EPA-540/1-86-056
                         Environmental Protection
                         Agency
	oe of Emergency and
Remedial Response
Washington DC 20460
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
                         Superfund
sEPA
                          HEALTH  EFFECTS ASSESSMENT
                          FOR LINDANE

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                                           EPA/540/1-86-056
                                           September 1984
       HEALTH  EFFECTS  ASSESSMENT
                FOR LINDANE
    U.S. Environmental Protection  Agency
     Office of Research and Development
Office of Health  and  Environmental Assessment
Environmental Criteria and Assessment Office
            Cincinnati,  OH  45268
    U.S. Environmental Protection  Agency
  Office of Emergency  and Remedial Response
Office of Solid Waste and  Emergency  Response
            Washington, DC  20460

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                                  DISCLAIMER

    The Information in  this  report  has been funded wholly  or  in  part by the
United States  Environmental  Protection Agency under  Contract  No.  68-03-3112
to Syracuse Research  Corporation.   It  has been subject  to  the Agency's peer
and administrative  review,  and  it  has been  approved for  publication  as  an
EPA  document.   Mention  of  trade  names   or   commercial  products  does  not
constitute endorsement or recommendation for use.
                                      11

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                                    PREFACE


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


    U.S.  EPA.   1980a.  Ambient Water Quality  Criteria for  Hexachloro-
    cyclohexane.  Environmental Criteria and  Assessment Office, Cincin-
    nati, OH.  EPA 440/5-80-054.  NTIS PB81-117657.

    U.S.  EPA.    1985.   Drinking  Water  Criteria  Document for  Undane.
    Prepared  by  the   Environmental  Criteria  and  Assessment  Office,
    Cincinnati,  OH,  OHEA for the Office of Drinking Water,  Washington,
    DC.  Final draft.
    The Intent 1n  these  assessments  1s  to suggest acceptable exposure levels
whenever sufficient  data were available.  Values were  not  derived  or larger
uncertainty  factors  were  employed  when  the  variable  data  were limited  In
scope tending  to  generate conservative  (I.e.,  protective) estimates.  Never-
theless, the  Interim values  presented reflect the  relative  degree  of hazard
associated with exposure or risk to the chemlcal(s) addressed.

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

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

                                      111

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

    For compounds for which there  1s  sufficient  evidence  of  carc1nogen1dty,
AIS  and  AIC values  are  not derived.   For a  discussion  of risk  assessment
methodology  for  carcinogens  refer to  U.S. EPA  (1980b).   Since cancer  1s  a
process that  1s  not characterized by  a threshold,  any exposure  contributes
an Increment of  risk.   Consequently,  derivation of  AIS and  AIC  values  would
be Inappropriate.   For  carcinogens,   q-|*s  have been  computed  based  on  oral
and Inhalation data 1f available.
                                      1v

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

    Llndane, given  orally,  produced  an Increase  1n  Hver tumors  1n mice  1n
one  study.   Other  animal  bloassays   (rats  and  mice) have  been negative  or
equivocal.  Data concerning the cardnogenldty of  Undane to humans are  not
available.   The  U.S. EPA  (1980a)  used the  mouse liver  tumor  data to cal-
culate  a  carcinogenic   potency  factor   for  Undane.    The  q-j*   1s   1.326
(mg/kg/day)"1  No  data  are  available to  assess  the potential  cardnogenl-
dty of Undane following inhalation  exposure.

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                               ACKNOWLEDGEMENTS
TECHNICAL REVIEW

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

         Office of A1r Quality Planning and Standards
         Office of Solid Waste
         Office of Toxic Substances
         Office of Drinking Water

EDITORIAL REVIEW

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

TECHNICAL SUPPORT SERVICES

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


    The  Initial  draft  of  this  report  was  prepared  by  Syracuse  Research
Corporation under Contract No. 68-03-3112.
                                      v1

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                              TABLE OF CONTENTS

                                                                        Page

 1.   ENVIRONMENTAL CHEMISTRY AND FATE	    1

 2.   ABSORPTION FACTORS IN HUMANS AND  EXPERIMENTAL ANIMALS 	    3

     2.1.    ORAL	    3
     2.2.    INHALATION	    3

 3.   TOXICITY IN HUMANS AND EXPERIMENTAL  ANIMALS 	    4

     3.1.    SUBCHRONIC	    4

            3.1.1.   Oral	    4
            3.1.2.   Inhalation	    7

     3.2.    CHRONIC	    8

            3.2.1.   Oral	    8
            3.2.2.   Inhalation	    9

     3.3.    TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS	   12

            3.3.1.   Oral	   12
            3.3.2.   Inhalation	   14

     3.4.    TOXICANT INTERACTIONS	   14

 4.   CARCINOGENICITY	   16

     4.1.    HUMAN DATA	   16
     4.2.    BIOASSAYS	   16
     4.3.    OTHER RELEVANT DATA	   21
     4.4.    WEIGHT OF EVIDENCE	   21

 5.   REGULATORY STANDARDS  AND CRITERIA 	   23

 6.   RISK ASSESSMENT	   24

     6.1.    ACCEPTABLE INTAKE SUBCHRONIC  (AIS) 	   24
     6.2.    ACCEPTABLE INTAKE CHRONIC  (AIC)	   24
     6.3.    CARCINOGENIC POTENCY (q-j*)	   24

            6.3.1.   Oral	   24
            6.3.2.   Inhalation	   24

 7.   REFERENCES	   25

APPENDIX A: Summary Table  for Llndane	   37

APPENDIX B: Cancer Data Sheet for Derivation of q-j*	   38

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                               LIST OF TABLES

No.                               Title                                Page

3-1     Design of Llndane Chronic Feeding Studies In Rats 	    10

3-2     Design of Llndane Chronic Feeding Studies 1n Mice 	    11

4-1     Investigations of the Carclnogenldty of Llndane 1n
        Laboratory Animals by the Oral Route	    17

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                            LIST OF ABBREVIATIONS

ADI                     Acceptable  dally Intake
AIC                     Acceptable  Intake chronic
AIS                     Acceptable  Intake subchronlc
BCF                     B1oconcentrat1on factor
bw                      Body weight
CAS                     Chemical Abstract Service
CNS                     Central nervous system
CS                      Composite score
DNA                     Deoxyr1bonucle1c add
EEG                     Electroencephalogram
LDso                    Median lethal  dose
NOAEL                   No-observed-adverse-effect level
ppm                     Parts  per million
STEL                    Short-term exposure limit
TLV                     Threshold limit value
TWA                     Time-weighted  average
                                      1x

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                     1.   ENVIRONMENTAL CHEMISTRY  AND  FATE



    The relevant physical  and  chemical  properties and environmental  fate  of

Undane,  also  known  as  Y-hexachlorocyclohexane  (CAS No.  58-89-9),  are  as

follows:


    Chemical class:          pesticide

    Molecular weight:        291 (Callahan et al.. 1979)

    Vapor pressure:          1.6xlO~* mm Hg (Mabey et  al.,  1981)

    Water solubility:        7.8 mg/8. at 25C (Horvath, 1982)

    Log octanol/water
    partition coefficient:   3.85 (Velth et al.,  1979)

    Log BCF:                2.26-2.67 (Velth et  al.,  1979)

    Half-life 1n
      Water:                >5-10 days (estimated)
      Soil:                 56 days 1n clay loam (Callahan et al.,  1979)
                            378  days  1n  sandy   loam  (Callahan  et  al.,
                            1979)


    The estimation of the  half-life  for  Undane  1n aquatic  media  Is based  on

the  anaerobic  mlcroblal  degradation  half-life   of this  chemical   1n  aquatic

sediments as reported 1n  Callahan et al. (1979).

