January 1992
y
                                      FINAL
                         DRINKING WATER CRITERIA DOCUMENT
                                        FOR
                               1,1,2-TRICHLOROETHANE
                     Health  and  Ecological  Criteria Division
                         Office of Science and Technology
                                  Office of Water
                       U.S. Environmental Protection Agency
                               Washington,  DC  20460
                                 HEADQUARTERS LIBRARY
                                 ENVIRONMENTAL PROTECTION AGENCY
                                 WASHINGTON, D.C. 20460

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                             TABLE OF CONTENTS
                                                                         Pace
     LIST OF FIGURES 	         v
     LIST OF TABLES	         v
     LIST OF ABBREVIATIONS   	  	        vi
     FOREWORD	' .	      viii

  I. SUMMARY	       1-1
 II. PHYSICAL AND CHEMICAL PROPERTIES  	 ,      II-l
     A.  General  Properties.	  .  .      II-l
     B.  Manufacture  and  Use	      II-l
        1.   Synthesis  of 1,1,2-Trichloroethane   	      II-l
        2.   Production and Use  	      II-4
     C.  Environmental  Fate	      II-4
     D.  Summary	      II-7
III. TOXICOKINETICS  .	     III-l
     A.  Absorption and Eliminaton	     III-l
     B.  Tissue Distribution  	     III-3
     C.  Metabolism	     III-3
     D.  Bioaccumulation  and  Retention  	     III-7
     E.   Summary	     III-9
 IV. HUMAN EXPOSURE	      IV-1
  V. HEALTH EFFECTS IN ANIMALS	V-l
     A.  Short-term Exposure  	       V-l
        1.   Lethality	       V-l
        2.   Other Effects	       V-8
             a.   Dermal/Ocular Effects  	       V-8
             b.   Biochemical/Pathological  Effects  	       V-9
     B.  Long-term Exposure  	      V-14
     C.  Reproductive/Teratogenic Effects   	      V-18
     D.  Mutagenicity	      V-19
                                     iii

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                        TABLE OF CONTENTS (continued)
                                                                          Pace
         1.  Gene Mutation Assays  (Category  1)  .	      V-20
         2.  Chromosome Aberration Assays  (Category Z)  	      V-20
         3.  Other Genotoxic Effects  (Category  3)	      V-20
             a.  Mammalian cell transformation  	      V-20
             b.  DNA binding	      V-21

      E.  Carcinogenlcity	'.'	      V-21
      F.  Summary	.	      V-24

  VI.  HEALTH EFFECTS  IN HUMANS	      VI-1

      A.  Clinical Case Studies  	      VI-1
      B.  Epidemiological  Studies 	  	      VI-2
      C.  High-Risk Populations	      VI-3
      0.  Summary	      VI-3

 VII.  MECHANISMS OF TOXICITY	     VIM

      A.  Metabolic Activation	     VIM
      *..  Binding to ONA,  RNA, Proteins, and  Lipids	     VII-4
         r"ee Radical Formation	     VII-6
      ...  Summary	     VII-7

.ill.  QUANTIFICATION  OF TOXICOLOGICAL  EFFECTS 	    VIII-1

      A.  Procedures for Quantification of  Toxicological Effects.  .  .    VIII-I

         1.  Noncarcinogenic Effects  	  ,  .    VIII-1
         2.  Carcinogenic Effects   	    VIII-3

      B.  Quantification of Noncarcinogenic Effects for  1,1,2-TCE  .  .    VIII-5

         1.  One-day Health Advisory  	    VIII-5
         2   Ten-day Health Advisory  	    VIII-6
         3.  Longer-term  Health Advisory 	    VIII-7
         4.  Reference Oose and Drinking Water  Equivalent Level.  .  .    VIII-8

      C.  Quantification of Carcinogenic Effects for 1,1,2-TCE.  .  .  .    VIII-9

         1.  Categorization of  Carcinogenic  Potential	    VIII-9
         2.  Quantitative Carcinogenic Risk  Estimates	VIII-11

      0.  Existing Guidelines and Standards 	   VIII-11
      E.  Summary	   VIII-11

  IX.  REFERENCES	      IX-1
                                      iv

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                                LIST OF  FIGURES

Figure No.                                                                Page
   III-l    Proposed Metabolic Pathway for l,l,2rTCE  	 8    III-9

                                LIST OF TABLES
Table No.
  II-l      Physical and Chemical  Properties  of  1,1,2-TCE	     II-2
   V-l      Summary of Acute Lethality of 1,1,2-TCE  	      V-2
   V-2      Summary of Short-term Effects of  1,1,2-TCE 	      V-5
   V-3      Summary of Long-term Exposure Toxldty of 1,1,2-TCE  .  .  .     V-15
   V-4      Occurrence of Tumors From 1,1,2-TCE   	     V-23
VIII-1      Summary of Quantification of Toxicological  Effects
            for 1,1,2-TCE  	  VIII-12

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                             LIST OF ABBREVIATIONS
ADI
AFC
ALA-dehydratase
DTH
DWEL
ET

g
gAg
GSH
HA/HAs
IARC
IgH
ip
kg
K.
K,
LCM
LDM
LTSO
tnCI
MCLG
MFO
mg
ml
mM
nrool
mmol/kg
mol
MTD
NADPH
NAS
NCI
NOAEL
ODW
OSHA
PAH
PBB
PEC
pmol/min/mg
ppb
ppm
ppt
Acceptable Dally Intake
antibody-forming cells
aminolevul1n1c acid dehydratase
delayed-type hypersenslvity
Drinking Water Equivalent Level
Median Effective Concentration
Median Effective Dose
Median Effective Time
potency factor
gram(s)
gram(s)/k11ogram
glutathlone
Health Advisory/Health Advisories
International Agency for Research on Cancer
ImmunoglobuHn M
intraperltoneal
kllogram(s)
Michaelis-Menton constant
substrate or dissociation constant
Median Lethal Concentration
Median Lethal Dose
35% Lethal Dose
Lowest Observed Lethal Dose
Median Tolerance Limit
millicurie(s)
Maximum Contaminant Level Goals
mixed-function oxygenases(s)
milligram(s}
milligram(s)/ki1ogram
milligram(s)/1iter
minillter(s)
millimolar
millimole(s)
mil11mole(s)/k1logram
mole(s)
Maximum Tolerated Dose
nicotinamide adenine dlnucleotlde phosphate
National Academy of Sciences
National Cancer Institute
No-Observed-Adverse-Effect Level
Office of Drinking Water
Occupational Safety and Health Administration
p-aminohippur1c acid
polybrominated biphenyls
peritoneal exudate cells
p1comole/minute/mi11igram
parts per billion
parts per million
parts per trillion
s
          vi

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                       LIST OF ABBREVIATIONS  (continued)
PSP
RfD
RQ
SAP
sc
SDH
SGOT
SGPT
sRBC
1,1,2-TCE
TO*
TLV-TWA
H«
UF
P9
fig/cm/hr
Vmax
phenolsulfonaphthale1n
Reference Dose
Reportable. Quantity
serum alkaline phosphatase
subcutaneous
sorbltol dehydrogenase
serum glutamlc-oxaloacetlc transamlnase
serum glutamlc-pyruvlc transamlnase
sheep red blood cells
1,1,2-tr1chloroethane
dose that will halve the probability that an
 animal will remain tumor*free through Its
 Hfespan
Threshold Limit Value-Time Weighted Average
mlcrocurle(s)
uncertainty factor
microgram(s)
m1crogram(s)/square centimeter/hour
mlcrogram(s)/m111111ter
mi crograms/1i ter
mlcroliter(s)
mlcromolar
mlcromole(s)
maximal velocity

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                                   FOREWORD
     Section 1412 (b)(3}(A) of the Safe Drinking Water Act, as amended 1n 1986,
requires the Administrator of the Environmental Protection Agency  to  publish
Maximum Contaminant Level Goals (MCLGs) and promulgate National Primary Drinking
Water  Regulations  for  each  contaminant,  which,  1n  the  judgment  of  the
Administrator, may have an  adverse effect on public health  and which Is known or
anticipated to occur 1n public water systems.  The HCLG 1s nonenforceable and 1s
set at a level  at which  no known or anticipated adverse health effects 1n humans
occur and which allows for  an adequate margin  of safety.  Factors considered In
setting the MCLG Include health effects data and sources of exposure other than
drinking water.

     This  document provides  the health  effects   basis  to  be considered  1n
establishing the MCLG.   To achieve this objective, data  on pharmacok1net1cs,
human exposure, acute and chronic toxldty to  animals and humans, epidemiology,
and mechanisms of toxldty  were evaluated.   Specific  emphasis 1s  placed  on
literature data providing dose-response Information. Thus, while the literature
search and evaluation performed 1n support of this document was comprehensive,
only the reports  considered most pertinent 1n the derivation of the MCLG are
cited In the document.  The comprehensive literature data base 1n support of this
document Includes Information published up to April 1987;  however,  more recent
data  have  been  added during  the review process  and 1n  response  to  public
comments.

     When adequate health effects data exist, Health Advisory values for less-
than-lifetime exposures (One-day,  Ten-day, and Longer-term, approximately 10% of
   individual's lifetime) are included in this document.   These values are not
     •^ setting the MCLG, but serve as informal  guidance to municipalities and
         Anizations when emergency spills or contamination situations occur.

                                                                James R.  Elder
                                                                      Di rector
                                     Office of Ground  Water and Drinking Water

                                                               Tudor T.  Davies
                                                                      Director
                                               Office  of Science of Technology
                                     viii

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                                  I.  SUMMARY
     The compound 1,1,2-trichloroethane (1,1,2-TCE)  1s  a colorless,
nonflammable liquid with a sweet, pleasant odor.  It is relatively insoluble
in water; miscible with alcohol, ether, and other organic liquids; and soluble
in chloroform.  Although its primary use is in the production of vinylidene
chloride, 1,1,2-TCE is also widely used in the production of Teflon tubing; as
an adhesive and lacquer; and as a solvent in the manufacture of fats, waxes,
natural resins, and chlorinated rubber.

     Environmental contamination by 1,1,2-TCE occurs mainly through spills,
leaks, and disposal of industrial and municipal wastes.  Escape from aquatic
environments proceeds through volatilization; chemical  degradation and
biodegradation do not contribute significantly to the breakdown of 1,1,2-TCE
in water.  Once in the atmosphere, 1,1,2-TCE will undergo photqoxldation, with
an estimated half-life of 24 days in unpolluted areas and 16 hours in polluted
atmospheres.  1,1,2-TCE is not well adsorbed by soils but readily diffuses
into groundwater, where it remains resistant to degradation.  Most human
exposure to 1,1,2-TCE occurs via drinking water with average exposure levels
of 0.1'to 8.5 parts per billion (ppb) or via ambient air near Industrial
sources at levels of 9.0 to 40.0 parts per trillion (ppt), respectively.

     In a study on the metabolic disposition of [1,2-14C]1,1,2-TCE in rodents,
     of an oral dose of the compound (300 and 70 mg/kg In mice and rats,
     rtively) was'absorbed within 48 hours after administration.
rvfc uximately 72 to 76% of the radiolabel appeared in the urine and feces, and
10 to 14.5% was present in expired air.  Whole carcasses retained 2 to 4% of
the labeled 1,1,2-TCE dose.  The primary route of elimination for 1,1,2-TCE
was the urine; up to 87% of an intraperltoneal dose of 1,1,2-TCE (0.1 to
0.2 g/kg) was excreted by mice via the urine.  Major urinary metabolites
included S-carboxymethylcysteine, thiodiacetic add, and chloroacetic acid.
                                      1-1

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     Oxidative and reductive dechlorlnatlon of 1,1,2-TCE are NADPH-requlrlng
reactions that proceed via microsomal cytochrome P-450-dependent mixed-
function oxygenase (MFO) enzyme systems.  Oxidation appears to provide the
major pathway for 1,1,2-TCE metabolism.  Initial hydroxylatlon of the compound
produces a chlorohydrln, from which chloroacetylchloride, the proposed
reactive metabolite of 1,1,2-TCE, 1s formed.  Further metabolism results In
the formation of the urinary metabolite chloroacetlc acid.  Conjugation of
chloroacetate with glutathlone (GSH) by glutathlone S-transferases may also
occcur, and subsequent transformation of this conjugated compound leads to the
formation of S-carboxymethylcystelne and thlodlacetic acid; both are excreted
in the urine of 1,1,2-TCE-dosed rodents.  In vitro reductive metabolism of
1,1,2-TCE to vinyl chloride proceeds very slowly; this pathway probably has
little significance on the metabolism of 1,1,2-TCE in vivo.

     Acute oral LD,0 values for 1,1,2-TCE of 378 and 491 mg/kg were obtained
    mice, and LD50 values of 100 to 200 and 835 mg/kg were reported for rats.
        i LDU for 1,1,2-TCE 1n dogs was 720 mg/kg.  Side effects accompanying
    . oral exposure to the compound Included gastric Irritation, red or hemor-
. ..aged lungs, and pale liver.

     Short-term oral  exposure to 1,1,2-TCE Is hepatotoxlc 1n several  species
of animals.  Rats administered 1,1,2-TCE at a level of 60 mg/kg (the Lowest-
Observed-Adverse-Effect Level, LOAEL) exhibited signs of liver dysfunction,
Including Increased serum transamlnase levels and decreased cytochrome P-450,
GSH, and aminolevullnic dehydratase (ALA-dehydratase).  A No-Observed-Adverse-
Effect Level (NOAEL) of 3.8 mg 1,1,2-TCE/kg was Identified for mice consuming
the compound 1n drinking water for 14 days.  Dogs given oral doses of 1,1,2-
TCE (144 to 748 mg/kg) developed renal and hepatic necrosis as well as fatty
liver.  Vacuol1zat1on of hepatocytes, dilation of renal collecting ducts, and
gastrointestinal Irritation were also observed.  1,1,2-TCE had an anesthetic
effect In all but the low-dose dogs.

     Nice given 1,1,2-TCE (3.8 to 380 ing/kg) In drinking water for 90 days
exhibited altered serum chemistries and changes 1n hepatic microsomal enzyme
                                      1-2

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activities.  Female mice were more severely affected than male mice.  Females
developed significantly decreased hematocrlt and hemoglobin levels; elevated
serum transaminase, serum alkaline phosphatase (SAP), and fibrinogen levels;
decreased microsomal cytochrome P-450 content and aniline hydroxylase
activity; and Increased liver weight. ' Females also exhibited a dose -related
Increase 1n hepatic GSH.  Hales, on the other hand,. developed only decreased
hepatic GSH levels and elevated SAP activity.  Cell -mediated Immunity remained
unaffected during the 90-day exposure to 1,1,2-TCE, but humoral Immune status
was depressed 1n both sexes 1n the mid- and high-dose groups.  These studies
established a NOAEL of 3.9 mg/kg for female mice and 4.4 mg/kg for male mice.

     The chronic toxicity of 1,1,2-TCE was evaluated as part of a lifetime
oral bioassay 1n both male and female rats and mice.  In rats treated by
gavage with average doses of 46 and 92 mg/kg/day, 5 days/week for 78 weeks,
hunched appearance, rough fur, dyspnea, and squinted eyes were noted after
about 6 months.  No other differences between treated and control rats were
observed.  This study established a LOAEL of 46 mg/kg/day for rats, based on
clinical signs.  No appreciable differences were noted between treated mice
receiving average doses of 195 or 390 mg/kg/day, 5 days/week for 78 weeks, and
c-'-trol mice except for abdominal distension In treated animals of both sexes
rect.,---, the higher dose late In the study; this was ascribed to the
development of liver tumors.  No nonneoplastlc changes were observed between
treated and control mice.

     Limited data were available in the literature regarding the developmental
effects of 1,1,2-TCE.  A screening test (Chernoff/Kavlock assay) revealed no
developmental effects 1n neonatal mice exposed to 350 mg/kg/day on gestation
  vs 8 to 12.  No other mammalian data were found.
       1,2-TCE was nonmutagenlc in various strains of Salmonella tvohinmrium
       with or without metabolic activation.  Weakly positive results were
reported in a mammalian cell transformation assay with BALB/C-3T3 cells. When
Injected 1ntraper1toneally (1p) Into rats and nice, [14C] 1,1,2-TCE bound
covalently to ONA, RNA, and protein of the liver, kidney, lung, and stomach.
                                      1-3

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     In the one study evaluating the oncogen1 city of 1,1,2-TCE,  the compound
was administered by gavage to male and female Osborne-Mendel rats 5 days/week
for 78 weeks at average dose levels of 46 and 92 mg/kg/day.  No significant
neoplastic changes were observed in-treated animals as compared with control
rats.  It was concluded that there 1s no convincing evidence to indicate
carcinogenicity of 1,1,2-TCE 1n Osborne-Mendel rats under the conditions of
the study.  In contrast, male and female B6C3F,  mice,  given the  compound at
average dose levels of 195 or 390 mg/kg/day, 5 days/week for 78 weeks,
developed hepatocellular carcinomas and adrenal  gland pheochromocytomas at
levels significantly greater (p <0.001) than those seen in control animals.
It was concluded that under the conditions of the bioassay, 1,1,2-TCE is
carcinogenic in B6C3F, mice,  causing hepatocellular carcinomas and adrenal
pheochromocytomas.
     Very little Information on the human health effects of 1,1,2-TCE could be
located.  Data from the only two studies available Indicated that direct
dermal contact with 1,1,2-TCE increased blood flow 1n human skin without
inducing erythema, edema, fissuring, or scaling.

     1,1,2-TCE-Induced toxicity appears to occur via bioactivation and
•  ^:-.quent covalent binding to DNA, RNA, proteins, and lipids.  Treatment of
rats and mice with known MFO Inducers, such as phenobarbital, acetone, and
polybrominated biphenyls (PBB), prior to 1,1,2-TCE dosing causes a significant
increase in tissue and cellular damage.- In vitro covalent binding of 1,1,2-
TCE to hepatic ONA 1s greater In mice than 1n rats, a finding consistent with
reports indicating that mice are more susceptible to 1,1,2-TCE-induced
hepatocarclnoma than are rats.  The toxicity of 1,1,2-TCE 1s potentiated by
GSH depletion and inhibited in the presence of GSH.  Binding of 1,1,2-TCE to
macromolecules 1s enhanced following metabolic stimulation of mlcrosomal
enzymes.

     The recommended value for the One-day Health Advisory (HA) for a 10-kg
child Is calculated to be 600 »g/L, based on a LOAEL for hepatotoxlcity
                                      1-4

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 induced  in  a  1-day oral  study with  rats.   A Ten-day HA of 400 #g/L  for a  10-kg
 child  was derived,  based on a NOAEL identified  in  a 14-day oral  toxtcity  study
 with mice.  The  Longer-term HAs and  the  DUEL are based  on  the  NOAEL  established
 in  a 90-day oral  toxicity study with mice.   The Longer-term HA for  a  10-kg
 child  was calculated to  be 400 »g/L, the  Longer-term HA for a 70-kg adult was
 1,000  *g/L, and the DWEL was  100 »g/L.  According  to EPA  guidelines,  1,1,2-TCE
 is  classified in  Group C:  Possible  Human  Carcinogen.   A value of 8.12 «g/day
 has been derived  as the  dose  of 1,1,2-TCE associated with an  increased
 lifetime cancer risk of  10"* in a 70-kg  adult.

     Individuals occupationally exposed to chloroethanes may represent
 a special risk group because  of absorption  following dermal contact with  or
 inhalation of this  class of chemicals.  In  addition, since  1,1,2-TCE  has  been
proven to be carcinogenic  in  at least one rodent species,  individuals  exposed
to :.,;-.atotoxins or  those with liver disease may constitute a subpopulation
	Jtive to 1,1,2-TCE.
                                     1-5

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                     II.   PHYSICAL AND CHEMICAL  PROPERTIES

A.   GENERAL PROPERTIES

     The compound 1,1,2-trichloroethane (1,1,2-TCE), an aliphatic, chlorinated
hydrocarbon, 1s a colorless, nonflammable liquid with a sweet, pleasant odor.
It 1s relatively Insoluble in water; mlscible with alcohol, ether, and other
organic liquids; and soluble 1n chloroform (Torkelson and Rowe, 1981;
Windholz, 1983; Weast, 1987J.  1,1,2-TCE Is incompatible with strong
oxidizers, strong caustics, and chemically active metals such as aluminum and
magnesium powders, sodium, and potassium.  Toxic gases and vapors such as
hydrogen chloride, phosgene, and carbon monoxide may be released in a fire
involving 1,1,2-TCE.  Liquid 1,1,2-TCE will attack some forms of plastics,
rubber, and coatings, and is corrosive to aluminum, iron, and zinc at reflux
 .,, 5.-jtures (NIOSH/OSHA, 1978; Archer, 1979).  Table II-l summarizes the
  .-vtant physical and chemical properties of 1,1,2-trichloroethane.

