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Slight  Increases  In  organ  weights were noted.  A dose  level  of  38  mg/kg  was
considered a LOAEL In mice  based  on  the  Increasesd  Incidence and severity of
nephrosls  1n  females and  an  Incidence  of hyperplasla  and  Inflammation  In
males and females.  The 19 mg/kg dose level was considered a NOAEL for  mice.

    In  the rat study  (SRI,  1981b;  Abdo et  al.,  1984),  dose levels of 10,  19,
38,' 75  and ISO mg/kg HEX 1n  corn oil  were administered by  gavage  to  groups
of 10 male and female F344 rats, 5 days/week for 13-weeks.   At  doses  of  >38
mg/kg  HEX,  epithelial   hyperplasla  and   Inflammation  of  the  forestomach.
Increased mortality and  toxic nephrosls  were observed  In  males  and females.
A  significant   (p<0.05)  dose-related  depression  In  body  weight  gain  was
observed  1n  males  at   levels  of   >38  mg/kg  and! females  at  >75  mg/kg.
                                                    t
Liver-to-brain  weight   ratios  were  significantly  (p<0.05)  Increased   In
females  at  >38 mg/kg  and  k1dney-to-bra1n  weight  ratios  at >75 mg/kg.   At
doses >19 mg/kg,  epithelial  hyperplasla  and focal  Inflammation  of  the fore-
stomach,  and   toxic  nephrosls  were  noted  1n  females.   Decreases  .In  body
weight  gain  relative to the  controls  were  observed  1n  males  at  all  dose
levels;  however,  these  were  not  significant  at  the  10 or  19 mg/kg  dose
levels.   In  females,  dose-related   decreases  In   body  weight  gain  were
observed  at   doses   >38  mg/kg/day.   No   significant  adverse  effects  were
observed In rats at the  10  mg/kg  dose  level.   A summary of these results  are
presented 1n Table V-3.
    Fourteen-week Inhalation.studies  In  rats  and  monkeys  have been performed
(Rand et  al.,  1982a,b; Alexander et  al.,  I960).   Groups  of  40  male  and. 40
female  Sprague-Dawley  rats, weighing 160-224 g  or  groups  of 12  cynomolgus
monkeys  (6/sex),  weighing 1.5-2.5  kg,  were  exposed  to HEX, 6  hours/day,  5
days/week, for  as long as  14  weeks.   Levels  of  exposure were 0,  0.01,  0.05
03650
V-9
04/12/91

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                          V-ll
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and  0.20  ppm HEX.   In  monkeys,  there  were no  deaths,  or adverse  clinical
signs,  or  significant   changes   1n  weight  gain,  pulmonary  function,  eye
morphology, hematologlc  parameters,  clinical  chemistry or  hlstopathology  at
any dose level tested.

    Male  rats  had a  transient  appearance of dark-red  eyes  at 0.05 and  0.2
ppm HEX.  At  12 weeks,  there were marginal  but  not  statistically significant
Increases  1n  hemoglobin  concentration  and erythrocyte  count  In  0.01  ppm
males,  0.05 ppm females, and 0.20  ppm males and females.  There were  small
but nonsignificant changes  In mean liver weight of all  treatment groups  and
similar  changes  In   the  kidneys  of   all  treated  males.   There  were   no
treatment-related  abnormalities   1n  gross  pathology  or hlslopathology.   On
this basis, the NOAEL In rats was 0.2 ppm HEX.

    In  another  study by  Rand et al.   (1982b),  no treatment-related  ultra-
structural changes were observed  1n monkeys  exposed  to HEX vapors.   Exposure
was Identical to  that described  1n the  previous  study (Rand  et  al.,  1982a).
This study took an In-depth  look  at  the Clara  cells  of the lung; the results
showed  a  statistically  significant (p<0.01) Increase  1n the mean  number  of
electron-lucent  Inclusions  1n the  apex and base of  the Clara  cells  In  the
exposed   animals   as  compared   with   the  controls.   According   to   some
researchers (Evans et al., 1978),  Clara cells  respond  to  Injury by regres-
sion  to a more  primitive cell type.  Rand  el al.  (1982b)  noted  that  some of
the  ultrastructural  changes 1n  the exposed animals  resembled  those of  the
Evans  study.    The  biologic  significance of  these  results  are "not  known;
however,  Clara  cells play an Important part 1n  producing  the extracellular
lining  of the peripheral airways.   Alteration  of this  lining may  result 1n
subsequent Impaired  breathing (Rand et al., 1982b).
03650                              V-12                              04/12/91

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    Treon et al.  (1955)  exposed two guinea pigs,  six  rabbits,  four  rats  and
five mice  to a concentration  of  0.34  ppm HEX  for 7. hours/day,  5  days/week
for 25-30 exposures.   Guinea  pigs survived the 30 exposures, while  only  two
rabbits  survived  and  no  rats  or  mice survived  5 exposures.   Degenerative
changes  were  observed  In   the  brain,  heart,  liver,  adrenal  glands  and
kidneys.  Severe  pulmonary edema,  hyperemla and  acute  necrotlzlng bronchitis
was also observed.   Using a  lower  concentration  (0.15 ppm HEX},  2/2  guinea
pigs, 3/3 rabbits and  4/4 rats  survived 150  seven-hour  exposure periods.  ,ln
mice, only 1/5  animals survived.   Slight  renal and 'hepatic degeneration  was
noted  In  all  species  and rats,  mice  and  guinea pigs  also  developed  lung
lesions.

    In  an  NTP-sponsored study  (Battelle  Northwest Laboratories,  1984;  Abdo
et a!., 1986),  F344  rats  and B6C3F1 mice  (10/group/sex)  were exposed  to  HEX
(99.42%) at  0',  0.04,  0.15,  0.4,  1  or  2  ppm  (0,  0.45,  1.67,   4.46, 11.1  or
22.3 mg/m3)  6  hours/day,  5  days/week  for  13  weeks.   All  .rats  and  mice
exposed to >1  ppm died;  5/10 male and  2/10  female mice at the  0.4  ppm also
died.    In   male   rats,  there  were   statistically   significant   (p<0.05)
reductions  1n body weight and Increases 1n relative lung weight at  0.4 ppm.
Similar  but  less   severe   effects  were   seen   In   females.    Dose-related
hlstopathologlc changes were  observed  1n the  respiratory  tract  epithelium of
males  and   females  at  >0.4  ppm.   Changes   Included  necrosis  and   acute
Inflammation.  No statistically significant adverse  effects were observed 1n
rats at <0.15 ppm.

    In  mice  (Abdo et al.,  1986),  exposure to >0.4 ppm  HEX  resulted  In a  10%
reduction  1n   body    weight   gain   In  males  and  females.    Dose-related
03650
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04/12/91

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hlstopathologlc  alterations   In   the   respiratory  epithelium,   Including
hyperplasla  and  metaplasia,  were  observed  1n  all  treated  mice  at  levels
>0.15 ppm.  No adverse effects were seen 1n mice exposed at 0.04 ppm.

    A chronic  oral  toxlclty  study of HEX  being  conducted  by  SRI for  the  NIP
was  terminated 1n  April  1982 because  Inhalation was  determined  to be  the
more  relevant  route of exposure.   No  other  chronic oral  toxldty  data  were
available  for  this  report.   There were no  chronic  dermal toxlclty  studies
found 1n the available literature.

    A 30-week  Inhalation study 1n  rats  of  technical  grade  HEX,  96% pure with
hexachlorobuta-l,3-d1ene  and   octachlorocyclopentene   as  Impurities,   was
conducted  by  Shell  Toxicology  Laboratory  (D.  Clark  et  a!.,  1982).   Four
groups  of  8 male  and 8  female  Wlstar  albino rats were  exposed  to HEX  at
nominal, concentrations of  0,  0.05, 0.1 and 0.5  ppm  for  6  hours/day,  5  days/
week, for  30 weeks  and were  observed  for  a 14-week recovery period  without
HEX  exposure.   At   the highest  dose level  4  males  and  2 females  died.   In
males,  there was a  depressed  body weight  gain  In  the 0.5  ppm group relative
to controls  beginning at  7 weeks  of exposure and persisting throughout  the
remainder  of  the  study.    In  females,  body  weights  were  significantly
Increased  during  the  first  half  of  the  exposure  period  but  were  signifi-
cantly  (p<0.01)  decreased  at  the  end  of  the  recovery  period at 0.5  and  0.1
ppm.   At  0.5  ppm,  there  were pulmonary  degenerative  changes  noted  1n  both
sexes although  the  males  were affected more severely.   At the  0.5  ppm  dose,
there were mild degenerative  changes 1n  the  liver  and  kidneys at 30 weeks 1n
a  few rats and kidney weights  were significantly Increased  1n the females.
After  30  weeks  of  study,  there  was  no  biologically   significant  toxldty
noted In animals exposed to concentrations of 0.05 or 0.1 ppm HEX.

03650                              V-14                              04/12/91

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Hutaqenldty
    Goggelman et al. (1978) found, that HEX was  not mutagenlc with or without
liver mlcrosomal  activation  at  2.7x10~3 M  1n an EscheMchla  coll  K12- back
mutation  system.   In  this  test there  was  7054  survival  of bacteria  at  72
hours.  HEX was not  tested at  higher  concentrations:because  1t was  cytotoxlc
to |_. coll.  A  previous  report  .from  the  same  laboratory (Grelm et al.,  1977)
Indicated  that  HEX  was also not mutagenlc In  Salmonella  typhlmurlum  strains
TA1535  (base-pair :mutant)  or  TA1538  (frame shift mutant) after  liver  mlcro-
somal  activation;,  however,  no  details of   the  concentrations tested we.«
given.   Although tetrachlorocyclopentadlene  Is  mutagenU 1n  these systems,
probably  through metabolic conversion  to  the  dlenone,  H  appears that  the
chlorine  atoms  at  the C-l position  of  HEX  hindered  metabolic  oxidation to
the  corresponding acylatlng dlenone  {Grelm et  al., 1977).

