MNAL
              United States                           ECAO-CIN-423
              Environmental Protection                      c
                                               September, 1988
SEPA       Research  and
              Development
              DRINKING WATER CRITERIA DOCUMENT
              FOR ENDRIN
              Prepared for

              HEALTH AND ECOLOGICAL CRITERIA DIVISION
              OFFICE OF SCIENCES AND TECHNOLOGY
              OFFICE OF WATER
              U.S. ENVIRONMENTAL PROTECTION AGENCY
              WASHINGTON, OC  20460
              Prepared by
              Environmental Criteria and Assessment Office
              Office of Health and Environmental Assessment
              U.S. Environmental  Protection Agency
              Cincinnati, OH  45268

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                                  DISCLAIMER

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

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                                   FOREWORD
    Section  1412  (b)(3)(A)  of  the  Safe  Drinking  Water  Act,  as  amended  In
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,  In  the
Judgment of  the Administrator,  may  have  an adverse  effect on public  health
and  which  Is known  or anticipated  to  occur  In  public  water  systems.   The
MCLG  Is  nonenforceable and  1s  set  at  a  level  at which no known  or  antici-
pated  adverse  health  effects   In  humans  occur  and which   allows  for  an
adequate margin  of  safety.  Factors considered  In setting the  HCLG  Include
health effects data and sources  of exposure other than drinking water.

    This document provides  the  health  effects  basis  to  be  considered  In
establishing  the  MCLG.  To achieve  this objective,  data  on pharmacoklnetlcs,
human  exposure,  acute and chronic  toxldty  to animals and humans,  epidemi-
ology and mechanisms  of toxldty  are evaluated.   Specific  emphasis Is  placed
on  literature  data  providing  dose-response   Information.  Thus,  while  the
literature  search  and evaluation performed  In support  of  this  document  has
been comprehensive, only  the reports considered most pertinent  In  the  deri-
vation of  the MCLG  are dted In  the document.   The comprehensive  literature
data base  In support   of  this document  Includes  Information published  up  to
1987;  however,   more   recent  data  may  have   been  added   during  the  review
process.    Editorial  changes were  also  made  1n  1991  when  this  document  was
finalized.

    When adequate health  effects  data exist,  Health Advisory  values  for less
than   lifetime   exposures  (1-day,   10-day  and   longer-term,   -10X   of   an
Individual's  lifetime) are Included In  this document.  These  values  are  not
used  In  setting the MCLG,  but  serve as  Informal  guidance to  municipalities
and  other  organizations  when  emergency  spills  or  contamination  situations
occur.
                                                 Tudor Davles
                                                 Director
                                                 Office of Science and
                                                  Technology

                                                 James Elder
                                                 Director
                                                 Office of Ground Water
                                                  and Drinking Water
                                      111

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                             DOCUMENT DEVELOPMENT
Annette M. Gatchett, Document Manager
Environmental Criteria and Assessment Office, Cincinnati
U.S. Environmental Protection Agency

Helen H. Ball, Project Officer
Environmental Criteria and Assessment Office, Cincinnati
U.S. Environmental Protection Agency
Authors

Shane S. Que Hee, Ph.D.
University of Cincinnati

Martha RadUe, Ph.D.
University of Cincinnati

Evelyn Uldner, B.S.
University of Clndnnnatl

Rita Schoeny, Ph.D.
University of Cincinnati

Ellen O'Flaherty, Ph.D.
University of Cincinnati

Stuart Baxter, Ph.D.
University of Cincinnati
Scientific Reviewers

Randall J.F. Bruins, M.S.
Annette Gatchett. B.S.
Richard Hertzberg, Ph.D.
Jennifer Orme, M.S.
William Bruce Pelrano, M.S.
Fred A. Reltman, B.S.
Environmental Criteria and Assessment
  Office, Cincinnati
U.S. Environmental Protection Agency
Scientific Reviewers (cont.)

Margaret L. Chu, Ph.D.
Robert McGaughy, Ph.D.
William E. Pepelko, Ph.D.
Carcinogen Assessment Group
U.S. Environmental Protection Agency
Washington, DC

Peter Gartslde, Ph.D.
Geraldlne Krueger, Ph.D.
University of Cincinnati

Keith Jacobson, Ph.D.
Life Systems, Inc.
Arlington, VA

Yogendra Patel, Ph.D.
Office of Drinking Water
U.S. Environmental Protection Agency
Washington, DC

Fumlo Matsumura
Dept. of Environmental Toxicology
  and Toxic Substances
Research and Testing Program
University of California

Geraldlne L. Krueger
University of Cincinnati
                                        Editorial  Reviewers

                                        Eriu Durden,  B.S.
                                        Judith Olsen, B.A.
                                        Environmental Criteria and Assessment
                                          Office,  Cincinnati
                                        U.S. Environmental Protection Agency
                                      1v

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Document Preparation

Technical Support Services Staff:  C. Cooper,  P.  Daunt,  C.  Fessler,  K.  Mann,
B. Zwayer, J. Moore. Environmental Criteria and Assessment Office, Cincinnati

Other  Contributors:   Becky  Clark,  Kay  Irlon,  Geraldlne Krueger,  Lorraine
Mercer, Ted Morris,  Jane Onslow, Maria Zlnam, University of Cincinnati

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                              TABLE  OF  CONTENTS
  I.  SUMMARY ...........................     i-l

 II.  PHYSICAL AND CHEMICAL PROPERTIES ...............    II-1

      SPECTROSCOPIC PROPERTIES ...................    11-11
      CHEMISTRY ..........................    11-11
      ANALYTICAL METHODS ................ . .....    11-12
      SUMMARY ...........................    11-14

III.  TOXICOKINETICS .................... ....   III-l

      ABSORPTION ..........................   III-T

           Oral ..........................   III-l

      INHALATION ..........................   III-3
      DERMAL ............................   III-3
      DISTRIBUTION AND METABOLISM .................   III-4

           Distribution In Human Tissues ..............   III-4
           Distribution 1n Animal Tissues .............   III-7

      MECHANISMS OF TRANSPORT AND METABOLISM ............   111-23
      ELIMINATION .........................   111-26
      SUMMARY ...........................   1 11-33

 IV.  HUMAN EXPOSURE ........................    IV-1

  V.  HEALTH EFFECTS IN ANIMALS ..................     V-l

      ACUTE TOXICITY ........................     V-l

           Experimental Lethality Studies .............     V-l
           Environmental and Acddentlal Intoxication .......     V-7
           Central Nervous System and Behavioral Effects ......     V-9
           Cardiovascular Effects .................     V-10
           Renal Effects ......................     V-12
           Hepatic Effects .....................     V-12

      SUBCHRONIC EFFECTS OF ENORIN .................     V-14
      CHRONIC EFFECTS ......... .  ..............     V-20

      TERATOGENICITY AND REPRODUCTIVE EFFECTS ........  ...     V-29

           Maimals ........................  .     V-29
           Birds .....................  .....     V-38

      MUTAGENICITY ......  .  ..................     V-39
      CARCINOGENICITY ........ ...............     V-41
      SUMMARY ...........................     V-56
                                     v1

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                                                                       Page

  VI.  HEALTH EFFECTS IN HUMANS	    VI-1

       ACUTE TOXICITY	    VI-1

            Accidental and Intentional Poisonings	    VI-1
            Effects of Occupational Exposures	    VI-3
            Immunology	    VI-4
            Ep1dem1olog1cal Studies	    VI-4

       SUMMARY	    VI-10

 VII.  MECHANISMS OF TOXICITY	   VII-1

       ACUTE TOXICITY	   VII-1
       INTERACTIONS	   VII-5
       SUMMARY	   VII-8

VIII.  QUANTIFICATION OF TOXICOLOGICAL EFFECTS 	  VIII-1

       INTRODUCTION	VIII-1
       NONCARCINOGENIC EFFECTS  	  VIII-6
       QUANTIFICATION OF NONCARCINOGENIC EFFECTS  	  VIII-10

            Derivation of 1-Day HA  	  VIII-10
            Derivation of 10-Day HA	VIII-11
            Derivation of Longer-Terra HA 	  VIII-11
            Assessment of Lifetime Exposure and Derivation of DUEL .  VIII-13

       CARCINOGENIC EFFECTS	VIII-14
       EXISTING GUIDELINES, RECOMMENDATIONS AND STANDARDS	VIII-17
       SPECIAL CONSIDERATIONS	VIII-19
       SUMMARY 	  VIII-21

  IX.  REFERENCES	    IX-1

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                                LIST OF  TABLES
 No.                                Title                              Page

 II-l    Nomenclature, Indexing Terras and Synonyms  Currently
         Used for Endrln	    II-3

 II-2    Chemical Information Related to Some Endrln Degradation
         Products	    II-4

 II-3    CAS Indexing Terms and CAS RN for  Endrln Metabolites.  . .  .    II-5

 II-4    Typical Composition of Technical Grade Endrln .......    II-6

 II-5    Some Pesticide Mixtures 1n which Endrln 1s not  the
         Only Pesticide	    II-8

 II-6    Analytical Methods for Determining Endrln  or Endrln
         Transformation Products 1n Tissues or Animal Fluids ....    11-13

III-l    Evidence of Absorption Using Residue and Biological
         Effect Data	III-2

III-2    Endrln Concentrations Found 1n Victims of  Endrln
         Poisoning	III-6

III-3    Distribution of Endrln and 12-KetoendMn at Day 148
         In Sykes Hybrid III Hens (2 kg Initially)  Fed 0.13 mg/kg
         Diet by Capsule	111-10

III-4    Radioactivity In Tissues of Five Hens After a 148-Day
         Period of Treatment with 0.3 yd/Day (as Capsules)	111-11

III-5    Endrln Distribution 1n Birds In the Post-1978
         Literature	111-13

III-6    Distribution of Endrln and 12-KetoendMn in Experimental
         Animals 	   111-17

III-7    Distribution of Radioactivity In Various Experimental
         Animals after an Acute Oral Dose of Endrln	111-19

III-8    Analysis of Urine from Endrln Plant Workers 1n
         England	<	111-30

III-9    Estimated Half-Lives 1n Various Species for Elimination
         of Endrln Administered by the Oral Route	111-32

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No.
V-l
V-2

V-3
V-4
V-5
V-6

V-7
V-8

V-9

V-10
V-ll

V-12

V-13
V-14
V-15

V-16

V-17

VI-1

VII-1


III-l
Title
Acute ToxUHy of Endrln 1n Experimental Animals 	
Median Lethal Doses 10 Days After Oral Administration
of Endrln and Its Metabolites to Rats 	
Endrln Short-Term Oral Dietary LCsg Values 	
Effects of Acute Endrln Exposure 	
Effects of Subchronlc Endrln Exposure 	
Mortality of Animals Exposed to 0.36 ppm (5.62 vg/m')
Endrln 'Vapor1 	
Effects of Oral Chronic Effects After Endrln Exposure . . .
Teratogenlclty and Reproductive Studies Performed
with Endrln 1n the 1960s 	
Reproductive Effects of Endrln for Studies Performed
since 1970 	
Negative Studies of the Carcinogenic Potential of Endrln. .
Incidence of Malignant Tumors In Male Rats Ingesting
Endln . 	 	
Incidence of Malignant Tumors 1n Female Rats Ingesting
Endln 	
Number of Osborne-Mendel Female Rats with Carcinomas. . . .
Number of Osborne-Mendel Male Rats with Carcinomas 	
Number of Osborne-Mendel Female Rats with Benign
Tumors 	
Number of Osborne-Mendel Male Rats Ingesting Endrln
with Benign Tumors 	
Analysis of Incidence of Primary Tumors In Osborne-Mendel
rats fed Endrln 1n the diet 	
Description of Plants Included In the Study of
Manufacturers of Organochlorlne (OC) Pesticides ......
Height Loss and Llpld Content (MeanX + S.E.) of Quail
Carcasses After Technical Chlordane, 98%-Pure Endrln,
and Chlordane-Endrln Treatments 	
Summary of Data Used to Derive HAs or DUEL 	
Page
V-2

