EPA-540/1-86-039
                                         Office of Emergency and
                                         Remedial Response
                                         Washington DC 20460
                     Superfund
&EPA
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
                      HEALTH EFFECTS ASSESSMENT
                      FOR  CARBON  TETRACHLORIDE

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                                           EPA/540/1-86-039
                                           September 1984
       HEALTH EFFECTS ASSESSMENT
        FOR CARBON TETRACHLORIDE
    U.S. Environmental  Protection Agency
     Office of Research and  Development
Office of  Health and Environmental  Assessment
Environmental Criteria  and Assessment Office
            Cincinnati, OH  45268
    U.S. Environmental  Protection Agency
  Office of  Emergency and Remedial Response
Office of Solid Waste and  Emergency Response
            Washington, DC  20460

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                                  DISCLAIMER

    This  report  has  been  funded  wholly  or  In  part by  the  United  States
Environmental  Protection  Agency under  Contract  No.  68-03-3112  to  Syracuse
Research Corporation.  It has been  subject  to  the Agency's peer and adminis-
trative review, and  1t has  been  approved  for  publication as an EPA document.
Mention of  trade  names or  commercial  products  does  not  constitute  endorse-
ment or recommendation for use.
                                      11

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                                    PREFACE
    This report  summarizes  and evaluates Information relevant  to  a prelimi-
nary  Interim assessment  of adverse  health effects  associated with  carbon
tetrachloMde.  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
environmental data  were located  through  on-Hne  literature searches  of  the
Chemical Abstracts, TOXLINE, CANCERLINE  and  the CHEMFATE/OATAL06  data bases.
The  basic  literature  searched supporting  this   document  1s  current up  to
September,   1984.   Secondary  sources  of  Information have  also been  relied
upon  1n the  preparation of  this report  and represent large-scale  health
assessment   efforts  that entail  extensive  peer  and   Agency  review.   The
following Office of  Health  and Environmental Assessment  (OHEA)  sources  have
been extensively utilized:


    U.S. EPA.  1980b.   Ambient Water  Quality Criteria  for  Carbon  Tetra-
    chlorlde.   Environmental   Criteria  and  Assessment   Office,  Cincin-
    nati, OH.  EPA-440/5-80-026.   NTIS PB 81-117376.

    U.S. EPA.   1983b.   Reportable Quantity  Document for Carbon  Tetra-
    chlorlde.   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.  1983c.   Review  of  Toxlcologlc Data  1n  Support  of Evalua-
    tion for  Carcinogenic Potential of:  Carbon Tetrachlorlde.   Prepared
    by  the  Carcinogen  Assessment  Group, OHEA, Washington,  DC for  the
    Office  of Solid Waste and Emergency Response,  Washington,  DC.

    U.S. EPA.   1984.   Health Assessment Document  for  Carbon  Tetrachlo-
    rlde.   Environmental  Criteria  and  Assessment  Office,  Cincinnati,
    OH.  EPA 600/8-82-001F.   NTIS PB  85-124196.
    The Intent 1n these assessments  Is  to  suggest  acceptable  exposure levels
whenever sufficient data were  available.   Values were not derived  or larger
uncertainty  factors  were employed  when the  variable data  were limited  1n
scope tending to  generate conservative  (I.e.,  protective)  estimates.   Never-
theless, the  Interim  values  presented  reflect the relative degree  of hazard
associated with  exposure or  risk to the chemlcal(s) addressed.

    Whenever possible, two categories of values  have  been  estimated for  sys-
temic toxicants  (toxicants for which cancer Is not the  endpolnt  of  concern).
The  first,  the  AIS  or  acceptable  Intake  subchronlc, 1s  an  estimate of  an
exposure  level  that  would  not  be  expected  to  cause  adverse effects  when
exposure occurs during  a limited  time  Interval  (I.e.,  for an Interval  that
does not  constitute  a  significant  portion of the Hfespan).   This  type  of
exposure estimate  has not been  extensively used  or  rigorously  defined,  as
previous  risk  assessment  efforts  have   been  primarily   directed  towards
exposures from toxicants  1n  ambient air or water  where  lifetime exposure  1s
                                      111

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

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

    For compounds for which there  Is  sufficient  evidence  of carclnogenlclty,
AIS  and AIC values  are not  derived.   For a  discussion  of risk  assessment
methodology for  carcinogens  refer  to  U.S. EPA  (1980a).   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 the
reader Is  referred to  the  Preface of  this  document.  The  preface outlines
limitations applicable to all documents of this  series  as  well  as the appro-
priate Interpretation and use of the quantitative estimates presented.

    Animal  bloassay  data 1n  three species  (rats,  mice,  hamsters)  Indicate
that  carbon  tetrachlorlde  Is a  hepatic  carcinogen.   Human  data  are  limited
and  equivocal.    The  Cancer  Assessment  Group,   as   explained  In  U.S.  EPA
(1984),  has  used  data  from the  following  for risk  assessment  purposes:
Delia  Porta  et  al. (1961);   Edwards et  al.  (1942);  NCI (1976)  (both  rat and
mouse).  Since none  of  these studies  were deemed adequate Individually, the
geometric  mean  of the  upper  limit unit  risk estimates (3.7xlO~6) has  been
employed.    The   corresponding    slope   estimate    (q-|*)    is    l.SOxlCT1
(mg/kg/day)"1.

    A  note  of caution 1s provided  by U.S.  EPA  (1984).  Some  evidence  Indi-
cates  that  carbon tetrachlorlde may  act via  a  nongenotoxic mechanism.   If
this  should  be  the case, then  low-dose risk  extrapolation  using techniques
developed   for  agents   which   presumably  act  through  genotoxicity  could
substantially overestimate  risk.   The reader  Is  referred  to U.S.  EPA (1984)
for  a thorough  discussion   of  this  question.   More  experimental  data  are
needed to resolve this Issue.

