TECHNICAL REPORT DATA
                            fftttte rttd liutructtont on the reverse btfort compltnnfl
'1. REPORT NO.
  EPA/600/8-89/097
                             a.
4. TITLE AND SUBTITLE

  Updated Health Effects Assessment for
  Trichloroethylene
                                                           3. RECIPIENT? ACCESSION NO
                                                             PB90-142498/AS
                                                           ft. REPORT DATE
                                                           •. PERFORMING ORGANIZATION CODE
 . AUTHOR(S)
                                                           •. PERFORMING ORGANIZATION REPORT NO.
B. PERFORMING ORGANIZATION NAME AND ADDRESS
                                                           10. PROGRAM ELEMENT NO.
                                                           11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
 Environmental  Criteria and Assessment Office
 Office of Research  and Development
 U.S. Environmental  Protection Agency
 Cincinnati.  OH  45268	
                                                             . TYPE OF REPORT AND PERIOD COVERED
                                                           14. SPONSORING AGENCY CODE

                                                              EPA/600/22
IS SUPPLEMENTARY NOTES
16. ABSTRACT
   This report  summarizes and evaluates information relevant to a preliminary  interim
 assessment  of  adverse health effects associated with specific chemicals or  compounds.
 The Office  of  Emergency and Remedial Response (Superfund) uses these documents  in
 preparing cost-benefit analyses under Executive Order 32991 for decision-making under
 CERCLA.  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.  The intent in  these assessments is to suggest acceptable
 exposure levels  whenever sufficient data are  available.  The interim values presented
 reflect the relative, degree of hazard associated with exposure or risk to the
 chemical(s) addressed.  Whenever possible, two categories of values have been
 estimated for  systemic toxicants (toxicants for which cancer is not the endpoint of
 concern).   The first, RfDs or subchronic reference dose, is an estimate of  an exposure
 level that  would not be expected to cause  adverse effects when exposure occurs  during
 a limited time interval.  The RfD is an estimate of an exposure level that  would not
 be expected to cause adverse effects when  exposure occurs for a significant portion
 of the lifespan.   For compounds for which  there is sufficient .evidence of
 carcinogenicity, qi*s have been computed,  if  appropriate, based on oral and
 inhalation  data  if available.
                               KEY WORDS AND DOCUMENT ANALYSIS
                  DESCRIPTORS
                                              b.IDENTIFIERS/OPEN ENDED TERMS
                                                                        c.  COSATi Field/Croup
 •. DISTRIBUTION STATEMENT

  Public
                                              It. SECURITY CLASS (This Report!

                                                Unclassified
                                                                         21. NO. OF PAGES
                                              20. SECURITY CLASS
                                                Unclassified
                                                                         22. PRICE
EPA Fan* 2220-1 (Rev. 4.77)   PREVIOUS BDITION is OMOLKTB

-------
                                            EPA/600/8-89/097
                                            February, 1988
          HEALTH EFFECTS ASSESSMENT
            FOR TRICHLOROETHYLENE
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
      OFFICE OF RESEARCH AND DEVELOPMENT
    U.S. ENVIRONMENTAL PROTECTION AGENCY
            CINCINNATI.  OH  45268

-------
                                  DISCLAIMER

    This  document  has  been  reviewed  In  accordance with  the  U.S.  Environ-
mental  Protection  Agency's   peer   and administrative  review  policies  and
approved  for  publication.   Mention of  trade names  or commercial  products
does not constitute endorsement or  recommendation for use.
                                      11

-------
                                    PREFACE


    This report  summarizes  and evaluates Information relevant  to  a  prelimi-
nary Interim assessment of  adverse  health effects  associated  with  trlchloro-
ethylene.   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
TOXLINE, CANCERLINE  and the CHEMFATE/DATALOG data bases.  The  basic  litera-
ture searched supporting  this  document  1s  current up to May,  1987.   Secon-
dary sources of  Information have also  been  relied  upon  In the preparation of
this report  and  represent  large-scale health assessment  efforts that entail
extensive  peer   and Agency  review.   The  following Off1ce . of  Health  and
Environmental Assessment (OHEA) sources have been extensively  utilized:

    U.S. EPA.   1980a.   Ambient  Water Quality  Criteria  for  TMchloro-
    ethylene.   Prepared  by the  Office  of  Health  and  Environmental
    Assessment,   Environmental  Criteria and  Assessment  Office,  Cincin-
    nati, OH  for the Office of Water Regulations  and  Standards,  Wash-
    ington, DC.   EPA 440/5-80-077.   NTIS PB  81-117871.

    U.S.  EPA.   1981.   The Carcinogen  Assessment  Group's  Carcinogen
    Assessment of  Trlchloroethylene.   Prepared  by the Office  of Health
    and  Environmental   Assessment,  Carcinogen Assessment Group,  Wash-
    ington, DC.   Internal  draft.

    U.S. EPA.   1982.   Hazard  Profile for Trlchloroethylene.   Prepared
    by  the  Office  of Health and  Environmental Assessment, Environmental
    Criteria  and Assessment Office,  Cincinnati, OH  for  the Office  of
    Solid Waste,  Washington, DC.

    U.S. EPA.  1983.  Review of Tox1colog1cal Data  In Support  of Evalu-
    ation for Carcinogenic  Potential  of  Trlchloroethylene.  Prepared  by
    the  Office  of  Health  and  Environmental   Assessment,   Carcinogen
    Assessment Group, Washington, DC  for  the Office of Solid Waste  and
    Emergency Response,  Washington,  DC.

    U.S. EPA.  1985.  Health Assessment  Document for Trlchloroethylene.
    Office   of   Health   and   Environmental  Assessment,   Environmental
    Criteria  and Assessment Office,  Research  Triangle  Park,  NC.    EPA
    600/8-82-006F.   NTIS PB 84-162882.

    U.S. EPA.  1987.   Integrated  Risk Information System  (IRIS).   Risk
    Estimate   for    Carcinogens   for   Trlchloroethylene.    On   line.
    (Preparation  date:  2/18/87).    Office  of Health and  Environmental
    Assessment,   Environmental  Criteria and  Assessment  Office,  Cincin-
    nati, OH.
                                      111

-------
    The Intent 1n these assessments  Is  to  suggest  acceptable exposure levels
for  noncarclnogens  and  risk   cancer   potency   estimates   for  carcinogens
whenever sufficient data were  available.  Values were not  derived  or larger
uncertainty  factors  were employed  when the  variable data  were limited  In
scope   tending   to   generate  conservative   (I.e.,   protective)  estimates.
Nevertheless,  the  Interim  values  presented  reflect  the relative  degree  of
hazard or risk associated with exposure to  the chemical(s) addressed.

    Whenever  possible,  two  categories  of values  have  been  estimated  for
systemic  toxicants   (toxicants   for  which  cancer  Is not   the  endpolnt  of
concern).  The first,  RfD$  (formerly AIS)  or subchronlc reference  dose,  Is
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  llfespan).
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   In  ambient air  or water  where  lifetime
exposure   Is  assumed.   Animal  data   used  for   RFD§  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.   These
values  are   developed   for   both   Inhalation  (RfD$i)   and   oral   (RfD$0)
exposures.

    The  RfD  (formerly  AIC)  Is  similar In  concept  and addresses  chronic
exposure.  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  llfespan  [see  U.S.  EPA  (1980b)  for a   discussion  of  this  concept].   The
RfD  1s  route-specific  and  estimates   acceptable  exposure  for either  oral
(RfDo)  or   Inhalation   (RfDi)  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  Identifying  reportable
quantities  and  the methodology  for their   development  Is explained  1n  U.S.
EPA  (1984).

    For compounds  for  which there  Is sufficient  evidence of carclnogenlcHy
RfD$  and  RfD values are  not derived.   For a discussion of risk  assessment
methodology  for  carcinogens refer  to  U.S. EPA  (1980b).  Since cancer  Is  a
process  that  Is  not characterized  by  a threshold, any  exposure contributes
an  Increment  of  risk.   For  carcinogens, q-j*s have  been  computed,  If appro-
priate, based on oral and Inhalation data If available.
                                      1v

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

    Two oral  bloassays  have yielded  positive results.   In  these  studies,
exposed mice showed   an   Increased  Incidence  of  hepatocellular  carcinoma.
Using  the  geometric   mean of  the  slope  estimates  from  these  studies,  a
carcinogenic potency of l.lxKT2 (mg/kg/day)"1 has been computed.

    Trlchloroethylene  has  been  shown to be  carcinogenic  In mice by  Inhala-
tion  exposure  1n  three   strains  and  1n  rats  In  one  experiment.    Human
ep1dem1olog1cal   studies  are Inadequate  to  assess the  potential  carclno-
genlclty of trlchloroethylene 1n humans.

    U.S.  EPA  (1987b)  used mouse data  based  on the Incidence  of  lung  tumors
and the corresponding  metabolized  dose  from the mouse  Inhalation  studies  to
estimate  a  unit risk  for  Inhalation  exposure.   Data concerning  the  pharma-
coklnetlcs  of  trlchloroethylene  1n  animals   and  humans  was  utilized  to
estimate  effective  dose  levels.    The resulting  unit  risk  was  1.7xlO~6
(yg/m3)"1.   Trlchloroethylene   has  been  classified   as  a  B2   carcinogen
(U.S. EPA, 1987b).

-------
                               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  John  Helms  (Office  of
Toxic  Substances)  was  the 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 Air Quality Planning and Standards
         Office of Solid Waste
         Office of Toxic Substances
         Office of Drinking Water

Editorial review for the document series was provided  by:

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

Technical support services for the document series was provided by:

    Bette Zwayer, Jacky Bohanon and Kim Davidson
    Environmental Criteria and Assessment Office
    Cincinnati, OH
                                      v1

-------
TABLE OF CONTENTS

1.
2.


3.










4.










5.


ENVIRONMENTAL CHEMISTRY AND FATE 	
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS , . .
2.1.
2.2.
ORAL 	
INHALATION 	
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 	
3.1.


3.2.


3.3.


3.4.
SUBCHRONIC 	
3.1.1. Oral 	
3.1.2. Inhalation 	 • 	
CHRONIC 	
3.2.1. Oral 	
3.2.2. Inhalation 	
TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral 	
3.3.2. Inhalation 	
TOXICANT INTERACTIONS 	
CARCINOGENICITY 	
4.1.


4.2.




4.3.
4.4.
HUMAN DATA 	
4.1.1. Oral 	
4.1.2. Inhalation 	
BIOASSAYS 	
4.2.1. Oral 	
4.2.2. Inhalation 	
4.2.3. Selected Pharmacok1net1cs Relevant to
Dose-Response Estimates 	
OTHER RELEVANT DATA 	
HEIGHT OF EVIDENCE 	
REGULATORY STANDARDS AND CRITERIA 	
Page
. . . . 1
. . . . 3
, . . . 3
, . . . 3
. . . . 4
. . . 4
, . . . 4
, . . . 8
, . . . 11
, . . . 11
, . . . 12
. . . . 13
... 13
, . . . 15
, . . . 15
... 17
... 17
, . . . 17
... 17
... 18
, . . . 18
... 23

... 26
... 33
... 40
... 41
       V11

-------
                          TABLE OF  CONTENTS  (cont.)

                                                                        Page

     RISK ASSESSMENT .........................   42

     6.1.   SUBCHRONIC REFERENCE  DOSE (RfDs)  ............     42
     6.2.   REFERENCE DOSE (RfD) ....................   42
     6.3.   CARCINOGENIC POTENCY  (*) ...............     42
            6.3.1.   Oral .......................   42
            6.3.2.   Inhalation ....................   44

 7.  REFERENCES ............................   51

APPENDIX: Summary Table for Trlchloroethylene Using the Mouse .....   64

-------
                               LIST OF TABLES

No.                               Title                                Page

3-1     Effects of Subchronlc Trlchloroethylene Exposure	    5

4-1     CarclnogenlcHy of Trlchloroethylene	   19

4-2     Disposition of 14C-Tr1chloroethylene 72 Hours After Single
        Oral Doses to Hale Osborne-Mendel and W1star-Derived Rats
        and to Male B6C3F1 and Swiss Mice	   28

4-3     Metabolism of Trlchloroethylene 1n B6C3F1 Mice: Effect of
        Chronic Dosing 	   29

4-4     Disposition of l4C-Tr1chloroethylene Radioactivity for
        72 Hours After Single Oral Dose (200 mg/kg) to Rats and
        Mice (NMRI)	   30

4-5     Metabolism of Radlolabeled Trlchloroethylene In Rats
        and Mice Following a 6-Hour Exposure Period 	   33

4-6     Predicted Relationship Between Inhalation Exposure Level
        and Trlchloroethylene Metabolites 	   39

6-1     Incidence Rates of Hepatocellular Carcinomas 1n Male
        and Female Mice In the NTP (1982) and NCI (1976) Gavage
        Studies	   43

6-2     Estimated Slope Values (q-j*) Based on Extrapolation
        from Data on Male and Female Mice	   45

6-3     Summary of Estimated Metabolized Dose from the Animal
        Bloassays, Corresponding Human Equivalent Dose (HED)
        and Tumor Incidence for the Mouse Bloassays 	   47

6-4     Summary of Estimated Metabolized Dose from the Rat
        Bloassay, Corresponding Human Equivalent Dose (HED)
        and Tumor Incidence	   48

6-5     Human q-|* Estimates per (mg metabolized dose/kg/day)	   50
                                     1x

-------
                              LIST  OF  FIGURES

No.                               Title                                Page

4-1     Relationship between administered single oral doses of
        14C-TC1 to rats and mice and amount of  dose metabolized
        1n 24 hours, expressed as mg/kg bw, as  calculated from
        l4C-rad1oact1v1ty excreted 1n urine, feces, and expired
        air (other than unchanged 14C-TC1)	     32

4-2     Relationship 1n the mouse of the doses  of TCI (po mg/kg:
        Inhalation mg eq/kg) and the amount of  total TCI metabo-
        lized (TTCIM mg eq)	   34

4-3     Relationship In the Rat of the Doses of TCI (po mg/kg:
        Inhalation mg eq/kg) and the Amount of  Total TCI Metabo-
        lized (TTCIM mg eq) as Predicted by Using Data from
        Tables 4-2 and 4-5	   35

4-4     Relationship 1n the Rat Between Airborne Concentrations
        of TCI and Total Amount of TCI Metabolized (TTCIM mg eq)
        Obtained by Computer Simulation 	   37

4-5     Relationship In the Mouse Between Airborne Concentrations
        of TCI and Total Amount of TCI Metabolized {TTCIM mg eq)
        Obtained by Computer Simulation 	   38

-------
                             LIST OF ABBREVIATIONS
ADI                     Acceptable  dally Intake
BCF                     B1oconcentrat1on factor
CAS                     Chemical Abstract Service
CS                      Composite score
Koc                     Soil sorptlon coefficient
Kow                     Octanol/water partition coefficient
LOAEL                   Lowest-observed-adverse-effect level
NOAEL                   No-observed-adverse-effect  level
ppm                     Parts per million
RfD                     Reference dose
RfDj                    Inhalation  reference dose
RfD0                    Oral reference dose
RfD$                    Subchronlc  reference dose
RfD$i                   Subchronlc  Inhalation reference dose
RfD$o                   Subchronlc  oral reference dose
SNARL                   Suggested no-adverse-response level
STEL                    Short-term exposure limit
TCA                     TMchloroacetlc add
TCE                     TMchloroethanol
TLV                     Threshold limit value
TWA                     Time-weighted average
v/v                     Volume/volume
                                      x1

-------
                     1.  ENVIRONMENTAL CHEMISTRY AND FATE

    The relevant  physical  and chemical properties and  environmental  fate of
trlchloroethylene (CAS No. 79-01-6) are as follows:

Chemical class:                   halogenated aliphatic hydrocarbon
                                  (purgeable halocarbon)
Molecular weight:                 131.4
Vapor pressure:                   57.9 mm Hg at 20°C (Callahan et al., 1979)
Water solubility:                 1100 mg/l at 20°C (Callahan et al.,  1979)
Log Kow:                          2.42 (Hansch and Leo, 1985)
Soil mobility:                    1.6 (Wilson et al., 1981)
(predicted as retardation
factor for soil depth of
140 cm and organic carbon
content of 0.087%)
Koc:                              87-150 (NLM, 1987)
BCF:                              17 (1n blueglll, Lepomls macrochlrus)
                                  (U.S. EPA, 1980a)
Half-lives In
  A1r:                            4-5 days (U.S. EPA, 1982; NLM, 1987)
  Water:                          1-4 days (river) (Zoeteman et al.,  1980)
                                  30-90 days (lake) (Zoeteman et al.,  1980)

    The primary  removal mechanism  for  trlchloroethylene In the atmosphere Is
reaction with  photochemically  generated hydroxyl  radicals.   Products  of  this
reaction  are  phosgene,  dlchloroacetyl  chloride  and  formyl  chloride.    In
photochemical  smog  situations,  trlchloroethylene  degrades  rapidly  with  a
half-life on the order of hours (NLM, 1987).
    The primary  removal mechanism  for  trlchloroethylene In water Is  expected
to  be  volatilization.   B1oaccumulat1on In  aquatic organisms  and  adsorption
to  suspended solids  and  sediments  are not  expected  to  be  Important  fate
processes (NLM, 1987).

