of Emergency and
 It at Response
.mgton DC 20460
Off'ce of Research and Development
Office of Health and Environmental
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
                        HEALTH EFFECTS ASSESSMENT
                        FOR  1,1-DICHLOROETHANE

                                           September  1984
    U.S. Environmental  Protection Agency
     Office of Research and  Development
Office of  Health and Environmental  Assessment
Environmental Criteria  and Assessment Office
            Cincinnati, OH  45268
    U.S. Environmental  Protection Agency
  Office of  Emergency and Remedial Response
Office of Solid Waste  and  Emergency Response
            Washington, DC  20460


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

    This report  summarizes  and evaluates Information relevant  to  a prelimi-
nary  Interim  assessment of  adverse health  effects  associated with  I,l-d1-
chloroethane.   All  estimates  of acceptable  Intakes  and  carcinogenic  potency
presented 1n  this  document  should  be  considered as preliminary and  reflect
limited  resources   allocated   to  this  project.    Pertinent  toxlcologlc  and
environmental  data  were located  through  on-Hne literature searches  of  the
Chemical Abstracts, TOXLINE,  CANCERLINE  and  the  CHEMFATE/DATALOG  data bases.
The  basic  literature  searched supporting  this   document  1s  current up  to
September,   1984.   Secondary  sources  of  Information have  also been  relied
upon  1n the  preparation of  this  report  and  represent large-scale  health
assessment   efforts  that entail  extensive   peer  and   Agency  review.   The
following Office of  Health  and Environmental Assessment  (OHEA)  sources  have
been extensively utilized:

    U.S. EPA.   1980b.   Ambient Water  Quality Criteria  for  Chlorinated
    Ethanes.  Environmental  Criteria and  Assessment  Office,  Cincinnati,
    OH.  EPA  440/5-80-029.    NTIS  PB  81-117624.   (Cited  1n  U.S.  EPA,

    U.S. EPA.    1983b.   Drinking Water  Criteria  Document   for  1.1-D1-
    chloroethane.   Prepared  by the  Environmental Criteria  and  Assess-
    ment Office, Cincinnati,  OH,  OHEA for  the Office of  Drinking  Water,
    Washington,  DC.  Final  draft.

    The Intent 1n  these  assessments  1s  to  suggest acceptable exposure levels
whenever sufficient data were available.   Values were not derived  or larger
uncertainty factors  were employed  when  the variable data  were  limited  1n
scope  tending to generate conservative  (I.e., protective)  estimates.   Never-
theless, the  Interim values  presented  reflect the relative  degree  of hazard
associated  with  exposure or  risk to the chemlcal(s) addressed.

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

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

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

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

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

    Tox1colog1cal data  are limited  to  subchronlc  Inhalation studies.   The
U.S.  EPA  (1983b)  has   employed  these  data  to estimate  an  acceptable  oral
exposure  level  of  8.1  mg/day  which  1s adopted  here as  the  oral  AIC.   An
Inhalation AIC of 9.7  mg/day  has been  estimated  based  on subchronlc Inhala-
tion  data.   A  CS  of  9.8  was   calculated  based  on  kidney  damage  1n  cats
exposed for 26 weeks to a  TWA level of 750 ppm.

    Limited data  Indicate  that  1 ,l-d1chloroethane may have the potential  for
carcinogenic  activity   1n  experimental  animals..   Data were  Inadequate  for
quantitative  risk  assessment.   Additional  experimental  data  are  needed  in
order to adequately address the Issue of potential cardnogenicHy.

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

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

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

Editorial review for the document series was provided by:

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

Technical support services for the document series  was provided by:

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

                             TABLE  OF  CONTENTS





3.1.1. Oral 	
3.1.2. Inhalation 	
3.2.1. Oral 	
3.2.2. Inhalation 	
. . . 3
, , 3
. . . 4
. . . 5
. . . 7

3.3.2. Inhalation 	

4.3.1. Mutagenldty Tests 	

                          TABLE OF CONTENTS  (cont.)


 6.   RISK ASSESSMENT	    15


            6.1.1.    Oral	    15
            6.1.2.    Inhalation	    15

     6.2.   ACCEPTABLE  INTAKE  CHRONIC (AIC)	    18

            6.2.1.    Oral	    18
            6.2.2.    Inhalation	    18

     6.3.   CARCINOGENIC POTENCY (q-|*)	    19

            6.3.1.    Oral	    19
            6.3.2.    Inhalation	    19

 7.   REFERENCES	    20

APPENDIX: Summary Table for  1 ,l-D1chloroethane	    25

                               LIST OF TABLES

No.                               Title

4-1     Summary of Incidence of Statistically Significant Primary
        Tumors 1n Osborne-Mendel Rats and B6C3F-| Mice	   10