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                               ACKNOWLEDGEMENTS
    The  Initial  draft  of  this  report  was  prepared  by  Syracuse  Research
Corporation under  Contract NO.  68-03-3112  for EPA's  Environmental  Criteria
and  Assessment  Office,  Cincinnati,  OH.   Dr.  Christopher  DeRosa and  Karen
Blackburn were the Technical Project Monitors  and  Helen Ball  wasithe Project
Officer.  The final documents  In  this  series  were  prepared for the Office of
Emergency and Remedial Response, Washington, DC.

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

         Environmental Criteria and Assessment Office, Cincinnati, OH
         Carcinogen Assessment Group
         Office of A1r Quality Planning and Standards
         Office of Solid Waste
         Office of Toxic Substances
         Office of Drinking Water

Editorial review for the document series was provided by:

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

Technical support services for the document series  was provided by:

    Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
    Environmental Criteria and Assessment Office
    Cincinnati, OH
                                      v1

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                              TABLE OF CONTENTS

1.
2.


3.










4.






5.
6.





7.

ENVIRONMENTAL CHEMISTRY AND FATE 	
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1. ORAL 	
2.2. INHALATION 	
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 	
3.1. SUBCHRONIC 	
3.1.1. Oral 	
3.1.2. Inhalation 	
3.2. CHRONIC 	
3.2.1. Oral 	
3.2.2. Inhalation 	
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral 	
3.3.2. Inhalation 	
3.4. TOXICANT INTERACTIONS 	
CARCINOGENICITY 	
4.1. HUMAN DATA 	
4.2. BIOASSAYS 	
4.2.1. Oral 	
4.2.2. Inhalation 	
4.3. OTHER RELEVANT DATA 	
4.4. WEIGHT OF EVIDENCE 	
REGULATORY STANDARDS AND CRITERIA 	
RISK ASSESSMENT 	
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 	
6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 	
6.3. CARCINOGENIC POTENCY (q-|*) 	
6.3.1. Oral 	
6.3.2. Inhalation 	
REFERENCES 	
Page
1
3
... 3
... 3
... 4
... 4
... 4
... 4
5
... 5
5
... 8
... 8
, . . 9
... 9
... 11
... 11
... 11
... 11
... 17
... 17
... 17
... 19
... 21
... 21
... 21
, . 21
... 21
... 21
... 22
APPENDIX: Summary Table for Carbon Tetrachlorlde 	   32

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                               LIST OF TABLES

No.                               Title                                Page

1-1     Selected Physical and Chemical Properties and Half-lives
        of Carbon Tetrachlorlde 	    2

4-1     Survival of Rats Treated with Carbon Tetrachlorlde	   14

4-2     Survival of Mice Treated with Carbon Tetrachlorlde	   15

4-3     Liver Tumors 1n Mice	   16

5-1     Current Regulatory Standards and Criteria for
        Carbon Tetrachlorlde	   20

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                             LIST  OF  ABBREVIATIONS

ADI                     Acceptable dally Intake
AIC                     Acceptable Intake chronic
AIS                     Acceptable Intake subchronlc
BCF                     Bloconcentratlon factor
bw                      Body weight
CS                      Composite score
PEL                     Frank-effect level
GI                      Gastrolntetlnal
LOAEL                   Lowest-observed-adverse-effect level
MED                     Minimum effective dose
ppm                     Parts per million
SGOT                    Serum glutamlc oxaloacetlc transamlnase
SGPT                    Serum glutamlc pyruvlc transamlnase
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
carbon  tetrachlorlde  (CAS No.  56-23-5),  also  known as  tetrachloromethane,
are shown In Table 1-1.
    The value  for  the retardation  factor  for  carbon tetrachlorlde  1s  esti-
mated  on  the basis  of  a  comparison  of  the octanol/water  partition  coeffi-
cient  and  water  solubility  of  this  compound  with  chloroform  and  the
estimated retardation factor  of 1.2 for chloroform (Wilson et a!., 1981).
    The half-life  of carbon tetrachlorlde  In  soil  could not be  located  1n
the literature searched; however,  evaporation  1s  expected to be  the predomi-
nant  loss mechanism  from the soil  surface.  In  subsurface soil,  blodegrada-
tlon  of carbon  tetrachlorlde  will probably  be a  very  slow process,  as  Is
true  of chloroform  (Wilson  et  al.t 1983).  Therefore,  carbon  tetrachlorlde
Is  expected to  leach  Into  groundwater.    This  has  been confirmed  by  Page
(1981), who detected carbon tetrachlorlde  with  a  64% frequency  1n  ground-
water.
                                      -1-

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                                   TABLE  1-1

           Selected Physical and Chemical Properties and Half-lives
                           for Carbon TetrachloMde
        Properties
        Values
 Reference
Chemical class:


Molecular weight:

Vapor pressure:


Water solubility:
Octanol/water partition
coefficient:
Soil mobility:
(predicted as retardation
 factor for a soil depth of
 140 cm and organic carbon
 content of 0.087%)

BCF:
Half-lives 1n A1r:
halogenated aliphatic
hydrocarbon

153.82

90 mm Hg at 20C


757 mg/l at 25C



437


537


>1.2 (estimated)
            Water:
30 1n blueglll
(Lepomls macroschlrus)

17 1n fathead minnow
(Plmephales promelas)

22 years
                                   -50 years
0.3-3 days 1n river
30-300 days 1n lake
Callahan
et al., 1979

