-related  development  of
 tumors  of  any  type  was  not  observed  In  NHRI  mice (Herbst  et  al.,  1975;
 Welsse and Herbst.  1977).  B6C3F1  mice  (NCI,  1977)  Osborne-Hendel rats  (NCI,
 1977) or  Wlstar rats  (Fltzhugh  et al., 1950).   The rat study conducted  by
 NCI (1977)  has  been  criticized for  poor survival,  changes-  In- dosing regime
 and  the possibility  that  male  rats   did  not  receive HTDs   (IARC.  1979).
 Reuber (1979) also  disputed the negative findings of NCI (1977) and reported
 that  an  Independent  Interpretation  of  the hUtologlcal data  leads to  the
conclusion that  y-HCH 1s carcinogenic  1n  both rats and mice.  The validity
of this  assessment Is uncertain.   The  negative   findings of Fltzhugh et-al.

0820p                               5-5                              04/22/88
-------
 (1950),  Ito  et  al.  (1973a,b,   1975)   and  Nagasaki   et  al.   (1972a)  are
 attributed  1n part  to  small numbers of  animals,  short  duration  or  failure to
 examine all  animals  In the study.   Table 5-3 summarizes these  oral carclno-
 genldty   studies.    A  metabolite   of  y-HCH,   2,4,6-trlchlorophenol,  1s
 carcinogenic 1n  rats and  mice and  has  been classified as a  "probable"  human
 carcinogen  (Group  B2).   This  metabolite has  been  Identified 1n rodents and
 humans.
 5.1.4.   4-HCH.    Oral   cardnogenldty   data   for   a-HCH  are   presented  In
 Table  5-4.   Dietary  4-HCH  did  not   cause  neoplastlc  or   nonneoplastlc
 changes 1n  the  livers  of male dd mice  (Ito et  al., 1973a;  Nagasaki et al.,
 1972a)  or  male  Hlstar rats  (Ito  et al.,  1975).   However,  these negative
 studies are of limited utility.  These  studies used  small numbers  of animals
 and were only conducted  for  24 weeks.  Furthermore, Nagasaki et al. (1972a)
 failed to examine all the mice started on the  test.
    Goto et  al.  (1972)  reported  that  a  mixture of 6-HCH  and  e-HCH  caused
 Increased Incidences of benign and malignant  hepatomas  1n ICR-JCL  mice  after
 26  weeks  of  dietary  administration, but  the  Individual  Isomers  were not
 tested 1n the study (see Section  5.1.1.).
 5.1.5.   e-HCH.    No direct   cancer   data   exist  for  e-HCH.   Goto et al.
 (1972)  reported  that  a  mixture of  4-HCH  and  c-HCH caused  an  Increased
 Incidence of benign  and malignant hepatomas  1n  ICR-JCL mice after 26  weeks
of dietary administration, but the Individual Isomers  were not  tested  In the
 study  (see  Section   5.1.1.).   Additional   pertinent data regarding the
cardnogenlclty   of  c-HCH could not  be   located  1n  the available  literature
as cited 1n the  Appendix.
5.1.6.   T-HCH.    The  T-HCH  mixture has  been  shown  to   cause  Increased
 Incidences of liver  neoplasms In  four  strains of mice (Hanada  et  al.,  1973;
Goto et al., 1972;  Kashyap et al.,  1979; N1gam  et  al., 1984a;  Bhatt et at.,

0820p                               5-6                               04/22/88
-------
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1981;  Munlr  et  al.,  1983;  Nagasaki  et al.,  1971,  1972b;  Nagasaki,  1973;
Munlr and Bhlde, 1984).   However, cardnogenlclty was not observed In Hlstar
rats (Munlr et al., 1983) nor 1n Syrian Golden hamsters  (Munlr et al., 1983)
(Table 5-5).
5.1.7.   General  Comments.   All  but  six  of  the  cardnogenlclty  studies
[Fltzhugh  et  al.,  1950 (a,  B,  y);  Herbst  et  al.,  1975  (Y);  Welsse  and
Herbst,  1977  (T);  Ito  et  al.,  1975  (a,  0,  Y.  *);  NCI,  1977  (Y);
Thorpe and Walker,  1973 (B, Y)] assayed only  for  hepatic  response,  I.e.,  a
full examination  of  other   tissues was  not  done.  A large  body of evidence
Indicates that  the nonneoplastlc changes In  the  liver  associated with expo-
sure to  Isomers  of  HCH  or  T-HCH  are associated with neoplastlc  development.
A  clear   progression  of  hepatic  changes,  which  ultimately  leads   to  the
development of malignant tumors  has been observed at gross, hlstologlcal and
ultrastructural   levels  of  examination;  these  changes,  proportional  to dose
and duration of  treatment,  are  reversible only  at  the very earliest  stages
before the development of nodular hyperplasla.   The  transition  from  reversi-
ble to  Irreversible  change  has  not been accurately  defined,  but 1s  charac-
teristic of  tumor  progression which  has  been  widely  reported  (Ito  et al.,
1975, 1976; Schulte-Hermann  and  Parzefall,  1981; Munlr  et  al., 1983; Munlr
and Bhlde, 1984; N1gam et al., 1982,  1984a; Suglhara  et al., 1975).
5.2.   MUTAGENICITY
    Y-HCH was not  found to be mutagenlc  1n  Ames tests on Salmonella  typhl-
murlum with  or  without  S-9  (Lawlor  et al.,  1979;  Probst  et  al.,  1981)  or
EscheMchla coll  (Probst et al.,  1981).   Negative  results  with Y-HCH were
also obtained  In an  oral  dominant lethal test  on  SPF:THOM rats  (Rohrborn,
1977), 1n  an  1ntraper1toneal  dominant  lethal  test  on  mice (U.S. EPA,  1973)
and 1n  a recessive lethal   test  on  DrosophUa  melanoqaster (Benes and  Sram,


0820p                               5-10                             03/18/88
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1969).   Rohrborn  (1977) reported  that  weakly  mutagenlc  effects were caused
by  Y-HCH  1n a host-mediated assay  with S. typhlmurlum.  while  Buselmaler et
al.  (1972)  reported   negative  results  for y-HCH   1n  host-mediated assays
with £.  typhlmurlum and Serratla  narcescens.   Tests of y-HCH-lnduced  geno-
toxldty  have  yielded  both  positive  and negative results.  Chinese  hamster
Hbroblasts  (Ishldate  and  Odashlma,  1977)  and human peripheral  lymphocytes
(Tzoneva-Maneva et  al., 1971).   In  contrast,  y-HCH did  not   cause  chromo-
somal  aberrations  1n  lymphocytes  of llndane  production  workers  (Klraly et
al., 1979)  or  1n bone  marrow from  Chinese  hamsters  (Rohrborn,  1977),  did not
cause  unscheduled   ONA  synthesis   1n  SV-40   transformed  human  flbroblasts
(Ahmed  et  al., 1977)  or human  lymphocytes  (Rocchl  et al.,  1980),  did  not
Increase   mlcronucleus   formation   In   epithelial   cells   from   C3H   mice
(DeBrabander et al.,  1976) or CBA  mice  (Jenssen and  Ramel,  1980),  and failed
to  Induce  DNA  repair  In primary cultures of rat  hepatocytes  (Probst  et al.,
1981).
    a-HCH  was  not  mutagenlc with  or without   S-9  In  reversion assays  with
Saccharomyces  cerevlslae  (Shahln  and Von  Borstel,  1977)  or £.  coll  (MoMya
et al., 1983), but caused  Increased m1tot1c activity 1n A.  cepa roots (Nybom
and  Knutsson,  1947)  and  In  hepatic  parenchymal  cells of  rats  fed  0.06X In
the diet for 3 weeks (Hitachi et al., 1975).
    Shlmazu et al. (1976)  reported  that S-HCH  caused chromosomal aberrations
In bone marrow cells  taken  from LE  rats Injected 1.p. with 0.01-10 mH/kg bw
B-HCH.  Which dose  levels were  considered positive were not reported.
    T-HCH  did  not  promote  mutation 1n  an Ames test with  S.  typhlmurlum
(Anderson  and  Styles,  1978),  but  yielded positive results  1n  a  dominant
lethal test where Swiss mice were  fed  500  ppm for  4,  6 or  8  months (Lakkad
et  al.,  1982).  Furthermore,  Babu et  al.  (1981)  reported  that  prolonged
                                                                         •>

0820p                               5-13                             03/18/88
-------
dietary  exposure  (5-8  months)  but  not  after  3  months  to  500  ppm  T-HCH
Inhibited  melotlc  division  In  the testes  but not mltotlc  division  1n  the
bone  marrow of  Swiss  mice.   Bone  marrow metaphases  did  not  Indicate  an
Increase In chromosome aberrations.
    A  mixture  of  <»-,  B- and y-UCH  was  not  mutagenlc  In a rec assay  with
Bacillus  subtlUs  or  In  reversion  assays with  E_.  coll  or S.  typhlmurlum
(Shlrasu  et  al.,  1976).   y-HCH  has  been  shown to cause  mltotlc arrest  at
metaphase  In  All 1 urn cepa  (Nybom and  Knutsson,  1947)  and  P1sum  satlvum
(Baquar  and Khan,   1971;  Sharma  and  Gosh,   1969),  and  caused  chromosome
aberrations  1n  A.  cepa  roots  (Sax and  Sax,  1968).   Additional  Information
for the above studies 1s given 1n Table 5-6.
5.3.   TERATOGENICITY
    A  majority  of   the  studies  available   suggest  that   y-HCH   Is  not
teratogenlc.
    Khera  et al.  (1979) administered 0, 6.25,  12.5  or  25 mg  y-HCH/kg  bw by
gavage (vehicle  =  corn  oil)  to groups  of  20  female Wlstar rats  on  days 6-15
of  gestation.   On day  22 of  gestation,  there  were  no differences  between
control  and   y-HCH-treated   rats   1n   terms  of  numbers   of  pregnancies,
abortions, corpora lutea/pregnancy,  live fetuses/pregnancy,  dead or  resorbed
fetuses,   anomalous   fetuses/number   examined  or  Utters   with  anomalous
fetuses/number   of  Utters examined.   Furthermore, there  were  no  compound-
related effects on fetal body weight.
    Palmer et  al.  (1978a)  conducted  a  3-generat1on reproduction study  on CD
rats.  Groups  of  10  male and 20 female  weanling rats were  fed  0,  25,  50 or
100  ppm  y-HCH   1n  the diet  for  60 days before mating, and  were then  mated
to  produce  two  Utters.  A  similar  protocol  was used  for  the F. and F_
generations.   Mating performance,  pup  mortality,  number  of  viable offspring


0820p                               5-14                             03/18/88
-------


















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0820p
5-17
>0/21/86
-------
and examination  for  external  and  Internal  malformations (at 21 days of  age)
was conducted  for  all  generations.  Ten males  and  10 females 1n each group
of  the F_   generation  were  examined  for  skeletal   defects;  organ weights
were measured  on an additional  10 pups/sex/group, and  hlstologlcal  examina-
tion of major organs was conducted on  10 pups/sex  from  the  high-dose groups.
There  were  no  compound-related  effects  on  reproduction   and  no  compound-
related teratogenlc  effects  1n any  generation.   A dose-related  Increase  1n
liver  weight  was observed, and  enlarged  hepatocytes were  observed In  some
controls and  treated males  and  females of  the  F0.  generation.   Palmer  et
                                                  3b
al. (1978a) considered the latter  findings to be  of  doubtful  Importance  when
compared with the lack  of effects  on  growth and  reproductive performance.
    Palmer   et  al.   (1978b)   did   not  observe  compound-related  teratogenlc
effects 1n  CFY  rats gavaged  with 0,  5, 10  or  15 mg y-HCH/kg on  days  6-16
of gestation, or 1n  New Zealand White  rabbits gavaged similarly  on  days  6-18
of gestation.
    In  an  effort to screen  compounds  to recommend  for teratology  testing,
Chernoff and Kavlock (1983) and Gray and Kavlock  (1984)  monitored the  growth
and  viability  of  progeny  from  CD-I  mice  gavaged  with 25  mg  y-HCH/kg  on
days  8-12  of  gestation.   There  were  no  effects on  Incidence  of  pregnant
females (-25/group  tested),  maternal  mortality  or  body weight.  There  were
no  significant   compound-related   effects  on  the  growth   and  viability  of
progeny observed for up to 250 days.
    In  contrast  to  the  negative findings,  Dz1erzawsk1  (1977)  reported  a
2- to  20-fold  Increase  1n the  number  of  resorbed fetuses  In  hamsters given
(route  not specified)  40 mg  y-HCH/kg on  day  8 of  gestation, 1n rabbits
given  40 or  60 mg  y-HCH/kg  on  day  9  of gestation.  In  rats given  50  or 100
mg  y-HCH/kg  on  day 9  of gestation  and  In rats  given 40  mg  y-HCH/kg  on
days 6, 8 and 10 of gestation.

0820p                               5-18                             03/18/88
-------
    Pertinent  data  regarding  the  teratogenldty  of  other  Isomers  of  HCH
could not be located 1n the available literature as cited 1n the Appendix.
5.4.   OTHER REPRODUCTIVE EFFECTS
    Palmer et  al.  (1978a)  failed to observe adverse  effects  on reproduction
In  three  generations of  CD rats fed  up to 100  ppm  y-HCH 1n  the  diet  (see
Section 5.3.).   In contrast,  Shtenberg  and Mametkullev  (1976)  reported  that
rats  exposed  orally to  5 mg/kg/day  y-HCH  for  5  months had  reduced  mating
and pregnancy  Indices,  regardless of whether  females were mated  to  treated
or  control males.   Administration of 0.05 mg/kg  for  9  months  had  no  adverse
effects on  the  gonads.   Other  details, such  as  whether  5  mg/kg and  0.05
mg/kg  represent  dietary  concentrations  or actual  doses were  not  reported.
Other  studies  suggest  that  low  doses   of  i-HCH given  to  rats and  rabbits
for several  generations causes  adverse  effects  on reproduction and  on  the
developing  fetus  (Khamldov,  1984;  Petescu et al.,  1974);   however,  these
studies were available only as abstracts and details were limited.
    Saxena et  al.  (1980) and  Wassermann et al.  (1982)  studied the possible
association between  body levels  of  organochlorlne pesticides  and  premature
labor  In  humans.   Although premature   labor  was  correlated  with  Increased
levels  of Y-HCH  In the  blood,  other   organochlorlne  pesticides   were  also
present at elevated concentrations.
    Pertinent  data  regarding  other  reproductive effects  of  other  Isomers of
HCH  could not  be   located  1n  the  available  literature  as  cited   1n  the
Appendix.
5.4.1.   Testlcular  Effects.   Testlcular atrophy has  been observed  1n  rats
and  mice   fed  T-HCH  and   In  rats  gavaged  with  y-HCH.   In  general,  the
atrophy  was   characterized  by  degenerative   changes   1n  the  seminiferous
epithelium,   reduction   In   number  of  spermatocytes  and  the  appearance  of
multlnucleated giant cells.

0820p                               5-19                             03/18/88
-------
    Shlvanandappa  and  KMshnakumaM  (1981, 1983)  fed  0, 100,  750 and  1500



ppm T-HCH  (equivalent  to 0, 80,  625  and  1174  mg/rat/90  days)  to  groups  of  10



weanling  male  Wlstar   rats   for  90  days.   Significant  effects   Including



mortality  (two  deaths at  8  weeks),  reductions  In body  weight  and  food



consumption  (7-13  weeks),  decreases   In  testlcular   weight,   seminiferous



tubule diameter,  Leydlg  cell  diameter  and testlcular enzyme  activities, and



Increases  In  total llpld  and  total  cholesterol  content  of  the testes  were



observed only among rats fed 1500 ppm T-HCH.



    Nlgam et al.  (1979)  fed  0 or 500 ppm T-HCH to male Swiss mice  for  up  to



10 months.   Groups of  six mice  were killed each  month  and  the testes  were



weighed and examined hlstologlcally.  Mice exposed  to T-HCH  had  hlstologlcal



evidence of testlcular  atrophy and  Increased  testlcular weight at  >3  months



of treatment.   This study provided few details.



    Dlkshlth and Datta (1977) and DlkshHh et al.  (1978)  reported  testlcular



atrophy  1n adult  ITRC rats  gavaged with  17.6  mg y-HCH/kg  bw  (1n  peanut



oil)  for 90 days.



5.5.    CHRONIC AND SUBCHRONIC TOXICITY



5.5.1.   o-HCH.   The  available   chronic  and  subchronlc  oral   studies  on



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    FHzhugh  et  al.  (I960)  conducted  a  lifetime  feeding  study  on  Wlstar
rats,  In  which  groups of  10  rats/sex  were fed 0,  50,  100 or 800 ppm a-HCH
In the diet until  they died or  were  killed when moribund.   Growth  rate,  food
consumption,  mortality,  organ  weights,  and  gross  and microscopic pathology
were examined.  Microscopic analysis, however, was not performed on  all  rats
(only on 8-15 rats/treatment) and detailed  sections were not  always  prepared
for  those  that were  examined.   There  was no  evidence  of  compound-Induced
development of  tumors.   Compared  with  controls,  high-dose  rats had  signifi-
cantly  reduced  survival,  reduced  growth  rate,  Increased  liver  weight  and
hlstologlcal evidence of slight to moderate kidney damage  and moderate liver
damage.  Increased  liver  weights  were also observed  1n  rats  fed 50  and  100
ppm, but  no  significant  changes  In  liver  histology  were  observed  at these
concentrations.   No effects  were  observed among rats  fed   10  ppm a-HCH.   In
a similar study, Ito  et al.  (1975) observed neoplastlc changes 1n  the livers
of Hlstar rats only at dietary levels >1000 ppm a-HCH.
5.5.2.    B-HCH.   Chronic  and subchronlc  oral studies  on   B-HCH  are  summa-
rized  1n Table  5-8.  Three of  the five  studies  (Ito et al.,  1973a,b, 1975)
were designed  to  Investigate and characterize hepatic carcinogenic  response
1n male  Wlstar  rats  and  dd  mice.   Neoplastlc  changes  were  not observed 1n
these  studies,  but  Increases   In  absolute and  relative  liver  weight  were
observed at  doses  >250  ppm.   Nonneoplastlc  hlstologlcal  changes  were  not
observed.  These studies  were conducted only for 24-72 weeks.
    In  a  110-week dietary  study on  CF1  mice.   Thorpe  and Walker  (1973)
observed enlargement  of  the  liver,  but  this  effect was probably  related to
the  development  of tumors.   No other  significant compound-related  effects
were observed.
0820p                               5-22                             10/21/86
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    In  a  lifetime  study,  Fltzhugh  et  al.  (1950) observed  early mortality
(average  llfespan  = 4.4*1.3  weeks),  histologlcal evidence  of  liver damage
and  Increased  relative  liver  weight  1n  Wlstar  rats   fed  800  ppm 13-HCH.
Significantly  reduced  body   weight.  Increased  relative  liver  weight  and
hlstologlcal evidence of liver  damage were  observed  among rats fed  100 ppm;
Increased relative  liver weight was  the only  effect  observed at  10  ppm.  No
tumors  were  observed at any  level  of  treatment; however,  only  5-14 rats/
level of  treatment  were  examined  microscopically, and detailed examinations
were not always prepared  for  those that  were examined.
5.5.3.   Y-HCH.   Long-term oral  studies  on   the toxldty  of  y-MCH  have
been  conducted  on  rats  (DlkshHh and  Datta,  1977;  01ksh1th  et  al., 1978;
NCI, 1977;  Ito  et  al.,  1975;  Fltzhugh et al., 1950; Research and  Consulting
Co., Ltd.,  1983;  Oesch  et  al., 1982),  mice  (Oesch et  al., 1982; Thorpe and
Walker,  1973;  Ito  et al..  1973a.b),  dogs (Rlvett et  al.,  1978; Earl  et al.,
1970;  Lehman,  1965)  and  monkeys  (SantolucHo,  1975)   (Table  5-9).   The
studies  conducted  by NCI  (1977)  on  rats  and  mice, by Ito et  al.  (1975) on
rats  and  by  Ito  et  al.  (1973a,b)   on mice  were designed  to  Investigate
oncogenlclty, but nonneoplastlc  effects  were also Investigated.
    A number  of  long-term  oral  studies  report  that  y-HCH can  cause hepatic
hypertrophy,  Induce mlcrosomal  enzyme  activity and   cause   nonneoplastlc
hepatic  changes In  the absence  of neoplastlc changes (DlkshHh  et al.,  1978;
Fltzhugh  et  al.,  1950;  Research  and Consulting Co., Ltd.,  1983;  Oesch  et
al.,  1982;  Ito  et al.,  1973a;  Rlvett  et al., 1978).    If these  studies,
however,  had  used  larger  number  of  animals  and  were  conducted  for  longer-
periods  of time, It  Is possible that  a  carcinogenic  response would have been
observed, especially  since y-HCH has  been  shown to cause  liver  tumors  1n
CF1 and dd  mice (Thorpe  and Walker,   1973; Hanada  et al.,  1973;  Goto et  al.,