    No reported  value for  the  half-life  of Undane   1n the  atmosphere  could

be  located  1n  the literature  searched.   Based  on the reactions  for  chlori-

nated  aliphatic hydrocarbons,  Undane  may undergo   reaction with  hydroxyl

radicals  1n the atmosphere  (Graedel,  1978).   Unfortunately, the  rate  con-

stant  value  for this  reaction  1s  not known.  Based   on the  saturation  vapor

pressure  data   and  the  predictions  of  CupHt   (1980),  Undane  may  not  be

sorbed onto  partlculate matter  In  the air.   In  air,  the  demonstrated  removal

mechanism for Undane appears to be ralnout (IARC, 1979).
                                     -1-

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    The average  K   for  Undane  was determined  to  be 735  (McCall  et  al.,
1980).   This  suggests  that  Undane  may  have a  low  soil  mobility;  however,
Undane may leach from soil  to groundwater, particularly  from  soils  with low
organic matter content (McCall et  al.,  1980).   Page  (1981) detected  Undane
1n -2154 of groundwater  samples  collected  from New  Jersey during 1977-1979.
                                     -2-

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           2.  ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL MAMMALS
2.1.   ORAL
    Llndane  (y-HCH)   1s   apparently   rapidly  absorbed  from   the   gastro-
intestinal  tract;  the rapidity  may be  enhanced  by  Incorporation  In  Upld
vehicles.  The  fact  that  Undane 1s unusually  water soluble for an  organo-
chloMne  Insecticide  may   contribute  to  the  rapidity  of  Us absorption
(Herbst and Bodenstein, 1972).
    Chadwlck et  al.  (1971,  1978)  treated  Fischer  344  rats with dally  oral
doses  (number  unspecified)  of  2  mg   [14C]-labeled  Undane.    Only  2-5%  of
the total  dose  was  recovered 1n the feces, Indicating  that -95% of  the  dose
was absorbed following oral administration.
2.2.   INHALATION
    Pertinent  data  regarding   absorption  of  Undane  following  Inhalation
exposure could not be located 1n the available literature.
                                     -3-

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               3.  TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1.   SUBCHRONIC
3.1.1.   Oral.   Studies  of  tox1c1ty due  to Undane  are  complicated by  the
fact  that  five  Isomers  of  hexachlorocyclohexane,  each  with  Its  own  toxic
effects on mammalian  species,  are  often Involved In  mixtures  of  hexachloro-
cyclohexane tested for  toxldty  1n laboratory animals.  According to  Delch-
mann  (1981),  commercially available  hexachlorocyclohexane 1s  a  mixture  of
predominantly  four  of  Its  five  Isomers.   As  an  Insecticide the y-isomer,
Undane, Is the most  effective.
    Llndane  1s  the most  acutely  toxic  Isomer  of  hexachlorocyclohexane  and
causes  (as  does  the   a-lsomer)   stimulation   of   the   CNS.    The  B-  and
S-isomers  generally  cause CNS depression.   Because Undane  1s more rapidly
eliminated  than  other   hexachlorocyclohexane   Isomers,   it   1s   the   least
chronically toxic Isomer.
    It' has  been  demonstrated  that young animals  are more sensitive  to  the
toxic  effects  of Undane than are adults  of the same species  (Radaleff  and
Bushland,  1960).   The increased  sensitivity among  the young may  be related
to  the  inability of  livers of  young animals to  produce,  as rapidly as  livers
of  adults, the  enzymes  that  detoxify  Undane  (Pouts  and  Adamson,  1959).
Diseased and distressed animals also show a similar sensitivity (Chen,  1968).
    Although cases of acute toxidty associated  with  Ingestlon of  Undane by
humans  have been reported, data  regarding  subchronic  oral  exposure of  humans
to  Undane have not been located in the available literature.
    An  abstract  of a  study  of  the toxldty of technical  grade  hexachloro-
cyclohexane  in  rats  was  located  (Barros and  Sallba, 1978).   Groups  of  10,
60-day-old  male  Wlstar  rats  were  fed  diets containing  0,  0.9  or  900  ppm
                                     -4-

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technical hexachlorocyclohexane  for 90  days.   The  high-dose group  experi-
enced growth rate  depression,  an  Increase 1n relative  liver  weight  and mild
hyaline degeneration of the kidneys.   Both  treated  groups  exhibited  degener-
ative liver  changes Including fatty accumulation.
    In a  range-finding  experiment  prior to a major  cardnogenlcHy  bloassay
(NCI,  1977),  groups of five  male  and  five female  Osborne-Mendel rats were
fed diets containing 0, 160,  320,  640,  1280 or  2500 ppm Undane for  6 weeks,
followed  by a  2-week  observation  period.   Dosage  levels  >1280  ppm  were
associated  with  Increased mortality when  compared  with controls.   A reduc-
tion  1n  weight  gain during the first 3 weeks was recorded  for  both  male and
female rats exposed  to  320 or  640  ppm  Undane.   After cessation of exposure,
weight gains of treated males approached those of controls.
    Concurrently,  groups  of  five male  and  five female B6C3F, mice  were fed
diets  containing  0, 40, 80,  160,  320,  640  or  1280  ppm Undane  for  6 weeks,
followed  by an  observation  period  of  2  weeks.  No effects  on  weight gain
were  recorded and  no mortality  occurred 1n  groups  of mice fed diets  contain-
ing <160  ppm Undane.   Mortality  of one male and two females  occurred 1n the
320 ppm  groups  and all  mice exposed to the  640  ppm had succumbed by 5 weeks
of  treatment.   Although these  subchronlc  studies  provide  some Information on
mortality,  the  small  group size and limited evaluation of  toxlclty  criteria
render these studies Inadequate for  use In risk assessment.
    More  recently,  the  hlstochemlcal   and  biochemical changes  1n  rats  fed
diets  containing  hexachlorocyclohexane  (grade  and  purity  not  specified) have
been   Investigated   (Shlvanandappa   and  KMshnakumarl,  1981).    Groups  of
28-day-old  weanling male  rats  (number  and strain  not specified)  were  fed
diets  containing 0, 100,  250,  750, 1500  or 3000  ppm Undane  for  90 days.
Dosage levels >250  ppm  resulted 1n progressive  accumulation of I1p1ds 1n the
                                     -5-

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peMportal hepatocytes and  adrenal  cortex.   At dosages of  750  and 1500 ppm,
sucdnlc dehydrogenase activity  decreased and alkaline  phosphatase activity
Increased  In  the bile canal1cul1  and kupfer  cells  of the liver,  as  deter-
mined  hlstochemlcally.   At  "higher  dietary  levels,"  serum glutamlc  oxalo-
acetlc  transamlnase  and  3-glucuron1dase were  elevated, and  lactate dehydro-
genase and alkaline  phosphatase  activities  were  reduced.   Hepatic  mlcrosomal
protein was markedly  elevated  at all dietary  levels.  The  authors concluded
that the dietary  level of 100 ppm hexachlorocyclohexane  resulted  1n  no sig-
nificant  hlstopathologlcal,  hlstochemlcal  or  biochemical changes  when  com-
pared with controls.  Therefore,  1n  this study 100  ppm  benzene hexachlorlde
1s designated a NOAEL.
    Subsequently, Shlvanandappa  et  al.  (1982)  fed  diets containing 0,  100,
250, 750 or 1500  ppm  hexachlorocyclohexane  to groups of  ten,  28-day-old male
CFT-W1star rats  to  Investigate Inhibition  of  adrenal  steroldogenlc activity
associated with   hexachlorocyclohexane.   The  hexachlorocyclohexane used  1n
this  experiment  was  reportedly  99%  pure  and consisted  of 72%  a-,  5%  B-,
13.5%  y-  8%  *- and a  trace  of   the  e-1somers.   Following  the  90-day
treatment  period,  rats   were  killed  and  adrenal  glands  were   collected  and
subjected  to  h1stolog1cal   and  hlstochemlcal  evaluation.   No  significant
changes associated with  treatment were noted  In adrenal  glands  from rats  fed
diets containing 100 or  250  ppm  hexachlorocyclohexane.  At  dietary levels  of
750 or  1500  ppm  of  hexachlorocyclohexane, marked hypertrophy of  the  adrenal
glands  was  noted  with   cortical  cells enlarged  and  showing  vacuollzatlon.
Hlstochemlcal  examination   revealed   accumulation   of  cholesterol-positive
I1p1ds  and  marked   reduction  1n  the  activities  of  several   steroldogenlc
enzymes.
                                     -6-