V-6
V-8
V-15
V-21

V-23
V-30

V-32

V-34
V-42

V-45

V-46
V-49
V-50

V-52

V-53

V-57

VI-9


VII-7
VIII-U
1x

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                             LIST  OF  ABBREVIATIONS

ATP                 Adenoslne tMphosphate
bw                  Body weight
CC1.                Carbon tetrachloMde
CMS                 Central nervous system
DHSO                Dimethyl sulfoxlde
ONA                 Oeoxyrlbonuclelc  add
dw                  Dry weight
DUEL                Drinking water Equivalent Level
EC                  Electron capture
EEG                 Electroencephalogram
GABA                Gamma -ami nobutyrlc add
GC                  Gas chromatography
GI                  Gastrointestinal
HA                  Health advisory
1.p.                Intraperltoneal
1.v.                Intravenous
LD50                Dose Lethal to 50% of the recipients
LDgo                Dose lethal to 90X of the recipients
LDH                 Lactic dehydrogenase
LOAEL               Lowest-observed-adverse-effect level
LOEL                Lowest-observed-effect level
MEL                 Minimal effect level
MS                  Mass spectroscopy
NADPH               N1cot1nam1de adenlne dlnucleotlde phosphate
                      (reduced form)
NAPH                Nlcot1nam1de adenlne dlnucleotlde   (reduced form)
NOAEL               No-observed-adverse-effect level
NOEL                No-observed-effect level
PCAA                Polychlorocycloalkane
ppm                 Parts per million
RfO                 Reference dose

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SGOT                Serum glutamlc oxaloacetk transamlnase
SGPT                Serum glutamlc pyruvlc transamlnase
ST5Q                Survival time of 50% of the recipients
TBPS                t-Buty1b1cyclophosphoroth1onate
TLC                 Thin-layer chromatography
TLV                 Threshold limit value
TWA                 Time-weighted average
ww                  Wet weight
                                      x1

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                                  I.   SUMMARY

    EndMn  1s  an  organochlorlne  a11cycl1c  pesticide  first  Introduced  Into
the  United States  1n  1951.  It  1s  produced  by  the epoxldatlon  of  Isodrln
obtained    from    the    reaction    of    hexachlorocycloheptadlene    and
cyclopentadlene.   It has  been  produced 1n the  United  States  by the Velslcol
Chemical  Corporation.   Endrln  currently  has United uses  (1979  usage:   176
megagram)  In the  cotton growing regions of  western  Oklahoma,  western Texas,
New Mexico,  Arizona and California.    It  controls  pale-western and army-cut-
worms and  grasshoppers, as  well as eastern pine voles,  western meadow voles,
sugar cane beetle and  1s used  to  treat conifer seeds.  Endrln  1s  no longer
commercially available 1n the United  States.

    Endrln 1s a compound  of  low solubility 1n  water, high  solubility  In  non-
polar organic  solvents,  low vapor  pressure (2.7x10~7  mm  Hg  at  25'C),  high
absorptive  potential  1n  high  organic-content  soils,  and  a  large octanol/
water coefficient  (2.18x10').

    The  major   analytical  methods   for   endrln  Include  extraction,   column
chromatography,   gas   chromatography/electron   capture   (GC/ECO)  and  gas
chromatography/raass   spectrometry     (6C/MS).      Acidification    or     high
temperatures will  decompose endrln.    Endrln has  low recoveries  from  waters
at  pH  2   (23%),  but >60X  recoveries  at pHs  >7.   In contrast.  Us  acid
decomposition product,  endrln  ketone,  Is  well  recovered  from waters  at all
pHs.  The photodecomposltlon product,  the  half-cage ketone,  has also  been
found In  environmental media.  Spills  of  endrln  1n  the  environment  have  been
detoxified  by  reaction  with acidified  zinc  dust.   Standard U.S.  EPA  and
NIOSH analytical methods are used  for measuring endrln.
00630                               1-1

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    Endrln  has  occasionally  been  found  In  drinking  water  and   In  food;
measurable  levels  of  endrln have  not been detected  1n adipose tissue or the
blood  of  the  general  population.  Endrln 1s  absorbed through  the  skin,  by
the  lungs  and  by  the gut,  but  no  quantitative  rates are  known.   Animals,
birds  and humans who  have  been exposed  to large amounts of endrln have shown
residues.   In  all  warm-blooded  species  studied thus  far, endrln  Is quickly
metabolized  and Us  metabolites  quickly  eliminated.   Endrln  deposition  in
tissues, especially  fat, does  occur  at  high  doses  In  experimental animals
and  1n birds.   Residues  have  been  detected  1n  liver,  brain, kidneys  and
fat.   Endrln  has a weighted average bloconcentratlon factor  (6CF)  of  3970
for the  edible portion  of  all  freshwater and estuaMne fish  and  shellfish
consumed by United States residents.

    Poisoning  Incidents have occurred 1n  animals  and man;  convulsions  In  man
are known to occur  above doses  of  0.2 mg  endMn/kg  bw.   Blood residues  have
been found  In  humans  grossly exposed  to  endrln In occupational and  poisoning
Incidents.    Endrln  poisoning  Incidents  have  been documented In Wales,  the
United Arab Republic,  Qatar,  Pakistan and Saudi Arabia.  The major  toxicant
In  mammals  1s   considered  to  be  the metabolite,  12-ketoendrln, but  endrln
Itself  Is  considered  the   toxicant  1n  birds;  residues In  brains   are also
supportive of  these hypotheses.   Modes of  elimination  are  species dependent,
but  1n mammals  the  measured  and  calculated  half-lives of  endrln  derived
material are between  1 and  4 days.  The  major  metabolite  In  mammals  Is antl-
!2-hydroxyendr1n  glucuronlde.    Hydroxylatlon  at  the  3-pos1t1on,   epoxlde
hydratlon and production of 12-ketoendrln also occur.
00630                               1-2

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    Endrln  has  been shown  to  penetrate the  placenta!  barrier In rats, mice
and hamsters.   In  rats,  >50% of endrIn-derived material 1s eliminated within
1  day  In the bile  as  glucuronldes, which  after enterobacterlal degradation
and  enterohepatlc  circulation are  eliminated  as  aglycones  In  the feces.
Excretion  occurs  slower  In  females   than  In  males.    Cows excrete  free
ant1-!2-hydroxyendr1n  conjugated  1n the  urine  as  the sulfate.   This also
occurs   1n   hens.    The   antl.-12-hydroxyendrln  has  been  detected  as  the
glucuronlde  In   the  urine  and feces  of humans.   Hens  appear  to  eliminate
endrln  faster  than other birds;  with  endrIn  Itself  being excreted.   Endrln
accumulates more 1n birds than  1n mammals.

    Exposure  to endrln  1n  humans  causes  CMS  effects,  convulsions, and  In
some  cases,  death.   In  endrln  poisoning  cases,  electroencephalograms  show
paroxysms  of  predominantly  bilateral  synchronous  theta waves.    In  mild
poisoning,  recovery  1s   usually   rapid  and  there  have  been no  permanent
effects.   This   1s  consistent  with   short  half-lives   for  elimination.
Epidemiology  studies  have   corroborated the existence  of  convulsions  and
other CMS effects In endrIn-exposed workers.

    The  acute  oral  LD,Q to mammals ranges  from 2.3-43.4 mg endr1n/kg  bw.
After dermal  exposure  ID., values  range from 11-92 mg  endr In/kg bw  and  are
vehicle-dependent.   Inhalation exposure  to  5.62 yg endrln/m£  for  7  hours
over  130 days   Is  not  lethal  to  rats,  hamsters and  gu'nea pigs.   Young
animals are  more sensitive  than adult  animals  to the effects  of  endrln.   In
acute  studies,   sublethal  endrln  exposures   elicited CNS effects  Including
convulsions  and  behavioral  changes. Depressed body weight gain was  reported
during  somewhat longer  exposures  (<1  month).    In  subchronlc  and  chronic

00630                               1-3

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studies,  dietary  exposure of rats  and  dogs to  endrln  concentrations  >1  ppm
reportedly  elicited  depressed  body  weight  gain,  elevated  organ-to-body
weight ratios and/or early mortality.

    Prenatal  exposure  to endrln   caused  adverse  reproductive  outcomes  In
rats, mice and hamsters.   In  the  latter  two species,  these outcomes Included
terata,   reduced  neonatal  weight   or   fetal   weight   gain  and  mortality.
Further,  evidence  of  altered  behavioral   development  was  reported   In  all
three species following prenatal endrln exposure.

    Endrln was not  nutagenlc  In bacterial   systems  with  or  without metabolic
activation.  There  are four  carclnogenldty  bloassays  for endrln  which  are
reported  by  their authors as negative.  An NCI  rat bloassay,  however,  upon
further analysis  shows  some  evidence of tumorIgenlcity.  Overall  the  animal.
studies  are  regarded  as  Inadequate  I.e.  Inconsistent  to  demonstrate  or
refute a  carcinogenic potential.   Ep1dem1olog1c  studies of which  there  are
several   are   also   Inadequate  because   of   nixed  exposures  and   design
limitations.

    The  toxic  and  convulsant potencies  of polychlorocycloalkane  pesticides
(Including  endrln)  have  been  correlated  with  Inhibition  of  GABA-med1ated
functions  1n  the  CNS,  particularly  chloride  1on transport.   Binding  of
endrln or  endrln  metabolites  to the SABA  receptor  may  therefore be Involved
In  the  mechanism  of  acute  endrln  toxlclty.   The  mechanlsm(s)   mediating
toxldty  following chronic endrln exposure  Is  not known.
00630                               1-4

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     The  occurrence  of convulsions  1s  believed to be  related  to blood-brain
permeability  changes  or  to direct  effects  on the CMS.   Although Inhibition
of  membrane  ATPases and mitochondria!  ATPases from brain  tissues  have  been
detected,  which  were  species-dependent,  sucdnyl  chollne  has  prevented
convulsions  1n  all  species  tested.   Concentrations  of cytochrorae  P-450  1n
endMn-reslstant animals  (mice,  pine voles) may be greater  than In suscept-
ible  species  (guinea  pigs); gender  may also be Important.   The conversion of
endrln  to  antl- and sj^n-12-hydroxyendrlns,  and conversion  of  the syn-Uomer
to  !2-ketoendr1n may  be dependent on the  level and type of cytochrome P-450.
The  acute ID,, values  for  all  these  unconjugated   metabolites  are  lower
than  for  endrln  Itself.   L1p1d peroxldatlon may also  play  a role.   The
correlation of  urinary D-glucar1c add  with  endrln exposure and the glucuro-
nlde  of an11-12-hydroxyendr 1 n  1n  the  urine  In  humans would  support  this
hypothesis.   D-glucar1c  acid has  not  been  detected   1n  human  urine  unless
ant 1-12-hydroxyendr1n   levels   1n   endrln   equivalents   were  >0.13   mg/g
creatlnlne.

    The U.S.   EPA has  set an  Interim standard  for  endrln 1n finished drinking
water of  0.0002 rag/l.  The. present ambient water quality criteria for the
protection of human  health  1s  0.001  mg/i  and  for  the  protection of  both
freshwater and  saltwater  aquatic   life  1s  0.0023  vg/l.    The World  Health
Organization   established  as  a  guideline  a  maximum Intake  of  2 wg/kg/day,
or  138.2 wg/day,  for a  69.1  kg  person.   The  proposed  Index  AHmentaMus
Commission's  maximum residue  limit 1n wheat  1s  20  vg/kg.

    The  threshold  limit  value (8-hour  TLV/TUA)  recommended by  the  American
Conference  of  Governmental  Industrial  Hyglenlsts  (ACGIH)  1s  0.10  mg/m'

00630                               1-5

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(0.10  yg/l),  with  a   short-time   exposure   limit   (15  minutes)   of  0.30
mg/m3.   Limits  set  by  the  Occupational  Safety  and  Health  Administration
are the same as those recommended by the ACGIH.

    The  1-day  health  advisory  (HA)  for  endrln  1n  drinking  water  Is  0.05
mg/l  for  children.   A NOAEL  of  0.5 mg/kg bw/day based upon  decreased loco-
motor activities 1n mice was used to derive the 1-day HA.