Banerjee
et al., 1980
Callahan et
al., 1979

Banerjee et
al., 1980

Wilson
et al., 1981
U.S. EPA,
1980b

Velth
et al., 1979

Singh
et al., 1981

U.S. EPA,
1984

Zoeteman
et al., 1980
                                     -2-

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           2.   ABSORPTION  FACTORS  IN  HUMANS  AND  EXPERIMENTAL  ANIMALS
2.1.   ORAL
    No pertinent  studies  of absorption of  carbon  tetrachlorlde from  the 61
tract of  humans  were located  1n  the available literature.   Little  Informa-
tion on absorption  from  the GI tract of  experimental  animals was  available.
In an early  study,  Robblns  (1929)  Investigated absorption  of  carbon  tetra-
chlorlde from  the GI  tract of dogs.  He  reported  that "considerable quanti-
ties" were  absorbed  from the small  Intestine, lesser  quantities  from  the
colon and  still  lesser quantities  from  the  stomach.   Lamson  et  al.  (1923)
suggested that the dynamics  and kinetics  of absorption from  the GI tract may
vary  from  species  to species.   They  observed more  rapid GI  absorption In
rabbits  than  1n  dogs.  Nielsen  and Larsen  (1965)  determined  that  both  the
rate  and  the  amount  of   carbon  tetrachlorlde  absorption  from the  GI  tract
were Increased by concurrent 1ngest1on of  fat or alcohol.
2.2.   INHALATION
    Pertinent  studies of  pulmonary absorption of  carbon  tetrachlorlde  In
humans were not  located  1n the available literature.   Few studies on  pulmo-
nary  absorption   1n  experimental   animals  were found.   Nielsen   and  Larsen
(1965)  stated  that   carbon  tetrachlorlde  is  "readily  absorbed" through  the
lungs but  the  species studied was  not  reported (U.S.  EPA,  1980b).   Lehmann
and  Hasegawa   (1910)  showed   that  the rate  of  absorption  decreased  with
duration  of  exposure.   von  Oettlngen  et  al.  (1949,  1950)   studied  blood
concentrations in  dogs  following  exposure   to  15  or  20  g/a.  in   air.   Peak
blood concentrations  of   -35  or   -38  mg/8. were attained after -300 minutes
of exposure to 15 or 20 g/a, 1n air, respectively.
                                      -3-

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               3.  TOXICITY  IN HUMANS AND EXPERIMENTAL ANIMALS
3.1.   SUBCHRONIC
3.1.1.    Oral.    Reports  of  acute  toxldty  from  accidental,  medicinal  or
suicidal 1ngest1on of  carbon  tetrachlorlde  are available, but  no  reports  of
subchronlc 1ngest1on  1n  man  were located  In  the available  literature.   One
study of  subchronlc  oral  exposure  described   the  toxldty  of  carbon  tetra-
chlorlde 1n Syrian golden  hamsters.  U.S. EPA  (1983c)  discussed the study by
Delia Porta  et  al.  (1961) 1n  which groups of  10  male and  10  female  Syrian
golden  hamsters  were  treated with 12.26  mg/week  carbon   tetrachlorlde  by
gavage for 30 weeks (-12.3 mg/kg/day).   Mortality  claimed  50% of the animals
of  each  sex before  treatment was  completed.   The  survivors  all  developed
hepatocellular  carcinoma within the next 13 weeks.
3.1.2.    Inhalation.    Prendergast  et al.  (1967)  performed   two studies  of
subchronlc Inhalation  exposure  In  animals.   In the  first  experiment,  guinea
pigs and  monkeys were  exposed  to  80 ppm  carbon  tetrachlorlde  for  8  hours/
day, 5  days/week  for 6  weeks  (30 exposures).   Increased  mortality  (3/15
guinea  pigs,  1/3 monkeys)  and  severe  liver   damage were  reported.   In  the
second experiment, animals were  exposed to either 1 or  10 ppm carbon  tetra-
chlorlde continuously  for  90  days.   At  10 ppm, guinea pigs  showed  Increased
mortality  (3/15  treated vs.  2/314 colony  controls),  growth  depression  and
liver enlargement with fatty Infiltration, hepatocytlc  degeneration,  flbro-
blastlc   proliferation  and collagen  deposition.  Rats,  monkeys and  rabbits
also experienced  depressed growth  rates and similar hlstopathologlcal  liver
lesions, but no  mortality  occurred  1n  these species.  No mortality or  gross
signs of  toxldty occurred 1n guinea pigs, rats, monkeys or rabbits exposed
to  1  ppm  carbon  tetrachlorlde  continuously  for  90 days.   A  depression  of
body weight  gain  was  observed  only  In  rats.  No  changes  were  noted  1n
                                      -4-

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hematologlc or hlstologlc parameters  1n  any of the  species  tested;  continu-
ous  exposure  to  1  ppm  carbon tetrachlorlde  (6.3  mg/m3)  was designated  a
LOAEL associated with  depression of body  weight gain.
3.2.   CHRONIC
3.2.1.   Oral.  Pertinent data  regarding chronic  exposure  of  man  to  carbon
tetrachloMde were  not  located  1n  the  available  literature.   Studies  of
chronic  exposure  of  animals  to  carbon   tetrachlorlde  were designed  to  be
cardnogenldty   bloassays  and,  as such,  used doses  >12.26  mg/week,  which
produced 50% mortality 1n Syrian  golden  hamsters.   These  studies  are,  there-
fore, not useful 1n deriving ADIs, and are reviewed 1n Chapter  4.
3.2.2.   Inhalation.   NIOSH  (1975) provides  an  In-depth  discussion of  the
pathology  of  chronic  Inhalation   exposure  of  carbon  tetrachlorlde 1n  man.
These  reports are  arranged  by  effects on organ  systems  and,  since exposure
data  are  lacking,  are not  useful  1n  risk assessment.  The  U.S.  EPA (1983b)
summarized human  studies  that are  more  relevant   to risk  assessment.   Smyth
et  al.  (1936) and  Smyth  and Smyth  (1935)  studied the  hematology,  kidney and
liver  function   (parameters  not   clearly  specified)  and  vision  of  carbon
tetrachlorlde-exposed  workers.   TWA exposures  were estimated  to  range  from
5-117  ppm, with  peak  exposures up  to  a  maximum of  1680 ppm.  Of  77 workers
examined,  9  showed  severely restricted visual fields and  26 showed slightly
restricted  visual  fields.    Of  67  men   tested,   13  had  elevated  Icterus
Indices.   Hematology,  kidney function  and  other  parameters  of  liver function
showed  no  significant alteration  associated  with exposure  to carbon  tetra-
chlorlde.
    Moeller (1973)  evaluated the  effects  of  chronic occupational  exposure to
carbon  tetrachlorlde   on  several  ophthalmologlc   Indices.   A  cohort  of  46
                                      -5-