0046H                               -1-                              08/26/87

-------
    The half-life of trlchloroethylene In soil was not  located  1n  the avail-
able literature.   Trlchloroethylene  1s expected  to  volatilize rapidly  from
soil surfaces.   The half-life  for  evaporation  from soil  should  be  longer
than Us  evaporation  half-life from  water  (Wilson  et  al.,  1981).   In  sub-
surface soil, no  significant  degradation  Is  expected to occur  under  aerobic
conditions, although some  blodegradatlon  may  occur  In anaerobic soils  (NLH,
1987).    Trlchloroethylene   Is   expected   to  be  fairly  mobile  1n  soil  as
Indicated  by  Us  K   and  the  retardation factor (velocity of  water  through
soil divided by apparent velocity of  the  compound  through  soil).   Undegraded
residue 1s  expected  to leach  Into groundwater.   Detection of  this  compound
In a number of groundwater  supplies  supports  this prediction  (NLH,  1987).
0046H                               -2-                              08/26/87

-------
           2.  ABSORPTION FACTORS IN HUMAN AND EXPERIMENTAL ANIMALS
2.1.   ORAL
    Rats  and  mice were  given single  10,  500, 1000  or  2000 mg/kg  doses  of
tr1chloro[14C]ethylene In  corn oil by  gavage  (Prout et al.,  1984).  Deter-
mination  of radioactivity  In  the  urine,  feces, expired air and carcass after
24-72  hours  showed that  92-100% of  the  doses were  absorbed.   Similar  data
were  reported  In an  earlier  study with  rats  (Daniel, 1963).   Data are not
available  on  the extent of gastrointestinal absorption  of trlchloroethylene
by humans.  See Section 4.3.2. for selected pharmacoklnetlc data.
2.2.   INHALATION
    In  humans,  absorption of  trlchloroethylene  through  the  lungs  Is rapid,
and complete tissue equilibrium  1s  achieved  after  ~8 hours of exposure (U.S.
EPA, 1985).  See Section 4.3.2. for selected pharmacoklnetlc data.
0046H                               -3-                              01/11/88

-------
                3.  TOXICITY  IN HUHANS AND  EXPERIMENTAL ANIMALS
3.1.   SUBCHRONIC
3.1.1.   Oral.  Tucker  et  al. (1982)  added trlchloroethylene  at four  dif-
ferent dose  levels  to the drinking water  of  mice for 6 months  (Table  3-1).
The dose levels were  calculated by measuring  the  concentration  of trlchloro-
ethylene  1n   the  drinking water,  and  multiplying by  the  amount  of  water
consumed by the animals each  day.  The  amount  of  water  consumed each day was
estimated  by  measuring the  water  remaining  1n  the  drinking water  bottles
twice  a  week.   Gas-I1qu1d  chromatography   Indicated  that   <20%   of  the
tMchloroethylene was lost from the drinking water  solution  1n  a 3-  to  4-day
period.   It  1s not  clear  whether  the authors  Included this  loss  of  tr1-
chloroethylene  with   time  1n  their  calculations;  however,   using  the  dose
levels reported,  the lowest  dose  levels,   18.4 mg/kg/day  In males  and 17.9
rog/kg/day  In  females, produced no  observed effects  In  the  mice.   The next
dose level of  216.7 mg/kg/day 1n males  and 193.0  mg/kg/day  In females  caused
an  Increase  In the  liver-to-body  weight  ratio  In  males  only.   At a  dose
level of 393.0 mg/kg/day 1n  males and  437.1 mg/kg/day 1n females, ketone and
protein levels were  elevated 1n  the urine  of  males but  not  females,  and the
relative  liver weight  remained  higher  1n males  but was not   Increased  In
females.   At  the  highest  dose levels  used 1n this experiment,  660.2  mg/kg/
day for males  and 793.3 mg/kg/day for  females, both male and female  mice had
decreased  body weights, Increased  liver  and  kidney  weights,  and  Increased
levels of ketone and protein 1n the  urine (Tucker  et al., 1982).
    In an  associated study,   groups of  male CD-I  mice were  given 24 or 240
mg/kg bw trlchloroethylene by gavage once  a day for 14  days  (Sanders et al.,
1982).   Cell-mediated  Immune response  to sheep  erythrocytes   was  signifi-
cantly Inhibited at  both  dose levels  compared to  vehicle controls.   Humoral
Immune response to sheep erythrocytes  was unaffected by treatment.

0046H                               -4-                              12/29/87

-------
/.8/63/2L
'Is
Ol V *
»» sr
3 e

-j * --  u ro £ ^ IB O O» <* ^ ^ IB O
U -J U «J 7 3 O U 9> OO 7 3
u-'otani no o -J * o i
v.'5.>.l5.n v. V.N.'^. o
 oi 01 o oi oi d oi o

-l> X 1» X
0 3» 0 »
O* 0*

1 1
7 9"


E E
o n
•i 5.
f^ f^
e e
i i





•" X

iii»3^» *»ii^i
eoeeeo oooooe



3 3 O 3 — » t0<2 OtoftiS— 'O— — XO
& <* m w *s* o «< t/i o* a. < *a ^ a,
a a c < • *• c • -* • •< CD a o«<
*» 33*ao.<*»— «£ 5 e — a. *
v* Ai * A v. & i^ a w*
ua — .— 7-0 e 7 ia ana -^ IB

Oi - fB < IB IB 9< >s — Oi O • -1 —J

»• -J IB • ia 7«- vi
*" " o* **
* — (
»• e
n
o> >r
— < IB



^
a
-s-
Ol
oT
•»
a
9
VI rt (4
via
if i
w
o
2
%
-1 Q. 7 13
^^^C C *A ^*
* vi i e 3
r c'is. 0.0
S-K-1% M ^


1 O"
Oi It
^ ^
«/> IB
•« a.
e
VI

Oi
1

31 * 3D

S3



< -n -n O IB 3 3
Oi — i1^ n
-lOl — 0 01 r» 1
B 3 3 |Q »• 1 IB
Ol ^ <•* ^ ^ IB Ol
— Si »• IB
3 vi Ol Oi 1 O.
« e i i —
1 O IB IB Oi <
IB X 1 vi 9 f» IB
vi e ia - oi vi i
IB Oi — • •
3 73 — VI 1 K IB
IB VI O C Z -•
j^ ^~ f* ^J S 3T .M
Bk ^* O VI 9 o ua
. e i vi o 7
•0 M. IB r*
•» IB T3 O 1>
7 7-O 3 IB O
O Oi IB • n 7
« 5"2 m* i
— 1 3 3 O <
n n S 3 IB
oi i* i a.


m TV
7 —
IB a
3 a
• Iv
1
\0 IB

U Ol
3

i
Oi

s
C4 Cd cd n u o
vi vi vi e vi e
n V ^ ** X) **
TJ « ^1 •« 1
1 I a o^ a o^




oo ee o o > o o »
19 13 19 19
^B ^* ^D ^" ^3 ^" M9 ^**
O 3 O 3 O 3 O 3
§ee e
a. o a, o a. o
oie oie oie o. c
« «J1 U CD VI »



7 1 IB TS Oi O 7
IB p IB 7 a. IB
7 fi n 7><
(BOO • — •<
Oi 1X3 n 1 Z ** 1*
— < -» O» IB O n
0 — i — (B
a Oi vi IB 9 n
1 -i < (B -tl »•
CO tti IB 1> r*
0. Oi _i 3 IB 7 C
3 •Q C n IB Oi
VI ^ (B O «• VI
• IB VI 3 VI ^*
oi 7 a.
1 O VI — 1 IB
M. M ^ ^ IK «•
Bl ^ c 3 »U ^3
3 1 IB 1
n ia < ai IB
IB 1 — 3 f VI
O VI Oi IB IB
-n  _• oi a.

IB
a.


IB T3
«» 1
IB
Ol 9
—• a.
• IB
ia
^ Ol
1C VI

t
3D
O
e
IB

£
VI
IB
^
m
M
•o
O
^|
e
IB
e
e
m 1
M Ol
•o ••
o —
1
IB e


IB
n
l»
VI

Ol

3

IB
X
S|
IB IB
a.i




m
5
IB
n









3D
IB

IB

3
n
IB

muu














m
S
VI
e
tn
g
7
O
7
|

n
^
o
O

7
IB
3
IB

K
O
e
IB
























-------
 g
 u
 I
n
             u

             £
             L.
             Ol
            tfck
             at
             u
             V
               tl
               «*

               Ol
K


,8
             01

             u
             e oi
               k
             C 3
             O VI


             •V H
             3
             O
                        CM
                        eo
                             »- a>
                                       sssiv,
                              _    _  _ OB C 0»    Ol
                         0)0>U    -N.      O <4- .O  >
                        *• r-    O O>«   ~      01
                         	          • +* e U i—
                                                 oi
                                                 VI
                                                 o
            guE
            o S K>  oi ni9> o> N
          3k.• 3  oi r-.-q _ u — <•- t-

          L. 01;

          B£9v—«v<
             -"^ c 1 £:

              cr> *« o^^ v. u
                      o>     t   >» I E —• •«
                      vi oi    -o o      vi u a>
                      a vi   «-> •o >•«' «' i- on— v •*
          eeoooo   eeeeee
          »i«ww»w   »>e»»*w
                       i

                      u
                                      ~
                                       •
                        r— >,>,>«>»     r— >>>,>«>,


                         t. "O "O "O "O     1- "O "O "O "O


                           §OI Ol Ol Ol     C Ol Ol Ol Ol
                           * ^ * M     O Jt
                                       u>   (— » i—
                      o^-             o^
                           	. O (M   kUO>Or-n
                      u >
                         L. U
                         O Ol
                                                          0)

                                                          i
                                              01


                                              •a
                                              u


                                              o.
                                              CL



                                              o
      0046H
                                                  -6-
12/29/87

-------
    Immune status was  also  evaluated 1n male and  female  CD-I  mice that were
administered  trlchloroethylene  In  the  drinking  water  for  4  or 6  months
(Sanders et  al.,  1982).  Reported average  doses for 6 months  were  0,  18.4,
216.7, 393.0 or 660.2  mg/kg/day  for  males  and  0, 17.9,  193.0, 437.1  or 793.3
mg/kg/day  for  females.   Parameters  evaluated  Included  humoral  Immunity,
cell-mediated  Immunity,  lymphocyte  responsiveness, bone marrow function and
macrophage function.   Treatment-related effects Included  suppressed  humoral
response to  sheep erythrocytes  at  >437.1  mg/kg/day  after 4 months  but not
after 6  months In the females (this was supported by concommltant Increases
In  hemagglut1nat1on  tHer),  suppressed  cell-mediated  Immune  response  to
sheep erythrocytes at  >17.9 mg/kg/day  after 4 months and  at 793.3 mg/kg/day
after  6 months   In  the  females.   Bone marrow  stem  cell  colonization  was
significantly  Inhibited  In  females  at  all  dose  levels  after 4  and  6 months
and In males at all doses after 4 months.
    Preliminary subchronlc  studies  for NTP  (1986)  carc1nogen1c1ty bloassays
were  conducted In which groups  of  10  ACI, August  or Marshall  rats/sex were
exposed  to  trlchloroethylene  1n  corn  oil  by  gavage,  5  days/week  for  13
weeks.   Male  ACI and  male August rats were administered  doses of  0,  125,
250,  500,  1000 or 2000 mg/kg.  Female  August and female ACI rats were admin-
istered  doses  of  0,  62.5,  125,  250,  500 or 1000  mg/kg.   Male  Marshall rats
were  treated with 0,  268,  308,  495, 932 or 1834  mg/kg, and female  Marshall
rats  were  treated with 0, 134, 153, 248, 466 or 918  mg/kg.   With  the excep-
tion  of  three  male August  rats that  were given  2000 mg/kg, all rats  survived
to  termination of the  study.  Reduced  final mean  body weights  In excess  of
10% of  control group  weights  occurred  In  males of all  strains at  the high
doses; body  weight depression  ranged from  12.1%  1n Marshall  rats to  17.1% 1n
ACI rats.   There were  no treatment-related behavioral or hlstopathologlcal
effects  1n any of the groups.

0046H                               -7-                              01/11/88

-------
    In preliminary  subchronlc  studies for the  NCI  (1976) bloassay,  0,  562,
1000, 1780,  3160  or 5620 mg/kg  doses of trlchloroethylene In corn  oil  were
administered to  groups of  five  Osborne-Mendel  rats/sex,  5  days/week for  8
weeks.  Groups of  five B6C3F1  mice/sex were treated  similarly with  doses of
0, 1000, 1780, 3160, 5260 or 10,000  mg/kg.   Body  weight gains of all treated
groups of rats were reported to  be below that  of  the control  group,  and  were
quantified as >20% for  females at doses  >1780 mg/kg and males at doses >3160
mg/kg.  Abnormal  clinical  signs at  >1780 mg/kg  and 100% mortality  at  5620
mg/kg also  occurred In male  and female  rats,  but  there were no  treatment-
related hlstopathologlcal effects.   There were no  treatment-related effects
on  body  weight or  histology  1n  the  mice,  but mortality  occurred  at  5260
mg/kg (80%) and 10,000 mg/kg (100%).
    Results  of 13-week preliminary   subchronlc  studies  for a  NTP  (1982)
bloassay  of  trlchloroethylene with   F344  rats  and  B6C3F1  mice  were  not
Included 1n the available summary (U.S. EPA,  1985) of this bloassay.
3.1.2.   Inhalation.   In  an  earlier  study,  Adams   et al.  (1951)  reported
that  exposure  to  trlchloroethylene  vapor 7  hours/day,  5  days/week  for  ~6
months decreased body  weights  1n guinea  pigs at a dose level  of  200 ppm.  At
a  dose  level of 400  ppm,  rats had  Increased  liver and  kidney  weights, and
guinea  pigs  and rabbits  had  Increased  liver   weights.   Male rats  and  male
guinea pigs  had  depressed  body weights at a dose level  of 400 ppm (Adams et
al.,  1951).   Rats  exposed  to  55 ppm  trlchloroethylene  vapor Intermittently
for  14  weeks  (see Table 3-1)  had  Increased  liver  weights,  but no hlsto-
pathology  was  reported  (Klmmerle  and  Eben,   1973).   Hepatic  and  renal
physiology,  as  well   as  clinical   hematologlcal   values,  appeared  normal.
Prendergast et al.  (1967) did  not  see any effects associated  with continuous
Inhalation  of  35  ppm  trlchloroethylene  by rats,  guinea  p1gs» monkeys  or


0046H                               -8-                              12/29/87

-------
dogs.  Depressed  body  weight  was observed 1n rabbits.   Except  for  the rats,
these  authors  used  extremely small  numbers of  animals and  only  one  dose
level.  Controls were described only for rats and rabbits.
    Rats that were  exposed  continuously to 320 ppm  trlchloroethylene  for  30
or  90   days   had  altered   fatty   add  composition  of   cerebral   cortex
ethanolamlne  phosphoglycerlde   (Kyrklund   et  al.,  1985   abstract   only).
Several  Unolelc  add  derived fatty adds were Increased and  Unolenlc  add
derived  fatty  add  were  decreased.    The  effects  were partially  reversed
after  30 days  rehabilitation and  not  observed  after   5  days of  exposure.
Continuous exposure to 60 or  300 ppm  trlchloroethylene  for  3 months followed
by  a  recovery period  of 4  months had Inconclusive effects  on  brain  S100
protein or DNA content In gerblls (Haglld et al.,  1981 abstract only).
    Groups of  10-20 NMRI mice  of  both sexes were  exposed  to 0  or 150 ppm
trlchloroethylene continuously  for  2,  5,  9, 16  or  30 days  (Kjellstrand  et
al., 1981).  Groups of 10-24  rats and  8-24  gerblls  were similarly exposed  to
150 ppm  for  30 days.  Relative  liver  weights were  Increased  1n  all species
and treatment groups, but the effect was more pronounced In  the mice (60-80%
enlargement) than  the  rats  or gerblls  (20-30%).   Examination of mice 5 and
30  days  after  cessation  of  treatment  Indicated   that  liver  weights  had
decreased but  were still significantly higher  than  controls.  Pathological
examinations were not conducted.
    In  a  related  study,   liver weights  and  plasma  butyrylchollnesterase
(BuChE)  activity  were  evaluated  In NMRI and nine  other  strains  of mice  of
both sexes  that  were exposed to 150  ppm trlchloroethylene  continuously for
30  days  (Kjellstrand et  al., 1983b).   Unexposed mice  of  each  strain  were
used  for  controls.  Liver  weights  were  significantly  Increased  1n treated
mice of  all strains  and plasma BuChE activity  Increased   1n  males  of all