     A study conducted  by  Industrial Bio-Test  Laboratories  (IBT,  1977)  also
suggests   that  HEX   Is  not  mutagenU  In  S.   typhlmurlum.   Both HEX  and  11s
vapors  were tested  with and  without  metabolic activation.   The  vapor  test
was  done  In desiccators with only the TA100  strain  of  S. typhlmurlum.  It  Is
 not  clear from the  data whether sufficient  amounts of HEX or  adequate times
 of exposure were used.  Exposure times  of  30, 60 or  120 minutes  were  studied.

     At  concentrations  of  <1.25xlO~3  iig/mi.  1n  the  presence of   an  S-9
 liver  activating  system,  HEX was not  mutagenU In the  mouse lymphoma muta-
 tion  assay.    MutagenUHy could  not be  evaluated  at  higher concentrations
'because of the cytotoxUHy of HEX (Litton Blonetlcs,  Inc., 1978a).
  03650
                                    V-15                              04/12/91

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    Williams  (1978)   found  that  HEX  (10~*  M)  was  Inactive  In  the  liver
epithelial  culture  hypoxanth1ne-guan1ne-phosphorlbosyl  transferase (HGPRT)
locus/mutation  assay.   At  10"5  M  It  also  failed  to  stimulate  DNA repair
synthesis  In  hepatocyte  primary   cultures.   Negative   results   were  also
obtained In an additional unscheduled DNA synthesis  assay  (Brat,  1983}.

    Two  recent  studies  provided  by  NTP  (Haworth  et a!.,  1983) also did not
demonstrate the mutagenldty of HEX.   In S.  typhlmurlum strains  1A98, TA100,
TA1535  and  TA1537,   levels  of  <3.3  yg/plate  were  not  mutagenlc without
activation  and  levels  of  <100.0 v9/plate were not mutagenlc  after mlcro-
somal activation.   Higher  levels could  not  be tested  because of  excessive
killing  of  the  bacteria.   In  the  DrosophUa sex-linked  recessive lethal
test, HEX  was  not mutagenlc.  The  doses  used  In this  study  were  40 ppm  by
feeding for 3 days or  a single Injection of 2000 ppm.

    HEX  has  also  been  assayed  In   the  mouse  dominant  lethal  test (Litton
Blonetlcs,  Inc.,  1978b).   In this  assay, -0.1.  0.3 or  1.0  mg/kg HEX was
administered by  gavage to 10 male CD-I mice for  5  days and these  mice were
then  mated  throughout  spermatogenesls  (7  weeks).   This  test  determines
whether  the compound  Induces lethal  genetic  damage  to  the • germ cells  of
males.  There was  no  evidence of dominant lethal activity at any  dose level
by  any  parameter  (e.g., fertility  Index,  Implantations/pregnancy, average
resorptlons/pregnancy).

Carc1nogen1c1ty
    An  NTP bloassay of  HEX  for  cardnogenlcHy  by the Inhalation  route  1n
rats  and mice  1s  1n  progress  (NTP,  1991).   The ability of  HEX  to Induce

03650                              V-16                       .       04/12/91

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morphologic  transformation  of  BALB/3T3 cells  jjn vitro  has  been studied  by
Litton B1onet1cs, Inc.  (1977),  Evaluation  of  the potential  for  carcinogenic
activity was based on the following criteria:

    The endpolnt of carcinogenic activity  Is determined  by  the  presence
    of f1broblast1c-l1ke colonies, which are altered  morphologically  1n
    comparison to the cells observed  In normal  cultures.  These  (trans-
    formed)  cells  grow  In  criss-cross,  randomly oriented  fashion  with
    overlapping  at  the  periphery  of the  colony.   The  colony  exhibits
    dense piling up of  cells.   On staining the  foci  are deeply  stained
    and  the  cells are  basophlllc In  character and  variable In  size.
    These  changes  are  not  observed 1n  normal cultures,  which'  stain
    uniformly.

    Assays   were  performed   at   levels   of  0.0,   l.OxlO*5,   2.0xlO~s,
3.9xlO"5,  7.8xlO~s   and   1.56x10"*  yl/mi.    The   cultures  were   exposed
for  48 hours  followed  by  an  Incubation  period of  3-4 weeks.  The  doses
selected  allowed an  80-100%'  survival  of  cells as  compared  with  solvent
negative  controls.   3-Hethylcholanthrene  at  a  dose  level  of .5  yg/mj.  was
used as a  positive  control.   Results Indicated  that  HEX was  not responsible
for any significant malignant transformation.

Teratogen1c1ty
   .The teratogenU potential of HEX was evaluated  1n pregnant  Charles  River
CD-I  rats  administered  HEX, (98.25%)  In corn  oil,  by gastlc  Intubation,  at
dose  levels  of 3,  10 and 30 mg/kg/day  from days 6 through  15  of  gestation.
A  control  group  received   the  vehicle (corn  oil)  at  a dose  volume  of  10
ml/kg/day.   Survival  was  100%,  and  there   was  no   difference   1n   mean
maternal body  weight  gain  between dosed  groups and controls.   A  persistent
anogenHal staining was observed  In  dams at the highest  dose.  There were no
differences  In  the  mean   number  of  Implantations,  corpora  lutea,   live
fetuses, mean  fetal  body weights  or  male/female sex  ratios  among  any of  the
03650
V-17
04/12/91

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groups.  There  were no  statistical  differences  1n malformation or  develop-
mental variations compared with, the  controls when external, soft  tissue and
skeletal examinations were performed  (IRDC,  1978).

    Hurray et al. (1980) evaluated the  teratogenlc potential of  HEX  {98%)  In
CF-1 mice and New Zealand white rabbits.  Mice were dosed at 0, 5,  25  or  75
mg/kg/day HEX by gavage.from  days 6-15 of   gestation while  rabbits  received
the  same  dose  from days 6-18 of gestation.   In the mice,  no evidence  of
maternal  toxUUy,  embryotoxUHy or  teratogenlc effects  was  observed.   A
total of 249-374 fetuses (22-33 Utters) were examined 1n each  dose group.

    In  rabbits,  maternal  toxlclty  was  noted  at 75  mg/kg/day  (diarrhea,
weight  loss  and mortality),  but  there  was  no evidence  of  maternal  toxldty
at  the  lower levels.  There were no embryotoxlc effects at any dose  level.
Although there  was  an Increase In the  proportion  of  fetuses with  13 ribs  at
75  mg/kg/day,  this  was  considered  a  minor  skeletal  variation,  and  the
authors concluded that HEX was not teratogenlc at the levels tested.

    Studies  on  the  teratogenlc potential of  Inhaled  HEX were  not  located  1n
the  review  of  the  scientific  literature.   No  data  were   located  that
addressed the reproductive effects of HEX.

Summary
    Although  there  are  some   Interspecles  differences among  guinea  pigs,
rabbits,  rats  and  mice,  HEX  vapors  are toxic  to all  species  tested.   HEX
appears  most toxic  when administered  by Inhalation, with oral  and  dermal
administration  being  less   toxic routes.   The  acute   lethal  concentration
03650
V-18
06/19/90

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(LC50)  of  1.6 and 3.5  ppm In male and  female  rats,  respectively,  has been
demonstrated.   The oral  L05Q  for  adult  animals  is  >500  mg/kg;  however,
approximate  lethal doses  of 180 and  280 mg/kg  were determined for  mice and
rats, respectively.

    Subchronlc oral  dosing of  rats  (38 mg/kg/day) and  mice (75 mg/kg/day)
for  91   days  produced  nephrosls  and  Inflammation and  hyperplasla  of  the
forestomach.  No overt,  signs  of toxUlty were noted when mice and rats were
exposed  by  Inhalation at  0.2 ppm  of  HEX (6  hours/day,  5  days/week)  for 14
weeks.   However, Inhalation exposure  of  rats  at 0.5 ppm for 30 weeks caused
degenerative changes  1n the liver,  respiratory  tract  and kidneys.  jUi vitro
test results from three species have  not  shown  HEX  to  be a mutagen.   HEX was
also  Inactive  In  the mouse  dominant lethal  assay.   In  rabbits,  maternal
toxUUy has been noted at high oral  levels of  HEX  (75 mg/kg/day), but there
was no  evidence  of maternal  toxUUy at lower  levels.   Other research has
not shown any  maternal  toxUUy to mice.   Long-term  studies of HEX  inhala-
tion are presently being conducted  by  the NTP.
03650
V-19
06/19/90

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                         VI.   HEALTH  EFFECTS  IN HUHANS

    According  to  a NIOSH  estimate,  1427  workers are  occupatlonally  exposed
to HEX  (NIOSH,  1980).   Velslcol officials  estimate  that -157 employees  are
potentially  exposed to  HEX  In their  production facilities.   Acute  human
exposure  has  been  reported  In homes  near  waste  sites where HEX has  been
disposed (C. Clark et al.. 1982; Ella et al., 1983).

    Very  little  detailed  Information  Is   available  concerning  the  human
health effects  of  HEX  exposure.  The most noticeable  effect  Is  the  pungent,
Irritating  odor produced  by  HEX.   Levins  (1980)  reported  that  the  odor
threshold  of  0.0017 mg/m3  (0.00015  ppm)  represented  the recognition  level
for 100%  of the Individuals  on a  test  panel.   The study design and  method-
ology  were  not  given.    Based upon  animal  studies  and  observations  by
researchers, HEX vapors are very Irritating  to all mucous membranes,  causing
tearing, sneezing and salivation; skin contact can cause blisters  and burns.
Inhalation of vapors or  mist  can result 1n  the  secretion of  excess  fluid In
the  lung,  while   Inhalation   or  Ingestlon may  cause nausea,   vomiting,
diarrhea,  lethargy,  respiratory   Impairment and  Injury  to  the  liver  or
kidneys.

Acute Exposure Studies
    Treon et al. (1955)  reported that members of a group conducting  toxlclty
tests  developed headaches  when they  were  accidentally  exposed to  unknown
concentrations  of   HEX,  which  had   escaped  Into the  room when  an  aerated
exposure chamber was opened.
03660
VI-1
08/25/88

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    A well-documented  Incident  of acute  human exposure  to  HEX occurred  1n
March 1977  at the Morris  Forman Wastewater  Treatment  Plant 1n Louisville,
KY.  The  Incident  has  been described and reviewed In several papers  (HUson
et  al.,  1978; Morse  et al.,  1979;  KomVnsky  et  al..  1980).   The complete
details  of  the  original   NIOSH  Hazard Evaluation and  Technical  Assistance
Report Number TA-77-39 are found In Komlnsky and Wlsseman  (1978).