5-1     Regulatory Standards and Criteria 	   14

6-1     Calculated Animal Dose 1n mg/kg/day	   17

                             LIST OF  ABBREVIATIONS

ADI                     Acceptable dally Intake

AIC                     Acceptable Intake chronic

AIS                     Acceptable Intake subchronlc

BCF                     B1oconcentrat1on factor

bw                      Body weight

CAS                     Chemical Abstract Service

CNS                     Central nervous system

CS                      Composite score

Kow                     Octanol/water partition coefficient

LOAEL                   Lowest-observed-adverse-effect level

MED                     Minimum effective dose

NOEL                    No-observed-effect level

ppm                     Parts per million

RV,j                     Dose-rating value

RVe                     Effect-rating value

SGOT                    Serum glutamate oxaloacetate transamlnase

SGPT                    Serum glutamate pyruvate transamlnase

STEL                    Short-term exposure limit

TLV                     Threshold limit value

TWA                     Time-weighted average

                     1.   ENVIRONMENTAL CHEMISTRY AND FATE

    The relevant physical  and  chemical  properties and environmental  fate  of
I,l-d1chloroethane   (CAS  Registry  No.  75-34-3),  also  known  as  ethylldene
chloride or ethylldene dlchloMde,  are given below.
     Chemical class:
     Molecular weight:
     Vapor pressure:
     Water solubility:
     Soil mobility:
      (predicted as retardation
       factor for a soil depth of
       140 cm and organic carbon
       content of 0.087%)
     Half-life 1n air:
     Half-life 1n water:
 halogenated aliphatic hydrocarbon
 182 mm  Hg at  20C  (Archer, 1979)
 5500 mg/S. at  20C  (Archer, 1979)
 61.6  (Valvan!  et al., 1981)
 1.2  (estimated)
 6.6  (estimated)
'l.5  months  (Callahan  et al.,  1979)
 1-5  days  (estimated)
    A  soil  retardation factor  of  1.2 has  been estimated for  1,1  dlchloro-
ethane  using  the  soil  adsorption  coefficient  and  K    (Schwarzenbach  and
Westall,  1981).    The   KQW  value  for  1,1-dlchloroethane  (61.6)  1s  Inter-
mediate  between  the K   values for  chloroform (93)  and 1,2-d1chloroethane
(30).   The  soil  retardation factor  for  a soil  depth  of  140 cm  and  organic
carbon  content  of  0.087% 1s 1.2  for both 1,2-d1chloroethane and  chloroform
(Wilson  et  al.,  1981).  Therefore,  the retardation  factor  for  1,1-dlchloro-
ethane has been estimated to be 1.2.
    The  BCF  value  of  6.6 given above has been  estimated from  the  following
equation:  log BCF = 0.85 log KQW - 0.70 (Velth et al., 1979).

    The  ratio  of  the  reaeratlon rate  constants  for  1 ,l-d1chloroethane  has
been experimentally  determined  to be 0.71  (Smith  et al., 1980).   The  half-
life value has been  estimated from  this  reaeratlon  rate ratio and the oxygen
reaeratlon  rates  1n representative  water  bodies   (0.19-0.96  day"1),  with
the assumption  that  the  volatilization  1s a  first order process  (Mabey  et
al., 1981).
    The half-life  value  for  1,l-d1chloroethane 1n  soil could not  be  located
1n the available literature; however, evaporation 1s  expected to  be the pre-
dominant  loss  mechanism  from  the   soil  surface.    The  half-life  for  soil
evaporation should be  longer  than Us evaporation  half-life  from  water.   In
subsurface  soil,  the  loss  of  1 ,l-d1chloroethane  through blodegradatlon  1s
expected  to be  Insignificant  (Wilson   et  al.,  1983).  Therefore,  I,l-d1-
chloroethane may persist  1n  soil  and  1s expected  to be removed  primarily
through leaching Into groundwater.

2.1.   ORAL
    No studies  have  been  conducted regarding gastrointestinal  absorption  of
1,l-d1cnloroethane.   Based on similarities of molecular  size  and  UpophlUc-
1ty as evidenced by olive oil/water partition coefficients  (69.2  for  I,l-d1-
chloroethane and 39.8  for 1,2-d1chloroethane)  (Sato and Nakajlma,  1979),  It
was  suggested   that  gastrointestinal   absorption of  1 ,l-d1chloroethane  may
proceed somewhat faster than absorption  of  1,2-d1chloroethane.  Spreaflco  et
al.  (1980)  reported  rapid  absorption  of 1,2-d1chloroethane  1n  rats  after
single oral doses of 25 mg/kg bw or 150 mg/kg bw 1n  corn  oil.
    No studies  regarding  the extent or rate  of  absorption  from Inhalation  of
1 ,l-d1chloroethane   have   been  located.   Goldstein  et al.  (1974)  suggested
that with  gases  having a blood/air partition  coefficient  of  >1.2,  respira-
tion  Is  the  limiting  factor  In  reaching  equilibrium.    Sato and  Nakajlma
(1979) reported  blood/air coefficients  of 4.7  and 19.5  for 1,1-  and  l,2-d1-
chloroethane,   respectively.   Therefore,   1t  might be  expected that  I,l-d1-
chloroethane would  be  absorbed  moderately  from Inhalation  exposure,  but
absorbed  less  and  eliminated   more  rapidly  than 1,2-d1chloroethane,  which
helps explain  the observation  that the  Inhalation toxldty of  1 ,l-d1chloro-
ethane 1s less  than  the toxldty of 1,2-d1chloroethane (Lazarew, 1929).