B.   MANUFACTURE AND USE

1.   Synthesis of 1.1.2-Trichlordethane

     1,1,2-Trichloroethane was first prepared around 1840 by the reaction of
chloroethylene with antimony pentachloride.  Currently, it is produced in the
United States either by the reaction of acetylene gas with a mixture of
hydrogen chloride and chlorine in the presence of a catalyst (CH-CH + HC1 -->
CH,  * CHC1 + Cl,  -->  CH2C1CHC12),  or  by chlorinatlon  of  ethylene followed  by
dehydrochlorination of the 1,2-dichloroethane Intermediate (CH2 * CH, + C12 -->
CH2C1CH2C1 + Cl, --> CH2C1CHC12 + HC1) (Hardie, 1964).  1,1,2-TCE has also been
identified as a by-product in the chlorinatlon of vinyl chloride and 1,1-
dichloroethane, and  in sewage water as a by-product of chlorinatlon treatment
(Archer,  1979; U.S. EPA,  1975a).
                                     II-l

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          Table  II-l.  Physical and Chemical Properties of 1,1,2-TCE
    Property
   Value
    Reference
CAS Registry No.

RTECS No.

EPA Hazardous Waste No.

Synonyms




Molecular formula
Molecular structure


  "--ular weight

         oint

..iHing point

Specific gravity  (20/4'C)

Vapor pressure
Solubility
    Water

    Alcohol
    Ether
    Chloroform

Log octanol/water
 partition coefficient
79-00-5

NIOSH/KJ 297500

U227

Vinyl trichloride
beta-Trichloroethane
Ethane trichloride
1,2,2-Trl chloroethane

CH-C1CHC1.
C2-H8-C1,


     Cl   Cl

Cl - C - C - H

     ,!   I

133.42

113.8eC

-36.5°C

1.4416

19 mmHg at 20°C
32 mmHg at 30°C
40 mmHg at 35°C
760 mmHg at 113.8°C
0.44 g/100 ml H,0 at
  20°C
Miscible
Mlsclble
Soluble

2.38 (estimated),
2.12 {measured)
NIOSH/OSHA (1978)
NIOSH/OSHA (1978)
Sax (1984)
Sax (1984)

Weast (1987)
Windholz (1983)
U.S. EPA (1980b)



Windholz (1983)

Weast (1987)

Weast (1987)

Windholz (1983)

Verschueren (1983)
Verschueren (1983)
Verschueren (1983)
Weast (1987)
Torkelson and Rowe
   (1982)
Windholz (1983)
Windholz (1983)
Weast (1987)

Konemann (1981)
Sato and Nakajima
 (1979)
                                                                    (continued)
                                      II-2

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                           Table II-l.  (continued)
Property                          Value                  Reference


Log bloconcentralon           <1   .                   Kawasaki (1980)
 factor

Half-life
   A1r                        24 days                 Singh etal. (1981)
   Water                      1.9  days                Zoeteman et al. (1980)
   Evaporation rate/          21 minutes              0111 ing et al. (1976)
    half-life                 35.1 minutes            01ll1ng et al. (1977)

Conversion factor             1 ppm  in air • 5.45     I ARC (1979)
                               rog/ro*
                                     II-3

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2.   Production and Use

     In 1985, the U.S. International Trade Commission reported production of
1,1,2-TCE by the Dow Chemical Company and R.S.A. Corporation; however, no
production volumes were stated (U.S. IK, 1986).  A minimum of approximately
124 million pounds of 1,1,2-TCE was produced during 1974, based on the
manufacture of vlnylldene chloride  (90 million pounds) (NCI, 1978).  The
Commission of the European Communities estimates that 30 million pounds per
year are produced 1n Europe and that annual world production is greater than
88 million pounds (CEC, 1986).  The U.S. EPA (1975a) estimates the gross
annual discharge of 1,1,2-TCE waste in the United States to be 4 million
pounds.

     1,1,2-TCE is mainly used as a chemical Intermediate in the production of
vinylidene chloride (Archer, 1979).  Other applications include its use in
adhesives and lacquer, in production of Teflon tubing, and as a solvent in the
manufacture of fats, waxes, natural resins, alkaloids, and chlorinated rubber
(NCI, 1978; U.S. EPA, 1975a);

C.   ENVIRONMENTAL FATE

     The presence of 1,1,2-TCE In raw and finished waters Is primarily from
spills, leaks, and disposal of Industrial and municipal wastes, with up to 5.4
ppm detected 1n Industrial effluent discharge (IARC, 1979).  Small amounts can
be formed by chlorination of drinking water or treatment of sewage (U.S. EPA,
1975a, 1980a).  A metropolitan water monitoring study has demonstrated
drinking water levels of 0.1 to 8.5 >g/L for 1,1,2-TCE (Keith et al., 1976;
U.S. EPA, 1975b).

     An average of 0.24 »g/L of 1,1,2-TCE was detected In chlorinated and
unchlorinated samples from water reclamation plants and potable groundwater
wells in the Los Angeles County Sanitation District (Baird et a.., 1980).
None was detected 1n the raw water of 30 Canadian water treatment facilities,
but 1,1,2-TCE was detected in the finished water with a maximum concentration
                                     II-4

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of 7 ppb 1n August/September; no 1,1,2-TCE was detected 1n samples obtained in
November/December (Units of detection, 1 to 2 ppb) (Otson et al., 1982).
Detectable levels of 1,1,2-TCE" 1n groundwater have been reported In 72 of
1,069 wells In New Jersey (maximum 31.1 ppb), with most of the polluted
samples under urban land use areas (Page, 1981).  In the same study, 53 of 603
samples from surface waters tested'positively with a maximum 1,1,2-TCE
concentration of 18.7 ppb.  Seawater adjacent to Point Reyes, CA, had an
average 1,1,2-TCE concentration of 0.153 ppb (Singh et al., 1977).

     Although the fate of 1,1,2-TCE in the environment has not been thoroughly
studied, relevant Information can be inferred from data available on Its
structural isomer, 1,1,1-TCE.  By analogy to 1,1,1-TCE, photooxidation in the
troposphere is predicted to be the predominant fate process for 1,1,2-TCE.
This is contingent upon volatilization as the primary transport mechanism for
the removal of 1,1,2-TCE from water (U.S. EPA, 1986d; Callahan et al., 1979).
Dill ing et al. (1975) estimated the experimental half-life for volatilization
of 1 mg/L of 1,1,2-TCE to be 21 minutes when stirred at 200 rpm in water at
approximately 25°C in an open container.  A subsequent study by Dili ing (1977)
was conducted using the same experimental conditions as the 1975 study,
  suiting in an average evaporation half-life of 35.1 minutes for 1,1,2-TCE.
	;ran et al. (1980), however, estimated the overall half-life of 1,1,2-TCE
in Rnine River water to be 1.9 days, based on a field study involving interval
sampling over 24.5 hours and assuming first-order processes.

     In a study by Wilson et al. (1981), 65% of 1,1,2-TCE applied to 140 cm of
a sandy, low organic soil readily percolated through and 27% was volatilized.
The observed volatilization flux calculated from soil (0.36 *g/cn*/hr)  was
inhibited compared to the flux calculated from water (5.0 »g/cmVhr).   The
high rate of transport is thought to be influenced by the low water solubility
and insignificant particle adsorption of 1,1,2-TCE, with no loss attributed to
biodegradation.

     1,1,2-TCE has been labeled "biodegradation resistant" in a study
correlating chemical structure to biodegradabllity, and the U.S. EPA (1975a)
                                     II-5

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has categorized 1,1,2-TCE as a refractory chemical  (Category 5)  (Kawasaki,
1980; U.S. EPA, 1975a).  One investigation reported very slow biodegradation
                           ";.•
of 1,1,2-TCE in a static culture flask, but the extent to which  evaporation
contributed to loss was difficult to ascertain.  When the initial
concentration of 1,1,2-TCE was 10 and 5-mg/L,  average total  loss was 0 and  6%,
respectively, after 7 days, and 39 and 44%, respectively, after  28 days;  loss
due to volatilization at 25'C for 10 days was  estimated to be 3  and 15%,
respectively (Tabak et al., 1981).  Hydrolysis of 1,1,2-TCE is slow, with one
study indicating no significant decrease in 1,1,2-TCE concentration in a
closed freshwater system, and less than a 5% decrease In a dark  or light
closed seawater system (Jensen and Rosenberg,  1975).  Based on the low_water
solubility and biodegradation resistance of 1,1,2-TCE and the evidence
                *
i-wi-2ting a high rate of transport through low organic soil, 1,1{2-TCE is
   tr-vi. to leach into groundwater.  Because of the nature of groundwater
     , anaerobic conditions, nonturbulent flow, and limited dilution), 1,1,2-
1CE may be persistent, possibly 100 times more so in groundwater than in river
water (Zoeteman et al., 1980).

     1,1,2-Trlchloroethane emitted into the atmosphere due to evaporation from
industrial, municipal, and laboratory waste sources will be expected to
partially wash out in rain because it has limited solubility in  water {U.S.
EPA, 1975a). When released into the atmosphere, 1,1,2-TCE will degrade by
reaction with hydroxyl radicals in the troposphere with a half-life of
24 days, based on a 2.8% loss per 12-hour day  (Singh et al., 1981).  Its
reaction under simulated smog conditions Is much faster, with a  half-life of
16 hours (DilUng et al., 1976).  The washout  of 1,1,2-TCE may be an
additional source of contamination in surface  and groundwater supplies.

     A U.S. EPA monitoring program has detected 1,1,2-TCE In ambient air in
Louisiana, New Jersey, Texas, and California with concentrations ranging from
36 to 17,000 ppt.  The highest concentration was found near a sanitary
landfill in Nf Jersey (U.S. EPA, 1980b).  1,1,2-TCE has been detected in the
air of Los Angeles and Oakland, CA, and Phoenix, AZ, at concentrations of 9.3,
7.9, and 16.1 ppt, respectively (Singh et al., 1981), and 1n New Jersey cities
                                     II-6

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at 10.0 to 37.0 ppt (Harkov et al., 1983).  In a survey of seven major U.S.
cities, average air concentrations were 10.0 to 40.0 ppt 1,1,2-TCE, with a
maximum concentration of 150 ppt (Singh et al., 1982).

0.   SUMMARY

     1,1,2-TCE 1s a colorless, nonflammable liquid used 1n the manufacture of
vlnylldene chloride, as an adhesive, and as a solvent 1n the manufacture of
fats, waxes, natural resins, and chlorinated rubber.  1,1,2-TCE enters the
atmosphere and terrestrial environment from spills, leaks, and disposal of
Industrial and municipal wastes.  The primary transport process for th~e
removal of 1,1,2-TCE from aquatic systems 1s volatilization; chemical
degradation (photolysis, oxidation, and hydrolysis) and biodegradation
processes do not contribute significantly to the breakdown of 1,1,2-TCE In
water.  Once 1n the atmosphere, photooxidatlon 1n the troposphere 1s predicted
to be the predominant fate of 1,1,2-TCE.  1,1,2-TCE will photodegrade by
reaction with hydroxyl radicals with an estimated half-life of 24 days in
unpolluted atmospheres and 16 hours in polluted atmospheres.  1,1,2-TCE is
poorly adsorbed by soils and will readily percolate Into the groundwater,
v^r-re .degradation is unlikely to occur.  Primary human exposure to 1,1,2-TCE'
      -: contaminated drinking water with levels of 0.1 to 8.5 ppb and from
a-bient air near Industrial sources at concentrations of 9.0 to 40.0 ppt.
                                     II-7

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                             III.  TOXICOKINETICS

A.   ABSORPTION AND ELIMINATION .

     The metabolic disposition of radlo'labeled 1,1,2-TCE was examined In mice
and rats for a 48-hour period after the animals had consumed unlabeled 1,1,2-
TCE (dose not specified) 5 days/week for 4 weeks (Mitoma et al., 1985).
Pretreated male B6C3F, mice received a single oral  dose of 300 mg [1,2-14C]-
1,1,2-TCE/kg, and pretreated male Osborne-Mendel rats received a single oral
dose of 70 mg/kg of the radiolabeled compound.  Doses were equivalent to the
maximum tolerated doses (KTD) established by the National Cancer Institute
(NCI, 1978).  The specific activities of the set of carbon-labeled chlorinated
hydrocarbons used by Mitoma et al. (1985) ranged from 7.5 to 19.5 mCi/mmol,
but the Individual specific activity of [1,2-14C]1,1,2-TCE was  not Identified.
The number of animals used also was not specified.  Mice and rats excreted
approximately 76 and 72% of the administered "C, respectively.  According  to
the authors, most of the radiocarbon appeared In the urine, but Individual
recoveries for urine and feces were not reported.  Expired 14COZ accounted for
about 3% of the radioactivity given to mice and about 5% of that administered
to rats.  Mice and rats eliminated an additional 7 and 9.5%, respectively, as
unchanged 1,1,2-TCE via expired air.  Whole carcass levels represented
approximately 2 to 4% of the original dose given to both rodent species.
P-iasma radioactivity levels were not measured, and some "C was reported lost
during the extraction procedures.  Although an accurate estimate of 1,1,2-TCE
absorption cannot be made, the data suggest that most of the "C dose  Is
readily absorbed from the gastrointestinal tract of mice and rats.

     Twenty-one female albino mice given an 1p dose of 0.1 to 0.2 g [1,2-"C]-
1,1,2-TCE/kg eliminated approximately 73 to 87% of the Injected radiolabel In
the urine and 16 to 22% 1n expired air within 3 days (Yllner,  1971b).  Small
amounts (0.1 to 3%) of radioactivity appeared 1n the feces or were retained by
the body.  Plasma "C  levels were not measured.  Jakobson et al.  (1977)
reported that 1,1,2-TCE rapidly appeared 1n the blood of nine outbred guinea
pigs (sexes combined) given a single 1p dose of 72 mg test material.  Blood
                                     III-l

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levels peaked at 15 ^g/mL 2 hours after injection and dropped rapidly
thereafter.  At 6 hours postdosing, blood concentrations were less than
5 jjg/mL, and within 12 hours, negligible amounts of the organic solvent were
present.

     Dermal absorption of 1,1,2-TCE' showed a large variation in guinea pigs,
but cutaneous injections of the organic solvent were slowly and evenly
absorbed (Jakobson et al., 1977).  In one study, a 1.0-ml (1.44 g) sample of
1,1,2-TCE was applied directly to the skin; in a second set of studies, single
50-nL (72 mg) doses of 1,1,2-TCE were Injected either intra- or subcutaneously
into groups of 14, 9, or 9 outbred animals (sexes combined).  Absorption of
1,1,2-TCE appeared to be biphasic following topical application of the test
compound.  Plasma 1,1,2-TCE levels peaked immediately after initial exposure
-"~ at 10 to 12 hours after dosing.  No saturation of the blood was noted
:-ring the experiment.  The pattern of absorption following direct dermal
exposure to 1,1,2-TCE was believed to be due to a local physical effect
(involving progressive skin damage) rather than to a systemic process.
Following Intra- and subcutaneous Injection of 1,1,2-TCE, blood levels
generally peaked and plateaued at 1 to 5 *g/mL.  The organic solvent appeared
to be taken up by and subsequently removed from the blood at a steady rate
during the 12 hours after dosing.

     1,1,2-TCE was readily absorbed from the lungs of healthy male human
subjects (age and number not specified) who Inhaled, In a single breath,
5.0 mg or 71 mg [*'Cl]l,l,2-TCE/kg (assuming a body weight of 70 kg) (Morgan
et al., 1970, 1972).  The authors cited several reasons for using MC1 in
place of the conventional MC1: the high specific activity of MC1 allows very
small amounts of radioactivity to be measured In the breath; the short half-
life of "Cl (37.2 minutes versus 30,000 years for MC1) restricts the dose,
and thus, exposure to radioactivity; and the gamma-ray energy of "Cl enables
absorbed material  to be counted in vivo via col11mated detectors.  Only 10% of
the original "adioactive dose remained In alveolar air when subjects held
their breath for 15 seconds after Inhalation.  Approximately 10X of the
original radioactivity was exhaled within 100 minutes after exposure,
                                     III-2

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suggesting that at  least 90% of the "C1  had  been  absorbed  by the body.   No
more than 0.6% of the  administered UC1 was eliminated  1n the urine  during the
first 60 minutes after Inhalation.

B.   TISSUE DISTRIBUTION

     Little Information on the tissue distribution of 1,1,2-TCE was found 1n
the available literature.  Hitoma et al.  (J985) reported that 2 to  4% of a
single oral dose of [1,2-14C]1,1,2-TCE, given at levels of  300 mg/kg to  B6C3F,
male mice and 70 mg/kg to male Osborne-Mendel rats, was recovered In the
animals' carcasses  48  hours after dosing.  Individual tissue "C  residue
levels were not reported.  Three days after  Yllner (1971b) gave 21  female
albino mice an ip dose of 0.1 to 0.2 g [l,2-14C]l,l,2-TCE/kg, only 1 to  3% of
the original radioactivity remained in the animals.  Individual tissues  were
not examined for radioactivity.  The chemical nature of the  radioactivity
retained by the bodies of [1,2-11C]-dosed rats and mice was not defined  in
either study.

     M
-------
proportion (6.8 to 9.5%) of the higher 1,1,2-TCE doses appeared unchanged in
expired air.

     Three major metabolites appeared in the urine of 21 female albino mice
injected intraperitoneally with 0.1 to 0.2 g [l,2-"C]l,l,2-TCE/kg.
Chloroacetic acid accounted for 6 to 31% of the total urinary radioactivity,
thiodiacetic acid for 38 to 42%, and S-carboxymethylcysteine for 29 to 46% as
free compound and 3 to 10% as a conjugated compound (Yllner, 1971b).  It was
not clear to what the S-carboxymethylcysteine was conjugated.  Small amounts
of 2,2-dichloroethanol, 2,2,2-trichloroethanol, oxalic acid, and
trichloroacetic acid also were detected in the urine, which contained 73 to
87% of the original 14C dose 3 days after injection.  Approximately  16 to 22%
of the administered radiocarbon was exhaled by the mice, with 60% recovered as
MC02 and 40% as unchanged parent compound.   Low levels of radioactivity (0.1
to 3%) were found in the feces (which were contaminated with urine) and
carcass.  The presence of minor urinary metabolites was attributed to chemical
impurities in the original 1,1,2-TCE formulation.

     Ikeda and Ohtsuji (1972) reported that in 48 Vistar rats (sexes combined)
inhaling 1,1,2-TCE vapors (200 ppm, equivalent to 370.9 mg/kg) for 8 hours,
       ttle parent compound was metabolized within 48 hours of initial
cv'-:'jre.  Urinary metabolites excreted by the rats were listed as "total
trichloro" compounds (0.6 mg/kg), trichloroacetic acid (0.3 mg/kg), and
trichloroethanol (0.3 mg/kg).  However, since there would have to be a shift
of a chlorine from 1,1,2-TCE to form 1,1,1-trichloroacetic add or 1,1,1-
trichloroethanol, Identification of these metabolites may be due to the
nonspecificity of the test.  Despite these findings, the author's conclusion
that 1,1,2-TCE 1s not extensively metabolized may be unsubstantiated, since
only minor urinary metabolites were monitored and no other tissues, excreta,
or exhaled matter were analyzed.