    In 1977,  the Louisville treatment  facility  was contaminated with  -6  tons
of  HEX  and  smaller amounts  of  OCCP,  a waste by-product  of HEX manufacture
(Horse et al., 1979).   The contamination was traced  to one  large  sewer  line
that passed through several populated  areas.   Concentrations of  HEX detected
In  the  sewage water  at the. plant  ranged  <1000 ppm,  and  levels 1n the  sewer
Hne  ranged  <100  ppm.   A1r   samples   from  the   sewer  line showed   HEX
concentrations <400  ppb.   Although  airborne  concentrations of HEX  at  the
time of  the  exposure  were unknown,  airborne  concentrations 1n the  primary
treatment areas  (screen and  grit chambers) ranged between 270  and 970  ppb 4
days after  the  plant  had closed.   (The ACGIH TWA   for  HEX was  10  ppb  1n
1977.)    During  the   cleanup,   when  workers  used  steam  to  remove   the
contamination, levels of 19.2 ppm HEX were reported (Komlnsky et al.,  1980).

    The  Centers  for Disease Control  (CDC) and NIOSH  developed  questionnaires
regarding the type and  duration  of  symptoms (Morse et al..,  1979; Komlnsky et
al., 1980).   A total  of  193  employees were  Identified as  those potentially
exposed  for  2 or more  days  during the 2 weeks before the  plant  was closed
(Morse  et al.,  1979).   Of the  193  employees  exposed, 145  (75X)  responded.
Physical  examinations  and  blood  and  urine  samples  were  collected  from
workers  reporting symptoms of mucous membrane Irritation.

03660                               VI-2                             08/25/88

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    Results of the  CDC  and NIOSH questionnaires showed that  the  odor  of  HEX
was detected  before the onset of  symptoms  by 94% of the workers.  The most
common  symptoms  reported  were  eye  Irritation  (59%),  headaches (45%)  and
throat  Irritation  (27%)   (Table   VI-1).   Of   the   41   workers   physically
examined,  6 had  physical  signs of eye Irritation  (I.e.,  tearing  or  redness)
and 5  had  signs  of  skin Irritation.  Laboratory analyses of  blood and urine
specimens  from these workers  showed  elevations  of  lactic  dehydrogenase (LDH)
In  27% and  protelnurla In  15%.   However,  no  clinical  abnormalities were
reported by  the  plant  physician,  the local  hospital, or by  the  Independent
laboratory 3 weeks later (Horse et al.,  1978,  1979).

    During  clean-up procedures,  clinical  chemistry parameters  were  moni-
tored.  The  only abnormalities  noted were  several   m1n1mal-to-m1ld  altera-
tions   In liver function  tests (Komlnsky et al., 1980).   These  abnormalities
are listed  In  Table  VI-2.   All  workers  showing these  symptoms also  had
physical signs  of  mucous  membrane  Irritation.  Table  VI-3  summarizes data
for nine workers  exposed  at the site (Komlnsky  et al.,  1980).   The  exposure
levels could  not  be estimated accurately because  of  possible prior  exposure
and because the workers had used protective equipment.

    A  questionnaire was also  given to a  selected sample of residents of  a
48-block area surrounding  the  contaminated  sewer   line.   A  total  of  212
occupants  were surveyed.   Very few  residents  noted  an unusual odor  (3.8%).
The most  prevalent  symptoms  were  stomachaches  (5.2%).  burning  or  watering
eyes  (4.7%) and  headaches  (4.7%).   There was no association  between  symptom
rates   and  the  distance of  households  from  the  contaminated  sewer  line.
03660
VI-3
08/11/88

-------
                                  TABLE VI-1

             Symptoms of 145 Wastewater Treatment Plant Employees
                 Exposed to HEX (Louisville,  KY, March 1977)*
Symptom
Eye Irritation
Headache
Throat Irritation
Nausea
Skin Irritation
Cough
Chest pain
Difficult breathing
Nervousness
Abdominal cramps
Decreased appetite
Decreased memory
Increased saliva
No. of Employees
with Symptom
B6
65
39
31
29
28
28
23
21
17
13
6
6
Percent of Employees
with Symptom
59
45
27
21
20
19
19
16
14
12
9
4
4
*Source:  Morse et al., 1978
03660
VI-4
09/19/85

-------
                                  TABLE VI-2
                  Abnormalities for 18 of 97 Cleanup Workers
                     at  the  Morris  Forman  Treatment  Plant3
                                                            Abnormal  Results
Laboratory Test Normal Range
Serum Glutamate-
Oxalacetate Transamlnase (SGOT) 7-40 mil/ml





Serum Alkaline Phosphatase 30-100 mil/mi


Serum Total BlUrubln 0.15-10 mg/%
Serum Lactate Dehydrogenase 100-225 mU/mst
Range

40-49
50-59
60-69
70-79
80-89
90-99
100-109
110-119
120-129
1.0-1.9
230-239
No.

5
1
4
0
1
1
3
1
1
lc
1
aSource: Komlnsky et a!., 1980
bFor  Individuals  with  more  than  one   serial   blood   test,   only   the  most
 abnormal result 1s tabulated.
Associated with serum glutamate-oxalacetate transamlnase of 66
U * Units of enzyme activity
03660
VI-5
08/11/88

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03660
VI-6
                                                                      08/11/88

-------
The  authors  stated  that  no  significant  ambient air  concentrations  of  HEX
were found 1n these  areas  (Komlnsky  and Wlsseman,  1978).   Residents  reported
the same types and frequency  of  symptoms  reported  by workers  assoclated'wilh
HEX  exposure,  which  led   the  authors to  suggest   that  these symptoms  were
unrelated to HEX  exposure or may  be due to  other  confounding environmental
factors (Horse et al., 1978).
    Several  papers  have  documented  'a similar  Incident of  HEX exposure  -In
Hardeman  County,  TN.  (C. Clark  et  aK,  1982;  Meyer, 1983;  EUa et  al.,
1983).   In  1978,  workers at  the  treatment  plant began  complaining  of  acute
symptoms similar to those found In  the Louisville plant.  Air and  wastewater
levels  were  monitored,   and  urine,  blood   and  liver   function  tests  were
analyzed, as  well  as  data  obtained  from an Illness symptom questionnaire.
In  the  original study  design,  workers  were compared  with  a  control  group
from another  Memphis  treatment  plant, which did  not  receive  wastes  from the
pesticide manufacturing  plant.    In  a  later survey,  workers  at  two  other
municipal  facilities  were  used  for comparison.   In  the analysis  of  the
various  monitoring   tests,  C.  Clark  et al.   (1982)   found  no  statistical
difference  1n  urine  samples  from both of  the  Memphis  treatment  facilities.
In  the  liver  function  tests,  there  were  no  statistically  significant
differences among the values  obtained for all survey groups.
    At  the  same  time  the  wastewater  treatment  plant  study  was  being
performed,  an   Investigation  of  residential  wells  In  Hardeman County  was
conducted  In  response  to  complaints  of  foul  odors and  bad taste  (Meyer,
1983).   In this area  also lies  a  200  acre chemical  land dump, which  was
operated from 1964-1972.  In 1978,  the  U.S.  Geologic Survey (Sprinkle,  1978;
Rlma,  1979)  confirmed  the  contamination  of wells.   However,  HEX  was  not
03660
VI-7
04/12/91

-------
detected  1n  any  samples.   Urine  surveys  and  liver  function analyses  were
conducted on residents.   A  summary of this data  Is  presented 1n  Table. Vl-4.
The  situation  at  the Memphis  treatment  facility  Is the  only known  existing
case of  essentially  continuous  low-level  chronic  exposures  with  Intermittent
higher acute  exposures,  especially  during  an accidental discharge .from the
nearby pesticide manufacturing facility (Ella et al., 1983).

Epldemlologlc Studies
    Mortality studies have been  conducted on  workers  Involved In  the produc-
tion of  HEX or  formulation  of  HEX  products.  The Shlndell  and  Associates
(1980)  report  was  a  cohort  study  of  workers  employed  at  the  Velslcol
Chemical Corporation plant at Marshall,  Illinois  between  1946 and  1979.   The
purpose  was  to  evaluate  the vital  statistics  of  all  former  and  current
employees (>3 months) who were present during  the  manufacture of  chlordane.
In preparing the  cohort,  the authors noted the difficulties  1n  tracing some
of  the  employees.   In  the  final  cohort of  783 Individuals, 97.4%  of  the
employees were  located  and  their  vital  status  Included 1n  the  study.   The
analysis showed no significant differences 1n mortality  rates between these
employees and  the  U.S.   population.   The  observed  deaths  for  all  causes,
Including heart disease and  cancer,  were fewer than  the  calculated  expected
deaths among members of  the U.S. population (Shlndell and Associates, 1980).

    Wang and MacMahon (1979)  conducted a  study  of 1403 males  employed at the
Marshall and Memphis plants for >3  months.  There  were  113  observed deaths
compared with 157  expected,  yielding  a  standardized  mortality ratio  (SMR) of
72.  The two highest SMRs were  134 for  lung cancer  and 183 for. cerebrovascu-
lar  disease,  but   only  the  latter  was  statistically  significant  (p<0.05).


03660                               VI-8                             08/11/88

-------
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VI-9
                                                                               08/11/88

-------
The authors suggested  that  these effects were unrelated  to  exposure  because
the deaths showed  no  consistent  pattern with duration  of  employment  or  with
duration of follow-up.

    A study of  >1000  employees  (93% of  the cohort) at  the Memphis, TN plant
from  1952-1979  was  conducted  by  Shlndell   and  Associates  (1981).   The
researchers found  no  significant  difference 1n mortality  between  the  control
and exposure groups and  fewer deaths 1n the  study  group  than predicted  from
vital statistics rates.  The  Investigators also  reported  there was  no excess
mortality by job function.