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    Oesch et al. (1982) Investigated  the  effects  of  llndane on liver weights
and  the  activities of  various  hepatic enzymes  1n CF,  and B6C3F.J  mice  and
Osborne-Mendel rats.  Groups  of  three animals of  each  sex  were allocated to
control,   low,  medium  or  high dose diets.   Diets  fed to CF1  mice contained
0 (control), 56 (low),  111  (medium)  or  360  (high)  ppm Undane.  Diets fed to
B6C3F, mice contained  0   (control),  56  (low),  170  (medium)  or  270  (high)
ppm  Undane.   Osborne-Mendel  rats  received diets  containing  0 (control), 56
(low), 111  (medium) or 360 (high) ppm Undane.   The Undane  used  1n these
studies  was  reportedly  99%  pure.   At  the  end  of  the   3-month  treatment
period,  the animals were killed,   livers  were weighed  and the  activity of
several hepatic enzymes was determined.
    Liver weights  were  significantly Increased  1n high dose  group  CF  mice
(p<0.01)   and  Osborne-Mendel  rats   (p<0.01)  when  compared  to  controls.   No
high-dose  group B6C3F,  mice  survived to  90  days.    Female  Osborne-Mendel
rats  In  the middle  dose group experienced a  significant (p<0.05) Increase 1n
body  weight  compared  with  controls.   Significant  Induction  of  several
hepatic  enzymes  was  observed 1n  both strains  of  mice and  Osborne-Mendel
rats.  The  most marked examples  were the Induction  of glutath1one-S-trans-
ferase 1n  all  treated  groups  of  female CF,  mice  (p<0.01)  and the Induction
of  epoxlde  hydrolase  1n  all  treated  groups  of Osborne-Mendel  rats.   Since
minimal  enzyme  Induction  without  hepatomegaly occurred  at the  lowest  dose
tested 1n  both  species of  animal,  this dietary concentration  (56  ppm)  1s a
NOAEL  1n  this study.  Assuming that  rats  and mice consume food equivalent to
5 and 13% of their body  weight,  respectively,  dally Intakes  of  2.8 and  7.3
mg/kg/day, respectively, can be estimated.
3.1.2.   Inhalation.   Repeated  Inhalation   of  Undane  by  humans  1s most
Hkely to result from occupational  exposure  and  will  be discussed 1n Section
3.2.2.
                                     -7-

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    Rats  exposed  to  0.78  mg  Undane/m3  for  7  hours/day,  5  days/week  for
180  days  showed   "some  hepatocellular   enlargement."    No  other   clinical
symptoms of toxldty were noted (Heyroth,  1952).
3.2.   CHRONIC
3.2.1.   Oral.  Reports  of  toxldty 1n humans associated with chronic  oral
exposure to Undane could not be located  1n  the available  literature.
    According to  Delchmann  (1981),  Lehman (1954) Indicated  that  the  highest
tolerated no-effect dose of  Undane In rats consume for  >2  years Is  -50 ppm
1n the diet,  or 5 mg/kg  bw,  assuming  that rats eat  food equivalent  to 10% of
their body  weight  per day.   FHzhugh  et  al.  (1950) suggested that  rats  can
tolerate  "long  term"  feeding  of  diets  containing  50  ppm  Undane,   but
experienced   "changes  of  questionable  significance"   at  that   level.    No
changes were  observed  1n rats  exposed  to  diets containing 0.15,  10  or 30 ppm
Undane (ACGIH, 1980).
    Administration  of 10  ppm Undane to the diets  of  rats  for 1-2  years
resulted  1n  noxious  effects  to them and  their offspring.   Body  weights  were
decreased after treatment  for 5 months;   Increased  urinary ascorbic  acid and
changes  (unspecified)  1n blood  levels  of  ascorbic add  were  noted.   Ascorbic
add content  1n both  Hver and adrenals was  reduced  (Petrescu et  al., 1974).
    Administration of  100  ppm Undane 1n the  diet  to male  and female beagle
dogs  resulted In  slightly  enlarged livers  without  h1stopatholog1cal  change
(Rlvett et  al., 1978).   In  this  study, dogs  were fed diets containing 25, 50
or  100  ppm  Undane  for 104 weeks.   Rlvett et al. (1978) reported that the 50
ppm diet was  a no-effect level.
    An  NCI   (1977)  cardnogenldty  bloassay  of  Undane was performed  using
Osborne-Mendel rats  and B6C3F, mice.  Groups  of 50 male and  50  female  rats
were  allocated  to high- and  low-dose groups.  Matched  controls  consisted of
                                     -8-

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10 rats  of  each  sex.   The dosage  schedule  for  rats  In this  experiment  1s
detailed 1n  Table 3-1.   Similar  numbers of  mice were allocated  to  matched
control, low and high dose groups  as Indicated 1n Table 3-2.
    Groups  of  treated  rats exhibited  no changes  1n body weights  when  com-
pared  with   those  of  matched  controls.     Individual  rats,  however,  did
exhibit decreases 1n body weight  occasionally.   Applying  the  Tarone test for
positive dose-related  trends  1n mortality to the Kaplan  and  Meier probabil-
ity of  survival  curves Indicated  no significant  effect  of  treatment  on sur-
vival.  Clinical  signs In all groups of  treated rats Included rough and dis-
colored hair coats,  pale  mucous membranes and vaginal  bleeding, particularly
during the second year of the study.
    Groups of  treated  mice  exhibited no  statistically  significant changes  1n
body  weight  when compared  with  that of  matched controls.   Low-dose female
mice,  however,  consistently  had  body   weights  less  than  that   of  matched
control,  or  high-dose  group female mice.   Clinical signs  In all  groups  of
treated  mice  Included rough  hair  coats,  alopecia  and  abdominal  dlstentlon
(particularly  1n  males)  during  the second year.   Female  mice appeared to  be
more  excitable when handled and  Increased  fighting was  observed  among male
mice.
3.2.2.   Inhalation.   Toxldty  to  Undane  by  Inhalation  1n  the workplace
has  been reported  by  Sas1nov1ch  et  al.  (1974), who  observed pathological
changes  1n  the  livers  of  55% of  59 female  and 29 male workers  exposed  to
hexachlorocyclohexane  (composition  not   characterized)   for  11-23  years.
Chronic  pancreatitis was  observed In 5%  of  the workers;  "biochemical abnor-
malities"  were  noted  in  60%  of  these  workers.   No  exposure   data  were
reported 1n  this  study.
                                     -9-

-------
                                  TABLE 3-1

              Design  of  Llndane  Chronic  Feeding  Studies  1n  Ratsa
Sex and
Treatment
Group
Male
Matched control
Low-dose


High-dose

Initial
No. of
Animals'5
10
50


50

Llndane
1n D1etc
(ppm)
0
320
160
0
640
320
0
Time
Treatedd
(weeks)
NA
38
42
NA
38
42
NA
on Study
Untreated6
(weeks)
109
NA
NA
30
NA
NA
30
TWA
Average Dose^
(ppm)
NA
236
NA
NA
472
NA
NA
F ema 1 e
Matched control 10
Low-dose 50



High-dose 50




0
320
160
80
0
640
320
160
0

NA
2
49
29
NA
2
49
29
NA

108-109
NA
NA
NA
29-30
NA
NA
NA
30

NA
135
NA
NA
NA
270
NA
NA
NA
 Source: NCI, 1977
 All animals were 35 days of age when placed on study.
cDoses  of   Undane  were  lowered  during  the  study,  as  Indicated,  due  to
 deaths among the treated animals.
 All animals were started on study  on the  same day.
eWhen  diets  containing  Undane were  discontinued,  treated  rats  and  their
 matched controls were fed diets without corn  oil for  15  weeks,  then  control
 diets (2% corn oil  added) for an additional 15 weeks.

fTWA = (dose 1n ppm x no. of weeks at that  dose)
           Z(no. of  weeks receiving each dose)

NA = Not applicable
                                     -10-

-------
                                  TABLE  3-2

              Design of Lindane Chronic Feeding Studies In M1cea
Sex and
Treatment
Group
Male
Matched control
Low-dose

High-dose

Female
Matched control
Low-dose

High-dose

Initial
No. of
An1malsb

10
50

50


10
50

50

Lindane
1n Diet
(ppm)

0
80
0
160
0

0
80
0
160
0
Time
Treated0
(weeks)

NA
80
NA
80
NA

NA
80
NA
80
NA
on Study
Untreatedd
(weeks)

90
NA
10
NA
10

90
NA
10
NA
10-11
aSource: NCI, 1977

^All animals were 35 days of age when placed on study.

CA11 animals were started on study on the same day.

dWhen  diets  containing  Undane were  discontinued,  treated  mice and  their
 matched controls were fed control diets (2% corn oil added).