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workers was exposed from 1 hour/week  to  1  hour/day  to an unspecified concen-
tration  of carbon  tetrachloMde  for an  average  of  7.7  years.   Of  these
workers, 28 were  found to have  reduced  corneal  sensitivity.  A group  of  62
locksmiths exposed to  6.4-9.5  ppm carbon tetrachlorlde  for  a  minimum of 1-3
hours/day  and  a  control  group  of  82 unexposed  persons were evaluated for
corneal  sensitivity  and other  visual parameters.  Of  the 62 exposed  lock-
smiths,  43 had  reduced corneal sensitivity, 4 had  subnormal  dark  adaptation
corneas, 4 had  restricted  outer limits of  white  visual  fields,  15 had color
limits  of  the  visual  field and 7  had Instrument-detectable changes In color
perception.   Further  Information  comparing  the  control  groups  and  the
exposed  groups was not presented 1n the available review.
    Barnes and  Jones  (1967)  reported elevated urinary  uroblUnogen  In 6/16
and  elevated  urine   protein   In  3/16  carbon  tetrachloMde-exposed  workers
compared  with  11  unexposed  controls.   Z1nc  turbidity  and  average  thymol
turbidity  tests  were  elevated  1n exposed  workers compared  with controls.
Carbon   tetrachloMde-exposed  workers   also   experienced   elevated    serum
bH1rub1n  and  slightly elevated SGOT, compared with  controls.  Rabes (1972)
associated  significant elevations  1n serum Iron and  glutamlc dehydrogenase
with  occupational exposure  for  >5  years  to  unspecified  concentrations  of
carbon  tetrachlorlde.
    Adams  et  al.  (1952) exposed guinea  pigs and  rats  to 5, 10,  25, 50, 100,
200  or 400 ppm carbon tetrachlorlde  for 7 hours/day,  5  days/week for  up to
184 exposures  over a  period  of 258 days.  The numbers  Initially Involved and
surviving  were not  specified,  but  apparently 8-9  guinea pigs  of  each sex
were  tested  at  each  concentration and -15 rats of  each  sex/group were tested
at  dosages  >25  ppm,  20  rats  of  each  sex were  tested at  10  ppm,  and  23
females and  26  males  were  exposed  to  5 ppm  carbon tetrachlorlde.
                                      -6-

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    Mortality among  guinea  pigs was  high 1n  the  200 ppm group  and  claimed
>50% of  the 400  ppm group.  Survivors  evidenced  elevated kidney  and  Hver
weights, fatty degeneration and  cirrhosis of the  liver.   Guinea  pigs  showed
hepatomegaly at all  concentrations  tested, moderately hepatic  fatty degener-
ation at  >10 ppm  and  moderate  liver cirrhosis  at >25 ppm.   Mortality  also
claimed >50%  of  the rats exposed  to 400 ppm  carbon  tetrachlorlde.  Hepato-
megaly was observed  In all  exposed  rats  but  liver  cirrhosis  was not detected
at exposure concentrations <50 ppm.
    Concurrently,  two  rabbits of  each sex were  exposed to 10,  25,  50  or 100
ppm carbon tetrachlorlde by the  same  exposure  schedule (Adams  et  al.,  1952).
Exposure  to  25  ppm, 178  times  (248  days)  resulted  In moderate  fatty  liver
degeneration  and   cirrhosis.   Additionally,   at  50  and  100  ppm,  decreased
growth  rate,  Increased  kidney  weights   and  Increased  blood   clotting  time
(Indicative of liver damage) were observed.
    Groups  of  two monkeys were  exposed  to  25,  50 or 100 ppm  carbon  tetra-
chlorlde  by  the  same  schedule  for  148-198 times  (-30-40 weeks)  (Adams  et
al.,  1952).   No  abnormal  findings   were  reported  1n  monkeys   exposed to  25
ppm.  Exposure  to 50  ppm resulted  1n weight  loss and  exposure  to  100 ppm
resulted  In  "some  Indications  of microscopic Hver change."   In  this  study,
guinea pigs appeared to be  the most  sensitive  species.  Moderate  (presumably
reversible)  hepatomegaly  occurred  at all exposures  tested,  but  evidence  of
fatty degeneration  was not  noted until  concentrations reached 10  ppm.   For
this study, 5 ppm carbon tetrachlorlde 1n guinea  pigs  constituted  a  LOAEL.
    Smyth  and Smyth  (1935)  and  Smyth  et al. (1936)  exposed groups of  22-24
guinea pigs  to  0,  50,  100,  200 or  400 ppm carbon  tetrachloride 8 hours/day,
4-6 days/week  for periods  of  up to  321  days.  All  guinea  pigs exposed  to
                                      -7-

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>100 ppm died  by  94 days of age,  necessitating  restructuring  of  the experi-
ment.  In  the  second trial, groups of  15  or  16 guinea pigs were  exposed  to
25,  50, 100  or  200 ppm carbon tetrachloride.  A group  of  7  unexposed guinea
pigs  served  as  controls.   Mortality  claimed 0/7,  12/15,  9/16,  11/16  and
11/15  of  the 0,  25,  50, 100 and  200 ppm-exposed groups,  respectively.   In
addition to  the  usual  hepatic  pathology, optic nerve  degeneration  was  noted
1n  1  or  2  guinea pigs  1n  each  exposure  group.   Fatty degeneration of  the
ocular muscles was observed 1n 3-6 guinea pigs 1n each exposed group.
    Groups  of  24  rats  were exposed  to 0,  50,  100,  200  or 400  ppm carbon
tetrachloride using  the  same dosage schedule  described  above for  guinea pigs
(Smyth and  Smyth,  1935;  Smyth  et  al.,  1936).   Liver degeneration,  regenera-
tion  and  cirrhosis were  observed  1n  rats  exposed  to >50 ppm  carbon tetra-
chloride.   Degeneration  of the   myelln  sheath  of   the   sciatic  nerve  and
degenerative changes  1n ocular  muscles, as  well  as  some  evidence  of kidney
damage, were observed sporadically In 50 ppm-exposed rats.
     Finally, these  Investigators  (Smyth  and  Smyth,  1935;  Smyth et al.,  1936)
exposed  four monkeys to  50 ppm  and  three  monkeys  to 200 ppm  carbon tetra-
chloMde  by  the  same   exposure   schedule  for  93-231  days.   Nerve  tissue
appeared  normal  in all  50 ppm-exposed monkeys.   Cloudy  swelling of  the
kidney  and fatty  changes  in the  liver  were  noted  at  the  50  ppm  level.   A
28-day  recovery  period demonstrated  the  reversible nature  of   these  mild
liver and  kidney  changes.
3.3.   TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1.   Oral.   No reports  of  teratogenldty  in  humans  or animals  orally
exposed to carbon  tetrachloride have been found in the available literature.
                                      -8-