    Buncher  et  al.   (1980)  studied  the mortality  rates of  workers  at  a
chemical  plant  that   produced  HEX.   The  Investigators   reviewed  personnel
records  for  those  who worked  for at least 90 days between   October  1,  1953
and December 31, 1974.  There were, 341  workers  (287 male  and 54  female) who
fit the  criteria.   Health  status  was  ascertained through 1978 and  expected
numbers  of.  deaths were  calculated   based   upon   the  U.S.   population  and
specifics  for   sex,  age and calendar   year.    The  SMR was   69 showing  the
workers  to be  healthier  than  the  general  population.   Deaths  caused  by
specific  cancers,  all  cancers,  disease of  the circulatory  and  digestive
systems  were  fewer than the expected  numbers.   The  authors  noted that the
time  since Initial exposure,  <25 years, reduced the  power  of the study to
detect cancers, which may have a 10-40 year  latent period.

Summary
    There  Is   only limited  Information on  the  effects   of   HEX  1n  humans.
Acute Inhalation exposure has  resulted  1n headaches and severe Irritation of
the eyes,  nose,  throat and  lungs.  Dermal contact may  cause  severe burns and
03660 -                             VK10                            08/25/88

-------
skin  Irritation.   Ep1dem1olog1c studies have  generally  shown no significant
differences  1n mortality rates  of workers  exposed  to HEX  1n  the workplace
and  the general population.   Although a  significant  excess of  deaths  from
cerebrovascular disease was reported  1n  one study,  no consistent pattern was
observed with duration of employment or follow-up.

    Current  human  exposure  1s  limited to  Improper handling  and disposal and
proximity to either manufacturing  sites  utilizing HEX or  disposal sites.  No
other chronic  human  health  effects data from  HEX exposure have been located
In the  literature.
03660
VI-11
08/25/88

-------

-------
                         VII.   MECHANISMS  OF  TOXICITY

    The mechanisms  underlying  HEX toxUHy  are  not  well  understood, mainly
because of  Us high chemical  reactivity  and ability  to  polymerize even at
low temperature.  HEX has been shown to react with oleflns and other organic
molecules, such as aromatic compounds.  In vitro studies by El Oareer et al.
(1983) have  Indicated that  HEX readily binds to organic material and can be
easily extracted.

    While the  available  literature does not  provide  any single mechanism to
account for HEX toxldty, Lawrence and Oorough  (1982)  showed  that all routes
of exposure  caused  necrotlc  lung  tissue.   Exposure to HEX vapors results In
Irritation of  the  respiratory  tract and  may lead  to bronchopneumonla and
respiratory  failure  (D.  Clark  et al., 1982).   In  comparison, the  degenera-
tive changes 1n the  liver and  kidneys  are  mild  and unlikely to contribute to
the chemical's toxlclty  (NAS,  1978;  SRI, 1980a,b).

    Absorption from  the  Gl  tract  was reported to  be  relatively  Inefficient.
This may  be  due  to the  poor bloavallabllHy of  HEX when administered by the
oral  route  or  to  Us  rapid  hepatic  metabolism and  biliary excretion (El
Dareer et al., 1983; Lawrence  and Dorough, 1962).  Studies by Yu and Atallah
(1981) Indicate  that the gut  and fecal  flora may have a  major  role In the
metabolism  of  HEX  and  that  enzyme  dependent  processes  may  be   limited.
Absorption  following  dermal  exposure resulted  In  marked  distinct   skin
discoloration, and  In some  cases, mortality.  This might suggest a  "site of
uptake" Interaction, which may be similar  to that  observed In the lung  after
pulmonary uptake.
03670
VII-1
08/25/88

-------
     Following  Inhalation  and  the  diffusion  of HEX through the lung tissue to
 the  blood,  metabolism to water-soluble compounds may  occur,  but  attempts to
 collect  and  Identify metabolites  have  been  unsuccessful.   The  relatively
 slow elimination  of the radlolabel from  the  systemic  circulation  after  1.v.
 dosing  with 14C-HEX  (approximate terminal  half-life  of 30  hours)  suggests
 potential  for  bloaccumulatlon  or  repeated  dosing  (Lawrence  and  Dorough,
 1981, 1982).

     Rand  et al.  (1982b)  showed  that  significant  changes  at  the  cellular
 level  1n  lung tissue  occurred  after  HEX Inhalation.   HEX  vapors  affect the
 extracellular  lining,  and 1n  some  cases,   cause  significant  Increases  1n
 hemoglobin  and red  blood cells.  Although more  severe effects  seem to occur
      1    i
 by  Inhalation,  Impaired  breathing was seen  1n most  experiments  regardless of
 the  route of exposure.

 Summary
     Little  1s  known  about the  mechanism of  HEX toxldty.   Because  of Us
 high reactivity  and  volatility,  attempts  to Identify  the  reactive  metabo-
 lites of  HEX and  to characterize Us  mechanism of toxldty have been largely
'unsuccessful.   Data  gaps  remain  In  several   areas:   1)  the  question  of
 whether similar metabolites are formed following administration by different
 routes; 2)  comparison  of  toxldty of  the  parent  compound and Its  metabolites
 1n  eliciting  the toxic  effects  seen  following  HEX exposure;  and 3) Inter-
 action  of HEX with organic  compounds  such  as hemoglobin.   Finally,  HEX Is
 often contaminated  by  products  used  1n Us  manufacture or 1n the manufactur-
 ing  of other products; therefore, the possibility for  co-exposure may exist.
 03670                              VII-2                             08/30/88

-------
                 VIII.   QUANTIFICATION OF  TOXICOLOGIC  EFFECTS

Introduction
    The  quantification  of  toxlcologlc effects  of  a chemical  consists of
separate  assessments  of  noncarclnogenU   and  carcinogenic  health  effects.
Chemicals that  do not  produce  carcinogenic  effects!  are  believed to have  a
threshold dose below which no adverse,  noncarcinogenic health  effects occur,
while carcinogens are assumed to act without  a  threshold.

    In  the  quantification   of   noncardnogenic  effects,  a  Reference   Dose
(RfD),  [formerly  termed  the  Acceptable  Daily  Intake (ADI)]   is  'calculated.
                                 -  .     .            i
The  RfD  1s  an  estimate (with  uncertainty spanning perhaps an order magni-
tude)  of a  dally  exposure   to the  human  population  (Including  sensitive
subgroups) that  is  likely to be without  an  appreciable  risk  of  deleterious
health effects  during   a  lifetime.   The  RfD  1s  derived  from  a  no-observed-
adverse-effect   level   (NOAEL),   or   lowest-observed-adverse-effect   level
(LOAEL),  Identified  from a  subchronlc or chronic  study, and divided  by  an
uncertainty factor(s)  times  a  modifying  factor.   The  RfD Is calculated  as
follows:                                        .
     RfD . 	    	 =      mg/kg bw/day
           [Uncertainty Factor(s) x Modifying Factor]
    Selection of the  uncertainty  factor  to  be  employed 1n the calculation of
the  RfD 1s based  upon professional  judgment,  while  considering  the  entire
data  base  of  toxlcologlc  effects  for the chemical.   In order to ensure that
uncertainty  factors  are  selected and  applied  in  a consistent  manner,  the
03680                               VIII-1                           04/12/91

-------
U.S.  EPA  (1991) employs  a modification  to the  guidelines  proposed by  the

National Academy of Sciences (NAS,  1977,  1980)  as follows:


Standard Uncertainty Factors (UFs)

        Use a 10-fold factor when  extrapolating  from valid experimental
        results from studies using  prolonged exposure to average healthy
        humans.  This  factor  Is Intended  to account for  the  variation
        In sensitivity among the members  of the human population.   [10H]

    •   Use an  additional  10-fold  factor  when extrapolating  from  valid
        results  of  long-term  studies  on  experimental  animals   when
        results of  studies  of  human exposure  are not available or  ares
        Inadequate.  This  factor 1s  Intended to  account for  the  uncer-
        tainty  1n   extrapolating  animal   data  to the  case  of  humans.
        [IDA]

        Use an  additional  10-fold  factor  when  extrapolating from  less
        than  chronic  results  on experimental  animals  when there  Is  no
        useful  long-term  human  data.   This   factor  Is   Intended  to
        account  for the  uncertainty  In  extrapolating  from  less  than
        chronic NOAELs to chronic HOAELs.   |10S]

        Use an  additional  10-fold factor  when deriving an  RfD from  a
        LOAEL Instead  of  a NOAEt.    This  factor   1s  Intended  to account
        for  the uncertainty  In extrapolating  from  LOAELs  to  NOAELs.
        [10L]

Modifying Factor (MF)

        Use  professional  judgment  to  determine  another  uncertainty
        factor  (MF) that 1s greater  than  zero  and less  than  or  equal  to
        10.   The  magnitude  of  the  MF  depends  upon the  professional
        assessment   of  scientific  uncertainties  of  the  study  and  data
        base  not  explicitly treated above, e.g.,  the  completeness  of
        the overall  data base  and the number  of species  tested.   The
        default value for the MF Is 1.
    The  uncertainty  factor  used for  a  specific  risk  assessment  Is  based

principally  upon  scientific  judgment   rather   than   scientific   fact  and

accounts  for  possible   Intra-  and   Interspedes   differences.    Additional

considerations not  Incorporated  1n  the  NAS/OOW  guidelines for  selection  of

an  uncertainty  factor Include  the  use  of a  less than  lifetime  study  for

deriving  an  RfD,  the .significance  of  the  adverse health  effects  and  the

counterbalancing of beneficial effects.



03680                               VII1-2                           04/12/91

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    From  the RfO,  a  Drinking  Water  Equivalent Level  (DWEL)  can.be  calcu-

lated.   The  DWEL  represents  a  medium  specific  (I.e.,  drinking  water)

lifetime  exposure  at  which  adverse,  noncarclnogenlc health effects are  not

anticipated  to  occur.   The  DWEL  assumes  100% exposure from drinking  water.

The DWEL  provides  the noncarclnogenlc health effects  basis  for  establishing

a  drinking  water  standard.   For  1ngest1on  data,  the  DWEL  Is derived  as
                                                    t
follows:
               DWEL
 (RfD) x (Body weight In kg)
Drinking Water Volume 1n i/day
mg/si
where:
        Body weight - assumed to be 70 kg for an adult
        Drinking water volume = assumed to be 2 l/day for an adult
    In addition  to  the RfD  and  the DWEL, Health Advisories  (HAs)  for  expo-

sures  of  shorter duration  (1-day, 10-day  and longer-term)  are'determined.