3.1.1.   Oral.   Few  studies  of  the  effects of  subchronlc oral  administra-
tion of 1 ,l-d1chloroethane on  animals  have been located.   In a  very limited
study, Larson  et al. {1955}  Intubated  three  mongrel dogs with  200  mg/kg  bw
1 ,l-d1chloroethane  6 days/week  for  8 weeks  to  study the  effects on  the
adrenal gland.   All  three test  animals  survived the treatment  and  none  had
significant  hlstologlcal   changes   1n   the adrenals.   Other  parameters  of
toxldty were not reported.
    Preliminary  to  conducting   a  long-term cardnogenesls  bloassay  In  rats
and mice,  NCI  (1978)  conducted  a subchronlc range-finding  study by  adminis-
tering 1 ,l-d1chloroethane  1n corn  oil  by  gavage.   Groups of five  male  and
five  female  Osborne-Mendel  rats  were  given  562,  1000,  1780,   3160  or  5620
mg/kg  bw/day  5 days/week  for 6 weeks.  Male  rats  1n the  1000 and  1780  dose
groups and females  1n  the  1780 and  3160 mg/kg/day  groups  exhibited  body
weight depression.  Mortality occurred  In  two  female rats  1n  the 3160 mg/kg/
day  group.   Groups  of  five  male and  five female  B6C3F,  mice  were treated
with 1000, 1780, 3160,  5620  or  10,000  mg/kg/day  5  days/week for  6 weeks.   No
body weight depression  occurred 1n  mice,   but mortality occurred 1n  two  male
and three  female mice  1n  the 5620 mg/kg/day dose  group.   These  studies  were
too limited 1n  their assessment  of  criteria of  toxlclty to be useful 1n  risk
3.1.2.   Inhalation.   In   a  subchronlc  Inhalation  study, Hofmann   et  al.
(1971) exposed  groups  of  10 rats,  4 cats, 4  rabbits  and 10 guinea pigs  to
500  ppm  (-2025  mg/m3}  1 ,l-d1chloroethane  6  hours/day, 5  days/week for  13
weeks.  No effects  were reported 1n any of the  animals tested.   Exposure  to
1000  ppm  (~4050  mg/m3)   6  hours/day,  5 days/week   using  the  same  test

animals continued  for  another  13  weeks.  The  most sensitive animal  tested
appeared to be the cat,  the  only animal  1n which adverse effects were noted.
Blood  urea  nitrogen  levels  were  Immediately elevated  and rose  steadily  to
week  24,  at which time  they peaked at  ~3 times the control  levels.   Blood
creatlnlne  levels showed a parallel  but  less  dramatic  Increase.   No Increase
of  SGOT  or SGPT  was  noted.   Hlstopathologlcal   examination   of  the  cats
revealed renal  tubular dilatation and degeneration. Indicating renal damage.
    Torkelson and  Rowe  (1981)  summarized  an unpublished  subchronlc  Inhala-
tion  study  by Dow  Chemical   Company 1n which  unspecified numbers of  rats,
guinea pigs, rabbits  and dogs were  exposed to  500  or  1000 ppm (2025  or 4050
mg/m3,  respectively)  1 ,l-d1chloroethane for  7  hours/day,  5  days/week  for  6
months.   Blood chemistries,  necropsy and  hlstologlcal  examinations revealed
no  changes  attributed to  the exposure.   Based  on the  studies  by Torkelson
and  Rowe  (1981)  and  Hoffman  et  al. (1971),  a  NOEL of  500  ppm  (2025 mg/m3)
can  be  suggested  for  subchronlc  Inhalation exposure to 1 ,l-d1chloroethane 1n
rats, cats, rabbits,  guinea pigs and dogs.
3.2.   CHRONIC
3.2.1.   Oral.    The  only  study  of  chronic  oral  toxldty to  1,l-d1chloro-
ethane was  reported  In the NCI  cardnogenldty  assay (NCI, 1978).  Groups of
50  male and 50  female  Osborne-Mendel  rats  and B6C3F, mice  were Intubated
with  I,l-d1chloroethane 1n  corn  oil.   Control and  vehicle  control  groups
consisted of 20  male  and 20  female animals of each species.  Treatments were
administered 5  days/week  for  3 weeks,  followed by 1  dose-free week  and  3
additional  treatment weeks over  the 78-week  treatment  period.  The following
time  weighted  dosages for  treatment days were  obtained:   male  rats,  high-
dose  group  764  mg/kg  bw/day,  low-dose  group 382  mg/kg bw/day;  female rats,
high-dose  group  950  mg/kg  bw/day,  low-dose  group  475 mg/kg bw/day.   Mice