     No metabolites were present In the blood of nine outbred guinea pigs
during the 12 hours following 1p dosing with 50 »L (72 mg) 1,1,2-TCE.  The
same finding was reported for groups of 14, 9, or 9 guinea pigs given,
                                     III-4

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i

-------
respectively, dermal applications (1.0 ml, 1.44 g) or intra- or subcutaneous
Injections (50 »L, 72 mg) of 1,1,2-TCE (Jakobson et al., 1977).
                                                                   *

     The urinary metabolic profile of mice dosed with [1,2-"C]1,1,2-TCE was
very similar to that of mice given [l-14C]chloroacetic acid  (Yllner, 1971a).
Yllner (1971b) suggested that 1,1,2-TCE is probably metabolized via
chloroacetic acid, undergoing oxidative chlorination or dechlorination
followed by oxidation of the carbon containing two chlorine atoms.  The
resulting compound, chloroacetaldehyde, is further oxidized to chloroacetate,
which either is excreted directly Into the urine or 1s conjugated to GSH and
metabolized to S-carboxymethylcysteine and thiodiacetic add.  Ivanetich and
Van Den Honert (1981) proposed that in vitro conversion of 1,1,2-TCE-to
chloroacetate occurs via the acylchloride of chloroacetate following
hydroxylation of carbon number two on the 1,1,2-TCE molecule.  Both in vivo
?r>d in vitro studies indicate that cytochrome P-450-dependent MFO systems are
 -volved in the oxidation and dechlorination of 1,1,2-TCE.

     Cytochrome P-450 appears to be the primary, and perhaps sole, site for
the initial metabolism of chlorinated hydrocarbons.  Van Dyke and Wineman
(1971) showed that enzymatic dechlorination of 1,1,2-TCE by hepatic microsomes
was enhanced 1.5 to 3 times over that of controls in male rats (number and
strain not given) pretreated for 3 days with the known MFO inducers
phenobarbltal (40 mg/kg) or benzopyrene (20 mg/kg).  A similar trend was
observed by Hales and Thompson (1985), who examined 1,1,2-TCE metabolism in
liver microsomes obtained from phenobarbltal-treated rats and from
phenobarbltal- and Aroclor 1254-induced cytochrome P-450 culture systems;
chloroacetate was the primary metabolite formed 1n both experiments.
Subsequent concentrations of substrates were not given, but the Michael 1s-
Menton constant (K,, value) for chloroacetate production was 3.3 mM, and the
maximal velocity (Vmax) value for 1,1,2-TCE oxidation was 40 nmol/min/mg
(Hales and Thompson, 1985).  Food deprivation also caused a significant
Increase 1n the rate at which 1,1,2-TCE (0.5 to 0.10%, v/v) was metabolized by
hepatic microsomes obtained from male and female Wistar rats (number not
specified) that were fasted for 24 hours (Nakajlma and Sato, 1979).  Although
                                     III-5

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both body and liver weights dropped after the 1-day fast, no changes in
hepatic protein or P-450 content were observed.  The increase in liver
microsomal enzyme activity following food deprivation therefore differs from
phenobarbital-induced enzyme activity, which results from an increase in both
microsomal protein and cytochrome P-450.

     Involvement of the MFO system 1s further supported by the reduced rate at
which MC1 was cleaved from the organic solvent following Incubation of
[S6C1]TCE and hepatic microsomes with carbon monoxide (Van Dyke and Uineman,
1971).  In another study, Incubation of 1,1,2-TCE and microsomal cytochrome
P-450 with metyrapone {2.3 mM) or carbon monoxide:oxygen (80:20, v/v) caused a
60 to 70% drop 1n the rate of monochloroacetate formation, when compared to
the untreated control value (Ivanetich and Van Oen Honert, 1981).  Incubation
with another cytochrome P-450 inhibitor, SKF 525A (200 mM), gave ambiguous
results but appeared to interfere with 1,1,2-TCE metabolism.

     In the studies described above, dechlorination was severely reduced or
absent in systems lacking NAOPH.  In addition, data supporting cytochrome
       - the site of enzymatic dechlorination of halogenated hydrocarbons were
      .. ay Ivanetich and Van Den Honert (1981), Takano et al. (1985), and
Ptlksnen and Valnio (1975), who reported that 1,1,2-TCE bound directly to the
cytochrome P-450 substrate binding site.  Substrate or dissociation constant
(KJ  values  for  1,1,2-TCE were  reported  to  be  0.81 mM  (Ivanetich  and  Van  Den
Honert, 2981} and 1.0 mM (Pelkonen and Valnio, 1975);  spectral changes (i.e.,
changes In absorbance that represented a conversion from the low
spin/substrate free ferric cytochrome P-450 to the high spin/substrate
complexed form) in cytochrome P-450 from perfused male Wlstar rat livers were
observed at 1,1,2-TCE concentrations above 45 *M (Tikano et al., 1985).

     The position and number of chlorine and hydrogen  atoms also appear
important in the metabolism of 1,1,2-TCE.  The amount  of MC1 removed from
radiolabeled hydrocarbon: was highest in compounds containing dlchloromethyl
groups (i.e., those with chlorinated carbons containing only one hydrogen, as
found on 1,1,2-TCE's carbon number 1).  Approximately 10% of the MC1 on
                                     III-6

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labeled 1,1,2TCE (1 »L, 1.44 mg) was enzymatlcally cleaved within a 30-minute
incubation period; the amount of "Cl removed was higher (at 13.5%) only for
2,2-dichloroethane (Van Oyke and Wineman, 1971).  Loew et al.  (1973) noted
that the dihalomethyl carbon (which lacks an electron in one of its orbitals)
is the most positive in a halogenated hydrocarbon, thus making that carbon an
excellent target for nucleophilic attack.  This was supported by results from
another study (Van Oyke, 1977), indicating that enzymatic attack of 1,1,2-TCE
is not on the carbon-halogen bond; rather, the carbon atom is oxidized first,
and the chlorine is subsequently released.

     Van Dyke (1977) also suggested that some dechlorination of 1,1,2-TCE may
occur under anaerobic conditions (i.e., in the presence of nitrogen).  The
latter observation suggests that 1,1,2-TCE goes through both reductive and
oxidative dehalogenation.  Thompson et al. (1984) demonstrated that
polychlorinated ethanes with more than two chlorine substituents are
susceptible to enzymatic degradation and reduction by rat liver microsomes,
especially under anaerobic conditions; however, these reactions proceeded
slowly (12.5 pmol to 2.5 nmol/mg protein).  In another study,  1,1,2-TCE
(1.0 mM) was converted by rat liver microsomes under anaerobic conditions to
vinyl chloride at a rate of 12.5 pmol/min/mg protein (Thompson et al., 1985).
All reactions were NADPH-dependent, and results indicated that reductive
metabolism of 1,1,2-TCE occurs via cytochrome P-450.  Van Dyke (1977)
postulated that saturated halogenated hydrocarbons also may pass through an
olefinlc intermediate prior to the final steps of metabolism.

     Figure III-l.presents the proposed metabolic pathway for 1,1,2-TCE.

        '.CCUMULATION AND RETENTION

     No - scific information on the bioaccumulation or retention of 1,1,2-TCE
following repeated dosing was found In the available literature.  However,
rapid elimination of the chemical from the body, plus low carcass levels (1 to
4% of the original dose) following oral and ip dosing suggest that 1,1,2-TCE
                                     III-7

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                          Q Q
                        H-C'C-H    1,1.2'TCI
J
                              CylMhronw M50
                              Monooxygtnisi*
                                O..NAOPH
                        -0,9
                          a H
                                    DfcNorMtfiylww
                                    Cttorohydrfn(uncublt)
                                 HCl(tponUnMut}
                        a
                         'C'C-H
                         f   •
                                        •HO
                                   Conjugation
                                              GS*CH,*COOH
                                              S-Caitoxyrmtfty*-
                       etitoroMttiit
                    (•zcrtttd uneftanetd In
                         INuiln*}
                        I
                                      HOOC • CH • (NHJ • CH, • S • CH, • COOH
                                             (•xcrattdintfMurint)
                                          HOOC •CHt*S*CHl> COOH
                                              TModikMtfc add
                                             (MOtUdinttwurint)
Figure III-1.  Proposed metabolic  pathway for 1,1,2-TCE.
Abbreviations used:   NADPH • n1cot1nam1de  adenlne  dlnucleotide phosphate;
                        GSK  • glutathlone.

SOURCE:  Adapted from Yllner (1971a,b); Laib (1982).
                                          III-8

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probably does not accumulate to any appreciable amount after administration by
the two routes.  In contrast, animal studies by Ikeda and Ohtsuji (1972)
suggested that very little of the 1,1,2-TCE vapors inhaled (at 200 ppm) by
48 Wistar rats (sexes combined) was recovered in the urine 48 hours after
exposure.  However, only very minor metabolites were monitored, and the actual
extent to which 1,1,2-TCE was metabolized and eliminated may have been greatly
underestimated.  In another study (Morgan et al., 1970), healthy male subjects
(age and number not specified) exhaled only 10% of a single dose of
[MC1]1,1,2-TCE administered at 71 mg/kg within 100 minutes after initial
exposure, suggesting that 90% was retained by the body.  During the first
postinhalation hour, "Cl was eliminated in the urine at a rate of
approximately 0.01% of the administered radioactivity/minute.  A shielded
scintillation detector placed against the subjects' calves showed an
increasing counting rate for more than 30 minutes after administration,
suggesting possible accumulation of radioactivity In subcutaneous fat.
Ak^cuch the Inhalation and collection periods were short, the authors (Morgan
         "0, 1972) postulated that during prolonged inhalation exposure,
     unds with a high lipid solubility, such as 1,1,2-TCE, will be readily
  j,orbed by the lungs, will accumulate rapidly in tissues, and will be
eliminated slowly from the body.

E.   SUMMARY

     Single oral doses of 300 and 70 mg [l,2-14C]l,l,2-TCE/kg given to mice
and rats, respectively, was readily absorbed by the gastrointestinal tract.
Approximately 76% of the original radioactivity appeared in the excreta (urine
and feces combined) and 10% in the exhaled air of mice within the 48 hours
following administration.  Rats excreted 72% and exhaled 14.5% of the "C dose
during the same time period.  Whole carcass levels ranged from 2 to 4% for
both species.  A similar pattern of elimination was obtained following ip
administration of 0.1 to 0.2 g [l,2-14C]l,l,2-TC£/kg to mice.  Within 3 days
of Injection, 73 to 87% of the radiolabel appeared in the urine, 16 to 22% was
found in expired air, and 0.1 to 3% was excreted In the feces or was retained
by the body.  1,1,2-TCE (72 mg) quickly entered the. blood stream of guinea
                                     III-9

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pigs given a single 1p Injection of the organic solvent; plasma levels of
15 *g/ml were recorded I hours after Injection, and only trace amounts were
detectable within  12 hours.

     The uneven rate of absorption 1n guinea pigs after dermal application of
1.44 g 1,1,2-TCE was thought to be related to physical damage at the
application site,  rather than to a systemic process.  Absorption from the
•-ood occurred at  a steady rate during the 12 hours after 1ntra- and
subcutaneous Injections of 72 »g 1,1,2-TCE were administered to guinea pigs.

     Inhaled doses of 71 to 143 mg [MC1]l,l,2-TCE/kg were readily absorbed by
healthy adult men.  Only 10% of the original radioactivity was exhaled within
100 minutes of exposure, suggesting that at least 90% of the administered
["Cl]1,1,2-TCE was absorbed by the lungs.

     Individual  tissue levels of 1,1,2-TCE were not reported in any studies in
the available literature, but retention of radioactivity remained low (1 to 4%
of the original  dose) 2 days after oral administration of 300 and 70 mg [1,2-
14C]l,l,2-TCE/kg to mice and rats, respectively, and 3 days after 1p injection
of 0.1 to 0.2 g [l,2-14C]l,l,2-TCE/kg to mice.

     Both oral  and 1p doses of radiolabeled 1,1,2-TCE were readily and
extensively metabolized by rodents.  The three primary urinary metabolites
were S-carboxymethylcysteine, thiodiacetic add, and chloroacetic acid.
Approximately 5 to 13% of the 1,1,2-TCE administered (by either route) to mice
and rats was exhaled as "C02.   By contrast, no 1,1,2-TCE metabolites could be
detected in the blood of guinea pigs exposed to the organic solvent via dermal
application (1.44 g), 1p dosing (72 mg), or intra- or subcutaneous Injection
(72 mg).  Little could be concluded about 1,1,2-TCE metabolism and elimination
in rats Inhaling 200 ppm (370.9 mg/kg)  1,1,2-TCE vapors for 2 hours.

     The metabolism of l,l,2-TCr appr—s to proceed through the formation of
chloroacetic add.  0x1 dative and reductive dechlor 1 nation of the organic
solvent occurs via mlcrosomal  cytochrome P-450-dependent MFO enzymes; NADPH is
                                    111-10

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 required for both reactions.   In  the  oxidative  (and primary) pathway,  1,1,2-
 TCE initially is  hydroxylated  to  form a  chlorohydrin; spontaneous removal of
 1  mol  HC1  produces chloroacetylchloride,  the proposed reactive metabolite of
 1,1,2-TCE.   Hydrolysis  of the  chloroacetylchlorlde produces the  urinary
 metabolite chloroacetate.   Conjugation of chloroacetate to GSH can  also take
 place, forming S-carboxymethyl GSH; loss of the third chlorine molecule occurs
 at this step.   Transformation  of  the  GSH conjugate to two additional urinary
 metabolites,  S-carboxymethylcysteine  and thiodiacetic acid, proceeds via a
.group  of cytosolic enzymes known  as GSH  S-transferases.  The primary product
 of reductive 1,1,2-TCE  metabolism in  vitro  has  been reported to  be  vinyl
 chloride;  however, vinyl  chloride has not been  recovered in vivo following
 ingestion of or exposure  to 1,1,2-TCE.

     Since  most of the  1,1,2-TCE  administered to rodents (approximately 86% in
 orally dosed rats and mice and 73 to  87% in ip-dosed mice) was eliminated
 within 2 to 3 days after  dosing,  and  only 1 to  3% of the original radiocarbon
         vered in  carcasses of  the same animals, accumulation and retention of
     Compound are  not expected  to  occur when exposure is by either of these two
  ,,utes.  Limited  animal and human data suggest  that inhaled 1,1,2-TCE
 (370.9.mg/kg for  rats,  71 mg/kg for humans) may be eliminated from  the body
 more slowly than  when the compound Is ingested  or Injected into  the peritoneal
 cavity.  However, the limitations of  these  studies (I.e., monitoring of only
 minor  urinary metabolites in rodents  and collection of expired air  and urine
 for only 1  hour after exposure In humans) preclude drawing definitive
 conclusions about the metabolism  and  elimination of Inhaled 1,1,2-TCE.
                                     III-ll

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                             IV.  HUMAN EXPOSURE
Water.
                                                                                  iW
     To be provided by the Science  and  Technology  Branch,  Office of Drinking     {•
                                    IV-1

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                         V.  HEALTH EFFECTS IN ANIMALS

A.   SHORT-TERM EXPOSURE

1.   Lethality

     Acute lethality data for 1,1,2-TCE are summarized in Table V-l.  A wide
range of oral and 1p LDM values were reported  1n the  literature.  Estimates
of oral LDIO  values  In mice and rats range  from 100 to 835 mg/kg.  In a study
by White et  al. (1985), 1,1,2-TCE was diluted  in emulphor and deionized water
and administered by gavage  to male and female  CD-I mice; the calculated LDSO
values were  378 and 491 mg/kg, respectively.   Most deaths occurred within 24
hours.  At the 500- to 600-mg/kg dose levels,  necropsies revealed gastric
Irritation 1n 100% of the mice, pale livers in 50 to  75%, and red or
hemorrhaged  lungs in 25%.   Smyth et al. (1969) reported an LDSO of 835 mg/kg
following administration of 1,1,2-TCE, by gastric Intubation to groups of five
Car-worth Wistar male rats  (90 to 120 g); it was unclear 1n what vehicle 1,1,2-
~".l was suspended.  Oral LDW values in rats have also been reported as 100 to
  .D mg/kg by Verschueren (1983).  Since this publication Is a secondary
source, it 1s not possible  to ascertain why the toxldty of 1,1,2-TCE is
reported to  be low.  Accordingly, one must Interpret these data with caution.
In a study designed to test the anthelmintic properties of 1,1,2-TCE, six dogs
were administered oral doses of the compound.  The animals were divided into
four groups  (one, two, two, or one per group), administered 1,1,2-TCE at
levels of 100, 200, 300, or 500 »L/kg (144, 288, 432, or 720 mg/kg,
respectively), and observed for 4 days (Wright and Schaffer, 1932).   The oral
LDLO  for dogs was determined to  be  approximately 720 mg/kg.

     Intraperitoneal LDM values for mice, rats, dogs, and guinea pigs ranged
from 265 to  970 mg/kg.  Injection of 1,1,2-TCE to groups of 10 Swiss-Webster
mice (25 to  35 g) resulted  1n a 24-hour LDW value of  504 mg/kg (Klaassen and
PI-"', 1966).  Four to six groups of mice (10 to 15 animals per group) were
killed 24 hours after 1p Injection of 1,1,2-TCE at various doses.   Tissues
were examined, and liver hlstopathology revealed cellular Infiltration and
vacuolization of the hepatocytes at low doses and centrllobular coagulative
necrosis at  the high doses.  Kidney function was determined to be  Impaired,

                                     V-l

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                 Table V-l.   Summary of Acute  Lethality  of  1,1,2-TCE
Route
Oral

Oral .

Oral
Oral
Oral

Intraperl tones!

Intraperi toneal


Intraperi toneal


Intraperi toneal
Intraperi toneal

Subcutaneous

inhalation
Inhalation
Inhalation

Dermal

Dermal

•— «1
Species
Mouse

Mouse

Rat
Rat
Dog

Mouse

Rat


Rat


Guinea pig
Dog

House

Mouse
Rat
Rat

Rabbit

Rabbit

Guinea pig
Sex
M

F

__fc
N
__»

N

F


F


M/F '


M

F
M/F
M/F

M

»

M/F
LD50 (mg/kg)
376
• (344-408)1
491
(452-550)*
100-200
835
720€

504
(403-634 )»
405

(301-545)*
265

(237-297)*
970
64B

227
(200-253)*
3.750 for 10 hr"
500 for 8 hr*
2.000 for 4 far'

5,371
(4.752-6,062)*
>2,000

1.930 (ID1S)
Observation
period
24 hr

24 hr

...
14 days
4 days

24 hr

24 hr


14 days


1 hr
24 hr

10 days

10 hr
14 days
14 days

14 days

24 hr

24 hr
Reference
White et al. (1985)

White et al. (1985)

Verschueren (1983)
Smyth et al. (1969)
Wright and Schaffer
(1932)
Klaassen and Plaa
(1966)
Lundberg et al .
(1986)

Lundberg et al .
(1986)
.
Wahlberg (1976)
Klaassen and Plaa
(1967)
Plaa et al. (1958)

Gehring (1968)
Smyth et al. (1969)
Carpenter et al .
(1949)
Smyth et al. (1969)

Torkelson and Rows
(1982)
Wahlberg (1976)
 :-.:,  c-  ficJp-'ee limits.

'bji.*.-.i»ticn not provided.
c> •,
j'-'te
"3.750 mg/L.

*500 mg/L; at this concentration, 4/6 animals died during the observation period.

'2.000 mg/L; at this concentration,  an unspecified number of animals died.
                                                 V-2

-------
based on a delay of protein, glucose, and phenolsulfonaphthalein (PSP)
excretion.  Lesions of the kidney Included the presence of hyaline droplets,
nuclear pyknosls, hydropic degeneration,  Increased eoslnophllia, necrosis with
karyolysls, and loss of epithelium of the convoluted tubules.

     Lundberg et al.  (1986) administered  1,1,2,-TCE diluted In  peanut oil, by
1p Injection, to groups of six female Sprague-Dawley rats (200  g) at levels of
0.1 to 1.0 ml 1,1,2-TCE and determined the LDH values to be 405 mg/kg after
24 hours and 265 mg/kg after a 14-day observation period.  Administration of
1/8 of the 24-hour LDM value caused a significant Increase (p <0.05) In
sorbltol dehydrogenase (SDH) activity, Indicating possible hepatic toxldty.
Hahlberg (1976) Injected groups of guinea pigs (370 to 378 g)  of both sexes
Intraperltoneally with 0.25, 0.5, or 2.0 ml 1,1,2-TCE [97Q, 1,930, and
7,619 mg/kg, respectively).  All animals receiving the two highest dose levels
and 80% of the animals receiving the low dose level died within 24 hours.  An
LDM value of 970 mg/kg (at a single total dosage of 0.25 ml) was reported
after 1 hour of exposure (5 of 10 guinea pigs died); the high dose
(7,619-mg/kg) produced 90% mortality, and the middle dose (1,930 mg/kg) killed
60% within 1 hour.