The  HA values  are  used  as  Informal  guidance to  municipalities  and  other

organizations when  emergency spills or contamination  situations  occur.   The

HAs are calculated  using an  equation  similar  to  the  RfD  and DWEL; however,

the NOAELs  or  LOAELs  are Identified  from acute or  subchronlc  studies.   The

HAs are derived as follows:
                   HA _ (NOAEL or LQAEL) x (bw) _
                          (UF) x (	 I/day)    = —
                                 mg/8.
    Using the above equation, the  following  drinking  water  HAs  are developed

for noncarclnogenlc effects:
    1.  1-day HA for a 10 kg child Ingesting 1 8. water per day.
    2.  10-day HA for a 10 kg child Ingesting 1 8, water per day.
    3.  Longer-term HA for a 10 kg child Ingesting 1 I water per day.
    4.  Longer-term HA for a 70 kg adult Ingesting 2 8. water per day.
03680
              VIII-3
         04/10/88

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    The  1-day  HA  calculated  for  a  10  kg  child  assumes  a  single  acute

exposure to  the  chemical  and Is  generally  derived  from a  study  of  <7 days

duration.  The 10-day HA  assumes  a  limited  exposure period of 1-2 weeks and

1s generally derived from a  study of  <30 days duration.  The longer-term HA

Is  derived  for  both  the  10 kg  child  and  a 70  kg  adult and  assumes  an

exposure period  of  -7  years  (or  10%  of  an Individual's  lifetime).   The

longer-term  HA  1s generally derived from  a  study of  subehronlc duration

(exposure for 10% of  animal's lifetime).



    The U.S. EPA categorizes the carcinogenic potential of  a chemical, based

on the overall  we1ght-of-ey1dence, according  to the  following scheme:


        Group  A:  Human  Carcinogen.  Sufficient  evidence  exists from
        epidemiology  studies  to  support  a   causal  association between
        exposure  to  the  chemical  and human cancer.

        Group  8:  Probable  Human Carcinogen.   Sufficient  evidence  of
        cardnogenlclty  In  animals  with  limited  (Group  81)  or  Inade-
        quate (Group  B2)  evidence 1n humans.

        Group  C:  Possible  Human  Carcinogen.   Limited   evidence  of
        cardnogenlclty  1n animals  In  the  absence of human  data.

        Group D:  Not  Classified  as to  Human Cardnogenlclty.    Inade-
        quate human  and animal evidence of cardnogenlclty  or for  which
        no  data are  available.

        Group  E:  Evidence   of   Noncardnoqenldty  for   Humans.   No
        evidence   of  cardnogenlclty  In  at  least   two  adequate  animal
        tests 1n  different   spedes  or  In  both  adequate  epldemlologlc
        and animal studies.


    .If  toxlcologlc evidence  leads  to the classification  of the  contaminant

as a  known,  probable  or possible human  carcinogen,  mathematical  models are

used  to calculate  the  estimated   excess cancer  risk  associated with  the

Ingesllo'n  of the contaminant  In drinking  water.   The  data used In these
03680      -,                         VIII-4                           04/12/91

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estimates  usually  come  from lifetime  exposure studies  using animals.   In
order to predict the  risk for humans from animal data, animal  doses  must  be
converted  to  equivalent  human  doses.   This  conversion  Includes  correction
for  noncontlnuous  exposure,  less than  lifetime studies and  for  differences
1n  size.   The factor  that  compensates  for the  size  difference 1s the  cube
root of  the ratio  of  the animal and human body  weights.   It  Is assumed  that
                                                    •t
the  average  adult  human  body weight  1s  70  kg and'  that the  average  water
consumption of an adult human 1s 2 I of  water  per day.

    For  contaminants   with  a  carcinogenic  potential,  chemical  levels  are
correlated with  a  carcinogenic  risk estimate  by employing a  cancer  potency
(unH risk) value  together with  the assumption  for;  lifetime  exposure  from
1ngest1on of  water.   The  cancer  unit risk Is  usually derived from a  linear-
ized multistage model with a 95%  upper  confidence  limit providing a low dose
estimate; that  Is,  the true risk  to humans,  while not Identifiable,  1s not
likely  to  exceed  the  upper  limit  estimate  and,  1n  fact,  may be  lower.
Excess cancer  risk estimates  may  also be calculated  using  other  models  such
as  the  one-hit, Welbull,  loglt  and problt.   There  1s  little basis  In the
current  understanding  of the  biologic  mechanisms  Involved  In  cancer  to
suggest that any one  of these models  Is able  to predict risk more accurately
than any other.  Because  each model  Is  based  upon  differing assumptions, the
estimates derived for each model can differ by several orders of magnitude.

    The  scientific  data  base used  to calculate  and  support  the .setting  of
cancer  risk  rate  levels  has  an  Inherent  uncertainty  that   Is  due  to the
systematic and random errors 1n scientific measurement.   In most  cases,  only
                                               v
studies  using experimental  animals  have been  performed.   Thus,  there  1s

03680                               VII1-5                           04/12/91

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uncertainty  when  the  data  are  extrapolated  to  humans.   When  developing
cancer risk  rate levels,  several other  areas of uncertainty exist,  such  as
the  Incomplete  knowledge concerning  the health effects  of contaminants  1n
drinking  water,  the  Impact   of  the  experimental  animal's  age,  sex  an.d
species,  the  nature of the  target  organ  system(s)  examined and  the  actual
rate of exposure of  the  Internal targets In  experimental animals  or  humans.
Dose-response data  usually  are  available  only for  high  levels of  exposure
and not for  the lower  levels  of exposure  closer  to  where a standard  may  be
set.   When  there 1s  exposure  to  more than  one  contaminant,  additional
uncertainty results from a lack  of  Information  about  possible  synerglstU  or
antagonistic effects,
                                                                   *.
Noncardnogenlc  Effects
    Limited quantitative Information 1s  available regarding  the  human health
effects resulting from HEX exposure; however,  transient or  acute exposure  to
HEX vapor   has been  associated  with  Irritation  to the eyes,  nose and  throat,
as  well   as  headaches  and  nausea.   In  animals,  comparative  studies  have
Indicated   that  HEX  exposure  1s more  toxic  following  Inhalation  than  oral
exposure.

    Short-term  studies  by  IRDC (1978)  and  SRI  (1980a,b, 1981a,b)  provide
substantial data  on  oral  toxldty  to  rats  and mice.  The  Southern  Research
Institute   (SRI,  1981a,b)  studies are of  longer duration  and provide  NOAELs
and  LOAELs.   A  Russian   study  by  Na1shte1n  and   Llsovskaya   (1965)  was
conducted   for  6  months  and  also  yielded no-effect  levels;  however,  an  HA
cannot be  recommended since  the complete study design was  not reported.
03680                               VIII-6                           06/19/90

-------
    More recent  studies  have been  published  (SRI,  1980a,b, 1981a,b), which
provide  greater   detail,   use  more  appropriate  toxlcologlc  endpoinU  .and
define NOAELs and LOAELs  than  the earlier study by •Nalshteen  and  llsovskaya
(1965) which served as the basis  for the  1980  Ambient  Hater  Quality  Criteria
Document (U.S. EPA,  1980).  These studies are reviewed below and have  been
used  1n  the calculations  of  the 1-day,  10-day  and  longer-term HAs and  the
lifetime DWEL.
    SRI (1980a) conducted a gavage study using HEX  with  male and female F344
rats and  B6C3F1  mice.   Dose levels  of, 0,  75, 150,  300, 600 and  1200  mg/kg
HEX In corn oil were administered  to  both  rats and  mice  by gavage.  One dose
at each of  the five levels was given to five animals  of each sex.%  Clinical
observations  related  to the  administration of  HEX Included  a decrease  In
activity,   ruffled  fur,  wet  fur  1n  the   anal  area  and  diarrhea.   These
alterations occurred within 6-24 hours of  dosing; severity and  duration were
related to  the dose level.  All rats  In the 600 and  1200  mg/kg dose  groups
died, while  1n the 300 mg/kg dose group,  two  female rats  died.   In  the 150
and 75 mg/kg  rat dose groups,  ruffled  fur occurred, but  no  deaths.   In the
mouse  study,  all  1200 mg/kg  dose  group  animals  died.   At  the 600  mg/kg
level, only  one  female and one male  mouse died.  At  the  other  levels, only
minor effects were  observed.  The  150 mg/kg  rat  level, was observed to be the
NOAEL In rats, while the 300 mg/kg was chosen as  the NOAEL In mice.
    The SRI  (1980b)  conducted a  repeated-dose  study In which  F344  rats  and
B6C3F1 mice  were exposed  to 0,  25,  50,  100, 200 and  400 mg/kg HEX  and  0,
50,  100,  200, 400 -and 800  mg/kg HEX In  rats  and mice,  respectively.   All
doses were  administered by  gavage  with  corn oil .used  as  the  vehicle.  Five
03680
VIII-7
04/12/91

-------
mice and five  rats  of each sex were  used  for  each dose level  on  a  schedule
of 12  dosing  days {days 1-5, 8-12,  15  and 16), with at least  2 consecutive
dosing days before the terminal  sacrifice began.

    In  the raj  study (SRI,  19805),  all  males  and 4/5 females at  the  400
mg/kg  HEX  dose level died, while  at the  200  mg/kg dose,  1/5  males  and  4/5
females died.  Clinical observations  were  performed twice  dally.  At  the  100
mg/kg dose level, ruffled  fur occurred  In  all  rats.  The Investigators Rioted
that  there was  significant  weight  depression  In  both  the  males   and  the
females  at this  dose  rate,  but  there were  no  deaths or  life-threatening
clinical and gross observations.   At  the 50  mg/kg  HEX dose level, there were
no significant  clinical  signs,  but  there  were gross changes  to the  stomach
wall and a depression  In  weight  gain.   The  gross observations  at   the  50
mg/kg  dose level  Included  discolored raised areas  on  the  mucosal  surface of
the  stomach  1n 3/5  females and  3/5  males.  The  decrease  In weight  gain  1n
males  was  -17% and  females -22%.   At  the 25  mg/kg level, the clinical  and
gross  observations  did  not  find  any  Irregularities.   The  weight  gain
depressions were  8%  for  males and 11%  for females.  The 25  mg/kg dose level
was selected as the NOAEL for rats.