 NA = Not applicable
                                     -11-

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    The ACGIH (1980) reported that minor  symptoms  and  signs  (unspecified)  of
neurological  disturbances  were  noted  in  14/37 workers  exposed  to  lindane
over a  2-year period  (Czegledl-Janko  and  Avar,   1970).   Of these  workers,
three had  "serious  EEG disturbances."   Blood  levels  of lindane  ranged  from
0.002-0.340 ppm;  levels  >0.02  ppm  correlated with more  severe  evidence  of
neurological dysfunction.   No exposure  data from this  study were reported.
    Treon  et  al.  (1951) reported  "minimal pathology  in  several  species  of
laboratory animals  exposed  7  hours/day,  5 days/week for ~1  year  at  an aver-
age of  0.7 mg/m3  lindane."   Rats  exposed continuously for  655 days  to  0.19
mg  lindane/m3 exhibited no  pathological  lesions   (Spear,  1952).  No  other
toxiclty parameters were reported.
3.3.   TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1.    Oral.   The  teratogenic  and   fetotoxic   effects   of  Undane  were
studied   in   four  groups   of   rats  (number  and  strain  not  reported)
(Mametkullev, 1978).   Group  1  received 25 mg  lindane/kg bw/day  on days  1-20
of  gestation.  Group  2  received  25  mg  lindane/kg bw/day  on  days   7-15  of
gestation.  Group  3 received 25 mg  Undane/kg bw/day on days  1-7 of gesta-
tion.   Group  4  received 12  mg  Undane/kg bw/day   on days  1-20  of gestation.
A  group  of untreated controls  was  maintained; no  vehicle  control group was
mentioned.   Lindane was  dissolved  1n  corn  oil   (strength  of  solution  not
reported)  and administered  by gavage.   All dams were  killed and examined  on
day  20  of  gestation.   Terata were  not  reported   in  the  offspring  from any
treated dams.   Post1mplantat1on fetal  death  was  reported  to be  13.2,  25.6,
11.2, 7.6  and 9.5% 1n the control group  and  groups 1-4,  respectively.  Sta-
tistical  significance  of  the  apparently  high  Incidence of  postlmplantatlon
fetal  mortality  in  Group  1  rats  was  not  reported.    Palmer  et  al.  (1978)
obtained similar results with white rabbits.
                                     -12-

-------
    A  4-generation  study  of  the  effects  of  Undane  on  reproductive  per-
formance  of  rats (strain  not  specified)  was  performed by  Petrescu  et  al.
(1974).   According  to  the U.S.  EPA  (1980a),  these authors  reported  that  5,
10  or   15  mg  Undane/kg  bw/day  administered  1n  the  diet  resulted In  an
Increase  1n  the  average  length  of gestation from  21-22  days 1n  control  rats
and  21-24  days  1n  treated animals.   A dose  of  15 mg/kg/day  was  associated
with a  decrease  1n  the number of births  compared  with  the  number  of  animals
1n  the parental  generation.   Delayed sexual  maturation and  longer  estrous
cycle  length were  noted  1n  F?  and  F_  females  from  all  treated  dams.   An
Increase  1n  the  number of  stillbirths was  also reported.   Additionally,  F,
and  F?  offspring  from  all  exposed  dams  exhibited   a high  Incidence  of
spastic paraplegia.
    Disturbed  estrous  cycles, lowered embryonic  viability,  reduced fertility
and delayed  sexual  maturation were  reported In female  rats  treated with  0.5
mg  Undane/kg  bw/day-  for   4  months.  Rats  treated with  0.05 mg/kg  bw/day
showed none of these effects  (Shtenberg and MametkuHev, 1976).
    In  beagle  dogs,  Earl  et  al.  (1973)  reported  that oral  doses  of  7.5  and
15  mg  Undane/kg bw/day  from day 5  of gestation to delivery  resulted  1n  an
Increase In stillbirths.
    Some  parameters of  reproductive  performance  1n  male  rats   exposed  to
Undane were Investigated  by  Shlvanandappa  and KMshnakumarl (1983).   Groups
of  10  male  28-day-old  CFT Wlstar  rats were fed diets  containing  0, 100,  750
or  1500  ppm  technical  hexachlorocyclohexane  for  90  days.  The  technical
hexachlorocyclohexane  reportedly  contained  72%  a-,  5%  B-,  13.6%  y-,  8%
6- and  a  trace  of  the  e-1somers.    The  dietary  concentration  of 1500  ppm
was associated with decreased food  consumption (p<0.01)  and  decreased growth
rate  (p<0.05)  beginning  at week  7.   Also  at  this  dietary  level, a  marked
                                     -13-

-------
decrease 1n testlcular weight (p<0.001), diameter  of  the  seminiferous  tubule
(p<0.001)  and  diameter  of  the  nuclei  of the  Leydlg cells  (p<0.001)  was
noted.  Total testlcular Upld (p<0.05) and cholesterol (p<0.02)  levels  were
Increased.   A marked  decrease  1n  the activity of  several  enzymes  related to
steroldogenesls   was  also  seen (no  statistical  analysis).   These  Investi-
gators  concluded  that  exposure  to  1500  ppm  Undane 1n  the  diet  markedly
reduced normal  testlcular maturation and function.
3.3.2.   Inhalation.   Pertinent data regarding  teratogenldty,  fetotoxldty
or  Impaired  reproductive performance associated with  Inhalation  exposure to
Undane  In  humans  or animals  could not be  located  In the available  liter-
ature.
3.4.   TOXICANT INTERACTIONS
    LHterst and Miller  (1975) determined  that  the dally  treatment of  beagle
dogs  with  phenobarbltal  for  60 days prior to  the Intravenous  administration
of  Undane  resulted  1n  reduced Undane concentrations 1n  the  brain compared
with  controls.   The Intravenous  administration  of   7.5  mg  Undane/mlnute
resulted   1n  convulsions   1n   nonphenobarbltal-pretreated dogs   within  27
minutes; Infusion  of Undane at this  rate failed to  trigger  convulsions In
phenobarbltal-pretreated dogs after  60-70  mlntues. These  Investigators  con-
cluded  that  phenobarbltal  may be  protective  against  the   ability  of  Undane
to  cause convulsions.
    Pretreatment of  Wlstar rats with  Undane  was  associated with  a reduction
of  the  teratogenlc effects of a carbamate Insecticide and of  sodium acetyl-
sallcylate (Shtenberg and Torch1nsk1i, 1977).
    The  chloMnatlon of  water containing  hexachlorocyclohexane  (not  further
characterized)  has been  shown to  decrease the subsequent LD5-s  1n mice and
rats,  presumably by  conversion  of  these  compounds   to more   toxic  products
(Shtannlkov et al.,  1977).

                                     -14-

-------
    Llndane  has  been  shown  to  Increase  the  sensitivity  of  mice  to  the
convulsion-producing effects  of pentylenetetrazol  (Hulth et al., 1976).
    Ulmann  (1972)  reported  that  the  toxic  effects  of  Undane  have  been
antagonized by various  tranqulHzers.
                                    --15-

-------
                             4.  CARCINOGENICITY
4.1.    HUMAN DATA
    No ep1dem1olog1ca1 studies of  cancer  1n  humans associated with exposure
to Undane have  been  reported.   Several  case histories link the development
of aplastlc  anemia  with exposure  to  hexachlorocyclohexane  or  Undane alone
(Hans, 1976;  Loge,  1965;  West, 1967; WoodUff  et  al., 1966)  or 1n combina-
tion  with  other  compounds, particularly  DDT (Hans, 1976;  WoodUff  et al.,
1966).  The concurrent development of acute  paramyeloblastlc leukemia  1n two
cousins simultaneously  exposed to Undane was  reported by  JedUcka  et al.
(1958).  Barthel  (1976)  reported  an  Increased  Incidence of  lung  cancer   1n
workers  who  had  applied  various  pesticides.   Including   Undane.   These
reports do  not  constitute  sufficient weight of  evidence  to  conclude that
Undane 1s a human carcinogen.
4.2.   BIOASSAYS
    Several  Investigators   have  examined  the  potential  cardnogenldty   of
Undane 1n laboratory animals.   These studies are  summarized 1n  Table  4-1.
    In  male  and female  Wlstar  rats,  FHzhugh et  al.  (1950)  observed   no
tumors  following lifetime  exposures  of  doses  up  to 800  ppm Undane  1n dry
diet  or 1600  ppm Undane  1n oil  solution  added  to  the  diet.  Dietary  concen-
trations of  500  ppm  Undane for  24 weeks  failed to result  1n  liver  tumors  1n
male  dd mice  (Nagasaki  et al.,  1972a;   Ito et al.,  1973a,b),  but 660 ppm
technical  hexachlorocyclohexane  for  24  weeks resulted   1n hepatomas 1n  20/20
mice  (Nagasaki  et al.,  1971,  1972b).  Hanada  et  al.   (1973) produced  hepa-
tomas  In  both male and  female dd  mice  fed  diets  containing 600 ppm  Undane
for 32  weeks.   In male  Wlstar  rats exposed to a dietary concentration  of 500
ppm Undane,  no  hepatocellular carcinomas  were  observed after 24 or  48 weeks
(Ito  et al.,  1975).
                                     -16-

-------
                                       TABLE 4-1



Investigations  of  the Carclnogenlctty of Llndane  In Laboratory  Animals by  the  Oral  Route
Species/
Strain Sex
Rat/ M.F
Ulstar









Nice/dd N



Mlce/dd N



Mlce/dd M






Nice/dd N



Nice/dd F



Dose of
Exposure
(ppm)
1600
800
400
100
50
10
5
800
100
10
0
660
66.0
6.6
0
500
250
100
0
SOO