were  treated  5  days/week  for  78  weeks with  the  dosage  Increased  after  6
weeks and  again after 9 weeks.   The TWA  doses  for treatment days  for  male
mice were  2885  and  1442 mg/kg bw/day for  low-  and  high-dose groups, respec-
tively;   for  female  mice,  these  doses were  3331  and  1665  mg/kg  bw/day,
respectively.   Rats were observed  for an additional 33 weeks and mice for an
additional  13  weeks,  after  which  survivors were  killed.   All  animals  that
died  or  were killed  when  moribund or  at  the  conclusion  of  the observation
period were subjected to necropsy.
    For   both male  and  female  rats, body weight  curves  for treatment  and
vehicle  control groups were  similar  and  somewhat  below  untreated controls.
All  groups  of  rats exhibited  a hunched appearance, abdominal  urine stains,
labored  breathing,  wheezing and nasal  discharge.   By  the  conclusion of  the
trial, all  surviving  rats  exhibited these  signs,  though  the incidence early
In  the  study  appeared to  be  slightly  higher  1n  the   treatment  groups.
Mortality was high  in both  male and female groups  of  rats and appeared to be
slightly  higher  1n  1,l-d1chloroethane-exposed  groups,  though   no   signifi-
cantly  greater  mortality   was  observed  1n the  high-dose  groups.   Chronic
murlne pneumonia and  kidney inflammation  accounted  for  the vast majority of
mortality among both  control and treatment  groups.
     Body  weight curves  for  male and female mice  seemed unaffected by treat-
ment  or  vehicle; there  appeared  to be no definitive  signs of  1,1-dichloro-
ethane  toxlcity  in  physical  appearance   or  behavior   throughout  the study.
Examination  of   statistically  predicted survival  curves  Indicated that sur-
vival of both  male and  female mice had been adversely affected by  the high
dose  of  I,l-d1chloroethane,  although  no  specific  pathological  lesions were
observed  at significantly  higher  incidences 1n  treated  groups.  Because of
the  Increased  mortality associated with   treatment,  no  NOEL  or  LOAEL  was
defined  by  this study for mice.

3.2.2.   Inhalation.  No pertinent  data  concerning  chronic Inhalation expo-
sure to 1 ,l-d1chloroethane could not be located 1n the available literature.
3.3.1.   Oral.   Pertinent  data  regarding  teratogenldty  or  reproductive
dysfunction 1n  humans  or animals associated with 1ngest1on  of 1 ,l-d1chloro-
ethane could not be located 1n the available literature.
3.3.2.   Inhalation.   Pertinent  data  regarding  teratogenldty or  reproduc-
tive  dysfunction  1n humans related  to Inhalation exposure  to 1,l-d1chloro-
ethane  could  not  be  located   1n  the  available  literature.   Schwetz et  al.
(1974)  exposed  rats to 0,  3800  or  6000 ppm 1,1-dlchloroethane for  7  hours/
day  on  days  5-15  of   gestation.   A  significantly  Increased  Incidence  of
delayed  ossification  of  sternebrae   resulted  from  exposure  to  6000  ppm
1 ,l-d1chloroethane.    Assuming  a body weight  of 0.35 kg  and  an  Inhalation
rate  of  0.26  mVday for rats,  exposure  to 3800 ppm  for 7  hours/day,  corre-
sponding to  an  Intake  of  -3333 mg/kg/day,  was  found to  be  a NOEL  1n  this
study.   Because this  Intake  (-3333 mg/kg/day)  1s  greater  than  the  Intake
(269  mg/kg/day)  calculated  for rats 1n  the study by Hofmann  et  al.  (1971),
the Schwetz et al.  (1974) study will not Impact risk assessment.
    Pertinent  data  on  the  toxic  Interactions   of   1,l-d1chloroethane  with
other xenoblotlcs  could  not be  located 1n  the  available  literature;  however,
1t can  be anticipated  that  exposure  to other  agents  which  deplete glutathlon
would enhance Us toxldty.
    Limited Information  1s  available concerning  the  effects  of 1,1-dlchloro-
ethane  on humans.   At  one time the compound was  used as an  anesthetic,  with
an  anesthetic  pressure of  0.026  atmospheres,   -105,000  mg/m3  (Miller  et

al.,  1965).   The  ability  of  the  compound  to  Induce  cardiac  arrhythmias

caused discontinuation of  Us  use  as  an anesthetic (Browning, 1965).  It 1s

probable  that  human exposure  to  sufficiently high  levels would  cause  CNS

depression  and  respiratory  tract  and  skin   Irritation,  since many  other

chlorinated  aHphatlcs  do  (Parker  et  al.,  1979).   No  dose-response data

concerning these phenomena are  available.