    The  10-day HA  for endrln  Is 0.02 mg/l for  children.   A NOAEL  of 0.150
mg/kg bw/day based upon  depressed maternal body  weight  gain 1n  rats was used
to derive the 10-day HA.

    The  longer-term  HAs  are  0.003  mg/l for  children  and 0.01  mg/l  for
adults,  based  upon  a  NOAEL  of 0.025  mg/kg/day  for  mild  hlstopathologlc
changes 1n the livers of exposed dogs.

    The  DWEL  for  chronic  exposure  to  endrln   Is   0.01  mg/l.  An   RfO  of
0.0003 mg/kg bw/day  (verified  by  the  U.S.  EPA  RfD  Work  Group  on  4/20/88}
based  upon  a NOAEL  of  0.025 mg/kg/day  for  mild hlstopathologlc changes  1n
livers of exposed dogs was used  to derive this DWEL.

    Using  the  criteria  In  the  U.S.  EPA guidelines  for   classification  of
carcinogens, endrln  1s   most  appropriately classified  In  Group 0  (there  1s
Inadequate  evidence   to  assess  the potential  carclnogenlclty  for  humans).
This  classification  1s   based  on the  nonposltlve  but  suggestive results  1n
some  of  the animal  studies.  The  negative  conclusions  as reported  by  the
study authors  of the  four  bloassays do not support  a Group E classification,
                                    1-6

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because  of  the  Inadequacies  of  the studies.   A U.S.  EPA  cardnogenlclty



Group  D welght-of-evldence  classification  was  verified  by  the  CRAVE  Work



Group on 10/19/88.
00630                               1-7

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                     II.  PHYSICAL AND CHEMICAL PROPERTIES
     Endrln   1s  an  organochlorlne  allcycllc  pesticide,  Introduced  as  an
 Insecticide  Into  the  United States In  1951.   It  has an empirical formula of
 C12H8C16°  and  a  IBolecular  weight  of  380.93.    It  1s  produced  by  the
 epoxldatlon  of  a  product  (1sodr1n)  obtained from the D1els-Alder reaction of
 hexachlorocycloheptadlene  and  cyclopentadlene (Brooks,  1974a).  The  major
 synthetic pathway  1s  shown 1n Figure II-l.   It  has  been manufactured In the
 United  States  by  the  Velslcol  Chemical Corporation.   D1p1col1n1c  acid  at
 levels  of  0.5-500 ppm relative  to endrln   content  1s  often  utilized  to
 stabilize solid endrln against  decomposition by metallic  Impurities during
 the  epoxldatlon step  (S1tt1g,  1977).  The synonyms  of endrln are provided 1n
 Table II-l.

     Chemical  names  and  Indexing terms  for  the  major chemical  degradation
products of  endrln are  given  1n  Table II-2, and for  Us major metabolites  In
Table II-3.   The  typical   composition of  technical  grade endrln  1s  provided
 1n  Table II-4.   No  other composition  data  were   found  In the  literature
 searched.

     The  1979 usage of  endrln  In the United  States  was -175,500 kg  (Anony-
mous, 1979).   It  was  used  as  an Insecticide  on cotton and  small grains  and
as  a rodentldde  1n  orchards  (Elchers,  1980).   UHh  certain  modifications
endMn's limited  use  still continues although widespread resistance  of  many
pests to 1t  may account for further  decline  In  Its  usage (Federal  Register,
1979).   Its  use 1s  still  permitted 1n  the  cotton growing  regions of  western
Oklahoma and western  Texas, New  Mexico,  Arizona  and California.  Endrln  1s
used  on  small  grains  to  control  the  following   Insects:   pale-western


00640                               II-l

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                           ZZZ  2000/4000
                                0.5/3.0 Hours
r:
                                                          VII
                          •cttont/to«th*nol  solvent;  «Jov
                                            rvactant  •ddatier.
                                          2.A;itatt,  h**tir.e
                                            •t 45°C for 1 hour
     1   htxachlorocycloptr.taiitnt      ZI
   III   •ettyltr.*                      ZV
     V   ey:loptr.t*ditnt                VI
                         VZZ   •ndrir.
                             noehlorocthyltnc
                             xaehl
                           iiodrin
                                   FIGURE  II-1

               The Major Industrial  Synthetic  Pathway for Endrln

                          (Modified from S1tt1g, 1977)
00640
                  II-2

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                                  TABLE  II-l
      Nomenclature,  Indexing Terms and  Synonyms Currently Used for EndMn
                          (SANSS data base, June  1983)
CAS  RN  72-20-8*       Molecular formula:  C12H8C160
2,7:3,6-D1methanonaphth[2,3-b]ox1rene, 3,4,5,6,8,9,9-hexachloro-la, 2,2a,3,-
     6,6a,7,7a-octahydro-(la a,2 B,2a 6,3 «, 6 a,6a 6,7 B,7a a)-(9CI)b
l,4:5,8-D1methanonaphthalene, l,2,3,4,10,10-hexachloro-6,7-epoxy-l,4,4a,5,-
     6,7,8,8a-octahydro-endo,endo- (8CI)c
Compound 269
Endrex
EndrUol
Endrln
Endrln  Isomer
Endrlne (FRENCH)
Experimental Insecticide 269
EN 57 (VAN)
ENT  17,251
Hexachloroepoxyoctahydro-endo,endo-dlmethanonaphthalene
Hexadrln
Mendrln
NCI-C00157
Oktanex
SO 3419
MLN: T E3 05 C555 A A- FO KUTJ AG AG BG JG KG LG ENDO ENOOd
l,2,3,4,10,10-Hexachloro-6,7-epoxy-l,4,4a,5,6,7,8,8a-octahydro-endo-l,4-endo-
    5,8-dlmethanonaphthalene
l,2,3,4,10,10-Hexach1oro-6,7-epoxy-l,4,4a,5,6.7,8,8a-octahydro-l,4-endo,endo-
    5,8-dlmethanonaphthalene

aChem1cal Abstracts Service Registry Number
bN1nth Collective Index,  Chemical  Abstracts
GE1ghth Collective Index, Chemical Abstracts
dW1swesser Line Notation
00640                               II-3

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                                                TABLE  11-2

                      Chemical  Information Related to Some Cndrln Degradation Products
  Common Chemical Names
  and Molecular Formula
     CAS Indexing Term and  CAS  RN
         Comment
                                                                      Reference
Endrln aldehyde
SO 7442
C12H8C160
Endrln ketone
A-ketoendrln
SO 2614
Ci2H8C160
No common chemical name
2.3,4,5.6-hexachloro-12-
oxopentacyclo[5.4.1.I"''
      .05»9]tr1decane
Endrln alcohol
1.2,4-Methenocyclopenta[cd]pentalene-5-
  carboxaldehyde.  2.2a,3.3.4.7-hexa-
  chlorodecahydro-(l  a.2  0.2a  B.  4  B,4a
  B.  5 B.  6a B,6b  0..7R)-

7421-93-4
2.5.7-Metheno-3H-cyclopenta[a]pentalen-
  3-one.  3b,  4,5,6.6,6a-hexach1orodeca-
  hydro-(2 a.3a  B,3b B.4  0.  5  0.  6a  B,
  7 «.7a  8.8R)-

S3494-70-5
6.2.3.5-[1.2]propaned1yl[3]yl1dene-2H-
  pentaleno(l,6-bc]furan,  2a,3,4,4,4a,
  6b-hexachlorooctahydro-

659S6-39-0

1.5,2,4-Ethaned1y11denecyc1openta[cd]
  pentalen-1(2H)-ol.  2.2a.3,3.4.8-hexa
  chlorooctahydro-
Stereochemlcal configura-
tion of aldehyde revised;
structure confirmed with
"C and »H nmr spectral
data.  Cpd Is produced by
thermal or photochemical
rearrangement of endrln

Principal product of
reaction of endrln with
H2S04
                                                                       nmr  spectra
                                          Minor  product (6-8X)  of
                                          acid catalyzed rearrange-
                                          ment of endrln; single
                                          crystal X-ray diffraction
                                          and nmr data

                                          iaC nmr spectra
                                                                     Bird et  al..
                                                                     1978
                                                                     Cox and
                                                                     McKlnney.
                                                                     1978

                                                                     ApSlmon
                                                                     et  al., 1982
                           Cox and
                           McKlnney,
                           1978

                           ApSlmon
                           et al.. 1982
                           Cox and
                           McKlnney,
                           1978
                          33058-12-7

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                                  TABLE II-3

             CAS Indexing Terms and CAS RN for Endrln Metabolites
                            (from CHEHLINE. 1983}
Common Chemical Names
and Molecular Formula
          CAS Indexing Term and CAS RN
12-KetoendMn
WL 41435
C12H6C1602
ant1-12-Hydroxyendr1n
WL 41434
C12H8C16°2
3-Hydroxyendr1n
C12H8C16°2
2,7:3,6-01methanonaphth(2,3-b)ox1ren-8-one,
3,4,5,6,9,9-hexachloro-la,2,2a,3,6,6a,7,7a-octa-
hydro-,(la o,2 B,2a 8,3 a,6 a,6a 6.7 B,7a <»)-
(9CI)
1,4:$,8-D1methanonaphthalen-9-one,
1,2,3,4,10,10-hexachloro-6,7-epoxy-l,4,4a,5,6,7,
8,8a-octahydro- (SCI)

28548-08-5

2,7:3,6-D1methanonaphth(2,3-b)ox1ren-8-o1,
3,4,5,6,9,9-hexachloro-la,2,2a,3,6,6a,7,
7a-octahydro-, (la a,2 6,2a 6,3 a,
6 *,6a 8.7 B.7a «)- (9CI)
l,4:5,8-01methanonaphthalen-9-ol,
l,2,3,4,10,10-hexachloro-6.7-epoxy-l,4,4a,5.6,7,
8.8a-octahydro- (SCI)

49748-76-7

2.7:3,6-01methanonaphth(2.3-b)ox1ren-2(laH)-o1,
3,4.5,6.9.9-hexachloro-2a.3,6,6a,7,7a-hexahydro-.
(la a.2 ».2a 8.3 a,6 a.6a 8.7 B,7a a)- (9CI)

57378-25-3
CI • Collective Index
00640
       II-5

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                                  TABLE  II-4
                Typical Composition of Technical  Grade EndMn*
                       Component                               X  (by weight)
EndMn                                                             96.6
HEOD (dleldMn)                                                     0.42
HHDN (aldrln)                                                       0.03
Isodrln                                                             0.79
Heptachloronorbornadlene                                            0.03
Heptachloronorbornene                                               0.08
4-Ketoendr1n                                                        1.57
1,2,3,4,5-pentachloro-7-oxo-l,4,5,6-tetrahydro-l,4-                  0.09
  methanobenzene
Endrln aldehyde                                                    <0.05
Acidity (as HC1)                                                    0.18
Unidentified                                                        0.12
Hater content                                                      <0.1
Xylene Insoluble residue                                           <0.5
•Adapted from Brooks, 1974a
00640                               II-6

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cutworm,  army  cutworm, and grasshoppers.   Additionally,  1t Is used  to  con-
trol  the sugarcane  beetle  and pine voles  In  the eastern  United  States  and
western  meadow  voles In the  western  United States and 1n  the treatment  of
conifer  seeds  (Federal  Register,  1979).   It  1s  also used  as a  bird  perch
toxicant  (Hadler,  1982).  EndMn  has been  generally  coformulated  to minimize
Us  tendency  to  decompose   In  some  common  formulation  carriers  (Brooks,
1974a).  Often,  up  to  15X (w/w)  of  hexamethylene  tetramlne  has been used  for
this  purpose.    Endrln  Is   often  coformulated  with  methyl   parathlon   In
emulslflable concentrates.  A selected 11st of pestlddal  mixtures  1n  which
endMn 1s not the  only  pestlddal component Is provided  1n  Table  II-5.   Pure
endrln appears  to  decompose above 245*C (Hetcalf, 1981), although technical
grade  endrln   (>92%  endrln)   decomposes   above  200*C   (Brooks,   1974a).
Presently, manufacture  and  use  has  been discontinued  1n  the  United States
(Merck Index, 1983).