0046H                               -9-                              12/29/87

-------
strains and  1n  females of two  of  the strains (A/sn and  NZB).   Pathological
examinations were not conducted.
    Relative liver weight  and BuChE  activity  were  also evaluated  In  groups
of NMRI mice  of both  sexes  that  were exposed to 0,  37,  75, 150 or  300 ppm
trlchloroethylene  continuously  for   30  days  (Kjellstrand  et  al.,  1983a).
Group sizes were  20  (10/sex)  at 37 ppm and  10 (5/sex)  ar  the  higher  concen-
trations.    Liver  weights  were  significantly  Increased and  concentrations-
related 1n  all   groups  (-25% Increase  at 37  ppm),  and  BuChE  activity  was
significantly Increased  In males   at  75 and  150  ppm and  both  sexes  at  300
ppm.    Intermittent exposure  30-day  experiments  In which exposures  ranged
from 225 ppm  for  16  hours/day to  3600 ppm for 1  hour/day, providing  average
dally concentrations of  150  ppm,  suggested that  liver  weight  Increases  were
Independent  of  exposure schedule.   Hlstologlcal  examination  of  the  livers
from  an unspecified   number  of  mice  showed that  continuous  exposure  to
trlchloroethylene  caused  alterations,   Including  enlarged  and   vacuolated
hepatocytes,  at all  concentrations.   The  hlstologlc   alterations  generally
were  more   pronounced  following   Intermittent   exposure  to   the   higher
concentrations  of  trlchloroethylene.  Liver  weights and serum  BuChE activity
were not significantly  Increased  In mice 120 days after  continuous exposure
to 150  ppm  for  30  days.  The  liver became hlstologlcally  similar  to controls
during  the  rehabilitation  period  except for  changes 1n cellular  and  nuclear
sizes,  suggesting reversibility of the hepatic effects.
    The results of a  study  In which groups  of  13 Sprague-Dawley  rats  were
exposed continuously  to trlchloroethylene  concentrations  of  0,  50,  200  or
800 ppm for  12  weeks were reported  by  Nomlyama et al.  (1986).   Increases 1n
liver weight and  hepatic Indices apparently  occurred  1n all of  the treatment
groups  (1t  was  reported that effects were noted  "especially"  1ri  the  800 ppm


0046H                               -10-                             01/11/88

-------
group).   Hepatic  Indices measured  Included total  protein,  albumin/globulin
ratio,  SGPT,  trlglycerldes,   cholesterol   and  chollnesterase.   Unspecified
pathological examinations appear to have been unremarkable.
3.2.   CHRONIC
3.2.1.   Oral.  In the  NCI  (1976)  cardnogenlclty  bloassay,  technical  grade
trlchloroethylene was  administered  by gavage to  groups  of 50 Osborne-Mendel
rats/sex at TWA doses  of  869  or  1739 mg/kg, 50 male B6C3F1 mice at TWA doses
of 1169  or  2339  mg/kg and 50 female B6C3F1 mice  at TWA  doses  of 869 or 1739
mg/kg, 5  days/week for 78 weeks, with 12 weeks  (mice) or  32 weeks (rats) of
observation  (Section  4.2.1.).   Vehicle  controls  consisting of  20  animals/
sex/species  were  maintained.   Treated  rats had  decreased  body  weights  and
survival  times, as well  as  slight to moderate  degenerative  and regenerative
alterations of renal  tubules  at both dose  levels;  however,  the control rats
also  had  poor survival and It  Is  difficult to determine  the  Impact  of trl-
chloroethylene on survival.  The mice did  not  have decreased body weights or
survival  times after  treatment with  trlchloroethylene.   Treated rats  of both
sexes  had  an Increased  Incidence  of  chronic  nephropathy,  compared  with
controls.   No noncancerous  hlstopathologlcal  changes were described  In mice
(NCI, 1976).
    In the  NTP (1982)  bloassay,  F344 rats  of  each sex were treated by gavage
with  0,   500  or  1000 mg/kg  trlchloroethylene,  5 days/week  for 103  weeks
(Section  4.2.1.).  B6C3F1 mice  of  each sex were  treated  similarly at a dose
level  of  1000  mg/kg.   Treatment-related  nonneoplastlc  effects  Included
reduced weight gain In the  low and  high  dose  male and female rats, decreased
survival  1n  the  low  and high  dose male  rats  and  toxic  nephrosls (character-
ized as  cytomegaly)  1n 98% of treated male and  100% of  treated female rats.
Effects In  the mice Included  reduced body  weight  gain and decreased  survival

                                                        i
0046H                               -11-                             12/29/87

-------
1n the  males,  and cytomegaly In the kidney  of  90% of the treated  males  and
98% of  the  treated females.  It  should  be noted that there were  neoplastlc
effects In the kidneys of the rats and  liver  of  the mice  (Section 4.2.1.).
    Groups  of  50 ACI,  August,  Marshall  or  Osborne-Mendel  rats/sex  were
administered tMchloroethylene by gavage at doses of  0,  500  or  1000 mg/kg,  5
days/week for  103 or  104 weeks  (NTP,  1986).  The final  body weights  of  all
dosed groups, except for high dose female  Osborne-Mendel  rats,  were somewhat
lower than those  of the  control  groups,  but  reductions >10%  occurred at 1000
mg/kg  In.ACI,  August  and Osborne-Mendel males  and Marshall  females,  and at
500 mg/kg In  ACI  males.  Treatment-related decreased  survival occurred  In
ACI males and Marshall females at both doses and  1n ACI  females and Osborne-
Mendel  females at  1000 mg/kg.   Nonneoplastlc  pathologic  effects  Included
cytomegaly of renal tubular cells and  toxic  nephropathy  In dosed rats of all
strains;  Incidences  ranged  from 82-98% and 17-80% for  the   two  types  of
lesions,  respectively.   Treatment-related  neoplastlc   renal   lesions  also
occurred  (Section 4.2.1.).
3.2.2.    Inhalation.    A  number   of  epldemlologlc  studies  with   occupational
exposure  to  trlchloroethylene,  primarily oriented  toward  carclnogenldty,
have  been  reviewed   by U.S.   EPA   (1985)  and  Axelson  (1986).   The  more
extensive review  and  evaluation was  performed  by  U.S.  EPA  (1985).   Of  the
epldemlologlc  studies,  two  (Axelson  et  al.,  1978;  Tola   et  al.,  1980)
reported  the  total  number  of observed deaths  from all  causes  compared with
the number  of expected  deaths based on  national  statistics (for  Sweden and
Finland,  respectively).  In  neither  study  did  the  number of observed deaths
significantly  exceed   the  number  expected,  and  In  most cases  the  number
observed  was substantially below the number expected.
0046H                               -12-                             12/29/87

-------
3.3.   TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1.   Oral.  Pertinent data  regarding  teratogenldty resulting from  oral
exposure  to  trlchloroethylene  could  not   be   located  1n  the  available
literature.
    Reproductive  function was  assessed  In  groups  of  ten 70-day-old  male
Long-Evans  rats  that  were   treated  with  trlchloroethylene 1n  corn oil  by
gavage at doses of 0,  10, 100  or  1000 mg/kg, 5 days/week for 6 weeks (Zenlck
et  al.,   1984).   Copulatory  behavior  and   semen  evaluations   (sperm  count,
motlllty and morphology) were conducted after  1  and  5  weeks of treatment and
at  4 weeks  postexposure.   Impaired  copulatory  behavior,   characterized  by
neglect  of females  and  Incomplete  genital  contact,  occurred  1n  the  1000
mg/kg group  only after  1 week  of exposure.   It was  suggested  that  these
effects  may  be attributed to  the  narcotic  properties  of  trlchloroethylene,
as  they  were not  apparent  after  5  weeks of  treatment because  of  presumed
tolerance.
    Groups  of  22 or  23  female  Long-Evans  rats  were  exposed  to trlchloro-
ethylene  1n  corn  oil by  gavage  at doses of 0,  10,  100 or  1000  mg/kg  for  2
weeks  before mating  through  day  21  of  pregnancy  (Hanson  et  al.,  1984).
There were  no effects on length of estrus  cycle or fertility  1n  any  of the
groups.    Maternal  toxldty   (Increased  mortality and decreased  weight  gain)
and  decreased  neonatal  survival,  which were primarily  due  to  deaths  at the
time of birth, occurred at 1000 mg/kg.
    Trlchloroethylene that was mlcroencapsulated In  a  gelatln/sorbltol  shell
was administered 1n the diet to CD-I  mice In a continuous  breeding fertility
study that consisted  of  a 7-day prematlng exposure  period,  a  98-day cohabi-
tation period and a  21-day  segregation period (George  et  al.,  1986a).   Diet
concentrations of  0,  0.15,  0.30 and  0.60% provided respective  approximate
trlchloroethylene Intakes of  0,  64,  248  and 653 mg/kg/day  during the  first

0046H                               -13-                             02/29/88

-------
week, 0,  53,  266 and 615  mg/kg/day during the  second  week and 0,  188,  375
and  750  mg/kg/day  during the remainder  of the  study.  Thirty-five  pairs  of
untreated and  17-19  pairs  of treated  mice were tested.   Final  Utters  from
the  control  and high dose-groups  were raised  to  sexual  maturity and  bred.
There  were  no  treatment-related   effects   on   fertility  or  reproductive
performance  1n either  the FQ  or  F,  mice  but  sperm  motmty was  reduced
by  45%  1n the high  dose FQ males  and by 18% In  the F^  males.   Effects  In
high-dose  F,  offspring  Included  Increased testls  and epldldymldls  weights
and a 2-fold decrease In perinatal  (days  0-21)  but  not postweanlng survival.
Hlstologlcal examination of  tissues  revealed  treatment-related  lesions  In
the  liver  and  kidneys  (but not 1n  the reproductive  tracts)  In the high-dose
FQ and F, mice.
    A similarly  designed  fertility  study with  mlcroencapsulated  trlchloro-
ethylene  was  conducted  with  F344 rats (George  et  al., 1986b).   This  study
used the  same  diet  concentrations as  the  mouse  study (Intake  estimates  were
not  reported)  and similar  numbers of animal  pairs,  but differed with respect
to  the  segregation  period (28 days as  opposed to  the  previously   used  21
days).  Treatment at  all concentrations had a marginal effect on  numbers  of
live Utters  per pair and  live pups per  Utter, but no effect  on fertility
or  other  measures  of reproductive performance.  Rats  1n the  high  concentra-
tion group had  Increased  testls  and  epldldymls  weights,  but  sperm evalua-
tions,  testls  histology and histology of other  tissues were  normal.  There
were  no  effects on  fertility, reproductive  performance,  histology  or  open
field behavioral  performance  In  the  F,  generation.  The  effects Indicated
In  the  George  et al.  (1986b)  study were  attributed to generalized  toxldty
rather  than  a  specific  effect  on the reproductive  system because decreased
body and  organ weights occurred 1n both FQ and F, rats.


0046H                                -14-                             02/29/88

-------
3.3.2.   Inhalation.  When  Swiss-Webster mice  and  Sprague-Dawley  rats  were
exposed  to trlchloroethylene  vapor  at a  concentration  of  300  ppm for .7
hours/day  on  days 6-15  of  gestation  (Schwetz  et al.,  1975),  no treatment-
related  Increase  1n  malformations was  seen; however,  slightly  reduced fetal
body weight,  delayed skeletal  development  and  an Increase 1n  the Incidence
of undescended testes were observed  1n  mice.   Decreased  maternal  weight  gain
occurred In the rats.
    Healy et al.  (1982)  exposed  32  mated Wlstar rats to  trlchloroethylene at
100  ppm 4  hours/day on  days  8-21   of  gestation.   A  group of 31  similarly
treated  mated  rats  served as controls.  Examinations  performed on gestation
day  21  revealed  no  evidence of  teratogenldty,  but fetotoxldty  was  mani-
fested  as  an  Increase  In the Incidence  of  dams with complete  Utter  resorp-
tlons,  reduced  fetal body weight and  delayed  ossification.  No  mention  was
made of maternal toxlclty.
    When pregnant rabbits were  exposed to  trlchloroethylene vapor  at  a  con-
centration  of  500 ppm  7 hours/day, 5  days/week  on  days  6-21  of gestation,
days 0-21 of gestation  or beginning  3  weeks before mating continuing  through
gestation,  the  offspring were  reported to have an Increased  Incidence  of
external hydrocephalus  (Bellies  et  al., 1980).  While the  Incidence  was  not
statistically  significant,  the  authors   felt  that  1t  was   biologically
significant.   Other,  less definitive,  teratogenldty  studies  Include  those
of  Taylor   (1936), Bell  (1977),  Dorfmueller et al.  (1981) and  York   et  al.
(1981).  Generally,   the  only effects observed  were reduced fetal  body weight
and body size and delayed ossification.
3.4.   TOXICANT INTERACTIONS
    Because trlchloroethylene  1s bloactlvated  by liver   mlcrosomal enzymes,
substances  that stimulate liver  mlcrosomal  enzymes may potentiate trlchloro-
ethylene toxldty, and  substances that depress liver  mlcrosomal  enzymes  may

0046H                               -15-                            02/29/88

-------
decrease trlchloroethylene toxldty  (U.S.  EPA, 1985).   In  addition,  Inter-
actions with  alcohol  (Bardodej  and  Vyskoch,   1956;  Seage and  Burns,  1971.;
Cornish and  Adefuln,  1966;  Ferguson and  Vernon,  1970;  Gessner  and Cabana,
1970) and carbon tetrachloMde (Pessayre et al.,  1982)  enhance the toxldty
of trlchloroethylene.   Trlchloroethylene potentiates  the effect of eplneph-
rlne on the myocardium (Dhumer  et al.,  1957; Defalque, 1961).
0046H                               -16-                             02/29/88

-------
                              4.   CARCINOGENICITY
4.1.   HUMAN DATA
4.1.1.   Oral.  Although  trlchloroethylene  has been reported  as a  contami-
nant  of  various  human water  supplies  (Zlgllo et al.,  1983),  pertinent  data
regarding carclnogenlclty  In  humans from oral  exposure to trlchloroethylene
were not located In the available literature.
4.1.2.   Inhalation.   Three  retrospective  epidemlologic  studies  Investi-
gating  human  exposure to  trlchloroethylene  1n the workplace  and  subsequent
tumor  development  (Axelson et al.,  1978;  Blair et  al.,  1979; Tola  et  al.,
1980)  were  reviewed 1n U.S.  EPA  (1985).   Individuals  1n  these  studies  were
assigned  to exposure  categories  on the  basis of  the amount of  tMchloro-
acetlc  add,  a  trlchloroethylene metabolite,  In  their urine or plasma.   In
the only  study  to  find a significant Increase  1n  the  Incidence  of  cancer  1n
exposed  Individuals  (Blair et al.,  1979),   the  workers had been exposed  to
tetrachloroethylene and  carbon  tetrachlorlde 1n conjunction  with  trlchloro-
ethylene.   The  relative  amounts  of  each chemical  during exposure were not
determined.   The  other two studies  (Axelson et al.,  1978)  did  not  find  an
Increased Incidence or rate of  cancer  development 1n  Individuals exposed  to
trlchloroethylene.
    A  more  recent   study  (Shlndell  and UlMch,  1985), which Is reviewed  1n
detail  In U.S. EPA  (1987b), reports  the  results  of  a cohort study  In a manu-
facturing  plant  where  trlchloroethylene was used  as a degreaslng agent.
This   study  failed  to  demonstrate  any  cause-specific   excess  mortality.
However, data concerning  exposure level, duration of  exposure and  follow-up
were  Inadequate.   The  conclusions of U.S.  EPA (1987b) were  that  these  data
were Inadequate  to fully  evaluate the absence of an effect.
0046H                               -17-                             03/01/88

-------
4.2.   BIOASSAYS
4.2.1.   Oral.  In the NCI  (1976)  study,  groups of  -50 B6C3F1 mice/sex  and
similar numbers of  Osborne-Mendel  rats were given trlchloroethylene  1n  corn
oil by gavage,  5  days/week  for 78 weeks (Table 4-1).   The mice were  5 weeks
old at their  first  treatment  and the  rats were 7 weeks old.   The tMchloro-
ethylene was  >99% pure  but contained  epoxlde  stabilizers,   Including  0.09%
eplchlorohydrln.  The experiments were  terminated after 90 weeks  (mouse)  and
110 weeks  (rat).  The  doses specified 1n Table 4-1  are TWA  doses calculated
for the  5  days/week  of  treatment  (the doses were changed during  the course
of  the experiments).   No compound-related  carcinogenic effects were  seen 1n
the rats,  but high  mortality  rates  within  all  groups  of rats  significantly
detracted  from  the  usefulness  of  the conclusions  (U.S.  EPA, 1985).   There
was a  significant Increase  In  the Incidence of hepatocellular carcinomas In
male mice  at  both dose levels.  Females had a  significantly  Increased Inci-
dence  of  hepatocellular  carcinomas,  but  only  at the  high  dose  level.   The
carcinogenic  effect of  trlchloroethylene  was greater 1n males than  females.
The  rate  of  hepatocellular   tumor   development  was  dose-dependent,  being
greater 1n the male  animals  exposed to the  high  dose  level  (NCI,  11976).
    The National  Toxicology Program (NTP,  1982) recently completed a cancer
bloassay using  Fisher 344  rats.  The trlchloroethylene used  had a  purity
>99.9%  and  eplchlorohydrln  was  not  detected  1n samples  (detection  level
0.001% v/v).   Fifty  male and  50  female rats were assigned to the following
treatment  groups:  untreated  control, vehicle control,  500 mg/kg trlchloro-
ethylene,  1000  mg/kg  trlchloroethylene.  Trlchloroethylene was  administered
In corn oil by gavage, 5 days/week for 103 weeks.
    A dose-related reduction 1n  survival was noted In  male  rats  (NTP, 1982).
Both  the  low and high  dose  groups  were significantly  different from  the
vehicle  control  group using survival  probabilities  estimated by  the Kaplan

0046H                               -18-                             02/29/88

-------





















Ol
c
Ol

8
b.
o
r^ u
- £
u
=j 0
p- i1
u
IP*
1
u
•o





























Ol
ly
e
Ol
Ol
01
at








Comments



*•*
k"S

p- e f oi oi
9 P- «~ 5 P- P—
p- — • 01 u a
p- vi E O>
01 o e vi vi
u in v iv p" o
e». i o-o
4-> 10 je vi b.
iv CM o> 01 •* jc
ex •- p- e «•
Ol e JC 3 O O
Ol
^
p-



SS5



KXK


>»r-
Sft
II


VI
jt
01
$

e

i/»
a it
a> a;
|$
vi eo

•O k
0
kO Ik

>« >»
IV IV
•o v
Ol Ol
JB> Jtf

Bl O>
i E
2 CO
i— CO
i— CM

IV
**
O








Ol O «—
k *• x, in p-
9 -x -o o o e
U •— 01 • O
o ^ TV 5 ° p-
•o 41 — a. ai
vi c k y — >
b. IV •< Ol
§•0 01 p-
— 41 41 U
41 J= l_ «- Ol
*« vi «< « E vi
O Q. O
k -O u- g 41 -D
i >>
>V IV
T) •O
O> Ol
Jt Jt

O) Ol
• •
O 0> Ol
kO CO
eo r>
p—













Ol
b.