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3.3.2.    Inhalation.   No reports  of  fetotoxldty In  humans  associated with
Inhalation of carbon  tetrachlorlde have  been found In  the available  litera-
ture.  Only  one  Investigation  of  fetotoxldty caused by  Inhalation  exposure
of animals  to  carbon  tetrachlorlde  has  been  found.   Schwetz et  al.  (1974)
exposed groups of  Sprague-Dawley  rats to  300  or 1000  ppm carbon  tetrachlo-
rlde for  7  hours/day on days  6-15  of gestation.  A  significant decrease  In
body weights and  crown-rump lengths  was  found  In fetuses from  dams  exposed
to either  300  or  1000 ppm  carbon tetrachlorlde, as  compared  with controls.
Gross examination  revealed  no  anatomical or developmental anomalies;  micro-
scopic  examination  revealed  delayed  ossification  of  the  sternebrae.   The
authors concluded  that  carbon  tetrachlorlde was  not  teratogenlc  to  rats  at
these  exposures.   Assuming that  rats  weigh 0.35  kg  and  Inhale 0.26 m3  of
air/day, exposure to 300 ppm carbon  tetrachlorlde  for 7 hours/day  results  In
an Intake of 406.7 mg/kg/day.
3.4.   TOXICANT INTERACTIONS
    Alcohol  1ngest1on  has  been clearly  shown  to potentiate  the toxlclty  of
carbon tetrachlorlde.  Tralger and Plaa  (1971)  Investigated  the  potentlatlon
of  carbon tetrachlorlde  toxldty by  methanol,  ethanol  and  Isopropanol  In
rats.  The  activity  of SGPT was  monitored  to evaluate  hepatotoxldty.   All
three alcohols tested potentiated the  toxldty of  carbon tetrachlorlde,  with
Isopropanol  being  the  most potent.   Neither  carbon  tetrachlorlde  nor  the
alcohols  alone  elevated SGPT  levels.    We1  et  al.  (1971)  Investigated  the
ability  of   ethanol  and  exposure  to  cold  to  potentiate hepatotoxldty  of
carbon  tetrachlorlde  In  rats.   Rats  were pretreated with  ethanol and  sub-
jected for  18  hours  to a  temperature  of 4C.   Elevated  SGPT  Indicated  that
ethanol  and  exposure  to  cold  potentiated   carbon  tetrachloMde-lnduced
                                      -9-

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toxldty.    von  Oettlngen  (1964)  reported  that  persons  who  were habitual
users or occasional  users  of alcoholic beverages  became  more seriously 111
than abstainers  when exposed  to  carbon  tetrachlorlde.
    In the  early 1900's, carbon  tetrachlorlde  was used as an  ant1helm1nt1c,
particularly  against  hookworm,   In  both  humans  and  animals.   SmllUe and
Pessoa (1923) reported on  severe carbon tetrachloMde-lnduced  toxldty  among
two  alcoholics  1n  a group  of 34 persons  treated with carbon tetrachlorlde
for  ancylostomlasls.   Since  then,  other  Investigators  (Guild et a!.,  1958;
McGuIre, 1932; Smetana, 1939; Gray,  1947) have  observed that  chronic  alcohol
1ngest1on  exacerbates  carbon tetrachloMde-lnduced  toxldty  resulting  from
single medicinal doses.
    Alcohol Ingestlon was suspected to play a  significant role In  the toxlc-
1ty  of  carbon tetrachlorlde  from nonmedldnal  exposure (Abbott  and  Miller,
1948),  particularly  where  renal  failure  was  a major  part  of the clinical
picture.   The  ACGIH   (1980)  suggested  that   ethanol   and  other  substances
(e.g.,  barbiturates  and  polychloMnated  blphenyls)   that   Induce   hepatic
mlcrosomal enzymes  enhance  the toxldty of carbon tetrachlorlde.
    Hafeman and Hoekstra (1977) claimed that vitamin E, selenium and  methlo-
nlne  offer partial  protection  from  carbon tetrachloMde-lnduced  toxldty.
By  monitoring the  evolution  of ethane,  a peroxldatlon  product  of  certain
unsaturated fatty  adds,  these  authors concluded  that  methlonlne, vitamin  E
and  selenium  protected against  carbon tetrachlorlde-lnduced  I1p1d  peroxlda-
tlon,  probably  by  maintaining  Intracellular  glutathlone  and   glutathlone
peroxldase.
                                     -10-