    Endrln 1s  soluble  In nonpolar solvents.   The solubility of pure endrln
(1n  g/100  mi at 25*C) Is  as  follows:  acetone,  17;  benzene, 13.8; carbon
tetrachlorlde,    3.5;   xylene,   18.3;   and  water,   0.000023   (0.23  rog/l)
(Hetcalf,  1981).   The  equivalent solubilities  for   technical  grade endrln
(55-57X  chlorine content)  Is  as follows:   acetone,  31;  benzene,   51; carbon
tetrachlorlde,   51;  Isopropanol,  3;  methanol,  2; methyl ethyl  ketone,  40;
toluene,  74; and xylene, 55  (Brooks,  1974a).  The  specific gravity of the
technical grade  compound  1s  1.7  at  20*C.    The  vapor pressure of  technical
grade endrln Is  2.7xlO"7  mm Hg  at  25*C (Brooks,  1974a).   Endrln   appears to
obey a Freundllch adsorption Isotherm  1n the presence of an  activated carbon
(200/400 mesh)  aqueous slurry  (U.S.  EPA, 1980b).  Kenaga (1980) has provided
the  following  physical  constants for endrln  at 25*C:  water  solubility,


00640                               II-7

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o
o
o»
                                               TABLE 11-5

                    Son* Pesticide Mixtures  In which Endrln  Is  not  the Only Pesticide
                                            (Chcmname.  1983)*
    CAS  Registry   Component CAS Registry
      Number             Numbers
                                               Component Chemical Names
                                            (endrln chemical name omitted)
                                                 Synonyms
     53858 08-5  (50-29-3. 72-20-8. 298-00-0) 1.1'-(2.2.2-tr1chloroethyl1dene)b1s(4-
                                             chlorobenzene)
00
58939-75-6  (72-20-8.  121-75-5)


59928824  (72-20-8.947-02-4)


64034 60-2  (57-13-6.  72-20-8)

8017-73-0   (60-57-1.  309-00-2)

            (72-20-8)



8066-55-5   (72-20-8.  640-15-3)
Phosphorothlolc acid. 0.0-dlmethyl-O-
(4-nttrophenyl) ester

Butanedlolc acid, ((dlmethoxyphosphlno-
th1oyl)thlo)-. dlethyl ester

Phosphoramldlc acid. 1.3-d1th1olan-2-
ylldene-, dtethyl ester

urea

2.7:3.6-D1methanonaphth(2.3-b)ox1rene.
mixture with (l.«..4.a..4a.B..5.a.,
8.a..8a.B.)-1.2.3.4.10.10-hexachloro-
1.4.4a.5.8.8a-hexahydro-1.4:5.8-d1metha-
nonaphthalene

Phosphorodlthlolc acid. S-(2-(ethyl-
th1o)ethy1)-0.0-d1methyl ester, mixture
                                                                                  DDT-endrln-methyl para-
                                                                                  thlon mixture
Nalathlon-endrln
mixture

Cyolane-endrln mixture
                                                                                       Endrln-urea mixture

                                                                                       Leplt; Aldrln-dleldrln
                                                                                       mixture; Blnarln
                                                                                       Veldrln EE 922:Veldr1n;
                                                                                       Ekadrln; Thlometon-
                                                                                       endrln mixture

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o
o
                                                       TABLE  11-5 (cont.)
          CAS Registry   Component CAS Registry
             Number             Numbers
       Component Chemical Names
    (endrln chemical name omitted)
       Synonyms
           8075-40-9   (72-20-8. 309-00-2)
           37247-09-9  (50-29-3. 72-20-8)
           37262-64-9  (72-20-8, 298-00-0)
           37338-61-7  (72-20-8. Ml-66-2)
           51602-20-1  (72-20-8. 21609-90-5)
           59928-83-5  (72-20-8. 950-10-7)
           61912-61-6   (72-20-8. 6923-22-4)
Nlxture with (l.a..4.a..4a.O..5.a.,
8.a..8a.B)-1.2.3.4.10.10-hexachloro-
1.4.4a.5.8.8a-hexahydro-1.4:5.8-d1metha-
nonaphthalene

Nlxture wtth 1.1'-(2.2.2-tr1ch1oroethy1-
Idene)b1s(4-chlorobenzene)

Phosphorothtolc acid. 0.0-dlmethyl-O-
(4-nttrophenyl) ester, mixture

Phosphoric acid. 3-(d1methylamtno)-1-
methyl-3-oxo-l-propenyl dimethyl ester.
mixture

Phosphonothlotc acid, phenyl-. 0-(4-
bromo-2.5-d1chlorophenyl) 0-methyl
ester, mixture
Phosphoramtdtc acid. (4-methy1-1.3-
dlthlolan-2-yltdene-. dlethyl ester.
mixture

Phosphoric acid, dimethyl-1-methyl-3-
(methylamlno)-3-oxo-l-propenyl ester.
(E)-. mixture
Aldrtn mixture with
endrln; Endlonal;
Nauxan; Tricot In
DOT-endrln mixture;
Endrln-DOT mixture

Endrln-methyl parathlon
mixture

Endrln-bldrln; Endrtn-
bldrln mixture; Endrln-
dlcrotophos

Endrln-leptophos
mixture

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                                                TABLE 11-5 (cont.)
CAS Registry   Component CAS Registry
   Number             Numbers
                                                    Component Cheatcal Names
                                                 (endrln chemical name omitted)
                                                 Synonyms
    62588-93-6  (56-38-2. 72-20-8)
     62815-24-1  (72-20-8. 13171-21-6)
    63952-62-5  (72-20-8, 16752-77-5)
£    63952-72-7   (72-20-8. 2104-64-5)
     65437  77-6   (72-20-8. 7704-34-9)
Phosphorothlolc acid. 0,0-dlethyl-O-
(4-nltrophenyl) ester, mixture

Phosphoric acid. 2-chloro-3-(d1ethyl-
amlno)-1-methyl-3-oxo-l-propeny1
dimethyl ester, mixture

Ethanlmtdothlolc acid. N-(«methyl-
amtno)carbonyl)oxy)-, methyl ester,
mixture

Phosphonothtolc acid, phenyl-. 0-ethyl.
0-(4-n1trophenyl) ester, mixture
                                          EndrIn-sulfur mixture
    •Dialog  Information Services. Inc.

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0.024  ppm  (compare  the  0.23  ppm  value  above);  octanol/water  partition
coefficient,  2.18xlOs;  and  a  calculated organic  soil adsorption  constant
of  3.4x10*.   Jarvlnen  and  Tyo  (1978)  reported  the water  solubility  of
endrln at 200
Spectroscoplc Properties
    Since  endrln  1s  not aromatic  and  does  not  contain  conjugated  double
bonds,   it   has   a   Iy   of   148V1   era'*    at   the   xmax   at   225   nm
(TewaM  and  Sharma,  1978).   Thus,  ultraviolet/visible  spectroscopy would  be
neither  sensitive nor useful analytically.
    Infrared analysis  1s  practical when utilizing  the  peak at  11.76 win  and
baseline  points  at 11.50  and  11.97 &  (Brooks,  1974b).  The mass  spectrum
1s diagnostic  (Safe and Hutzlnger, 1973a).   The  molecular Ion  (m/e 378)  Is.
small with  successive  losses of Cl  (m/e 343, 308).  These latter peaks  are
Intense enough to  be utilized for  specific  1on  monitoring  purposes.  A Retro
Dlels-Alder process also  occurs.  Chemical 1on1zat1on mass spectrometry  has
also  been  performed (Safe  and  Hutzlnger,  1973b).   Cox  and HcKlnney (1978)
measured  the  "C-NHR  spectra of endrln, endrln aldehyde,  endrln ketone  and
endrln alcohol.

Chemistry
    Endrln  decomposes  at  temperatures above  200*C  or when  stored  for  long
periods,  with  endrln  aldehyde  and a  pentacycllc  aldehyde as decomposition
products  (Brooks,  1974a).   This  process  1s  Important  for gas chromatographlc
analysis 1n metal  columns  (Phillips et al., 1962).   Endrln undergoes epoxlde
ring  opening  and  rearrangement  1n the  presence  of add or  of  metal  cata-
lysts, I.e., Iron  compounds  (Brooks, 1974a).  Endrln  ketone Is the principal

00640                               11-11

-------
product  of  add decomposition  (ApSlmon et  al.,  1982).  Endrln  can  undergo
the  usual  addition reactions, and  also complex transannular rearrangements.
Uhen  exposed  to wavelengths of  253.7  and  300 nm and  to  sunlight,  endrln  In
hexane and cyclohexane decomposes to the following half-cage ketone, 1,8-exo-
9,n,ll-pentachloropentacyclo[6.2.1.13t6.02'7.04'10]dodecan-5-one,  with 60%
conversion  1n  8 hours.   This  product  has  been Identified  In  environmental
samples  (ZabHc  et  al., 1971).   Photorearrangement  1s  possible above  300  nm
1n the  presence of appropriate photosensltlzers, e.g., silica  gel  (Iv1e and
Caslda,  1971a)  and rotenone on  bean  leaves  (Iv1e and Caslda,  1971b).  For
the  latter   'se jut  not  the former,  endrln  ketone and endrln  aldehyde are
the  major  produ.::.  The  nomenclature,  CAS  Indexing  terms  and CAS RNs for
the  major  degradation products  are given  1n Table  II-2.   The reaction  of
acidified zinc  dust  with  endrln has  been suggested  as  a  degradation pro-
cedure 1n the field (Butler et  al.,  1981).

Analytical Methods
    The  most  recent  analytical  methods  for endrln  1n animal  tissues and
fluids are summarized In Table II-6.   Most  of the  methods  Involve extraction
to separate endrln  from  Us matrix, then cleanup or extraction  before  elec-
tron capture gas chromatography  (EC/GC) or  gas  chromatography/mass  spectrom-
etry (GC/MS).  Heating above 200*C  or  acidification In  any of the analytical
steps will  cause  degradation  of the  endrln as described  In  the  chemistry
section.  This  may be the  reason for  the  highly variable recoveries quoted
In the  literature   or  for  residues  not being  detected 1n  the majority  of
studies.  For water analysis, 1f waters are already addle,  probably most of
the  endrln  will have been  degraded already to endrln  ketone.   In  water  at
25"C  and pH  2, endrln  recovery 1s  23%;   at  pH  7-10  Us  recovery  Is 88%
(Millar  et  al..  1981).   At 4*C and pH  2.  however,  the recovery 1s  92%; 85%
00640                               11-12

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o
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o>
                                 TABLE  11-6

Analytical Methods for Determining Endrln  or  Endrln  Transformation Products
                        In Tissues or  Animal  Fluids
    Human Tissue or Fluid
            Compound Determined
             Method
   Reference
    Human urine
    Human adipose tissue
    tow milk
    Bird brain
         ant 1-12-hydroxyendrIn and
         B-glucuronlde conjugate
         endrln
         endrln
         endrln
oxidation of conjugate with meta
perlodate hydrolysis;hexane
extractlon/EC/GC

hexane extraction/gel permeation
chromatography cleanup/EC/GC
(100* recovery at 3.2 ppm)

hexane extraction/gel permeation
chromatography cleanup/EC/GC
(105X recovery)

extractlons/Florlsl! cleanup/
EC/GC (BOX recovery; detection
limit 0.5 ppb)

sodium sulfate/mllllng/soxhlet
extraction (dlethylether and
petroleum etherJ/EC/GC (70»6X
recovery; detection limit 0.05
ppm for a 1 g sample)
Baldwin and
Hutson. 1980
MacLeod et al.,
1982
                                                                                                Tessarl  et al..
                                                                                                1980
Frank et al..
1979
Ludke. 1976

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of  endMn  aldehyde 1s  recovered  at pH  2,  7  or 10  at  4* or  25°C  but  1s
degraded  1n  the  presence  of  chlorine  at  pH  10  (Millar et  al.,   1981).
Carbopack  B  columns have also  been used to  concentrate  8 ppb endMn  from
water  (Manganl et  al.,  1981), as  have XAD-2 resins (Rees and Au, 1979).  A
standard NIOSH  method  1s available  for  monitoring airborne  endMn  In  the
personal sampling  mode  (solid  sorbent/battery powered pumps) (Taylor, 1980).