0820p                               5-24                             TO/21/86
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1972)  and since  the nonneoplastic  changes  have  been associated  with  the
development of  tumors  in rats and  mice  exposed to a-HCH  and  T-HCH (Ito et
al.,  1975,  1976;  Schulte-Hermann and  Parzefall,  1981; Munir  et al.,  1983;
Nigam  et  al.,  1982;  1984b).   Although  negative  results  were  found  for
oncogenicity in the  Fitzhugh  et  al.  (1950) and NCI (1977)  lifetime  studies,
Fitzhugh  et al.  (1950)  examined only  a  portion of the  treated  rats  in  the
study  (criteria   for  selection  not  reported), and   the  NCI   (1977)   study
yielded negative results  for both neoplastic  and nonneoplastlc  effects.
    Two  studies   have  reported  that  y-HCH  adversely affects  the  kidney.
Fitzhugh et al. (1950) reported  gross  and  histological evidence  of  slight to
moderate  kidney  damage   (focal  nephritis,  hyaline  granular  degeneration,
pitted kidneys)  In  rats  fed  800  ppm Y-HCH as  powder  mixed in  the  diet  for
life  but  not  in rats treated similarly  with 800 or  1600 ppm dietary  Y-HCH
dissolved  in   corn  oil.   The  Research   and  Consulting  Co.,   Ltd.,  (1983)
observed  tubular   degeneration,   hyaline  droplets,  tubular  casts,  tubular
distension, interstitial  nephritis  and basophlUc  tubules  in  Wlstar KFM-HAN
SPF  rats  fed   20  or 100  ppm Y-HCH  (1.55  or  7.25 mg/kg/day)  for  12  weeks,
but not 1n rats exposed  similarly to 0.2, 0.8 or 4  ppm Y-HCH.
    Olkshith and  Oatta  (1977) and 01ksh1th  et  al.  (1978)  demonstrated that
Y-HCH  (17.6 mg/kg/day   in  peanut  oil  for  90  days)  can  cause  testlcular
atrophy in ITRC rats.
    Fitzhugh et al. (1950)  observed  nervous symptoms and  convulsions in rats
fed  800  or  1600  ppm  Y-HCH  for   life.   Dlkshlth  et al.  (1978)  reported
significant decreases In  AchE activity in the  blood and  brains  of ITRC rats
given  17.6  mq  y-HCH/kg/day  1n  peanut  oil   for   90  days.    Shorter-term
studies  also  suggested   that  Y-HCH  causes  neurotoxic  effects.   Des1   (1974)
reported  that  the  number  of  lever  presses In an  operant  conditioning box


0820p                               5-28                             10/21/86
-------
were   significantly   Increased   1n  Wlstar  rats  exposed  orally  to  25  mg
Y-HCH/kg/day  for  40  days;  an   Increased  number of  errors  In  maze-running
and  Increased  maze-running times were observed  1n  rats  treated  similarly at
doses  >5  mg/kg/day.   Muller et al.  (1981)  reported  significantly reduced
conduction velocity 1n Hlstar rats fed 25 mg Y-HCH/kg/day for 30 days.
    Czegledl-Janko  and  Avar  (1970)  reported  that  male  workers  1n  a ferti-
lizer  plant  with  "mild  but definite"  symptoms of  neurotox1c1ty   (clinical
exam  and  EEG)  had >0.02  ppm y-HCH  In  their  blood;  however,  22  of  the 37
men  1n the study  had been exposed  to  aldrln  2 years  before  their  examina-
tion.   Examinations   of  these men  before Y-HCH  exposure  revealed  a  strong
association between exposure  to  aldrln and neurotoxlc effects.
    Hematologlcal  effects resulting  from exposure  to y-HCH have also  been
reported.  Earl  et al.   (1970)  reported that  adverse  hematologlcal effects
(decreased  numbers of   retlculocytes and  platelets,  crenated  RBCs and  a
myelo1d:erythro1d  ratio  >750:1)  occurred  In  dogs  fed  225  mg  Y-HCH/kg/day
In the diet  for  24 weeks.   These effects were  not  reported for  dogs fed 7.5
or 15.0 mg/kg/day.  A case-report  (Morgan  et  al.,  1980)  also  suggests  that
anemia  may result from  prolonged  exposure to  Y-HCH; severe  but  reversible
hypoplastlc anemia was  observed In  a   2.5-year-old  boy  who was  exposed to
Y-HCH  since  birth  through use  of  a  vaporizer  1n  his  home.   Other  family
members were not affected.
    Short-term  studies   suggest  that  Y-HCH may cause  Immunosupresslon.   A
dose-related  decrease  In   Immunological  tlters  was  observed  1n  rabbits
gavaged  with  1.5-12   mg  Y-HCH/kg/day,   5  days/week  for   5-6  weeks,  then
challenged with  S. typhlrourlum  (Desl et al.,  1978).  Similar  results  were
reported  In  rats exposed  orally to either 6.25 or 24 mg  Y-HCH/kg  In olive
oil on alternate days  for 35 days (Dewan et al.. 1980).
0820p                               5-29                             10/21/86
-------
5.5.4.   6-HCH.   Long-term  oral   studies   on  6-HCH  are   summarized   In
Table 5-10.   Significant  compound-related  changes  were not observed In male
Wlstar  rats  fed  500  or  1000  ppm 6-HCH  for  up  to  48 months  (Ito et al.,
1975).   Ito  et al.  (1973a)  observed significant  elevation  In  relative and
absolute  liver  weights  among male dd mice  fed 500 ppm  6-HCH  for  24  weeks;
however,  no  hlstologlcal  or ultrastructural  changes  were observed  1n the
livers of these mice.  No  effects on  the  liver  were observed  In mice fed 100
or 250 ppm 6-HCH for 24 weeks.
5.5.5.   e-HCH.   Pertinent  data  regarding  the chronic  toxlclty  of  e-HCH
could not be located In the available literature as dted  In the Appendix.
5.5.6.   T-HCH.  Long-term oral  studies  on the  toxlclty  of  T-HCH  have been
conducted on rats (Fltzhugh  et al.,  1950;  Barros and  Sallba,  1978;  Barros  et
al.,  1982;  Shlvanandappa  and  KrlshnakumaM,  1981,   1983;  Shlvanandappa  et
al.,  1982)  and mice  (Nlgam  et  al..  1979,  1982,  1984a,b;  Munlr  and  BMde,
1984; Kashyap et al., 1979).   These  studies  are summarized In  Table  5-11.
    A number of these studies have shown  that  T-HCH has  adverse effects  upon
the  liver  (Fltzhugh et  al.,  1950;  Barros and  Sallba,  1978;  Barros et  al.,
1982; Shlvanandappa  and  Krlshnakumarl,  1981;   Nlgam  et  al.,  1982,  1984a,b;
Munlr  and  Bhlde,   1984).    These  effects  Include  Increased  relative and
absolute weight of  the liver and hlstologlcal  (cellular  alterations,  degen-
erative  and  prollferatlve changes,  glycogen accumulation),  ultrastructural
and  hlstochemlcal  changes.   Barros  and Sallba  (1978)  reported  T-HCH-lnduced
changes  In the  livers  of Wlstar rats exposed to as little as 0.9 ppm  for  90
days.   In general,  these changes  Increased  1n   Incidence and   severity  1n
proportion to  dose  and  duration of   treatment.  Nlgam  et  al.  (1982, 1984a,b)
and  Munlr  and  Bhlde  (1984)  demonstrated  that the  progression  of  hepatic
0820p                               5-30                             1.0/2T/86
-------
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changes  caused  by T-HCH  leads  ultimately to  the  development of  tumors and
are  reversible  only  If  exposure ceases at the  very  earliest  stages  sometime
before tumor formation.
     High  doses  of T-HCH  have been  shown  to cause  kidney  damage 1n  Wlstar
rats.  FHzhugh et al.  (1950) reported focal nephritis  (tubular  atrophy and
hyaline  cast  formation),  brown  pigmentation  and basal  vacuollzatlon  In the
kidneys  of  rats fed  800  ppm  T-HCH  for life.  Barros and Sallba  (1978)  also
reported  hyaline  degeneration  1n the kidneys of rats  exposed  to  900  ppm for
90  days.   Barros  et  al.  (1982) reported a  40% reduction In  renal  alkaline
phosphatase  activity  after 90  days of  exposure.   Shivanandappa  and  KMsh-
nakumarl  (1981) observed  Increased  relative kidney weight but  no hlstologl-
cal  changes In male CFT-Wlstar rats  fed 750 or 1500 ppm T-HCH for 90  days.
     Dietary  T-HCH has  been  shown  to  cause  testlcular  atrophy  1n rats and
mice.   These  effects  were   observed   In  rats  fed  1500 ppm for  90  days
(Shlvanandappa and KrlshnakumaM, 1981,  1983) or 800 ppm for  life (FHzhugh
et  al.,  1950),  and In  mice  fed 500 ppm  for  up to 10 months  (N1gam  et  al.,
1979).   Testlcular  effects were  not  seen 1n  rats fed  10,  100  or 750  ppm;
lower concentrations  were not  tested 1n mice.
     In  two  separate  studies,   Shlvanandappa  and  KrlshnakamuM   (1981) and
Shlvanandappa et  al.  (1982) observed  Increased  adrenal  weight and hlstologl-
cal  and  hlstochemlcal  evidence  of   steroldogenlc  Inhibition  In  the  adrenal
cortex of male CFT-W1star  rats  fed  >750 ppm  T-HCH  for  90  days.   Adrenal
changes were not observed In rats fed <250 ppm.
    Two oral studies  suggest  that T-HCH may  cause  neurotoxlc effects.  In a
90-day study, Shlvanandappa and  KMshnakumarl  (1981)  reported 100% mortality
1n male  CFT-Wlstar  rats  fed  3000 ppm  which  was accompanied  by  signs  of CNS
stimulation; signs of CNS stimulation were  not  reported 1n  rats  fed <1500


0820p                               5-35                             10/21/86
-------
ppm.  Hlstologlcal or ultrastructural changes in the nervous system were not
examined.   Kashyap  et al.  (1979)  observed  convulsions  and a  "tendency  to
circle  in  one  direction  with  drooping ears" among Swiss mice fed 100 ppm  1n
the diet or gavaged with 10 mg/kg/day  for  100 weeks.   These  signs of  Intoxi-
cation were said  to be "not prominent."  Kashyap et al.  (1979)  also reported
unl- and bilateral corneal  opacity  In the T-HCH-exposed mice.
5.6.   OTHER RELEVANT INFORMATION
    Oral LD5Qs for Isomers  of  HCH are summarized  In  Table 5-12.
5.7.   SUMMARY
5.7.1.   a-HCH.   Dietary a-HCH  has   been   shown  to  cause  Increased  Inci-
dences of  liver  tumors   In five  strains  of  mice  (Ito  et al., 1973a,b, 1976;
Nagasaki et al.,  1972a,  1975; Hanada  et  al., 1973;  Goto  et al., 1972) and  1n
Wlstar  rats  (Ito et  al.,  1975;  Schulte-Hermann and  Parzefall, 1981).  The
teratogenlc and  reproductive  effects  of a-HCH  have  not  been  Investigated.
Nonneoplastlc   hepatic changes  have  been  observed  in  rats  and  mice   fed
a-HCH  (Schulte-Hermann   and  Parzefall,  1981;   Ito  et   al.,  1973a,b, 1975,
1976; Fltzhugh et al., 1950).
5.7.2.   B-HCH.   Dietary B-HCH  has  been  shown   to  cause  definite  Increased
Incidences of   liver tumors In CF1  mice  (benign and  malignant)  and  possibly a
marginal Increase In  ICR-JCL mice  (hepatomas) (Thorpe  and  Walker,  1973;  Goto
et  al.,  1972) but  clearly  not   In dd mice  (Ito et al.,  1973a,b; Hanada  et
al.,  1973;  Nagasaki   et  al.,  1972a)   nor  In Hlstar rats (Ito   et al.,  1975;
Fltzhugh et al.,  1950).   The reproductive  and  teratogenlc effects of  B-HCH
have  not  been  Investigated.   Nonneoplastlc   and  neoplastlc  hlstologlcal
changes  In the  liver were not  observed  In  studies   that were designed  to
Investigate  hepatic  carcinogenic  response (Ito   et  al.,  1973a,b,  1975);
Increases  In  absolute and  relative   liver  weight  were  observed at  dietary


0820p                               5-36                             TO/27/86
-------
Oral
                                  TABLE 5-12

                               Values for Isomers of HCH*
                    Isomer
                       Species
  "SO
(mg/kg)
          a-HCH


          B-HCH


          Y-HCH




          4-HCH

          Mixture of Isomers
          (proportions not reported)
                      mouse
                      rat

                      mouse
                      rat

                      mouse
                      rat
                      rabbit
                      guinea pig

                      rat

                      rat
                      mouse
  1000
500-1700

  1500
  2000

   86
124-230
 60-200
100-127

750-1000

600-1250
  700
'Source: WHO, 1969
0820p
               5-37
         10/21/86
-------
concentrations >250 ppm.  FHzhugh et at. (1950) observed Increases In liver
weight  accompanied" by  hlstologlcal   changes  In  rats  fed  >100  ppm  S-HCH;
Increased  relative Hver weight  was  the  only  effect  observed  at  10  ppm.
Early mortality  was  also observed among rats  fed 800 ppm.   No  tumors  were
observed  1n  this  study; however,  not all  of  the  rats  started  on the  test
were  examined  h1stolog1cally  (no  criterion for  selection  was  given).   No
other chronic effects  were  reported.
5.7.3.   Y-HCH   (Llndane).     Dietary   y-HCH   was   shown    to    cause   an
Increased  Incidence of  liver  tumors  In  male CF1 mice fed 400  ppm for  110
weeks (Thorpe and  Walker, 1973), a marginal response In male  dd  mice  fed  600
ppm  for  32 weeks  and then  examined  5-6  weeks  posttreatment  (Hanada et al.,
1973), and a marginal  response  1n male ICR-JCL mice  fed  600 ppm for 26 weeks
(Goto et al., 1972).  No liver  tumors were observed  1n dd mice  fed up to  500
ppm  for  24 weeks  (Ho  et al., 1973a,b; Nagasaki et  al.,  1972a)  or  In Wlstar
rats  fed  500  ppm  for   up  to  48  weeks  (Ito   et  al.,  1975).    Significant
compound-related development of tumors of  any  type  was not observed  In NMRI
mice  treated with Y-HCH for  80  weeks  (Herbst  et  al..   1975;  Welsse  and
Herbst,   1977),  B6C3F1  mice  also treated for  50 weeks  (NCI,  1977), Osborne-
Mendel rats  (NCI,  1977) or  Wlstar rats  {FHzhugh  et al.,  1950).   The  study
conducted  by NCI  (1977) has  been  criticized  for  poor survival  of  rats,
changes   1n dosing  regimen and  the possibility that male  rats  did not  receive
MTDs (IARC,  1979).  The  negative findings of FHzhugh  et al.  (1950) are also
Inconclusive  since only small  numbers of animals  were  examined hlstologl-
cally.   The  negative  findings of  Ito  et al.  (1973a,b),  Nagasaki  et  al.
(1972a)   and  Ito   et  al. (1975)  might  be attributed  to   small  numbers  of
animals   and  short  duration.   A metabolite  of  Undane,  2,4,6-trlchlorophenol,
has  been  Identified 1n  exposed rodents and humans and 1s considered  to  have
a we1ght-of-ev1dence for human cardnogenlclty  of Group 62.

0820p                               5-38                              03/18/88
-------
    Orally-administered f-HCH  was not  found  to  be teratogenic or  fetotoxlc
 1n  Wlstar  rats  (Khera  et  a"!.,  1979),  CD rats  (Palmer  et  al., 1978a),  CFY
 rats  (Palmer  et al.,  1978b),  New  Zealand  White  rabbits   (Palmer  et  al.,
 1978b)  or  CD-I  mice  (Chernoff and Kavlock,  1983;  Gray and  Kavlock,  1984).
 In  contrast, a  study  by  Dz1erzawsk1  (1977)   reported  Increased  numbers  of
 resorbed fetuses In hamsters  (40  mg/kg  on day 9 of gestation), rabbits  (40
 or  60 mg/kg  on day 9 of gestation) and rats  (40, 50 or  100  mg/kg  on  various
 days  of gestation).  Maternal  toxldty  was  not  reported.   These  doses  are
 higher  than  any  of those  tested  1n  the  negative  studies  of y-HCH,  though
 Chernoff and Kavlock (1983)  reported  that  25  mg/kg/day  was  the maximum dose
 that was not toxic  to maternal CD-I mice.
    Palmer et  al.  (1978a)  failed to observe  adverse effects  on  reproduction
 In  three  generations  of  CD  rats  fed  up to  100 ppm y-HCH  In  the  diet.
 Dlkshlth and  Datta  (1977)  and  Dlkshlth  et  al.  (1978),  however,  observed
 testlcular atrophy 1n  ITRC   rats  gavaged with  17.6  mg  y-HCH/kg  1n  peanut
 oil  for 90  days,  suggesting  that  f-HCH might  have  adverse effects  upon
 reproduction.
    Long-term  oral  studies have associated exposure to  HCH  with nonneoplas-
 t1c liver  changes  (Dlkshlth  et  al.,  1978; FHzhugh et  al.,  1950);  Research
 and Consulting  Co.,  Ltd.,  1983;  Oesch  et   al.,  1982; Ito  et al.,  1973a,
 Rlvett  et  al..  1978),  kidney changes  (FHzhugh  et al., 1950; Research  and
 Consulting  Co.,   Ltd.,  1983),  hematologlcal  effects   (Earl  et  al.,  1970;
Morgan  et  al.,  1980)  and  neurotoxldty   (FHzhugh et  al.,  1950;  Czegledl-
 Janko and  Avar,  1980).   Short-term  studies  suggest   that  y-HCH  may  cause
 Immunosupresslon (Dewan et  al., 1980;  Des1 et al., 1978).
0820p                               5-39                             VO/21/86
-------
5.7.4.   6-HCH.   Dietary  s-HCH  did  not  cause  neoplastlc  or  nonneoplas-
t1c changes  1n the livers of  male  dd mice (Ito et  al.,  1973a; Nagasaki et
al.,  1972a)  or male  Wlstar  rats  (Ito  et  al.,  1975).  These  studies  used
small numbers  of animals and were only conducted for  24 weeks.  A mixture of
6- and  e-HCH   caused  benign  and  malignant hepatomas  1n  male  ICR-JCL  mice
when  fed  In the diet  at  600  ppm  for  26 weeks  (Goto  et  al.,  1972).  Other
pertinent data regarding the teratogenlc,  reproductive or chronic effects of
4-HCH  could  not  be located  In   the  available  literature  as   cited  1n  the
Appendix.
5.7.5.   e-HCH.    A   mixture   of   5- and   e-HCH   caused   benign   and
malignant hepatomas In male ICR-JCL mice when  fed  In  the diet at 600 ppm for
26  weeks  (Goto et  al.,  1972).   Other  pertinent  data  regarding  the  health
effects  associated with  exposure  to c-HCH  could  not  be  located  1n  the
available literature as cited In  the Appendix.
5.7.6.   T-HCH.  T-HCH has  been  shown  to  cause   Increased   Incidences of
liver neoplasms 1n  four  strains  of mice  (Hanada et  al.,  1973; Goto et  al.,
1972; Kashyap  et  al.,  1979;  N1gam  et al.,  1984a;  Bhatt  et al., 1981; Munlr
et al., 1983;  Nagasaki et al., 1971,  1972b; Nagasaki,  1973; Munlr  and  Bhlde,
1984) but not  1n Wlstar  rats (Munlr et al., 1983) or  Syrian golden  hamsters
(Munlr et al.,  1983).
    The teratogenlc effects  of T-HCH have  not been Investigated.   N1gam  et
al. (1979) and Shlvanandappa  and KMshnakumarl (1981. 1983) have  shown  that
orally-administered T-HCH causes testlcular atrophy  1n  rats  and mice (>800
ppm, rats; 500 ppm, mice).
    Long-term  oral  administration  of T-HCH has  been  shown to  cause  adverse
effects on the liver  (Fltzhugh et  al., 1950;  Barros  and  Sallba, 1978;  Barros
et  al..  1982;   Shlvanandappa  and  Krlshnakumarl,  1981; N1gam  et  al.,  1982,