VI

u
Ol
Ik
Ik
01
U
c •
01 vi
f4*
-2
u e
k «-
Sc
Ol
e 01
^E vi
£
e
e


000
p- in in
Iss



555
Ik Ik Ik

,
OP
e p-
k 01
^ O -D
w ja c


VI
!
e




ttf QJ
|$
vi eo
>.co
IV

o
m « >-
IV 

eu
p-


s>
o,srl

^S >»
•Q ^  P-
VI IV VI Z
oi 01 a
p- k E >»
» JC
<*• VI
k Ik


VI
Jt
01
s
eo
e



Ol
>v Ol
VI Ol
IV
•o co
0
in •—
o
•^ "o
C k
o ••
u e
o o> oi
•o u jt jt
Ol >. >.

oi "o
i j= O O
e oi m o
9 > •—

IV

jc «
Ol
o «-•

Ol C
t Incldenc
arclnoma 1
females.
c u
IV -0
U k C
— » 01
VI Ol
>> >
•V
^ eo
0
m r—
o
^ "o
C k
O 1-1
"So.
•o u jt
Ol X.
*< oi y
8-3 •
iS8
e oi o
9 > i—

IV
IV
o

^)
^^
Ol

Jj
l—
p- a!
p- vi J= Z
SOl Ol P- v>
JC i 	 P- k >»
Oi *> a vi oi iv ja
k E •— o K
CO __^ 01
O Ol •• flj vi 
— p- vio"~»** if
Ol O vi >> Ol
no • — e CM oi
VI k VI > VI —
IV *O O Oi VI vi
k 9 in o oi iv
UJS.S'N.^Ei— vi
£ = »£.= = I«
01
e
e
e

X^ X,
x e
Oi —
vi IV Ol
•N. k VI
o •* o
m vi v



5

»
if^e-p-
* vi JC k Oi
V 9 VI O V
:!£i!



s
P* VI
1 Jt
eo oi
2$
tn

J*t  Ol
jt jt

Dl D)
E t
e o o
0 0
m o


J3
IV
O


•
^
5io
p- eo


i t
>. o e
— C i— *" Ol
P- Ol U •< I—
•O -O 3 J= S
k" Ol IV --
e ex o>p- c
"O E
C 1 IV
"~ vi iv v> E
Ol O C Ol Ol
v> a oi p- Jt
Ol B 41
k ' e p-
e oi — c
« VI VI
"OIU. k O i k
Ol
c
o
c


ssg
sss



!k"

i
s>.
O> Ol


VI
Ol
S
o

Jt
Ol VI
Ol Jt
3 oi
>>
•V Pkl
•o m

in k
1 O


o
k

c
o
u oi oi

At ^^ ^^
o-fi1
JC O O
Oi m in
> CM

JO.
IV
O






-

0 ^
•0 v0
JC IV •
** — °
k VI
o ex vi
Ik 3 Ol
So.1
i€5
X 1
p- O u •
>0 CM iv X
VI CO
E ^
co o ?• c














































-19-
02/29/88

-------

Ol
u
Ol

Ol

Ol
ee




VI
e
i


Ol C
0> IB
L. O>
|2 O
L. O)
11


K
U)
">*
Ol —
— 

§ i

^J IB
(O 4>
k. u
9 *—
O

Of
L.
I/I
x
xl
Of
I/I
(S

3
e
ee

• '
P"
•B
^j
Ol

•— 09
»— r-
22

•o i • in 41
vi e u 41 f o «-
SIB Ol C *« • IB
2 £•,*•_• ° *
§0 oi >> o.**
i— -o u je oi —
x oi ** u c
C r- i/i • 41 — viOl
"o W o. 0,2 o $
i_ - x a. o 01 E «-
iBinOl i— On 3 41 -—
u en o .c x «-• .0 41
X Ol O U 00 u
U 00 U tO — P- u C —
IB CM — k IB O •
3 C C  -o 2 ° vi oi 6.«-
oS'S^-colo
i!£o-'i£ik^
djvroo^ottoe

^
O)
-

o» tn O r-
O1! O» O O*


_ _



^^ ^»
S"

2 SB

•A

^^


^
CM
VI
>t^ £
»S 0.10
* VI k £ w*
en e •* oi e
c x a. *oiuv>oi
— enxEO— uoi
u 41 & i- E C 3 -~
U • Q, O E •* VI
5«r ^ fe o "c
3 C r— e (B3—U
^— J«Blg ^l_^
41 -O E O vi 41 O. C
UOl< e o 5
iBOen •OI«'lB 3
tax o > e o. L. o
41 o o — eoiou

^
Ol
-

c»o ^ a»
W»O O> 9t






^^ ^~
«v *^
tfl ^o
3 U
8"
fl

^^
e
i
^
eg
i*
• JB
|CM

O
vo m t*.




iii
o, o. o.

OOOO
000
f— P> lO















oi
VI
§
a.
VI
9t
u
£
V
Ol
e
e
u
L.
IB
U
O


Ol
c
e
e

s


x 5 5
u. u. u.

y%
Ol
^ L.
X U 01
•• IB >
»CM

O
.




Ill

OOOO
°gs



CO
09
en

^
IB •

IB IB
^^
3 «-"
u. Ol
S. ' "°
O. vi 1 p^ — vi vi l f
OEOEv>3CO.k.
in— — — 3XOf
e E4IVIOIOU —
O £ T3 C Ol u
in 01 i — 4 e E IB
r- 41 C 3 • « — 5. Q
C3Ovi**3 O.E
*• F- O >B 4OU
>*u. 41 i. u oi fi in
OI«-> •* C >Z *• C IB
vi 41 L. O — ~ "O 3
eeoieuccue
*"iS "1 "" * '^'S *" o S
fcoi«'V> omp-
OIU > >. C C i— ><


O> 01
1 I
OOOO — i— f— r-
in m m m in in m m
i i i i i i i i
enonenen enenenen






x a
Ol 
VI X,
3 U ••
See IB
•• L.
VI VI

•5 •£

S X
0 0

VI VI
>%Jt Ol >>.* Ol
IB Ol Ol .<— 3 >»•—
5 5 1. f 5 k
O O
r» m *. r> in ik




if.i i.§.ii
Q. CL a. a, a o, o.
OOOO OOOO
in in in in in m
c
o
IB
e









.
1 X Q.
e "o '"S o
u •< k e»
k C Ol k
 3 o E
u u u. 5.
O VI O.
v IB e x in
oi •&
c o u e c
3 ^9 C IB IB
<— 1 i— .
SO 0
in m
Or— • X i—
k X*
^ •< E o m
E — m












































oo
en

_^ ^
c •
O P*

^*
s^;
e
0.
o
»
,,
I/I
lilt
O. CL O.
f— O O O
41 O O O
U r- Pi iC
_jr- CM CM
VI

«*
VI
Oi

in
i— O O O
xco « o
in
CO
P- bk U* U.
^w X. ^w ^^
CKKX
I
at
a a*
oi oi
X. IB rr
^a?
k Vi 0
vi

Ol

*
in
p"
VI
>»^ Ol
IB 41 41
X 3 *
vi X. 09
k vi O
3 >«P-

O
r» in n.




itii
a. a. o. o.
elll
c
o
S
c
0046H
-20-
02/29/88

-------


























1
u
1
kVJ
OD
^




































Oi
u
c
01
oi
^_
01
oe





VI
4-t
e

u




O) C
Ol IB
u oi
IB L.
t— O
«
«. Ol
Of **
II

£

X,
— IB
u u

Ck^O

«- e
0|
£ f
— • L.
oi x
^ i*j

o *•»
c
e o;
0 E

•» IB
IB Ol
t- k.
O

Oi
o
x
UJ
01

O
o





01
«J
o
et


09

r™
•P- •
C •
O i—
•• IB

*£
O)
—• Ol
e «
o u
E3
0
& a.
x
g*
*0 u
*••• OJ
icarclnoma
F IX. othi
g x
l.s


^
0)
c





































e
o
^
IB
•B

e








l|£
*0 O Ok S. wi • 5.
• *"~2 =oS eto
E •* ** g O
gX IB -M >.r- •* on

giB *< «••«•'
X C IB X IB IB

Ksl& a".eUǤ
^eo ex -o E a g o.>o
""«5»io o^oSolS
IB IB « £ O « 10 O
— X Vi Qkr- X
S 36*' ****£*-*
^ -p- Ol IB
41 S. •• J- 'iBP->oeXe
-J OkC I- X i— 
* :=

O) Ol
1 1



o o o o

^^^^
^k ^b ^k ^k
VI
VI
^^
Jin

3 CO

VI
Ol

U1

»>M J2
•B O> Ol

VI >v
L. VI OO
3 xr~
O IB
^ ^ o
r-tn «»-



iiii
a. 0.0. a.

0000
^B ^} 1^










u»
eo
JJ
^
O i—
«rf IB
5 **
"
.. ig
•• m t> e
vi B. i— Q.O «-
b. Ok<-> 2 B-O IB
o IB E  r- 1— f- IB
*"** *~ "* ** S C §.

"s E* S S" E* Q.IB *
Ok CX £ Ok •*
Q.O OkO X IB
seSS°8..jc
g IB IB IB IB Ot *

0)

•-

Ol
C
3



O O O O

1^ tk U* UB


•S. 1—
4) u. —
VI CO 1^
3 0 U

VI
Oi
Si
£

jj^ JS
IB Ol Ol

VI \
U. VI 00
3 >ir»
O IB
j^^ 0




iiii
Ok a. Ok CL

o o o o
OOO
p- r> O>U*'OliB.O>
S- o u. E ^ — c o>
VI — 4> iBOk.C
f^iBOl£eoiXCOOIO
oi •• o *«* u
p-Oo-OiviCnp-OOOl
O C k. E —  P- £ 01 09
ellS^iEl|S~f
5 Ol "o > £ i£ i-^"? Oi C
VI L. U U X VI IB
«-OliBOluC-i o r- -a ^

u
IB 01
£ 3
tvi O) 01 Oi
vi e c c
— o o o
i- •* e c c

OOO OOO
CO CO CO CO CO CO
^^ ^3 00 O ^3 ^3 O ^3 ^3 C3 ^3 CD
CM CO fNJ CO CO CO CO CO CO CO CO CO

U.U.U. XXK **5 **5

^^ ^w

O> Z IB •< IB

J^
V?
VI VI VI

c c c
i i i
SvC O
CT CO
VI VI VI
>^.x 5 >»j« £ >»^ 5
laote IB«C IQOIC

VI "Xi VI X, VI X
k. vi eo k.vioo i- vi co
3 >>i— 3 >>r— 3 >lf—
O IB O IB O IB
£-Ok. ^ "° 0 ^""o
^ hft Ife ^ h/l (^ 10 m *fe



iii iii iii iii
ev a. Ok ex a. Ok 0.0.0. 0.0.0.

OOO OOO OOO OOO
OO OO OO OO
r»tn r-UI r-irt r-*n


C
o
^
IB
IB
£
C





















































— O
O
Ol Oi
C > r-
O P- IB
u O ^
VI VI IB
SIB >
X IB

* * -s
U U Z
£ £ U
Ol Ol

IB .a z
02/29/88

-------
and Meier technique.  High dose males  showed a  significant  (p<0.05)  Increase
In  kidney  tubular  adenocardnomas  (3/16)  compared  with  vehicle  controls
(0/33) at  terminal  sacrifice by  life table  (p=0.028)  and Incidental  tumor
(p=0.028)  tests.    The   Cochran-Armltage   test  for  linear  trend  was  also
significant  (p=0.038).   Historical  control data  showed  a renal  tumor  Inci-
dence of  3/748 for  this strain of  rat;  however,  the  comparison of  kidney
adenocardnomas between  high dose males  and vehicle controls did  not  show a
significant difference using the Fisher Exact test.   Other  treatment-related
Increases 1n tumor  Incidence were  not apparent.  The high dose  used  1n  this
study appears  to  have exceeded  the maximally  tolerated  dose as  defined  by
NCI.  Despite  the Increase  1n  renal adenocarclnomas,  NTP has concluded  that
this  study  1s  Inadequate for judging the carclnogenldty of  trlchloroethy-
lene.
    B6C3F1 mice were also tested 1n  this  study  (NTP,  1982).   A  single  gavage
dose  of  1000 mg/kg/day  trlchloroethylene  1n corn  oil,  5 days/week for  103
weeks was  used.   Fifty  males and  50 females were assigned to  the untreated
control,   vehicle  control  and   trlchloroethylene  groups.   Body  weights  and
survival  were  reduced In treated  males when compared with vehicle controls.
There was  a significant  (p<0.002)   Increase  1n Incidence of  hepatocellular
carcinoma  In  treated male  and  female  mice.    Females  showed Incidences  of
2/48  and  13/49  1n  the vehicle  and  treated  groups,  respectively.   The  corre-
sponding Incidences In males were 8/48 and  30/50.   In addition,  hepatocellu-
lar adenoma Incidence was significantly (p<0.05)  Increased 1n  female mice by
the  life  table,  Incidental  tumor  and  Cochran-Armltage and  Fisher  Exact
tests, while 1n males significance  was only  found using  life  table analysis.
Historical  control  data  Indicated  hepatocellular  tumor  Incidence  of 18% and
2.9%  for  males and  females,  respectively.  These  results  confirm those  of
the NCI  (1976)  study  that reported an Increased  Incidence of  hepatocellular

0046H                               -22-                             02/29/88

-------
carcinoma  In  male and female B6C3F1 mice  given  trlchloroethylene stabilized
with  eplchlorohydrln  and  other  epoxldes.   These  results Indicate  that  the
epoxldes were not a requisite factor 1n the response.
    Groups  of  50 ACI,  August,  Marshall   or Osborne-Mendel  rats/sex  were
administered  eplchlorohydrln-free  trlchloroethylene  In  olive  oil  by  gavage
at  doses  of 0,  500  or 1000  mg/kg,  5 days/week for  103 or 104  weeks  (NTP,
1986).  Treatment  was associated with significantly  Increased  Incidences of
renal  tubular  cell adenomas  In the  low  dose male Osborne-Mendel  rats  and
Interstitial cell  tumors of the  testls  1n  high dose male Marshall rats.   NTP
(1986)  concluded  that these  bloassays  were Inadequate  for  assessing  either
the  presence  or  absence  of  cardnogenlclty because  of chemically  Induced
toxldty and  reduced  survival (see Section 3.2.1.), and  deficiencies  1n  the
conduct of the studies as revealed by data  audits.
    Maltonl et  al. (1986)  treated male  and female  Sprague-Dawley rats  by
gavage  with trlchloroethylene (99.9X  pure) 1n olive oil  at  50  or 250  mg/kg,
4-5 days/week for  52  weeks.   The rats were observed  until  death.  There  was
a  dose related  Increase  1n   the  Incidence  of  leukemia and  1mmunoblast1c
lymphosarcomas In  males, with no Increased tumor  Incidence  In  females.   The
rats were  13  weeks old before trlchloroethylene treatment began.   As  a  part
of a much  larger  experiment,  Van Duuren  et al.  (1979) treated  30 male  and 30
female  ICR/Ha Swiss mice by gavage with  0.5 mg  trlchloroethylene once  a  week
for 622 days.   No effects were reported.
4.2.2.   Inhalation.    Bell   et   al.   (1978)   reported  the   Manufacturing
Chemists Association's audit  findings on a bloassay conducted  from 1975-1977
at Industrial  Bio-Test Laboratories, Inc.  In this  study, mice  and rats  were
exposed to 100, 300 or 600 ppm of  trlchloroethylene 6 hours/day, 5 days/week
for  24  months (see Table  4-1).    No  carcinogenic   effect was  seen  In  rats.
Hepatocellular  carcinoma   occurred  In  mice.    In   males, the  Incidence  of