     1,1,2-TCE diluted 1n corn oil was administered 1p to five  mongrel  dogs
    o 14 kg) divided Into three groups (two, two, or one per group) at dose
it-veU of 504, 648, or 792 mg/kg, respectively (Klaassen and Plaa, 1967).  The
24-hour LD50 value was 648 mg/kg.  Mild hepatic centrllobular necrosis and
kidney dysfunction and necrosis were noted.. These hlstopathologlc changes
were similar to those observed In mice (Klaassen and Plaa, 1966, 1967).

     Subcutaneous Injections of 160,  200, 267, and 387 mg 1,1,2-TCE/kg  diluted
1n peanut oil administered to male albino Princeton mice (18 to 25 g) resulted
in a 10-day LDW of 227 mg/kg  (Plaa et al.,  1958).  After 24 hours, 100%
mortality was observed at the highest dose; at the 267- and 200-mg/kg dose
levels, 30 and 20% mortality occurred, respectively.  No animals d*»d at
160 mg/kg, the lowest dose level.  Tubular lesions within the kidney cortex
were seen, and livers appeared pale with distinct mosaic lobular mottling,
which increased 1n severity 1n a dose-related fashion.  Microscopically, the
livers showed degrees of central necrosis.  At the higher dose levels,  the

                                      V-3

-------
centra] veins were dilated and congested, and the adjacent parenchyma!  cells
displayed flbrinoid necrosis.  Cytoplasmic vacuolizatlon and alterations of
cellular staining characteristics were observed at lower doses.

     Inhalation studies reveal  LOW values of 500 to 3,750 mg/L in mammals,
depending on exposure duration.  Gehrlng (1968) dosed 20 female Swiss-Webster
white mice with 1,1,2-TCE vapors at a concentration of 3,750 mg/l.  Half of
the mice died after 6 hours of exposure.  Concurrently, a significant Increase
In serum glutamlc-pyruvlc transamlnase (SGPT) activity, suggesting a possible
hepatotoxlc effect, was observed.  In a range-finding study, groups of six
albino rats (sex not specified) were subjected to 1,1,2-TCE vapors for up to
8 hours and observed for 14 days.  Exposure to a concentration of 500 mg/L for
8 hours resulted 1n the death of four of six rats (Smyth et al., ,1969).  No
other Information was given.  In an Inhalation experiment by Carpenter et al.
(1949), six Sherman albino rats (100 to 150 g, sex not specified) were exposed
to 2,000 mg 1,1,2-TCE/L for 4 hours.  Animals were observed for 14 days.
1,1,2-TCE was rated a moderate hazard and was grouped with other chemicals
that caused the death of two, three, or four of the six study animals.  No
other Information was provided.

     In a dermal toxldty study, the clipped skin of four male albino New
Tr-'V-f rabbits (2.5 to 3.5 kg) was exposed to 1,1,2-TCE (specific doses not
viven) for a 24-hour contact period; the chemical was held under an Impervious
 ^-;tic film.  After 14 days of observation, a dermal LOM value of 5,371
ing/kg was determined (Smyth et al., 1969).  Torkelson and Rowe (1982) reported
the results of an unpublished study by the Dow Chemical Company, where three
of four rabbits survived single 24-hour applications of 1,000 or 2,000 mg
1,1,2-TCE/kg.  These doses, along with a 500 mg/kg dose, caused Illness,
delayed recovery, and liver and Kidney Injury.  Hahlberg (1976) reported that
a single application of 1,930 or 7,619 mg 1,1,2-TCE/kg to 0.7% of the skin
killed all 20 guinea pigs (370 to 378 g, sexes combined) In 3 days, but a
970 mg/kg dose killed only. 5 of 20 animals after 28 days.  Weight gain of the
15 survivors was significantly (p <0.05) lower than that of controls.

     A summary of the acute effects of 1,1,2-TCE 1s presented In Table V-2.
                                      V-4

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                           Table V-2.  Sunury of Short-Tenn Effects of 1,1.2-TCE
Species
(sex) Route*
Rat (M) oral
Rat (N) oral
Dog (M/F) oral
Dose
(mg/kg bw)
SO. 100.
233
1.080
403-749
Treatment
regimen
Single dose
Single dose
Single dose
Effect*
LOAEL: 60 mg/kg bw.
Significant Increases
In S6PT and SGOT at
all doses.
Decreases In mlcro-
somal cytochrome P-450
hepatic ALA-dtfhydra-
tase. and hepatic
glutatMone.
Renal necrosis and
dilation of cotlect-
Reference
Tyson et al .
(1963)
Moody and
Smuckler (1986)
Klaassen and
Plaa (1967)
Dog (N.P.J*    oral
Mouse (M)      oral
Mouse (M)      ip



Mouse (M)      Ip


Mouse (M)      1p





Mouse          Ip



Rat (F)        Ip
144-720
Single dose
 3.80

 3S.O
                            144-504




                             72-144


                            268-576

                              576



                            213



                            12.7-51
Given dally
for 14 days
               Single dose
Ing ducts; renal
function Impaired

Fatty degeneration
and central necrosis
of the liver, gastro-
intestinal Irritation
and Inflaimatlon,
kidney discoloration
and congestion.
Narcotic effect
observed at all doses
except 144 mg/kg.

HOAEL: 3.80 mg/kg.

Significant increase
over controls In abso-
lute might of brain,
thyaus. testes; de-
crease in LDH.

Renal and hepatic
necrosis; protelnurla
and glucosurta.
               Single dose    Protelnurla.
               Single dose

               Multiple
               (three)
               doses

               Single dose
               Single dose
               Renal  necrosis and dys-
               function and swelling
               of proximal  convoluted
               tubules, and protelnurla
               and glucosurla.

               Significant  reduction
               tn PAN accumulation by
               renal  cortical slices

               LOAEL:  51 mg/kg.
               Increased SDH activity
               observed.
                                                                                        Wright;  and Sanders
                                                                                        et al.  (1S85)
                                                                                        White et  al.  (1985)

                                                                                        Sanders et  al.
                                                                                        (1985)
                                             Klaassen  and  Plaa
                                             (1966)
                              Plaa and Larson
                              (1965)

                              Plaa and Larson
                              (1965)
                              Kluwe et al. (1978)
                              Lundberg et al.
                              (1986)
                                                                                                 (continued)
                                                    V-5

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                                                Table V-Z.  (continued)
Species                      Dose        '   Treatment
 (sex)        Route1       (mg/kg bw)        regimen
                                       Effect*
                                               Reference
Rat (H)     1P
Oog (H/F)   tp
Mouse (H)   sc
    C (M)   SC
    706
  345-720
144 and 288
                             .144
                             144
 173. 240,
 280. 320.
    347
Single dose
Single dose
Single dose
                  Two doses,
                  6 hours
                  apart
Multiple
(four)
doses

Single dose
A 3.5-fold Increase In
hepatic trlglycertdes;
no Increased liptd
peroxldatlon In vitro
or in vivo

Renal and hepatic
necrosis; elevated
S6PT; decreased
renal function.

Renal dysfunction Indi-
cated by reduced PAH
uptake by renal corti-
cal slices.

Renal dysfunction Indi-
cated by reduced PAH
uptake by renal corti-
cal slices.

Protection against
nephrotoxlc effects
of 1,1,2-TCE.

Hepatic and renal ne-
crosis at higher (un-
specified) doses; vacu-
oltzatlon and altera-
tions in staining char-
acteristics at lower
(unspecified) doses;
renal lesions at all
doses; anesthesia In-
duced at doses of 240
mg/kg and greater.
Klaassen and Plaa
(1969)
Klaassen and Plaa
Plaa (1967)
Watrous and Plaa
(1972)
                                             Vatrous and Plaa
                                             C1972)
Plaa et al. (1958)
Mouse (M)
Mouse (F)


Guinea (M/
t) pig


inhal ,
Inhal


dermal



890"
3.750*


2.880-
3.600


2 hours
24 hours


15 minutes
to 12 hours


No effect.
Hepatic damage as Indi-
cated by Increased SGPT
levels; anesthesia.
Morphological changes
In epidermis, liver;
decrease in hepatic.
glycogen content.
Carl son
Gehri ng


Kronevi
(1977)


(1373)
(1968)


et al.



                                                                                                  (continued}
                                                    V-6

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                                                Table V-2.  (continued)
Species
 (sex)
Route*
  Dose
(mg/kg bw)
Treatment
 regimen
Effect1
Reference
Guinea (M/  dermal
 F) P19
Rabbit (M/  dermal
 F)

Rabbit (F)  dermal
Rabbit (F)  ocular
              240-3571




               0.144"


             960-1.200*




             960-1,300*
                At least 10
                days
                At least 10
                days

                Single dose
                Single In-
                stillation
              Edema, erythema,  fls*
              surlng, and scaling of
              skin at application
              site (for both species).
              Moderate to severe
              swelling and various
              lesions .observed at
              application site.

              Severe eye irritation.
              reversible conjunc-
              tivitis, epithelial
              abrasions, and epithe-
              lial keratopathy
              developed.
                        Wahlberg (1984a,
                        19846)
                        Ouprat et al.  (1976)
                        Duprat et al. (1976)
        ations used:
    1p « i~:-aperitoneal; sc • subcutaneous; inhal » inhalation;  N.P.  • not provided;
    LCAiL * Lwest-Observed-Adverse-Effect Level;  SGPT • serum glutamlc-pyruvlc transaminase;
    S5D1 - -"M glutamic-oxaloacetlc transmlnase; ALA » aminolevulinlc acid;
            iO-Observed-Adverse-Effect Level; LDH • lactate dehydrogenase;
        * p-anrinohlppuric acid; SDH » sorbitol dehydrogenase.

      range based on  weight of animal.  Total dose was 0.144 dig/guinea pig.
   .al  dose In mg; weight of animals not provided.
 I oral  application was 2.0 mL.
                                                    V-7

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2.   Other Effects

     a. Permal/ocular effects

     In a dermal toxlcity study by Kronevi et al, (1977), 11 outfared guinea
pigs (sexes combined) were exposed'to 1 ml (1.44 g) of pure 1,1,2-TCE applied
directly to the clipped skin of the back for periods ranging from 15 minutes
to 12 hours.  At an unspecified time before 1,1,2-TCE application, animals
were given 1p injections of pentobarbital (40 mg/kg).  Degenerative changes in
the epidermis were observed as early as 15 minutes after 1,1,2-TCE application
and continued to progress with prolonged exposure.  Morphological changes
included pyknotic nuclei, perinuclear edema of basal and suprabasilar cells,
and a focal separation of the epidermis from the corium with vesicle
formation.  Within 6 hours of exposure, the hepatic glycogen content had
dropped significantly, and liver tissue showed hydropic changes in the
"-ntrilobular areas.  Liver changes were less marked 12 hours after exposure
uid were absent in anesthetized animals not exposed to TCE as well as in
nonanesthetized, TCE-exposed animals.  The  authors suggest that pentobarbital
interacted with 1,1,2-TCE or its metabolites, possibly inducing 1,1,2-TCE's
toxic.action.

     1,1,2-TCE was applied to clipped skin on the backs of four New Zealand
rabbits and on the flanks of six Hartley guinea pigs for a minimum of 10 days
(Hahi berg, 1983, 1984b).  A total of 144 mg 1,1,2-TCE was applied to each
animal; guinea pigs received doses of 240 to 357 mg/kg, depending on body
size.  Heights of rabbits were not reported, and the sex of the animals was
not given.  Initial exposure to the organic solvent produced edema and
erythema; repeated daily treatments resulted in fissuring and scaling of the
skin at the test sites.  During the first 10 days of exposure, skinfold
thickness measurements (used to reflect degree of edema) Increased by 220 and
170X in rabbits and guinea pigs, respectively, when compared to pretreatment
skinfo'M valir.s.  With continued exposure, dermal responses to 1,1,2-TCE
peaked at 24 hours after the first application, reached a minimum at 72 hours,
and began to rise again after 96 hours.  Species-specific effects and.
differences were not observed.
                                      V-8

-------
     Ouprat et al. (1976) reported that 2.0 ml 1,1,2-TCE (960 to 1,200 rog/kg,
depending on weight) was a mild dermal Irritant and a severe ocular Irritant
when applied directly to the skin and eyes of groups of six female New Zealand
rabbits.  Animals in the ocular study developed conjunctivitis with epithelial
abrasions that were visible by fluorescent lamp.  On day 7 postexposure,
microscopic examination of the eyes revealed epithelial keratopathy.  Eyes
returned to normal within 2 weeks.  In the dermal study, moderate to severe
swelling and lesions were observed at the site of 1,1,2-TCE applications.  No
other information was provided.

     b.   Biochemical/pathological effects

     Tyson et al. (1983) fasted three to five adult male Sprague-Dawley rats
prior to administering a single oral dose of 60, 100, or 233 mg 1,1,2-TCE/kg.
Hepatotoxicity was Indicated by increases in serum glutamic-oxaloacetlc
'--samlnase (SCOT) and SGPT activities, which peaked 48 hours after dosing.
    release of these cytosolic enzymes of the liver signals a compromise in
the Integrity of the cell membrane.  The EDM value for elevated serum
transarainases was 60 mg/kg, which could be a LOAEL for the oral hepatotoxicity
of 1,1,2-TCE. In a study by HacOonald et al. (1982a), the amount of hepatic
necrosis in acetone-pretreated male Sprague-Oawley rats corresponded directly
to SGPT levels after the animals received a single 1p dose of either 168 or
233 mg 1,1,2-TCE/kg.

     Following administration of a single oral dose of 1,080 mg 1,1,2-TCE/kg
to a group of 18 male Sprague-Dawley CO rats, microsomal P-450 and hepatic
ALA-dehydratase and GSH levels were, respectively, 20, 68, and 45% lower than
corresponding values from vehicle-only treated control animals (Moody and
Smuckler, 1986).  Liver protein and porphyrin levels remained unchanged
throughout the 18-hour postdosing period.

     Wright and Schaffer (1932) reported that a single oral dose of 0.1, 0.2,
0.3, or 0.5 ml 1,1,2-TCE/kg (144, 288, 432, or 720 mg/kg, respectively) given
to six dogs produced fatty degeneration and central necrosis of the liver,
gastrointestinal irritation and inflammation, and discoloration and congestion
                                      V-9

-------
of the kidneys.
lowest dose.
The organic solvent also had a narcotic effect at all but the
     In 14-day oral range-finding studies conducted by White et al. (1985)  and
Sanders et al. (1985), three groups of.11 or 12 male CD-I mice were adminis-
tered, by gavage, dally doses of 3.8 or 38 mg 1,1,2-TCE/kg (1/100 and 1/10 the
LDM, respectively).  Body and organ (brain, spleen, liver, lungs,  thymus,
kidneys, and testes) weights, hematology, serum chemistry, and cell-mediated
and humoral Immune function were examined.  Absolute weights of the brain,
thymus, and testes were significantly (p <0.05) greater in the high-dose group
than in vehicle (10% emulphor)-treated animals; however, when compared on a
body or brain weight basis, organ weights from these 1,1,2-TCE-dosed animals
were not different from those of controls.  A statistically significant
(p <0.05) Increase in liver weight, when normalized for body weight, was
reported for low-dose mice only.  Lactate dehydrogenase (LDH) activity In
animals dosed with 38 mg 1,1,2-TCE/kg was 21% lower (p <0.05) than in
controls; a 10% difference 1n LDH activity between the 3.8 mg 1,1,2-TCE/kg
group and the vehicle-only treated group was not significant at the 95%
confidence level.  No other changes in treated animals were noted.

     Klaassen and Plaa (1966) reported that at 0.10 ml/kg (144 mg/kg),  50% of
the treated animals showed elevated activity (EOM for SGPT) following 1p
administration of 0.10, 0.12, 0.13, 0.15, 0.25, or 0.35 ml 1,1,2-TCE/kg (144,
173, 187, 216, 360, or 504 mg/kg, respectively) to groups of 10 to 15 male
-  -'-^-Webster mice.  The EDM for sulfobromophthaleln retention was 0.25 ml/kg
      •>/kg).  Further Investigation revealed cellular Infiltration and
         *ion of hepatocytes at lower 1,1,2-TCE doses.  At higher doses,
           sloped centrllobular coagulative necrosis.  Oral administration of
5 g 6ur» <..  idnol/kg for 3 days prior to 1,1,2-TCE dosing (187 mg/kg) did not
enhance the hepatotoxic effects of 1,1,2-TCE.  However, a single oral dose of
60% ethanol 12 hours before 1,1,2-TCE 1ngest1on (173 mg/kg) caused a
significant (p <0.05) Increase 1n SGPT activity.  Excretion of glucose and
protein, and low levels of urinary PSP, suggested 1,1,2-TCE-induced kidney
dysfunction.  H1sto1og1cal examination of the kidneys revealed hyaline
droplets, nuclear pyknosis, hydropic regeneration, and Increased eoslnophilia
as well as necrosis with karyolysis and loss of epithelium of the convoluted

                                     V-10

-------
tubules.  Pretreatment with ethanol for 3 days had no effect on kidney
function In 1,1,2-TCE-dosed mice.  When ethanol was given 12 hours before
1,1,2-TCE, however, renal function was significantly (p <0.05) Impaired.  The
authors (Klaassen and Plaa, 1966) commented that kidney changes did not appear
related to 1,1,2-TCE-Induced hepatic effects.

     1,1,2-TCE produced marked nephrotoxiclty 1n groups of 4 or 10 male Swiss
mice given a single ip dose of 0.05, 0.1, 0.2, or 0.4 ml/kg (72, 144, 288, or
576 mg/kg, respectively) of the organic solvent (Plaa and Larson, 1965).
Significant renal Impairment, as measured by urinary protein levels of at
least 100 mg% and urinary glucose levels of at least 250 mg%, was present 1n
50 to 60% of mice dosed with 0.2 ml 1,1,2-TCE/kg (288 mg/kg} and in 100% of
those given 0.4 ml/kg (576 mg/kg); 10 and 40% of the animals exhibited only
proteinuria following Injection of 0.05 and 0.1 ml 1,1,2-TCE/kg (72 and 144
mg/kg), respectively.  Multiple 1p doses of 1,1,2-TCE (576 mg/kg every other
day for a total of three doses) resulted in renal dysfunction in all animals
tested.  The EDM for proteinuria and glucosuHa was 0.15 ml/kg  (216 mg/kg).
Histological examination of the kidneys showed that all high-dose mice had
necrotic and swollen proximal convoluted tubules.  All animals dosed with 0.2
ml 1,1,2-TCE (288jng/kg) exhibited tubular swelling, but only 40% developed
renal necrosis.  The presence of protein and glucose In the urine correlated
well with necrosis, but not swelling, of the proximal tubules.

     '  'ingle 1p Injection of 0.15 ml 1,1,2-TCE/kg (213 mg/kg) to adult male
          Dumber of animals not specified) caused a 22% reduction in p-amino-
hippu,       1 (PAH) accumulation in renal cortical slices when compared to PAH
uptake by nuney tissue from vehicle-only treated animals (Kluwe et al.,
1978).  1,1,2-TCE had no effect, however, on liver or kidney weight-to-body
weight ratios, SGOT activity, and blood urea nitrogen.  When mice Ingested 100
ppm polybromlnated biphenyls (PB8) 1n their diet for 14 days before being
dosed Ip with 0.15 ml 1,1,2-TCE (216 mg/kg), the liver weight-to-body weight
ratio was Increased by nearly 50% over that of 1,1,2-TCE-dosed mice fed a
normal diet.  In the same experiment, the overall reduction In PAH uptake by
renal cortical slices from 1,1,2-TCE/PBB-dosed nice was approximately 39%
below that of vehicle-only treated controls consuming no PB8 and 17% less than
that of TCE-dosed mice.  The data suggest that 1,1,2-TCE alone Impairs renal
        4
                                     V-ll

-------
function and that PBB  (which activate the mixed-function oxygenase (HFO)
enzyme systems believed responsible for the bloactlvation of 1,1,2-TCE)
potentiate the toxic action of the organic solvent.