                             4.  CARCINOGENICITY
    Pertinent data  concerning  the  cardnogenldty  of 1,1-dlchloroethane  1n
humans could not be located 1n  the  available  literature.
    The only  cardnogenldty  bloassay concerning 1 ,l-d1chloroethane  located
1n  the available  literature was conducted by  NCI  (1978).  The protocol and
noncardnogenlc  data generated by  this  study were  discussed In Section  3.2.
Under the  conditions  of  this study,  male  rats showed no significant change
1n  the  Incidence  of  neoplasla  which were  compound related.   Female   rats
(Table 4-1) showed a significant dose-response relationship 1n  the  Incidence
of  hemanglosarcoma  when  measured  by  the  Cochran-ArmHage test  for linear
trend 1n  proportions  comparing  the two  dose groups with either the  matched
vehicle control  (p=0.041)  or  the  pooled  vehicle  control groups  (p=0.021).
By  the Cochran-ArmHage test, a  significant  (p=0.043) dose-related  Incidence
of  mammary  adenocardnomas  was  also  observed.   Results  of  the Fisher  Exact
test showed no  significant  Incidence  of  either of   these  tumors.   Because  of
high mortality  early  1n  the  study,  statistical  analysis  of  data  only  from
survivors   of  >1 year  of   exposure  was  also  performed.   Using the  Cochran-
ArmHage  test,  statistical  significance  (p=0.034)  was demonstrated  only for
mammary adenocardnoma 1n  female rats.   Results  using the Fisher  Exact  test
were statistically negative.
    In male mice surviving  >1 year, the  Cochran-ArmHage  test  demonstrated a
significant  (p=0.016)   dose-related  Incidence  of   hepatocellular   carcinoma
compared  with  pooled  vehicle  controls.   Using  the Fisher  Exact  test,  a
probability  level  of  p=0.027  was  calculated  by   comparing  high  dose and
pooled  vehicle  control  groups.   Applying  the  Bonferronl  criterion,  which

                                                                   TABLE 4-1

                   Summary of Incidence  of  Statistically Significant Primary Tumors  In Osborne-Hendel  Rats  and  B6C3F)  N1cea>b
Species Tumor Type
Female rats mammary adenocarclnoma
p values0
Female rats hemanglosarcoma
p values0
Female rats mammary adenocarclnomas
>52 weeks
p values0
Female mice endometrlal stromal polyp
p values0
Hale mice hepatocellular carcinoma
>52 weeks
p values0
Pooled Vehicle
1/39 (0.03)
0/39 (0.00)

0/79 (0.00)
6/72 (0.08)

Hatched Vehicle
0/19 (0.00)
0/19 (0.00)
0/16 (0.00)

0/20 (0.00)
1/19 (0.05)

Low Dose
1/50 (0.02)
0/50 (0.00)
1/28 (0.04)

0/47 (0.00)
8/48 (0.17)

High Dose
5/50 (0.10)
4/50 (0.08)
5/31 (0.16)

4/46 (0.09)
8/32 (0.25)

aSource: NCI. 1978

bExper1mental design summarized In text

cThe  probability  level  for  the  Cochran-Armltage  test  Is  given  beneath  the  Incidence of  tumors  In  the corresponding  control  group  when
 p<0.05; otherwise, not significant (NS) Is Indicated.  The probability  level  for  the Fisher Exact test for the comparison  of  a  treated group
 with a control group  Is given  beneath  the  Incidence  of  tumors  In  that  treated group when p<0.05;  the  asterisk (*)  Indicates comparison of the
 treated group with the pooled vehicle control  group.

dThe Fisher Exact test probability level of  p=0.027 was marginal  and  not  considered significant  under  the Bonferronl  criterion.

NR  Not reported; NS = Not significant

requires  that  the  normally  accepted  level  of  statistical  significance
(p<0.05) be divided by  the  number  of  dose  levels  (2),  resulted 1n an accept-
able p value of <0.025  for  statistical  significance.   By this criterion,  the
Incidence of hepatocellular  carcinoma  1n the high dose  group was considered
to  be  marginal and  not  statistically  different  from  the Incidence  1n  the
pooled vehicle control group.
    In  female  mice,  the  Cochran-Armitage  test  showed a  significantly posi-
tive dose-response relationship  1n  the  Incidence  of  benign endometMal stro-
mal  polyps  when  compared  with  the  matched  vehicle  control  (p=0.036)  or
pooled vehicle control  (p=0.005)  groups.  By the Fisher  Exact  test, the  In-
cidence of  endometrlal  stromal polyps  1n  the high groups  was  significantly
(p=0.017) higher  than In pooled vehicle controls.
    Based on the results  of  statistical  analysis  and  the low survival of  all
groups, the NCI  (1978)  concluded that "these findings  are Indicative of  the
possible  carcinogenic  potential  of  the test  compound.    However,  ...  there
was no  conclusive  evidence for  the carclnogenldty of  1 ,l-d1chloroethane 1n
Osborne-Mendel rats or B6C3F, mice."
4.3.1. Mutagen1c1ty Tests.   Simmon et  al.  (1977) tested  the mutagenlc  ac-
tivity  of  several  chemicals   Identified   1n  drinking  water  1n  the  Ames
Salmonella  typh1mur1um/m1crosomal  activation  assay.   Doses of  the chemicals
ranged  up  to  5 mg/plate.   Negative  results were reported for  1  ,l-d1chloro-
ethane  1n  S.   typhlmurlum strains  TA1535,  TA1537,  TA1538,  TA98  and  TA100,
although  the   specific   dose  of  1,l-d1chloroethane   used  and  corresponding
plate counts were not specified.
    Nesnow  (1982)  reported a  positive  response  of 1,1-dlchloroethane  In an
enhanced  viral  transformation  assay  1n Syrian  hamster  embryo cells,  using
the methods of Hatch et al. (1982).  Details of protocol were not reported.