0046H                               -23-                             02/29/88

-------
hepatocellular carcinoma was greater  at  each dose level than  1n  females  and
occurred at all  dose  levels  tested.   Hepatocellular carcinoma occurred at  a
significantly  Increased  Incidence   In   females  only  at  the  highest  dose
level.  Several  problems,  Including  greatly vacillating exposure  levels  and
replacement of animals  during  the  experiment,  challenge the validity  of  the
results (U.S. EPA, 1982).
    Female  ICR  mice and  SO rats  were   exposed  to 50,  150  and  450 ppm  of
trlchloroethylene 7 hours/day, 5 days/week  (Fukada et al., 1983)  (see  Table
4-1).  Exposure began for both mice and  rats at  7  weeks of age.   No signifi-
cant effects on body weight or mortality were  produced  by  trlchloroethylene.
After  1  year  of exposure,  some animals  developed  bloody  nasal  discharge
(rats),  local  alopecia  (mice and  rats),  respiratory  disorders   (mice  and
rats)  or  a  hunching  appearance  (mice),  but the  Incidence  and duration  of
these  clinical  observations were  not  discussed  by  the authors.   Although
hematopoletlc and mammary tumors 1n mice and pituitary  and mammary tumors  In
rats  occurred  frequently, the  only   tumor  type  that occurred  significantly
more  frequently  1n treated  compared with  control animals  was  lung  adeno-
cardnoma  1n  mice.   The development   appeared   dose-related  and  species-
specific  1n that  150  and  450  ppm  trlchloroethylene   caused  an  Increased
Incidence of pulmonary adenocardnomas 1n mice  only (Fukada et  al., 1983).
    After  exposure  to 100 or  500  ppm  of  trlchloroethylene,  6 hours/day,  5
days/week  for  18 months,  no effect  on the  body weights of  rats, mice  or
hamsters was observed, and Increased  mortality was observed  only  1n the mice
(Henschler  et  al.,  1980)  (see Table  4-1).   Age  of the  animals at the start
of  exposure was  not   reported.   The only  statistically significant  effect
(p<0.05)  was  an  Increased  Incidence and  rate  of development of malignant
lymphomas  In female  mice.   The  response  was  greater,  but  apparently  not
significantly greater,  In the high  dose than  In  the low  dose  animals.   The

0046H                               -24-                             02/29/88

-------
authors suggested that Immunosuppresslon  1n  the  female  mice was a contribut-
ing factor  In  the Increased  rate  and Incidence of  the malignant lymphomas,
but they  provided no  experimental  basis  for the  suggestion.   The  control
mice  In  the  Henschler   et   al.   (1980)  study  had  a   higher  Incidence  of
lymphomas  (30%)  than  the  average   (16%)  reported  by  Luz   (1977).   In  a
preliminary  report on  a  short-term  study,  Sanders  et  al.   (1980)  Indicated
that  14 days  of treatment  with  24 or  240 mg/kg  of  trlchloroethylene  by
gavage decreased the Immune response In male CD-I mice.
    Maltonl  et  al.  (1986)  conducted a number of  Inhalation studies  In which
rats or mice were exposed to trlchloroethylene at 0,  100,  300 or 600 ppm,  7
hours/day, 5 days/week.  Exposure  of  Sprague-Dawley  rats by this  regimen  for
8  weeks  (observed  for   164  weeks)  did  not  result  1n  Increased  tumor
Incidences.  A  slight  but nonsignificant Increase 1n  hepatomas  was  observed
1n male but  not female Swiss mice exposed  to trlchloroethylene for  8 weeks,
with a total observation period of 134 weeks.
    Exposure  of  groups   of  130   Sprague-Dawley   rats  of  each   sex   to
trlchloroethylene by  this regimen for  104  weeks  (observed  for 150  weeks)
resulted  1n  a  significant  dose-related  Increase  In testlcular  Leydlg  cell
tumors  (Maltonl et  al.,  1986).   Slight Increases  In  leukemia,  especially
Immunoblastlc  lymphosarcomas,  and  renal   adenocardnomas  were  also  noted
among  the  exposed males.   Tumor  Incidences  were not Increased  among  female
rats.
    Maltonl et al. (1986) also exposed  groups of  90 male and 90 female Swiss
mice,   similar  groups  of  B6C3F1   (NCI)  mice, and  groups of  90  male  B6C3F1
(CRL)  mice  to  trlchloroethylene  by  this  regimen for 78  weeks  (observed  for
154 weeks).   Increased Incidences  of hepatomas  (4,  2,  9 and 14%) and  lung
tumors  (11,  12,  26  and 30%)  occurred  1n  some of the treated  groups  of  male
Swiss   mice.   The Incidences  were  significantly  Increased at  the high  and

0046H                                -25-                             02/29/88

-------
mid-exposure concentrations  for  lung tumors,  and  at the  high  concentration
for liver  tumors.   Although  lung  tumors were not  significantly  Increased  In
female Swiss mice,  the Incidence data (15/90,  15/89,  13/90,  20/89)  suggested
a  trend.   Incidences of  hepatomas  (2/90,  4/90,   4/89,  9/89)  and  pulmonary
tumors (2/90, 6/90,  7/89,  14/87)  were Increased among treated  female  B6C3F1
(NCI) mice,  but  the  only Increase  that was  statistically  significant  was
pulmonary  tumors  In the  high  dose group.  The Increase  1n  total  number  of
malignant  tumors  among  the  females was  statistically  significant  at  all
exposure levels.  The study  In male B6C3F1  (CRL)  mice was conducted  because
survival of the male B6C3F1  (NCI)  mice  was  reduced due  fighting.  Among male
B6C3F1  (CRL)  mice, tumor   Incidences  were  not   Increased  at  any  of  the
exposure levels when compared with controls.
4.2.3.   Selected Pharmacok1net1cs  Relevant to  Dose-Response  Estimates.   A
complete discussion  of  the pharmacoklnetlcs of tHchloroethylene  Is  outside
the  scope  of   this document.   The  pharmacoklnetic  data  are  extensively
reviewed 1n  U.S.  EPA (1985).  A brief  summary of  the data relating to satu-
ration  kinetics  Is  Included  here  since these data  are  an Integral part  of
dose estimates  used for  quantitative risk assessment for  trlchloroethylene.
    Experimental  data  Indicate  that  the   magnitude  of  trlchloroethylene
metabolism  1s dose-dependent  1n rodents,  showing saturation  kinetics  1n both
the  mouse  and  rat  at  high  dose  levels.   The  dose required for  saturation
appears to be -2000 mg/kg 1n mice and between 500  and 1000 mg/kg 1n rats.
    Experimental  evidence Indicates  that metabolic pathways for  trlchloro-
ethylene are qualitatively  similar  among mice, rats and humans  (U.S.  EPA,
1985).
    Studies  regarding  trlchloroethylene  metabolism considered  by U.S.  EPA
(1985)  to  be most  relevant  to Interspedes dose-response extrapolation are
summarized  In the following paragraphs.

0046H                               -26-                             03/08/88

-------
    Prout  et  al.  (1985)  administered l4C-tr1ch1oroethylene  1n corn  oil  as
single 1ntragastr1c  doses  of 10,  500,  1000 and 2000 mg/kg  to  male Osborne-
Mendel and  W1star-der1ved  rats and  to  male B6C3F1 and  Swiss  mice.  Exhaled
breath,  urine,  feces  and  carcass  were  analyzed  for  radioactivity  and
unmetabollzed  trlchloroethylene  for  up  to  72   hours  after  dosing.   The
results of these studies are shown In Table 4-2.
    The conclusions drawn from this study by U.S.  EPA (1985) were as follows:

    1.  Virtually  complete  gastrointestinal  absorption  of  trlchloro-
        ethylene occurred for all doses In mice and rats.
    2.  No Intraspecles strain differences were apparent.
    3.  Saturation of metabolism  In  the  mouse began to  occur at  a dose
        of  1000  mg/kg  based on  excretion  of  unmetabollzed  trlchloro-
        ethylene 1n the expired air.
    4.  Saturation of metabolism  1n rats began  to  occur  at  500  mg/kg as
        Indicated  by  exhalation  of unchanged trlchloroethylene  at this
        dose level.

    Green and Prout  (1984)  orally dosed  rats  and  mice  for  180 days with 1000
mg/kg/day  trlchloroethylene  In  corn oil.  Metabolism was evaluated by quan-
tifying urinary metabolites  (TCA  and  TCE-glucuron1de).   These  data are shown
In Table 4-3.  The fractional metabolism appeared  to be  constant across time
although the  ratio of  TCA to TCE-g1ucuron1de  Increased.   These  data  Indi-
cated  that  trlchloroethylene did not accumulate  significantly  with repeated
dally dosing.
    DeKant et al.  (1984),  using balance studies,   compared  the  metabolism  of
trlchloroethylene  In female  Wlstar  rats  and  female  NHRI  mice.   A  single
gavage  dose of  200  mg/kg  l*C-tr1chloroethylene  was  administered to  each
animal.  Radioactivity was measured  1n urine, feces, carcass  and exhaled air
for 72 hours after  administration.   Virtually  complete oral absorption was
apparent.   Data  are  shown  1n Table  4-4.  The  amount  of  trlchloroethylene

0046H                               -27-                             03/08/88

-------
                     : o"


                      e
                    ,

                    o*
                    C V
                    01 01
                    II
                     I
                    u
                    e
                    o


                                  S =
                                  X O"
                                  ii
                                  «•• 01
                                  01
                                  si
                                0>;

                                e
                                              o   o  e
                                           o  r-   »
         P>4  I—
 *  9.  8  5
 i—  10  ««  O
     10  I—  CO
                                          
-------
                                  TABLE 4-3

               Metabolism of TMchloroethylene In B6C3F1 Mice:
                  Effect  of  Chronic Dos1nga (1000 mg/kg/day)b
           Day            Metabolized            Expired  Unchanged
                        (mg equivalent)            (mg equivalent)

1
10
180

1
10
180
CHRONIC
18.27
22.50
15.75
SINGLE-DOSE CONTROLS
18.27
19.35
16.86

5.28
4.08
7.11

5.28
4.62
3.75
aSource: U.S. EPA, 1985

bBased  on  experimental weight  of mice  averaging  30 g, the  dally dose per
 mouse equals 30 mg 1n 0.5 corn oil.
0046H                               -29-                            03/08/88

-------
                                  TABLE 4-4

       Disposition of 14C-Tr1chloroethylene Radioactivity for 72 Hours
         After Single Oral  Doses  (200 mg/kg)  to Rats  and Mice (NMRI)a
                    Mice (average of 3)b
                 Absolute dose 5.1  mg/an1mal
                  mg equivalent per animal
                  Rats  (average of  2)D
               Absolute dose  48 mg/anlmal
                mg equivalent per animal
Expired
Unchanged
Metabolized
i*C02
Urine
Feces
Carcass
Washes

Total

0.56 (11.0%)

0.31
3.89
0.25
0.10
0.01
4.56 (89.4%)
5.12

24.96

0.91
19.78
0.86
1.39
0.10
23.04
48.0

(52.0%)






(48.0%)

aSource: U.S. EPA, 1985

bfiased on  experimental  weight of animals:  female  rats, 140 g;  female  mice,
 25.5 g.
0046H
-30-
03/08/88

-------
metabolized by rats and mice,  as  estimated by U.S.  EPA (1985), Is also shown
In Table  4-4.   Based on  these data,  U.S.  EPA (1985)  estimated  the  ratio of
metabolized trlchloroethylene  as  5.05  for  rattmouse.   This ratio agrees well
with  the  estimated surface  area  ratio  for  the two  species  [(240/24.4)
= 4.46].
    Buben  and 0'Flaherty (1985)  examined  trlchloroethylene metabolism  In
male  Swiss-Cox mice administered  trlchloroethylene  by gavage  5 days/week for
6  weeks.    Doses  used  were   0,   100.  200,  400,  800,  1600,   2400 and  3200
mg/kg/day.   Metabolism  was   evaluated  by  monitoring urinary  metabolites.
These  data showed  a  linear  relationship  between  urinary  metabolites  for
doses  In   the  range  of  0-1600 mg/kg  trlchloroethylene.   At higher  doses,
saturation of metabolism 1s Indicated by an abrupt plateau.
    The data  of  Prout et  al.  (1985) which  were  presented In Table  4-2 are
Illustrated graphically 1n Figure 4-1.   Using least square regression, these
data  were  fitted  to  a M1chaels-Meten  type equation  of:   amount metabolized
(H)=594.1  mg  x  administered  dose  (d 1n  units of  mg/day)  * [702.97 mg + d].
This  equation was utilized to  estimate  the animal  metabolized doses  for each
administered dose 1n  the  NTP  (1982)  and  NCI  (1976)  cancer bloassays  1n mice.
Using  the  conclusions  previously  discussed, the  animal metabolized  doses
were  then converted to human metabolized doses using a surface area ratio.
    U.S.  EPA  (1987b)  utilized a  similar approach for  the development of  an
Inhalation  unit  risk for  trlchloroethylene.  In this  document  the  data  of
Prout et  al.  (1985)  (see Table 4-2) were  combined  with  that  of  Stott et al.
(1982)  shown  In  Table  4-5.    The  pooled data from  the  Inhalation and  oral
exposures were evaluated  using linear  regression  and  the resultant relation-
ships between  trlchloroethylene exposure  (TCI) In  units  of  mg/kg and total
trlchloroethylene metabolites  (TTCIM)  1n mgs are shown  for rats  and  mice In
Figures 4-2 and 4-3, respectively.

0046H                               -31-                             03/08/88

-------
        MO
       1*00
        •00
                      «00
1000          1UO
TCI DOSAGE,
                                  FIGURE 4-1

    Relationship  between administered  single oral doses  of 14C-TC1  to  rats
and mice  and  amount of  dose  metabolized  1n 24 hours, expressed  as  mg/kg bw,
as  calculated from  l4C-rad1oact1v1ty  excreted  1n urine,  feces and  expired
air  (other  than  unchanged  14C-TC1).   Each  data  point  represents  four  rats
or mice.
Source:  U.S. EPA, 1985

-------
                                   TABLE  4-5

             Metabolism of Radlolabeled Trlchloroethylene 1n Rats
                 and Mice Following a 6-Hour Exposure Period*
ppm
Rats
10
600
Mice
10
600
Total uptake
(mg/rat)

1.18
35.31

0.36
14.4
Exhaled
(mg)

0.03
7.46

0.003
0.346
Metabolized
(mg)

1.15
27.82

0.36
14.0
'Source:  U.S. EPA, 1987b

Data of Stott et al., 1982
0046H                               -33-                             03/08/88

-------
                                                                1
                                                                i_  •
                                                                O 00
                                                              ,2 •« r-

                                                                <  CM
                                                          2  sis
                                                          *
                                                          O  «> H

                                                          1-1  £«
                                                          u.  p jr
                                                              O ^
                                                              .£• o o>

                                                              ^**s
                                                              2«-"5
                                                              £ ot-
                                                              51
                 BUJ '
0046H
-34-
03/08/88

-------
                                                                                    CM
                                                                                     i
                                                                                  o **
                                                                                  »*-   oo
                                                                                  60   o«
                                                                                  o -
                                                                                  a
                                                                             co   —
s
                                                                             3    u    o
                                                                                 .C I—   CO
                                                                                  o -o
                      6iu
                                                                                  Q.CJ
                                                                                  O *»
                                                                                 •- O
                                                                                  a, o
0046H
                               -35-
03/08/88

-------
    Transformation of  these curves  Into ppm exposure  vs.  metabolized  dose
are  shown  1n Figures  4-4  and 4-5  for  rats  and  mice,  respectively.   These
curves were  constructed  by  first estimating the amount of  trlchloroethylene
Inhaled using estimated ventilating volumes.  These curves  Illustrate  a two-
compartment solution with a  log-log  solution  1n the first  compartment  and  a
L1neweaver-Burk  solution for the  second  compartment.
    The data from Figures 4-4 and 4-5 are presented  In  tabular  form 1n Table
4-6.   It  Is  these metabolized dose  estimates which form  the basis for  the
quantitative risk estimates  for  Inhalation exposure.
4.3.   OTHER RELEVANT DATA
    Trlchloroethylene  1s  often  contaminated  with  carbon  tetrachlorlde,
chloroform, epoxldes  and other   chemicals (Henschler  et a!., 1977;  Loprleno
et al., 1979), some of which are mutagenlc.   In order to eliminate the muta-
genlclty caused by contaminants, purified trlchloroethylene has  been  tested.
Purified trlchloroethylene caused Increased mutagenesls In  Salmonella  typhl-
murlum (Bartsch et al.,  1979; Baden  et  al., 1979; Simmon et  al.,  1977),  and
In Saccharomyces cerevlslae, strains D4 and 07  {Bronzettl et  al.,  1978) only
after metabolic activation  (U.S. EPA, 1981).  Abrahamson and  Valencia  (1980)
reported negative  results  1n testing for  sex-linked recessive  lethal  muta-
tions  In Drosophlla melanoqaster.  Trlchloroethylene did not  Induce dominant
lethal mutations  1n  NMRI-Han/BGA mice (Sladk-Erben et  al.,  1980).   Results
of  mutagenlcHy  testing  In  the mouse  spot  test,  however,  were  positive
(Fahrlg, 1977).
    Negative results  were  observed 1n  mouse  skin painting and  subcutaneous
Injection  studies with  trlchloroethylene  (Van  Duuren et  al.,  1979)  and
trlchloroethylene epoxlde (Van Duuren et al.,  1983).
0046H                    •           -36-                             03/08/88