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                             4.  CARCINOGENICITY
4.1.   HUMAN DATA
    A few  cases  of  "Mver  cancer associated  with  exposure to  carbon  tetra-
chlorlde have been  reported,  but no ep1dem1olog1cal studies  from  which  risk
figures   can  be  derived  have  been  located   In  the  available  literature.
Slmler  et  al. (1964)  reported  the  case of a fireman who  developed  eplthe-
Homa of the  liver  4 years after being  acutely poisoned  by carbon  tetrachlo-
rlde.  Tracey and Sherlock (1968) suggested that  hepatocellular carcinoma 1n
a  59-year-old man  was  caused by  a 5-day  exposure to  carbon  tetrachlorlde
used  to clean his  rug.  The  patient  denied  Ingesting  alcohol since  being
exposed   to  carbon  tetrachlorlde, but admitted  to  having used  1t  before the
exposure to  carbon  tetrachlorlde.    Blair  et  al.  (1979) reported 87  cancer
deaths  1n  a  group of  330 exposed workers  1n  which 67.9 cancer  deaths  would
have  been  expected.   Concurrent   exposure   to   other  workroom   chemicals
precluded  attributing  the observed  Increase   1n  cancer  Incidence to  carbon
tetrachlorlde alone.
4.2.   BIOASSAYS
4.2.1.   Oral.   Sufficient  evidence   for  the  carclnogenlclty   of   carbon
tetrachlorlde  1n  laboratory  animals   exists   1n   the  available  literature.
Many  early studies, although  too  short 1n  duration  to be useful for  risk
assessment, demonstrated  the  hepatocarc1nogen1c1ty of carbon tetrachlorlde.
Edwards   (1941) administered  by gavage  0.1  mj, of a 40%  carbon  tetrachlorlde
solution 1n  olive  oil  to C3H  and   A-stra1n  mice  2-3  times/week  for  23-58
doses.   Necropsies  performed  2-147  days  after   the  last   administration
revealed a  progression  of  events beginning with liver necrosis  and  followed
by cirrhosis  and  eventually  hepatomas  In C3H  mice.  Hepatomas  were  found In
126/143   C3H  and  all 54 A-stra1n mice.  Delia  Porta  et  al.  (1961)  reported
                                     -11-

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administrating  30  weekly  doses  of  6.25-12.5  y9.  (10-20  mg)  carbon  tetra-
chloride to  five Syrian  golden hamsters of  each  sex.   Liver cell carcinomas
were discovered in all animals  (5 of  each  sex) that survived >10 weeks after
the end of treatment.
    Subsequently,  C3H and  strains A,  Y, C  and L  mice  were exposed to carbon
tetrachloride  to  further  elucidate  the process  of carcinogenesis  (Edwards
and Dalton,  1942;  Edwards  et al., 1942).   Small  numbers  of mice were killed
and necropsied after one  or  more doses.    Liver  necrosis  and regenerative
processes  were observed throughout  the study.   Atypical  mitotic  forms such
as  triple  mitoses were  frequent  findings.    In  mice  treated  for  >1  month,
enlarged  hepatocytes with  small   nuclei were concentrated  along  strands  of
fibrous  tissue.   Hepatic  tumors  were  usually multiple;  neither  invasion of
blood  vessels  nor  metastases were seen.   These  authors  reported  finding no
evidence of  tumors in other organs.
    Eschenbrenner  and Miller  (1944)   administered  30  doses of  0.16, 0.32,
0.64,  1.27 or  2.54  g  carbon tetrachloride/kg  bw by  gavage  to  groups of 60
strain  A mice.  The  interval  between  doses  varied from  1-5 days; thus,  the
treatment  period  varied from  30-150  days.   The  incidence  of  hepatomas  was
23/60,  23/60,  25/59,  32/60 and  33/60  in the  five groups,  respectively.  In a
later  study, Eschenbrenner and Miller  (1946) demonstrated that single doses
of  12.5  y8./kg,  but  not   6.25  y9./kg,  by   gavage  would  cause  liver  cell
necrosis  in both  male  and  female strain  A mice.  Administration  of 6.25,
12.5,  25  or  50 y8./kg/day  for  120  days  resulted  in  hepatoma  formation  in
mice  exposed to >12.5 yi/day.  Other  mice  were  given 30  doses  of 25, 50 or
100  ya./kg   at  4-day  intervals.   Microscopic   examination  revealed  small
hepatomas   in   2/10  mice  given   25  yJ./kg.   Grossly  visible  tumors  were
                                      -12-

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present  in  the higher-dosed  groups.   These  Investigators  theorized  that  a
necrotlzlng action  of carbon  tetrachloride  on  the  liver  was an  Important
factor in the development of a carcinogenic response.
    NIOSH  (1975)  and U.S.  EPA  (1980b) discussed  short-term  carcinogenicity
bioassays involving carbon tetrachloride.
    In  an NCI-sponsored  bioassay  (NCI,  1976;  Weisberger,  1977),  Osborne-
Mendel  rats  were  exposed  to  47  or  94  mg/kg  (males)  or  80  or  160 mg/kg
(females)  carbon  tetrachloride  by  gavage  for  78 weeks.   Observations  were
continued  for  33  additional weeks.   Survival data, summarized  in Table  4-1,
indicate  that  excessive  mortality had occurred  in high dose  rats  of either
sex.   Although  a  slight  increase  in  the  incidence of  hepatocellular carci-
nomas  was noted  in  both  males  and  females,  a clear  dose-related response
could  not be demonstrated.
    Mice  were  also included  in  the  NCI  (1976)  bioassay.   Groups of  50  male
and  female 35-day-old  mice  were  treated  by gavage  with  1250  or  2500  mg
carbon  tetrachloride  in  corn   oil/kg  bw/day,  5  days/week   for  78  weeks.
Observations  continued  for an  additional  13 weeks.   Vehicle  control groups
consisted  of  20  mice of  each   sex.   All  mice  were  subjected  to  necropsy.
Survival  data are  presented  in  Table 4-2.   Mortality claimed  most carbon
tetrachloride-exposed mice  by the end of  the 78-week exposure period.  Most
carbon tetrachloride-treated  mice were  discovered  to have  hepatocellular
carcinomas.   The  first  carcinomas in female  mice  were found  at  16 weeks and
19  weeks in  low  and  high  dose  groups,  respectively.  Among  male  mice, the
first  carcinomas  were  found  at  48  and  26  weeks  in  the  low and  high  dose
groups,  respectively.  The  incidences of  hyperplastic nodules  and   hepato-
cellular  carcinomas are presented in Table 4-3.
                                      -13-

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 Dose
                                   TABLE  4-1



              Survival  of  Rats  Treated  with  Carbon  Tetrachlorlde*
Initial
*Source: NCI, 1976
78 Weeks
110 Weeks
Males
Control
Low
High
Females
Control
Low
High
100
50
50

100
50
50
67 (6754)
34 (68%)
34 (68%)

75 (75%)
38 (76%)
21 (42%)
26 (26%)
14 (28%)
7 (14%)

51 (51%)
20 (40%)
14 (28%)
                                     -14-

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  Dose
                                  TABLE 4-2