    In  the mouse study (SRI, 1980b), all  of the. animals  treated  at  the  800
and 400  mg/kg  dose level  died.   However,  one  of  these deaths was attributed
to Improper gavage technique.  At  the 200  mg/kg dose level,  two animals died
because  of Inappropriate experimental techniques,  as did one  at the  50 mg/kg
level  and  two of  the controls.   One animal's  death at the  200 mg/kg level
was attributed  to chemical toxlclty.  The 100  mg/kg HEX  dose was determined
to be  the NOAEL, since there were effects but none  considered adverse.


03680                               VIII-8                           04/12/91

-------
    In a  "13-week  oral  toxldty study (SRI, 1981a,b; Abdo  et  al.,  1984),  HEX
was administered  In  corn oil  by  gavage to groups  of  10 male and  10  female
F344 rats at doses of  0,  10,  19,  38,  75 and 150 mg/kg  and  to 10  mice of  each
sex at  doses of  0,  19,  38,  75,  150 and  300 mg/kg.   The doses were glve'n
dally, 5  days  a  week  for 13  weeks.   Compared with the previously-reviewed
shorter-term studies,  HEX was found  to  be  more  toxic at  the lower  dose
levels.   All  10  male  and  3  female  mice  died at' the 300  mg/kg HEX  dose
level.  At  the  150 mg/kg level, six male rats died, while one rat  \n  the 75
mg/kg group  died  as  a  result  of  chemical  toxlclty.   Other  deaths  occurred,
but  these  were  attributed  to Improper  gavage  technique  by  the  Investi-
gators.   Stomach  lesions  (hyperplasla and  focal  Inflammation) were observed
1n male  and female  rats  at  the  38,  75 and  150  mg/kg dose  groups  and  only
female /ats at  the  19  mg/kg  dose level.   At  higher doses  (>150  mg/kg)  toxic
nephrosls  In  females  was  observed.  According  to, the  Investigators,  these
lesions decreased  1n  severity  with  decreasing dose, with hyperplasla  being
the  primary lesion.   One female  rat  at  the  19 mg/kg  dose  level  had  a
squamous cell papllloma of the  epithelial  surface.   The only effect reported
for the  10 mg/kg  dose was a  slight  depression In  body  weight 1n  both  males
and females.

    In mice  (SRI,  1981a), the  stomach  lesions occurred at  the  38  mg/kg and
higher  dose levels,  Including deaths  at  the two  highest  levels.  In  the
published results (Abdo  et al,., 1984),  the "no  observed toxic  effect  level"
of HEX  was  stated to  be  at  the  19  mg/kg  level for rats.   In addition,  the
authors  stated  that rats  of  both  sexes and  female mice are  approximately
equally susceptible  to the toxic  effects.of  HEX  administered by gavage  over
a  90-day  period.   Therefore,  the  NOAEL  was  10  mg/kg  HEX  for  rats and  19
03680
VIII-9
04/12/91

-------
mg/kg  for  mice.   The  lower "level  1n rats  was  selected because'  the  lesions
were still considered  toxic  effects,  but 1n the long-term may  or may  not  be
adverse.   Therefore,   by  using  this  level,  an added  margin  of  safety  Is
Inherent  In  the  calculation  of the  DUEL.   Because  HEX toxldty  Increase's
with duration,_this NOAEL would accommodate  the  possibility  of  these  effects
becoming adverse over the longer-term.

Quantification of Honcardnogenlc Effects
    Although there  1s  some  question  as  to the route of  HEX  transport  In the
body,  the  kidneys, liver  and lungs  appear  to  be  the  major target  organs.
Investigators have observed sex and species  differences  In  toxic  response  to
HEX.   In addition,  some  observed  effects In these  studies  may  have  resulted
from a  combined exposure  to  HEX and other  compounds.   In  the Abdo  et al.
(1984)   study,  hexachloro-1,3-butad1ene  (HCBD) was  present  as  a  contaminant
of  HEX.   Since HCBD Is a  known  nephrotoxln  1n  rodents, some of  the  adverse
effects seen 1n the study may be attributed  to either  or both compounds.

    Derivation  of  1-Day  HA.   In  the  range-finding  study  by SRI  (1980a)
rats exposed  to  a single oral dose of 150 mg/kg HEX experienced  "wet  fur  1n
anal area" and  ruffled  fur  when  observed  for 14  days.    No other  toxic
effects  were  seen  at  this  dose  level.   At  higher   doses,  mortality  and
diarrhea were  observed.   A NOAEL of  ISO mg/kg can be  derived  based  on the
absence of adverse effects seen at  this  level.

The 1-day HA for a child 1s calculated as follows:
                    i H*U UA   150  mg/kq x 10 kg   1C  m  .a
                    1-day HA = 	a—•	a =15  mg/l
                                 100 x 1  a/day
03680                               VI11-10                          04/12/91

-------
where:
        150 mg/kg = determined to be  the  NOAEL of  the  SRI  (19803). rat
                    study
        10 kg     = assumed body weight of a child
        1 l/day   = assumed water consumption by a child
        100       = uncertainty   factor   chosen   In  accordance   with
                    NAS/ODW and  Agency guidelines  In using  a  NOAEL  from
                    an animal study
This  HA 1s  equivalent  to 15  mg/day  or 1.5  mg/kg/day.   It  should  be  noted
that  this  level  (15 mg/l)  1s above  the  reported  water  solubility of  HEX
(1.2-3.4  mg/l)  under  normal  ambient  conditions;   however,  under  certain
conditions  (e.g..  Increased   temperature)   the  water  solubility  of  HEX  can
                                                                  &
Increase.

     Derivation  of  10-Day  HA.   The SRI  (1980b)  repeated-dose toxldty study
was   used.   In  this  study  a NOAEL  of 25  mg/kg,  based  on  no  significant
decreases  1n  weight  gain  1n .male  and  female  rats was  defined   following
-exposure  to 25, 50,  100.  200 and 400 mg/kg HEX for  12 days  (days 1-5, 8-12,
and  15 and 16).

 The  10-day HA for a child Is calculated as  follows:
       10-day HA  =  2S  "^ x  10 k9  x  °-714 =  i.e ng/t (rounded to 2  mg/t)
                        100 x  1 l/day               y
 where:
     25 mg/kg  * determined  to  be the  NOAEL  of  the  SRI (1980b)  female
                 rat study
     10 kg     = assumed body weight of a child
     0.714     = the  correction factor  (5/7)  to  adjust for  continuous
                 exposure from a 5- to 7-day exposure
  03680
                                     VIII-11       .                   06/11/91

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    100       = uncertainty factor  chosen  1n  accordance  with NAS/ODW
                and  Agency  guidelines  for  use  with  a  NOAEL  from  an
                animal study
    1 s,/day   = assumed water  consumption by a  child
This HA Is equivalent to 1.8 mg/day or 0.18 mg/kg/day.
    Derivation of  Longer -Term HA.  The  13-week oral  tox1c1ty  study by  SRI
(1981b)  1s   the  only  longer-term  oral   study  of  sufficient  duration  and
experimental  design  that  can  be  used for  calculating longer-term  HAs.   In
this study,  HEX was  administered  In corn oil by gavage to  groups  of 10 male
and  female  F344   rats  at  doses  of  0,  10,  19,   38,  75  and  150  mg/kg.
TreatmentTrelated   dose-dependent  adverse effects  Including Inflammation  of
the  stomach  were  seen  with  . Increasing  severity at  >19  mg/kg.   The  only
                                                                   «
effect reported at the  10 mg/kg dose was a  slight depression  In  body weight
1n males and females.

The longer-term HA for  a chl.ld Is  calculated as  follows:
             Longer-term HA . 10 "^ x 10 "* x °'714 . 0.7 mgA
                                    100  x  1  t/day
This HA Is equivalent to 0.07 mg/kg/day.
where:
        10 mg/kg  = NOAEL from the SRI (1981b; Abdo et  al.,  1984)  study
                    based on absence of stomach lesions
        10 kg     = assumed body weight of a child
        0.714     = the   correction   factor   (5/7)   to   adjust    for
                    continuous exposure from a 5- to 7-day exposure
        100       = uncertainty   factor   chosen   1n   accordance   with
                    NAS/ODW and  Agency guidelines for use with  a  NOAEL
                    from an animal study
03680                               VIII-12                          04/12/91

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        1 I/day   = assumed water consumption by a chUd
For an adult:
            u*
Longer-term HA .
                    10 mq/kq x 70 kg x 0.714
                    -    2i/day xlOOj    roundeo 3 ng/i)
                                                       _ ? 5   .
                                                              ll't
where:
        10 mg/kg  = NOAEL from the SRI  (19815; Abdo- et al.,  1984)  study
                    based on absence of stomach lesions
        70 kg     = assumed body weight of an adult
        0.714     = the   correction    factor   {5/7')   to   adjust    for
                    continuous exposure from a 5- to 7-day exposure
        2 I/day   = assumed water'consumption by  arradult
        100       = uncertainty   factor   chosen   1n   accordance   with
                    NAS/ODW and  Agency guidelines for use with  a  NOAEL
                    from an animal study
    Assessment of  Lifetime Exposure and  Derivation of  DHEL.   In a  13-week
oral  toxlclty study  by SRI  (1981b),   rats  (10/sex/group)  were  exposed  by
gavage  with  0,  10,  19,  38,  75  or   150  mg  HEX/kg  bw 'for  5  days/week.
Epithelial  hyperplasla,  focal  Inflammation  of the  forestomach and  stomach
lesions,  and  nephrosls  were  observed  with  Increased Incidence and  severity
1n  both  sexes at  >38  mg/kg  bw.   At  the 19  mg/kg/day  dose similar  effects
were observed In males only.  A  slight  but  nonsignificant depression  1n  body
weight  gain was  seen at  10 mg/kg In males  and, 1n  females  at 19  mg/kg.
Therefore the 10  mg/kg  dose was  considered a  NOAEL  and the 19 mg/kg  dose  a
LOAEL.
       Step 1; Determination of RfD
    RfD
10 mq/kq x 0.714
    100 x 10
               0.00714 mg/kg/day (rounded to 0.007 mg/kg/day)
03680
                        .  VIII-13
                                                       06/11/91

-------
where:
    10 mg/kg  = NOAEL  from  the  SRI  (19815; Abdo  et al.,  1984)  study
                based on a lack of adverse effects
    0.714     = the  correction  factor  (5/7)  to adjust  for. continuous
                exposure from a 5- to 7-day exposure
    100       •* uncertainty  factor  chosen  In  accordance  with NAS/ODW
                and  Agency  guidelines  for  use  with  a  NOAEL  from  an
                animal study
    10        = uncertainty factor appropriate for  use  with study data
                that are significantly Iess-than-l1fet1me 1n duration
       Step 2: Determination of the Drinking Hater Equivalent Level  (DWEL)

       DHEL = 0.007  mq/kq/dayx  70  kq  __                 ^       '
                     2 a/day
where:                                                              .
    0.007 mg/kg/day  = RfD
    70 kg            = assumed weight  of an adult
    2 I/day  •        = assumed water consumption by an adult

A summary of noncarclnogenlc effects 1s listed 1n Table VIII-1.