250

100

0
600
300
100
0
600
300
1 100
0
Duration
of
Treatment
(weeks)
llfespan
llfespan
llfespan
llfespan
llfespan
llfespan
llfespan
llfespan
llfespan
llfespan
llfespan
24
24
24
NA
24
24
24
NA
24

24

24

NA
32
32
32
NA
32
32
32
NA
Duration
of
Study
(weeks)
llfespan
llfespan
llfespan
llfespan
llfespan
llfespan
llfespan
llfespan
llfespan
llfespan
llfespan
24
24
24
24
24
24
24
24
24

24

24

24
37-38
37-38
37-38
37-38
37-38
37-38
37-38
37-38
Purity
of
Compound
>98X
>98X
>98X
>98X
>98X
>98X
>98X
>98X
>98X
>98X
NA
technical
technical
technical
NA
NR
NR
NR
NA
>99X

>99X

>99X

NA
NR
NR
NR
NA
NR
NR
NR
NA
Vehicle or
Physical
State
10X oil In diet
10X oil In diet
10X oil In diet
10X oil In diet
10X oil In diet
10X oil In diet
10X oil In diet
dry diet
dry diet
dry diet
dry diet
diet
diet
diet
diet
diet
diet
diet
diet
diet

diet

diet

diet
diet
diet
diet
diet
diet
diet
diet
diet
Target
Organ
all organs
all organs
all organs
all organs
all organs
all organs
all organs
all organs
all organs
all organs
all organs
liver
liver
liver
liver
liver
liver
liver
liver
liver

liver

liver

liver
liver
liver
liver
liver
liver
liver
liver
liver
Tumor
Type
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
hepatoma
hepatoma
hepatoma
hepatoma
hepatoma
hepatoma
hepatoma
hepatoma
hepatocellular
carcinoma
hepatocellular
carcinoma
hepatocellular
carcinoma
hepatocellular
hepatoma
hepatoma
hepatoma
hepatoma
hepatoma
hepatoma
hepatoma
hepatoma
Tumor
Incidence
(p value)
0/10
0/10
0/10
0/10
0/10
0/10
0/10
0/10
0/10
0/10
0/10
20/20
0/20
0/20
0/20
0/20
0/20
0/20
0/20
0/20

0/20

0/20

0/20
3/4
0/9
0/10
0/14
1/3
0/7
0/8
0/15
Reference
Fltzhugh
et al..
1950








Nagasaki
et al.,
1971.1972b

Nagasaki
et al.,
1972a

Ito
et al..
1973a,b




Hanada
et al.,
1973

Hanada
et a-1..
1973


-------
                                                                             TABLE  4-1  (cent.)
oo
i
Species/
Strain
Rat/
Hlstar




Hlce/
Chbl
NNRI












Nice/



Rats/
Osborne-
Nendel







Sex
N





H.F














N
F
M
F
N
N
N


F
F
F


Dose of
Exposure
(ppm)
500

500

0

50



25


12.5




0


400
400
0
0
472C
236C
0
(matched
controls)
270d
135
-------
                                                               TABLE 4-1 (cont.)
Species/
Strain


Nice/
B6C3F!











Sex


N

H

N


F
F
F


Dose of
Exposure
(ppm)

160

80

0
(matched
controls)
160
80
0
(matched
controls)
Duration
of
Treatment
(weeks)
80

80

NA


80
80
NA


Duration
of
Study
(weeks)
90

90

90


90-91
90
90


Purity
of
Compound

100X

100X

NA


100X
100X
NA


Vehicle or
Physical
State

diet

diet

diet


diet
diet
diet


Target
Organ


liver

liver

liver


all organs
all organs
all organs


Tumor
Type


hepatocellular
carcinomas
hepatocellular
carcinomas
hepatocellular
carcinomas

NA
NA
NA


Tumor
Incidence Reference
(p value)

9/46
(NS)
19/49
(p=0.001)
2/10
(NS)

NS
NS
NS


Includes neoplasla and hyperplastlc nodules
DBased on numbers of animals alive subsequent  to  first  tumor
CTUA dose reflecting  38 weeks  of  treatment at  640  or  320 ppm and 42 weeks of  treatment  at  320 or 160 ppm for the high dose-group  or  the low-
 dose group, respectively (dose lowered due to  death among the  treated  rats).
dTWA dose reflecting  2 weeks of  treatment at 640 or 320 ppm. 49 weeks of treatment at 320  or  160 ppm, and 29 weeks of treatment at 160 or 80
 ppm for the high-dose group or the low-dose group, respectively (dose  lowered  due to  death  among the treated animals).
 NA = Not applicable
 NS . Not significant
 NR = Not reported

-------
    Welsse and Herbst  (1977) fed  diets  containing  12.5,  25 or 50 ppm Undane
to groups  of  100 male and  female Chb1 NMRI  mice.   Groups of  200  males  and
females were maintained  as  controls.   The Incidence of  liver  cell  adenomas,
after 80  weeks  of treatment, was  5/200,  2/100, 0/100 and  2/100  1n control,
low-,  mid-  and  high-dose   groups,  respectively.   Tumor  Incidence was  not
reported  by  sex.   The Incidence  of  tumors  1n other organ  sites  was 41/200,
22/100,  13/100  and  22/100   1n  control,  low-,  mid-   and   high-dose  groups,
respectively.
    The  NCI  (1977)   published   the   results  of  an  extensive  bloassay  1n
Osborne-Mendel  rats   and B6C3F..   mice.   The   protocol  of  this  study  was
described  1n  Section  3.2.1.  After  80 weeks  of  exposure  and  an additional
29-30  weeks  of  observation,  no  significantly  exposure-related  Increase  1n
the  Incidence  of tumors  was found  1n rats  of either  sex.   Only  1n low-dose
male   B6C3F,   mice   was   a   significantly  Increased   Incidence   of  tumors
(hepatocellular  carcinomas)  found (p=0.001,  Fisher  exact  test).   The  Inci-
dence  1n  the high-dose  group  was not  significant and  the Cochran-Armltage
test for  dose-related  trend  was  not  significant.   Combining the Incidence of
neoplastlc nodules with  hepatocellular carcinomas  did not  Increase the sig-
nificance  of  the findings.   No  hepatic  hyperplasla was observed  In mice of
either  sex.   These  factors, coupled  with  a  relatively  high  (23%)  Incidence
of  hepatocellular carcinoma combined  with  neoplastlc  nodules  1n  control
mice, led  the NCI (1977)  to  conclude  that  "under  the conditions of this bio-
assay llndane was not carcinogenic for Osborne-Mendel rats or B6C3F, mice."
    Thorpe  and  Walker  (1973)  demonstrated   a  substantial  Increase 1n  the
Incidence  of  malignant  liver  tumors   1n  both male and  female CF,  mice  fed
                                     -20-

-------
diets containing 400  ppm  Undane  for 110 weeks.  Malignancies  were  observed
1n 16/29  treated  males  and 10/29  treated  females compared to  Incidences  of
2/45 and 0/44 1n control male  and  female mice,  respectively.
4.3.   OTHER RELEVANT DATA
    Mutagenldty of  llndane has  been studied by  several  Investigators,  pre-
dominantly  with  negative  results.   Buselmaler  et  al.  (1972)  reported  that
Undane  had no  effect  on  the reversion  of Salmonella  typhlmurlum G46  or
Serratla marcescens a21  1n a  host-mediated assay.  Schubert  (1969)  found  no
Increased  Incidence  of  respiratory-deficient   mutants  In   yeast  (species
unspecified) associated  with  Undane.   Negative  results  In  dominant  lethal
assays  were reported 1n  mice (U.S.  EPA,  1973;  NAS,  1977).    No  sex-Hnked
recessive mutants  were  found  In  Drosophlla  melanogaster  exposed  to Undane
(Benes  and  Sram,  1969).   No unscheduled DNA synthesis  was reported  by  Ahmed
et  al.   (1977)  1n  SV-40  transformed  human  flbroblasts   (VA-4)  exposed  to
llndane.
    Chromosomal breaks  and gaps  1n Chinese  hamster flbroblasts  were related
to  Undane  exposure  (Ishldate   and Odashima,   1977),  and  alterations  1n
mltotlc  activity were reported  by Tsoneva-Maneva et al.  (1971).   A  positive
dominant  lethal response  1n  D.  melanogaster related to Undane  was  observed
only  1n  the  third  and subsequent  generations from adults  fed  food containing
20  ppm   Undane  (S1nha  and S1nha,  1983).    Technical  grade  hexachlorocyclo-
hexane  was  also  associated with  a dominant  lethal  effect  1n  Swiss mice when
fed  continuously  to males at  500  ppm diet  for  4,  6 or 8 months  (Lakkad  et
al.,  1982).
4.4.   WEIGHT OF EVIDENCE
    Although  Undane  has  been  associated with  aplastlc  anemia,  possibly  a
preneoplastlc  lesion  (Hans,  1976; Loge, 1965;  West,  1967; WoodUff  et al..
                                     -21-