Summary
    EndMn   is an   aliphatic  organochloMne  Insecticide  with  a  molecular
weight of  380.93,  water solubility of 0.024 ppm,  specific  gravity of 1.7 at
20*C,  vapor pressure of  2.7xlO~7  mm Hg  at 25'C and an octanol water parti-
tion  coefficient  of 2.18x10*.  It  was  used  predominantly  to control  cut-
worms  and  grasshoppers,  but  has  also  been used  as  a  rodentklde  In  the
control of  eastern  pine voles  and western meadow voles.

    EndMn   decomposes  at temperatures  >200*C  Into  endMn aldehyde  and a
pentacycllc aldehyde.  Adds  or  metals  (Iron) will  also decompose  endMn
Into  endMn  ketones and  aldehydes.  Following  extraction  methods,  endMn
levels  In  tissue  and water  analysis  may be  determined  by EC/GC or  GC/MS
techniques.
00640                              11-14

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                              III.  TOXICOKINETICS

    This  section refers only  to data relevant to warm-blooded vertebrates.

Absorption
    Endrln  Is  absorbed through the  skin,  by the lungs and  by  the gut (U.S.
EPA,  1980a).   Rates  of  absorption  have not been documented.   That absorption
does  occur  Is  demonstrated  by  the  data  In Table III-l  concerning  residue
levels and biological effects after exposure.

    Oral.   U1ld  and  domestic  animals  that  have absorbed endrln  through
1ngest1on of  treated foliage can  show residues 1n fat, blood  and milk  (see
Table  III-l).   Several poisoning Incidents  have occurred through  animal
feeds  (Long  et  al.,  1961;  TerMere et  al., 1958; Kllgemagl  et  al.,  1958;
Hunter  et al.,  1960;  U.S.  EPA,  1980a).   For  an  early review  of poisoning
Incidents see Brooks (1969).

    Animals and  birds  at the top of  food chains as  well  as  humans may  be
particularly affected  by  the oral route  of exposure  If the chemical or  Us
metabolites bloaccumulate.  The weighted  average BCF  for endrln  1s 3970  for
the  edible portion  of  all  freshwater  and estuarlne  fish  and  shellfish
consumed by U.S. residents (U.S. EPA. 1980a).

    Humans have  Ingested endrIn-treated agricultural products  (Carey  et al.,
1979)  as  well as  meat  from  domesticated  and wild  animals,  birds and  fish.
Poisoning  of  humans   after  accidental   contamination  of  food  has  been
attributed to doses of 0.2 ng/kg bw (U.S.  EPA. 1980a).

00650                                III-l

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o>
in
o
                                TABLE II1-1

       Evidence of Absorption Using Residue and Biological Effect Data
     Route of
   Absorption
    Applied Dose
     Residues
     Biological
      Effects
    Reference
    Oral
IV)
    Inhalation/
     deriul
    Dermal
not known on
pasture
                   510 mg over 30
                   days to pigs

                   20 mg/day/cow
>0.2 mg/kg bw
In humans
•grossly exposed"
humans

animal mortality
data

Carworth Farm Strain
E (CFE) rats In acute
dose response experi-
ments
up to 24 pg/g
fat. 6.4-14
after 42 days
                        up to 2  pg/g  fat
up to 0.2S |ig/g
milk

up to 10 ug/g
blood 400
fat
residues >1
blood
not reported
Not reported
                       Not reported
                                               Not  reported
Poisoning symptoms
In humans; convul-
sions
Convulsions at >0.2
mg/kg bw
Ratio of dermal to
acute oral L0$n for
20* emulslflable con-
centrate Is 1.6; and
for 2X dust Is 13
Long et al.. 1961
                         Hunter et al..
                         1960

                         U.S. EPA. 1980a
U.S. EPA. 1980a
Hayes. 1963
Coble et al.. 196?
Weeks. 1967
Cur ley et al.. 1970
Tewarl and Sharma.
1978; Rowley et
al.. 1987

Jager. 1970
Nulr. 1968

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 Inhalation
     Since  the vapor pressure  of  technical  endMn  Is  2.7xlO~» on  Hg at 21*C
 (see Chapter II),  this  Is  equivalent to  a  vapor  density  of 5.5  ng/m*  of
 air.   Consideration  of  endrln's  inhalation  hazard to humans  led the American
 Conference  of Governmental  Industrial Hyg1en1sts  (ACGIH,  1982)  to  set  the
 threshold  limit  value, 8-hour  time weighted average  (TLV-TUA),  to  be 0.10
 mg/m>  with  a  short-term  exposure limit  (STEL)  for  15  minutes  of  0.30
 mg/m*  (skin).   The OSHA  standard  based  on  the  1968  ACGIH TLV  1s  0.10
 mg/m*  (skin)  (NIOSH,   1978).   Dermal  absorption  occurs  concurrently  with
 air exposure as denoted by the "skin* designation.

    Few blood residues  have been found In endrln-exposed workers, except  In
 those grossly exposed (Jager,  1970).   The absence of  residues  may  Imply fast
metabolism  or negligible  absorption.   In  this case,  fast  metabolism  Is
 responsible.

 Dermal
    The  most significant  dermal  exposures   to  endMn  1n  the occupational
environment  have  occurred  during  field  applications  (Wolfe  et  al.,  1963.
1967).  Unfortunately,  no residues  have been  reported  to confirm absorption.
Both  inhalation and  dermal  exposure have occurred  during endMn manufacture
and distribution, but only grossly  exposed workers  have ever shown residues.
Nevertheless, convulsions  have been reported  In  such workers  (Jager,  1970).
    The  dermal  acute  ID5Q value  for  male  CFE  strain  rats was  1.6 times
that  for  the oral acute  value (diet) when  the rats were  exposed  to a 20X
00650                                III-3

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emulslMable  concentrate  (Hulr,  1968).   Similarly,  for  exposure  to  a  20%
field  strength  dust,  the  ratio  was   13  (Hulr,  1968),  Illustrating  the
Importance  of  the carrier  1n  dermal  absorption  (see Chapter  V).   Such data
demonstrate that  endrln  Is  absorbed through  the skin  of rats  and 1s probably
also  absorbed  through human  skin,  as  the •skin1 designation  for  the  ACGIH
TLV-TWA Implies.

Distribution and Metabolism
    In contrast  to Us stereolsoner dleldrln,  endrln 1s  rapidly metabolized
In  mammals and  the  metabolites are  also  quickly eliminated.   Thus,  the
distribution of  endrln  itself  1n tissues even  after high  doses may be  below
detection  limits.   Under such  conditions,  distribution studies with  radio-
labeled endrln may not  reflect endrln distribution, but that  of Us  metabo-
lites.  However  at very  high doses, e.g.  human  poisoning  cases,  gross  occu-
pational  exposures  or  1n suicide cases,  endrln can be detected  In  tissues.
Endrln appears   to  accumulate  more  In   birds  (excluding  chickens)  than  In
mammals.

    Distribution  1n Hunan  Tissues.  Endrln  Is  a  relatively  nonperslstent
pesticide  1n humans.  Measurable  levels  of endrln have not been detected  In
adipose tissue  (Kutz  et  al.,  1979)  or  the blood of the general  population,
even  In those areas where endrln was used extensively,  such as  India or the
lower  Mississippi  delta  area  (Brooks,   1974a).  Endrln  also  has  not  been
found  In the blood of workers  who manufacture or  formulate endrln (Hayes and
Cur ley, 1968;  Baldwin and  Hutson,  1980)  except In the  case  of  very  high
levels of exposure (Jager, 1970).
00650                                III-4

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    Measurable  tissue endrln  concentrations are  reached in  cases  of acute
poisoning.   The  time  of sample  collection  1s  Important to  these  measure-
ments,  as  endrln residues  decline rapidly  1n  tissues  after  cessation  of
exposure.   Endrln concentrations  as high as  10  tog/kg In blood and 400 mg/kg
1n  fat have  been reported  (Hayes, 1963).   In  an  Incident  Involving three
acutely poisoned  humans  1n  the  United Arab  Republic  1n  1967,  no endrln was
detected  (<4  tig/kg)  1n cerebrosplnal  fluid  (Coble  et al.,   1967).   The
serum,  30 minutes after  one patient's  convulsion,  contained 53 ng  endrln/
mi.   After  20  hours  the  serum concentration  was  38  ng/rai,  and  after  a
further 10 hours,  21  ng/rai.   In  the  same  patient,  the endrln  level  1n  a
24-hour urine  sample after  convulsion  was  20 ng/mt.   Levels  of endrln much
lower  than  10 mg/kg tissue  were  obtained  In autopsies  of 26  Saudi  Arabians
poisoned  by endrIn-contaminated  bread (Weeks,  1967;  Curley et  al.,  1970).
In  the same  Incident  874  people  were  hospitalized,  and  another  500-750
people  were also  exposed.   Blood  from the  hospitalized patients  contained
7-32  ng  endrln/mi  blood.   Blood  and  urine  samples  taken  from  patients
29-31 days  after  the episode contained no  detectable  amounts  of endrln.   In
the  Punjab province  of  Pakistan  between  July  14  and  September 26,  1984.
there  were 192 cases  of probable  endrln  poisoning (Rowley et  al.,  1987).
Blood  levels  from 12 of 18  patients  with  convulsions  had measurable  levels
of  endrln  ranging  from  0.3-254  ppb  (0.3-254   tig/kg).   No   endrln was
detected  in the  urine  (Rowley et  al.,  1987).   Summary data  are given  In
Table III-2.

    TewaM  and  Sharma (1978)  studied  the  concentration of  endrln  by  TIC/
ultraviolet spectrophotometry  of  autopsy materials of eleven cases of  fatal
poisoning.  These  results are  also  summarized In Table  III-2.   High concen-
trations were found  In fat-containing  tissues, even  for  a time  to death of 6

00650                                III-5

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                                 TABLE II1-2
                         EndMn Concentrations Found
                        1n  Victims  of  EndHn Poisoning

Sample


Blood
Urine
Vomltus
Tissues (autopsy) from:
Stomach
Liver
Kidney
Spleen
Heart
Lung
Intestine
Endr

In Saudi Arabia3
(»g/kg)
0.007-0.032d
0. 004-0. 007d
5.24

0.16
0.685
0.116
NA
NA
NA
NA
1n Concentrations

In Pakistan* 1n
Ug/kg)
0.3-254
oe
NA

NA
1430
1760
NA
NA
NA
13,690


Su1ddesc
(mg/kg)
4.3-8.5
2.5-5.5
32.5-81.2

10.4-145
9.4-200
7.5-51.7
2.4-21.7
5.6-19.9
3.8-10.8
13.1-660
aCurley et  al.,  1970  (Includes  first and  third  Oohar  outbreaks and Hofuf
 outbreak)
°Rowley et al.,  1987  (192  cases of endrln poisoning)
cTewar1 and Sharma,  1978  (11  suicides)
dOn day of onset
«None detected 1n 12  patients
NA . Not analyzed
00650
III-6

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poisoning.  These  results  are also summarized  In  Table  III-2.   High concen-
trations were  found  In  fat-containing tissues,  even for  a time to death of 6
hours.  There  was  some  evidence  to suggest that endrln In combination with a
fatty  carrier, such  as milk, caused death  faster  than when  Ingested with
solid  food.   The  levels quoted  may be In  error  as  endrln,  12-hydroxyendrln
or 12-ketoendMn were not separated.

    Little  1s still  known  of  the  distribution  and  persistence of  endrln
metabolites  In human  tissues.    Baldwin  and Hutson  (1980)  were unable  to
detect ant 1-12-hydroxyendrln  or  12-ketoendr1n 1n  the blood  of endrln workers
at a  Shell manufacturing plant  In  England.  The  method  used had a detection
limit of 2 ng/mi for both compounds.