             Survival of Mice Treated with Carbon Tetrachlorlde*
Initial
78 Weeks
91-92 Weeks
Males
Control
Matched
Pooled
Low
High
Females
Control
Matched
Pooled
Low
High
20
77
50
50
20
80
50
50
13 (65%)
53 (69%)
11 (22%)
2 (4%)
18 (90%)
71 (89%)
10 (20%)
4 (8%)
7 (35%)
38 (49%)
0 (0%)
0 (0%)
17 (85%)
65 (81%)
0 (0%)
1 (2%)
*Source: NCI, 1976
                                     -15-

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                                  TABLE 4-3
                            Liver Tumors 1n Mice*
                      Dose
 Carcinomas
                    Males
                    Control
                      Matched
                      Pooled
                    Low
                    High
 2/19 (IT/.)
 5/77 (6%)
49/49 (100%)
47/48 (98%)
                    Females
                    Control
                      Matched
                      Pooled
                    Low
                    High
 1/20 (5%)
 1/80 (1%)
40/40 (100%)
43/45 (96%)
'Source: NCI, 1976
NR = Not reported
                                     -16-

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4.2.2.   Inhalation.    Little  data  concerning  cardnogenldty  of  carbon
tetrachloMde from  Inhalation exposure  have  been  located  1n the  available
literature.  Costa et al.  (1963)  exposed albino rats to  unspecified  concen-
trations of  atmospheric  carbon  tetrachloMde  for  up to 7 months.   Rats  were
killed serially from 2-10 months after the beginning of  exposure.   Of the  30
rats  that  completed  the experiment, 12  had  adenodrrhosls  and 10  had  liver
nodules  measuring up   to  1  cm,   which  were  microscopically  diagnosed  as
Incipient hepatocellular carcinoma.
4.3.   OTHER RELEVANT DATA
    Scarce pertinent data  regarding  the  mutagenlclty of  carbon  tetrachlorlde
were  located 1n  the available  literature.   Kraemer et  al.   (1974) found  no
mutagenlclty  In  either  the Salmonella typhimurium  or   Escher1ch1a  coll
reversion  tests.   Details of the  experimental  protocol  were not  available.
Likewise,  IARC  (1979)  reported a  lack  of  mutagenlclty  in  S.  typhimurium
strains  TA100,  TA1535,  TA1538 (McCann and  Ames,  1976;  McCann et  al.,  1975;
Uehleke  et al., 1976) and . coll  (Uehleke et al.,  1976).
4.4.   WEIGHT OF  EVIDENCE
    There  is sufficient  evidence  1n mice,  rats  and  hamsters  to  designate
carbon   tetrachlorlde  a  potent  hepatic  carcinogen in  animals.   Prolonged
exposure (NCI,  1976; Welsburger,   1977)  results  1n  a very high  incidence  of
hepatocellular carcinoma.
    The  few case   reports  associated  with  carbon  tetrachlorlde  provide
limited,  but  not sufficient,  evidence  to  confirm  human  carcinogenicity.
Only  one epidemlologic  study (Blair  et al.,  1979) was  found  in  the available
literature.   Blair  et  al.  (1979)  observed  87  cancer  deaths  in a  cohort  of
330  exposed  workers  in  which 67.9 cancer  deaths would  have  been  expected.
                                     -17-

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Concurrent  exposure   to  other  chemicals  precluded ascribing  the  observed
Increase 1n cancer Incidence to carbon  tetrachlorlde alone.   On  the basis of
the criteria proposed by the Carcinogen  Assessment  Group  of  the  U.S. EPA for
evaluating  the  overall  weight of  evidence  for  carclnogenlclty   to  humans
(Federal  Register,   1984),   carbon   tetrachlorlde  1s   most  appropriately
classified as a  Group B2 -  Probable  Human Carcinogen.
                                     -18-

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                    5.  REGULATORY STANDARDS AND CRITERIA







    The American  Conference  of  Governmental  Industrial  Hyglenlsts  (ACGIH,



1980,  1983) and  the  U.S.  EPA  (1980b)  have established regulating  standards



for carbon tetrachlorlde as  dted 1n  Table 5-1.
                                     -19-

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                                   TABLE  5-1

      Current Regulatory Standards and Criteria for Carbon Tetrachlorlde
Criterion
TLV
STEL
NIOSH celling level
Value
5 ppm, 30 mg/m3
20 ppm, 125 mg/m3
2 ppm
Reference
ACGIH,
ACGIH,
ACGIH,
1983
1983
1980
to prevent cancer

Japan and most
European nations

Most eastern
European nations

Tolerance 1n food
10 ppm


3-7.5 ppm


exempt
Ambient water
criteria associated
with cancer risk:
10"7
10"6
lO's
consumption of
6.5 g fish only
0.69 yg/8,
6.94 yg/S,
69.4 yg/8.
2 a, water +
6.5 q fish
0.04 yg/8.
0.40 vg/J.
4.0 yg/9.
ACGIH, 1980