-------
                                  II
                                  o

                                  I/I
                                  =
                                  o
                                    o  ^
                    I
                    a
                     »
                   O
                N
*   fff  -
bU   «^     •
oe   < «•  «/>
      SS
    c«  =
I-N   a; L_
      *•'   ^B

    ** i^   O
    «0 ^  CO

    86 o
                                  ^"
                                  lo

                                  11
I  I  I  I  I  I  I
      ^ n N *• .O
                                  m

-------
                                                                          o
                                                                         4-«
                                                                       •0,2
                                                                       Si
                                                                       s
                                                                   un   o  £  <:
                                                                    i   .o  °*  a.
                                                                   *   uff  ^
                                                                   i^   ^C      *
                                                                   oe     »-  co
                                                                   s   si  =
                                                         o
                                                                              o>
                                                                              u
                                                                         «-   o
                                               »-   e
                        DUJ
0046H
-38-
01/11/88

-------
                                   TABLE  4-6

              Predicted Relationship Between Inhalation Exposure
                   Level and Trlchloroethylene Metabolites*
Airborne TCI
Concentration
(ppm)
600
450
300
150
100
50
10
Predicted TTCIM
Rat (200 g)
21.81
18.19
13.85
8.83
5.85
3.57
0.96
(mq)
House (30 g)
10.2
7.87
5.45
2.91
1.74
1.08
0.25
*Source:  U.S. EPA, 1987b
0046H
-39-
12/29/87

-------
4.4.   WEIGHT OF EVIDENCE
    Inhalation  of   trlchloroethylene  has  caused  pulmonary  adenocarclnomas
(Fukada et  al.,  1983); lymphomas  (Henschler  et al.,  1980)  In female mice,
and hepatocellular  carcinomas  1n  both  male and  female mice  (Bell  et al.,
1978)   and  leydlg  cell  tumors  1n  male  rats.   Oral exposure  to trlchloro-
ethylene has  caused  hepatocellular  carcinomas  1n both  male  and female mice
(NCI,   1976;  NTP,  1982).   This  constitutes sufficient  evidence of  cardno-
genldty In animals since carclnogenldty has been demonstrated for multiple
strains of mice exposed by Inhalation or gavage treatment.  The evidence for
cardnogenlclty In humans  Is  Inadequate  to demonstrate or refute a carcino-
genic   potential.   Based  on EPA carcinogen  risk  assessment  guidelines (U.S.
EPA,   1986a),   the  overall   weight   of   evidence  for  cardnogenlclty  of
trlchloroethylene  was  classified  In  Group 82 -  Probable Human Carcinogen.
This classification system and ranking Is contained In  several  recent Agency
analyses (U.S. EPA, 1985,  1986b,c,  1987a,b).
    U.S. EPA  (1987b) also noted that a metabolite of trlchloroethylene, TCA,
has  been  shown to  Induce  liver   carcinomas  In  male  mice,   thus   further
supporting the Group B2 classification.
0046H                               -40-                             03/08/88

-------
                     5.   REGULATORY STANDARDS AND CRITERIA

    The  current  OSHA  (1985)  standards  for occupational  exposure  to  trl-
chloroethylene  are  air  concentrations  of 100 ppm  as  an 8-hour TWA  and 200
ppm as a  celling.  The  acceptable maximum peak  above  the acceptable celling
concentration Is  300 ppm  for  5  minutes  In any 2 hours.  Trlchloroethylene Is
regarded  as  a  potential  carcinogen by  OSHA.   NIOSH has proposed  an 8-hour
TWA  of  25  ppm  for  trlchloroethylene  {Page and Arthur,  1978).   The  ACGIH
(1986) currently  recommends  a TWA-TLV  of 50 ppm (270 mg/m3) and an  STEL of
200 ppm (1080 mg/m3) for trlchloroethylene.
    A  10~5   risk  level  ambient   water  concentration  of   27   yg/i   was
derived by  the  U.S. EPA  (1980a).   This value assumes a  dally  Intake of 2 I
water and 6.5 g  fish and  shellfish with a  BCF  of  10.6, and was  calculated
from  a  q *  of  1.26xlO~2  (mg/kg/day)"1 that  was  derived  from  the  NCI
(1976) bloassay.   More  recently, U.S.  EPA (1986b)  estimated  a  concentration
of  2.8  yg/i  In  drinking  water  associated  with  an excess  cancer  risk  of
10~6 using the recent EPA approach, which 1s discussed In Chapter 6.
    U.S.  EPA  (1985) estimated  a unit  risk  for  trlchloroethylene  1n  air  of
1.3xlO~6   (wg/m3)"1.   This   value  Is   based   on   extrapolation   from   the
human  q *  of  1.3xlO~2   (mg  metabolized  dose/kg/   day)"1  which  was  based
on  the  geometric  mean  of  values  derived  from  the  NTP and  NCI   oral  bio-
assays.    The  oral  q *  was  converted  to an Inhalation  unit  risk  based  on
human pharmacoklnetic  data.   U.S.  EPA  (1987b)  has  provided   a  unit  risk
estimate  for  Inhalation  of  1.7xlO~*   (vg/m3)"1  based  upon   more  recent
Inhalation data.
0046H                               -41-                             03/08/88

-------
                              6.   RISK  ASSESSMENT
6.1.   SUBCHRONIC REFERENCE DOSE (RfDc)
                                     x>
    Trlchloroethylene 1s a  chemical  that  1s demonstrated to  be  a carcinogen
In experimental animals, and  data are sufficient for  estimation  of carcino-
genic  potencies  by  both  the  oral and  Inhalation routes.   It   Is  Inappro-
priate,  therefore,  to  calculate  an  oral  or  Inhalation  Rfl)_  for  this
chemical.
6.2.   REFERENCE DOSE (RfD)
    Trlchloroethylene 1s a  chemical  that  1s demonstrated to  be  a carcinogen
1n experimental animals, and  data are sufficient for  estimation  of carcino-
genic  potencies  by  both  the  oral and  Inhalation routes.   Based upon  the
guidelines for this  series of documents,  an oral or  Inhalation  RfD for this
chemical  1s  not  calculated.   It  should be  noted that an  RfD for the non-
carcinogenic  effects  of trlchloroethylene  1s  currently under review  by  the
Reference Dose Workgroup of the U.S. EPA.
6.3.   CARCINOGENIC POTENCY (q^)
6.3.1.   Oral.  U.S.  EPA (1985)  has estimated the 95% upper-bound estimates
for  hepatocellular  carcinoma  using the linearized multistage  model of Crump
and  adopted  by the U.S. EPA  (1980b)  for  the  data  from both  the NCI  (1976)
and NTP (1982) studies.  These data are shown In Table 6-1.
    Metabolized doses (see  Table 6-1) were calculated from doses  administered
to  rodents  based  on  the data from Prout et  al.  (1984) using a  "Mlchaeles-
Menton" type  equation,  M=a  x  (d/bnl):   d  represents  the experimental  dose, M
represents  the metabolized  dose  and  a  and  b  are   empirically  determined
constants.  Using  least-square estimates, a  was  determined  to be 594.1 and b
702.79   (r2=0.99)   (U.S.   EPA,   1985).    Using  the   multistage   model,  q^
values  were   determined  from  animal  metabolized  doses.  The q *s 1n terms
of  human  metabolized doses were  estimated  from the animal q *s  In terms of

0046H                               -42-                             03/08/88

-------
                                   TABLE  6-1

     Incidence Rates of Hepatocellular Carcinomas In Hale and Female Mice
               1n the NTP (1982) and NCI (1976) Gavage Studies8
Study

NTP
NCI

NTP
NCI
Continuous Human
Equivalent (animal
nominal) Doses
(mg/kg/day)b

0
47.39b
0
45.11
85.80

0
45.62
0
31.65
61.43

(0)
(1000)
(0) H
(1169)d
(2339)d

(0)
(1000)
(0) A
(869)d
(1739)d
Animal
Metabolized
Dose
(mg/day)
MALE
0
31.98C
0
30.90C
58.77C
FEMALE
0
28.17C
0
18.49C
35.89C
Incidence Rates
No. with Tumor/Total
(%)

8/48 (17%)
30/50 (60%)
1/20 (5%)
26/50 (52%)
31/48 (6554)

2/48 (4%)
13/49 (27%)
0/20 (0%)
4/50 (8%)
11/47 (23%)
aSource: U.S. EPA, 1985

bAll  95% upper-limit  slopes q-j*  calculated using  continuous human  equiv-
 alent doses.
 Equivalent  human  dosage
 (Wa/70)1}3
animal  metabolized  dose  x  5/7  days  x  lc/Lc
 where Wa  = weight  of  the mice.   The average weight  of  males 1s  taken  as
 40 g for  dosed  males  and 35 g for dosed females  for the  NTP  study;  for  the
 NCI  study the  average  weights are  33 g  for  males and  26 g for  females.
 Lc,  the   length  of  experiment,  =   2  years   and  lc,   the  duration   of
 exposure,  1s 2 years for the NTP study and  1.5 years for the NCI  study.

°Determ1ned  using  data  from  Prout et  al.   (1984)  and   a  "MUhaeles-Menton"
 type equation by U.S.  EPA (1985)

dTWA gavage dose over 78-week treatment period.
0046H
      -43-
03/08/88

-------
metabolized dose  using a  surface  area approximation.   Human  q,*s  In  terms
of  exposure dosage  were  then back-calculated  from  the  q *s  1n  terms  of
human metabolized doses (Table 6-2) (U.S.  EPA,  1985).
    The potency  for  humans,  q ,*,  to be used  for  estimates of  risk related
to  exposure  was  estimated  as  the geometric mean  of  the  human  administered
dose  q,*s,  l.lxKT2  (mg/kg/day)'1.   This  value  has  been   verified  and
1s available on IRIS (U.S. EPA, 1987a).
6.3.2.   Inhalation.   U.S.  EPA (1985)  estimated a  unit risk  for  tMchloro-
ethylene   In   air   of   1.3x10"*  (vg/m3)"1.    This   value   Is  based   on
extrapolation  from  the  human  q  *  of  1.3xlO~2  (mg  metabolized  dose/kg/
day)-1, which  was based  on the geometric  mean of  values derived  from  the
NTP  and  NCI oral  bloassays.   The oral  q * was converted to  an  Inhalation
unit risk based on human pharmacoklnetlc data.
    The study  by Monster  et  al.  (1976) was used  for  estimating  the  amount
metabolized when  a  subject  1s exposed  to 1  jig/m3  of  trlchloroethylene  In
air.
    The median amount  metabolized by  four  subjects  exposed to 70 ppm  for  4
hours  1s 439 mg.   Assuming that the dose metabolized  1s  linearly  related  to
the  level  and duration  of exposure,  the  dose corresponding  to 1  vg/m3  of
trlchloroethylene In air was estimated as:
                          439 mg x (24 hours/4  hours)
                          —   ^ -     -
            .    ...
           dose/1                    ,..-.,-
                            70 ppm x 5475 mg/m3/ppm
                        = 6.9xlO~3 (mg/dayMvg/m3)'1
                        = 6.9xlO~3/70 kg = 9.9xlO~5 (mg/kg/day)~^

Therefore,  the  unit  risk  for  trlchloroethylene  1n  air  Is   1.3xlO~2  (mg
metabolized    trlchloroethylene/kg/day)'1   x   9.9xlO~5    (mg   metabolized
trlchloroethylene/kg/day/vg/m3)     =     1.3x!0~*     (vg/m3)'1     expressed
1n terms of ambient concentration.

0046H                               -44-                             03/08/88

-------
                                   TABLE 6-2

           Estimated Slope Values  (q-|*) Based on Extrapolation from
                        Data  on Hale and Female M1cea»D
    Study
Geometric mean
      q-l*
   (Animal)
(mg metabolized
 dose/kg/day)'1
   1.0xlO~3
      q-,*
    (Human)
(mg metabolized
 dose/kg/day)'1
   1.3xlG~2
    (Human)
(mg administered
 dose/kg/day)"1
NTP
male mice
female mice
NCI
male mice
female mice

1.8xlO~3
7.5xlO'4

1.6xlO~3C
5.0xlO~«c

2.2xlO"2
9.5xlO~3

2.1xlO'2
6.9xlO"3

1.9xlO~2
8.0xlO"3

1.8xlO~2
5.8xlO~3
    l.lxlO'2
aSource: U.S. EPA, 1985

bq-j*  Is  the  95%  upper  limit  of   the   linear  component   (slope)  1n  the
 multistage model.   Since the dose-response curve  1s  virtually linear  below
 1  mg/kg/day,  the  slope  1s  numerically  equal  to  the  upper  limit of  the
 Incremental lifetime risk estimates at 1 mg/kg/day.
cSlope  Is  Increased  by  (104/90)3  because  the
 was less than the Hfespan of the test animal.
                              duration  of  the  experiment
0046H
                 -45-
                             03/08/88

-------
    In a more recent assessment, U.S.  EPA  (1987b)  utilized  animal Inhalation
bloassays to  calculate  a unit risk  for  Inhalation exposure.  The  data sets
chosen  for  quantitative  analysis  were:   Leydlg  cell  tumors In male  rats
(Maltonl et al., 1986);  liver and  lung tumors  1n  male Swiss mice (Maltonl et
al, 1986);  lung tumors  1n  female swiss  mice  (Maltonl  et al.,  1986),  liver
and lung tumors In female B6C3F1 mice  (Maltonl  et  al.,  1986) and lung tumors
In female ICR mice (Fukada et al., 1984).
    Animal metabolized  doses were  estimated  for  each  experimental  exposure
condition utilizing  the  data  shown 1n  Table  4-5.   Extrapolation  from  the
doses shown 1n  Table  4-5 to those  shown In Table  6-3 Involved First  extrap-
olating  to  animals of  different  body weight  by  multiplying the dose  from
Table 4-5  by  the 2/3 power  of  body weight.   The  doses were  then  corrected
for a 7-hour  vs.  a 6-hour  exposure by multiplying by 7/6.   In  addition  the
animal  doses  were  converted  Into  estimated  human  equivalent  metabolized
doses by  using  the  ratio of the body  weights  to the  2/3  power.   These  doses
were further  adjusted by multiplying by  the percent  of  the animals  lifetime
that  the experimental  time  period  represented.   An animal  lifetime of  28
months  was  assumed for  this calculation.   As  a  result,  the human  HEDs  In
Table 6-3  derived  from studies  using  Swiss  and B6C3F1 mice were multiplied
by 0.133 to  account for  78  weeks  of exposure, 5 days/week,  7 hours/day  and
the  HEDs derived  from  the  study  using  ICR mice  (107-week  exposure)  were
multiplied by 0.183.
    Similarly,  the  data for metabolized dose  and  human equivalent dose  for
Sprague-Dawley  rats  are shown  In  Table   6-4.   For  this  104-week  study,
exposure time adjusted doses could be calculated by multiplying by 0.178.
    The  U.S.  EPA  (1987b)  then  calculated slope  estimates  (q^)  utilizing
the  multistage  model  for  each  of  these  data sets.   Slope  estimates  were


0046H                                -46-                             03/08/88

-------
                                  TABLE  6-3

       Summary of Estimated Metabolized Dose from the Animal Bloassays,
                 Corresponding  Human  Equivalent  Dose  (HED)  and
                   Tumor Incidence for the Mouse Bloassays*
Trlchloroethylene
Exposure
Swiss




Swiss




B6C3F1




Mice, Male (47
600
300
100
0
Mice, Male (40
600
300
100
0
Mice, Female (
600
300
100
0
ICR Mice, Female (40




450
150
50
0
Metabolized
Dose (mq)
Animal
grams)
16.1
8.59
2.74

grams)
14.4
7.71
2.46

32 grams)
12.4
6.64
2.12

grams)

11.1
4.12
1.53
HED

2148
1148
367


2148
1148
367


2148
1148
367



1658
613
227
Lung Liver
Tumor Tumor
Incidence Incidence

27/90 13/90
23/89 8/89
11/89 2/89
10/89 4/88

20/89
13/90
15/89
15/90

14/87 9/89
7/89 4/89
6/90 4/90
6/90 3/90

11.46
13/50
5/50
6/49
Reference

Maltonl
et al.,
1986


Maltonl
et al.,
1986


Maltonl
et al..
1986


Fukada
et al.,
1983

'Source:  Adapted from U.S. EPA, 1987b
0046H
-47-
03/08/88

-------
                                  TABLE 6-4

         Summary of  Estimated  Metabolized  Dose  from the  Rat  Bloassay,
        Corresponding Human Equivalent Dose (HED)and Tumor Incidence*
TMchloroethylene
Exposure
600
300
100
0
Metabolized
Dose (mq)
Animal HED
52.0 1289
33.0 818
13.9 346