0820p                               5-40                             10/21/86
-------
1984a.b;  Hunir  and Bhide, 1984),  kidney  (FHzhugh  et al., 1950,  Barros and
Sallba,  1978;  Barros et  al.,  1982;  ShWanandappa and KrlshnakumaM,  1981),
adrenal  cortex  (Shlvanandappa  and  Krlshnakumarl,  1981; ShWanandappa  et  al.,
1982) and CMS  (Shivanandappa and Krlshnakumarl,  1981;  Kashyap  et  al.,  1979).
Kashyap  et  al.  (1979)  also  reported  that  long-term oral exposure  to  T-HCH
was associated with Increased corneal opacity.
    It has  been  proposed  that  In  sensitive  species/strains  the nonneoplastlc
changes  In  the liver associated with  exposure to certain Isomers of  HCH  or
to T-HCH  are associated with neoplastlc development.   In  some  studies,  clear
progression of  hepatic  changes  that ultimately  lead  to  the  development  of
malignant   tumors  has  been  observed  at  gross,  hlstologlcal  and  ultra-
structural  levels  of examination.   These  changes  are proportional   to  dose
and  duration  of  treatment and  appear to  be  reversible only  at  the  very
earliest  stages  sometime  before the development  of  nodular  hyperplasla  (Ito
et al.,  1975,  1976;  Schulte-Hermann  and Parzefall,  1981;  Munlr et al., 1983;
Munlr and Bhlde,  1984; N1gam  et al., 1982,  1984a;  Suglhara  et  al.,  1975).
Although  nodular hyperplasla may  appear  to regress  shortly after  HCH treat-
ment 1s  discontinued, If  the observation  period  Is  extended,  the development
of  hepatocellular  carcinoma becomes apparent {Suglhara  et  al.,  1975)  (see
Tables 1n  Sections 5.1. and 9.2.).   Suglhara et al.  (1975)  postulated  that
surviving  cells  from  areas  of  nodular   hyperplasla ultimately  progress  to
hepatocellular  carcinoma.  As such,  tissues  affected  by  HCH  would  have
"memory"  to later  respond In  a recurrent manner  to  further  HCH treatment  or
to  another  tumor  progressor  producing an  additive  cardnogenlclty  testing
with cancer-positive HCH Isomers.
0820p                               5-41                             10/21/86
-------
                             6.   AQUATIC TOXICITY

    T-HCH  Is  a mixture  of  the  five HCH  Isomers  1n  the  following  ranges:
a-,  55-70%;   B-,  6-8%;  Y-.  10-18%; 4-,  3-4%;  and  trace  amounts  of  the
c-lsomer.   The   y-lsomer   has   Insectlddal  properties  and   preparations
containing  at  least  99%  y-HCH  are   called  Undane.   The   y-^omer   Is
considered to  be  the most  Important since H 1s  the  most  toxic to  aquatic
organisms (U.S. EPA, 1980b).
6.1.   ACUTE
    Since there Is a large  volume of Information dealing with acute toxlclty
of HCH to  freshwater animals, only acute toxlclty  data pertinent to fish  and
Invertebrate  species  found  1n  North  American  waters  will  be presented.
Exceptions may be made 1f  data  for other species provide general Information
regarding HCH toxlclty (relative toxlclty of  the  various Isomers).
    Information  concerning  toxlclty  of  Undane   to   freshwater   fish  and
amphibians Is  shown  1n  Table 6-1.    The  most  sensitive species was  the  brown
trout,  Salmo  trutta.  which  had  a   96-hour  LCrn  of  1.7  ^g/8,   (Johnson  and
        	  	                           iu
Flnley, 1980), the lowest  reported acutely toxic concentration.  The  data  In
Table  6-1  Indicate that  salmonlds  generally are  more sensitive to  Undane
than other species.
    Data  concerning  the  acute  toxlclty  of  HCH  Isomers other   than  Undane
(y-HCH)  to  freshwater  fishes   and   amphibians   are  shown   In   Table  6-2.
Sufficient  Information  Is  not available   to  draw  conclusions  about  the
relative  toxlclty of other  HCH Isomers,  but  they  appear  to  be less  toxic
than  Undane.  The  mixture of Isomers referred to as  HCH  1s much less  toxic
than  Undane.   This  Is   not  only due  to a  lower  y-HCH  content   than pure
Undane;  1t Is  possible  that the other  Isomers either reduce the solubility
of y-HCH or somehow antagonize Us  toxlclty (U.S.  EPA,  1980b).

0821p                               6-1                               06/27/86
-------


















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    Data concerning the acute  toxldty  of  HCH to marine fishes are  shown  In
Table   6-3.    The" lowest  reported   lethal   concentration  was  7.3
Undane, the  96-hour  LC5Q for  the  striped  bass,  Horone saxatnis  (Korn  and
Earnest, 1974).  The only data  for  HCH  compounds  other  than  Undane Indicat-
ed that HCH  was  less  toxic  than Undane  to  the plnflsh, Lagodon  rhomboldes.
with  96-hour  LC£    values   of  86.4  yg/j.  for  HCH  and   30.6   vg/l   for
Undane (Schlmmel et al., 1977).
    Acute toxldty of HCH to  fishes  1s  not  greatly  Influenced by  temperature
or  water   hardness.   In  experiments  where  temperature  effects  have  been
demonstrated,  the  results   are  conflicting.    Undane  LC™  values   for
rainbow trout  decreased  2.3  times  over the  temperature range  of  2-18°C,  but
blueglll LC5Q  values  Increased 2.6  times  over  the range of  7-29°C (Johnson
and Flnley,  1980).  Macek et  al. (1969) also reported  that  Undane toxldty
to bluegllls  Increased  slightly with  Increasing  temperature, with 96-hour
LC    values   of  54  yg/8.   at   12.7°C  and  37  vg/i  at   23.8°C.    Acute
toxlclty to  eels,  Anglulla anglulla.  decreased  slightly  at  higher  tempera-
tures   (48-hour  LC5Q  =  600   yg/i   at  11.5°C  and  1000  vg/l  at  22.5°C),
which was  attributed  to  Increased  mucus  production  at  the  higher  tempera-
ture,   thereby   Inhibiting   pesticide  uptake  (Foulquler  et  al.,   1971).
Variations 1n  water hardness  have  been found to  have little  or no effect on
toxlclty of  Undane or  HCH  to fishes  (Henderson  et  al . ,  1959; Johnson  and
Flnley, 1980).
    It  1s  likely that Insecticide-resistant  populations of  aquatic organisms
can develop  1n areas where organochlorlde pesticides  have been used for  long
periods.   Culley and Ferguson  (1969)  studied  this  phenomenon In  mosquito-
fish, Gambusla aff 1n1s.  populations  1n Mississippi.   They conducted  acute
bloassays using  fish from an  area with  no  history of  Insecticide  application
0821p                               6-7                              06/27/86
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-------
and compared  the results with  those obtained  using  fish from a  population
with  a  history  of  exposure to  different  Insecticides.   For  Undane,  they
found that  the  fish  from the contaminated  area were  42  times  more resistant
to  Undane.   The  48-hour   LC    values  were  3104  and  74  yg/8,,  respec-
tively.    Development  of  such  resistant populations  may  be  the  result  of
selection for resistant  Individuals  over several generations of  exposure,  or
may also  be  due to  Induction  of detoxification  mechanisms  In  previously-
exposed fish.
    Table 6-4  contains   Information  about  the acute  toxlclty  of  Undane  to
freshwater  Invertebrates.   Cladocerans  generally  seem to be the most  resis-
tant  freshwater  species, while  other crustaceans  and Insects  are  among  the
most  sensitive  (U.S.  EPA, 1980b).  The  lowest  reported  acutely toxic  concen-
tration  was  1   yg/l,  the   96-hour  LC    for  stonefHes,  Pteronarcys  sp.
(Cope, 1965;  Snow,  1958).  Although Undane  1s  used as  an  Insecticide,  the
most  sensitive   Invertebrate species  are only  slightly more  sensitive  than
the most sensitive fishes (U.S.  EPA,  1976).
    Among   saltwater  Invertebrates,  crustaceans   were  more   sensitive  to
Undane  than mollusks   or  annelids  (see  Table  6-4).    The  most  sensitive
saltwater Invertebrate was  the pink  shrimp, Penaeus  duorarum.  with a  96-hour
LC    of 0.17 vg/l Undane (Schlmmel  et  al.,  1977).
    Data  concerning  effects of  HCH  compounds other  than Undane  on  fresh-
water and  saltwater   Invertebrates are  found  In Table  6-5.  Llndane  appears
to  be more  toxic  than  other HCH compounds.   The  species most  sensitive  to
HCH compounds  was still  the stonefly,  Pteronarcys sp.,  with  a  96-hour LC5Q
of  <18  vg/i  HCH  (Johnson  and  Flnley,  1980)  and the  pink  shrimp,   with  a
96-hour LC5Q of 0.34 yg/i HCH (Schlmmel et al., 1977).
0821p                               6-10                             06/27/86
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6-14
                                                                    06/12/86
-------
6.2.   CHRONIC
    The available  Information  concerning long-term effects of HCH  compounds
on  freshwater  organisms  Is  shown  In   Table  6-6.   No  data  for  saltwater
species were  available.   The  lowest concentration reported to cause  chronic
toxldty was  3.3  jig/9.  Undane,  which  was  a  chronic value  for  the  midge,
Chlronomus  tentans  (Macek et  a!.,  1976).  Acute toxldty, however, has  been
reported at  lower  concentrations  1n  more sensitive  species,  such as  brown
trout  and  stonefHes.   Data  for  these  most  sensitive  species  are  needed
before  the chronic toxldty of  Undane  can  be fully evaluated.   The  avail-
able data  for other HCH  compounds  are  Insufficient  to draw  any  conclusions
about their chronic toxldty relative to Undane.
6.3.   PLANTS
    Table 6-7 contains the available  Information regarding effects  of  HCH  on
aquatic plants.   Aquatic plants  are less  sensitive to  HCH  compounds  than
fish and Invertebrates (U.S.  EPA,  1980b).  The  lowest concentration reported
to  cause  toxic  effects   was  80  yg/l  HCH,  which  Inhibited  growth and DNA
synthesis In  the blue-green algae, Anabaena aphanlzomenoldes and  Anabaenop-
sls  radborskll  (Das  and Singh,  1977).   Most  reported toxic  concentrations
for freshwater and marine plant species  were  >1000 (see Table  6-7).
6.4.   RESIDUES
    There are several studies  available concerning  the  kinetics  of  uptake
and elimination  of  HCH  compounds by aquatic  organisms (Table 6-8).   Because
several of these studies were of  short  duration,  the BCFs that were  deter-
mined  do  not represent  steady-state  values;  however, the steady-state  BCFs
that have  been  determined Indicate that  HCH  compounds do not  bloaccumulate
to  the  same   extent as  organochlorlne compounds such  as  PCBs and  DDT  (U.S.
EPA, 1980b).   BCFs for  HCH  compounds are generally <1000 (see Table  6-8),


0821p                               6-15                             06/27/86
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06/12/86
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probably  becasue   a-  and   y-HCH  are  less   UpophHlc   than  most  other
organochlorlnes  (Rlckard  and  Dulley,   1983).   Like  other  organochlorlnes,
however, the primary  site  of HCH accumulation  Is  also  fat  (Suglura et al.,
1979).
    Some studies have addressed the relative Importance of uptake  from water
vs.  uptake  from  food  1n  determining   levels  of   HCH  accumulation.  Hansen
(1980)  found  that  Undane uptake  from water by  Daphnla  magna and  stickle-
backs,  Gasterosteus  aculeatus.  was  very  rapid,  while uptake  from food was
relatively slow and  dependent  on  the  duration  of  exposure and  feeding rate.
In a  study  In  which fish,  Goblo goblo. were exposed to Undane In  water and
fed  contaminated  or uncontamlnated  diets for  433 hours, uptake   from food
appeared to  be less Important  than  uptake  from  water  (Harcelle and Thome,
1984).  Since  the  difference  1n  Undane  content  between "contaminated" and
"uncontamlnated" food, however, was only  2-fold (100 ppm vs.  50 ppb), these
results are  of questionable validity.   In a similar  study  (Canton et al.,
1975),  Daphnla  magna and  rainbow  trout,  Salmo qalrdnerl.  exposed to a-HCH
In food and water, accumulated slightly higher  residues than animals exposed
to  a-HCH  1n  water  alone.   Rainbow  trout  receiving  a-HCH  only  1n  food
were  found  to have  concentration  ratios  (I.e., ppm  1n  fat/ppm In diet)  of
0.1-0.7.  Great  Lakes  coho  salmon, Oncorhynchus  klsutch, fed  natural diets
containing  organochlorlne  compounds  were  found to  accumulate a-HCH,  B-HCH
and   Undane   1n   proportion  to  dietary  concentrations  (Leatherland  and
Sonstegard,  1982).   Concentration  ratios  1n this  study   ranged from 0.4-0.8
In Lake Ontario fish,  the  only  fish  found to have detectable HCH  residues  In
the diet and their tissues.
    HCH  compounds  are generally eliminated  more  rapidly than  other organo-
chlorlne compounds  such  as DOT and dleldrln (Tooby  and  Durbln, 1975), which


0821p                               6-22                             06/27/86
-------
could also contribute to the  relatively  low  steady-state  BCF  values.   Elimi-
nation half-times  for HCH  compounds 1n various species range  from 10
years.  Llndane  Hself  was detected  only occasionally  1n  fishes, but a-HCH
was  found  rather  frequently.   Concentrations  of  a-HCH   1n   Intestinal  fat
samples  were  740  ppb  1n  goldeye,  Hlodon alosoldes,  from the  Saskatchewan
River,  but  were  -100   ppb  or less  In  other  species and  In other  areas.
0821p                               6-23                             10/27/86
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0821 p
6-26
                                                                     06/12/86
-------
Occurrence  of   the  other  organochlorlne  compounds  was  widespread  1n  all
species at  low concentrations,  despite the  fact  that  they  were no  longer
used.  This observation Is consistent with  the  high BCFs  and  long half-lives
of  these  compounds   1n  fish  tissues.   Relative  to these other  organochlo-
rlnes, HCH does not  accumulate appreciably  In fish (Chovelan  et al.,  1984).
    These and other monitoring data  1n  Table  6-9  Indicate that HCH compounds
do  not  undergo  ecological  magnification to  a great extent.    HCH  concentra-
tions  1n  carnivorous fish  species  are comparable  to  those   1n  herbivorous
fish  species  (Sackmauerova  et al.,  1977).   In addition,  laboratory  studies
with  experimental food  chains  also Indicate that HCH 1s  not  blomagnlfled to
a  great  extent  (Strelt,   1979),  especially  compared  with  other  organo-
chlorlnes.
    Schmltt et al. (1985) reported the  results  of a monitoring study  of fish
tissue  residues  from 107  freshwater stations  In  the  United States  (Table
6-10), and concluded that HCH  was  relatively  short-lived  compared  with  other
organochlorlnes.   A  decline  1n  tissue  concentration  and   occurrence  of
detectable HCH  residues In  fish  tissues were  observed from  1976-1981.   In
the  1980-1981  sampling  period,  whole-body  Undane  residues  were >10  ng/g
only at one station  In  Hawaii, where levels  were  20-30  ng/g.   Tissue  concen-
trations  of  a-HCH  were  generally  higher  than   Undane,  and  the  highest
concentrations  (30-40 ng/g)  were found  1n  fish from stations  1n  the  south-
west and midwest.
    In a monitoring study of marine  species,  Tanabe et  al.  (1984)  found that
the   primary   form   of   HCH   1n   seawater,   zooplankton,  squid,   Todarodes
padflcus, and  myctophlds,   Dlaphys  suborbUalls.  was  a-HCH.   In a marine
mammal, the  striped  dolphin,  Stenello  coeruleoalba. >50% of the total  HCH
concentration was B-HCH  (Tanabe et al.,  1983, 1984).

0821p                               6-27                             06/27/86
-------



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                                    6-28
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-------
    Tanabe et al.  (1983, 1984) presented  Information  concerning  HCH  residues
In marine mammals  of  the Pacific Ocean.  Blubber of  these  species  contained
the highest reported  HCH residues.   The highest  concentration,  13,000-15,000
ng/g,  was found  In blubber of  the  Pacific  white-sided dolphin,  Lagenorhyn-
chus  obUquldence. which  Inhabits   northern  temperate waters  that  contain
high levels of organochlorlnes relative to other  areas.   Species  from Arctic
and Antarctic  waters contained  lower  HCH  residues.   Tanabe  et al.  (1983)
concluded  that  because of   their   long  Hfespans  and  their  position  as
top-level carnivores, marine mammals  are  likely  to  accumulate  high  levels  of
organochlorlnes Including HCH.
6.5.   SUMMARY
    There 1s  a  large volume  of  Information  available concerning effects  of
HCH  on   aquatic  organisms.   Llndane  (f-HCH)   1s  generally  more  toxic  to
freshwater and  saltwater fish and  Invertebrates than  other  HCH Isomers  or
mixtures  (U.S.  EPA,  1980b).   The lowest reported  acutely toxic concentra-
tions for  freshwater  species were  1.7  yg/i  Undane, which  was a  96-hour
LC5Q  for  brown  trout   (Johnson and  Flnley,  1980)  and  1   yg/8,   Undane,
which was  a  96-hour  LC5Q for  stonefHes   (Cope,  1965,   Snow,  1958).  The
lowest  reported  acutely  toxic   Undane  concentrations for marine  fish and
Invertebrates,  respectively,  were   7.3  yg/l,   a 96-hour   IC__  for  striped
bass  (Korn  and  Earnest,  1974),  and  0.17  vg/l,  a  96-hour  LC  Q  for  pink
shrimp  (Schlmmel  et  al.,  1977).   Among  the  freshwater  fishes,  salmonlds
appeared  to  be more  sensitive  than other  species.   Crustaceans other  than
cladocerans  were  generally the most  sensitive  Invertebrate species both  In
freshwater and saltwater  (U.S. EPA, 1980b).   Fish  and  Invertebrates  appeared
to be about  equally sensitive to HCH.
0821p                               6-29                             06/27/86
-------
    In chronic toxldty studies,  no adverse effects were reported at concen-
trations lower than the acutely toxic levels for the most sensitive species;
however, chronic  toxldty  data  for the most acutely  sensitive species were
generally unavailable.
    The available  Information  Indicated that aquatic  plants  were much less
sensitive to HCH than  fish  or  Invertebrates.
    HCH accumulates In aquatic biota primarily 1n fatty tissue; however, HCH
Is less UpophlUc and less persistent  than other organochlorlnes and  there-
fore 1s not bloaccumulated  or  b1omagn1f1ed  to a great extent.
 0821p                               6-30                             06/12/86
-------
                     7.   EXISTING  GUIDELINES AND STANDARDS
7.1.   HUMAN
    The existing guidelines for human  exposure  to  HCH  from ambient  water  are
based on  cancer  data.  These  values,  summarized  1n Table  7-1,  were  derived
by  the  U.S.  EPA  (1980a,  1982b).   The q^ for y-HCH  (Undane) reported  In
Table 7-1  1s  also  reported  In a  Health  Effects Assessment  (U.S.  EPA,  1984a)
and a Drinking  Water Criteria Document  {U.S.  EPA, 1985a).  Values were  not
available for either 6- or e-HCH.
    In addition,  an RfD  for  oral exposure to  y-HCH  has been  estimated  and
verified  by  the  U.S. EPA (1985a,  1986a).   This ADI of  0.023  mg/day  (0.0003
mg/kg/day)  for  a  70  kg  human was  based on a  rat subchronlc  oral NOAEL  of
0.33 mg/day (Research and  Consulting Co.,  Ltd.,   1983)  and  an  uncertainty
factor of 1000.
    OSHA  (1985)  and  ACGIH  (1985-1986)  recommend  a   TWA  of  0.5  mg/m3  for
Undane (y-HCH)  and Indicate that  dermal  exposure  may  be  substantial.
7.2.   AQUATIC
    U.S.   EPA  (1980b)  derived  an  ambient  water quality criterion  for  Undane
for  the   protection of  aquatic  life.   For  the   protection  of  freshwater
species,   the concentration  of  Undane  should  be <0.8  ug/fc   as  a  24-hour
average and should  be <2.0 yg/j.  at  any time.   For  saltwater  species,  the
Undane  concentrations   should be  <0.16  yg/i  at any  time.    No criteria
were derived  for  other  HCH Isomers or BHC,  but U.S.  EPA  (1980b) noted  that
acute toxldty  to  freshwater  and saltwater  species  occurred  at  concentra-
tions as  low as  100 and  0.34 yg/l  HCH,  respectively,  and would occur  at
lower concentrations In  species more sensitive than those tested.
    U.S.   EPA   (1976)  recommended   criteria  of  0.01   yg/l   to    protect
freshwater organisms and  0.04  yg/8. to  protect  saltwater organisms.