     A single 1p Injection of 51 mg 1,1,2-TCE/kg {1/8 of the 24-hour LDM) to
six female Sprague-Dawley rats significantly (p <0.05) Increased SDH activity,
Indicating that liver damage had occurred within 18 hours after dosing
{Lundberg et al., 1986).  Administration of 12.7 and 25.3 mg 1,1,2-TCE/kg
(1/32 and 1/16 of the LOW, respectively) had no apparent effect on SDH
levels.  A LOAEL of 51 ing/kg for hepatotoxldty of 1,1,2-TCE was suggested by
the data.

     Klaassen and Plaa (1969) observed a 3.5-fold Increase In hepatic trlglyc-
eride levels 36 hours after 18 male Sprague-Dawley rats received a single ip
dose of 0.49 ml 1,1,2-TCE/kg (75% of the LDM).  There was ho enhancement of
I1p1d peroxldatlon, as measured by Increased production of thlobarblturlc acid
reactants in vitro and dlene conjugates in vivo.  Therefore, no apparent
association between free radical formation and 1,1,2-TCE metabolism was
evident.

     1,1,2-TCE,  given 1n single 1p doses to male and female mongrel  dogs,  was
toxic to the kidneys and liver (Klaassen and Plaa, 1967).  Two of five animals
given 0.24 to 0.50 ml 1,1,2-TCE/kg (345 to 720 rag/kg) exhibited elevated SGPT
activity 24 hours after exposure, but responses were not dose-related.  SGPT
levels peaked 2 days after a single 1p dose of 0.45 ml/kg (647 mg/kg), or 75%
of the 1p LDM.  The EDM for  SGPT was calculated as 0.35 ml/kg  (507 mg/kg).
Exposure to 1,1,2-TCE resulted 1n centrllobular necrosis, subcapsular
necrosis, and vacuollzatlon of centrllobular hepatocytes.  Another group of
five dogs was administered a single oral dose of 0.28, 0.40, or 0.52 ml 1,1,2-
TCE/kg (403, 576, and 749 mg/kg, respectively).  Excretion of PSP was markedly
reduced In 40% of the animals, Indicating Impairment of renal function.
Kidney tissue was necrotic upon hlstologlcal examination; at near-EDM doses
(576 mg/kg), slight changes, such as mild dilation of the collecting ducts,
were observed.  A single oral dose of 50% ethanol (4 g/kg) had no effect on
the hepato- or nephrotoxlc action of 1,1,2-TCE.
                                     V-12

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     Interference with normal  renal  function was Indicated  by results  of a
series of experiments conducted by Watrous and Plaa (1972), who gave
subcutaneous (sc) Injections of 0.1 or 0.2 ml 1,1,2-TCE/kg  (144 or 288 mg/kg)
to groups of male Swiss-Webster mice.  Single doses of 1,1,2-TCE reduced
(p <0.025) the ability of renal cortical slices to concentrate PAH. Multiple
doses of 0.1 mi 1,1,2-TCE/kg (144 mg/kg), given on days 1,  3, 6, and 8 of a
9-day study, afforded significant (p <0.025) protection against the apparent
nephrotoxic effects of one 1,1,2-TCE Injection; uptake of PAH by kidney slices
from repeatedly dosed mice was essentially the same as that from control
animals.  In another experiment, however, pretreatment with a single sc
Injection of 0.1 mL 1,1,2-TCE/kg (144 mg/kg) had no effect  on renal function
when a challenge dose (of the same concentration) was given 6 hours later.
Renal dysfunction 1n any of the single, multiple, or challenge dose studies
was observed within 24 hours of injection only; kidney activity returned to
normal after this time.
     Plaa et al. (1958) gave each of 37 male albino Princeton mice a single sc.
dose of 173, 240, 280, 320, or 347 mg 1,1,2-TCE/kg (assuming an average weight
of 20 g).  Doses of 240 mg/kg and greater Induced a prolonged, dose-related
sleeping time (anesthesia) 1n 20 to 100% of the animals.  Gross and
microscopic examination of livers from 1,1,2-TCE-dosed mice was combined with
that from animals exposed to other chlorinated hydrocarbons (e.g., chloroform,
carbon tetrachloride, 1,1,1-TCE).  The appearance of mouse livers varied
vaely, from paling to distinct mosaic lobular mottling.  Friable, yellow
livers also were observed.  At higher doses, necrosis was present; in severely
affected livers, the central veins were dilated and congested, and the
adjacent parenchymal cells showed flbrinold necrosis.  Cytoplasmic
vacuolization and alterations in the staining characteristics were noted at
lower doses.  The kidneys of animals given 1,1,2-TCE exhibited tubular lesions
that consisted of broad bands of fibrlnold necrosis within the renal cortex.
These lesions were apparent at the lowest 1,1,2-TCE dose (173 mg/kg) and were,
therefore, not coincidental with extensive liver damage.  Since the EOW and
the LDW were nearly  Identical, there appeared to be an association between
doses leading to liver damage and those leading to death.
                                     V-13

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     In an Inhalation study conducted by Carlson (1973),  groups of three to
five adult male albino mice were exposed to 890 pprn (mg/L) 1,1,2-TCE vapors
for Z hours.  Treated animals*showed no signs of hepatic damage; liver-to-body
weight ratios and glucose-6-phosphatase, SGPT, and SCOT activities were
comparable to those of mice Inhaling only air.  Exposure to 890 ppm 1,1,2-TCE
for 2 hours, therefore, had no apparent effect on liver tissue 1n mice.

     1,1,2-TCE was rated a moderate hepatotoxin following exposure of female
Swiss-Webster mice to 3,750 ppm 1,1,2-TCE vapors (the LOM for a 9- to 12-hour
exposure period) for 24 hours (Gehrfng, 1968).  Increases In SGPT levels were
used as a measure of liver dysfunction and hepatotoxlcity.  The time at which
50% of treated animals exhibited measured parameter (ETW) value for SGPT
elevation was 17.5 minutes, which was approximately equal to the.time required
to Induce anesthesia In dosed mice.  The duration of time between Initial
exposure and death of 50% of treated animals (UM) was 600 minutes.

B.   LONG-TERN EXPOSURE

     A summary of the long-term exposure toxlclty of 1,1,2-TCE Is presented In
Table V-3.
     Based on the 14-day range-finding study for determination of appropriate
     ., White et al. (1985) administered 1,1,2-TCE (95% purity) In drinking
water to male and female CD-I mice, 16/sex, at levels of 20, 200, and 2,000
mg/L for 90 days.  Twenty-four mice of each sex served as controls.  The
desired doses were 3.8, 38, and 380 Dig/kg (1/100, 1/10, and 1/1 of the LOM as
previously determined).  On the basis of water consumption and body weight
data, time-weighted average Intakes for males were 0, 4.4, 46, and 305
mg/kg/day, and for females, 0, 3.9, 44, and 384 mg/kg/day.  Toxlclty
parameters measured Included fluid consumption, tissue weight (brain, liver,
spleen, lungs, thymus, kidneys, and testes), hematology, serum chemistry (14
parameters), liver glutathlone, and hepatic mlcrosomal activities.
Hlstologlcal examination of tissues was not performed.

     Water consumption 1n high-dose (380 mg/kg) males was depressed 30%, and a
dose-related reduction In weight gain was statistically significant (p <0.05)

                                     V-14

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                       Table V-3.   Summary of Long-term Exposure Toxicity of 1,1,2-TCE
                           Dally
Species                    dose
 {sex}         Route       (mg/kg)
                            Duration
                                 Effect
                                                  Reference
House (H)
oral
{drinking
 water)
4.4

46
                             305
Mouse (F)
oral
(drinking
 water)
  3.9

 44
                             384
House (H/F)
oral
(gavage
 in corn
 oil)
Rat (H/F)
    (H/F)
oral
(gavage In
 com oil)
195
                             390
 46
                92
90 days        NOAEL.

               LOAEL;  reduced
               liver gluta-
               thlone; depressed
               hemagglutlnin
               tUers.

               Decreased liver
               glutathione; In-
               creased serum al-
               kaline phosphatase;
               depressed macro-
               phage function and
               hemagglutlnln
               liters

90 days        NOAEL.

               LOAEL;  reduced hepa-
               tic cytochrome P-450
               and aniline hydroxy-
               lase activity; depressed
               hemagglutinln liters.

               Reduced hemoglobin
               and hematocrlt.  In-
               creases in liver glu-
               tathione end other
               liver parameters; de-
               creased macrophage
               function and
               hemagglutinin liters.

78 weeks       Increased mortality;
               hepatocellular carcin-
               omas and adrenal pheo-
               chromocytomas.

               Increased mortality;
               hepatocellular carcin-
               omas and adrenal pheo-
               chromocytooifts.

78 weeks       LOAEL;  clinical
               signs of toxicity.
                             Clinical  signs of
                             toxicity.
White et al. (1985);
Sanders et al.
(1985)
»>ite et al. (1985);
Sanders et al.
et at. (19S5)
NCI (1978)
NCI (1976)
                                                   V-15

-------
at this level.  Females showed no effects with respect to water consumption
and weight gain.  Mice of both sexes had altered serum chemistries that
indicated possible adverse effects on the liver.  The only significant
(p <0.05) dose-related effects In males in the 90-day study by White et al.
(1985) were decreased 6SH levels (at the middle and high doses) and elevated
serum alkaline phosphatase (SAP) levels (at the high dose only), indicating
effects on the liver.  However, there were no elevations of SGOT or SGPT in
males, which would have been expected if 90-day exposure resulted in liver
damage.  Several hematological and blood chemistry parameters were affected in.
high-dose females; significantly (p <0.05) decreased hematocrit and hemoglobin
levels and significantly Increased numbers of leukocytes and platelets were
observed.  Females also exhibited a dose-dependent increase in fibrinogen
levels and a decrease in prothrombin time.

     SGOT and SAP levels were significantly Increased In all  female groups,
but not in a dose-related manner.  High-dose females had significantly higher
     and serum protein levels than control mice, and female mice from both the
   - and high-dose groups had significantly depressed cytochrome P-450 and
aniline hydroxylase activities.  Females also exhibited a dose-dependent
Increase in hepatic GSH.  In addition, absolute liver, spleen, and kidney
weights of females administered 380 rog 1,1,2-TCE/kg were significantly
Increased, as were brain and liver weights adjusted for total body weight. In
these studies, the LOAEL seen in females was at a dose of 0.2 mg 1,1,2-TCE/mL
of drinking water (44 mg/kg), which resulted in a reduction of cytochrome P-
                              •
450 levels and aniline hydroxylase-activity and an Increase In SGOT and SAP
activities.  In males, the LOAEL was 46 mg/kg, based on reduction of liver
glutathione.  The NOAEL in both males and females was at the 0.02-mg/mL (4.4
and 3.9 mg/kg, respectively) dose level.

     Sanders et al.  (1985) assessed 1mmunolog1cal  effects of 1,1,2-TCE on the
same CD-I mice used 1n the White et al. (1985) study following 90-day exposure
to the chemical In drinking water 44.4, *3, and 305 mg/kg for males and 3.9,
44, and 384 mg/kg for females).  Humoral immune status was evaluated by
enumeration of IgM antibody-forming cells (AFC) against sheep erythrocytes
(sRBC), measurement of hemagglutlnin tlters, and evaluation of spleen
lymphocyte responsiveness to lipopolysaccharides (LPS).  Cell-mediated immune

                                     V-16

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status was evaluated by the delayed-type hypersensltivity (DTK) and popliteal
lymph node proliferation responses to sRBC.  Cell-mediated immunity was
unaltered in both .sexes by exposure to 1,1,2-TCE at any of the levels used.
Humoral Immune status, on the other hand, was depressed in mice of both sexes
in the mid- and high-dose groups, particularly when determined by
hemagglutinin liters.  Nacrophage function was depressed only in the high-dose
males and was indicated by the ability of thioglycolate-recruited peritoneal
exudate cells (PEC) to phagocytize sRBC.  Spleen lymphocyte responsiveness to
the B cell mitogen, IPS, was unalterifl.1n males, but was significantly
decreased in females exposed to the highest concentration of the 1,1,2-TCE.
Females also exhibited a greater degree of hemagglutinin depression than males
following exposure to 1,1,2-TCE.  The authors concluded that there are" sex
differences in the immunological response of animals to the chemical, which
can be seen only when certain assays are employed.  The NOAEL and LOAEL values
in mice, as measured by the effects of 1,1,2-TCE on Immune response, are the
same as from those established through measurement of the standard
toxicological indices.

     The chronic toxicity of 1,1,2-TCE was evaluated by the National Cancer
T-«*1tut« (NCI, 1978} as part of a lifetime oral study in both male and female
     (Osborne-Mendel) and mice (B6C3FJ.   Technical  grade  1,1,2-TCE  (95.1%
  .rage purity) in corn oil was administered by stomach tube to 50 male and 50
female animals of each test species at two dose levels, 5 days per week for 78
weeks.  The average high dose for male rats was 92 mg/kg/day, and the low dose
was 46 mg/kg/day.  For mice, the average high dose was 390 mg/kg/day, and the
low dose was 195 mg/kg/day.  After 78 weeks of treatment,  rats were observed
for an additional 35 weeks; mice were observed for an additional 13 weeks.
Control groups consisted of 20 untreated animals of each sex and species, and
an additional 20 animals of each sex and species, which were treated with corn
oil by gavage.  Histopathology consisted of gross and microscopic examination
of major tissues, organs, or gross lesions.  Slides were prepared from
approximately 32 tissues.

     During the first 6 months of the study,  the appearance and behavior of
the treated rats and untreated controls were generally comparable.  In later
stages, treated .rats showed clinical  signs that Included a hunched appearance,

                                     V-17

-------

-------
rough fur, urine stains on the abdominal area, dyspnea, and squinted eyes,
sometimes with reddish exudate; the Incidence and frequency of symptoms were
comparable 1n high- and low-dose groups.  Increased respiratory difficulty was
noted In treated animals when compared to controls as the study approached
termination.  Otherwise, no statistically significant neoplastlc or
nonneoplastlc changes due to treatment were reported for either sex.  This
study established a LOAEL of 46 rog/kg/day for rats, based on clinical signs,
since other signs of toxlclty were not apparent.

     There was no appreciable difference In body weight gain between treated
and untreated mice.  During the first year of the study, the appearance and
behavior of treated mice were generally similar to those of controls.  After
46 weeks of compound administration, however, abdominal distension was evident
f" L few high-dose males and females and thereafter was observed In gradually
    easing numbers In these groups.  Subsequent necropsy Indicated that liver
  .nors were the cause of the abdominal distension.  In female mice, the Tarone
.est Indicated a significant (p <0.001) association between Increased dose and
accelerated mortality.  No nonneoplastlc hlstopathologlcal changes between
treated and control mice were reported.

     Torkelson and Rowe (1982), quoting unpublished data from the Dow Chemical
Company, reported that 6 months of repeated 7-hour Inhalation exposures, 5
days/week, to 15 ppm of 1,1,2-TCE was tolerated by male and female rats,
guinea pigs, and rabbits.  No hlstopathologlcal changes were observed at
necropsy, and the usual parameters of growth, mortality, organ weights,
hematology, and clinical chemistry were not affected.  However, sixteen 7-hour
exposures to 30 ppm resulted In minor fatty changes and cloudy swelling 1n the
livers of female rats.  Hale rats appeared unaffected, although pneumonltls
was slightly higher 1n the 10 exposed rats than In the controls.

C.   REPRODUCTIVE/TERATOGENIC EFFECTS

     No pertinent data regarding the reproductive effects of 1,1,2-TCE could
be located In the available literature, and only very limited data were found
on developmental effects.
                                     V-18

-------
     Seldenberg et al. (1986) screened 1,1,2-TCE for developmental toxiclty by
administering the compound, by gavage, to pregnant ICR/SIM mice at a dose
level of 350 mg/kg/day on gestation days 8 to 12.  Corn oil was used as the
vehicle and the control substance.  The mice were allowed to deliver, and the
neonates were examined and weighed on the day of birth (day 1) and day 3.
Maternal mortality occurred 1n 3 of 30 cases.  No significant effects on
litter size, pup survival, or pup weights were observed.

     Chick embryos (10/group) were dosed with 5, 25,  50, or 100 »mol 1,1,2-
TCE/kg 1n olive oil on day 3 or 6 of Incubation (Elovaara et al., 1979).
Examinations on the 14th day of Incubation revealed dose-related lethality for
embryos treated on either day of development.  The LDSO was estimated to be
between 50 and 100 »mol/egg.  The lengths of the dead embryos decreased with
dose, Indicating that embryos died earlier as the dose Increased.
Malformations were noted In 5 of 55 survivors receiving 5 to 100 *mol/egg
(doses received by Individual malformed embryos were not specified).
Malformations Included exteriorized viscera, profound edema, eye
abnormalities, and skeletal abnormalities. The presence of only eye and
skeletal abnormalities was noted In 2 of 56 controls.

     Brine shrimp (Artemia sallnal  cysts and the hatched nauplll were exposed
to "1,1,3-trichloroethane" [sic] at 0.25 to 25 ppm (Kerster and Schaeffer,
1983). Examinations of the nauplll 48 hours after wetting revealed
significantly different body lengths (reduced or Increased was not specified)
when compared to controls.
                f
     Although developmental effects were observed In  chick embryos and brine
shrimp exposed to 1,1,2-TCE, the relevance of these data to humans Is unknown.

0.   MUTAGENICITY
     Few studies Investigating the genotoxlc potential of 1,1,2-TCE have
appeared 1n the published literature.  This section Includes the published
studies and unpublished assays that were performed to meet U.S. EPA
registration requirements.  These are categorized Into gene mutation assays
(Category 1), chromosome aberration assays (Category 2), and studies that

                                     V-19

-------
assess other mutagenic mechanisms  (Category 3).  The findings are discussed
below.

1.   Gene Mutation Assays (Category 1)

     Simmon et al. (1977) reported, results on mutagenic activity of 71 chemi-
cals, Including 1,1,2-TCE, Identified In drinking water.  1,1,2-TCE was non-
mutagenlc both with and without activation (S9 mix from Arochlor-Induced rat
livers) 1n the Ames Salmonel1a/m1crosome assay 1n $. tvohlmurlum strains
TA1535, TA1537, TA1538, TA98, and TA100.  In these assays, a wide range of
doses was tested: up to 5 ing/plate or a dose that gave a toxic response,
whichever was lower.

     Rannug et al. (1978) also found 1,1,2-TCE to be nonmutagenlc in S_. tvohi-
murlum strain TA1535.  The compound was tested both with and without metabolic
activation by the S9 fraction from phenobarbital-induced rat livers at 20, 40,
and 60 #mol/p1ate.

     Barber et al. (1981) reported that 1,1,2-TCE was not mutagenic in the S.
tvphlmurlum reverse mutation assay.  The compound was tested both with and
without metabolic activation (S9) from Aroclor-Induced rat livers in strains
iV.1535, TA98, and TA100.  Since the test material 1s volatile, the assays were
conducted in a closed Incubation apparatus.  The doses tested ranged between
12.7 and 158.9 *mol/plate.

2.   Chromosome Aberration Assays (Category 21

     No assays under this category were found In the literature searched.

3.   Other Genotoxic Effects (Category 3)

     a.   Mammal1 an cell transformation

     Tu et al. (1985) reported weakly positive results for 1,1,2-TCE in the
8ALB/C-3T3 cell transformation assay.  The cells were exposed to the volatile
test material 1n sealed glass incubation chambers at concentrations of 0,  5,

                                     V-20

-------
 10,  25,  and 50 »g/ml.   The untreated control  and  the positive control
 exhibited acceptable levels of transformation 1n  this assay.   1,1,2-TCE
 induced  a low, but statistically significant,  transformation  response  at  25
 and  50 jtg/mL.

     b.   DMA binding
     DIRenzo et al.  (1982) reported covalent binding of  [MC]1,1,2-TCE,  at 0.35
mmol/mg  DNA/hour,  to calf thymus  DMA In vitro  following  bloactlvatlon by
hepatic  micro somes Isolated  from  phenobarbltal -treated rats.   No  other  details
were given.  A relationship  between hepatotoxldty  and binding was  suggested,
but extrapolation  to In vivo binding was not made.