    The only  bloassay of  the  cardnogenldty of  1,1-d1chloroethane  located
was the NCI (1978) bloassay described previously.    High  mortality  among  all
groups  probably  precluded  significant  occurrence  of  tumors   related   to
long-term  exposure.   Welsburger  (1977)  reviewed  NCI  bloassays  of  several
halogenated  allphatlcs   and  noted  striking  similarities  In  the  types   of
tumors produced.   An example was  the  formation of  hepatocellular  carcinoma
Induced 1n mice  by 1 ,l-d1chloroethane and tetrachloroethylene.   Although  the
Incidence  of  hepatocellular  carcinoma  1n mice  exposed  to 1 ,l-d1chloroethane
was not  significant  (see Section  4.2.),  the  similarity  1n  lesions  produced
by  other  halogenated allphatlcs raises a concern  that the  marginal  results
obtained  with  1 ,l-d1chloroethane  are  biologically,  1f  not  statistically,
significant.   Nevertheless, neither IARC  nor  the Carcinogen Assessment  Group
of  the U.S.  EPA has  officially classified 1 ,l-d1chloroethane as  to cardno-
genlcHy,  based  presumably  on a lack  of  evidence   for  human cardnogenlcHy
and the  marginal  slgnflcance of the  NCI  bloassay  which  1s  considered  to be
limited  evidence  for animal  cardnogenlcHy.  Applying  the  criteria  for
evaluating weight  of evidence  proposed  by  the Carcinogen  Assessment  Group
(Federal  Register,  1984), 1 ,l-d1chloroethane  1s  most  appropriately  classi-
fied a Group D-Not Classified chemical.


    Table  5-1   lists  the   various  regulatory  standards  and  criteria  for
    The  AC6IH   (1980)  recommended a  TWA-TLV  of   200  ppm  (-810  mg/m3)  for
occupational exposure  to 1 ,l-d1chloroethane, with  a STEL  of  250 ppm  (-101
mg/m3).   This  recommendation  1s  based  In  part on  the data  of  Hofmann  et
al.  (1971)  and the  unpublished data  of  the Dow  Chemical  Company  cited  In
Torkelson and  Rowe  (1981)  (see Chapter 3).   The  current OSHA standard  for
occupational exposure  to  1 ,l-d1chloroethane Is  100 ppm  (-405 mg/m3),  but
no NIOSH criterion for  occupational  exposure exists (Parker  et al.,  1979).
    In  discussing  the   derivation  of  ambient water   quality  criteria  for
chlorinated ethanes,  the U.S.  EPA  (1980b)  concluded that  "Insufficiency  In
the available  data"  precluded establishment of a  satisfactory  criterion  for
1 ,l-d1chloroethane.  The nature  of   the  deficiencies   1n  the  data  was  not
discussed.  In  a  subsequent  review  (U.S.  EPA,  1983b),  'an ADI  of  8.1  mg/day
for a  70 kg man was proposed.  This  estimate  was  based on the NOEL of 2025
mg/m3  defined  1n   Hofmann  et al.  (1971) and  employed  a rat  24-hour breath-
Ing  volume  of   0.22  mVday, an absorption  coefficient  of  0.5 and an  uncer-
tainty factor of 1000.
    No currently  available Information described  human  populations  that  may
be  particularly  sensitive  to  1,l-d1chloroethane.   The  U.S.  EPA  (1980b,
1983b)  stated  that  no  Information  was  available  on unusual  sensitivity  of
any  groups  to  any of  the  chlorinated ethanes.   The  U.S.  EPA  (1980b)  sug-
gested,  however,   that  Individuals  with Hver  Insufficiency  or  exposure  to
other  hepatotoxlns may  be  at Increased risk.  Presumably,  Individuals with
Impaired  renal function may  also  be unusually  sensitive  to  exposure  to

                                  TABLE 5-1

                       Regulatory Standards and Criteria
Criterion                    Standard                          Reference

  TLV                         200 ppm                     AC6IH,  1980
                           (-810 mg/m3)

  STEL                        250 ppm                     ACGIH,  1980
                           (-1010 mg/m3)

  OSHA                        100 ppm                     Parker  et al., 1979
                           (-405 mg/m3)

                             6.   RISK ASSESSMENT

    Risk  assessment  data  for   1,l-d1chloroethane   are   presented   in   the
Appendix to this report.
6.1.1.   Oral.   Only  two  reports  were  located  regarding  subchronic  oral
exposure in animals.  These  reports and their limitations were  discussed  in
Section  3.1.   Because  of  the  limited  scope of  these studies,  it  was  not
possible  to  derive  a  maximum  tolerable  daily  dose  for  subchronic  oral
exposure.  However, U.S. EPA (1983b) has  used  the  subchronic  Inhalation  data
of  Hofmann  et  al.  (1971)  to estimate acceptable oral  exposure.   Using their
approach,  this  study  defines  a  NOEL  for  rats  in  units  of  mg/kg/day  as
            (2025 mq/m3) (0.22 mVday)  (0.5) (6 hr/24 hr)  (5 days/7 days)
                                       0.35 kg
          =115 mg/kg/day