0822p                               7-1                             03/18/88
-------












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7-2
06/27/86
-------
                              8.   RISK  ASSESSMENT
8.1.   a-HCH
    Dietary a-HCH  has been  shown to  cause  an Increased Incidence  of  liver
tumors 1n  five  strains  of mice (Ito et al.,  1973a,b,  1976;  Nagasaki et a!.,
1972a, 1975; Hanada et al.,  1973;  Goto et  al., 1972)  and In Wlstar rats (Ito
et  al.,  1975;  Schulte-Hermann and  Parzefall, 1981).   The teratogenlc  and
reproductive  effects  of  a-HCH have  not  been Investigated.   Nonneoplastlc
hepatic  changes  have occurred  1n rats  and  mice  fed a-HCH  (Shulte-Hermann
and Parzefall, 1981; Ito et al., 1973a,b,  1975, 1976;  FHzhugh  et al., 1950).
    According to EPA criteria,  there 1s sufficient  evidence  to  conclude that
a-HCH  1s  carcinogenic   to  animals.   A  past  assessment  for  a-HCH  (U.S.
EPA,  1982b)  derived  a  q *  for  humans of  11.1  (mg/kg/day)'1  on the  basis
of  an  Increased Incidence of  liver  neoplasms  1n male  DDY  mice  fed  250  and
500 ppm  a-HCH  1n the diet for  24 weeks  (Nagasaki et al., 1972a).   The data
from  the  past  assessment of  the U.S.  EPA  (1982b)  to  estimate the  a-HCH
q,* are presented 1n Table 8-1.
    There  are,   however,  a  number of  problems  with  these two data  sets.
Nagasaki et  al.  (1972a)  reported only the  Incidences  of macroscopic  liver
nodules  1n groups  of mice  fed  0,  100 ppm  (13 mg/kg/day),  250 ppm  (37.5
mg/kg/day)   or   500  ppm  (65.0 mg/kg/day)  of  a-HCH  1n  the  diet.   Although
Nagasaki et al.  (1972a)  mentioned  that  hlstologlcal  examination  revealed
benign  and malignant hepatomas  1n the  livers of  mice fed 250 or  500  ppm
a-HCH,  they did  not  report  Incidences  of  h1stolog1cally  verified  tumors
and did  not Indicate whether  the livers  of  mice  fed  0 or  100  ppm  of  a-HCH
were examined histologlcally.  Hence,  the Incidence data used  In the past by
U.S. EPA (1982b)  to estimate a q *  1s for grossly observable  liver nodules
0823p                               8-1                               03/18/88
-------
                                   TABLE  8-1

                 Summary of Pertinent Data for q-j* for a-HCHa
    The water  quality  criterion  for  a-HCH  1s  derived  from  the  oncogenlc
effects observed In  the livers  of male dd  mice  fed 0, 250 or  500  ppm a-HCH
In the  diet  for 24 weeks.   These dietary levels correspond  to  TWA doses of
0, 37.5  or 65  mg/kg/day,  respectively.  The  criterion was  calculated from
the following parameters without the 13 mg/kg/day dose:


                                       Incidence of Grossly
                  Dose               Observable Liver Nodules^
               (mq/kg/day)           (No.  responding/No, tested)

                   0                            0/20
                  13.0                          0/20
                  37.5                          9/20
                  65.0                         20/20

    le = 24 weeks   w = 0.030 kg
    LE = 24 weeks
    L = 90 weeks
    With  these  parameters the  carcinogenic  potency factor  for  humans, q-|*,
Is 11.12 (mg/kg/day)~1C.


aSource: Nagasaki et a!., 1972a

bThese  tumors  are  not  hepatocellular  carcinomas  nor do  they appear  to be
 hepatomas, but rather are swellings leading "nodules."

cWhen dose-response  data  for the  lowest  dosage group (dose = 13 mg/kg/day,
 Incidence =  0/20)  Is  Included  In  the analysis, the q-|*  for  humans 1s 3.03
 (mg/kg/day)"1 for L = 90 weeks or 4.68 (mg/kg/day)'1 for L  =  104 weeks:

 Animal q-|* = 4.335761xlO"3 (mg/kg/day)'1

 Human q-|* = 3.03 (mg/kg/day)"1 = animal q-|* x (70/0.03)1/3  x  (90/24)3

 Human q-j* = 4.68 (mg/kg/day)"1 = animal q-)* x (70/0.03)1/3  x  (104/24)'
0823p                               8-2                              10/24/86
-------
only,  and  omits  the  Incidence  1n  the  lowest  dosage group.   If the  dose-
response for this previously omitted group  (dose  =  13 mg/kg/day;  Incidence =
0/20)  1s  Included  In  the  q^*  derivation,  the  resulting  q^  Is  3.03
(mg/kg/day)'1  with  a  mouse  Hfespan  of  90  weeks,   or  4.68  (mg/kg/day)'1
when the Hfespan of  the mice 1s assumed to  be 104 weeks,  a  time correction
consistent with current methodology (U.S. EPA, 1985b).
    Ito et  al.  (1973a) performed a  similar  study on  male dd mice using the
same dietary  levels  and duration  (but  a larger 250  ppm  group) and  obtained
similar results.  The  Ito et  al.  (1973a)  study,  however,  provides  combined
Incidence  data  for  hlstologlcally  confirmed liver  tumors   (nodular  hyper-
plasla  and  hepatocellular  carcinoma).   The data  of  Ito  et  al.  (1973a),
summarized  In  Table  8-2,  yield  a  q *  for  humans of  6.3  (mg/kg/day)'1
when the  Hfespan of  the mice 1s  assumed  to be  104 weeks,  consistent  with
current methodology  (U.S.  EPA,  1985b).   The  q  *  of  6.3  (mg/kg/day)"1  Is
recommended  as  the  best  estimate  of  the  carcinogenic  potency  of  a-HCH.
The  corresponding  water  levels  associated  with  maximum Increased  lifetime
cancer   risks    for   humans    of   10~5,    10~6   and   10~7   are   5.52xlO~5,
5.52xlO"6  and  5.52xlO"7,   respectively.    The  Ito   estimate  [6.34  (mg/kg/
day)"1]  of cancer  potency  does  not  vary  greatly  from  the  above-reviewed
Nagasaki estimate [4.6 (mg/kg/day)"1].
    A  q *  was  also  derived  from  the  only  available  oral  study  that
Involved chronic administration  (I.e., >24-32 weeks of  the  other  studies)  of
o-HCH  and  that  reported  combined  Incidences of  benign  and  malignant  liver
tumors  (Section  9.2.1.).   In   the  26-month  study   by  Schulte-Hermann  and
Parzefall  (1981),  the  combined  Incidence  of hepatic neoplastlc  nodules  and
hepatocellular  carcinomas 1n  Wlstar rats was 6/6 In female  Wlstar  rats  fed
-20  mg/kg/day  of  a-HCH  for  20-26 months   vs.  1/6   1n  controls  (p=0.008,


0823p                               8-3                              03/18/88
-------
                                  TABLE 8-2
                         Derivation  of a q-|*  for a-HCH
Reference:  Ito et al., 1973a
Specles/straln/sex:  mouse/dd/male
Route/vehicle:   oral/diet
Tumor site and  type:  liver, nodular hyperplasla3 and hepatocellular
                      carcinoma
le = 24 weeks
LE = 24 weeks
L = 104 weeks
bw = 0.03 kg (assumed)
Exposure
(ppm)
0
100
250
500
Transformed Dose"
(mq/kq/day)
0
13.0
37.5
65.0
Incidence

0/20
0/20
10/38
20/20
aThe hyperplasla  was considered  to  be a  precursor  to tumor  development In
 this experiment and as such was added Into the tumor counts.
^Dose was  transformed by  multiplying dietary ppm by  a food  factor  of 0.13
 to obtain doses 1n mg/kg/day.
 Animal qi* = 5.870060xlO"3 (mg/kg/day)'1
 Human q-|* = 6.34 (mg/kg/day)"1 = animal qi* x (70/0.03)1/3 x (104/24)3
0823p                               8-4                              10/24/86
-------
Fisher Exact  test).  Because Global  82  will  not  converge  when  there are only
two groups  (control and exposed) with 100%  response  1n  one of  the groups,  H
was necessary to reduce  the  Incidence  to  a value  <100% and  to  adjust  the
dose  proportionally  (Table  8-3).   The  adjusted  data yield a  q,*  for  humans
of  1.3  (mg/kg/day)'1,  which  Is  only  somewhat  smaller,  but of  the  same
order  of magnitude  as  the q *  derived  for a-HCH from  the much  shorter
(24-week)  study by  Ito  et al.  (1973a).   Such  relative  agreement  may  be
fortuitous  but  does  suggest that  the true upper  limit  estimate  Is  likely  to
He 1n the  1.33-6.38 (mg/kg/day)"1 range.
8.2.   B-HCH
    Dietary B-HCH  has  been  shown  to cause  an  Increased   Incidence of  liver
tumors 1n CF1  mice  (Thorpe  and Walker,  1973).  Tumors  were  not  Increased  In
dd mice  (Ito  et al., 1973a,b; Hanada et  al., 1973;  Nagasaki  et  al.,  1972a)
or Wlstar  rats (Ho et al.,  1975;  FHzhugh  et  al., 1950).   The Thorpe and
Walker (1973)  study  Is  the  only positive cancer  study  for B-HCH.   As  previ-
ously  discussed (see Section  5.1.1.),  an  additional   report  (Goto et  al.,
1972)  Indicates that mice  fed  600  ppm of   B-HCH  had  no   grossly  observable
liver  nodules  but  had  hlstologlcal  evidence   of   benign hepatomas  at  an
unspecified Incidence,  which Is considered to be marginal  evidence at  best.
    The reproductive and teratogenlc effects  of B-HCH have not been Investi-
gated.   Ito  et  al.  (1973a,b,  1975) found  neither  nonneoplastlc  nor  neo-
plastlc hlstologlcal changes 1n  the  livers  of mice  and rats 1n  studies that
were   designed   to   Investigate   hepatic  carcinogenic   response;   however.
Increases In  absolute  and  relative  liver  weight were observed  at  dietary
concentrations  >250  ppm.    FHzhugh  et  al.  (1950)  observed Increased  liver
weight accompanied  by  hlstologlcal  changes 1n  rats   fed >100  ppm  B-HCH;
Increased relative  liver  weight  was the  only  effect  observed  at 10  ppm.


0823p                              8-5                              03/18/88
-------
                                  TABLE  8-3
                         Derivation  of a  q-|*  for a-HCH
Reference:  Schulte-Hermann and Parzefall, 1981
Spec1es/strain/sex:  rat/WIstar/female
Route/vehicle:  oral/diet
Tumor site and type:  liver, neoplastlc nodules  and hepatocellular carcinomas
le = 20-26 months
LE = 20-26 months3
L = 20-26 months3
bw = 0.35 kg (assumed)

           Exposure            Transformed Dose           Incidence
          (mq/kq/day)            (mq/kq/day)
               0                  0                      1/6
              20                 16.67 (20)b             5/6 (6/6)b
aAssumed; data are unclear  (Section 9.2.1.)
bS1nce GLOBAL  82 will not  converge  when there  are only  two  groups  and when
 one of  the groups has  100X  response,  1t was necessary  to  reduce the Inci-
 dence from  6/6  to 5/6 and to  adjust  the dose  to 5/6  of  the original value
 (5/6x20 = 16.67).
 Animal q-|* = 2.27421068X10"1 (mg/kg/day)"1
 Human q-|* = 1.33  (mg/kg/day)'1 = animal q-)* x (70/0.35)1/3
0823p                               8-6                              06/10/86
-------
Early  mortality was  also  observed among  rats  fed  800  ppm.   Although  no
tumors were observed  1n  this  study, not all of  the rats  started  on  the  test
were  examined  h1stolog1cally  (no  criterion  for  selection  was given).   No
other chronic effects were reported.
    According  to  EPA  criteria,  there  1s  limited  evidence that  B-HCH  1s
carcinogenic to mice.  This limitation  1s based  1n part  on only one  positive
mouse  study (CFI  strain),  a  marginal  mouse  study  (ICR-JCL   strain),  four
negative  mouse  tests  In  24-week  studies   (all  dd  strain mice),  and  two
negative  long  duration  studies  using  Wlstar   rats.   U.S.  EPA (1980a)  has
previously  derived  a  q,*  for  humans  of  1.84   (mg/kg/day)'1  based  on  the
Increased  combined  Incidence  of  hepatic  hyperplastlc  nodules and  hepato-
cellular carcinomas  In male CFI mice  fed 200  ppm B-HCH 1n  the diet  for  110
weeks  (Thorpe  and  Walker, 1973).   These data  are summarized and  quantified
In Table 8-4 and are  recommended  to best represent any putative carcinogenic
potency of B-HCH, keeping In mind  the  limitations of  the weight of evidence.
No additional  studies of the  cardnogenldty  of  B-HCH  have been  published
since  the  U.S.  EPA (1982a)  document.   The  corresponding water levels  asso-
ciated  with maximum  Increased  lifetime cancer  risks  for  humans  of  10~5,
10"6   and    10~7    are    1.90xlO~4,    1.90xlO~5   and    1.90xlO"6    mg/l,
respectively.
8.3.   Y-HCH (Llndane)
    Dietary  y-HCH   was   shown   to  cause an  Increased  Incidence  of  liver
tumors 1n male CFI mice  fed 400 ppm for 110 weeks (Thorpe and Walker, 1973).
Marginal cancer responses were  also observed In  three other  studies:   1) In
male dd mice fed 600  ppm for 32 weeks  and examined 5-6 weeks after treatment
(Hanada et  al., 1973);  2)  1n   male ICR-OCL mice  fed 600  ppm  for 26  weeks
(Goto  et  al.,  1972); and  3)  1n   B6C3F1 mice  dosed  up  to 160  ppm,  when


0823p                               8-7                              03/18/88
-------
                                  TABLE 8-4

                 Summary of Pertinent Data for  q-|* for B-HCH3
    The  water  quality  criterion  for  B-HCH  1s  derived  from the  oncogenlc
effects  observed  1n  the  livers  of  male  CF1  mice fed  200  ppm B-HCH  In  the
diet for 110 weeks  (Thorpe  and Walker, 1973).  A TWA  dose  of 26.0 mg/kg/day
was  derived from this  exposure.   The  criterion   1s  calculated  from  the
following parameters:
                  Dose
               (mq/kq/day)

                   0
                  26.0
                        Incidence^
                (no. responding/no, tested)

                           11/45
                           22/24
    le = 110 weeks
    LE = 110 weeks
    L = 110 weeks
w = 0.030 kg
    With  these  parameters the carcinogenic  potency factor for  humans,  q-]*,
1s 1.84 (mg/kg/day)"1.


aSource: U.S. EPA, 1982a

^Combined  Incidence  of hyperplastlc  nodules and  hepatocellular  carcinomas,
 subsequent to the finding of  the  first  tumor  1n any tissue In each group of
 mice (Section 9.2.2.)
0823p
                8-8
06/27/86
-------
compared  with  pooled  controls  at 90  weeks.  On  the other  hand,  no  liver
tumors were  observed  In  dd mice fed up to 500 ppm  for 24 weeks  (Ito  et  al.,
1973a,b;  Nagasaki et  al.,  1972a)  or In Wlstar rats fed 500 ppm  for up  to  48
weeks  {Ito  et  al.,   1975).    Significant   compound-related  development  of
tumors  of any  type  was  not observed  1n NMRI  mice   (Herbst  et al.,  1975;
Welsse and Herbst,  1977),  B6C3F1 mice  (NCI,  1977),  Osborne-Hendel  rats  (NCI,
1977)  or  Wlstar  rats  (FHzhugh et al.,  1950).   The  study  conducted by  NCI
(1977)  has   been  criticized for  poor   survival  of rats, changes  1n  dosing
regimen  and  the  possibility  that male  rats did  not receive  MTDs  (IARC,
1979).  The  negative  findings  of  FHzhugh et al.  (1950) are  also  Inconclu-
sive  since only  small numbers  of animals were examined hlstologlcally.   The
negative  findings of  Ito et al.  (1973a,b),  Nagasaki  et  al.  (1972a)  and  Ito
et al.  (1975)  1s likely to  be  attributable  to small  numbers  of animals  and
short duration.
    Orally-administered y-HCH  was  not  found to  be teratogenlc  or  fetotoxlc
In Wlstar  rats (Khera et  al.,  1979),  CO rats  (Palmer  et  al., 1978a),  CFY
rats  (Palmer  et  al.,  1978b),  New  Zealand   White  rabbits   (Palmer  et  al.,
1978b) or  CD-I mice  (Chernoff  and Kavlock,  1983;  Gray  and  Kavlock,  1984).
In contrast,  a  study by  Dzlerzawskl  (1977) reported  Increased numbers  of
resorbed  fetuses  1n hamsters (40  mg/kg  on  day 9 of  gestation), rabbits  (40
or 60  mg/kg  on day  9 of gestation) or  rats  (40, 50  or 100 mg/kg  on  various
days  of  gestation).  Maternal  toxldty,  1f  any,  was not  reported.   These
doses  are higher  than any of  those tested  1n  the negative  result studies,
though  Chernoff  and  Kavlock   (1983)   reported  that   25  mg/kg/day was   the
maximum dose  that was not toxic  to maternal  CD-I  mice.
0823p                               8-9                              10/24/86
-------
    Palmer et  al.   (1978a)  observed  no  adverse  effects on  reproduction In
three  generations' of  CD  rats   fed  up  to  100  ppm  y-HCH   1n   the  diet.
D1ksh1th  and  Datta  (1977)  and  DlkshHh et  al.   (1978),  however, observed
testlcular atrophy  In  ITRC  rats  gavaged  with  17.6  mg y-HCH/kg  In  peanut
oil  for   90  days,   suggesting  that y-HCH  might  have adverse  effects  upon
reproduction.
    Long-term oral  studies  have  associated  exposure to HCH with nonneoplas-
t1c  liver  changes  (DlkshHh et  al.,  1978;  Fltzhugh  et  al.,  1950; Research
and  Consulting  Co.,  Ltd.,  1983;  Oesch  et  al.,   1982;  Ito  et  al.,   1973a,
Rlvett et  al.,  1978),  kidney  changes  (Fltzhugh  et  al.,  1950; Research  and
Consulting Co.,  Ltd.,  1983),  hematologlcal   effects   (Earl  et  al.,  1970;
Morgan et al.,  1980)  and neurotoxlclty  (Fltzhugh et  al.,  1950;  Czegledl-
Janko  and Avar,  1970).  Short-term  studies  suggest  that y-HCH  may cause
Immunosupresslon (Dewan et al.,  1980;  Desl et  al.,  1978).
    According to  EPA  criteria,  there  1s  sufficient  limited evidence  that
Y-HCH  Is  carcinogenic  to  animals.   U.S.  EPA   (1980a)  has  1n   the  past
derived  a  q,*  of   1.3  (mg/kg/day)"1  based  on  the  Increased combined
Incidence  of  hepatic  hyperplastlc nodules  and  hepatocellular carcinomas 1n
male  CF1   mice  fed 400 ppm y-HCH  1n  the  diet  for  110  weeks  (Thorpe  and
Walker, 1973).  These data  are  summarized  In  Table 8-5.   There are no  more
recent data available that  could provide a  better estimate  of carcinogenic
potency  for   y-HCH.   Corresponding  water  levels  associated  with   maximum
Increased  lifetime cancer  risks  for  humans  of  10~5, 10~« and  10~7   are
2.64xlO~4, 2.64xlO"5 and 2.64xlO~« mg/l,  respectively.
0823p                               8-10                             03/18/88
-------
                                   TABLE  8-5