     Mazzullo  et al.  (1986)  reported that [MC]1,1,2-TCE  bound  covalently to
D!JA, RNA,  and  proteins  of the liver, kidney, lung,  and stomach, 22  hours after
in 1ntraper1toneal  Injection of 127 »C1  (6.35  »mol)  [14C]l,l,2-TCE/kg
administered to 4  adult male Wistar rats and 12 BALB/c mice.   No  specific in
Yiyfl DNA or RNA adducts were Identified,  but DNA  and RNA were  Isolated
adequately, and macromolecules were washed exhaustively  until  no  radioactivity
could  be -extracted from these fractions.  The  Influence  of several  parameters
jon degree  of binding also was monitored.  DNA  binding In the mouse  liver was
approximately  two  to three times  higher than In the rat  liver.  These data
parallel results of chronic  exposure studies (NCI,  1978} that  show  the  mouse
1s more  susceptible to  hepatocellular carcinoma than the rat.  Overall, data
from the Hazzullo  et al.  (1980) study provide  good  supplementary  Information
that are suggestive of  an Interaction between  1,1,2-TCE  and DNA,  RNA, and
other  macromolecules.
E.   CARCINOGEN I CITY
     Only one study was found evaluating the oncogenlclty of 1,1,2-TCE.  A
lifetime oral bloassay of  1,1,2-TCE  for possible carclnogenlclty was  .onducted
by the National Cancer Institute  (NCI, 1978) on both male and female  rats
(Osborne-Mendel)  and nice  (B6C3F,).  Technical  grade 1,1,2-TCE (95.1% average
purity) 1n  corn oil was administered by stomach tube to 50 male and 50 female
animals of  each test species at two  dose levels, 5 days per week for  78 weeks.

                                     V-21

-------
During the experiment, doses for rats were Increased from 70 (high dose) and
30 (low dose) mg/kg/day to 100 and 50 lag/kg/day, respectively.  The'high time-
weighted average dose was 92 mg/kg/day; the low was 46 mg/kg/day.  Doses for
mice were increased from 150 and 300 mg/kg/day to 200 and 400 mg/kg/day,
respectively, with a high time-weighted average dose of 390 mg/kg/day, and a
low time-weighted average dose of 195 mg/kg/day.  After 78 weeks of dosing,
rats were observed for an additional 35 weeks.  Control groups consisted of 20
untreated animals of each sex and species, and an aditional 20 animals of each
sex and species that were treated with corn oil by gavage.  Each animal was
necropsied regardless of whether it died, was killed when moribund, or was
sacrificed at the end of the bioassay.  Histopathology consisted of gross and
microscopic examination of major tissues, organs, or gross lesions taken from
sacrificed animals, and whenever possible, from animals found dead.  Slides
were prepared from approximately 32 tissues.

     Table V-4 shows the recurrence of tumors resulting from administration of
  " !-TCE.  Although some differences were apparent in the incidences of
   .rs occurring in control as compared with treated rats, these were not
,kat1stically significant.  NCI (1978) concluded that the results of the study
do not provide convincing evidence for the cardnogenlcity of 1,1,2-TCE in
Osborne-Nendel rats.  Some question was raised,'however, about whether the
maximum tolerated dose had been reached in rats.  .

     In both male and female mice,  a significant Increase in the incidence of
hepatocellular carcinomas (p <0.001), as shown by both the Fisher Exact test
and the Cochran-Armitage test, occurred as a result of administration of
1,1,2-TCE.  Hepatocellular carcinomas were observed In 2 of 20 (10%) vehicle
rontrol males, 18 of 49 (37%) low-dose males, and 37 of 49 (76%) high-dose
Oes.  In females, hepatocellular carcinomas were seen In 0 of 20 vehicle
control mice, 16 of 48 (33%) low-dose nice, and 40 of 45 (89%) high-dose mice.
Time to first observed hepatocellular carcinoma was also markedly decreased
fo- nice treated with 1,1,2-TCE, with the first tumor observed at 19 and 49
weeks In high-dose males and females, respectively; in vehicle controls, the
first tumor was observed at 90 weeks.
                                     V-22

-------
                 Table V-4.   Occurrence of Tumors From 1,1,2-TCE
Hales
Species Tumor Control
Rat Mammary fibroma and
fibroadenoma
Mammary adenocarcinoma
Pituitary adenoma
Adrenal adenoma
. Thyroid tumors
Kemanglosarcoma
Kidney hamartoma
Netastases
Total tumors
Number of animals
examined
Animals with tumors
' ouse Hepatocellular
carcinoma
Lung adenoma and
carcinoma
• Malignant histiocytic
lymphoma
Adrenal pheochromocytoma
Stomach squamous cell
carcinoma and papilloma
Metastases
Total tumors
Number of animals examined
Animals with tumors
6

1
1
0
1
0
1
0
9
20

6
2

0


2
0

0
0
6
20
6
Low
0

1
5
0
2
4
1
1
26
50

21
18

3


7
0

2
1
36
49
28
High
1

1
1 •
1
0
1
0
0
14
50

11
37

1


1
8

1
7
51
49
38
Females
Control
2

0
2
0
0
0
0
0
4
19

4
0

0


4
0

0
0
5
20
5
Low
18

0
9
3
3
1
4
0
50
50

34
16

3


4
0

0
0
24
48
20
High
9

4
5
1
1
0
-1
4
28
50

22
40

2


1
12

1
5
63
45
41
SOURCE:  Adapted from Welsburger (1977).
                                     V-23

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     A positive dose-related association between 1,1,2-TCE administration and
 the  Incidence of adrenal gland pheochromocytomas in mice of both sexes was
 indicated by the Cochran-Armitage test.  Fisher Exact tests confirmed these
 results for high-dose female mice but not for other groups.  There were no
 other neoplasms for which statistical tests indicated a positive association
 between dosage and tumor incidence*1n mice.  It was concluded that under the
 conditions of the bioassay, 1,1,2-TCE 1s carcinogenic in B6C3F, mice, causing
 hepatocellular carcinomas and adrenal pheochromocytomas.

 F.   SUMMARY

     Table V-l summarizes reported acute LDM values for 1,1,2-TCE.   Estimates
 of oral LDM values in mice, rats, and dogs range from 100 to 835. mg/kg.  Oral
 LDM  values of 378 and 491 mg 1,1,2-TCE/kg were obtained for mice, and values
 of 100 to 200 and 835 mg/kg were reported for rats.  The- oral LDLO value  for
 1,1,2-TCE in dogs 1s 720 mg/kg.

     Acute Intraperitoneal  LDM values for mice, rats, guinea pigs, and dogs
 range from 265 to 970 mg 1,1,2-TCE/kg.  In mice, the LDM value was 504 mg/kg
 after .24 hours of observation, while the 1p LDM value for rats was 405 mg/kg
 after 24 hours and 265 mg/kg after 14 days of observation.  Guinea pigs
 injected 1ntraper1toneally with 970, 1,930, or 7,619 mg 1,1,2-TCE/kg displayed
 50, 60, and 90% mortality,  respectively, only 1 hour after administration.
After 24 hours, 100% mortality was observed at the two highest dose levels,
with 80% mortality at the lowest level.  An LDW value of 648 mg/kg is
reported for dogs injected intraperitoneally with 1,1,2-TCE.  Subcutaneous
 injection of 160, 200, 267, and 387 mg 1,1,2-TCE/kg in mice resulted In 0,  20,
30, and 100% mortality after 24 hours and an LDW value of 227 mg/kg.

     Acute Inhalation studies for rodents reveal  various LDW values for 1,1,2-
TCE.  The Inhalation LCW value for mice Is 3,750 mg/L (6-hour exposure)
compared to an LCM value of 500 mg/L for rats (8-hour exposure).  ,\n
unspecified number of rats  exposed to 2,000 mg/L for 4 hours died during a  14-
day observation period.
                                     V-24

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     Dermal LDM values for rabbits and guinea pigs vary widely.  In one study,
three of four rabbits died after dermal exposure to 1,000 to 2,000 mg 1,1,2-
TCE/kg for 24 hours.  Application of 970, 1,930, or 7,619 mg 1,1,2-TCE/kg to
guinea pigs resulted in 0, 35, and 40% mortality after 24 hours, respectively.
At the two highest dose levels, all animals died after 3 days, while only 5 of
20 guinea pigs at the low-dose level died by day 28.  The LDSO for rabbits 1s
5,371 mg 1,1,2-TCE/kg when the agent 1s applied to the skin for 24 hours and
animals are observed for 14 days.

     Overall, 1p and sc Injections of 1,1,2-TCE.appear to be the most lethal
routes of administration.  No appreciable differences in susceptibility to
lethal effects of 1,1,2-TCE are observed among species.

     In short-term animal studies, dermal contact with 1,1,2-TCE caused sig-
nificant physical and morphological changes In the epidermis at and
surrounding the 1,1,2-TCE application site.  Guinea pigs exposed from 15
minutes to 12 hours to 1 ml 1,1,2-TCE (a dose equivalent to 2,880 to 3,600
mg/kg) developed pyknotic nuclei, perlnuclear edema of basal and suprabasal
cells, and focal separation of the epidermis from the cor1urn; the
administration of pentobarbital prior to application may have altered 1,1,2-
TCE activity, however.  Animals also lost significant amounts of glycogen from
the liver, and hepatic tissue showed hydropic changes In the centrilobular
areas.  Unspecified amounts of 1,1,2-TCE produced edema, erythema, fissuring,
and scaling of skin of rabbits and guinea pigs.  1,1,2-TCE applied to the eyes
of rabbits caused severe Irritation, producing conjunctivitis, epithelial
abrasions, and epithelial keratopathy; ocular effects were reversed within 2
weeks of application.

     Significant liver damage occurred following administration of single oral
doses of 60 to 1,080 mg/kg to rats and 144 to 748 mg/kg to dogs.
Hepatotoxicity In rats was Indicated by increases in SGOT and SGPT and by
decreases 1n microsomal cytochrome P-450, GSH, and ALA-dehydratase.  A
disturbance in heme metabolism was suggested In one study with rats, and a
LOAEL of 60 mg/kg was identified  1n another.  In dogs given oral doses of
1,1,2-TCE, both histological and  hematologlcal evidence of tissue damage were
observed.  Serum transaminase levels rose and PSP excretion rates dropped

                                     V-25

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following 1,1,2-TCE administration.  Histological examination revealed renal
and hepatic necrosis and fatty degeneration of the liver; vacuolization of
hepatocytes, dilation of renal collecting ducts, and Irritation of the
gastrointestinal tract also were observed.  At doses of 288 mg/kg or greater,
1,1,2-TCE Induced sleep.  A 14-day ora.l range-finding study Identified a NOAEL
of 3.8 mg/kg for mice; all physical, chemical, Immunological, and
hematological measurements were normal at this dose.  At 38 mg/kg, however,
absolute weights of the brain, thymus, and testes were greater, and activities
of LDH and SGPT were lower than In vehicle-only-treated animals.

     Intraperitoneal dosing of 1,1,2-TCE (51 to 504 mg/kg) produced a wide
variety of effects 1n mice and rats.  At 51 mg/kg, Increased SDH activity in
rats suggested liver damage, and since no changes were observed In animals
given 12.7 or 25.3 mg 1,1,2-TCE/kg, 51 mg/kg was Identified as an 1p LOAEL for
rrts.  Slightly higher doses (72 to 144 mg/kg) given to mice resulted in
    cinuria; above 144 mg/kg, proteinuria, glucosurla, and a reduction In PAH
  -umulation by renal cortical slices were observed, suggesting kidney
 ysfunction.  Histological examination of renal tissue from high-dose mice
showed necrotic and swollen proximal convoluted tubules.  All animals given
doses of 288 mg/kg or less exhibited tubular swelling, but only 40% had
developed renal necrosis.  The degree of proteinuria and glucosurla appeared
to be a good Indicator of renal necrosis.

     A 3.5-fold increase in hepatic triglycerides was observed in rats given a
single 1p dose of 706 mg 1,1,2-TCE/kg.  However, there was no Increase in
lipid peroxidation (in vitro or in vivo), and an association between free
radical formation and 1,1,2-TCE toxiclty could not be made.

     Single sc Injections of 144 or 288 mg 1,1,2-TCE/kg to mice reduced PAH
Accumulation by renal cortical slices, Indicating kidney damage.  Multiple
.  ses (i.e., four single Injections of 144 mg/kg over an 8-day period)
appeared to offer protection against the nephrotoxic effects of a single
1,1,2-TCE dose.  All mice given a single sc dose of 173 to 347 mg 1,1,2-TCE/kg
exhibited tubular lesions of fibrinold necrosis In the renal cortex and
cytoplasmic vacuollzation and altered staining characteristics in hepatocytes.
At the higher doses, hepatic necrosis and congestion also were observed.

                                     V-26

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 Injections of 240 mg/kg and greater resulted in a prolonged sleeping time for
 20 to 100% of the animals.

     Inhalation of 890 ppm 1,1,2-TCE vapors for 2 hours had no apparent effect
 on mice, but exposure to 3,750 ppm 1,1,2-TCE vapors (the 6-hour LCM) for 24
 hours Induced hepatic damage  (as indicated by increases in SGPT levels) and
 anesthesia in mice.
     In subchronic toxlcity studies, mice were given 1,1,2-TCE In drinking
water at doses of approximately 3.8, 38, and 380 mg/kg for 90 days.  Mice of
both sexes developed altered serum chemistry and changes 1n hepatic microsomal
activities.  Female mice showed significantly decreased hematocHt and
hemoglobin levels at the high dose; elevations In SCOT, SAP, and fibrinogen
levels at all three doses; Increased SGPT at the high dose; a decrease in both
microsomal cytochrome P-450 content and aniline hydroxylase activity at the
middle and high dose; and Increased liver weight only at the high dose.  Male
mice from the mid- and high-dose groups had decreased liver GSH levels, and
those 'in the high-dose group showed an elevation In SAP activity.  In an
extension of this study, in which immunological parameters were measured,
cell-mediated immunity was unaltered in both sexes by exposure all of dose
groups to 1,1,2-TCE for 90 days.  Humoral Immune status, on the other hand,
was depressed in mice of both sexes in the mid- and high-dose groups.  The
subchronic toxiclty and Immunological studies established a NOAEL of 3.9 mg/kg
for female mice and 4.4 mg/kg for male mice exposed to 1,1,2-TCE In the
drinking water for 90 days.

     The chronic toxicity of 1,1,2-TCE was evaluated as part of a lifetime
     bioassay in both male and female rats and mice.  In rats given, by
      , average 1,1,2-TCE doses of 46 and 92 mg/kg/day 5 days/week for 78
weeks, hunched appearance, rough fur, dyspnea, and squinted eyes were noted
after about 6 months.  This study established a LOAEL of 46 mg/kg for rats,
based on clinical signs.  No oti.w-r clinical and no histopathological
differences between treated and control rats were observed.  There were no
appreciable differences between treated mice receiving average doses of 195 or
390 mg/kg/day, 5 days/week for 78 weeks, and control mice except for abdominal
distension late in the study in treated animals of both sexes receiving the

                                     V-27

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higher dose; this was ascribed to the development of liver tumors.
Nonneoplastic changes 1n treated mice were similar to those in control mice.

     Limited data were available in the literature regarding the developmental
effects of 1,1,2-TCE.  In the one mammalian study found, a screening test
(Chernoff/Kavlock assay) revealed no developmental effects In neonatal mice
exposed on gestation days 8 to 12.

     1,1,2-TCE was nonmutagenic in various strains of £. tvphimurium either
with or without metabolic activation.  Weakly positive results were reported
in mammalian cell transformation assay with BALB/C-3T3 cells.  ['*C]1,1,2-TCE
bound covalently to DNA, RNA, and protein of the liver, kidney, lung, and
stomach when injected 1p Into rats or mice.

     In the one study available evaluating the oncogenicity of 1,1,2-TCE, the
compound was administered by gavage to male and female Osborne-Mendel rats, 5
 ays/week for 78 weeks, at average dose levels of 46 and 92 mg/kg/day.  No
significant neoplastic changes were observed 1n treated animals as compared
with control rats.  It was concluded that there is no convincing evidence for
the cardnogenicity of 1,1,2-TCE in Osborne-Mendel rats under the conditions
of the study.  In contrast, male and female B6C3F, mice, given the compound  at
average dose levels of 195 or 390 mg/kg/day, 5 days/week for 78 weeks,
developed hepatocellular carcinomas and adrenal gland pheochromocytomas at
levels significantly greater than those seen In control animals.  It was
concluded that under the conditions of the bioassay, 1,1,2-TCE 1s carcinogenic
in B6C3F,  mice,  causing hepatocellular carcinomas  and adrenal
pheochromocytomas.
                                     V-28

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                         VI.   HEALTH  EFFECTS  IN HUMANS

A.   CLINICAL CASE STUDIES   "

     Information on the health effects of 1,1,2-TCE In humans 1s scarce.
Moreover, some of the available references are secondary, providing little, If
any, data and few reference citations.  In reviewing the toxlclty and
potential dangers of trlhalogenated ethane derivatives, Von Oettlngen (1955)
notes that no reports were found on human poisoning from exposure to 1,1,2-
TCE.  Hardle (1964), 1n the second edition of the Encyclopedia of Chemical
Technology, states that 1,1,2-TCE has a narcotic action at low concentrations
and an Irritant effect on the eyes and mucous membranes of the respiratory
tract.  Hardle adds that 1,1,2-TCE produces cracking and erythema when in
contact with the skin; long-term exposure to the vapor produces chronic
gastric symptoms, fat deposition in the kidneys, and damage to the lungs.  In
a more recent edition of the encyclopedia, Archer (1979) does not mention the
effects of 1,1,2-TCE on humans, except to state that 1,1,2-TCE 1s more toxic
than 1,1,1-TCE in acute exposure studies.

     Arena (1979) and Arena and Drew (1986) review the effects of 1,1,1-  and
1,1,2-TCE jointly and do not differentiate between the Individual agents.
They Indicate that exposure to vapor concentrations near 2,000 ppm for 5
•inutes may cause equilibrium disturbances and anesthetic effects (narcosis).
Symptoms and signs are Irritation of the eyes, mucous membranes, and lungs;
Inhalation or IngestIon can produce central nervous system depression,
headache, lassitude, Incoordination, vertigo, hypertension, anesthesia, and
coma.  Other possible symptoms of TCE vapor exposure are cardiac arrhythmias,
hepatic injury, and renal Injury.  It appears likely that the effects noted
relate mostly to 1,1,1-TCE, since the section heading under which these
effects are described 1s "Trichloroethane (Methyl Chloroform)," even though
1,1,2-TCE (beta-trichloroethane) 1s also briefly mentioned.  Distinction
between the two compounds may not be critical in describing various Irritation
and CNS effects, however, since both halocarbons have similar physical
characteristics (e.g., volatility and lipophillclty) (U.S. EPA, 1980c).
                                     VI-1

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     In evaluating the effects of chloroethanes on the eye, Grant (1974) also
does not differentiate between 1,1,1-TCE and 1,1,2-TCE.  The author cites one
case in which a splash of trichloroethane on a human eye led to transient
Injury, with recovery within 48 hours.' In a later edition, however, Grant
(1986) ascribes this one incident of splash injury to the human eye
specifically to 1,1,1-TCE and does not mention 1,1,2-TCE.

     It must be pointed out that considerable caution must be observed in
arriving at conclusions on the human toxicity of 1,1,2-TCE based on
information gleaned from secondary sources.

     In an original study on the erythema-inducing effects of solvents follow-
ing epicutaneous administration to humans, Wahlberg (1984a) exposed the volar
region of the forearm of a healthy male to 1.5 ml of "pure" 1,1,2-TCE for 5
minutes and observed a slightly increased blood flow to the skin, as measured
with a laser Doppler flowmeter.  Macroscopic examination, however, did not
     ate any visible erythema, which might be anticipated from increased blood
       Blood flow rate peaked 10 minutes after exposure and returned to normal
     « end of 60 minutes.  A stinging and/or burning sensation was experienced
, ier exposure to 1,1,2-TCE; whitening of the skin was also observed.