Leydlg
Cell Tumor
Incidence
31/129
30/130
16/130
6/135
Reference
Fukada
et al.,
1983


*Source:   Adapted from U.S.  EPA,  1987b
0046H
-48-
03/08/88

-------
calculated  both  by  using  body weight  as  the  scaling  factor  and  by  using
                                 2/3
estimated  surface  area ((weight)   ) as  the scaling  factor.   The estimates
seemed  to  be  1n  closer agreement  when  a  surface  area assumption  was  uti-
lized.  These  data are shown  1n Table  6-5.  The slope  estimates  are  all  In
the same  range as that calculated  by U.S. EPA  (1985),  1.3xlO~2,  based  upon
mouse gavage studies.
    The  geometric  means of  the mouse  potency  estimates  were  8.7xlO~3  and
1.7xlO~2  (mg/kg/day)"1 for  the liver  and  lung,  respectively.   The  higher
of  the  two  values was chosen for use  1n subsequent  extrapolations.   This
value was  chosen over  that  based  upon the  Leydlg  cell tumors  1n  male  rats
for  several  reasons:   the  fact   that   It reflects  a  first  pass  effect
resulting  from Inhalation  and because  1t 1s based  on a  response seen  In
multiple mouse strains and  In both sexes  (U.S. EPA, 1987b).
    This  q * was  then converted  Into  a  unit  risk for Inhalation  exposure
by  utilizing the  same data base  described In  Section  6.3.2.  where H  was
estimated  that  exposure  of   humans  to  air   containing   1   yg/m3  should
result  In  a  metabolized   dose of  lxlO~4  mg  metabolized  trlchloroethyl-
ene/kg/day.  Therefore the unit risk  for Inhalation  exposure  to  trlchloro-
ethylene was calculated as follows:

   [1.7xlO~2(mg metabol1zed/kg/day)~l]x[lxlO~« mg metabol1zed/kg/day/vg/m3]
                             = 1.7xlO~« (vg/m3)'1
0046H                               -49-                             03/08/88

-------
                                  TABLE  6-5



            Human q-j*  Estimates per  (mg  metabolized  dose/kg/day)*
Data
Hale Rats
Leydlg cell
Swiss Hale Mice
Liver
Lung
Swiss Female Mice
Lung
B6C3F1 Female Mice
Liver
Lung
ICR Female Mice
Lung
qi*

2.7xlO~

1.1x10"
2.4x10"

9xlO~3

7.1x10"
1.3x10"

2xlO"3


3

2
S



a
2


*Source:  Adapted from U.S. EPA, 19875
0046H                               -50-                             03/08/88

-------
                                7.   REFERENCES

Abrahamson, S. and R. Valencia.  1980.  Evaluation of  substances  of  Interest
for genetic  damage using  DrosophUa  melanoqaster.   Final sex-1 Inked  reces-
sive  lethal  test  report  to FDA  on 13  compounds.   Prepared  for FDA  under
Contract No. 233-77-2119.   (Cited 1n U.S.  EPA, 1981)

ACGIH  (American  Conference  of Governmental  Industrial  Hyg1en1sts).   1986.
Threshold  Limit  Values  for  Chemical  Substances  1n  the  Work  Environment
Adopted  by  ACGIH  with  Intended  Changes  for  1986-1987.   Cincinnati, OH.
p. 32.

Adams,  E.N.. H.C.  Spencer, V.K.   Rowe,  D.D.  HcColHster  and  D.D.  Irish.
1951.   Vapor toxldty  of  trlchloroethylene  determined  by  experiments  on
laboratory  animals.    Am.   Ned.  Assoc.   Arch.  Ind.   Hyg.  Occup. Med.   4:
469-481.  (Cited  1n U.S.  EPA, 1982)

Axelson, 0.  1986.  Ep1dem1olog1cal studies of workers with exposure to trl-
chloroethylene tetrachloroethylene.   Toxlcol.  Environ.  Sc1.   (Netherlands).
12: 223-230.

Axelson,  0.,  K.  Anderson,  C.  Hogstedt,  et al.   1978.   A cohort  study  on
trlchloroethylene  exposure  and cancer mortality.  J.  Occup.  Med.  20: 194.
(Cited 1n U.S. EPA, 1985)

Baden, J.M., M.  Kelley, R.I. Mayze and V.F.  Simmon.   1979.  Mutagenlclty of
Inhalation anesthetics: Trlchloroethylene,  dlvlnyl  ether,  nitrous oxide and
cyclopropane.  Br.  0.  Anaesth.   51: 417-421.  (CHed  1n U.S. EPA,  1981)

0046H                               -51-                             03/08/88

-------
Bardodej, Z.  and J.  Vyskoch.   1956.   The  problem of  trlchloroethylene In
occupational medicine.  AHA Arch.  Ind. Health.  13: 581-592.  (CHed In U.S.
EPA, 1980a)

Bartsch, M., C.  Malavellle, A.  Barbln and G.  Planche.  1979.  Hutagenlc and
alkylatlng  metabolites   of haloethylenes,  chlorobutadlenes  and  dlchloro-
butenes  produced by  rodent  or human liver  tissues.   Arch. Toxlcol.   44:
249-277.  (CHed In  U.S.  EPA,  1981)

Bellies, R.B.,  D.J.  Bruslck and  F.J.  Heeler.  1980.   Teratogenlc-mutagenlc
risk  of  workplace  contaminants:   Trlchloroethylene,  perchloroethylene  and
carbon  dlsulflde.   Prepared for  U.S.  DHEW under  Contract  No.  210-77-0047.
(CHed 1n U.S.  EPA,  1981, 1982)

Bell, Z.  1977.  Written communication with contractor reports of: (a) Domi-
nant lethal  study with  trlchloroethylene  1n albino rats  exposed via Inhala-
tion,  February  9,  1977,  and  (b) Teratogenlc  study via   Inhalation  with
TMchlor 132,  trlchloroethylene  1n albino  rats,  Harch  8,  1977.   (CHed 1n
U.S. EPA, 1981, 1982)

Bell,  Z.G.,  K.3.  Olson and  T.G.  Benya.    1978.   Final  report of  audit
findings  of  the  HanufactuMng  Chemists  Association   (HCA):  Administered
trlchloroethylene  (TCE)   chronic   Inhalation  study at   Industrial  B1o-Test
Laboratories,  Inc.,  Decatur, IL.   Unpublished.   (Cited 1n  U.S. EPA, 1981)

Blair, A.,  P.  Decoufle and  D. Grauman.  1979.  Causes of  death among laundry
and dry  cleaning workers.  Am. J.   Pub.  Health.  69: 508-511.  (CHed In U.S.
EPA, 1985)

0046H                               -52-                            03/08/88

-------
Bronzettl,  G.f  E. Zelger  and D.  Frezza.   1978.  Genetic  activity of  tr1-
chloroethylene 1n yeast.   3.  Environ.  Pathol.  Toxlcol.  1: 411-418.   (Cited
1n U.S. EPA, 1981)

Buben, J.A. and  E.J.  O'Flaherty.   1985.   Delineation of the role of metabo-
lism  1n   the  hepatotoxlclty  of  tMchloroethylene and  perchloroethylene: A
dose-effect study.  Toxlcol.  Appl.  Pharmacol.   78: 105-122.  (Cited In  U.S.
EPA, 1985)

Callahan,  M.A.,   H.W.   Sllmak,  N.W.  Gabel,  et  al.   1979.   Water-Related
Environmental  Fate of 129 Priority Pollutants, Vol.  II.  U.S. EPA,  Office of
Mater  Planning  and  Standards, Office  of Mater  and  Maste  Management,  Wash-
ington, DC.  EPA 440/4-79-029b.

Cornish,   H.H.  and J.  Adefuln.   1966.   Ethanol  potentlatlon  of halogenated
aliphatic  solvent  toxldty.  Am.  Ind.  Hyg. Assoc.  3.  27: 57.   (Cited In
U.S. EPA, 1980a)

Daniel,  J.M.   1963.   The  metabolism of  Cl-labeled  trlchloroethylene  and
tetrachoroethylene In  the  rat.   Blochem.  Pharmacol.   12: 795.   (CHed In
U.S. EPA, 1980a)

Defalque, R.J.   1961.   Pharmacology  and  toxicology of  trlchloroethylene.  A
critical   review  of  the  world  literature.   Clln.  Pharm.  Ther.   2:   665.
(Cited 1n U.S. EPA,  1980a)
0046H                               -53-                            03/08/88

-------
DeKant, W., M.  Hetzler  and D.  Henschler.   1984.   Novel metabolites of  tr1-
chloroethylene  through  dechlorlnatlon reactions  In  rats,  mice  and humans.
Blochem. Pharmacol.   33: 2021-2027.   (Cited  In  U.S. EPA,  1985)

Dhumer,  K.G.,   et  al.    1957.   Cardiac  Irregularities  1n  trlchloroethylene
poisoning.   Influence  of  various   drugs  on  arrhythmia.   Acta   Anaesth.
Scandlnav.  1: 121.   (Cited In U.S.  EPA,  1980a)

Dorfmueller, D., et  al.  1981.   Evaluation  of teratogenlclty and behavioral
toxlclty  with  Inhalation  exposure  of  maternal   rats  to  trlchloroethylene.
Toxicology.  14: 153-166.  (Cited 1n U.S.  EPA,  1980a,  1982)

FahMg,  R.   1977.   The  mammalian  spot  test (Fellfleckentest)  with  mice.
Arch. Toxlcol.  38:  87-98.  (Cited 1n  U.S. EPA, 1981)

Ferguson,  R.K.  and  R.J.  Vernon.   1970.   Trlchloroethylene  In  combination
with CNS  drugs.  Effects  on visual-motor tests.   Arch. Environ. Health.   2:
462.  (Cited In U.S.  EPA, 1980a)

Fukada,  K.,  K.  Takemoto  and  H. Tsuruta.  1983.   Inhalation cardnogenlclty
of trlchloroethylene 1n mice and rats.  Ind.  Health.   21:  243-254.

George,  J.D.,   J.R.  Reel,  C.B.  Myers, A.D.  Lawton  and  J.C.  Lamb.   1986a.
Trlchloroethylene:  Reproduction  and fertility assessment  In  CD-I mice  when
administered  In the  feed.   Prepared by Research Triangle  Institute,  Research
Triangle  Park,  NC for  the National  Toxicology   Program.   NTP  86-068,  NTIS
PB86-173150.
0046H                               -54-                             03/08/88

-------
George,  J.D.,  3.R. Reel,  C.B.  Myers  and A.D.  Lawton.   1986b.   TMchloro-
ethylene:  Reproduction  and  fertility  assessment  In F344  rats  when  admin-
istered  1n the  feed.   Prepared  by  Research Triangle  Institute,  Research
Triangle  Park,  NC for  the National  Toxicology  Program.   NTP  86-085,  NTIS
PB86-190782.

Gessner,  P.K.  and B.E.  Cabana.   1970.   A  study of  the  Interaction of  the
hypnotic  effects  and  of  the  toxic  effects  of  chloral  hydrate and  ethanol.
J. Pharmacol.  Exp. Ther.  174: 247.   (Cited In U.S.  EPA,  1980a)

Green,  T.  and  M.S.  Prout.   1984.   Species  differences  In   response  to
trlchloroethylene.  II.  B1otransformat1on 1n rats and mice.  Toxlcol.  Appl.
Pharmacol.  (In press)  (CHed In  U.S.  EPA,  1985)

Haglld,  K.G.,  C.  Br1v1ng,  H.A.  Hansson  et  al.  1981.   Trlchloroethylene:
Long-lasting changes  1n  the  brain  after rehabilitation.   Neurotoxlcology.
2: 659-673.

Hansch,  C. and   A.J.  Leo.   1985.   MedChem  Project Issue  No.  26,  Pomona
College, Claremont, CA.

Healy,  T.E.,  T.R. Poole  and A.  Hopper.   1982.  Rat  fetal  development  and
maternal exposure to trlchloroethylene at  100 ppm.   Br.  J.  Anaesth.   54:  337.

Henschler, D.,  E. Eder, T. Heudecker and  M.  Metzler.  1977.  CardnogenlcHy
of  trlchloroethylene:  Fact   or   artifact?   Arch.   Toxlcol.    37:   233-236.
(Cited In U.S.  EPA, 1981)
0046H                               -55-                             03/08/88

-------
Henschler, D., W.  Romen,  H.M. Elasser, D.  Relchert,  E.  Eder and Z.  Radwan.
1980.  Carclnogenldty study of trlchloroethylene by  long-term  Inhalation  In
the animal species.  Arch.  Toxlcol.   43: 237-248.   (Cited  1n  U.S..  EPA,  1981)

Klmmerle, G.  and  A.  Eben.   1973.  Metabolism,  excretion,  and toxicology  of
trlchloroethylene  after   Inhalation.    1.   Experimental   exposure  on   rats.
Arch. Toxlcol.  30: 115-126.   (Cited  1n U.S.  EPA,  1982)

Kjellstrand,  P.,   M.  Kanje,  L.   Mansson  et  al.  1981.    Trlchloroethylene:
Effects  on  body  and organ  weights  1n mice,  rats and gerblls.   Toxicology.
21: 105-115.

Kjellstrand,  P.,   B.  Holmqulst,   P.  Aim  et  al.  1983a.    Trlchloroethylene:
Further  studies of the effects on body and organ weights  and plasma  butyryl
chollnesterase activity 1n  mice.   Acta  Pharmacol.  Toxlcol.  53:  375-384.

Kjellstrand,  P., B.  Holmqulst, N.  Mandahl  and H. Bjerklmo.  1983b.   Effects
of  continuous  trlchloroethylene  exposure  on  different  strains  of  mice.
Acta. Pharmacol.  Toxlcol.   53: 369-374.

Kyrklund, T.,  P.  Kjellstrand and  K.G. Haglld.   1985.   The  development and
rehabilitation  of changes  among  polyunsaturated  fatty   acids  In  cerebral
cortex   ethanolamlne  phosphoglycerlde,   following   exposure   of  rats   to
trlchloroethylene.  Acta  Neuro.  Scand.   72:  264.

LopMeno, N., R.  Barale,  A.M.  Rossi,  et  al.   1979.  .In vivo  mutagenlcHy
studies  with  trlchloroethylene  and  other   solvents  (preliminary  results).
Unpublished.  (Cited In U.S. EPA,  1981)

0046H                               -56-                             03/08/88

-------
Luz,  A.   1977.    The  range  of  Incidence  of  spontaneous  neoplastlc  and
nonneoplastlc  lesions  of  the  laboratory  mouse.   Z.  Versuchstlerkd.   19:
342-343.  (Cited In U.S. EPA,  1981)

Maltonl,  C.,  G.  Lefemlne  and  G.  Cottl.   1986.   Experimental  research  on
trlchloroethylene  cardnogenesls.   Arch.  Res.   Industrial   Cardnogenesls
Series.   C.  Maltonl  and  M.A. Mehlman,  Ed.  Vol.  V.   Princeton  Scientific
Publ. Co. Inc., Princeton,  NY.  393  pp.  (Cited  1n  U.S.  EPA, 1987)

Hanson, J.M., H. Murphy, N. Rlchdale and  M.K. Smith.   1984.  Effects  of oral
exposure  to  trlchloroethylene on female  reproductive  function.  Toxicology.
32(3): 229-242.

Monster,  A.C., G.  Boersman and W.C.  Duba.   1976.   Pharmacoklnetlcs  of  trl-
chloroethylene 1n  volunteers: Influence of workload and  exposure  concentra-
tion.  Int. Arch.  Occup.  Environ. Health.  38:  87-102.   (Cited  In  U.S.  EPA,
1985)

NCI  (National Cancer  Institute).  1976.   Bloassay  of Trlchloroethylene.   NCI
Cardnogenesls Tech.  Rep.  Ser.  No. 2.   197  p.    [Also publ.  as DHEW  (NIH)
76-802]

NLM  (National  Library  of  Medicine).   1987.   National Library  of Medicine
Hazardous Substance Data Base.  Report  No. 133.   On line.

Nomlyama, K.,  H.  Nomlyama and  H. Aral.   1986.   Reevaluatlon of  subchronlc
toxldty of trlchloroethylene.  Toxlcol. Lett.   31  (Suppl.): 225.   (abstract)


0046H                               -57-                            03/08/88

-------
NTP  (National  Toxicology  Program).   1982.   Cardnogenesls   bloassay   of
tMchloroethylene.   NTP Tech.  Rep.  Ser. No. 81-84.   [Also published as  NIH
82-1799.]  (Cited 1n U.S.  EPA,  1985)

NTP (National Toxicology  Program).   1986.   NTP Board Draft Technical Report
on  the  Toxicology  and  Cardnogenesls  Studies of  Trlchloroethylene In Four
Strains  of  Rats (ACI,  August, Marshall,  Osborne-Hendel)  (Gavage  Studies).
NTP Tech. Rep. Ser.  No.  273.   [Also  published as NIH  86-2529.]

OSHA  (Occupational  Safety and  Health  Administration).   1985.   Occupational
Health Standards.  29 CFR  1910.000.