                 Summary of Pertinent Data for q-|* for f-HCHa
    The  water  quality  criterion for  y-HCH  1s  derived  from the  oncogenk
effects  observed  1n the  livers  of male  CF1  mice  fed  400 ppm y-HCH  In  the
diet (Thorpe and  Walker,  1973).  The  TWA dose of 52 mg/kg/day was  given In
the  feed for  110 weeks.   The  criterion Is  calculated  from the  following
parameters:


                  Dose                      Inc1denceb
               (mg/kg/day)          (no. responding/no,  tested)

                    0                          11/45
                   52                          27/28
    le = 770 days    w = 0.030 kg
    LE = 770 days
    L = 770 days


    With these parameters, the q-|* for humans Is 1.326 (mg/kg/day)"1.


aSource: U.S. EPA, 1980a

''Combined  Incidence  of hyperplastlc  nodules and  hepatocellular  carcinomas,
 subsequent to the finding of  the  first  tumor  1n any tissue 1n each group of
 mice (see Section 9.2.3.)
0823p                               8-11                             06/10/86
-------
8.4.   4-HCH
    Dietary 6-HCH Tlld  not  cause neoplastlc  or  nonneoplastlc  changes 1n  the
Hvers of  male  dd  mice (Ito et al.,  1973a;  Nagasaki  et al.,  1972a) or  male
Wlstar  rats  (Ito   et  al.,  1975).   These  studies  used  small  numbers  of
animals, were conducted  for  only  24  weeks  and examined only liver  effects.
Goto  et al.  (1972)  reported  that  a  mixture  of  6-  and  e-HCH  caused  an
Increased  Incidence of benign  and  malignant hepatomas 1n ICR-JCL mice  after
26  weeks   of  dietary  administration,  but  the  Individual   Isomers  were  not
tested  In  this  study.  This  constitutes  limited animal evidence and thus  Is
In   EPA   Group  C.    Other   pertinent   data   regarding  the   teratogenlc,
reproductive  or  chronic   effects   of  6-HCH  could  not  be  located  1n  the
available  literature as dted 1n the Appendix.
8.5.   e-HCH
    Goto et al. (1972)  reported   that a  mixture of  6- and  e-HCH caused  an
increased  Incidence of benign  and  malignant hepatomas In ICR-JCL mice  after
26  weeks   of  dietary  administration,  but  the  Individual   Isomers  were  not
tested  1n  this  study.  This  constitutes  limited animal evidence and thus  Is
1n  EPA  Group  C.   Other   pertinent  data  regarding   the   health  effects
associated  with exposure  to e-HCH could  not  be located  1n  the  available
literature as cited 1n the Appendix.
8.6.   T-HCH
    T-HCH  has been  shown to  cause  Increased Incidences  of  liver neoplasms In
four  strains  of mice  (Hanada  et  al.,  1973; Goto et  al.,  1972; Kashyap  et
al.,  1979; Nlgam  et  al.,  1984a;  Bhatt  et  al., 1981;  Munlr  et al.,  1983;
Nagasaki et al., 1971, 1972b; Nagasaki,  1973;  Munlr  and Bhlde,  1984) but not
1n Wlstar  rats  (Munlr  et al.,  1983) or  Syrian  golden hamsters (Munlr et al.,
1983).

0823p                               8-12                             03/18/88
-------
    The teratogenlc  effects  of  T-HCH have  not  been Investigated.  N1gam  et
al. (1979) and  Shtvanandappa  and  KrlshnakamuM  (1981,  1983) have  shown  that
orally-administered  T-HCH  causes  testlcular atrophy 1n  rats and  mice  (>800
ppm, rats; 500 ppm, mice).
    Long-term oral  administration  of T-HCH has  been  shown to cause  adverse
effects on the  liver  (FHzhugh et al.,  1950;  Barros and  Sallba,  1978;  Barros
et  al.,  1982;  Shlvanandappa  and  Kr1shnakamur1,  1981;  Nlgam  et  al.,  1982,
1984a,b; Munlr  and Bhlde,  1984),  kidney  (FHzhugh  et  al., 1950,  Barros and
Sallba, 1978;  Barros et al., 1982;  Shlvanandappa and Kr1shnakamur1,  1981),
adrenal cortex  {Shlvanandappa and Kr1shnakamur1,  1981; Shlvanandappa  et  al.,
1982) and CNS (Shlvanandappa and Krlshnakamurl,  1981; Kashyap  et  al.,  1979).
Kashyap et  al.  (1979)  also  reported that  long-term  oral  exposure to  T-HCH
was associated with Increased corneal opacity.
    According to  EPA criteria,  there  Is  sufficient evidence  that T-HCH  Is
carcinogenic  1n animals  (Group  B2).   U.S.  EPA (1982b)  1n  the  past derived  a
q *  of   4.7   (mg/kg/day)"1   based  on  Increased  combined   Incidences   of
hepatic hyperplastlc  nodules  and  hepatomas In male dd  mice fed 6.6, 66 and
660 ppm T-HCH for 24 weeks  (Nagasaki  et  al., 1972b)  (Table 8-6).  However,
this 1s not  a malignant tumor endpolnt,  but  1t  Is  assumed  that  the  nodules
would progress  to  hepatomas  and  the hepatomas to carcinomas.  In  estimating
this q.^,  the  U.S.   EPA  (1982b)  assumed  the Hfespan  of the  mice  was  90
weeks.   If the  Hfespan  1s  assumed to be 104 weeks, consistent  with  current
methodology (U.S.  EPA, 1985b),  the q   for  humans Is 7.3  (mg/kg/day)'1.
0823p                               8-13                             03/18/88
-------
                                   TABLE  8-6

                 Summary of Pertinent Data for q-[* for T-HCH3
    The  water  quality  criterion for  T-HCH  1s  derived  from the  oncogenlc
effects observed  In  the livers  of male dd mice fed  6.6,  66  or  660 ppm T-HCH
1n  the  diet for  24 weeks  (Nagasaki  et al.,  1972b).   These dietary  levels
correspond to TWA doses of  0.858, 8.58  or  85.8 mg/kg/day, respectively.  The
criterion Is calculated from the following parameters:


                  Dose                      Incidence**
               (mq/kg/day)          (no. responding/no, tested)

                  0                             0/14
                  0.858                         0/20
                  8.58                          0/20
                 85.8                          20/20
    le = 24 weeks  w = 0.036 kg
    LE = 24 weeks
    L = 90 weeks (104 weeks)c


    With  these  parameters the  carcinogenic  potency factor  for  humans,  q-j*,
Is 4.75 (mg/kg/day)~ic.


aSource: U.S. EPA, 1982b

^Combined Incidence of hyperplastlc nodules and hepatomas

cUse  of an  assumed  llfespan  (L)  of  104  weeks,  which  1s  consistent  with
 current  methodology  (U.S.  EPA,  1985b),  gives  a  q-|*  for  humans  of  7.35
 (mg/kg/day)"1 as follows:

 Animal q-|* = 7.232384xlO"3

 Human q-|* = 7.35 (mg/kg/day)'1 = animal qi* x (70/0.036)1/3 x (104/24)3
0823p                               8-14                             11/17/86
-------
    There  are  additional data  available  from  which a  q  *  can be  derived.
Munlr et  al.  (1983)  observed  a dose- and  duration-related  Increase  1n  the
combined  Incidence  of hepatic  benign  nodules and  hepatocellular  carcinomas
In male Swiss mice  fed 0, 125, 250  or  500 ppm T-HCH from 8-10  weeks  of  age
until either 8-11,  12-14,  15-17 or 18-22 months  of  age.   Once  100% response
was  observed  at a  particular  level  of  treatment,  mice  were  no  longer
examined  at  that level  of  treatment.   Instead,  data  from  age groups  that
Include one  group  with  100% response and  response data  for  more  than  one
dosage  (12-14  months;  15-17  months)  were  used  to calculate  q *  values.
These data are  summarized In Tables  8-7 and 8-8.   (Detailed  Incidence  data
for  all  groups   are  provided  1n  Section  9.2.6.).   A  human   q  *  of  1.17
(mg/kg/day)'1 was  obtained  from  data   on  mice  that  were  killed  at  12-14
months  of age;   a human  q,*  of 1.76  (mg/kg/day)"1 was  obtained  from  data
on mice  that  were  killed at 15-17  months of age.  These  values are similar
to,  but  somewhat lower than,  the  q *  values based  on  the 24-week  study  of
Nagasaki et al.  (1972b).
    The data of  Munlr et al. (1983) for mice killed at 15-17 months  of  age
are  recommended   as  the  best  basis for a  q *  [1.76  (mg/kg/day)"1].   This
q *  Is  considered  to  be the  best  estimate because  treatment  was  for  a
greater, proportion  of the animals'  Hfespan  and was  at  a dosage that defined
dose-response relationships more clearly  than do  the data  of  Nagasaki  et  al.
(1972b).   Water  levels  corresponding   to   the  recommended   q *  of  1.76
(mg/kg/day)'1 and associated with  a maximum Increased  lifetime cancer  risk
for   humans   of  10"5,   10"*   and   10"7   are   1.99xlO~4,   1.99xlO"5   and
1.99xlO~6 mg/l,  respectively.
0823p                               8-15                             10/24/86
-------
                                  TABLE 8-7
                         Derivation of a q-|*  for T-HCH
Reference:  Munlr et al., 1983
Species/strain/sex:  mouse/Swiss/male
Route/vehicle:  oral/diet
Tumor site and type:  liver, benign nodules and hepatocellular carcinomas
le = LE = from 8-10 weeks of age to 12-14 months of age (=12 months)
L = 104 weeks (24 months)
bw = 0.03 kg (assumed)
Exposure
(ppm)
0
125
250
500
Transformed Dose3
(mq/kq/day)
0
16.25
32.50
65.00
Incidence

0/16b
0/10
9/12
10/10
aDose was  transformed  by multiplying  concentration  In ppm by  a  food factor
 of 0.13.
bControl  data  are  from  a  similar  experiment  In  male Swiss mice performed
 In the same laboratory and reported 1n the same paper.
 Animal q-|* = 1.1033241xlO"2 (mg/kg/day)'1
 Human qi* = 1.17 (mg/kg/day)"1 = animal q-|* x (70/0.OS)1^ x (24/12)3
0823p                               8-16                             10/24/86
-------
                                   TABLE  8-8

                        Derivation  of  the q-|*  for  T-HCH
         Recommended as the Best Estimate of Cancer Potency for T-HCH
Reference:  Munlr et al., 1983

Spec1es/strain/sex:  mouse/Swiss/male

Route/vehicle:  oral/diet

Tumor site and type:  liver, benign nodules and hepatocellular carcinomas

le = LE = from 8-10 weeks of age to 15-17 months of age (-15 months)

L = 104 weeks (24 months)

bw = 0.03 kg (assumed)
Exposure
(ppm)
0
125
250
Transformed Dose3
(mg/kq/day)
0
16.25
32.50
Incidence

2/22c
8/20
12/12
aAn1mals at  500 ppm were  not  examined at  this  age since 100%  response  was
 observed at this level among mice that were 12-14 months of  age.

''Dose was  transformed  by multiplying  concentration In ppm by a food factor
 of 0.13.

cControl data  are  from  a  similar  experiment 1n  male Swiss mice  performed
 In  the same  laboratory  and  reported  In  the  same  paper.   The  controls,
 however, were killed at 15-20 months of age.

 Animal q-|* = 3.2323128xlO~2 (mg/kg/day)'1

 Human q-j* = 1.76 (mg/kg/dayT1 = animal q-!* x (70/0.03)1/3 x (24/15)3
0823p                               8-17                             10/24/86
-------
                            9.   REPORTABLE  QUANTITY
9.1.   REPORTABLE QUANTITY (RQ) RANKING BASED ON CHRONIC TOXICITY
    A large body of  evidence  Indicates  that  the nonneoplastlc  changes  In  the
liver associated with  dietary  exposure to Isomers of HCH  or T-HCH  are  asso-
ciated with  neoplastlc development.   A clear progression  of hepatic  changes
that  ultimately  lead  to  the  development  of  malignant  tumors  has   been
observed  at  gross,   hlstologlcal  and  ultrastructural levels of  examination.
These changes,  proportional  to dose and  duration of treatment,  are  revers-
ible  only  at  the very  earliest  stages before  development of  nodular  hyper-
plasla;  the  transition  from  reversible  to  Irreversible   change  Is  not
well-defined  (Ito  et al.,  1975,  1976; Schulte-Hermann and Parzefall,  1981;
Munlr  et  al.,  1983;  Munlr and  Bhlde,  1984;   Nlgam  et  al.,  1982,  19£4a;
Suglhara  et  al., 1975).  Therefore,  preneoplastlc  hepatic changes were  not
considered 1n the derivation of RQs for chronic  toxlclty.
    CSs  for  HCH are summarized  1n Table  9-1.   Data from  which RQs  could be
derived were not available for 5- or  c-HCH.
9.1.1.   a-HCH.   Available  long-term  studies   for  a-HCH  are   summarized
1n  Table  5-6.  All  studies  used oral  routes  of exposure;  five of  the  six
studies were  designed  to  Investigate  hepatic carcinogenic  response (Schulte-
Hermann  and  Parzefall, 1981;  Ito et  al.,  1973a,b,  1975,  1976).   The  study
conducted  by  FUzhugh et al.  (1950)  was  conducted  for the Hfespan of  the
animal (rats) and examined endpolnts other than liver  histology,  but  not all
animals  started  on  the test were examined.   Despite the  latter  deficiency,
the study  by  FHzhugh et al.  (1950)  Is the only study available from which
an RQ can be derived.
0824p                               9-1                              06/27/86
-------




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0824p
                                   9-2
06/10/86
-------
    A CS of  15  can  be  derived  from the lifetime rat study by FHzhugh  et  al.
(1950)  (Table  9-2").   A  PEL of  800  ppm  can be  defined on  the  basis of  a
significantly reduced  llfespan.  Assuming  that  a  rat  consumes  the  equivalent
In  food  of  5X  of   Its body  weight/day,  800 ppm  Is equivalent to an  animal
dose  of  40 mg/kg/day.   Multiplying  40  mg/kg/day  by the product of  the  cube
root  of  the  ratio  of rat to human body weight  and  human  body  weight  (70  kg)
yields  a  human  MED of 479  mg/day,  which  warrants  an RV.  of 1.5.    An  RV
of  10 can  be  assigned on  the  basis  of  early mortality.   Multiplying  the
RV   by  the  RV   yields a  CS  of  15, which  corresponds to  an RQ for  a-HCH
of 1000 (see Table 9-2).
9.1.2.   S-HCH.  The available  long-term  studies  on B-HCH are summarized In
Table  5-7.  Most   of  these studies were  designed  to Investigate  hepatic
carcinogenic response  (Ito et  al.,  1973a,b,  1975).   Thorpe and Walker  (1973)
Investigated multiple  endpolnts  but observed  no  effects  aside  from those
related to  development of  liver tumors.   FHzhugh  et  al.  (1950)  conducted a
lifetime dietary study on  rats and  Investigated  multiple endpolnts,  but  did
not examine  all  animals  (rats)  that were started on  the test.   Despite  the
latter  deficiency,  FHzhugh et  al.  (1950)  1s  the only  study that  provides
appropriate data from which an  RQ can be derived  (Table 9-3).
    The lifetime oral  rat  study by  FHzhugh et al.  (1950) provides  a  FEL of
800  ppm for  significantly  reduced  llfespan   and  a  LOAEL  of  100  ppm  for
significantly reduced  body  weight.   The highest  CS  Is  obtained from the FEL
1n  the  following manner.   Assuming  that  a rat  consumes the  equivalent In
food  of  554 of  Hs  body weight/day,  800 ppm 1s equivalent to  an  animal dose
of 40 mg/kg/day.   Assuming  that  a  rat  weighs  0.35  kg,  a  human  MED  of  479
mg/day 1s obtained  by multiplying  the animal dose by the product of the cube
root  of  the ratio  of rat  weight  to human body weight and  by  human body
0824p                               9-3                              06/27/86
-------
                                  TABLE 9-2



                                    a-HCH



          Minimum Effective Dose (MED) and Reportable Quantity (RQ)







Route:                   oral



Dose*:                   479 mg/day



Effect:                 early mortality



Reference:               FHzhugh  et  al.,  1950



RVd:                    1.5



RVe:                    10



Composite Score:         15



RQ:                     1000
'Equivalent human dose
0824p                               9-4                              06/10/86
-------
                                  TABLE 9-3



                                    B-HCH



          Minimum Effective Dose (MED) and Reportable Quantity (RQ)