    By analogy with  observations made In experimental   animals,  1t may  be
speculated that  endrln and  Its  metabolites are  rapidly eliminated.   It  Is
noteworthy In  this regard that  recovery  from an acute  poisoning  episode  Is
rapid, on  the order  of a  day. (Davles and Lewis,  1956).  so that  If  toxic
metabolites are formed In humans  they are  not persistent.

    Distribution 1n Animal Tissues.
       Birds — Researchers  agree  that  orally  dosed  endrln  Is  absorbed
from  the  avlan  gut  and  stored   In various body  tissues by  both wild and
domestic species (Terrlere et al., 1959; Relchel et al.,  1969).

    After absorption of endrln, residues have been  reported  to  be distribut-
ed among  liver,  brain,  adipose,  eggs, breast  muscle and gonadal  tissues.
00650                                III-7

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Adipose   tissues  generally  contained  the  highest  concentration  (Gregory,
1970;  Terrlere  et  al.,  1959),  while  brain  tissues  usually  contained  the
lowest (Rekhel  et al., 1969).

    Terrlere et  al.  (1959)  examined  the tissues and eggs of chickens exposed
to  levels of  0.1,  0.25  and  0.75 rag  endMn/kg  feed.   In  one experiment,
1-month-old male Delaware X New  Hampshire  chicks were fed the various endrln
levels  for 6  weeks  and  then  sacrificed, while  6-month-old  White  Leghorn
pullets  were   exposed to  the endrIn-fortified feed  for 8  weeks  and  were
returned  to  the basal  diet for 4 additional  weeks.   A repeat of  the  male
chick experiment  using New  Hampshire X Delaware chicks  was  also  performed.
In all endrln  exposures,  the amount  of  adipose tissue was found to  be meager
even  though weight gain  and feed consumption  appeared  to be  normal.  At  a
level of  0.25  mg/kg  feed  or higher,  definite deposition of endrln  In the  egg
tissue occurred within 2-4  weeks after  exposure had ceased.   Accumulation of
endrln In  adipose  tissue was found 1n both experimental  groups with even  the
lowest dietary level  showing evidence of deposition.   Analysis of breast  and
tibia tissue revealed  endrln deposition at both the 0.25 and  0.75 mg/kg  feed
Intake levels.

    The fat tissue of  the plain  chachalacas,  Ortalls  vetula.  was analyzed by
Marlon (1976)   for  pesticide residues  during 1971 and  1972.   In four  differ-
ent  study areas 24  birds  had an  average  endrln residue of  0.13+0.52 mg/kg
weight.   There was  no evidence that  these birds  died  of endrln  exposure.
Only 8 of  the  24 birds sampled contained detectable endrln residues.
00650                                II1-8

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    The  percentage of  the dose  retained by  bobwhUe quail  appears  to  be
dependent  upon  administration  time and  dose  according  to  Gregory  et al.
(1972).   Analyses  of  whole  birds   fed  equal  doses  of  endrln-contamlnated
beans  or  beetles  revealed  retention  of  -16X  of  the  total  acute   dose
Ingested,  while  21X of  the total  chronic dose was retained.  The residues
found  1n  the body  tissues  during  the acute and  chronic  experiments differed,
but not  consistently.  The average  endrln content 1n adipose  tissues 1n the
acute  dosage  group was  0.01 ML002 mg/kg ww,  as compared with  0.010+0.001
mg/kg  found  1n  the chronic dosage  group.   Gonadal  tissues from  both groups
contained  traces of endrln, while the concentration of  liver  residues 1n the
chronic test was 0.007 mg/kg and In  the  acute  test,  0.004  mg/kg.

    Baldwin  et  al.  (1976) fed  10   Sykes  Hybrid  III  hens  (-2 kg)  0.13 rag
endr1n/kg  diet  by  capsule over 148  days.  At  day 148,  the levels of endrln
and  !2-ketoendr1n  were  measured  1n muscle,  liver,  kidney and  fat  (Table
III-3).  Levels of  12-ketoendMn, deltaketoendHn, antl-  and  syn-12-hvdroxy-
endMns  were  below detection.   The distribution of  l«C-endr1n provided at
0.3  pCVday  for  148  days Is  given 1n  Table  III-4  for  day  148.   These
results for radioactivity  essentially are for endrln distribution Itself, as
supported by the data  In  Table III-3.

    Ludke  (1976)  determined lethal   brain residues  for  several compounds In
an  Investigation  of associated  mortality  with addltlvUy  of  chlordane and
endrln.   Twenty  male and  female, 14-week-old, bobwhUe  quail  (Collnus
vlrg1n1anusl   were  fed  diets  containing  10  ppm  chlordane   for  10  weeks
followed  Immediately  by  10 ppm  endrln  1n the  diet  for  10 weeks;  20  other
quail  received  10  ppm  endrln  In  the  diet  only  (duration   unspecified).

00650                                III-9

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                                  TABLE III-3
          Distribution of Endrln and 12-KetoendMn at  Day  148  1n  Sykes
        Hybrid  III  Hens  (2 kg  Initially) Fed 0.016 ng/kg Diet by Capsule*
Tissue
Breast meat
Leg meat
Liver
Kidney
Fat
Concentration
Endr1nb
<0. 0032-0. 001 3
0.017-0.095
0.013-0.20
0.035-0.13
0.32-1.21
(mq compound/kg ww)
12-Ketoendrln
<0.002
<0.003
<0.0006
<0.03
<0.0004
aSource: Baldwin et al.,  1976
^Metabolites were  considered  absent  1f  their  concentrations  were <10%  of
 the detected endrln value.
00650                                111-10

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                                 TABLE II1-4
            Radioactivity 1n Tissues of Five Hens After a 148-Oay
             Period of Treatment with 0.3 yd/Day (as capsules)*
            Tissue                     Radioactive Residues
                                   (ng endrln equivalent/kg w)
         Breast neat                       0.008-0.011
         Leg meat                          0.008-0.030
         Fat                               0.50-1.28
         Liver                             0.07-1.06
         Kidney                            0.13-0.23
         Brain                             0.017-0.050
         Sciatic nerve                     0.096-0.64
         Bone marrow                       0.14-0.58
         Skin                              0.13-0.39
         Feathers                          0.005-0.024

•Source: Baldwin et al., 1976
00650                                111-11

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After  9-10  days on an uncontanlnated  diet,  survivors were sacrificed.  In a
control  group,  eight  quail  given  10 ppra  chlordane In  their diet  did  not
experience  arty mortality.   All  quail  treated  with endrln  and with  both
endrln  and  chlordane  had  significant loss  In weight.   This  loss  of weight
was  associated  with  fat  mobilization and  Increasing brain  residues.  Birds
that  died  from  endrln   treatment  alone  had  brain residues ranging  from
0.34-1.84 ppm;  survivors ranged from 0.28-0.62 ppm.

    Birds that  died from  endrln  exposure preceded by chlordane treatment  had
brain  residues  ranging from  0.17-1.25 ppm; survivors ranged  from 0.14-0.56
ppm.   Brain  residues   of  survivors  were lower  than  those of  dead  birds  and
approached   significance   (0.05
-------
brains.  The  year/number/levels  1n eggs  were as follows:  1971, 3, 0.08-0.12
mg/kg ww;  1972,  12,  0.11-0.29;  1973,  21, 0.03-0.46; 1974, 25, NO-0.73; 1975,
30, 0.29-1.06; 1976, 25, NO-1.47.

    In  September 1978,  ducks  1n  Montana  were  found  to  contain  up  to  1.2
rog/kg ww endrln  In  their  fat  resulting from endrln applied on wheat crops to
destroy an Infestation of Army cutworms (Anonymous, 1979).

    Table  III-5  shows  some typical residue  levels found  since  1977  In wild
and laboratory  birds known to  be exposed to  endrln.  These  data  Illustrate
that  endrln  1s   absorbed  and  then  distributed  throughout   the  body.   No
12-ketoendMn was detected  In  the tissues of  wild  or  domestic birds,  unless
the birds  had  Ingested  endrIn-killed fauna  (Stkkel  et  al..  1979a).   The
connection of brain residues with  lethality Is discussed  1n Chapter V.

       Mammals — Little  1s  known of  the   transport  and  distribution  of
endrln  1n  mammals.   No  evidence of  storage  1n  any particular  tissue  or
organ,  other  than  fat,  has  been  found.   Residues of  endrln  ranging  from
0.001-23.7 mg/kg ww, however,  have been  detected  In a variety  of  mammalian
tissues.

    Brooks  (1969)  reviewed  studies  showing  that  steers,   lambs  and  hogs
receiving 0.1 mg endrIn/kg  diet for 12 weeks  had  little  tendency  to deposit
endrln  In  body  tissues.   Continuous   feeding  of endrln  at   levels  up to  2
mg/kg diet  resulted In  a  maximum body  fat  concentration  of  1  mg  endr In/kg
ww.   Cattle  with only  ambient environmental  endrln  exposure were  analyzed
for the presence of  endrln  residues In their  tissues by  the  U.S.  Department
of Agriculture In 1967 (Spauldlng, 1972).  Of  the  2785 animals  studied,  2783

00650                                II1-13

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                      TABLE  III 5



Endrln Distribution In Birds In the Post-1978 Literature
Species
Heron (wild)
Kestrel (wild)
(falco sparverlus)
Broadwlnged
hawk (wild)
(Buteo platypterys)
White pelican
(dead) (wild)
(Pelecanus
erythrorhynchos)
Pelican (wild)
Bobwhlte quail
(Collnus
vlrglnlanus)
Bullfinch
Crackles
(Qulscalus
qulscula)
Exposure Type
NR
NR
NR
NR
NR
S.8 tig/kg fed/
day/bird
0.15X endrln
(48 hours)
0.0375* endrln
(24 hours)
(via pear buds)
10 »g/kg diet
Tissue
carcass3
carcass
Gl tract
carcass
carcass
brain
brain
brain
liver
liver
carcass
brain
Concentration (number or

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                                               TABLE  III-5 (cont.)
o
o»
in
Species Exposure Type
Mallard* 10 mg/kg diet
(Anas (26 days)
platyrhynchos)
Quail (dead) 50 mg/kg diet
(Coturnlx
Japonlca)
Bald Eagle (dead)c20 mq/kg diet
(Hallaeetus
£ leucocephalus)
Z Eagle |wlld)« MR
Tissue
carcass
brain
liver
carcass
carcass
•uscle
brain
carcass
brain
Concentration (number or sex) Reference
(mg/kg ww)
1.4-1.9b at day 26 (2)
0.54-0.77»
1.1-1.9
1.1 (N)b on day 14-20 (4)
1.0 (f )b on days 13-15
1.5 (F)
0.63 (N)
0.92-1.2 (N/f)
0.5-2.5 (N)
0.71-1.2 (H)
Sttckel et al.. 1979a
Stlckel et al.. 1979a
Stlckel et al.. 1979b
Sttckel et al.. 1979b
   aAfter head.  skin.  feet, wlngtlps and GI tract were removed


   b!2-Ketoendrtn was  below the detection Unit


   °The lower 11«1t of detection was 0.10 ppn endrln
         lower  llMlt  of  detection  was  0.05 ppm  for  endrln and  12-keto  endrln.

    detection for all Stickle et al.  (1979a)  referenced Materials.


   NR - Not reported
Used  as  the  Unit  of

-------
 contained  no endMn residues;  one  animal  contained between  0.01  and 0.1 mg
 endrln/kg  fat, and  another contained  between 0.11 and  0.5 rag/kg  fat.   By
 1971,  however,  similar  testing revealed that endMn Incidence 1n tissues  was
 Increasing.   Of 2403 cattle tested,  42 had  levels  of  0.01-0.1  mg endrln/kg
 fat  (Spauldlng, 1972).