Carcinogenic Effects
    The  data  base   1s  neither  extensive  nor   adequate  for 'assessing  the
cardnogenldty of  HEX.  The  National  Toxicology Program  (NTP)  has  completed
a subchronlc  animal  Inhalation  study  and Is presently conducting a lifetime
animal  Inhalation  bloassay  using  both  rats   and  mice.    A   judgment   of
carcinogenic  potential will  be deferred  until  the results  of  the  long-term
NTP bloassay are available.   Using  the  IARC  criteria,  the available evidence
matches the  overall  Group  3 category.  According  to  the U.S. EPA Guidelines
for Carcinogen  Risk Assessment, this   chemical  1s classified 1n the  Group  0

03680                               VIII-14                          06/11/91

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                                 TABLE VIII-1
              Summary  of  HAs  and  DWEL  for Noncarclnogenlc Effects
                                     Drinking Water
                                     Concentration
                                       (mg/l)
                        Reference
1-Day HA (10 kg child)
10-Day HA (10 kg child)
Longer-term HA (10 kg child)
Longer-term HA (70 kg adult)
DWEL
    15
     2
     0.7
     3
     0.3
SRI, 1980a
SRI, 1980b
SRI, 1981b
SRI, 1981b
SRI, 1981b
03680
VIII-15
         06/12/91

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category,  which  Indicates  that  the  available data  base  1s  Inadequate  to
assess the carcinogenic potential of this substance (U.S.  EPA,  1986).

Exlsuing Guidelines. Recommendations and Standards
    EPA  Guidelines.    An  RfD  of 0.007  mg/kg/day was  verified  by  the  RfO
Work  Group  on-10X09/85  (U.S.  EPA,  1991).  The CRAVE  Work Group verified  a
classification  of   Group  D  (not   classifiable  as  to  cardnogenlcHy  for
humans) for HEX on  10/05/89 (U.S. EPA, 1991).

    Occupational Standards.   There  1s  no  current  Occupational  Safety  and
Health  Administration  (OSHA)  standard  for  HEX   levels   In  the workplace.
However,  the  American  Conference  of  Governmental  Industrial  Hyg1en1sts
(ACGIH,  1986)  has  adopted  a  TIV,   expressed  as  an  8-hour  TWA of'0.1  mg/m3
(0.01  ppm}.   The  levels are based  on the data from the  Inhalation  study  by
Treon et al. (1955).

    The National Institute  for  Occupational Safety and Health  (N10SH,  1978)
classlfed  HEX  1n  the  Group  II  pesticide  category and recommended  criteria
for  standards  for   occupations  1n  pesticide  manufacturing and  formulating.
These  standards  rely  on engineering  controls,  work  practices   and  medical
surveillance programs,  rather  than  workplace  air   limits,  to protect  workers
from  the  adverse effects of pesticide  exposure  In manufacturing and  formu-
lating (NIOSH, 1978).

    Transportation   Regulations.    The   Hazardous  Materials   Transportation
Act  specifies  the  requirements  to  be observed 1n the preparation for  ship-
ment  and transport  of hazardous materials.   The transport of  HEX  by  air,


03680    .                           VIII-16                          04/12/91

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land and water  1s  regulated  by these statutes, and the Department of Trans-
portation has designated HEX as "hazardous material," a "corrosive material"
and  a  "hazardous  substance."   The  maximum  net  quantity  for  transport by
passenger-carrying  aircraft  or  rallcar  has  been  set  at  10  gallons   per
package.   Transport on deck or  below deck by  cargo vessel  1s also permitted.

    Solid Haste  Regulations.   Under  the  Resource Conservation  and  Recovery
Act  (RCRA),  the  U.S.  EPA has  designated HEX  as a  hazardous   toxic waste.
Hazardous Haste  No.  U 130,  subject  to disposal  and  permit regulations  (40
CFR 262-265 and 122-124).

    Food Tolerances.   Under  the  Federal  Insecticide  Fumlgant   and  RodenU-
dde Act (F1FRA),  a  tolerance  of  0.3 ppm  has  been  established  for  chlordane
residues, which are not to contain >1% of HEX (40 CFR  180.122).

    Hater  Regulations.   Under  Section  311  of  the: Federal Water  Pollution
Control Act, the  U.S. EPA  designated  HEX as  a  hazardous  substance and estab-
lished a reportable quantity (RQ) of  1  pound (0.454 kg)  for HEX.  Discharges
equal  to or  greater  than .the RQ  Into or  upon  U.S.  waters are prohibited
unless the discharge Is 1n compliance with applicable  permit programs.

    Under  the  Clean Water Act, the U.S.  EPA  has designated HEX as  a  toxic
pollutant  (I.e.,  priority pollutant).   Effluent  limitations guidelines, new
source performance  standards,  and  pretreatment standards  have been developed
or will  be developed for the.priority pollutants  for 21 major Industries.

    Under  the  Clean Water Act, an  ambient  water quality criteria  level for
HEX  was  also developed  (U.S.  EPA,  1980).   Based on  available  toxlclty  data

03680                               V1II-17                          04/12/91

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for  the  protection  of  public  health  the   level  derived  was  206
Using  organoleptlc  data  for  controlling undesirable   taste  and  odor  of
ambient water, the estimated  level was 1 vg/i (U.S. EPA, 1980).
    A1r  Regulations.   HEX  1s  not  regulated  under  the  Clean Air  Act.   The
U.S.. EPA,  after  evaluating the current exposure  data  and  ambient air levels
of HEX, Issued a decision not to list HEX as a hazardous air pollutant.

    Other  Regulations.   Pursuant to  rules  under  sections  8(a)  and  8(d)  of
the  Toxic  Substances  Control  Act  (TSCA),  all  manufacturers   of  HEX  are
required  to  report health  and safety Information  on  HEX  to  the  U.S. EPA's
Office  of Toxic  Substances.   The   deadline  for  submission  of  Preliminary
Assessment Information Manufacturer's Report on HEX was November  19, 1982.

    In 1979, the Interagency Testing  Committee  (ITC) recommended  that HEX be
considered for  health  and  environmental  effects testing under  Section  4{a)
of  the  TSCA  (44  FR 31866).  This  recommendation was  based  on   evidence  of
potential  human  exposure and  a  potential for environmental  persistence  and
bloaccumulatlon.   The  U.S.  EPA  (1982)  responded  1n  the   Federal  Register.
The following 1s the statement from that notice:

    EPA has  decided not  to Initiate rulemaklng  to require  testing  of
    HEX under section 4  of  TSCA  because  EPA does not believe that there
    Is a  sufficient basis  to  find  that  current  manufacture,  distribu-
    tion  In commerce, processing, use or  disposal of HEX may present an
   •unreasonable risk of  Injury  to  the environment  or  of  mutagenlc and
    teratogenlc  health   effects.   Neither  has  the  EPA found  evidence
    that  there  Is   substantial  or  significant environmental  release  of
    HEX.   In  addition,  certain new studies have  become  available since
    the  ITC's  report  or are  underway,   making  additional  testing  for
    chronic and oncogenlc effects unnecessary.
03680                               V1II-18                          04/12/91

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Special Groups at  Risk
    While  very  little  data  are  available  concerning  the  effects  of  HEX
exposure on humans,  H  1s apparent  that  those  Individuals with respiratory
problems or diffidences  will  be  most  sensitive to  HEX  exposure.  Workers
repeatedly exposed to HEX  vapors  are  also  at  high  risk.
03680
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04/12/91

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                               IX.  REFERENCES

Abdo, K.. C.A. Montgomery, W.M. Kluwe, D.R. Farnell and J.D. Prejean.  .1984.
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by gavage to F344 rats and B6C3F1  mice. 0.  Appl.  Toxlcol.   4{2): 75-81.

Abdo, K.H.,  C.A. Montgomery,  J.  Roycroft,  H.A.  Ragan,  R.A. Renne and W.E.
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ACGIH  (American  Conference  of Governmental  Industrial  Hyglenlsts).   1986.
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Aldrlch  Chemical Company.  1988.   Handbook  of  Fine Chemdals.   Aldrlch Chem.
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Amoore,  J.E.  and E., Hautala.   1983.   Odor  as an aid to chemical safety: Odor
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272-290.
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Atallah, Y.H.,  D.M.  HhHacre,  R.G.  Butz..   1980.   Fate of  hexachlorocyclo-
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Battelle Northwest Laboratories.   1984.   Inhalation Carclnogenesls  Bloassay
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Environ. Contam. Toxlcol.   27:  303-308.
                                                                  *
Boyd,  K.W.,  M.B.  Emory and  H.K.  Dillon.   1981.    Development  of  personal
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Brat, S.V.   1983.  The hepatocyte primary  culture/DNA repair  assay on  com-
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Buncher, C.R.,  C.  Moomaw and  E.  S1rkosk1.   1980.   Mortality  study of  Mon-
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Butz, R.G., C.C. Yu and Y.H. Atallah.  1982.  Photolysis  of  hexachlorocyclo-
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03690                               IX-2                             04/12/91

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Chopra, N.M.,  B.S.  Campbell  and 3.C.  Hurley.   1978.   Systematic studies  on
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                                                                  %

Clark, D.G., A. Pllcher,  D.  Blair, et al.   1982.  Thirty  week  chronic  Inha-
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Cole,  E.J.   1954.    Treatment  of  sewage  with  hexachlorocyclopentadlene.
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Dal  Monte,  R.P. and  C.C.  Yu.  1977.   Water Solubility  of  MC-984   and  Hex.
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DeLeon, I.R.,  M.A.  Maberry,  E.8.   Over ton, et  al.   1980.  Rapid  gas chroma-
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Chromat. Scl.  18: 85-88.
03690                               IX-3                             04/12/91

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Oorough,  H.W.    1979.   The  accumulation,  distribution  and  dissipation  of
hexachlorocyclopentadlene (C56)  1n tissues  of  rats  and  mice.  Unpublished
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Dorough,  H.W.    1980.    Disposition  of  "C-hexachlorocyclopentadlene   (C56)
In  rats  following Inhalation  exposure.   Unpublished  report  prepared for
Velslcol Chemical Corp.,  Chicago,  IL.   53 p.