Route:                  oral



Dose*:                  479 mg/day



Effect:                 early  mortality



Reference:               FHzhugh  et  al.,  1950



RVd:                    1.5



RVe:                    10



Composite Score:         15



RQ:                     1000
'Equivalent human dose
0824p                               9-5                              06/10/86
-------
weight  (70  kg);  this  MED  warrants  an  RVd  of 1.5.   An RVg  of  10  can  be
assigned  on  the  tasls  of  early  mortality.   Multiplying  the  RV    by  the
RVg  yields  a  CS  of  15,  which corresponds to  an  RQ for 8-HCH  of  1000 (see
Table 9-3).
9.1.3.   Y-HCH   (Llndane).    Long-term   oral    studies   on   y-HCH   have
associated  exposure  to  HCH  with  nonneoplastlc  liver   changes  (D1ksh1th  et
al.,  1978;  FHzhugh  et al.,  1950; Research  and  Consulting  Co., Ltd., 1983;
Oesch et  al.  1982;  Ho et al.,  1973a;  Rlvett  et  al.,  1978),  kidney  changes
(FUzhugh et  al., 1950;  Research  and  Consulting  Co.,  Ltd.,  1983),  hemato-
loglcal  effects (Earl  et  al., 1970; Morgan  et  al., 1980)  and  neurotoxlclty
(FHzhugh et  al.,  1950;   Czegledl-Janko  and Avar,  1970)  (see  Table 5-8).
Short-term  studies  suggest that  Y-HCH  may cause  Immunosupresslon   (Dewan et
al., 1980; Des1  et al., 1978) (see  Section 5.5.).
    Orally-administered y-HCH  was  not   found to be  teratogenlc or  fetotoxlc
In  Hlstar rats  (Khera  et  al., 1979).   CD rats (Palmer  et  al., 1978a), CFY
rats  (Palmer  et  al.,  1978b),  New  Zealand  White  rabbits  (Palmer  et al.,
1978b)  or CD-I  mice (Chernoff and Kavlock,  1983;  Gray and Kavlock,  1984).
In  contrast,  a  study  by  Dz1erzawsk1  (1977) reported  Increased  numbers  of
resorbed  fetuses  1n  hamsters (40 mg/kg  on day  9  of gestation), rabbits  (40
or  60 mg/kg on  day  9 of  gestation) and rats  (40,  50 or  100 mg/kg on  various
days  of  gestation).   Maternal toxlclty was  not  reported.   These   doses  are
higher than  any of those tested  In  the  negative studies, though Chernoff  and
Kavlock  (1983)  reported  that 25  mg/kg/day was  the  maximum dose that  was  not
toxic to maternal  CD-I  mice.
    Palmer  et  al.  (1978a) observed no adverse  effects on  reproduction  In
three  generations  of  CD  rats  fed  up  to  100   ppm   Y-HCH   In  the  diet.
0824p                               9-6                              03/18/88
-------
DlkshHh  and  Datta  (1977)  and  DlkshHh et  al.  (1978),  however,  observed
testlcular  atrophy  In  ITRC  rats  gavaged with  17.6  mg  y-HCH/kg  1n  peanut
oil  for  90  days,   suggesting  that  y-HCH   may  have   adverse  effects  on
reproduction.
    Studies that  provide adequate  Information  for the  derivation  of  an RQ
for  T-HCH are  those  of  DlkshHh  et  al. (1978),  Fltzhugh  et  al. (1950),
Research and Consulting Co., Ltd.  (1983), Earl  et  al.  (1970)  and Dz1erzawsk1
(1977).
    OlkshHh et al.  (1978) observed  a  LOAEL of  17.6 mg/kg/day for  testlcular
atrophy  In  ITRC  rats   fed  T-HCH   for  90  days.   Fltzhugh  et  al.   (1950)
observed early mortality, gross  and  hlstologlcally-deflned  kidney damage  and
nervous  symptoms  and  convulsions  1n rats fed  800 ppm  y-HCH for life.  . The
Research and  Consulting Co.,  Ltd.  (1983) reported degenerative  hlstologlcal
changes  In  the kidneys  of rats  fed  y-HCH  (1.55 mg/kg/day)  for  12 weeks.
Earl et  al.  (1970)  reported  hematologlcal  effects  In  dogs  fed Y-HCH  (22.5
mg/kg/day)  for  24 weeks.  Oz1erzawsk1  (1977) observed  Increased numbers of
resorptlons In  rats,  rabbits  and  hamsters  given 40 mg y-HCH/kg/day  on >1
days of gestation.
    Although  each of  these  studies has  some deficiencies  (short  duration.
Incomplete examination  of  animals, small numbers  of animals),  taken collec-
tively,  the  studies  Indicate  that  the  RQ   for  y-HCH   Is  1000.   The  study
that provided  the highest CS  (17)  1s  the Research and  Consulting  Co.,  Ltd.
(1983)  study.   The  LOAEL  of  1.55 mg/kg/day for  kidney  damage Is  assigned an
RV   of 6.  Dividing  1.55  mg/kg/day  by an  uncertainty factor  of 10  (for
Iess-than-chron1c  exposure) then multiplying  by the product of  the  cube root
of the ratio of rat body  weight  to human body weight (assuming a body  weight
of 0.35  kg  for rats) and  by  the  human  body  weight  (70  kg), yields a  human
0824p                               9-7                              06/27/86
-------
MED of  1.86  mg/day;  this  Is  equivalent  to an RV.  of  5.1.   Multiplying the
RVd  by   the  RVg  yields  a  CS  of  31,  which corresponds  to an  RQ  of 100
(Table 9-4).
9.1.4.   T-HCH.   Long-term  oral  administration  of  T-HCH  has been  shown to
adversely affect the liver  (FHzhugh et al., 1950;  Barros and Sallba  (1978),
Barros et  al.,  1982; Shlvanandappa  and  Krlshnakamurl ,  1981; N1gam et  al.,
1982,  1984a,b; Munlr and Bhlde, 1984), kidney (FHzhugh et al., 1950;  Barros
and  Sallba,   1978;  Barros  et  al.,  1982;  Shlvanandappa  and Krlshnakamurl,
1981), adrenal  cortex  (Shlvanandappa  and Krlshnakamurl, 1981; Shlvanandappa
et  al.,  1982)  and  CNS   (Shlvanandappa  and Krlshnakamurl, 1981;  Kashyap et
al.,  1979).   Kashyap  et   al.  (1979)  also  reported   that   long-term  oral
exposure to T-HCH was associated with Increased corneal  opacity.
    The  teratogenlc  effects  of T-HCH have not  been Investigated.  N1gam et
al. (1979) and  Shlvanandappa  and  Krlshnakamurl  (1981.  1983)  have shown  that
orally-administered  T-HCH  causes  testlcular  atrophy In  rats and mice  (>800
ppm, rats; 500 ppnt, mice) (see Table 5-10).
    Studies  that  demonstrated  adverse  effects  at  the  lowest  levels of
exposure are  those of  FHzhugh et  al.  (1950),  Shlvanandappa et  al.  (1982),
N1gam  et al.  (1979) and  Kashyap et  al.   (1979).   FHzhugh et  al.  (1950)
observed early  mortality  and  degenerative  changes 1n the kidneys and testes
of  rats  fed  800  ppm y-HCH for  life.   Shlvanandappa et al.   (1982)  reported
gross, hlstologlcal  and  hlstochemlcal  changes  1n the adrenal glands  of rats
fed  750  ppm  Y-HCH  (625  mg/rat/90  days)  for 90  days.  Testlcular  atrophy
was  observed  among  mice  fed  500 ppm  y-HCH for  10 months  (N1gam  et  al.,
1979), and corneal opacity and  a  slight  tendency  to convulse  were observed
among  mice fed  100 ppm y-HCH  or  gavaged  with  10 mg  y-HCH/kg/day  for  80
weeks (Kashyap et al.. 1979).
0824p                               9-8                              06/10/86
-------
                                  TABLE 9-4
                                    Y-HCH
           Minimum Effective  Dose  (MED) and Reportable Quantity (RQ)

Route:                  oral
Dose*:                  1.86  mg/day
Effect:                 degenerative changes  1n kidney
Reference:              Research and Consulting Co.,  Ltd.,  1983
RVd:                    5.1
RVe:                    6
Composite Score:        31
RQ:                     100
'Equivalent human dose
0824p                               9-9                              06/10/86
-------
    The  study  of Sh1vanandappa et  al.  (1982)  yields  the  highest composite
score.   The  animal- dose  of  19.8 1s adjusted  to a  human  MED  of 24 mg/day  In
the  following  manner.   The animal  dose 1s  first  divided  by an  uncertainty
factor  of  10  to account for  less than  chronic  exposure.   This  yields  an
adjusted animal  dose of  1.98  mg/kg/day.  An MED of 24 Is  obtained by  multi-
plying  1.98  by  the  product  of the cube root of the ratio  of  rat  body  weight
(0.35  kg,   assumed) to  human  body  weight  (70   kg).   An  RV.  of   3.4  1s
assigned on  the  basis  of the  MED.  An  RV   of  7 1s assigned on the  basis  of
h1stolog1cal and hlstochemlcal  adrenal changes  Indicative of  steroldogenlc
Inhibition.  Multiplying the  RV.  by  the  RV   yields  a composite  score  of
24.  The RQ for T-HCH 1s  therefore 100 (Table 9-5).
9.2.   HEIGHT OF EVIDENCE AND  POTENCY  FACTOR (F=1/ED1Q) FOR CARCINOGENIC1TY
9.2.1.   a-HCH.   Dietary  a-HCH  has   been   shown  to   cause   an Increased
Incidence  of  liver  tumors  1n  five  strains of mice  (Ito et al.,  1973a,b,
1976; Nagasaki  et al., 1972a,  1975;  Hanada et al., 1973;  Goto  et al.,  1972)
and In  Wlstar  rats  (Ito  et  al., 1975;  Schulte-Hermann and Parzefall,  1981).
The  teratogenlc  and reproductive  effects  of  a-HCH have  not been  Investi-
gated.   Nonneoplastlc  hepatic  changes  have occurred  1n  rats  and  mice  fed
a-HCH  (Shulte-Hermann  and  Parzefall,  1981;   Ito  et  al.,   1973a,b,  1975,
1976; FHzhugh  et al.,  1950).
    According  to IARC  (1979), as well  as  the  EPA Guidelines  for  Cancer
Assessment (U.S. EPA,  1986b),  there  1s sufficient evidence  to  conclude that
a-HCH  1s carcinogenic  to  mice.   Since there are  no  human  data available,
a-HCH  Is placed 1n  IARC Group 28  and EPA  Group  B2,  meaning  that  a-HCH 1s
considered probably carcinogenic to man.   Data  for  the positive studies that
reported  Incidences of  h1stolog1cally verified  tumors  are  summarized  In
Tables  9-6 through 9-12.   Positive  studies  lacking  this  type of  Incidence
0824p                               9-10                             03/18/88
-------
                                  TABLE 9-5
                                    T-HCH
           Minimum  Effective  Dose  (MED) and Reportable Quantity  (RQ)

Route:                  oral
Dose*:                  24 mg/day
Effect:                 hlstologlcal   and   hlstochemlcal   adrenal   changes
                        Indicative of  steroldogenlc Inhibition
Reference:              Shlvanandappa  et  al.,  1982
RVd:                    3.4
RVe:                    7
Composite Score:        24
RQ:                     100
*Equ1valent human dose
0824p                               9-11                             06/10/86
-------
                                  TABLE 9-6

            Incidence of Liver Neoplasms In Male DDY Mice Fed a-HCH
                           (>99X pure)  In  the D1eta
Dose        Duration of  Exposure
(ppm)             (weeks)
                 Duration  of  Study
                      (weeks)
                Tumor Incidence0
   0
 500
 500
 500
 500
 500
 500
 500
 500
 500
 500
 500
 500
 500
 500
 500
 500
NA
16
20
20
20
20
24
24
24
24
24
24
24
36
36
36
36
72
16
20
24
28
32
24
28
32
36
40
48
60
36
48
60
72
 0/18
 5/21
14/20
 8/20
 5/20
 2/19
20/20
18/19
 9/16
 7/17
 8/16
12/15
14/14
14/14
11/13
12/12
13/13
Strengths of study:


Weakness of study:

Overall adequacy:

Comments:
          QUALITY  OF  EVIDENCE

time-to-tumor  Information;  comprehensive  examination  of
the liver

short duration of exposure

adequate

100X  response was  observed  at  >24  weeks  of  exposure.
Hepatocellular carcinoma  was  the predominant  tumor  type
60-70 weeks from the beginning of the study.
aSource: Ho et al.. 1976

bComb1ned Incidence of hepatocellular carcinoma and nodular hyperplasla

NA = Not applicable
0824p
               9-12
                         06/10/86
-------
                                   TABLE  9-7



       Incidence oT Hepatic Neoplasms In Mice Fed a-HCH for 24 Weeksa-b
Strain
DOY


ICR

DBA/2

C57BL/6

C3H/He

Sex
M
M
M
H
F
F
M
M
F
F
M
M
F
F
H
M
F
F
M
N
F
F
Dose
(ppm)
0
500
0
500
0
500
0
500
0
500
0
500
0
500
0
500
0
500
0
500
0
500
Incidence of
Nodular
Hyperplasla
0/16
20/20
0/20
20/20
0/20
16/20
0/20
18/23
0/19
15/29
0/13
8/16
0/16
5/15
0/22
4/21
0/16
3/18
0/17
13/20
0/18
11/20
Tumors0
Hepatocellular
Carcinoma
0/16
6/20
0/20
13/20
0/20
5/20
0/20
8/23
0/19
6/29
0/13
1/16
0/16
1/15
0/22
0/21
0/16
0/18
0/17
0/20
0/18
2/20
0824p
9-13
06/10/86
-------
                              TABLE 9-7 (cont.)
                             QUALITY OF EVIDENCE

                      five strains  and  both  sexes  tested

                      purity of  compound  not   reported;  short  duration  of
                      exposure

                      adequate
Strengths of study:

Weaknesses of study:


Overall adequacy:
aSource: Nagasaki et al..  1975

DPur1ty not reported

cComb1ned Incidence not reported
0824p
                                     9-14
                                                                      06/10/86
-------
                                   TABLE  9-8
            Incidence of Liver Neoplasms 1n Male dd Mice fed a-HCH
                     (>99X pure)  In  the  Diet  for  24 Weeks3
Dose
(ppm)
0
50
100
250
Duration of Study
(weeks)
24
24
24
24
Incidence
Nodular
Hyperplasla
0/20
0/28
0/26
23/30
of Tumors'5
Hepatocellular
Carcinoma
0/20
0/28
0/26
8/30
Strengths of study:
Weaknesses of study:
Overall adequacy:
        QUALITY  OF  EVIDENCE

three different  doses  tested; relatively  large  number
of mice examined/treatment

short duration  of  exposure; only  the  liver  was exam-
ined microscopically

limited
aSource: Ito et al., 1973b

''Combined Incidence not reported
0824p
              9-15
06/10/86
-------
                                  TABLE 9-9

            Incidence of Liver  Neoplasms  In  Male  dd  Mice  fed o-HCH
                     (>99X pure)  1n the Diet for 24 Weeks3
Incidence of Tumors
Dose
(ppm)
0
100
250
500
Duration of Study
(weeks)
24
24
24
24
Nodular
Hyperplasla
0/20
0/20
30/38
20/20
Hepatocellular
Carcinoma
0/20
0/20
10/38
17/20
Comb1nedb
0/20
0/20
30/38
20/20
Strengths of study:
Weaknesses of study:
Overall adequacy:
       QUALITY OF EVIDENCE

three doses  tested;  relatively  large  number of  mice/
treatment

short  duration  of  exposure;   only   the  liver  was
examined  microscopically

adequate
aSource: Ito et al., 1973a

^Combined Incidence of nodular hyperplasla and hepatocellular carcinoma
0824p
              9-16
06/10/86
-------
                                  TABLE 9-10

           Incidences of Hepatomas In dd Mice Fed a-HCH 1n the Diet
                                for  32  Weeks3-b
Sex
M



F



Dose
(ppm)
0
100
300
600
0
100
300
600
Duration of Study
(weeks)
37-38
37-38
37-38
37-38
37-38
37-38
37-38
37-38
Tumor Incidence0
0/14
1/8
7/7
7/7
0/15
0/8
2/3
6/8
                              QUALITY  OF  EVIDENCE

Strengths of study:   three levels of exposure

Weaknesses of study:  small  numbers  of  mice/treatment;  only  livers  were
                      examined  h1stolog1cally;  the purity  of a-HCH was  not
                      reported

Overall adequacy:     limited


aSource: Hanada et al., 1973

^Purity not reported

cNumber  of  mice  started  on  test  was 10-1 I/sex  for  each treated  group  and
 20-21/sex for controls.  Only mice that survived >36 weeks were examined.
0824p                               9-17                             06/10/86
-------
                                  TABLE  9-11
               Incidences of Liver Neoplasms In Male Wlstar Rats
                      Fed a-HCH  (>99X pure)  1n  the  Diet3
Tumor Incidence15
Dose
(ppm)
0
500
500
1000
1000
1000
1500
Duration of
Treatment
(weeks)
NA
24
48
24
48
72
72
Duration
of Study
(weeks)
72
24
48
24
48
72
72
Nodular
Hyperplasla
0/8
0/6
0/5
0/8
5/12
12/16
10/13
Hepatocellular
Carcinoma
0/8
0/6
0/5 .
0/8
0/12
1/16"
3/13
Strengths of study:

Weakness of study:
Overall adequacy:
        QUALITY OF EVIDENCE
three doses  used;  time-to-tumor  Information; all  major
organs examined
small numbers of rats/treatment
limited
aSource: Ito et al., 1975
bComb1ned  Incidence  not  reported;  rats  that  died  during  the  experiment
 were not examined.
NA = Not applicable
0824p
               9-18
06/10/86
-------
                                  TABLE 9-12
              Incidences  of  Liver  Neoplasms  1n Female Wlstar Rats
                    Exposed Orally to e»-HCH (99.5X) pure)3
Vehicle
NA
Diet
Vegetable oil
NA
Vegetable oil
NA
Diet
Vegetable oil
NA
Diet
Vegetable oil
Dose and Duration
0 mg/kg/day
-20 mg/kg/day for 8 months
420 mg/kg every 3rd week for
7 months
0 mg/kg/day
200 mg/kg every 2nd week for
12 months
0 mg/kg/day
-20 mg/kg/day for
13.5-17 months
420 mg/kg every 3rd week for
11 .6-16 months
0 mg/kg/day
-20 mg/kg/day for 20-26 months
420 mg/kg every 3rd week for
Age at
Deathb
(months)
9-10
9-10
9-10
12
12
14-19
14-19
14-19
23-34.5
23-34.5
23-34.5
Tumor
Incidence
0/4
0/3
0/1
0/9
3/8
0/3.
2/4
1/4
1/6
6/6c
7/8d
                  21.5-33 months
                              QUALITY  OF  EVIDENCE
Strengths of study:   sufficient duration  of exposure;  time-to-tumor  Infor-
                      mation
Weaknesses of study:  small numbers of  rats/group;  liver was the only  organ
                      examined
Overall adequacy:
limited
aSource: Schulte-Hermann and Parzefall, 1981
DRats were -1.25-2 months old at start of treatment
cComb1ned Incidences of neoplastlc nodules and hepatocellular carcinomas
done of these tumors was a hepatocellular carcinoma
NA = Not applicable
0824p
              9-19
06/27/86
-------
data  (Nagasaki  et  al.,  1972a;  Goto  et al.,  1972)  and  a  negative  study
(Fltzhugh et al.,  1950)  are summarized  In Table  5-1.
    The  study  that provides  the best  estimate of  carcinogenic  potency Is
that  of  Ito  et  al.  (1973a);  an  adjusted  potency  factor of  69.5 (mg/kg/
day)'1  Is  based  on  an   Increased  Incidence  of  liver  neoplasms  In  male dd
mice  fed  100,  250  and  500  ppm  o-HCH  for   24  weeks  (Table  9-13).   The
potency  factor was  adjusted  for  body weight and less-than-llfctime  exposure
                                 1/3
[unadjusted  1/ED1Q  x   (70/0.03)    )  x   (104/24)*].   The   currently recom-
mended  1/ED-iQ  °f  69.5   (mg/kg/day)'1  Is thus  different  from  the  value of
211 reported by U.S. EPA (1984b);  the U.S.  EPA  (1984b) value apparently was
based on  the  data  of Ito  et al. (1976).  A  potency factor of 69.5 (mg/kg/
day)'1  (Potency  Group  3)  and  an   EPA  Group   rating of 82 place  <*-HCH 1n
the MEDIUM category of  the CERCLA hazard ranking scheme.
9.2.2.   B-HCH.    Dietary  B-HCH  has  been  shown   to  cause   an   Increased
Incidence of  liver  tumors  1n GF1 mice  (Thorpe  and Walker, 1973) but not 1n
dd mice  (Ho  et  al., 1973a,b; Hanada et al.,  1973; Nagasaki  et al., 1972b)
or Wlstar  rats  (Ito et al.,  1975;  FHzhugh  et al.,  1950).   As  previously
discussed  (see  Section   5.1.1.), an additional  report  (Goto  et  al.,   1972)
Indicates  that  mice fed  600 ppm of  B-HCH  had  no grossly observable  liver
nodules  but  had hlstologlcal  evidence  of  benign  hepatomas  (Incidence not
specified).
    According to  IARC   criteria, and the  EPA  cancer  guidelines  (U.S.  EPA,
1986b), there 1s limited evidence that  B-HCH  Is carcinogenic  to mice.   Since
there were no human  data available, B-HCH 1s placed 1n EPA Group  C, meaning
B-HCH  Is  considered a  possible human  carcinogen.  Incidence  data for  the
only  study that provided positive  results and  actual  Incidences  (Thorpe and
Walker, 1973) are summarized 1n  Table 9-14.   Negative  studies  are summarized
In Table 5-2.