     Long et  al.  (1961)  reported high  levels of storage 1n the adipose tissue
 of  six lambs using a dechloMnatlon method  of analysis.   Higher levels were
 detected  1n   the  Internal  fat  surrounding  the  stomach and  thoracic  cavity
 than  1n  external  fat deposits.   Lambs  were allowed to graze for  55  days on
 pastures treated  with  2% endrln granules, applied  six  times  In  Nay  and June
 at  a  rate   of  '1.1 kg endrln/acre.   The  lambs  were  then  transferred   to
 untreated pasture;  endrln  In  fat was measured after 0, 14 and  42 days.   At
 the  start of  grazing In untreated pastures,  lambs  had  18.3-23.4  mg endrln/kg
 Internal fat  and  11.5-14.0 mg/kg  external fat.  After  14  days,  endrln levels
 were  surprisingly higher,  with  20.3-23.7 mg/kg Internal  fat, and 14.6-20.1
 mg/kg  external  fat.  Some loss  did  occur  after 42  days.  Internal  fat levels
 dropped to concentrations of  8.9-13.8 mg/kg fat, and external fat contained
 only  6.4-11.0 mg/kg.   These  findings  seem  to contradict  later reports   by
 Brooks  (1969)  of no storage  and no  retention.  In the  Long et al.  (1961)
 study, however,  much higher levels of  endrln were fed to younger  animals;
younger animals have relatively more  fat  than  adults.   In  addition the lambs
 Initially  were  1n   "poor  condition.'   Sharraa  and Gautam  (1971)  detected
 endrln residues  In the  brain  and  liver tissue of  calves.   In  the  domestic
 dog  endrln  was detected  1n the  abdominal  viscera  (Reins et  al.,  1966)   as
well as 1n fat (Richardson et al., 1967).
00650                                111-16

-------
     Richardson et al.  (1967),  using  three  9-month-old  beagle  dogs  fed  0.1 mg
endr1n/kg  bw/day and  two  control  animals  fed  uncontamlnated diet over  the
128-day  feeding  period,  found  that endMn  In jugular  vein blood In each  dog
reached  a  plateau at  3-8 rag/kg after  2  days  of  feeding.   The  distribution of
endMn  1n  tissues  after  128  days  of  feeding  is provided  1n Table  III-6.
Only  the levels  In  fat were related  to levels  of endMn 1n  blood.  In con-
trast,  administered dleldrln  accumulated  In the  blood  after 114-121  days.
Rats  dosed  at  8  vg  of  14C-endrIn/day   by  the  oral   route  achieved  a
steady-state  1n  the  blood  In  9-10 days  (Brooks, 1969), but  the  label was
quickly  eliminated after cessation of  exposure.

    Korte  (1967)  showed that  conversion of  endMn  to metabolites  was  not
dependent  on  enterobacteMa but  occurred  In  the liver,  and  1n  1970  found
that  the steady-state storage  level  after  6 days for female rats dosed  at
0.4  mg  l4C-endr1n/kg  diet  (16,  64 and  128  yg  endMn/kg/bw)   was  about
twice that  for  males dosed similarly (27%  vs.  14%,  respectively)  (Korte  et
al.,  1970).   After  1.v.  Injection  of  200  t>g  l«C-endrIn/kg  1n  two  doses,
male  rats  retained  5.2% and females  12.1%  after 24 hours.  This Illustrated
that  the results  for different  genders  were  probably  not   due  to  gender-
dependent  absorption  variability.   Baldwin  et al.  (1970)  also  found  that
concentrations of endMn  metabolites  1n female rats were dependent on  the
duration of feeding  (4  mg/endrln/kg  feed over several  weeks), whereas  those
1n  males were not.   Walsh  and  Fink  (1972)  gave five Carworth Far*  No.  1
adult mice  5  mg "C-endrln/kg  bw  by 1.v.  using  OffSO as  a  vehicle.   After
10  minutes the  radioactivity   distribution  was  as  shown  1n Table  III-7.
EndMn was as penetrative to the blood-brain barrier as  dleldrln;  no endMn
was found In the bile up to  2 hours after administration.


00650                                111-17

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                          TABU Ill-b
Otstrtkuttwi of  fndrln  and 12-Ketoendrtn In f Kperlewnm Anleu Is
J\ • — — 	 — 	 — — —
Concentration
IM coovound/kfl t Issue 1
An (Ml (Nuaber)
•eagle dog (3)
(9-aonlk-eld)





CM rat |t)
(faaale. 200-250 g)

CM rat (t)
M (aale. 200-2SO g)
i- Cff rat |3)
o> (Mle. 200-2SO g)
Holsteln cows (2)





•a It us nervegtcus (?)
(Ml*. 301 g. S33 g)
Nus ausculiis aeuse (k)

lose
(•I/kg kw)
0.1 ag/kg kw/day ever
120 days





2.S In arackls ell


2.5 In arackls ell

10 In aracklt ell

O.I ag/kg diet twice
dally for 21 days





SO In diaetkylsnirextde

dose net given

1 Issue
spleen*
fat*
auscle*
pancreas*
kearl*
liver*
kidney center*
blood*
fat*
liver"
kidney*
fat*
liver*
kidneys*
kralnc

rear leg at at*"
• ia^B»aj» eaajai i
liver4
kidney*
renal fat4
aownlal fat4
subcutaneous rat*
kraln*

kraln*
carcass*
fndrtn
0.12-2.t2
2SO-7tO
120-310
•1-280
12S-I70
11-04
30-02
1-0
S.4«»0.32
0.10»0.01
O.H
0.20*0.03
<0.004
0.02-0.11

0.001-0.002
0.001-0.002
0.000-0.011
0. 000* -0.0008
0.021-0.110
o.oso-o.oto
0.041-0.070
0.20 (533 g)

0.01-1.00
0.00-2.00
12-Ketoendrtn







7.27.0.47
o.otTo.oi

1.. 5,0. IS
o.soTo.oi
0.04"
0.2S-0.31

<0.0001
<0.0001

-------
                                                              1AILE  Ill-t (cont.)



Anlaal (Hunter)
foltfen Syrian Matter
(21)» (feaile)

CO
(fe



rat (27)"
•ale. 115-200 g)
(29)*
""'

Dose
(•g/kV ow)
l.S day via corn oil
over 11 days
2.S day via corn oil
over 11 days
O.IS day
0.30 day
0.44 day (all doses via
corn oil over 13 days)

1 Issue
liver'
fetal tissue' (10)*
liver'
fetal tissue' (7)*
liver •
fetal tissue!
liver*
fetal tissue*
liver*
fetal tissue* (ftp
Concentration
(•a conpound/kfl tissue)
••ference
fndrln 12-Ketoendrln
1.45 p Chernoff ot al.. •
0.021*0.004 p 1979
2.SS p
7S»3ft p
0.052-0.074 Kavlock el al..

-------
                                                                        TAIL! III-?
                               Distribution of Radioactivity In Various Experimental Animals After an Acute Oral  DOS* of  fndrln
o
0
c»«
cr>
o










, ,
M
1
l^t
s



AntMl Spec Us Admin. Sei
•out*

Adult rat oral II
(CFE strain)

r


Adult mice t.v. N
(Cf no. i)
Mult rabbit oral N
(Outcn strain}
Cow (Holsteln) oral f

"
-


Ooio
J«g/koj

2.S


2.5


s.o
2.12

0.1 mg/kg tftot
(twice dally
for 21 days)



Carrltr

aracMs
oil
(1 a*)
arackti
oil
n •»!
dliwthyl-
sulfoildo
oltvo oil
(10 M)
corn oil;
adoilnts-
Itrod as
captulo
!

AnlMl TIM of
Heights Analysis
(a)
200-2SO at day 3
<»)

200-250 at day 3
(M

not given at 10 Minutes
15
2.2 kg at day 13
n;»
450-tSO kf at day 21
*



Percentage of Radioactivity Administered found
In Remaining
Urine Feces Liver Kidney fat Skin Carcass Total

2.15 M 1.2 O.M 1.T 2.3 12.2 M.9


T.50 3? 2.0 0.35 1.0 4.0 20.1 17.2


•A MA 52* M 21* HA 23«>b NA
5.2«.c
37.3 49.2 M .HA NA 13.5 100

55-57 19-21 0.*-1.5 111 0.0 HA 3.1-5.3 00-91
Major organs




Reference
•
Hutson
ot al.. 1975




Ualsh and
Fink. 1972
Oedford et
al.. 197Sb
Oaldwln
ot al.. 1976


*«g/kg tissue basis
••rain level
clleod level
HA - Hot analyied; N . Mlo; F • feaale;  l.v. -  Intravenous

-------
     Hutson  et al.  (1975)  showed  that  endMn  administered  in  the  diet  to 6
male  and 6 female  rats  (200-250 g) was quickly  metabolized and then elimi-
nated  as conjugates.   The amount  of conjugate  was  shown to be gender-depen-
dent,  confirming  the earlier work of  Korte (1967), Korte  et  al.  (1970)  and
Baldwin  et al.   (1970).   Three  days  after an acute  oral dose  of 2.5  mg
endr1n/kg  bw  In  arachls  oil  by oral gavage,  the fat,  liver  and  kidneys  of
male  rats  contained the levels shown 1n Table  III-6 and 31% of the adminis-
tered  dose was  still  retained  by the animals.   For females  the corresponding
levels are  again  provided 1n  Table III-6; 56X of  the administered  dose  was
still  retained.   Female  rats  accumulated  more endrln  than male rats,  but
mostly In  fat and skin.  Uhen 3  male rats were administered 60 mg endrln/kg
bw  by gavage, the  brains  of the  dead  animals  (after  7-22 hours)  contained
0.02-0.11  mg  endr1n/kg  tissue  and  levels of  0.25-0.31  mg 12-ketoendrln/kg
tissue.   The   brain  levels   of   delta-ketoendMn,  3-hydroxyendrln,  syn-12-?
hydroxyendrln   and  ant 1-12-hydroxyendr1n   were  <5  wg/kg tissue.   Distribu-
tion  of  radio-labeled  14C-endr1n  in  the  experiments   for  both  genders   Is
provided 1n Table III-7.

    Baldwin et  al.  (1976)  dosed  two  Holsteln  cows  (500   kg)  with 0.1   mg
"C-endr1n/kg  diet  twice dally  for  21  days.  At  day  21,  the  tissue levels
of  endrln  and !2-ketoendr1n  In Table III-6 were found.  Endrln  constituted
the  vast majority of the residues In  rear  leg  and lumbar   meat, the liver,
kidney  and  In renal,   oraental   and  subcutaneous  fat.   12-Ketoendrln  was
detected 1n the  fat but not  the lean meat.  Some  ant 1 -12-hydroxyendr In was
detected  (0.020 mg/kg ww) In  the subcutaneous  fat of  one  cow.  .Otherwise,
the  amounts   of   antl-  and  s^n-12-hydroxyendr1ns  and  3-hydroxyendrln  were
below  detection   limits.   The  distribution  of  radlolabeled  endrln   Is
00650                                111-21

-------
provided  1n  Table  III-7  for  the  residues  3  weeks  after  administration.
Minor  residues remained  1n  the  major  organs.   All  of the  tissue  residues
were essentially endrln Itself (see Table III-6).

    Stlckel  et al.  (1979a),  using two old,  large rats  (Rattus  norveqlcus;
381 g  and  533 g),  administered  a dose  of  50  mg  endMn/kg bw  In a  DMSO
carrier.  12-Ketoendr1n was  detected In the  brains and carcass  of both rats
and endrln  was also  found In the carcass  of  the fatter animal  (see  Table
III-6).   One male (542 g) and one female  (331 g)  rat  were  also  fed a  diet
containing  150  mg  endrln/kg  diet until death  (16  days  for the  male; 24 days
for the  female).   No endrln was  detected  1n  the  brain or carcass of either
animal.  The  levels  of  !2-ketoendr1n In the  brain and  carcass  were  0.18 and
0.28 m/kg  tissue for  the male;   and  0.13 and 0.13 for the  female,  respec-
tively.   The number  of  animals  1n  the  rat  experiments  1s  too small  for
statistical  purposes but  the results  do  agree  In  general with those  of
Hutson et  al.  (1975).  Stlckel  et al.  (1979a) also  found that  the  residues
of  endrln  In  the brains  and carcasses  of  6  white mice killed by eating
endrln-treated  pine  seed,  and   pooled   In   groups  of  three,   varied   from
0.70-1.00,  and  0.88-2 mg endr1n/kg tissue, respectively.  The  corresponding
figures  for 12-ketoendr1n were  0.04-0.08 and 0.07-0.10  mg/kg tissue.    The
lower   limit  of detection  for  endrln and 12-ketoendr1n 1n homogenized   duck
tissue was 0.05 ppm.