ACGIH, 1980
Code of Federal
Regulations,
1982

U.S. EPA, 1980b
                                     -20-

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                              6.   RISK ASSESSMENT
6.1.   ACCEPTABLE INTAKE SUBCHRONIC (AIS)
    Carbon tetrachlorlde 1s amply  demonstrated  to  be  carcinogenic  1n animals
and  data  are  sufficient  for derivation  of a  q *.    It  1s  Inappropriate,
therefore, to calculate an AIS for this  chemical.
6.2.   ACCEPTABLE INTAKE CHRONIC (AIC)
    Carbon tetrachlorlde 1s amply  demonstrated  to  be  carcinogenic  1n animals
and  data  are  sufficient  for derivation  of a  q,*.    It  Is  Inappropriate,
therefore, to calculate an AIC for this  chemical.
6.3.   CARCINOGENIC POTENCY (q^)
6.3.1.   Oral.   The  Carcinogen Assessment  Group,  as  described  1n  U.S.  EPA
                                                                    i
(1984), used  data from  the  following  for  risk assessment  purposes:   Delia
Porta et al.  (1961); Edwards  et  al.  (1942);  NCI (1976)  (both rat and mouse).
Since  none  of these studies  was  deemed  adequate  Individually and  no  study
could be selected as "best" or  "most appropriate",  the  geometric mean of the
upper  limit  unit risk  estimates  (3.7xlO~6) has  been calculated  for  drink-
Ing  water  containing  1  vg/9..   Assuming  human  consumption   of   2  l  of
water/day,  a  cancer  risk  of  3.7xlO~6   1s  associated with  a dose  of   2  yg
carbon  tetrachlor1de/day.    For   a   70  kg   human,   a  q  *  of   l.SOxlO'1
(mg/kg/day)"1 can be calculated from the following formula:
                       q.j*  = 70 kg x  3.7xlO~6 *  (2xlO~3)
where  3.7xlO~6  1s   the  risk associated  with  a  dally  dose  of   2  yg  or
2xlO~3mg/day.   U.S.  EPA   (1984)  contains  an   1n-depth  explanation of  the
rationale applied and the calculations  employed.
6.3.2.   Inhalation.   Sufficient  data  regarding  the  carclnogenlcHy   of
carbon tetrachlorlde 1n laboratory animals  exposed  by Inhalation,  from  which
to calculate a q *  were not located  1n  the available  literature.
                                     -21-

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                                7.   REFERENCES

Abbott, G.A.  and  M.J. Miller.   1948.   Carbon  tetrachloMde  poisoning   A
report on  ten cases  at  the U.S. Marine  Hospital,  Seattle,  WA,  since  1937.
Pub. Health Rep.   63:  1619-1624.  (Cited in NIOSH,  1975)

ACGIH  (American  Conference  of   Governmental  Industrial  Hygienists).   1980.
Documentation of  the  Threshold  Limit Value  for  Substances in  Workroom  Air,
4th  edition  with   supplements  through  1981.   Cincinnati,  OH.   p.  74-75.
(Cited 1n U.S. EPA, 1983b)

ACGIH  (American  Conference  of   Governmental  Industrial  Hygienists).   1983.
Threshold  Limit  Values for  Chemical  Substances and  Physical  Agents  in  the
Workroom Environment with Intended Changes for 1983-84.   Cincinnati,  OH.

Adams,  E.M., H.C.  Spencer,  V.K.   Rowe,  D.D.  McColHster and  D.D.  Irish.
1952.  Vapor  toxicity of  carbon  tetrachloride determined by  experiments  on
laboratory  animals.   Arch.  Ind.  Hyg.  Occup. Med.  6: 50-66.   (Cited in  U.S.
EPA, 1980b; 1983b)

Banerjee,  S., S.H.  Yalkowsky and S.C.  Valvani.  1980.   Water  solubility  and
octanol/water partition  coefficients  of organics.  Limitations  of  the solu-
bility-partition  coefficient   correlation.    Environ.   Sci.   Technol.    14:
1227-1229.

Barnes,  R.  and  R.C.   Jones.   1967.    Carbon  tetrachloride  poisoning.   Am.
Ind. Hyg. Assoc. J.  28:  557-560.  (Cited In U.S. EPA, 1980b)
                                     -22-

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Blair, A., P. Decoufle and D. Grauman.   1979.   Causes  of  death  among laundry



and  dry  cleaning workers.   Am.  J.  Publ.  Health.   69:  508-511.   (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.  II.   U.S. EPA,  Office  of



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



Washington, DC.   EPA-440/4-79-029b.







Code  of   Federal   Regulations.   1982.   Carbon   tetrachlorlde;   exemption.



180.1005.  Para.   67,310.05.







Costa, A.,  G.  Weber, F.S.O.  Bartolon!  and  G.  Campana.   1963.   Experimental



cancerous  cirrhosis  from  carbon  tetrachlorlde  1n  rats.   Arch.  DeVecchl.



(Ita.) 39: 303-356.   (Cited 1n  NIOSH, 1975)







Delia Porta,  G.,  B. Terradnl  and  P.  Shublk.  1961.  Induction  with  carbon



tetrachlorlde of  liver  cell  carcinomas  1n  hamsters.   J.  Natl.   Cancer  Inst.



26: 855-863.  (Cited In U.S.  EPA,  1983c)







Edwards,  J.  1941.   Hepatomas In mice  Induced with carbon tetrachlorlde.   J.



Natl. Cancer Inst.  2: 197-199.   (Cited 1n  U.S.  EPA,  1980b)







Edwards,  J.  and  A.   Dalton.  1942.   Induction  of  cirrhosis of  the  liver and



hepatomas  1n mice  with  carbon  tetrachlorlde.    J.  Natl.  Cancer  Inst.   3:



19-41.  (Cited 1n U.S. EPA,  1980b)
                                     -23-

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Edwards,  J., et  al.   1942.  Induction  of  the carbon tetrachloMde  hepatoma



In strain  L  mice.   3. Natl. Cancer  Inst.   3:  297-301.   (Cited In U.S.  EPA,



1980b)







Eschenbrenner,  A.B.  and  E. Miller.   1944.   Studies  on  hepatomas.  I.  Size



and spacing of multiple doses  In the  Induction  of  carbon  tetrachlorlde hepa-



tomas.  J.  Natl.  Cancer Inst.   4:  385-388.   (Cited  In U.S.  EPA,  1983c)







Eschenbrenner,  A.B. and E.  Miller.   1946.   Liver necrosis and  the Induction



of carbon  tetrachlorlde  hepatomas  1n strain  A  mice.  J. Natl. Cancer Inst.



6: 325-341.  (Cited In U.S. EPA, 1980b)







Federal   Register.    1984.    Environmental    Protection   Agency   proposed



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                                     -31-

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                                                          APPENDIX


                                           Summary Table for Carbon Tetrachlorlde
ro
I
Carcinogenic
Potency

Inhalation
Oral





Experimental
Species Dose/Exposure Effect
(mg/kg/day)

mice 1250-2500 liver
tumors





Ql*

ND
1.3X10"1
(mg/kg/day) *





Reference


Delia Porta
et al., 1961;
Edwards
et al., 1942;
NCI, 1976;
U.S. EPA, 1984
        ND = Not derived

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