0824p                               9-20                             03/18/88
-------
                                  TABLE  9-13
                  Derivation of Potency  Factor  (F)  for  a-HCH
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:
Llfespan of animal:
Target organ:
Tumor type:

Experimental doses/exposure (ppm):
Transformed doses (mg/kg/day)a:
Tumor Incidence^:
Unadjusted 1/ED10:
1/ED10 (F Factor):
   Ito et  al.,  1973a
   oral
   mouse
   dd
   male
   diet
   0.03 kg (assumed)
   24 weeks
   24 weeks
   104 weeks
   liver
   nodular hyperplasla and hepatocellular
   carcinoma
0
0
0/20
100
13.0
0/20
250
37.5
10/38
500
65
20/20
   0.0644114
   69.5 (mg/kg/day)'1
aAssumes a food factor of 0.13
bGLOBAL 82  and GLOBAL 79  will  not converge when  there are only  two levels
 of  treatment  and  100%  response  1n  one  of  the  groups.   It was  therefore
 necessary to  reduce  the  Incidence to  a  value <100% and  to adjust  the dose
 proportionally.
0824p
9-21
06/10/86
-------
                                 TABLE 9-14

        Incidence of Liver Neoplasms In CF1 Mice Fed B-HCH (>99X pure)
                       1n the Diet for up to 110 Weeks3
Sex
M





F



F

Duration of Exposure
0-17 months0
0-21 months0
0-25 months0
26 monthsd
Total (0-26 months)
Adjusted total Incidence6
0-17 months0
0-21 months0
0-25 months0
26 monthsd
Total (0-26 months)
Adjusted total Incidence6
Dose
(ppm)
0
200
0
200
0
200
0
200
0
200
0
200
0
200
0
200
0
200
0
200
0
200
0
200
Tumor Incidence15
(p value, 2x2 Exact Test)
0/4
6/13 (<0.05)
2/18
10/17 (<0.05)
2/25
18/26 (<0.01)
9/20
4/4 (>0.05)
11/45
22/29 (<0.01)
11/45
22/24 (<0.01)
0/4
2/16 (<0.01)
0/11
5/20 (<0.01)
5/30
9/25 (>0.05)
5/14
4/5 (>0.05)
10/44
13/30 (>0.05)
10/44
13/19 (<0.01)
0824p
9-22
06/10/86
-------
                              TABLE 9-14 (cont.)
                             QUALITY OF EVIDENCE

Strengths of study:  study was  conducted  over  the Hfespan  of  the  animal;
                     comprehensive  hlstologlcal  examination  was  performed;
                     time-to-tumor Information

Overall adequacy:    adequate


aSource: Thorpe and Walker, 1973

bComb1ned Incidence of hyperplastk nodules  and hepatocelltrlar carcinoma

cThese  are  cumulative Incidences  for  mice  that died  and were  subsequently
 examined.

dThe Incidences are for mice killed at  the end of the experiment.

elnc1dence  subsequent  to  the  finding  of the first tumor  In any  tissue  1n
 each group of mice (I.e., excluding mice examined  before the first tumor)
0824p                               9-23                             06/27/86
-------
    An  adjusted  potency factor  of  10.7 can  be  derived on  the  basis of an
 Increased  combined  Incidence  of hepatic  hyperplastlc  nodules  and  hepato-
 cellular carcinomas  1n  male CF1  mice fed 200  ppm  B-HCH 1n the diet  for  110
 weeks (Thorpe and  Walker, 1973).  This  value  was obtained  by  multiplying  the
 unadjusted potency factor by the cube root of  the  ratio of human  body weight
 (70 kg)  to mouse  body  weight  (0.03 kg).   Adjustment  for  Iess-than-l1fet1me
 exposure was not  necessary  since the mice were treated  for 110 weeks (Table
 9-15).   The  potency  factor  of 1.7  reported  1n U.S. EPA (1984b)  was  derived
 from  the Thorpe  and  Walker  (1973)  study, but was  based on malignant  liver
 tumors only.  The  value of  10.7  1s  based  on  the  combined Incidence  of benign
 and malignant hepatic tumors and  1s  therefore the  recommended  value.
    A chemical with  a  potency  factor  of 10.7  and a  EPA  Group  C  Classifi-
 cation has a LOW hazard ranking under CERCLA.
 9.2.3.   Y-HCH  (Llndane).   Dietary  y-HCH was  shown  to  cause   a  definite
 Increase In  the  Incidence  of liver  tumors 1n  male  CF1 mice fed  400  ppm  for
 110  weeks  (Thorpe  and  Walker,  1973).    Borderline  responses  were  also
 observed 1n  two  other  studies  1n male dd mice fed  600 ppm for 32  weeks  and
 examined  5-6 weeks  after  treatment  (Hanada et  al.,  1973),  and   In  male
 ICR-JCL  mice fed  600 ppm for 26 weeks  (Goto  et al.,  1972).   No  liver tumors
were  observed  1n  dd mice  fed  up  to  500  ppm  for  24 weeks (Ito  et  al.,
 1973a,b; Nagasaki  et  al.,  1972a) or 1n Wlstar rats fed  500 ppm for  up to 48
weeks  (Ito  et   al.,  1975).   Significant  compound-related  development  of
 tumors  of  any  type  was  not observed  1n NHRI  mice  (Herbst  et  al.,  1975;
Welsse and Herbst, 1977), B6C3F1 mice  (NCI.  1977),  Osborne-Mendel rats (NCI.
 1977) or Wlstar  rats  (FUzhugh  et  al.,  1950).   The study conducted by  NCI
 (1977)  has  been   criticized  for poor  survival  (rats),  changes  1n dosing
 regime  and  the   possibility  that  male  rats  did  not  receive   MTDs  (IARC.
 1979).   The  negative   findings  of   FUzhugh   et  al.   (1950)  are  also

 0824p                               9-24                             04/22/88
-------
                                  TABLE  9-15
                  Derivation of Potency  Factor  (F)  for  B-HCH
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:
Llfespan of animal:
Target organ:
Tumor type:

Experimental doses/exposure (ppm)
Transformed doses (mg/kg/day)*:
Tumor Incidence:
Unadjusted 1/ED10:
1/EDio (F Factor):
   Thorpe and  Walker,  1973
   oral
   mouse
   CF1
   male
   diet
   0.03  kg
   110 weeks
   110 weeks
   110 weeks
   liver
   hyperplastlc nodules  and hepato-
   cellular carcinoma
   0
   0
   11/45
200
26
22/24
   0.804783634
   10.7
*Assumes a food factor of 0.13
0824p
9-25
                    06/10/86
-------
 Inconclusive   since   only   small    numbers   of   animals   were   examined
 historically.  The  negative  findings  of  Ito et al. (1973a,b),  Nagasaki  et
 al.  (1972a)  and Ito  et  al.  (1975)  might be  attributed  to small numbers  of
 animals and short duration of study.
    Incidence  data  for  the  positive  studies  that  reported  Incidences  of
 h1stblog1cally  verified  tumors are  summarized  In Tables  9-16  and 9-17.   A
 positive  study  lacking this type of  Incidence  data (Goto et al.,  1972)  and
 negative  studies  are   summarized  1n  Table 5-3.   According to IARC  criteria,
 and EPA  guidelines  (U.S.  EPA,  1986b),  there 1s  sufficient  evidence  1n  one
 study and  1n  two borderline  studies  that give rise  to some uncertainty about
 the strength  of carcinogenic evidence  1n animals.   Notably  a metabolite  of
 Undane,  2,4.6-tr1chlorophenol  has  a Group  B2  weight of evidence and  this
 metabolite has  been  Identified  In  both exposed  rodents  and humans.   Since
 there are no human data available,  f-HCH  1s placed EPA Group  B2-C  (I.e.,
 between Groups B2 and  C)  (U.S.  EPA,  1985a,  1986a).   This  range  reflects some
 uncertainty 1n the strength of the animal  cardnogenldty  data.
    The  study that  provides  the best  estimate  of  carcinogenic potency  Is
 that of Thorpe  and  Ualker  (1973).  An  adjusted potency factor of 7.4  can be
 estimated  from  this  study and  1s  based on the  Increased combined  Incidence
 of hyperplastlc  nodules  and hepatocellular carcinomas  1n male  CF1  mice  fed
 400 ppm  T-HCH for  110 weeks  (Table 9-18).   The  adjusted  value  was obtained
 by multiplying  the  animal value  (unadjusted  value)  by  the cube  root  of  the
 ratio of  human  body weight (70 kg)  to  mouse  body weight  (0.03  kg).  Adjust-
ment  for  Iess-than-l1fet1me  exposure  was  not  necessary  since  mice  were
exposed for 110 weeks.   This  potency factor of  7.4  differs from the value of
 1.7 reported  by  U.S.  EPA (1984b); the  U.S. EPA  (19845) value was also based
on the  data  of Thorpe and  Ualker (1983) but was estimated on  the basis of


 0824p                               9-26                             04/22/88
-------
                                  TABLE 9-16

          Incidence  of  Hepatomas  1n  dd  Mice  Fed y-HCH  1n  the Diet for
                   32 Weeks and Examined After 37-38 Weeks3
Sex
M



F




Dose
(ppm)
0
100
300
600
0
100
300
600
QUALITY OF
Tumor
0/14
0/10
0/9
3/4
0/15
0/8
0/7
1/3
Incidence**








EVIDENCE
Strengths of study:

Weaknesses of study:



Overall adequacy:
three doses tested; organs other than liver examined

short  duration;   small   numbers   of   mice/treatment;
purity of  compound was not  specified;  survival  In  600
ppm group was poor

limited
aSource: Hanada et a!., 1973

bNumber  of  mice  started  on test  was  10-11/sex  for  each treated  group and
 20-21/sex for controls.  Only mice that survived >36 weeks were examined.
0824p
              9-27
06/10/86
-------
                                 TABLE 9-17

       Incidence  oT  Liver Neoplasms  1n CF1 Mice Fed y-HCH  (>99.5% pure)
                       In the Diet for up  to 110 Weeks3
Sex
M





F



F

Duration of Exposure
0-17 months0
0-21 months0
0-25 months0
26 monthsd
Total (0-26 months)
Adjusted total Incidence6
0-17 months0
0-21 months0
0-25 months0
26 monthsd
Total (0-26 months)6
Adjusted total Incidence6
Dose
(ppm)
0
400
0
400
0
400
0
400
0
400
0
400
0
400
0
400
0
400
0
400
0
400
0
400
Tumor Incidence**
(p value, 2x2 Exact Test)
0/6
6/86 (<0.01)
2/11
14/15 (<0.01)
2/25
23/24 (<0.01)
9/20
4/5
11/45
27/29 (<0.01)
11/45
27/28 (<0.01)
0/4
9/18 (<0.01)
0/11
14/23 (<0.01)
5/30
19/28 (<0.01)
5/14
1/1 (<0.05)
10/44
20/29 (<0.05)
10/44
20/21 (<0.05)
0824p
9-28
                                                                      06/10/86
-------
                              TABLE  9-17  (cont.)
                             QUALITY OF EVIDENCE
Strengths of study:  study was  conducted  over  the Hfespan  of  the  animal;
                     comprehensive  hlstologlcal  examination  was  performed;
                     t1me-to-tumor Information given
Overall adequacy:    adequate

aSource: Thorpe and Walker, 1973
^Combined Incidence of hyperplastlc nodules  and hepatocellular carcinomas
cThese  are  cumulative Incidences  for  mice  that  died  and were  subsequently
 examined.
dThe Incidences are for mice killed at  the end of the experiment.
elnc1dence  subsequent  to  the  finding  of the first tumor  In any  tissue  In
 each group of mice.
0824p                               9-29                             06/10/86
-------
                                  TABLE  9-18
                Derivation of the Potency Factor  (F)  for  y-
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:
Ufespan of animal:
Target organ:
Tumor type:

Experimental doses/exposure (ppm)
Transformed doses (mg/kg/day)*:
Tumor Incidence:
Unadjusted l/ED-jo:
1/E010 (F Factor):
    Thorpe  and  Walker,  1973
    oral
    mouse
    CF1
    male
    diet
    0.03 kg
    110 weeks
    110 weeks
    110 weeks
    liver
    hyperplastlc  nodules  and hepato-
    cellular  carcinoma
    0
    0
    11/45
    0.557044101
    7.4
400
52
27/28
*Assumes a food factor of 0.13
0824p
9-30
                   10/24/86
-------
malignant  liver  tumors  only.   The  potency  factor of  7.4  Is  based on  the
combined  Inddence'of  benign and  malignant  liver  tumors  and Is therefore the
recommended value.
    A  potency  factor  of 7.4 and  a CAG  Group  rating  of B2-C  place  y-HCH  In
the MEDIUM-LOW categories of the CERCLA hazard ranking scheme.
9.2.4.   4-HCH.   Dietary   s-HCH   did  not   cause  neoplastlc  or   nonneo-
plastlc changes  In  the  livers  of  male dd mice (Ito  et  a!.,  1973a;  Nagasaki
et al.,  1972a)  or male  Wlstar  rats  (Ito et al.,  1975).   These  studies  used
small  numbers  of  animals and were conducted  for  only 24 weeks.   Goto et al.
(1972)  reported  that   a   mixture  of  6-  and  c-HCH  caused   an  Increased
Incidence  of  benign and malignant hepatomas  1n  male ICR-JCL mice  after  26
weeks  of  dietary administration,  but  the  Individual  Isomers were not tes.ted.
There were no human data available.
    According  to  the   EPA  cancer  guidelines  (U.S.   EPA,   1980),  there  1s
limited   evidence   that  4-HCH   Is   carcinogenic   In  animals.    Therefore,
6-HCH  1s  placed  1n  EPA Group C,  but  It  Is  not possible to derive  a potency
factor.   Accordingly,   a default  potency  category  of 2  Is  assigned.   A
potency Group  of  2 and  a Group C we1ght-of-evidence result In  a  LOW hazard
ranking under CERCLA.
9.2.5.   c-HCH.   Data  pertaining  to  the  carcinogenic  effects  of  e-HCH
could  not  be  located   In the  available literature as  cited 1n the Appendix.
Goto  et  al.  (1972)  reported  that a  mixture of  4-HCH  and c-HCH  caused  an
Increased  Incidence of benign  and malignant  hepatomas  In  male  ICR-JCL  mice
after  26  weeks of  dietary  administration,  but  the  Individual  Isomers  were
not tested.
0824p                               9-31                             03/18/88
-------
    According  to  the  EPA  cancer  guidelines  (U.S.  EPA,  1980),   there  1s
limited  evidence - that   e-HCH   Is  carcinogenic  In  animals.   Therefore,
e-HCH  falls  Into EPA Group  C,  and  H  Is  not possible  to  derive  a potency
factor.   Accordingly,  a  default  potency  category  of  2  Is   assigned.   A
potency Group  of 2 and a Group  C  we1ght-of-evidence  result  In a LOW hazard
ranking under CERCLA.
9.2.6.   T-HCH.   T-HCH  has  been  shown  to  cause  Increased   Incidences  of
liver  neoplasms  1n  four  strains of mice (Hanada  et  al.,  1973; Goto et al.,
1972;  Kashyap  et al.,  1979; N1gam et al., 1984a;  Bhatt  et  al., 1981; Munlr
et al., 1983;  Nagasaki  et al.,  1971, 1972b;  Munlr  and  Bhlde,  1984) but not
In Wlstar  rats (Munlr et al., 1983)  or Syrian  golden  hamsters  {Munlr et al.,
1983).
    According  to  the  EPA  cancer  guidelines  (U.S.   EPA,  1986b),  there   Is
sufficient  evidence to  conclude  that   T-HCH Is  carcinogenic  to animals.
Since  there  are  no human data  available,  T-HCH   Is placed  1n  EPA  Group 82.
This  Is  Interpreted  to  Indicate that  T-HCH 1s probably  carcinogenic   to
humans.  Incidence  data  from the  positive  studies  that  reported  Incidences
of  h1stolog1cally  verified  tumors  are  summarized  In  Tables  9-19  through
9-23.  Positive  studies  lacking this type of  data  and negative studies are
summarized 1n Table 5-5.
    The study  that provides  the  best  estimate   of  carcinogenic potency  Is
that of Munlr  et  al. (1983).  An adjusted  potency factor  of  8.08 Is based  on
an  Increased  Incidence  of  benign  and malignant  liver  tumors   In  male  Swiss
mice fed 0,  125  or 250 ppm T-HCH  from  8-10  weeks of age to 15-17 months  of
age (Table 9-24).   The potency  factor was  adjusted  for  body  weight and less-
                                                           1/3
than-Hfetlme  exposure   [unadjusted  1/ED1Q  x  (70/0.03)"°   x   (24/15)3]
(Table 9-25).
0824p                               9-32                             03/18/88
-------
                                  TABLE 9-19
          Incidence of  Hepatomas  In  dd  Mice  Fed  T-HCH  In  the Diet for
                32 Weeks and Examined 5-6 Weeks  Posttreatment3
Sex
M



F




Dose
(ppm)
0
100
300
600
0
100
300
600
QUALITY OF
Tumor
0/14
0/10
4/4
4/4
0/15
0/8
3/5
5/5
Inc1denceb








EVIDENCE
Strengths of study:   three doses tested
Weaknesses of study:  small  numbers  of mice/treatment;  short  duration  of
                      exposure; 1somer1c composition not specified
Overall adequacy:     limited

aSource: Hanada et al., 1973
^Number  of  mice  started  on test  was 10-1 I/sex  for  each treated  group and
 20-21/sex for controls.  Only mice that survived >36 weeks were examined.
0824p                               9-33                             06/27/86
-------
                                  TABLE  9-20
            Incidence of Liver  Neoplasms  In Male  dd Mice  Fed T-HCH
                          In the Diet for 24 Heeksa'b
Dose
(ppm)
0
6.6
66
660
Tumor Inc1dencec
0/14
0/20
0/20
20/20
                             QUALITY OF EVIDENCE
Strengths of study:   composition of compound  reported;  three doses  tested;
                      hlstopathologlcal examinations were performed  on  major
                      organs
Weaknesses of study:  short duration of exposure
Overall adequacy:     adequate

aSource: Nagasaki et al.. 1971, 1972b;  Nagasaki, 1973
b66.5X a-HCH, 11.4X B-HCH, 15.2% y-HCH, 6.4X 4-HCH and 0.5X "other"
GComb1ned Incidence of hyperplastlc nodules and hepatomas
0824p                               9-34                             06/10/86
-------
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9-35
06/10/86
-------
                                  TABLE 9-22
    Incidence of  Liver  Neoplasms  In Male Swiss Mice Fed T-HCH In the Diet*
Dose/Exposure
0 ppm/NA
500 ppm/2 months
500 ppm/2 months
500 ppm/2 months
500 ppm/4 months
500 ppm/4 months
500 ppm/4 months
500 ppm/6 months
500 ppm/6 months
500 ppm/6 months
500 ppm/8 months
500 ppm/8 months
500 ppm/8 months
Duration
of Study
(months)
18
2
6
12
4
8
14
6
10
16
8
12
18

Neoplastlc
Nodules
0/75
0/6
0/6
0/15
0/6
0/6
6/15
4/6
5/6
7/15
2/6
2/6
3/15
Tumor Incidence
Trabecular Cell
Carcinoma
0/75
0/6
0/6
0/15
0/6
0/6
0/15
0/6
• 0/6
8/15
4/6
4/6
12/15

Pulmonary
Metastasis
0/75
0/6
0/6
0/15
0/6
0/6
0/15
0/6
0/6
2/15
0/6
1/6
14/15
                              QUALITY  OF  EVIDENCE
Strengths of study:  conducted for  most  of  the  animals'  llfespan;  time-to-
                     tumor Information
Weakness of study:   Isomerlc composition not reported
Overall adequacy:    adequate

*Source: N1gam et al., 1984a
0824p
9-36
06/10/86
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                                  TABLE  9-23

       Incidence  of  Liver  Neoplasms  In Male  Swiss Mice Fed T-HCH In the
              Diet  from 8-10 Weeks of Age up to 22 Months of Agea
Age at Examination
(months)
8-11



12-14



15-17



18-22



Dose
(ppm)
125
250
500
0
125
250
500
0
125
250
500
0
125
250
500
0
Tumor Incidence15
0/10
4/17
28/37
0/22
0/10
9/12
10/10
0/16
8/20
12/12
not examined
2/22c
9/15
not examined
not examined
2/22c
Strengths of study:
Weaknesses of study:
Overall adequacy:
        QUALITY  OF  EVIDENCE

sufficient duration of exposure; several doses  tested;
time-to-tumor Information

composition  of  compound  not  reported;  no   matched
controls0

Adequate
aSource: Hunlr et al., 1983

^Combined Incidence of benign hepatic nodules and hepatocellular carcinomas.
 Control Incidences  are  taken from  a  similar experiment  1n  male  Swiss mice
 conducted 1n the same laboratory and reported In the same paper.