-------
1966)  and  paramyeloblastlc  leukemia  (JedUcka et  al.,  1958),  Insufficient
evidence exists to classify  Undane as a  human  carcinogen.   The  carclnogenl-
city  of  Undane  1n  the mouse has  been  clearly  demonstrated  by Thorpe  and
Walker (1973),  who  reported liver cancers  1n  55  and 34% of male and  female
mice, respectively,  fed diets containing 400 ppm  Undane for  110 weeks.   The
Incidence 1n control males and females was  4 and  0%, respectively.   Applying
the  criteria  for  weight  of  evidence proposed  by the Carcinogen Assessment
Group of the U.S. EPA,  Undane 1s most appropriately classified  a Group  B2  -
Probable Human Carcinogen (Federal Register, 1984).
                                     -22-

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                    5.  REGULATORY STANDARDS AND CRITERIA

    Based primarily on  the work  of  Treon et  al.  (1951),  who  found  minimal
pathology  In  several  species  (unspecified)   exposed  to  0.7  mg  Undane/m3
for 7 hours/day,  5  days/week  for  ~1  year, and the work  of  Spear  (1952),  who
reported "no  pathology"  1n rats  continuously  exposed  to 0.19  mg  llndane/m3
for 655  days,  the ACGIH  (1980)  has  recommended a TWA-TLV of  0.5  mg/m3  and
a STEL of 1.5 mg/m3.
    The  FAO/WHO  Interim  ADI   1s  1  yg/kg/day,  which  was  revised  downward
from an  original  recommendation  of  12.5 mg/kg/day made  In  1972 (NAS, 1977).
The U.S.  EPA  (1980a)  reported  a  tolerance for  Undane  1n animal   fats of  7
ppm, and  In  milk of 0.3  ppm.   The  tolerance  for most fruits  and  vegetables
1s  1  ppm.  Finished  drinking water  should  contain  no  more  than  0.004  ppm
(U.S. EPA, 1980a).
    Based on  the  carcinogenic  potency  derived  from  the cardnogenlcHy assay
data of  Thorpe  and Walker  (1973),  the U.S.  EPA (1980a) has determined that
an  ambient water  quality  criteria of  186 and 625 ng/a,  should  be  protective
for the  consumption of 2  8. water and  6.5 g  fish and shellfish/day,  or  the
consumption of fish and shellfish alone, respectively.
                                     -23-

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                             6.  RISK ASSESSMENT
6.1.   ACCEPTABLE INTAKE SUBCHRONIC (AIS)
    Llndane Is a  chemical  that  1s  a known carcinogen  1n mice,  and  for  which
data are  sufficient  for computing  a q^.   It  1s,  therefore,  Inappropriate
to calculate an oral  or Inhalation  AIS for llndane.
6.2.   ACCEPTABLE INTAKE CHRONIC (AIC)
    Llndane Is a  chemical  that  Is  a known carcinogen  In mice,  and  for  which
data are  sufficient  for computing  a q  *.   It  1s,  therefore,  Inappropriate
to calculate an oral  or Inhalation  AIC for llndane.
6.3.   CARCINOGENIC POTENCY (q^)
6.3.1.    Oral.   The  U.S.   EPA  (1980a)  derived  a  q^  of  1.326  (mg/kg/
day)"1   for  human exposure  to  Undane  based   on  the  Incidence  of  liver
tumors   that  occurred   1n  male   CF,  mice  1n the  Thorpe  and  Walker  (1973)
study.   This  risk estimate reflects  the  lack of  additional data between 1980
and  the  present.   A   q *  of  1.326  (mg/kg/day)'1 was   also  presented  1n
U.S. EPA  (1985).  The  complete  data  base from which this computation Is made
1s presented  In Appendix B.
6.3.2.    Inhalation.    Since  no reports  of  cancers  In  either  humans  or
animals  exposed  to  Undane  by  Inhalation have  been found  In  the  available
literature, no q * for  Inhalation of Undane can be calculated.
                                     -24-

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                                7.   REFERENCES







ACGIH  (American  Conference  of  Governmental  Industrial  Hyglenlsts).   1980.



Documentation of the Threshold Limit Values, 4th  ed.   (Includes  Supplemental



Documentation for 1981, 1982, 1983).  Cincinnati,  OH.   p.  246-247.







Ahmed, F.E., R.W.  Hart and N.J.  Lewis.  1977.  Pesticide  Induced  DNA  damage



and Us repair  In cultured human cells.  Mutat.  Res.   42:  161-174.







Barros, S.B.DeM. and  A.M. Sallba.  1978.   Toxldty  of  hexachlorocyclohexane



In rats.  Toxicology.   10(3): 271.   (Cited In U.S. EPA,  1980c)







Barthel,  E.   1976.  High  Incidence of  lung  cancer  In persons  with  chronic



professional exposure  to  pesticides 1n  agriculture.   Z.  Erkrank  Atm.-  Org.



(Ger.)  146: 226-274.







Benes,  V. and  R.   Sram.   1969.   Mutagenlc  activity of  some  pesticides  1n



Drosophlla melanogaster.   Ind. Med.  38: 442-444  (Cited In IARC, 1979)







Buselmaier,  W.,  G.  Rohrborn  and  P. Propping.   1972.   Mutagenldty  Investiga-



tions with pesticides  In  the host  mediated  assay  and dominant  lethal test 1n



mice.  Blol. Zbl.  91:  311-325.  (Cited  1n IARC, 1979)







Callahan,  M.A.,  M.W.  SUmak,   N.W.   Gabel,  et  al.   1979.   Water-Related



Environmental Fate  of  129 Priority Pollutants.  Vol.  I.   U.S.  EPA, Office of



Water  Planning  and Standards,  Office  of Water  and  Waste  Water Management,



Washington,  DC.  EPA-440/4-79-029a.
                                     -25-

-------
Chadwick, R.W.,  M.F.  Cranmer  and A.J.  Peoples.   1971.   Comparative  stimu-
lation  of  yHCH  metabolism  by  pretreatment  of  rats with  yHCH,  DDT,  and
DDT + HCH.   Toxlcol.  Appl.  Pharm.  18:  685-695.   (Cited In U.S.  EPA,  1980c)

Chadwick, R.W., E.J.  Faeder,  L.C.  King,  M.F.  Copeland, K. Williams  and L.T.
Chuang.  1978.  Effect  of  acute and chronic  Cd exposure on llndane  metabo-
lism.  Ecotoxlcol.  Environ. Safety.   2: 301-316.  (CHed  1n  U.S.  EPA,  1980c)

Chen,  C.P.   1968.   The  effects  of  protein  deficient diet on the  acute tox-
1c1ty  of Undane.    M.S.   Thesis,  Queens Univ.,  Kingston,  Ontario,  Canada.
(Cited 1n U.S. EPA, 1980a)

CupHt,  L.T.   1980.    Fate  of  Toxic  and  Hazardous  Materials   In  the  Air
Environment.    U.S. EPA,   Environmental  Sciences   Research  Laboratory,  ORD,
Research Triangle Park,  NC.  EPA-600/3-80-084.  NTIS PB80-221948.

Czegledl-Janko, G.  and  P.  Avar.   1970.   No  title  provided.   Br.  J. Ind. Med.
27: 283.  (CHed in ACGIH,  1980)

Delchmann,   W.B.   1981.    Halogenated  cyclic   hydrocarbons.    in:   Patty's
Industrial Hygiene and  Toxicology,  3rd  ed.,  G.D.  Clayton and  F.E.  Clayton,
Ed.  John Wiley and Sons,  Inc., NY.   Vol. 2B., p.  3603-3771.
                                     -26-

-------
Earl, F.L., et al.  1973.  Reproductive, teratogenlc and  neonatal  effects  of
some pesticides  and  related compounds  1n  beagle  dogs  and miniature  swine.
In:   Papers  on the  8th  Inter-America  Conference  on  Toxicology and  Occupa-
tional   Medicine,  Pesticides  and  the   Environment:  Continuing  Controversy,
W.B. Delchmann, Ed.   2: 253.   (Cited In IARC,  1979)

Federal  Register.   1984.   Environmental  Protection  Agency Proposed  Guide-
lines for Carcinogenic Risk Assessment.  Fed.  Reg.   49:  46294-46299.