     In another study by Wahlberg (1984b), the edema-indueing effects of
solvents following topical administration were evaluated.  1,1,2-TCE was
rubbed into the skin of the volar forearm of a healthy human male daily for 15
days.  Skinfold measurements were taken daily, and the site of application was
also examined for the presence of erythema, edema, fissuring, and scaling.  No
changes from normal were found in any of the measured parameters.

B.   EPIDEHIOLOGICAL STUDIES

     No epidemiological studisi using 1,1,2-TCE were found in the available
literature.
                                     Vl-2

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C.   HIGH-RISK POPULATIONS

     In Us Ambient Water Quality Criteria for Chlorinated  Ethanes,  the U.S.
EPA (1980c) stated that workers occupationally exposed to chloroethanes by
Inhalation or dermal absorption or both represent a special group at risk for
1,1,2-TCE toxicity.  It Is difficult to determine to what extent this
assessment applies specifically to 1,1,2-TCE.

     Individuals exposed to known MFO Inducers,  such as PBB,  phenobarbltal,
acetone, and alcohol, should be considered to  be at risk, since these
chemicals potentiate the hepatorenal toxidty  of 1,1,2-TCE.

D.   SUMMARY

     Data on the human health effects of 1,1,2-TCE are scarce.   However,  two
brief studies Indicate that 1,1,2-TCE may Induce Increased  blood flow In  human
*   n without Inducing erythema, edema, flssurlng, or scaling.
                                                                                 *
                                     VI-3

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                         VII.  MECHANISMS OF TOXICITY

     1,1,2-TCE 1s fairly stable, like many halogenated hydrocarbons,  and must
undergo metabolism or bloactlvation to exert Its toxic effects.  Results from
a number of studies Indicate that metabolism by cytochrome P-450-dependent MFO
systems 1s Involved 1n 1,1,2-TCE toxlcity (see Chapter III, Toxlcoklnetics).
Oxidation, reduction, and dechlorlnation of 1,1,2-TCE via this mlcrosomal
fraction produce chloroacetaldehyde and a carbon-centered free radical that,
when dissociated from the enzyme, can Interact with various cellular
components.  In vitro studies suggest that covalent binding of 1,1,2-TCE to
RNA, DNA, or other proteins, or to Uplds, may occur in vivo: 1f so,  such
binding could be associated with the toxic effects of 1,1,2-TCE.

     The tox1city of 1,1,2-TCE appears to be tempered in the presence of GSH,
which can act as a scavenger, picking up free radicals generated by 1,1,2-TCE
metabolism.  GSH can also conjugate to 1,1,2-TCE Intermediates to produce S-
carboxymethylcystelne and thlodiacetlc add, both of which are excreted 1n the
urine of 1,1,2-TCE-dosed mice.

A.   METABOLIC ACTIVATION

     Liver damage was observed by Tyson et al.  (1983) after groups of three to
five fasted adult male Sprague-Dawley rats were administered a single oral
dose up to 233 mg 1,1,2-TCE/kg.  Hepatotoxiclty was Indicated by Increases 1n
SCOT and SGPT activities, which peaked 48 hours after dosing.  The EDM value
(when SOX of treated animals showed elevated enzyme activity) for elevated
serum transaminases was 60 mg/kg.  Parallel in vitro studies that used
hepatocytes from male Sprague-Dawley rats gave ECn values (the dissolved
1,1,2-TCE concentration required to release 50% of the cell content of each
enzyme after 2 hours of exposure) of 8.8 mM for SGOT and of 6.1 mM for LDH.
Pretreatment with phenobarbital (a known MFO inducer) lowered the SGOT ECM
value to 7.4 mM, indicating a slight Increase in tox1city as a result of
metabolic stimulation.  Histological examination of tissues was not made, but
                                    VIM

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the release of S60T, SGPT, and LDH suggests a loss of integrity of both plasma
and mitochondria! membranes.
     MacDonald et al. (1980, 1982a) noted that the amount of hepatic necrosis
In untreated or acetone-pretreated male Sprague-Dawley rats corresponded
directly to SGPT levels after a single ip dose of either 168 or 233 mg 1,1,2-
TCE/kg. (Lower 1,1,2-TCE doses were not severely hepatotoxic, and they were
not greatly affected by acetone.)  Nonpretreated animals exhibited a dramatic
Increase in hepatic Injury' as the ip 1,1,2-TCE dose Increased from a no-effect
level of 133 mo/kg to 168 and 233 mg/kg; the latter two 1,1,2-TCE doses were
accompanied by 10- and 100-fold Increases in SGPT activity, respectively, over
that of the 133 -mg/kg dose.  Oral administration of 0.1 to 0.5 ml acetone/kg
(16 hours before 1,1,2-TCE Injection) enhanced the hepatotoxiclty of 1,1,2-TCE
in a dose-related fashion, and ingestlon of doses of acetone greater than 0.5
ml/kg appeared to reduce liver damage.  Potent 1 at ion was greatest at toxic
threshold levels of 1,1,2-TCE, an effect believed to be related to the severe
(73%) reduction In hepatic GSH levels that occurred 2 hours after
administration of 227 mg 1,1,2-TCE/kg to acetone-pretreated rats.  The effect
of acetone on 1,1,2-TCE hepatotoxicity was thought to be due primarily to the
increased bioactivation of reactive metabolic Intermediates and to the reduced
availability of glutathlone in the control of peroxidation, free radical
generation, and detoxification.  The authors speculated that high doses of
acetone may have reduced tissue damage by further altering some aspect of
cellular function associated with 1,1,2-TCE toxlclty (e.g., bioactivation and
detoxification pathways, cellular membranes, or Intermediary metabolism).

     In another study by NacDonald et al. (1982b), male Sprague-Dawley rats
 ere treated orally with acetone (0.5 ml/kg) 16 hours prior to receiving a
single 1p dose of uniformly labeled [14C] 1,1,2-TCE (160 mg/kg).  in xixfi
binding of 1,1,2-TCE to protein was relatively low (approximately 3.6 mmol
[14C] 1,1,2-TCE equivalents bound/mg protein) when only cytosolic subcellular
fractions were Isolated from rat hepatocytes; binding rates were nearly
tripled In hepatic microsomal isolates.  Since 1,1,2-TCE- protein-binding may
lead to the destruction of kidney and liver tissue (see Section B, this
                                     VII-2

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chapter), these data point to mlcrosomal bioactivation as a means by which
1,1,2-TCE may exert its toxic effects.                             •

     Kluwe et al. (1978) found that PBB potentiated the toxicity of 1,1,2-TCE.
In this study, adult male ICR mice consumed 100 ppm PBB in their diet for 14
days before receiving a single 1p dose of 0.15 ml l,l,2-TC£/kg (216 mg/kg).
Within 24 hours after injection, the liver-to-body weight ratio was
approximately 50% greater than that of similarly dosed mice on a normal diet.
SGOT levels in 1,1,2-TCE-dosed mice rose by 25% following PBB consumption;
although this was not statistically significant, it does suggest that some
liver damage probably had occurred.  Uptake of PAH by'renal cortical slices
from 1,1,2-TCE/PBB-dosed mice was 39% below that of vehicle-only-treated
controls consuming no PBB and 17% below that of 1,1,2-TCE-dosed animals on a
PBB-free diet.  These data suggest that severe renal impairment occurred in
the PBB-fed group.  Since PBB activate the MFO enzyme systems responsible for
*v? metabolism of 1,1,2-TCE, bioactivation of the organic solvent appears to
   -losely related to the nephro- and hepatotoxic effects observed in this
  -dy.

     Carlson (1973) demonstrated enhanced hepatotoxicity of 1,1,2-TCE in adult
male albino mice pretreated with phenobarbital.  In this study, groups of
three to five animals were exposed to 890 ppm 1,1,2-TCE vapors for 2 hours
after having been injected on 4 consecutive days with single ip doses of
phenobarbital.  Neither nonpretreated animals Inhaling 1,1,2-TCE nor
phenobarbital-dosed mice Inhaling only air showed any signs of hepatic damage;
liver-to-body weight ratios and glucose-6-phosphatase, SGPT, and SGOT levels
were all comparable to (I.e., not statistically different from) those of
nonpretreated mice Inhaling air.  For mice exposed to both 1,1,2-TCE and
phenobarbital, however, glucose-6-phosphatase levels were significantly (p
<0.05) reduced, and serum transaminase activities were 15 to 25 times higher
than in controls.  The l,l,2-TCE-/phenobarbita1-dosed animals also had a
moderate (17%), but statistically nonsignificant, increase In the liver-to-
body weight ratio.  The data suggest a strong association between
bioactivatlon of 1,1,2-TCE and the chemical's hepatotoxicity.
                                     VII-3

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B.   BINDING TO DNA, RNA, PROTEINS, AND LIPIDS

     The formation of 1,1,2-TCE-DNA or 1,1,2-TCE-RNA adducts has been
suggested as one means by which 1,1,2-TCE Initiates cell death and tissue
Injury.  DiRenzo et al.  (1982) studied the In vitro covalent binding of 1.0 mM
14C-labeled  1,1,2-TCE  (and other aliphatic halides) to calf thymus DNA
following bloactlvatlon  by hepatic microsomes from phenobarbltal-treated rats.
1,1,2-TCE binding occurred at a rate of 0.35 nmol/mg DNA/hour.  Although no
structural  Identification of modified bases was made, it was estimated that a
covalent binding rate of 0.5 nmol/mg DNA/hour would result In an alteration of
1 out of every 2,000 nucleotlde bases.  Results of the study Indicated that
the halogenated hydrocarbons with the highest DNA binding rates also were the
most carcinogenic to laboratory animals.  In a similar study (Sipes and
Gsrdolfi, 1980), the 1,1,2-TCE binding rate was only 0.04 nmol/mg calf thymus
DNA/hour after male Sprague-Dawley rats were treated with phenobarbltal (0.1%
w/v, in drinking water for 10 days) or with Arochlor 1254 (500 mg/kg/day ip
for 5 days).  The presence of 1 mM GSH greatly Inhibited the binding activity
of 1,1,2-TCE, particularly In the presence of oxygen, suggesting that
deacti.vation of 1,1,2-TCE and Us metabolites may occur via GSH conjugation.

     Hazzullo et al. (1986)  reported that 1,1,2-TCE was covalently bound to
DNA, RNA, and protein of the liver, kidney, lung, and stomach of adult male
Wistar rats given a single Ip dose of uniformly labeled [14C]1,1,2-TCE at 847
mg/kg (127>C1).  DNA binding in the liver of BALB/c mice was significantly
higher than that In rats; this 1s consistent with data showing that mice are
nore susceptible to 1,1,2-TCE-Induced hepatocardnomas than are rats.  RNA and
p. .rteln binding rates were one to two times higher than DNA rates; no species-
specific differences were observed.  In vitro pretreatment with phenobarbltal
enhanced the binding to DMA, RNA, and protein by factors of 5-, 2.8-, and 6.5-
fold, respectively.  The authors commented that covalent binding to DNA was
due to reactive metabolites (rather than to unchanged pare..* compound) that
originate in the liver.  Overall, they rated 1,1,2-TCE as a moderate-weak
oncogenic Initiator in the mouse and a weak Initiator in the rat.  The
                                     VII-4

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carcinogenic potential of 1,1,2-TCE, as measured by In vitro binding activity,
was overestimated for rats, however; this 1s evident In chronic exposure
studies that show no significant Increase 1n the tumor Incidence rate of
1,1,2-TCE-treated rats when compared with control rats.

     In a similar study, Bergman (1982) demonstrated that [l,2-"C]v1ny1
chloride (a product of In vitro reductive dechlorlnatlon of 1,1,2-TCE) binds
Irreversibly to RNA and ONA of mouse lung, liver, kidney, spleen, pancreas, or
testes following a single 1p dose of 3.25 mg (25 »C1) of the radiolabeled
compound to male albino NMRI mice.  No specific in vivo DNA adducts were
Identified by Nazzullo et al. (1986) or Bergman (1982).

     Hale Sprague-Dawley rats (number not specified) were treated with
acetone, fasted for 16 hours, and then Intravenously administered a single
160-mg/kg dose of uniformly labeled [14C]1,1,2-TCE (NacDonald et al., 19825).
Some rats also received 1p and oral doses of phenobarbltal to Induce hepatic
microsomal enzymes; others were given a single 1p Injection of diethyl maleate
(prior to 1,1,2-TCE administration) to deplete the liver of 6SH.  Controls
were non-acetone-treated,, fasted animals.  The control group exhibited a
sixfold Increase 1n 1,1,2-TCE-protein binding when compared with fed animals,
whose covalent binding rate was 1.5 nmol [14C] 1,1,2-TCE equivalents/ing
protein.  Acetone-pretreated, 1,1,2-TCE-dosed rats had protein binding rates
equivalent to the fasted controls (i.e., 9.5 nmol/mg), and hepatic GSH levels
of the acetone-1,1,2-TCE-treated animals were 30X lower than those of control
animals.  Covalent binding 1n diethyl maleate-dosed rats was twice that of
controls, and phenobarbltal pretreatment produced a fourfold Increase in the
rate at which [14C]1,1,2-TCE was bound to microsomal proteins.

     Incubating microsomes from acetone-pretreated rats with 1 mM [14C]1,1,2-
TCE resulted In a 35% Increase over control systems In the rate of covalent
binding to hepatic proteins (NacOonald et al., 1982b).  This increase in
apparent bioactivation occurred despite equivalent levels of hepatic
cytochrome P-450 1n both fasted and pretreated animals.  Addition of 1 mM GSH
to 1,1,2-TCE-bathed microsomes Inhibited binding by 80%f suggesting a direct
                                     VII-5

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Interaction of 6SH with 1,1,2-TCE Intermediates, rather than an Involvement of
6SH transferases.         .                                         •

     Sipes and Gandolfi (1980) reported that binding of 1,1,2-TCE to
mlcrosomal protein and 11p1d was low.  Binding occurred at rates of 1.5 nmol
bound l,l,2TCE/mg protein/15 minutes and 0.9 nmol bound l,l,2-TCE/«mol 11p1d
phosphorus/15 minutes following Incubation of 2 »mol (1 »C1) uniformly 14C-
labeled 1,1,2-TCE with mlcrosomal cytochrome P-450 Isolated from
phenobarbital- or Aroclor 1254-pretreated male Sprague-Dawley rats.  These
rates were five to eight times higher than binding rates of nonpretreated
animals.  Optimal binding occurred in an oxygenated environment, and binding
was Inhibited when 1 mH GSH was added to the Incubation medium.  Similar
results were reported for hepatocytes Isolated from the same strain of animals
(DiRenzo et al., 1984).  Although a relationship between binding and
hepatotoxiclty was suggested, extrapolation to in vivo binding was not made,
since the experimental systems were designed for maximal in vitro binding
(Sipes and Gandolfi, 1980; DiRenzo et al., 1984).

C.   FREE RADICAL FORMATION

     Free radicals were produced under in vitro hypoxic conditions following
incubation of 5 »L (7.2 mg) 1,1,2-TCE with hepatocytes isolated from male
Wlstar rats that had been pretreated for 5 days with phenobarbital (1% w/v, 1n
drinking water) (Tomasi et al., 1984).  The extent of free radical formation
was regulated by the amount of oxygen present in the medium.  There seemed to
be no relationship between free radical formation/1,1,2-TCE activation and the
1,1,2-TCE's covalent binding capacity or carcinogenic potency (as reported in
the literature).  A similar conclusion was made by Klaassen and Plaa (1969),
who gave each of 18 male Sprague-Dawley rats a single 1p dose of 0.49 ml
1,1,2-TCE/kg (706 mg/kg, or 75X of the LDJ.  In this study, liver
triglyceride levels Increased from 5 mg/g tissue to approximately 22.5 mg/g
diring t^ 36 hours after dosing.  No association was noted between llpid
peroxldatlon (as measured by enhanced thiobarblturlc acid reactants in vitro
and diene conjugates jfl vivo) and 1,1,2-TCE metabolism.
                                     VII-6

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D.   SUMMARY

     The toxic action of 1,1,2-TCE may proceed by b1oact1vat1on and subsequent
covalent binding to DNA, RNA, proteins, and I1p1ds, since toxlclty 1s greatly
enhanced with GSH depletion.  Another possibility Is that 1,1,2-TCE may act
via 11p1d peroxldatlon, but limited data from the available literature do not
lend much support to this hypothesis.

     Both in vivo and in vitro studies have shown that when MFO Inducers
(I.e., phenobarbltal, acetone, and PBBs) are administered prior to 1,1,2-TCE
dosing or Incubation, significant Increases 1n cellular damage occur.  In rats
given a single oral dose of 60, 168, or 233 mg 1,1,2-TCE/kg, pretreatment with
phenobarbltal lowered the ECW value for SCOT by approximately 20%, suggesting
an Increase 1n hepatotoxldty following metabolic stimulation.  Phenobarbltal
pretreatment also caused significant Increases 1n plasma levels of hepatic
enzymes 1n mice Inhaling 890 ppm of 1,1,2-TCE vapors for 2 hours.  Oral
administration of 0.1 to 0.5 ml acetone/kg enhanced 1,1,2-TCE-Induced liver
damage 1n a dose-related fashion; the greatest effect was observed at the
toxic .threshold level of 1,1,2-TCE (227 ing/kg) when hepatic GSH concentrations
had dropped to 73% of the normal value.  Ingest1on of PBB potentiated the
renal and hepatic toxlclty of 1,1,2-TCE 1n mice.  Animals consuming 100 ppm
PBB for 14 days prior to 1p administration of 216 mg 1,1,2-TCE/kg exhibited a
25% Increase 1n SCOT levels, a 50% Increase In the llver-to-body weight ratio,
=»nd a 17% reduction In PAH uptake by renal cortical slices when compared to
  ?,2-TCE-dosed mice on a PBB-free diet.  The data from these studies suggest
    -ong association between b1oact1vat1on of 1,1,2-TCE and the chemical's
      y to damage hepatic and renal tissues.

     i   degree of binding to DNA, RNA, and protein appeared to be related to
1,1,2-TCt's hepatotoxlc and carcinogenic potential.  Covalent binding was
observed In the liver, kidney, lung, and stomach «,c ro£Mits given 1p or oral
doses of 1,1,2-TCE; similar observations were made In hepatocytes Incubated
with either 1,1,2-TCE or vinyl chloride (a product of In vitro reductive
                                     VII-7

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dechloHnatlon of 1,1,2-TCE).  DMA binding In the liver of mice was_ greater
than that in rats, consistent with reports that mice are more susceptible  to
1,1,2-TCE-induced hepatocardnoma than are rats.  Binding was inhibited  by up
to 80% in the presence of 1 mM 6SH.

     Free radical formation in 1,1',2-TCE-bathed hepatocytes and increases  in
hepatic triglyceride levels 1n 1,1,2-TCE-dosed rats were reported,  but no
association between either of these two parameters and 1,1,2-TCE-Induced
hepatotoxlclty was made.

     The effects of GSH availability or depletion suggest that GSH  protects
against tissue damage, acting as a scavenger of free radicals produced through
1,1,2-TCE metabolism or as a detoxifying agent that conjugates to 1,1,2-TCE
intermediates.
                                     ViI-8

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                VIII.  QUANTIFICATION OF TOXICOLOGICAL EFFECTS

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

A.   PROCEDURES FOR QUANTIFICATION OF TOXICOLOGICAL EFFECTS

1.   Noncarcinoaenic Effects

     In the quantification of noncarcinogenic effects, a Reference Dose (RfD),
formerly called the Acceptable Daily Intake (ADI), 1s calculated.  The RfD is
an estimate (with an uncertainty spanning perhaps an order of magnitude) of a
daily exposure of the human population (including sensitive subgroups) that is
likely to be without an appreciable risk of deleterious health effects during
a lifetime.  The RfD 1s derived from a No-Observed-Adverse-Effect Level
(NOAEL), or Lowest-Observed-Adverse-Effect Level (LOAEL), Identified from a
subchronic or chronic study, and divided by an uncertainty factor(s).  The RfD
is calculated as follows:

        RfD -   (NOAEL or LOAEll     -	tag/kg bw/day
              Uncertainty factor(s)

     Selection of the uncertainty factor to be employed in the calculation of
the RfD 1s based on professional judgment while considering the entire data
base of toxlcologlcal effects for the chemical.  To ensure that uncertainty
factors are selected and applied In a consistent manner, the Office of
Drinking Hater (ODW) employs a modification to the guidelines proposed by the
National Academy of Sciences (NAS, 1977, 1980) as follows:

     •   An uncertainty factor of 10 Is generally used when good chronic or
        subchronic human exposure data identifying a NOAEL are available and
        are supported by good chronic or subchronic toxlclty data in other
        species.