Clnc1dence In controls killed at 15-20 months of age (see footnote b)
0824p
              9-37
06/10/86
-------
                                  TABLE 9-24

           Incidence of Liver Tumors In Mice Fed T-HCH 1n the Diet
           from 8-10  Weeks  of  Exposure  up  to 20  Months of Exposure3
Strain Sex
Swiss M
M
M
F
F
F
BALB/c M
N
F
F
Dose and Duration
of Exposure
none
none
none
500 ppm continuous
500 ppm continuous
500 ppm continuous
500 ppm 2 months
500 ppm 2 months
500 ppm 2 months
none
none
none
500 ppm continuous
500 ppm continuous
500 ppm continuous
500 ppm 3 months
500 ppm 3 months
500 ppm 3 months
none
none
none
500 ppm continuous
500 ppm continuous
500 ppm continuous
none
none
none
500 ppm continuous
500 ppm continuous
500 ppm continuous
Age at
Examination
(months)
8-11
12-14
15-20
8-11
12-14
15-20
8-11
12-14
15-20
8-11
12-14
15-20
8-11
12-14
15-20
8-11
12-14
15-20
8-11
12-14
15-20
8-11
12-14
15-20
8-11
12-14
15-20
8-11
12-14
15-20
Tumor
Incidence**
0/22
0/16
2/22
28/37
10/10
12/12
0/15
0/10
0/10
0/20
0/16
1/20
3/16
6/16
14/14
0/10
0/8
11/12
0/8
0/8
1/15
9/10
10/10
NR
0/8
0/9
2/20
7/10
10/10
NR
0824p
9-38
06/10/86
-------
                              TABLE 9-24 (cent.)
                              QUALITY  OF  EVIDENCE
                     sufficient duration of  exposure;  time-to-tumor  Informa-
                     tion; two strains and both sexes examined
                     composition of compound not reported
                     adequate
Strengths of study:

Weakness of study:
Overall adequacy:
aSource: Munlr et al., 1983
^Combined Incidence of benign hepatic nodules and hepatocellular carcinomas
NR a Not reported
0824p
                                    9-39
06/10/86
-------
                                  TABLE  9-25
                  Derivation of  Potency  Factor  (F)  for  T-HCH
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment:

Duration of study:
Llfespan of animal:
Target organ:
Tumor type:

Experimental doses/exposure (ppm)
Transformed doses (mg/kg/day)*:
Tumor Incidence:
Unadjusted 1/ED^p:
1/ED10 (F Factor):
  Munlr et al., 1983
  oral
  mouse
  Swiss
  male
  diet
  0.03 kg
  from 8-10  weeks  of  age  until  15-17
  months of  age  (-15  months)
  same as  above
  24 months
  liver
  benign hepatic  nodules  and  hepato-
  cellular carcinomas
   0
   0
   2/22
125
16.25
8/20
250
 32.5
12/12
   0.148735599
   8.1
*Assumes a food factor of 0.13
0824p
9-40
                     06/10/86
-------
    A  potency  factor  of 8.1 and a CAG  Group  rating  of  B2  place T-HCH' \n  the
MEDIUM  category  of the  CERCLA  ranking  scheme.  A summary  of  all  HCH  cancer
data  Is presented  In Section 9.3.
9.3.   SUMMARY OF  ALL HCH CANCER DATA
    The   summary   of   the   animal   cardnogenldty   data   for   a-,  B-,   Y-»
6- and  e-HCH  Is  presented  1n  Table   9-26.    Such  summary  considerations
Indicate  that at  dietary doses  In excess of 100-200 ppm,  cancer of the liver
often  results  mainly  In the mouse and  sometimes  1n the  rat.   Tumor  occur-
rence  can take place  as early  as 24-36 weeks  following  commencement  of  the
HCH dosing regimen.  The resulting  estimates  of cancer  potency from a number
of  studies  place  the  q *  parameter  In  the  1.3-6.3  (mg/kg/day)'1  range
(corrected   for   body   weight  differences   and  Iess-than-l1fet1me  dosing
schedules).  The  technical  mixture,  which  Is  a  mixture of the Isomers,  most
closely  relates   to a-HCH  In  category 82  and q *  comparisons.   a-HCH  Is
the  largest  component  at   65%;  therefore,  1t  suggests  a  general  additive
contribution  of   the  components  with  the  largest   (a)  Imposing  the  cancer
characteristics of T-HCH mixture.
0824p                               9-41                             10/27/86
-------











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                                                                    03/18/88
-------
                               10.  REFERENCES

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Ahdaya, S.M., R.J.  Monroe and F.E. Guthrle.  1981.  Absorption and  distribu-
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Ahmed, F.E., R.W.  Hart and  N.3.  Lewis.  1977.   Pesticide  Induced  DNA damage
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0825p                               10-1                             06/10/86
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0825p                               10-2                             06/10/86
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0825p                               10-3                             06/10/86
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Benes,  V.  and  R.  Sram.   1969.   Mutagenlc activity  of  some  pesticides  1n
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0825p                                10-4                             06/10/86
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0825p                               10-5                             06/27/86
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Canton, J.H.,  G.J.  Van Esch, P.A. Greve  and  A.B.A.M.  Van Hellemond.  1977.
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0825p                               10-6                             06/10/86
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Chlou, C.T.,  V.H.  Freed.  L.J. Peters  and R.L.  Khonert.   1980.   Evaporation
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0825p                               10-7                             06/10/86
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0825p                               10-8                             06/10/86
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Davis, H.C. and H. H1du.  1969.  Effects of pesticides on embryonic develop-
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0825p                               10-9                            06/10/86
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DlkshHh,  T.S.S.,  S.K.  Tandon,  K.K.  Oatta,  P.K.  Gupta  and  J.R.  BehaM.
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0825p                               10-10                            06/10/86
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0825p                               10-12                            06/10/86
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Falandysz,  J.   1982.   Chlorinated  hydrocarbons  In salmon netted  In  Gdansk
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0825p                               10-14                            06/27/86
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Grey, U.E., O.E.  Marthre and  S.J.   Rogers.    1983.   Potential  exposure  of
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0825p                               10-15                            10/28/86
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Gupta,  P.K.,  V.S.  Mujumdar  and  P.S.  Rao.   1984.  Studies on the toxldty of
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0825p                               10-16                            10/28/86
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Hartley,  D.M.  and  J.B.  Johnston.   1983.   Use  of  the  freshwater   clam
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Herbst, M.,  I. Uelsse and H.  Koellmer.   1975.   Possible  hepatocarclnogenlc
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0825p                               10-17                            10/28/86
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Hill,  O.W.   and  P.L.  McCarty.    1976.   Anaerobic  degradation  of  selected
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0825p                               10-18                            10/28/86
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0825p                               10-19                            10/28/86
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Juarez,  A.  and J.A.  Guzman.   1984.   Chronic effect  of  five organochlorine
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Kaiser,  K.L.E.   1982.   Early  determination  of  organochloMne contamination
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Kanazawa,  J.   1981.  Measurement of  the  bloconcentratlon factors of  pesti-
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0825p                               10-20                            10/28/86
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Katz,  M.   1961.    Acute   toxldty  of  some  organic  Insecticides  to  three
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Kaur,  K.  and   S.   Kirk.   1983.   Effect  of  BHC  and  sumlthlon  on  ovarian
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0825p                               10-21                            10/28/86
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0825p                               10-22                            10/28/86
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0825p                               10-23                            10/28/86
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0825p                               10-25                            10/28/86
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0825p                               10-27                            10/28/86
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0825p                               10-28                            10/28/86
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0825p                               10-29                            10/28/86
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0825p                               10-31                             10/28/86
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Portlg,  J.P.,  et al.   1973.   B1odegradat1on  of a-hexachlorocyclohexane.
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Probst,  G.S.,  R.E.  McMahon,  L.E.  Hill,  C.Z.  Thompson,  J.K.  Epp and  S.B.
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0825p                               10-34                            10/28/86
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 Reuber, M.D.  1979.   CardnogenlcHy of Undane.  Environ. Res.   19: 460-481.


0825p                               10-35                            10/28/86
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Rlckard, O.G. and O.E.R. Dulley.  1983.  The levels of  some heavy metals and
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1978.   Effects  of  feeding  llndane to  dogs  for  periods  of up  to  2  years.
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Rocchl, P.,  P. Perocco,  H.  Alberghlnl, A.  Flnl and G.  Prodi.   1980.   Effect
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Saleh,  F.Y.,  K.L.  Olckson and  J.H.  Rodgers,  Jr.   1982.  Fate of  llndane  In
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SantolucHo,  J.A.   1975.  The  use of  quantitative  EEG  for  detecting  low-
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Schulte-Hermann,  R.  and  U.  Parzefall.   1981.    Failure  to  discriminate
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 Schwarzenbach,  R.P.  and  J.  Westall.   1981.   Transport  of nonpolar  organic
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 Shahln, M.M.  and  R.C. Von Borstel.   1977.   Mutagenlc and  lethal  effects  of
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Sharom. M.S., J.R.W. Miles, C.R.  Harris and F.L. McEwen.  1980.   Persistence
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0825p                               10-39                            10/28/86
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Shell Oil Co.   1982.  The  effects  of  water  hardness,  temperature  and  size of
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Shlmazu,  H.,  N.  Shlralshl,  T.  Akematsu,  N.  Ueda  and  T.  Suglyama.   1976.
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Shlrasu, Y., M. Morlya, K. Kato, A. Furuhashl, and  T.  Kada.   1976.   Mutagen-
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Shlvanandappa, T. and M.K. Krlshnakumarl.   1981.  H1stochem1cal  and  biochem-
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Shlvanandappa,  T., M.K.  Krlshnakumarl and  S.K.  Majumder.  1982.   Inhibition
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0825p                               10-40                            10/28/86
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Shukla,  G.S.  and  Omkar.   1983.   Acute  toxlclty  of   Insecticides   to  a
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0825p                               10-42                            10/28/86
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0825p                               10-43                            10/28/86
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Takeda,  T.    1978.   Effects of  DOT,  BHC  and  PCB  on  the  growth  of  fish.
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0825p                               10-45                            10/28/86
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U.S.  EPA.    1982b.   Health and  Environmental  Effects  Profile for  Llndane.
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01/22/86).    Office  of  Health  and  Environmental  Assessment,  Environmental
Criteria and Assessment Office, Cincinnati, OH.
0825p                               10-47                            03/18/88
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U.S.  EPA.   1986b.    Guidelines   for  Carcinogen  Risk  Assessment.   Federal
Register.  51(185): 33992-34003.

Velth, G.D., D.L. OeFoe and B.V.  Bergstedt.  1979.  Measuring and estimating
the bloconcentratlon  factor of  chemicals  In  fish.   J. Fish. Res. Board Can.
36(9): 1040-1048.

Velson, F.P.J. and O.F. Alderdlce.  1967.  ToxkHles of two Insecticides  to
young coho salmon.  J. Fish.  Res.  Board  Can.  24:  1173-1175.

Vonk,  J.W.  and  J.K.  Qulrljns.   1979.   Anaerobic  formation  of alpha-hexa-
chlorocyclohexane  from gamma-hexachlorocyclohexane  In   soil  and  by  Esche-
rlchla coll.  Pestle.  Blochem.  Physlol.   12(1):  68-74.

Wassermann, M.,  M. Rorv,  B.  Bercov1c1,  0. Wassermann, S. Cucos and A.  Pines.
1982.   Premature  delivery  and  organochlorlne  compounds:  Polychlorlnated
blphenyls  and  some   organochlorlne  Insecticides.    Environ.   Res.    28(1):
106-112.

Welsse,  I.  and M. Herbst.   1977.  CarclnogenlcHy  study  of  llndane  In  the
mouse.  Toxicology.   7: 233-238.

Welch, R.M. and  J.W.A. Ftndlay.  1981.   Excretion  of drugs In  human  breast
milk.  Drug Metab. Rev.  12(2): 261-278.

Wellborn, T.L.J.  1971.   ToxkUy of  some compounds to  striped  bass flnger-
Ungs.  Prog.  FIsh-CultuMst.   33(1):  32-36.
0825p                               10-48                            03/18/88
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WhHten,  O.K.  and C.J. Goodnight.   1966.   ToxIcHy of some common  Insecti-
cides to  tublflcldS.  J. Water Pollut. Control Fed.   38:  227-235.

WHO  (World  Heath Organization).   1967.   1966 Evaluations of  some  pesticide
residues  1n food.  WHO/Food Add.767/32.  p. 126-147.  (Cited  In IARC,  1979)

WHO  (World  Heath Organization).   1969.   1968 Evaluations of  some  pesticide
residues  In food.  WHO/Food Add./69.35.  p. 17-31.  (Cited In IARC,  1979)

Williams, D.T.,  E.R.  Nestmann, G.L.  Lebe,  F.M.  Bevolt and  R.  Olson.   1982.
Determination of  mutagenlc potential  and  organic  contaminants  of  Great  Lakes
drinking water.  Chemosphere.  11: 263-276.

Wilson, A.J.   1965.   Chemical assays.   lt±:  Ann.  Rep. Bureau  of  Comm.  F1sh.
Blolog. Lab.,  Gulfbreeze,  FL.  U.S.  Bur.  Comm.  Fish. C1rc-. 247.   (CHed  In
Plmental, 1971)

Wlndholz,  M.,   Ed.    1983.   Merck  Index,  10th  ed.   Merck  and  Co.,  Inc.,
Rahway, NJ.   p. 789.

Yamamoto, T.,  T.  Egashlra,  Y.  Yamanaka,  T.  Yoshlda and Y. Kurolwa.   1983.
Initial  metabolism  of  gamma-hexachlorocyclohexane  (f-HCH)  by  rat  Hver
mlcrosomes.   J. Pharmacoblo-Dyn.  6(10): 721-728.

Yamato, Y., M.  Koyanaga and  T.  Watanabe.   1983.   Comparative bloaccumulatlon
and elimination of  BHC Isomers  In  short-necked  clam Venerupls  japonlca  and
guppy Poedlla retlculata.   Bull. Environ. Contain. Toxlcol.   31(3):  352-359.
0825p                               10-49                            03/18/88
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Zarooglan, G.E., J.F. Heltsch and  M.  Johnson.   1985.   Estimation of blocon-
centratlon  In  marine   species  using  structure-activity  models.   Environ.
Toxlcol. Chem.  4(1):  3-12.

Zesch, A., K. NHzsche and M. Lange.  1982.  Demonstration of  the percutane-
ous  resorptlon  of  a  UpophlUc  pesticide  and  Us possible  storage  In  the
human body.   Arch.  Dermatol.  Res.   273:  43-49.   (Cited  1n U.S.  EPA,  1985a)

Zoeteman, B.C.J.,  K.  Harmsen,  J.8.H.J.  Unders, C.F.H.  Morra  and W. Sloof.
1980.   Persistent  organic  pollutants  In river  water  and  groundwater on  the
Netherlands.   Chemosphere.   9:  231-249.
0825p                               10-50                            03/18/88
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                                   APPENDIX

                              LITERATURE SEARCHED



    This  profile  1s  based  on data  Identified  by  computerized  literature

searches of the following:


         CASR online (U.S. EPA Chemical  Activities Status Report)
         CAS online STN International
         TOXLINE
         TOXBACK 76
         TOXBACK 65
         RTECS
         OHM TADS
         STORET
         SRC Environmental Fate Data Bases
         SANSS
         AQUIRE
         TSCAPP
         NTIS
         Federal Register


These searches  were  conducted In  October, 1985.   In addition,  hand  searches

were  made  of   Chemical  Abstracts  (Collective  Indices  6  and 7),  and  the

following secondary sources were reviewed:


    ACGIH  (American  Conference of  Governmental  Industrial  Hyglenlsts).
    1980.   Documentation  of  the  Threshold Limit Values, 4th  ed. .  (In-
    cludes  Supplemental  Documentation,  1981,  1982,  1983).   Cincinnati,
    OH.   486 p.

    ACGIH  (American  Conference of  Governmental  Industrial  Hyglenlsts).
    1985.   TLVs:  Threshold  Limit  Values for  Chemical  Substances  and
    Physical Agents  In the  Workroom  Environment  with  Intended Changes
    for  1985-1986.  Cincinnati, OH.  114 p.

    Clayton,  G.D.  and F.E.   Clayton,  Ed.   1981.  Patty's  Industrial
    Hygiene  and Toxicology,  3rd   rev.  ed..  Vol. 2A.   John Wiley  and
    Sons, NY.  2878 p.

    Clayton,  G.D.  and F.E.   Clayton,  Ed.   1981.  Patty's  Industrial
    Hygiene  and Toxicology,  3rd   rev.  ed..  Vol. 2B.   John Wiley  and
    Sons, NY.  p. 2879-3816.
0826p                               A-l                              06/10/86
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    Clayton,  G.O.  and  F.E.  Clayton,   Ed.   1982.   Patty's   Industrial
    Hygiene and  Toxicology,  3rd  rev.   ed.,  Vol.  2C.   John  Wiley and
    Sons, NY.   p. 13817-5112.

    Grayson, M. and  D.  Eckroth,  Ed.   1978-1983.  K1rk-0thmer  Encyclo-
    pedia of Chemical Technology,  3rd ed.  John Wiley and Sons,  NY.  23
    Volumes.

    Hamilton,  A.  and H.L. Hardy.  1974.  Industrial Toxicology,  3rd ed.
    Publishing Sciences  Group,  Inc.,  Littleton,  MA.   575 p.

    IARC  (International  Agency for  Research  on Cancer).   IARC  Mono-
    graphs  on  the  Evaluation  of Carcinogenic  Risk  of  Chemicals  to
    Humans. WHO,  IARC,  Lyons.  France.

    ITII (International  Technical  Information  Institute).  1982.   Toxic
    and  Hazardous  Industrial  Chemicals Safety  Manual  for Handling and
    Disposal with  Toxldty and Hazard Data.   ITII,  Tokyo,  Japan.   700 p.

    NTP  (National  Toxicology  Program).   1986.   Toxicology Research and
    Testing  Program.   Chemicals   on   Standard  Protocol.    Management
    Status.

    Ouellette,  P.P.  and  J.A.  King.   1977.    Chemical  Week  Pesticide
    Register.   McGraw-Hill Book Co..  NY.

    Sax, N.I.   1979.  Dangerous Properties of  Industrial  Materials, 5th
    ed.  Van Nostrand Relnhold Co., NY.

    SRI  (Stanford  Research  Institute).   1984.   Directory  of  Chemical
    Producers.  Menlo Park,  CA.

    U.S. EPA.   1985.   Status  Report on Rebuttable Presumption  Against
    Registration  (RPAR)  or  Special  Review Process.  Registration Stan-
    dards and  the Data Call  In  Programs.  Office  of  Pesticide Programs,
    Washington, DC.

    U.S. EPA.   1985.  CSB Existing Chemical  Assessment  Tracking System.
    Name and  CAS  Number  Ordered  Indexes.   Office of Toxic  Substances,
    Washington. DC.

    USITC  (U.S.   International Trade   Commission).    1983.    Synthetic
    Organic Chemicals.   U.S.  Production  and  Sales.  1982.  USITC Publ.
    1422, Washington, DC.

    Verschueren,  K.   1983.   Handbook  of  Environmental  Data  on Organic
    Chemicals, 2nd ed.  Van Nostrand  Relnhold Co., NY.

    Worthing,   C.R.  and  S.B. Walker, Ed.   1983.  The Pesticide Manual.
    British Crop  Protection Council.   695 p.

    Wlndholz,  M.,  Ed.  1983.   The Merck  Index,  10th  ed.   Merck and Co.,
    Inc., Rahway,  NJ.
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    In  addition,  approximately  30 compendia  of  aquatic  toxlclty  data were

reviewed,  Including the following:


    Battelle's  Columbus  Laboratories.   1971.   Water  Quality Criteria
    Data  Book.   Volume  3.   Effects  of   Chemicals   on  Aquatic  Life.
    Selected  Data  from the Literature  through 1968.   Prepared for  the
    U.S. EPA under Contract No. 68-01-0007.  Washington, DC.

    Johnson,  W.W.  and  M.T.  Flnley.   1980.  Handbook  of Acute Toxldty
    of  Chemicals  to  F1sh  and  Aquatic   Invertebrates.   Summaries  of
    Toxldty  Tests  Conducted  at  Columbia National  Fisheries Research
    Laboratory.   1965-1978.   U.S. Oept.  Interior,  Fish  and Wildlife
    Serv. Res. Publ. 137, Washington, DC.

    McKee,  J.E.  and  H.W.  Wolf.   1963.  Water  Quality Criteria, 2nd  ed.
    Prepared  for  the  Resources  Agency  of  California,  State  Water
    Quality Control Board.  Publ.  No. 3-A.

    Plmental, D.  1971.   Ecological  Effects of Pesticides  on  Non-Target
    Species.  Prepared  for  the U.S. EPA, Washington,  DC.   PB-269605.

    Schneider, B.A.   1979.   Toxicology  Handbook.   Mammalian and Aquatic
    Data.   Book  1: Toxicology  Data.   Office of Pesticide  Programs, U.S.
    EPA, Washington, DC.  EPA 540/9-79-003.  NTIS PB  80-196876.
0826p                               A-3                               06/10/86
                                     U.S. Environmental Protection
                                     Region 5. library (PL- 1?J)
                                     7 / West Jackson Boulevard, \2U\ Flow
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