Fltzhugh, O.G., A.A.  Nelson and  J.P. Frawley.   1950.  The chronic  toxldtles
of technical benzene hexachlorlde and  Us alpha, beta and gamma Isomers.   J.
Pharmacol. Exp. Therap.  100:  59-66.  (Cited  in ACGIH,  1980)

Fouts,  J.R. and R.H. Adamson.  1959.   Drug metabolism 1n  the  newborn  rabbit.
Science.  129: 897-898.  (Cited 1n U.S. EPA,.1980a)

Graedel, T.E.  1978.   Chemical Compounds 1n the Atmosphere.   Academic  Press,
New York.  p. 334.

Hanada,  S.,  C.  Yutanl  and T.  M1yaj1.   1973.   Induction  of hepatoma of mice
by benzene hexachlorlde.   Gann.  64: 511-513.

Hans,  R.J.   1976.    Aplastlc  anemia   associated  with  gamma-benzene  hexa-
chlorlde.  J. Am. Med.  Assoc.   236:  1009-1010.
                                     -27-

-------
Herbst, M.  and  G.  Bodensteln.  1972.   Toxicology  of llndane.  In:  Llndane,
E. Ulmann,  Ed.   Natl.  Pestle.  Monitor. Progr.  Pestle.  Monitor.  J.   p.  23.
(Cited In U.S.  EPA,  1980c)

Heyroth, F.F.  1952.  In.:  Chem.  Spec.  Manuf. Assoc. Proc.,  S.3.  Leland,  Ed.
6: 110.  (Cited 1n  U.S.  EPA,  1980a)

Horvath, A.L.  1982.   Halogenated Hydrocarbons: Solubility  M1sc1b1lHy  with
Water.  Dekker, Inc.,  New York.   p.  533.

Hulth,  L.,  M.  Larsson,  R.  Carlsson and  J.E.  Klhlstrom.  1976.   Convulsive
action  of  small   single  oral  doses   of  the  Insecticide  Undane.   Bull.
Environ. Contam.  Toxlcol.  16: 133-137.   (Cited 1n  U.S.  EPA,  1980a)

IARC  (International Agency for  Research on  Cancer).   1979.   Hexachlorocyclo-
hexane.  Ln: Some  Halogenated Hydrocarbons.   IARC Monographs on  the Evalua-
tion  of the  Carcinogenic  Risk  of   Chemicals  to Humans.   WHO,   IARC,  Lyon,
France.  Vol. 20,  p. 195-239.

IARC  (International Agency for  Research on  Cancer).   1981.   Hexachlorocyclo-
hexane  (Technical   HCH   and  Undane).    In:  Some  Halogenated  Hydrocarbons.
IARC  Monographs on  the  Evaluation  of  the  Carcinogenic   Risk  of Chemicals  to
Humans.  WHO, IARC, Lyon,  France.   Vol.  20,  p.  195-239.   (Cited  1n  U.S.  EPA,
1983b)
                                     -28-

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Ishldate,  M.,  Jr.  and S.  Odashlma.   1977.   Chromosome  tests  with 134  com-
pounds on  Chinese  hamster cells  in  vitro -- A  screening for  chemical  car-
cinogens.   Mutat.  Res.   48:  337.   (Cited In IARC,  1979)

Ito,  N.,  H. Nagasaki  and M.  Aral.   1973a.  Interactions  of  liver  tumoM-
genesls 1n  mice treated  with technical  polychlorlnated blphenyls  (PCBs)  and
benzene hexachloMde  (BHC).   In;  New Methods of  Environmental Chemistry  and
Ecological Chemistry, F.  Coulston, F.  Korte and M. Goto, Ed.   International
Academic Printing Company,  Tokyo,   p.  141-147.    (Cited  1n  IARC,  1981;  U.S.
EPA, 1983b)

Ito,  N.,  H.  Nagasaki,  M. Aral,  S.  Suglhara and S. Maklura.   1973b.   H1sto-
loglc  and  ultrastructural  studies  on  the hepatogenldty  of  benzene  hexa-
chlorlde In mice.   J.  Natl.  Cancer  Inst.   51: 817-826.   (Cited  1n  U.S.  EPA,
1983b)

Ito,  N.,  H.  Nagasaki,  H. Aoe, et  al.  1975.  Development  of  hepatocellular
carcinomas 1n rats treated with benzene hexachloMde.  J. Natl.  Cancer  Inst.
54: 801-805.  (Cited  1n U.S.  EPA,  19835)

Jedllcka,  V., Z. Hermanska,  I.  Smlda and A.  Kouba.   1958.   Paramyeloblastlc
leukaemia  appearing  simultaneously  1n  two  blood  cousins after  simultaneous
contact with  g-ammexane   (hexachlorocyclohexane).   Acta  Med.   Scand.    161:
447-451.
                                     -29-

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Lakkad, B.C., S.K. N1gam,  A.B.  Karnlk,  et al.  1982.  Dominant-lethal  study
of  technical-grade  hexachlorocyclohexane   In   Swiss  mice.   Mutat.   Res.
101(4): 315-320.

Lehman, A.J.   1954.   A  toxlcologlcal  evaluation  of  household  Insecticides.
Assoc. Food Drug  Officials.  Q.  Bull.   18: 3-13.   (Cited  1n  Delchmann,  1981}

LHterst,  C.L. and  E.  MUler.  1975.   Distribution  of Undane 1n brains  of
control and  phenobarbltal  pretreated dogs  at the onset  of Undane  Induced
convulsions.  Bull. Environ. Contam. Toxlcol.  13: 619.   (Cited In U.S.  EPA,
1980a)

Loge,  J.P.    1965.   Aplastlc  anemia  following   exposure  to  benzene  hexa-
chlorlde (Undane).  J. Am. Med. Assoc.   193: 104-108.

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

Mametkullev,  C.H.  1978.   Study of  embryotoxlc and  teratogenlc  properties  of
the gamma  Isomer  of HCH 1n  experiments with rats.   Zdravookhr.  Turkm.   20:
28.   (Cited 1n U.S. EPA, 1980a)
                                     -30-

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McCall, P.J.,  R.L.  Swann,  D.A. Laskowski,  S.M.  Unger,  S.A. Verona and  H.J.
Dlshburger.   1980.   Estimation  of  chemical  mobility  1n  soil  from  liquid
chromatographlc  retention   times.    Bull.   Environ.   Contam.   Toxlcol.    24:
190-195.

Nagasaki,  H., S. Tomii, T. Mega, M.  Marugam!  and  N.  Ito.   1971.   Development
of hepatomas 1n mice treated  with benzene hexachlorlde.   Gann.   62:  431.

Nagasaki,  H., S. Tom11, T. Mega, M.  Marugaml  and  N.  Ito.   1972a.   Hepatocar-
dnogenlc   effect  of  alpha-,  beta-, gamma-,  and delta-1somers  of  benzene
hexachlorlde 1n mice.   Gann.   63:  993.

Nagasaki,   H.,  S.  Tom11,  T.  Mega,  M. Marugaml and N. Ito.  1972b.  Cardno-
genldty of  benzene hexachlorlde (BHC).  In.:  Topics  1n  Chemical  Cardnogene-
s1s, W. Nakahara, S.  Takayama, T.  Suglmura and S. Odashlma,  Ed.   University
of Tokyo Press, Tokyo,   p.  343-353.

NAS  (National  Academy  of  Sciences).   1977.   Safe Drinking Water  Committee.
Drinking Water and Health,   p. 939.  (Cited 1n U.S.  EPA, 1980c)

NCI  (National  Cancer   Institute).   1977.  A  bloassay for  possible carclno-
genldty  of Undane.    NCI  Cardnogenesls  Tech.  Rep.  Ser. No.  14.   99  p.
[Also publ. as DHHS  (NIH) 77-184)]   (Cited  1n U.S. EPA,  1983b)
                                     -31-

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Oesch,  F.,  T. FMedberg,  M.  Herbst,  W.  Paul,  N.  Wllhelm  and  P.  Bentley.
1982.   Effects of  Undane treatment on drug  metabolizing enzymes and  liver
weight  of  CF1  mice  1n  which  H  evoked  hepatomas  and  In  non-susceptible
rodents.  Chem.-B1ol. Interact.   40: 1-14.

Page, G.W.   1981.   Comparison  of  groundwater  and surface water  for  patterns
and  levels   of  contamination  by  toxic substances.   Environ.  Sc1.  Technol.
15: 1475-1481.