                                    VIII-1

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     •   An uncertainty factor of 100 Is generally used  when  good  chronic
        toxicity data identifying a NOAEL are available for  one or more animal
        species (and human data are not available),  or  when  good  chronic  or
        subchronlc toxicity data Identifying a LOAEL in humans are available.

     •   An uncertainty factor of 1,000 1s generally  used when limited or
        Incomplete chronic or subchronlc toxicity data  are available, or  when
        good chronic or subchronlc toxicity data Identifying a LOAEL, but not
        a NOAEL, for one or more animal species are  available.

     The uncertainty factor used for a specific risk assessment  1s based
principally on scientific judgment rather than scientific fact  and accounts
for possible Intra- and Interspecies differences.  Additional considerations,
which may necessitate the use of an additional uncertainty factor of 1 to 10,
not incorporated in the NAS/ODW guidelines for selection of an  uncertainty
factor Include the use of a less-than-Hfetime study for deriving an RfD, the
significance of the adverse health effect, pharmacokinetic factors, and the
counterbalancing of beneficial effects.

     From the RfD, a Drinking Water Equivalent Level (OWEL)  can  be calculated.
The DUEL represents a medium-specific (I.e., drinking water) lifetime
exposure, at which adverse, noncarclnogenic health effects are  not anticipated
to occur.  The DUEL assumes 100X exposure from drinking water.   The DUEL
provides the noncarclnogenic health effects basis for establishing a drinking
water standard.  For Ingestion data, the DUEL 1s derived as follows:

     DUEL •    RfD x (body weight in kg)    .	mg/L (	>g/L)
             Drinking water volume in L/day
where:
              Body weight - assumed to be 70 kg for an adult.
    Drinking water volume • assumed to be 2 L per day for an adult.
                                    VIII-2

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     In addition to the RfO and the DUEL, Health Advisories (HAs) for
exposures of  shorter duration  (One-day, Ten-day, and Longer-term) are
determined.   The HA values are used as Informal guidance to municipalities and
other organizations when emergency spills or contamination situations occur.
The HAs are calculated using an equation similar to the RfO and DUEL; however,
the NOAELs or LOAELs are Identified from acute or subchronic studies.  The HAs
.are derived as follows:
     HA -  (NOAEL or LOAEL) x (bw)  .
             (UF) x  (_L/day)
     Using the above equation, the following drinking water HAs are developed
for noncarcinogenic effects:

     1.  One-day HA for a 10-kg child ingesting 1 L water per day.
         Ten-day HA for a 10-kg child Ingesting 1 L water per day.
     ..  Longer-term HA for a 10-kg child Ingesting 1 L water per day.
     41  Longer-term HA for a 70-kg adult Ingesting 2 L water per day.

     The One-day HA calculated for a 10-kg child assumes a single acute
exposure to the chemical and 1s generally derived from a study of less than
7 days duration.  The Ten-day HA assumes a limited exposure period of 1 to 2
weeks and is generally derived from a study of less than 30 days duration.
The Longer-term HA 1s derived for both a 10-kg child and a 70-kg adult and
assumes an exposure period of approximately 7 years (or 10% of an Individual's
lifetime).  The Longer-term HA 1s generally derived from a study of subchronic
duration (exposure for 10% of an animal's lifetime).

2.   Carcinogenic Effects
     The EPA categorizes the carcinogenic potential of a chemical, based on
the overall weight of evidence, according to the following scheme:

     .  Group A:  Human Carcinogen.  Sufficient evidence exists from
                  epidemiology studies to support a causal association between
                  exposure to the chemical and human cancer.
                                    VI11-3

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     .  Group B:  Probable Human Carcinogen.   Sufficient evidence ofrcarcino-
                  gen1city in'animals with limited (Group Bl)  or inadequate
                  (Group 62} evidence in humans.

     •  Group C:  Possible Human Carcinogen.   Limited evidence of carcinogeni-
                  city in animals in the absence  of human data.

     .  Group D:  Not Classified as to Human  Carcinooenicitv.   Inadequate
                  human and animal  evidence of cardnogenicity or for which  no
                  data are available.

     •  Group E:  Evidence of Noncarcinogenicitv  for Humans.   No .evidence of
                  cardnogenicity in at least two adequate animal tests in
                  different species or in both adequate epidemiologic and
                  animal studies.

     If toxicological evidence leads to the classification of the contaminant
as a known, probable, or possible human carcinogen, mathematical models are
used to calculate the estimated excess cancer risk associated with the
ingestion of the contaminant in drinking water.  The data used in these
estimates usually come from lifetime exposure studies in animals.  To predict
the risk for humans from animal data, animal  doses must be converted to
equivalent human doses.  This conversion includes correction for noncontinuous
exposure, less-than-lifetime studies, and for differences in size.  The factor
that compensates for the size difference is the cube root of the ratio of the
animal and human body weights.  It is assumed that the average adult human
body weight 1s 70 kg, and that the average water consumption of an adult human
Is 2 liters of water per day.

     For contaminants with a carcinogenic potential, chemical  levels are cor-
related with a carcinogenic risk estimate by  employing a cancer potency (unit -
risk) value together with the assumption for  lifetime exposure via Ingestion
of water.  The cancer unit risk is usually derived from a linearized
multistage model with a 95% upper confidence  limit providing a low-dose
estimate; that 1s, the true risk to humans, while not Identifiable, is not

                                    VIII-4

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likely to exceed the upper limit estimate and, in fact, may be lower.  Excess
cancer risk estimates may also be calculated using other models such as the
one-hit, Weibull, logit, and probit.  There is little basis in the current
understanding of the biological mechanisms Involved in cancer to suggest that
any one of these models is able to predict risk more accurately than any
others.  Because each model is based on differing assumptions, the estimates
that are derived for each model can differ by several orders of magnitude.

     The scientific data base used to calculate and support the setting of
cancer risk rate levels has an inherent uncertainty due to the systematic and
random errors in scientific measurement.  In most cases, only studies using
experimental animals have been performed.  Thus, there is uncertainty* when the
data are extrapolated to humans.  When developing cancer risk rate levels,
several other areas of uncertainty exist, such as the incomplete knowledge
concerning the health effects of contaminants in drinking water; the impact of
the experimental animal's age, sex, and species; the nature of the target
organ system(s) examined; and the actual rate of exposure of the internal
targets in experimental animals or humans.  Dose-response data usually are
available only for high levels of exposure, not for the lower levels of
exposure closer to where a standard may be set.  When there is exposure to
more than one contaminant, additional uncertainty results from a lack of
information about possible synergistic or antagonistic effects.

B.   QUANTIFICATION OF NON CARCINOGEN 1C EFFECTS FOR 1,1,2-TCE

     One-dav Health Advisory
                 considered for calculation of the One-day HA are listed  in
Table V-2.  It is apparent that only the study of Tyson et al. (1983) with
rats is suitable for estimation of the One-day HA, since it Is the only recent
oral study of appropriate duration (1 day) in which parameters other than
lethality were considered.  Hepatotoxidty was induced in rats given 1,1,2-TCE
at doses of 60 mg/kg or greater, as Indicated by Increases In serum
transaminase values.  The
                           'SO
value for elevated serum transaminases was
60 mg/kg, which can be considered the LOAEL for 1,1,2-TCE in this 'study.   It
                                    VIII-5

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should be noted that the liver also appears to be a target organ for 1,1,2-TCE
in mice (White et al., 1985) and dogs (Klaasen and Plaa, 1967).

     Based on the adverse effects in liver, as Indicated by the  Increased
serum transamlnase activities observed 1n the Tyson et al. (1983) study,  the
One-day HA for a 10-kg child 1s calculated as follows:

     One-day HA » (60 mq/ka/davH10 ka)  - 0.6 mg/L (600 *g/L)
                    (1,000)(1 L/day)

where:

     60 mg/kg/day - LOAEL, based on an EDU for liver dysfunction In rats
                    exposed to single doses of 1,1,2-TCE.
            10 kg « assumed weight of a child.
          1 L/day - assumed water consumption of a 10-kg child.
            1,000 • uncertainty factor,  chosen 1n accordance with NAS/ODW
                    guidelines for use with a LOAEL from an animal  study.

2.   Ten-dav Health Advisory

     The 14-day range-finding oral toxicity studies of White et  al.  (1985)  and
Sanders et al. (1985) In the mouse, as shown 1n Table V-2, are the most suit-
able studies for estimation of the Ten-day HA.  In these studies, a dose of
3.8 mg/kg/day of 1,1,2-TCE produced no toxic effects and nay be considered the
NOAEL.  On the other hand, 38 mg/kg/day produced significant Increases 1n the
weights of several organs.

     The Ten-day HA for a 10-kg child Is calculated as follows:

     Ten-day HA » (3.8 mg/ko/davUlO kg) - 0.38 mg/L (400 »g/L)
                      (100)(1 L/day)
                                    VIII-6

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where:
     3.8 mg/kg/day
NOAEL, based on absence of adverse effects 1n mice
exposed to 1,1,2-TCE by gavage for 14 days.
             10 kg - assumed weight of a child.
           1 L/day - assumed water consumption of a 10-kg child.
               100 • uncertainty factor, chosen In accordance with NAS/ODU
                     guidelines for use with a NOAEL from an animal study.

3.   Longer-term Health Advisory

     The toxicity studies by White et al. (1985) and Sanders et al. (1985),  in
which mice were exposed to 1,1,2-TCE In drinking water for 90 days, are the
only suitable studies for estimation of the Longer-term HA of 1,1,2-TCE.  As
shown in Table V-3, these studies established a NOAEL of 3.9 mg/kg/day in the
female mouse and a NOAEL of 4.4 mg/kg/day 1n males.  The LOAEL for females was
44 mg/kg/day, based on significantly increased SGOT and SAP levels as well as
reduced hepatic microsomal cytochrome oxidase and aniline hydroxylase
activities; in males the LOAEL was 46 mg/kg/day, based on reduced liver GSH.
The NOAEL of 3.9 mg/kg/day in the female mouse is chosen as the basis for the
Longer-term HA.

     The Longer-term HA for a 10-kg child is calculated as follows:
     Longer-term .HA
 H.9 ma/kQ/davHlO ko) - 0.39 mg/L (400 ,g/L)
     (100)(1 L/day)
    e:
     3.9 ing/kg/day
NOAEL, based on absence of consistent effects on the
liver and serum enzymes in female nice.
             10 kg • assumed weight of a child.
           1 L/day • assumed water consumption of a 10-kg child.
               100 - uncertainty factor, chosen in accordance with NAS/ODW
                     guidelines for use with a NOAEL from an animal study.
                                    VIII-7

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     It is to be noted that the Ten-day and Longer-term HAs for a 10-kg child
 are essentially the same.   It would therefore appear that the Longer-term HA
 for a  10-kg child could also serve as a conservative estimate of the Ten-day
 HA.

     The Longer-term HA for a 70-kg adult is calculated as follows:

     Longer-term HA « f3.9 mq/kQ/davH70 kg) - 1.37 mg/L (1,000 *g/L)
                          UdOMZ L/oayJ

 where:

     3.9 mg/kg/day » NOAEL, based on absence of consistent effects on the
                     liver and serum enzymes in female mice.
             70 kg • assumed weight of an adult.
           2 L/day - assumed water consumption of a 70-kg adult.
               100 » uncertainty factor, chosen in accordance with NAS/ODW
                     guidelines for use with a NOAEL from an animal study.

 4.   Reference Dose and Drinking Water Equivalent Level

     Two choices were considered for estimation of the RfD and DUEL for 1,1,2-
 TCE (Table V-3):  (1) utilization of the 90-day drinking water studies of
 White et al. (1985) and Sanders et al. (1985), with application of an
 additional uncertainty factor to account for a Iess-than-lifet1me exposure;
 and (2) selection of the NCI (1978) chronic toxlcity/oncology study with rats
 in which the lower dose used inTthe 78-week study might serve as a LOAEL.
 The studies by White et al. (1985) and Sanders et al. (1985) were selected as
 the basis for the derivation of the oral RfD because they are adequate studies
 in which mice of both sexes were exposed to 1,1,2-TCE in drinking water for
 90 days.  Animals Ingested 0, 20, 200, or 2,000 mg 1,1,2-TCE/L water;
 corresponding Intakes were 0. 4.4, 46, and 305 mg/kg/day for males and 0, 3.9,
 44, and 384 mg/kg/day for females.  Clinical chemistry parameters and organ
weights Indicated adverse effects on the liver of mid- and high-dose females
 and high-dose males.  Hematologlcal effects occurred In high-dose female mice
 only, and depressed humoral Immune status was observed In both sexes consuming

                                    VIII-8

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200 or 2,000 mg/L.  The 20-mg/L (3.9 mg/kg/day) dose for female mice was the
NOAEL used in the calculation of the oral RfD; at this dose, no significant
adverse effects were observed;                   "
     Using these studies, the DUEL 1s derived as follows:
Step 1:  Determination of the Reference Dose (RfD)
RfD • 3.9 iM/kQ/dav - 0.004 mg/kg/day (after rounding from 0.0039 mg/kg/day)
        1,000
where:
     3.9 mg/kg/day

             1,000
NOAEL, based on the absence of consistent effects on
the liver and on serum enzymes 1n female mice.
uncertainty factor, chosen 1n accordance with NAS/ODW
guidelines for use with a NOAEL from an animal  study.
Step 2:  Determination of the Drinking Water Equivalent Level (DUEL)

      •  DUEL - f0.0039 mq/kQ/davU70 kg] - 0.137 mg/L (100 *g/L)
                     z L/aay

where:

     0.0039 mg/kg/day • RfD (before rounding).
                70 kg * assumed weight of an>adult.
             2 L/day  • assumed water consumption of a 70-kg adult.

C.   QUANTIFICATION OF CARCINOGENIC EFFECTS FOR 1,1,2-TCE

1.   Categorization of Carcinogenic Potential

     In a bloassay of 1,1,2-TCE for possible cardnogenlcity performed on male
and female mice, NCI (1978) reported a significant Increase In the Incidence
of hepatocellular carcinomas and a positive dose-related  association between
                                    VIII-9

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administration of the agent and the incidence of adrenal gland
pheochromocytomas in mice of both sexes.  NCI (1978) concluded that .under the
conditions of the bioassay, 1;1,2-TCE is carcinogenic in B6C3F, mice,  causing
hepatocellular carcinomas and adrenal pheochromocytomas.  In a bioassay on
Osborne-Hendel rats, however, no neoplasms were observed at statistically
significant incidences in either males or females, and the NCI (1978)
concluded that the results of the study do not provide convincing evidence for
the careinogenicity of 1,1,2-TCE in rats.

     Gold et al.  (1986) looked for an association between carcinogenic potency
and tumor pathology in 88 NCI rodent carcinogenesis bioassays, including the
assay on 1,1,2-TCE (NCI, 1978).  In the absence of tumors for a given target
site in control animals, they defined a TDW as the chronic dose .(in mg/kg
day) that would induce tumors in half the test animals at the end of a
standard lifespan for the species.  Since tumors at the site of interest often
do occur in control animals, they defined TDM more precisely as the dose rate
that will halve the probability of remaining tumor-free throughout the
lifespan of the species.  On the basis of this definition, 1,1,2-TCE had a
TOH of 47.6 mg/kg/day for production of liver tumors in female mice.

     In its evaluation of the carcinogen1city of 1,1,2-TCE, the International
Agency for Research on Cancer (IARC, 1979) has concluded that there is limited
evidence that 1,1,2-TCE is carcinogenic in mice.

     Applying the criteria described 1n the U.S. EPA's guidelines for
assessment of carcinogenic risk (U.S. EPA, 1986a), 1,1,2-TCE may be classified
 s Group C: Possible Human Carcinogen.  This category is used for substances
  th limited evidence of cardnogenicity in animals in the absence of human
o.  a.  Utilizing this weight-of-evidence assessment and a potency factor (F)
of 0.36 (mg/kg/day)*1, as derived according to the Methodology developed by
the Carcinogen Assessment Group of the U.S. EPA (1986b), the U.S. EPA Office
of Emergency and Remedial Response (U.S. EPA, 19ft6c) has assigned 1,1,2-TCE a
"LOW" hazard ranking for the purposes of Reportable Quantity (RQ) adjustment.
                                    VIII-10

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2.   Quantitative Carcinogenic Risk Estimates

     Based on the NCI (1978) carcinogenesis data on mice and using a
linearized multistage model, the U.S. EPA (1980c) has estimated that the level
of 1,1,2-TCE in ambient water calculated to keep the lifetime cancer risk
below 10~( for a 70-kg adult  1s 6.0 »g/L.  This estimation was based on
considering the length of the NCI study, 630 days, to be equal to the lifespan
of the mice.  To make the risk assessment consistent with the actual Hfespan
assumption for mice of 730 days, the U.S. EPA (1983) applied a correction
factor to the cancer risk previously calculated, deriving a dose of 1,1,2-TCE
associated with an Increased lifetime cancer risk of 10** in a 70-kg adult as
8.12 »g/day or 4.06 »g/L.

0.   EXISTING GUIDELINES AND STANDARDS

     The American Conference of Governmental Industrial  Hygienists (ACGIH,
1986) recommended a Threshold Limit Value-Time Weighted Average (TLV-TWA) of
10 ppm (approximately 45 mg/m')  for 1,1,2-TCE.   OSHA recommended a standard  of
10 ppm (45 mg/m3)  for 1,1,2-TCE  (U.S.  EPA,  1985).

     In  Its  Health Advisory on 1,1,2-TCE Issued In September 1986, the ODW
(U.S. EPA, 1986d) proposed a Lifetime HA of 0.15 mg/L, based on a NOAEL of
4.4 mg/kg/day, Identified from the studies of White et al.  (1985) and Sanders
?t al. (1985) with mice.

     SUMMARY
in
The quantification of lexicological effects for 1,1,2-TCE 1s summarized
ble VIIM.
     The recommended value for the One-day HA for a 10-kg child Is estimated
to be 600 »g/L, based on a LOAEL for hepatotoxidty Induced 1n a 1-day oral
study with rats.  A Ten-day HA of 400 »g/L for a 10-kg child was derived,
based on a NOAEL Identified In a 14-day oral toxiclty study with mice.  Both
the Longer-term HAs and the DWEL are based on the NOAEL established 1n a
90-day oral toxiclty study with mice.  The Longer-term HA for a 10-kg child

                                    VIII-11

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       Table VIII-1.  Summary of Quantification of Toxicological Effects
                      for 1,1,2-TCE
       Value
                                    Drinking Hater
                                    Concentration
                   Reference
One-day HA for 10-kg child

Ten-day HA for 10-kg child


Longer-term HA for 10-kg child


Longer-term HA for 70-kg adult


DWEL for 70-kg adult


Excess cancer risk  (10**)
  600

  400


  400


1,000


  100


 s.ir
Tyson et al. (1983)
White et al.
Sanders et al

White et al.
Sanders et al

White et al.
Sanders et a

White et al.
Sanders et al

NCI (1978)
(1985);
.  (1985)

(1985);
.  (1985)

(1985);
.  (1985)

(1985);
.  (1985)
*!'tfined as ng/day.
                                    VIII-12

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was estimated as 400 ng/L, and the Longer-term HA for a 70-kg adult was
1,000 ng/L.  The DWEL was estimated to be 100 «g/L.  According to U.S. EPA
guidelines, 1,1,2-TCE may be classified 1n Group C:  Possible Human
Carcinogen.  A value of,8.12 »g/day has been derived as the dose of 1,1,2-TCE
associated with an Increased lifetime cancer risk of 10"s 1n a 70-kg adult.
                                   VIII-13

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                               IX.  REFERENCES


ACGIH.  1986.  American Conference of Governmental Industrial Hygienists.
TLVs: Threshold limit values and biological exposure Indices for 1986-87.
Cincinnati, OH:  ACGIH.

Anders MM.  1982.  B1oact1vat1on of halogenated hydrocarbons.  J. Toxicol.
din. Toxicol. 19:699-706.

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