The  value  of  0.22  mVday  represents  the  default  24-hour  rat  breathing
volume  employed,  0.5  represents the assumed absorption coefficient  and  0.35
kg  the default  rat  body  weight.   Multiplying  by  70  kg  and dividing by  an
uncertainty factor of 100  (10  for  interspecies  variability and  10 for inter-
Individual variability) results  in an estimated AIS of 81  mg/day.
6.1.2.   Inhalation.   Reports   of   two   subchronic   inhalation   studies  of
1 ,l-d1chloroethane  1n  animals  were  discussed  in  Section  3.1.  The  study  by
Hofmann  et al.   (1971)  demonstrated  a  NOEL  of  500 ppm  (-2025 mg/m3)  in
rats,  cats,  rabbits and  guinea pigs when  exposed  for  6  hours/day,  5 days/
week  for  13  weeks.  After  this  exposure  schedule,  the  1,1-dichloroethane
concentration  was  increased to  1000 ppm  (4050  mg/m3)  for an  additional  13

weeks.   The  1000  ppm  level also  represented a  NOEL  for  all  test  animals
except cats  In  which elevated  blood  urea nitrogen was  detected and  adverse
hlstologlc changes 1n the kidney observed.   For  the cat, 1000 ppm represents
a LOAEL.  An unpublished subchronlc Inhalation study  conducted by Dow Chemi-
cal Company  and summarized  by  Torkelson and  Rowe (1981) supports the  NOEL
suggested by the earlier study.
    Estimated Inhaled  doses may be calculated  for each  exposed  species  and
will  vary  1n accordance with  the ratio  of ventilation  volume/time  to  body
weight.   Estimates of  ventilation volume  are  rough  estimates  since  these
values are  particularly sensitive to experimental conditions  and  manipula-
tions.   The  estimated  animal doses  are  presented  1n Table  6-1.   Since  the
cat data provide  the  most  protective  dose  estimate  (138 mg/kg/day),  this
dose  1s  chosen  as a starting point  for the AIS estimate.  Assuming  a  human
body weight of  70  kg and applying  an  uncertainty factor of 100 results  1n an
AIS of 96.6 mg/day.
    A  CS for 1,l-d1chloroethane was  calculated based  on the  kidney  damage
observed by  Hofmann  et al.  (1971)  1n cats  exposed  to  500 ppm  for 13  weeks
and 1000 ppm for  an  additional 13 weeks.   An RV  of  7 was   chosen  for  the
effects  on  the kidneys  because  there was  hlstologlc  evidence of  kidney
damage with  demonstrable  decrement 1n  organ  functions  (I.e.,  elevated  blood
urea  nitrogen).   A human MED was  calculated by expanding  the TWA  exposure,
750 ppm, from  6-24  hours/day  and from  5-7  days/week.    It was  also  assumed
that  humans  Inhale   20 m3 of a1r/24  hours  and  that  1,l-d1chloroethane
absorption Is 50%.   An  uncertainty factor of  10 was  applied  to convert  from
subchronlc  to  chronic  data resulting  1n  a  human  MED  of 542  mg/day,  which
corresponds  to  an  RV,  of  1.4.   A   CS of  9.8,  the  product  of  RV.  and
RVg, 1s  calculated.

                                  TABLE  6-1
                     Calculated Animal Dose 1n mg/kg/daya
Dose 1n mq/kq bw/day
Guinea pigs
Inhalation Rate
Body Weight
2025 mg/m3
4050 mg/m3
aSource: Hofmann et a!., 1971
bEst1mated Inhalation rates and body weights

6.2.1.   Oral.   The  only report  of  chronic  oral  exposure  to  1,1-dichloro-
ethane  was  the  NCI  (1978)  bloassay  discussed  In  Section  3.2.   As  noted
before, animals  In  both  dosage levels and  control  groups  experienced  pro-
nounced  early  mortality.   Although  not  statistically  significant,  some
potentlatlon of mortality In rats  appeared  to be  related to treatment.  U.S.
EPA (1983b) has  used  the  subchronlc  Inhalation  data  for  the rat from Hofmann
et  al.  (1971) to develop an ADI.   It 1s  suggested  that  their  estimate  be
used for the  AIC.  The  basis for  the proposed AIC of 8.1 mg/day 1s explained
1n  Section 6.1.1. with  the addition  of an uncertainty  factor of 10 (combined
uncertainty  factor   of   1000)   to extrapolate  from  subchronlc  to  chronic
6.2.2.   Inhalation.  No  reports  of chronic  Inhalation  exposure  of  humans
or  animals  to  1,l-d1chloroethane  could  not be  located  1n   the  available
literature.    The AC6IH  (1980)  recommended  a  TLV of 200  ppm,  based  on  the
studies by Hofmann  et al. (1971) and  Dow Chemical  Company (n.d.),  while  the
OSHA  standard  for  occupational  exposure  to  1,1-dichloroethane  is  a  TLV  of
100 ppm.  The  TLV  of 100 ppm could  be used  to estimate  acceptable exposure,
using an uncertainty  factor  of  10.  The  uncertainty factor  of  10  1s  used  to
protect especially sensitive members of populations.
    Calculation  of  the  dose  is  as  follows:  The  TLV  (405  mg/m3) x 10  m3
Inhaled/workday  x   (5  workdays  *  7  days/week)  *  10  (UF) = 289  mg/day.
The AIC derived  from the TLV is  ~3-fold  higher than  the Interim AIS  derived
for  subchronlc  exposure.   The  discrepancy  may  reflect  differences   and
uncertainties   in  the  methodologies  for  obtaining  TLVs  and  calculating
acceptable Intakes  from  animal  data,  or  species  differences 1n  sensitivity
between  cats   and  humans to  the  toxicity  of   1,l-d1chloroethane.   It  Is
proposed that  the more  protective approach to AIC development  be  employed.