Palmer, A.K., A.M.  Bottomley,  A.N.  Worden,  H. Frohberg and  A.  Bauer.   1978.
Effect  of  Undane  on  pregnancy  In  the  rabbit  and  rat.   Toxicology.   9:
239-247.  (Cited 1n U.S.  EPA,  1980a)

Petrescu, S., V.  Dobre,  M. Le1bov1c1,  Z.  Petrescu  and  S.A.  Ghelberg.   1974.
The  effects  of  long  term administration  of  organochlorlne  pesticides  (Un-
dane, DDT) on the white  rat.   Rev. Med. Ch1r.   78:  831-842.   (Cited In U.S.
EPA,  1980a)

Radaleff, R.D.  and R.C.   Bushland.  1960.   The nature and  fate  of chemicals
applied  to  soils, plants  and  animals.   Agrlc. Res.  Service,  USPE,  Washing-
ton,  DC.  p.  134.   (Cited  1n U.S. EPA,  1980c)

Rlvett,  K.F., H.  Chesterman,   D.N.  Kellett,   A.J.  Newman  and  A.N.  Worden.
1978.   Effects  of  feeding Undane  to dogs for  periods  of >2  years.   Toxi-
cology.  9:  273-289.  (Cited 1n U.S. EPA,  1980c)
                                     -32-

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Saslnovich,  L.M., S.M.  Alekhina  and  I.L.  Odlntsova.  1974.  Toxic  hepatitis



due  to  prolonged exposure  to BHC.   Vrach.  Delo.  10:  133-135.    (Cited  1n



U.S. EPA, 1980c)







Schubert, A.   1969.   Investigations  on  the  Induction  of  respiration  defi-



cient yeast mutants by chemical herbicides.  Z. Allg. Mlkroblol.   (Ger.)   9:



77.  (Cited 1n IARC,  1979)







Shlvanandappa, T.  and  U.K.   KMshnakumaM.   1981.   Hlstochemlcal  and  bio-



chemical  changes  1n  rats  fed dietary  benzene hexachlorlde.   Ind.  J.  Exp.



B1ol.  19(12): 11&3-1168.







Shlvanandappa,  T.  and  M.K.  KMshnakumaM.   1983.   Hexachlorocyclohexane-



Induced  testlcular  dysfunction In  rats.   Acta  Pharmacol.  Toxlcol.   52(1):



12-17.







Shlvanandappa, T., M.K.  KrlshnakumaM  and S.K. Majumder.  1982.   Inhibition



of  steroldogenlc  activity  1n  the  adrenal  cortex of  rats  fed benzene  hexa-



chlorlde  (hexachlorocyclohexane).   Exper1ent1a.  38(10):  1251-1253.







Shtannlkov,  E.V.,  et al.   1977.   Hygienic  study  of  the  transformation  of



poisonous chemicals  1n  the process of water  chlorlnatlon.   G1g.  Sanlt.   7:



18.  (Cited 1n U.S. EPA, 1980a)







Shtenberg,  A.I.  and  C. Mametkullev.   1976.   The effect  of  gamma-1somer  of



hexachlorocyclohexane (HCCH)  on  the  state  of sexual glands  1n rats.   Vop.



PHan.   (Rus.)  4: 62.   (Cited 1n IARC,  1979;  U.S. EPA,  1980c)
                                     -33-

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Shtenberg, A.I.  and  A.M. Torch1nsk11.   1977.   Adaptation  to  the action  of
some  teratogens  due  to  preliminary administration  of  pesticides to  female
rats.  Byull. Eksp.  B1ol. Med.   3:  227.   (Cited 1n U.S.  EPA,  1980a)

S1nha, R.R.P. and S.P. S1nha.  1983.  Induction of  dominant  lethal mutations
in  Drosophlla  melanogaster  by  three pesticides   Gamma-hexane, Sevln  and
Folldol.   Comp.  Physiol.  Ecol.   8(2): 87-89.

Spear, P.J.  1952.  Thesis,  Univ. Mass. Lib.,  Amherst,  MA.   (Cited  In  ACGIH,
1980)

Thorpe,  E.  and   A.I.T.  Walker.   1973.   The  toxicology  of  dleldrln  (HEOO).
II. Comparative  long-term oral  toxldty  studies  in mice with dleldrln,  DOT,
phenobarbltone,  beta-BHC  and gamma-BHC.   Food Cosmet.  Toxlcol.   11: 433-442.

Treon, J.F., et  al.   1951.   Report  from KetteMng  Laboratory,  University  of
Cincinnati.  (Cited  1n  ACGIH,  1980)

Tzoneva-Maneva,   M.T.,  F.  Kalolanova and V.  Georgleva.   1971.   Influence  of
dlazlnon   and  Undane  on the mltotlc  activity and the  karyotype  of  human
lymphocytes cultivated  1n vitro.   Blbl.  Haematol.   38:  344-347.

Ulmann,  E.,  Ed.   1972.   Llndane:  Monograph  of  an  Insecticide.   Verlag  K.
Sch1ll1nger Publishers, Freiburg,  West  Germany.  (Cited  1n U.S.  EPA,  1980a)
                                     -34-

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U.S.  EPA.   1973.  BCH-L1ndane.   Unpublished report.   Office of  Pesticides



Programs,  Criteria  and   Evaluation   Division.    Washington,   DC.    p. 280.



(Cited In U.S. EPA, 1980c)







U.S.  EPA.  1980a.  Ambient  Water  Quality Criteria for Hexachlorocyclohexane.



Environmental   Criteria   and   Assessment   Office,   Cincinnati,   OH.    EPA



440/5-80-054.  NTIS PB 81-117657.







U.S.  EPA.   1980b.   Guidelines  and Methodology  Used  In  the  Preparation  of



Health Effects  Assessment  Chapters  of the Consent  Decree  Water  Quality Cri-



teria.  Federal Register.  45:79347-79357.







U.S.  EPA.   1980c.   Hazard  Assessment  Report  on  Hexachlorocyclohexanes.



Environmental  Criteria  and Assessment  Office,  Cincinnati,   OH.   (Internal



Draft)







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



minations  Based  on  Chronic Toxldty Data.   Prepared by  the Environmental



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



Waste and Emergency Response, Washington, DC.







U.S.  EPA.   1983b.  Review  of  Tox1colog1c Data  In  Support  of  Evaluation for



Carcinogenic  Potential  of Gamma Hexachlorocyclohexane.  Prepared by the Car-



cinogen  Assessment  Group,  OHEA,  Washington,  DC,  for the  Office of  Solid



Waste and Emergency Response, Washington, DC.
                                     -35-

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U.S. EPA.  1985.  Drinking Water  Criteria  Document  for  Undane.   Prepared by
the  Environmental  Criteria  and Assessment  Office,  Cincinnati, OH,  OHEA  for
the Office of Drinking Water,  Washington, DC.   Final draft.

VeHh, G.D., D.L. DeFoe and B.V.  Bergstedt.   1979.   Measuring and estimating
the  bloconcentratlon  factor  of chemicals  1n  fish.   J.  F1sh  Res.  Board  Can.
36: 1040-1048.

Welsse,  I.  and  M.  Herbst.  1977.   Carc1nogen1c1ty  of Undane In  the  mouse.
Toxicology.  7:  233-238.

West,  I.   1967.   Llndane  and  hematologlc reactions.  Arch.  Environ.  Health.
15: 97-101.

Woodllff,  H.J.,  P.M.  Connor  and  J.  Scopa.   1966.   Aplastlc  anaemia  associ-
ated with Insecticides.  Med.  3. Aust.   1:  628-629.
                                     -36-

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                                  APPENDIX  A



                          Summary Table for Llndane
Experimental
Species Dose/Exposure Effect q-|*
Inhalation
AIS
AIC
Carcinogenic
potency
Oral
AIS
AIC
Carcinogenic mice Hver 1.326
potency malignancies (mg/kg/day) 1
Reference

NO
ND
ND

ND
ND
Thorpe
Walker







and
, 1973
ND = Not derived
                                     -37-

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                                  APPENDIX B
                            Cancer  Data  Sheet  for
                              Derivation of  q-|*
Compound:  Undane
Reference:  Thorpe and Walker (1973); U.S. EPA (1980a)
Species, Strain, Sex:  mice, CF, male
Body weight:  0.03 kg (assumed)
Length of exposure (le) = 770 days
Length of experiment (Le) = 770 days
Llfespan of animal (L) = 770 days
Tumor site and type:  liver, "malignant"
Route, vehicle:  oral, diet
Experimental Doses
   or Exposures
      (ppm)
Transformed Dose
  (mg/kg/day)
                                                         Incidence
No. Responding/No. Tested
       or Examined
         0
       400
       0
      52
          11/45
          27/28
Unadjusted q-|* from study = 1.0x10 * (mg/kg/day) 1
Human q-j* = 1.326 (mg/kg/day)'1
                                     -38-

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