Page, N.P.  and  J.L.  Arthur.   1978.   Special  Occupational  Hazard Review  of
Trlchloroethylene.   79 p.   DHEW NIOSH 78-130  (Cited  1n  U.S. EPAI(  1985)

Pessayre,  D.,  B. Cobert,  V.   Descatolre,  et al.   1982.   Hepatotoxlclty  of
trlchloroethylene-carbon tetrachlorlde mixtures  In  rats.   A possible conse-
quence  of  the  potentlatlon  by trlchloroethylene of  carbon   tetrachlorlde-
Induced  Upld  peroxldatlon  and  liver  lesions.   Gastroenterology.  83(4):
761-762.

Prendergast,  J.A.,   R.A.  Jones,  L.J.   Jenkins,  Jr.   and   J.  Slegel.   1967.
Effects  on  experimental animals  on  long-term Inhalation  of  trlchloroethyl-
ene,  carbon  tetrachlorlde,   1,1,l-tr1chloroethane,   dlchlorodVfluoromethane
and  I,l-d1chloroethylene.   Toxlcol.  Appl.  Pharmacol.   10: 270-289.   (Cited
In U.S.  EPA, 1982)
QQ46H                               -58-                             03/08/88

-------
Prout,  M.S.,   W.M.  Provan  and  T.   Green.   1985.   Species  differences  In
response  to  trlchloroethylene.   I.  Pharmacoklnetlcs  In  rats  and  mice.
Toxlcol. Appl. Pharmacol.  79:  389-400.   (Cited 1n U.S. EPA,  1985)

Sanders, V.M.,  A.N.  Tucker,  K.L. White  Jr.,  et al. 1980.  Humoral  and  cell
mediated Immune  status   In mice exposed to drinking  water.   Toxlcol.  Appl.
Pharmacol.   62: 358-368.

Schwetz,  B.A.,  B.K.J.   Leong   and   P.3.  GehMng.    1975.   The  effect  of
maternally  Inhaled  trlchloroethylene,  perchloroethylene,  methyl chloroform,
and methylene  chloride  on  embryonal  and fetal  development In mice  and  rats.
Toxlcol. Appl. Pharmacol.  32:  84-96.  (Cited  1n U.S.  EPA,  1982)

Seage,  A.J.  and M.H. Burns.   1971.   Pulmonary  edema  following exposure  to
trlchloroethylene.  Med. J. Aust.  2: 484.   (Cited 1n  U.S.  EPA,  1980a)

Simmon, V.F.,  K.  Kauhanon and  R.G.  Tardlff.    1977.   Mutagenlc activity  of
chemicals Identified 1n  drinking water.  In: Progress  In  Genetic Toxicology,
D.  Scott,  B.A. Bridges  and F.H.  Solves,  Ed.   Elsevler/North  Holland  Bio-
medical Press, Amsterdam,  p.  249-258.   (Cited  1n U.S.  EPA, 1981)

Sladk-Erben, R., R. Roll, G. Franke and H. Uehleke.   1980.   Trlchloroethyl-
ene vapours  do not produce  dominant lethal mutations In male mice.   Arch.
Toxlcol.  45: 37-44.  (Cited In U.S.  EPA, 1981)

Taylor, H.  1936.   Experiments  on the physiological properties  of  trlchloro-
ethylene.  J. Ind. Hyg.  Toxlcol.  18: 175-193.   (Cited  In U.S.  EPA,  1982)


0046H                               -59-                             03/08/88

-------
Tola, S., R.  VHhuner,  E.  Jarulnen and M.L. Korkale.  1980.  A  cohort  study
on  workers   exposed  to  trlchloroethylene.   J.   Occup.  Hed.   22:  737-740.
(Cited In U.S. EPA, 1985)

Tucker, A.N.,  V.M.  Sanders,  D.W.  Barnes,  et  al.   1982.  Toxicology  of  trl-
chloroethylene 1n the mouse.   Toxlcol.  Appl. Pharmacol.   62(3):  351-357.

U.S.  EPA.    1980a.   Ambient  Water  Quality Criteria  for  Trlchloroethylene.
Prepared by  the  Office  of  Health  and  Environmental  Assessment,  Environmental
Criteria and Assessment Office, Cincinnati, OH for  the Office of Water  Regu-
lations and Standards, Washington, DC.   EPA 440/5-80-077.  NTIS  PB 81-117871.

U.S.  EPA.   1980b.   Guidelines  and Methodology  Used  In  the Preparation  of
Health  Effects  Assessment Chapters  of the Ambient  Water Quality  Criteria.
Documents.  Federal Register.  45: 49347-49357.

U.S.  EPA.  1981.   The Carcinogen  Assessment Group's Carcinogen  Assessment  of
Trlchloroethylene.   Prepared  by  the   Office  of  Health  and  Environmental
Assessment, Carcinogen Assessment Group, Washington,  DC.   Internal Draft.

U.S.  EPA.    1982.   Hazard Profile  for Trlchloroethylene.   Prepared by  the
Office  of  Health  and  Environmental Assessment,  Environmental   Criteria  and
Assessment Office, Cincinnati, OH  for  the  Office  of Solid  Waste, Washington,
DC.
0046H                               -60-                             03/08/88

-------
U.S. EPA.  1983.   Review  of  lexicological Data In Support  of  Evaluation  for
Carcinogenic   Potential  of  TMchloroethylene.   Prepared  by   the  Office  of
Health  and  Environmental  Assessment,  Carcinogen  Assessment  Group,  Wash-
ington, DC for the Office of Solid Waste  and  Emergency Response,  Washington,
DC.

U.S. EPA.  1984.   Methodology  and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Toxlclty  Data.  Prepared by  the Office  of Health
and Environmental  Assessment,  Environmental  Criteria and  Assessment  Office,
Cincinnati, OH for  the  Office of  Solid  Waste and Emergency Response,  Wash-
ington, DC.

U.S. EPA.  1985.   Health  Assessment Document for TMchloroethylene.   Office
of  Health  and Environmental  Assessment,  Environmental Criteria and  Assess-
ment  Office,   Research  Triangle   Park,   NC.   EPA  600/8-82-006F.   NTIS  PB
84-162882.

U.S.  EPA.   1986a.   Guidelines   for  Carcinogen  Risk  Assessment.    Federal
Register.  51: 33992-34003.

U.S.  EPA.   1986b.   Drinking  Water Criteria  Document  for  TMchloroethylene
(Draft).  Office of Drinking  Water, Washington,  DC.   NTIS PB86-118106.

U.S.  EPA.   1986c.   Reportable  Quantity  Document   for  TMchloroethylene.
"Evaluation of Potential  Cardnogenlclty  of  Trlchloroethylene."   Prepared  by
Office  of  Health  and Environmental Assessment, Carcinogen  Assessment Group,
Washington,   DC   for  the  office   of   Emergency  and   Remedial   Response,
Washington, DC.  December, 1986 Draft.

0046H                               -61-                              03/08/88

-------
U.S. EPA.  1987a.  Integrated Risk Information System (IRIS).  Risk Estimate
for  Carcinogens   for   Trlchloroethylene.    On-Hne.    (Preparation  date:
2/18/87).   Office  of  Health  and  Environmental  Assessment,  Environmental
Criteria and Assessment Office,  Cincinnati,  OH.

U.S. EPA.  1987b.  Addendum to the Health Assessment Document for Trlchloro-
ethylene:  Updated  Carclnogenldty  Assessment  for  Trlchloroethylene.   EPA
600/8-82/006FA.   External  Review Draft.

Van  Duuren,  B.L.,  B.H. Goldschmldt,  G.  Lowengart,  et  al.   1979.  Carclno-
genldty  of  halogenated  oleflnlc  and aliphatic  hydrocarbons 1n  mice.   J.
Natl. Cancer Inst.   63: 1433-1439.   (Cited 1n  U.S.  EPA,  1981)

Van Duuren, B.L., S.A. Kline, S. Melchlonne and  I. Seldman.  1983.  Chemical
structure and carclnogenldty  relationships  of  some chloroalkane oxides and
their parent aleflns.   Cancer  Res.   43: 159-162.   (Cited 1n U.S.  EPA, 1985)

Wilson,  J.T.,  C.G.  Enfleld, W.J.  Dunlop, R.L.   Cosby,  D.A.  Foster  and L.B.
Baskln.  1981.  Transport and fate of selected organic  pollutants 1n a sandy
soil.  J. Environ.  Qual.   10:  501-506.

York,  R.,  B. Sowry,  L.  Hastings and  J.  Hanson.  1981.   Evaluation  of the
prenatal toxldty of methyl chloroform.   Tox1colog1st.   1(1): 28 (abstract).
(CHed In U.S. EPA, 1980a, 1982)

Zenlck  H.,  K.   Blackburn.  E.  Hope.  N.   Rlchdale  and  M.K.  Smith.   1984.
Effects  of trlchloroethylene exposure on  male reproductive function 1n rats.
Toxicology.  31(3-4):  237-250.

0046H                               -62-                             03/08/88

-------
Z1gl1o,  G.,  G.M.  Fara,  G.  BeltramelH  and  F.  Pregllasco.   1983.    Human
environmental exposure  to  tMchloro-  and  tetrachloroethylene from water and
air In Milan, Italy.   Arch.  Environ.  Contam.  Toxlcol.   12(1):  57-64.

Zoeteman, B.C.J., K.  Harmsen,  G.B.H.J.  Llnders,  C.F.H. Horra and W.  Slooff.
1980.  Persistent organic  pollutants  1n river water  and groundwater  of the
Netherlands.   Chemospnere.   9:  231-249.
0046H                               -63-                            03/09/88

-------
0046H
















4>
VI
i
4>
^^

0»
e
*^
1^
•»
4>
CB
41
>»
X *
X ^j
S *
Z °
£ 1
a. f
S
u
h-
tk
o
4fc»
41
^^
.a
*9
^
>t
L»
S
C
g
CO























41
U
e
4i
u.
4*
(fck
4>
OK






4)
a.
o
f~
l_ CO
0
JX
* VI
D'QC

**
MM
e
=5






+*
U
ft\
V
a.
ib
LU









41
^- U
 VI
C O
4* Q.
S X
•*• LU
t. N.
4> 4>
O. V>
X 0
LU a




u

e
4) >»
O> U
o e
c a>
u o
u. a.
<9
u
.a
. r>» LO
* *"* * * CO 00
i— C «O en en
19 O 00 f— i—
4-* on .» .»
4-> ^ I— • vO CM »
4> flj «C r-> ao <
Z -Q- on on Cu
(Q • LU ^ r— LU
^ •• ^
ITJ f) >9 • • • «
^00 CO I— I CL CO
3 en *• • cj t— •
LU f— 4» 3 Z Z 3


H .
1

« >»
— (H
"1 *W
i -o
« a>
S .*
-^ ^
? !*
*BBf •«•*
« <1
O O
r— r-
X X
P» r**
• •




l_
19
r«
VI 3
fa* ^^
§r- *
OJ C»
v^ c
3 U O
** o e
*^ «^»
o* »
CL CO <«
co -o
O » —
A e
3
•1
I 4>
^"* ^~
>Ȥ.
TS S
•o -^
^ VI
0>
^^ m
Jft >w
O> vi
s*»
— 0
• 4)
O 
X L.
wD
1/1
O -^
*- f
h-
•W
«
** •
b. O>
4> ^
>
C 0
o r*
u
u-
4) 0
^
4->
>lf
SO) •
— 4>
.—
 O vi
A 4"
1/1
•^ m ^*
•^ »v ^
fi 0
*•* TQ ^
C 4->
• «o a.
V> LB
< « 0
LU S <"
Z .0
O  e
«- u- rg
^- O
U 4)
ra 4) "O
CU E 3
3 r-
JZ r- 0
4-> O C
*cl
COO
o — c
VI 1-»
»- ig 1/1
u, r- 4>

-------
U.S. EPA.  1987a.  Integrated Risk Information System (IRIS).  Risk Estimate
for  Carcinogens   for   TMchloroethylene.    On-Hne.    (Preparation   date:
2/18/87).   Office  of  Health  and  Environmental  Assessment,  Environmental
Criteria and Assessment Office, Cincinnati, OH.

U.S. EPA.  1987b.  Addendum to the Health Assessment Document for TMchloro-
ethylene:  Updated  CardnogenlcHy  Assessment  for  TMchloroethylene.   EPA
600/8-82/006FA.   External  Review  Draft.

Van Duuren,  B.L.,  B.M.  Goldschmldt,  G.  Lowengart,  et al.   1979.   Cardno-
genlcHy  of  halogenated   oleflnlc  and aliphatic  hydrocarbons  1n  mice.   J.
Natl.  Cancer Inst.  63: 1433-1439.   (Cited  1n  U.S. EPA, 1981)

Van Duuren, B.L., S.A.  Kline, S.  Melchlonne and I. Seldman.  1983.   Chemical
structure and carclnogenlcUy relationships  of  some chloroalkane oxides  and
their  parent aleflns.  Cancer  Res.   43: 159-162.   (Cited 1n U.S. EPA, 1985)

Wilson,  J.T., C.G.  Enfleld, H.J.  Dunlop,  R.L.  Cosby, D.A.  Foster  and  L.B.
Baskln.  1981.  Transport and fate of selected organic pollutants 1n a sandy
soil.   J. Environ.  Qua!.   10:  501-506.

York,   R.,  B. Sowry,  L.  Hastings and  J.  Hanson.   1981.    Evaluation  of  the
prenatal toxldty of methyl chloroform.  lexicologist.  1(1): 28 (abstract).
(Cited 1n U.S. EPA, 1980a, 1982)

Zenlck  H.,  K.   Blackburn,  E. Hope.   N.  Rlchdale  and H.K.  Smith.   1984.
Effects  of trlchloroethylene exposure on male reproductive function 1n rats.
Toxicology.  31(3-4):  237-250.

0046H                               -62-                             03/08/88

-------
Zlgllo,  G.,  G.H.  Fara,  G.  Beltramelll  and F.  Pregllasco.   1983.   Human
environmental exposure  to  tMchloro- and  tetrachloroethylene from water and
air In Milan, Italy.   Arch. Environ.  Contam.  Toxlcol.  12(1): 57-64.

Zoeteman, B.C.3., K. Harmsen,  J.B.H.J.  Llnders,  C.F.H.  Morra and W. Slooff.
1980.  Persistent organic  pollutants  In river water  and  groundwater  of the
Netherlands.   Chemosphere.  9:  231-249.
0046H                               -63-                             03/08/88

-------
-------



















fll
V
irt
pu.
s
K
fli
w
jj

m
w

VI
a
a;
c
tt
f^
>»
_^
x £
§ 3
S 1
Q. ^
< 0
*""
w
UM
P**
^
0
^i

O)
jQ
IB
>>
l_
K
J5
3
CO


























O)
U
c
o>
U>
0>
(^
0)
oe









0)
Q.
O

t- CO
0
*
* VI

eF5

**
c






^^
u
4>
IU.

^ (_
 I/I
C O
O) Q.
E X
•^ LU
U "V
O) O)
Q. i^
X O
LU Q





U

c
o> >>
D> u
o c
c o>
u o
u a.
"9
U
ja
• r-
• *^ • • oo
i— C tO on
«O O 00 r-
•M en

O) ro <
X *O.
fO . LU
T3 • * ^™
*D CO «O •
H CO CO
3 CT> <-> •
LU r— O) 3







*
H
^^
n
S
V.
o
-i_r
«
1
O
r—
X
•^^
r*
•






i/i
^

g
3
•>->
O>
e
3







E
Q.
O.
O
O
CM
1
0
LO







C
o

**
•B
TJ
f

Ifi
00
en

• • • •
vO CM •
f— CO <
en on O.
r— r— LU
» • •
1-1 a. 
tj t— •




rt
1

>.
«O
•o
•N.
CD
J<
•N.
I

M
1
O
X
^




u
1C

3
r— • ra
a; 6
u o
0 C
•f «^
t
CO 
en ^t
*o °*^
i— O>
i— E












,_

>»••-
A C
3
f4
1 0)
•~«i—
>> a.
T5 E
•o »-
>^ irt
O>
^ 
i ^>
O «4-
r- 0)
X u,
vO
(/i
O —
-U £
1—
•o
a>
4-> •
i_ en
a> ^
>
e o
o r^
u
^i
>-C
gen .
«- a>
U H->
O) 3 g
r- >» —
ItJ -O H-»
> O ut
JQ u
(^
•^ IQ C
£ O
** -o «-
e •*•
• «O CL
i/> i_
<: » o
LU E VI
z ^
O T3
U CM
a> c
w- «- «O
i— O
u a>
fVi rti T^
•w W ^3
a> S 3
3 i—
£ r- 0
l-> O C
•^ > «^
C •*-«
COO
o — c
VI •*•>
*- IB V«
U. ^- O)
IO IQ O
t£ -O
c
o — -o
u c
C I?
u- 13
o E c
3 0
VI £ w-
a> t->
i/i rQ ro
O E
a. o> i_
t_ C O
3 — «-
CL E VI
3^
^H
U I/I IQ
O VI L.
u*» ^9 ^^
«
0046H
-64-
03/08/88