Starting with  the  AIS  of 96.6 mg/day and  applying  an additional uncertainty
factor of  10  to extrapolate  from  subchronlc to chronic  exposure  results 1n
an AIC of 9.7  mg/day.   This  value  should be reevaluated when additional data
are available.
6.3.1.   Oral.   Results of  the NCI  (1978)  bloassay  of  1 ,l-d1chloroethane
suggested that  this compound  may have  carcinogenic  properties.   The signifi-
cant  positive  treatment-response  associations  elucidated  by   the  Cochran-
Armltage test  for  hemanglosarcoma  and mammary  adenoma 1n  female rats are not
necessarily Invalidated by the  negative results of  the  Fisher exact  test.
Heavy mortality among the  control  groups as well  as the treatment  groups and
application of  the Bonferronl criterion undoubtedly  contributed to  the lack
of  statistical  significance  of  the  Fisher  exact test.  The  heavy mortality
among  treatment   groups   probably  resulted  1n   underestimating   the   true
carcinogenic  potential   of  1 ,l-d1chloroethane,  especially  In  light of  the
positive  treatment-response  association  manifest  by  the  Cochran-Armltage
test.  Furthermore, as  pointed out by Welsburger (1977)  (see  Section  4.4.),
striking similarities  1n the  types  of  tumors  produced by  other chlorinated
allphatlcs are suggestive of a carcinogenic role for 1,1-dlchloroethane.
    Nonetheless, as  Indicated by  the  review panel  for the NCI (1978)  bio-
assay on 1,1-dlchloroethane,  the compound should be  retested  to resolve the
Issue of  cardnogenlclty.   Heavy mortality among both  treatment and control
groups precluded  using  the  data from  this  study  to generate  unit  carcino-
genic  risk  estimates.   Also,  the  physical  condition  of   the  animals  was
markedly stressed and did not appoxlmate a normal human population.
6.3.2.   Inhalation.    Pertinent   data   regarding   the  cardnogenlclty   of
1,1-dlchloroethane could not be located 1n the available literature.

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Archer, W.L.   1979.   Other  chloroethanes.   In.:  K1rk-0thmer  Encyclopedia  of

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Browning,  E.   1965.   Toxldty   and  Metabolism  of  Industrial   Solvents.

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Environmental Fate of  129 Priority  Pollutants,  Vol.  II.   Office  of  Water

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Hatch,  G.G.,   P.D.   Mamaz,  M.L.  Ayer,  B.C.   Casto  and  S.  Nesnow.   1982.
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Hofmann,  H.T., H. B1rnst1el and P.  Jobst.   1971.   The  Inhalation toxldty of
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Nesnow, S.   1982.   Summary of Results  of  Bloassays  of Volatile  Carcinogens
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Parker, J.C.,  G.E.  Casey  and  L.J. Bahlnon.   1979.   NIOSH current  Intelli-
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chlorinated  hydrocarbons.    Arch.  Environ. Health.   34:   69-75.   (Cited  1n
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Schwarzenbach,  R.P.  and J.  Westall.   1981.   Transport of nonpolar  organic
compounds  from  surface water  to groundwater.  Laboratory  sorptlon  studies.
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Schwetz, B.A.,  B.K.J.  Leong  and  P.O.  Gehrlng.  1974.  Embryo- and fetotoxlc-
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Simmon, V.F.,  K.  Kaufanen and  R.G.  Tardlff.   1977.   Mutagenlc activity  of
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Smith,  J.H., D.C.  Bomberger,  Jr.  and D.L. Haynes.  1980.   Prediction  of  the
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Spreaflco,  F.,  E.  Zuccato  and  F.  Murcurcl.   1980.   Pharmocoklnetlcs  of
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Torkelson,  T.R.  and V.K.  Rowe.   1981.  IrK  Patty's  Industrial Hygiene  and
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24: 225-?:^.


                                        Summary Table for 1,l-D1chloroethane

Species Experimental Effect Acceptable Intake
Dose/Exposure (AIS or AIC)

cat 500 ppm none 96.6 mg/day
(2025 mg/m3)
cat 500 ppm none 9.7 mg/day
(2025 mg/ma)
cat TWA 750 ppm kidney damage, 9.8
6 hours/day, elevated blood urea
5 days/week nitrogen (RVe = 7)
for 26 weeks
(RVd = 1.4)

rat 500 ppm none 81 mg/day
(2025 mg/ma)
rat 500 ppm* none 8.1 mg/day
(2025 mg/ma)

Hofmann et al
Hofmann et al
Hofmann et al

Hofmann et al

* *
* t

Hofmann et al.,
U.S. EPA, 1983b
    'Based on Inhalation data as proposed by U.S. EPA (1983b)