Dorough,  H.U.  and  T.A.   Ranlerl.   1984.   Distribution  and  elimination  of
hexachlorocyclopentadlene  In rats  and  mice.   Drug  Chem.  Toxlcol.    7(1):
73-89.                                    .
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EUhler,  D.L.    1978.   Quantitative analysis  of  mixtures  containing   trace
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El Dareer,  S.M.,  P.E.  Noker, K.F.  TUlery and D.L. H1T1.   1983.   Investiga-
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Ella, V.J.,  C.S.  Clark,  V.A. Majetl,  et  al.   1983.   Chemical exposure at  a
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Evans, M.J., L.J.  Cabral-Anderson  and  G.  Freeman.  1978.   Role of  the  Clara
cell In renewal of the bronchlolar  epithelium.  Lab.  Invest.   38: 648-655.
03690                               IX-4                            04/12/91

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Goggelman, W., G.  Bonse,  D.  Henschler  and H. Grelm.  1978.  NutagenUHy of



chlorinated  cyclopentadlene  due  to metabolic  activation.   Blochem.  Phar-



macol.  27: 2927-2929.    .                                          .







Grelm, J., D. Blmboes, H. Goggelmann and H.  Kramer.   1977.  Hutagenldty and



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malian enzyme-mediated formation  reactive  metabolites.   Arch. Toxlcol.  39:



159-169.







Hawley,  G.G.,  Ed.   1977.   Condensed  Chemical  Dictionary,   9th  ed.   Van



Nostrand.Relnhold Co.,  New York.





                                                                  &

Haworth,  S.,  T.  Lawlor,  K.  Mortelmans,  W.  Speck and  E. Zelger.   1983.  Sal-



monella  mutagenldty  test  results  for  250 chemicals.   Environ.  Mutagen.



Suppl. 1: 3-142.                                                       .







Horvath,  A.L.  1982.   Halogenated  Hydrocarbons.  Solub1l1ty-M1sc1b1l1ty with



Water.  Marcel Dekker,  Inc.   New York,  NY.   p.  522.







Hunt,  G.E.  and  G.W. Brooks.   1984.   Source assessment for hexachloropenta-
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dlene: Final  report.  Prepared  under  EPA  Contract  No. 68-02-3818.  Radian



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Incorporated  1n  the  test  medium tested against five  strains  of  S.  typhlmux-



lum and as a volatllate against tester  strain TA-100.   Northbrood, IL.
03690
IX-5
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1RDC  (International   Research  and  Development  Corporation).   1968.   Hexa-      *
chlorocyclopentadlene and  octachlorocyclopentene: Acute  oral  toxlclty  L05Q      *.
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Corp.  4 p.                                                                 ,
IRDC  (International   Research  and  Development  Corporation).   1972.   Acute
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chlorocyclopentadlene.  Teratology  study  1n  rats.   Unpublished  report  pre-
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Irish, O.D.   1963.   Halogenated hydrocarbons:  II.  Cyclic.   Hexachlorocyclo-
pentadlene.   ITK  Industrial  Hygiene  and  Toxicology,  2nd ed.  rev.,  F.A.
Patty, Ed.  John Wiley & Sons,  Inc., New York.  p.  1333-1363.

Johnson, L.D. and  J.C.  Young.   1983.  Inhibition of an  aerobic  digestion by
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Komlnsky, J.R. and C.L. Wlsseman.   1978.   Morris Forman  Uastewater  Treatment
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03690                               IX-6                             04/12/91

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Komlnsky,  J.R.,  C.L.  Hlsseman and D.L. Morse.   1980.   Hexachlorocyclopenta-

dlene  contamination  of  a  municipal  wastewater  treatment  plant.   Am.  Ind.

Hyg. Assoc. J.  41: 552-556.



Lawrence, L.J. and H.H. Dorough.  1981.  Retention and  fate of  Inhaled hexa-

chlorocyclopentadlene  In   the  rat.   Bull.  Environ.  Contam.  Toxlcol.   26:

663-668.



Lawrence.  L.J.  and H.H.  Dorough.   1982.   Fate  of Inhaled  hexachlorocyclo-

pentadlene In albino rats and comparison to  the  oral and  1v routes  of  admin-

istration.  Fund. Appl. Toxlcol.   2:  235-240.


                                                                  %
Levins, A.P.   1980.   Memorandum on  Hooker  special priority  samples  — odor

properties.   Case 84204.   A.O.  Little Company.   Submitted  by  Occidental

Chemical Corp. during public  comment  period.  2 p.



Litton  81onet1cs,  Inc.  1977.   Evaluation  of  hexachlorocyclopentadlene  Iji

vitro  malignant  transformation  1n  BALB/3T3 Cells. : LBI  Project No.  29840.

Prepared for  Velslcol  Chemical Corp.,  Chicago,  IL.   7 p.

                                                    i

Litton  Blonetlcs,  Inc.   1978a.   Mutagenldty  evaluation  of  hexachlorocyclo-

pentadlene 1n  the mouse lymphoma  forward  mutation assay.   LBI Project  No.

20839.  Prepared for  Velslcol  Chemical Corp., Chicago,  IL.  10 p.

                                                    t

Litton  Blonetlcs,  Inc.   1978b.   Mutagenldty  evaluation  of  hexachlorocyclo-

pentadlene In the mouse dominant lethal assay.   LBI Project No.  20862, March

1978, Revised August  1978.   Kensington, MD.  13 p.
03690
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Look, M.   1974.  Hexachlorocyclopentadlene adducts  of  aromatic  compounds  and
their reaction products.  AldMchemlca Acta.   7(2):  1974.
Habey, H.R.,  3. H.  Smith and  R.T.  Podall.   1982.  Aquatic  fate  process  data
for  organic  priority pollutants.  Monitoring  and  Data Support  D1v.(  Office
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440/4-81-014.  p. 174.
                                                 r-.
Mehendale,  H.H.   1977.   Chemical  reactivity-absorption,  retention,  metabo-
lism  and  elimination  of  hexachlorocyclopentadlene.    Environ.  Health  Per-
spect.  21: 275-278.

Meyer, C.R.   1983.   Liver dysfunction In residents exposed  to  leachate  from
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|£: Environmental Exposure from Chemicals,  Vol.  1,  W.B. Neely and G.E.  Blow,
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Morse,  D.L.,  P.J.  LandrVgan  and  3.H.  Flynt.   1978.  Internal  CDC  report
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Morse,  D.L.,  J.R.  Komlnsky  and   C.L.  Wlsseman,  III.   1979.   Occupational
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Assoc.  241: 2177-2179.
03690
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Murray,  F.J.,  B.A. Schwetz,  M.F.  Balmer and  R.E.  Staples.   1980.   lerato-
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NAS (National Academy of Sciences).   1977.   Drinking Water  and Health.   Safe
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NAS  (National   Academy  of  Sciences).   1978.   Kepone/M1rex/Hexachlorocyclo-
                                                                  %
pentadlene: An Environmental Assessment.   NTIS  PB 280-289.

NAS (National Academy of Sciences).   1980.   Drinking Water  and Health..  Vol.
3, p. 25-67.

Neunielster, C.  and R.  Kurlmo.   1978.   Determination of hexachlorocyclopenta-
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cinnati, OH.   Measurements  Support Branch, D1v.  Phy. Scl  Eng., N10SH.

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cinnati, OH..
03690                               IX-9                             04/12/91

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NIOSH (National Institute for Occupational  Safety  and  Health).   1979.   NIOSH
Manual, of  Analytical  Methods,  2nd  ed., Vol.  1-5.   DHEW Pub. No.  77-157-A.
Cincinnati, OH.

NIOSH (National Institute for Occupational  Safety  and  Health).   1980.   Hexa-
chlorocyclopentadlene.  NIOSH  Quarterly Hazard  Summary Report,  Cincinnati,
OH.

NTP   (National  Toxicology   Program).    1991.   Management   Status   Report.
01/04/91.

Rand, G.M.,  P.O.   Nees,  C.J. Calo,  D.J. Alexander  and G.C. Clark.   1982a.
Effects  of  Inhalation  exposure  to  hexachlorocyclopentadlene   on  rats  and
monkeys.   J. Toxlcol.  Environ. Health.   9:  743-760.

Rand, G.M.,  P.O.  Nees, C.J.  Calo,  G.C.  Clarke  and N.A. Edmondson.   1982b.
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dlene.  0. Toxlcol. Environ. Health.  10: 59-72.

Rlma, D.R.   1979.  Susceptibility of  the Memphis water  supply  to contamina-
tion  from the  pesticide waste disposal  site In Northeastern Hardeman County,
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Roberts,  C.U.   1958.   Chemistry of  hexachlorocyclopentadlene.   Chem.  Ind.
February 1, 1958.   p.  110.
03690
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 f

•iV
Shlndell  and  Associates.   1980.    Report   of  Ep1dem1olog1c  Study  of  the-
                                                   !

Employees   of   Velslcol   Chemical   Corporation   Plant   Marshall,   Illinois,


January 1946-December 1979.  Velslcol Chemical Corp., Chicago, IL.





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                                                                                 —^
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