    Bedford  et al.  (1975b),  1n  experiments   on  male  adult  rabbits (Dutch
strain; 2.2  kg)  Involving an acute oral dose of  2.12 mg endr1n/kg bw,  found
low levels  of endrln  In  the carcass  at  day  13  (13*  retention)  (see Table
III-7).  At day 49. only 3.2% remained 1n  the  body.


00650                                111-22

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    EndMn  and 12-ketoendrln  were detected  and confirmed  by  GC/MS  in  the
 liver  and  fetal  tissue of the  hamster  (Chernoff et al., 1979).  Timed preg-
 nant Golden  Syrian  hamsters  (LVG strain)  were housed two per cage at 22-24'C
 under  controlled  lighting (16-hour light)  after successful  copulation.   The
 animals  were  fed  commercial  lab chow  and  water  ad  lib.   The  endrln  was
 administered at day 4 or at day  8 after  copulation by gastric  Intubation In
 a  corn  oil  vehicle.   Single  dose exerlments  on  nonpregnant  and  pregnant
 animals  were at 0,  0.5, 1.5, 5.0,  7.5  and 10 mg/kg bw  (the  number  of preg-
 nant  animals were  76,  10,  34,  50, 34 and 24, respectively).    In  multiple
 dose  experiments,  the  doses were 0,  0.75,  1.5, 2.5 and 3.4 mg/kg/day  (the
 number  of  surviving animals were 50, 19,  21,  12 and  2,  respectively).   At
 sacrifice  (day 15)  the 2.5 and 1.5 mg/kg/day dose  groups  yielded the endrln
 levels  given  1n  Table  III-6.   These results Indicated that endrln  crosses
 the  placental   barrier  in  hamsters.   Although  the  authors   stated  that
 12-ketoendrln  crossed   the  placental  barrier,  It  Is  uncertain   whether
 12-ketoendrln  was  formed  from  endrln  1n  the  fetus  or   penetrated   the
 placental barrier  from the mother.

    A  similar  type  of  study on  rats was also  performed  by the  same group
 (Kavlock  et al.,   1981).   Again  12-ketoendr1n  and endrln  were  found   In
maternal liver  and  In  the  fetus.   Pregnant  CO rats  (175-200  g)  were  exposed,
as  1n  the Chernoff  et  al.  (1979)  study, to  endrln doses  of  0.450,  0.300.
0.150, 0.075 and 0  mg/kg/day on  days  7-20 of gestation,  and  killed on day  21
of  gestation.   The   number  of   pregnant  animals studied  for the  respective
doses  were  12, 29,  27, 14 and  29.  The  results for the three  highest doses
are contained 1n Table  III-6.  Although 12-ketoendr1n was Identified,  It was
not quantUated.   The  average  ratio of  peak  height  of  12-ketoendrln  to that


00650                                111-23

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 of  endrln was  0.19  (range  0.07-0.47) for  maternal  livers and  0.35 (range
 0.07-0.71)  for  the  fetus.   In the  hamster  fetus the ratio was  3.2*0.6 (10
 fetuses)  at  a maternal  dose  of 1.5 ng/kg/day.  Thus 1n  the  rat,  passage of
 endrln  through  the  placenta  will  occur   above a  critical  concentration
 threshold  In the  blood produced  by an  oral  dose  between 0.300  and  0.450
mg/kg/day.

Mechanisms of Transport and Metabolism
    The metabolic  pathway for  endrln 1n mammals  1s complex  (Figure III-1)
and  varies  from  species  to  species.   In all   species   the  unsubstUuted
methylene  bridge  (C,-)  1n endrln  (compound  I  1n Figure  III-l)  Is  preferen-
tially  attacked  to  form mostly antl- and lesser  amounts  of  syn-12-hydroxy-
endrln, the  latter  being  quickly  oxidized  by mlcrosomal  mono-oxygenases  to
produce 12-ketoendr1n (compound IV  In  Figure III-1).   To a  smaller  extent
hydroxylatlon at  the 3-pos1ton also  probably  occurs,  and  the  epoxlde  func-
tional  group 1s  probably  hydrated.  Syn- and  antl-12-hydroxyendrln are  most
Hkely  Interconvertible in vivo probably  by  !2-ketoendr1n.   Hydroxylatlon at
C-3  and  C-4 1s   Inhibited  by the  presence  of  the  bulky  hexachlorlnated
fragment (Hutson,  1981).  Studies  1n  rats (Cole  et al.,  1970)  have  Indicated
that   "C-radlolabeled-endMn   1s   quickly  metabolized   to   the  antl-12-
hydroxyendrln (compound II In  Figure III-l),  which  Is  excreted 1n the  bile
(70%  within   24  hours)  as the  glucuronlde (Hutson  et  al.,  1975)r  After
enterobacterlal   deconjugatlon  and  enterohepatlc  circulation,  elimination
occurs  as  the aglycone  (-45X) In  the  feces  together with two other minor
metabolites,   3-hydroxyendrln   (compound V  In  Figure III-l)  and 4,5-trans.-
d1hydro1sodr1nd1o! (compound VI 1n  Figure III-l).  The major urinary  metabo-
lite  In male  rats  (only  1-2X of  the administered  dose)  Is  !2-ketoendr1n


00650                                111-24

-------
                                                            (VI)
                                 FIGURE III-1
                    Blotransforraatlon of Endrln In Manuals
                             Source: Hutson, 1981
00650
111-25

-------
 (compound IV  In  Figure  III-l).   This  metabolite 1s produced by the action of
mlcrosomal  mono-oxygenases  on  sjtn-12-hydroxyendMn (compound III  1n  Figure
III-l)  (Hutson  and Hoadley,  1974),  which, 1n  turn,  1s formed by  attack  at
the   unsubstHuted  methylene   functional   group  of   endrln.    The  primary
hydroxylatlon rates  In  the liver  for the rat and  rabbit  are  50:7:1.5:1  and
40:5:4:1, respectively,  for  ant1-C-12. C-3, nn-C-12  and  C-4 1n  that  order
(Bedford  and  Hutson, 1976).   In  the rabbit the  major metabolite  Is  still
ant1-!2-hydroxyendr1n.  but  1t Is  conjugated  with  sulfate and eliminated  1n
the  urine (Bedford et  al., 1975b).   Some ^n-12-hydroxyendrln  sulfate  was
also  found  1n the  urine as were  the  glucuronlde conjugates  of the antl-  and
s_yji-l2-hydroxyendr1n,  3-hydroxyendr1n,  and  the 4.5-trans-d1ol  (compound  VI
1n  Figure  III-l).    The  reason   for  this  variability 1s  related  to  the
molecular weight thresholds  for  biliary excretion  of  anlons  In  the rat  and
rabbit;  e.g., 325+50 and  475+50, respectively  (H1rom et  al.,   1972).   The
threshold  for man  Is  between  these  values  but  Is  closer  to  that of  the
rabbit.

    The rapid metabolism has been  explained In  terms of the  sterlc  Influence
of the  epoxlde anlon  on C-12-hydroxylatlon 1n promoting antl-C-12-hydroxyla-
tlon.  The bulky hexachloMnated fragment Inhibits  attack at  C-3  and C-4.

    Antl-12-hydroxyendr1n has been detected  1n  the feces of factory workers
and  Us  B-glucuronlde has been  detected  In  the urine (Baldwin  and Hutson,
1980).   The  levels of  the latter appear  to be dose-dependent.   The  toxic
metabolite 12-ketoendrln  was  not  detected 1n the  urine  and  feces, neither
was 3-hydroxyendr1n (compound V In Figure  III-l) or the dlol (compound  VI  In
Figure III-l).


00650                                111-26

-------
    These  transformations  are of  Interest  because syn- and ant_U12-hydroxy-
endrln  and  12-ketoendrln  all  have lower  LQ    values  than  endrtn  Hself.
As  these  metabolites are produced  quickly  they  could be responsible for the
toxic  effects  elicited by  endrln administration.   12-Ketoendrln has  been
suggested as  the acute  toxicant (Bedford et a!.,  1975a).
Elimination
    Endrln  1s  rapidly eliminated both  In  animals and  1n  humans.   The  urine
1s  the  major  excretory route 1n cows and  rabbits but  1s  of minor  Importance
In  the  rat.  Endrln  Is  both metabolized  and excreted unchanged  In  propor-
tions that vary with species and gender.

    When  "C-labeled  endrln was given  orally and by 1.v.  to  rats, the  Ice to
metabolite of endrln and other  hydrophHlc  metabolites  were present 1n  trace
amounts  1n  the  urine  (Klein et  al.,  1968).   After a  single 1.v. dose  of
14C-endr1n, 90%  of the label was  eliminated 1n  the bile  by  the  second  day
(Cole et al.,  1970).

    Baldwin et al.  (1970)  found that  endrln was  metabolized 1n the rat  to at
least  three  metabolites.    One  metabolite,  !2-ketoendr1n,  was found  1n  the
urine.   The other  two metabolites  were excreted  In the  feces and were  not
found   In  body   tissues.    The    second   metabolite   was   an   Isoroer  of
12-hydroxyendrln.   This Isomer  had the hydroxyl  group  antl with  respect to
the  epoxy  group.   According  to  Korte  et  al.  (1970),  12-hydroxyendrln
accounted  for  95X  of  the  radioactivity  excreted  by   rats.    The   third
metabolite was  a  monohydroxylated  endrln.  but   1t  was not  substituted at
carbon  12  (Baldwin et al..  1970).   The unsubstUuted  methylene bridge was


00650                                111-27

-------
thus  hydroxylated,  and  the  corresponding  ketone was found In adipose tissue,
liver and brain.

    Rabbits  excreted   radioactivity  after  1.v.   administration   of   14C-
labeled  endrln  mainly  in  the  urine and  only  as metabolites  (Korte  et  al.,
1970).   Four metabolites  were found  In  order  of decreasing  polarity In the
ratio  of  1:1:3:1.   The   second   most   polar   one  was   Identical   to  the
12-hydroxyendr1n, which was  the  main metabolite found 1n  rats.   The biolog-
ical half-life of endrln  In  male  rats  receiving 0.4 mg/kg diet was  2-3  days;
In  females,  -4  days (Korte  et  al., 1970).  Following l.v.  Injection of 200
vg  of 14C-labeled  endrIn/kg  bw In  two  doses,  male  rats retained  5.2X and
females  12.IX  of the radioactivity after  24  hours.   The radioactivity  was
totally  excreted as  metabolites   (Korte  et  al..   1970),   When  "Clabeled
endrln was fed  to male  and female  rats, the males  excreted 60%  of 1t 1n the
feces within the  first  24 hours, and  the  females only 39X; <1X  was  excreted
In  the   urine.   Of  the  total  radioactivity  excreted 1n  the feces. 70-75X
occurred  1n  the  form  of  hydrophlllc  metabolites.   Twenty-four  hours after
the last dose only metabolites  were excreted (Korte  et al., 1970).

    The  elimination  and   distribution of  »4C-1abe1ed  endrln  administered
acutely  to rats  (Hutson et  al.,  1975), mice (Walsh and F1nk,  1972),  rabbits
(Bedford  et  al., 1975b)  and cows  (Baldwin et  al.,  1976)  are  provided  In
Table III-7.

    Hutson et  al.  (1975)   showed  that 55-57X of  "C-endMn  was  eliminated,
mostly as  the  glucuronlde  of  antl-12-hvdroxyendrln.  1n  the  bile within  24
hours of administration  to  rats of  0.76-1.53  mg  »*C-endr1n/kg bw.  Other
minor  components  (<10X)  were the  glucuronldes of 3-hydroxy- and   12-keto-

00650                                111-28

-------
endrln.   Hale  rats  eliminated 69X of  the  label  within  3 days whereas female
rats  eliminated  45X.  Feces  from male and  female rats  fed  for 2  weeks  on
endrln  diets contained  the  following:  endrln  (11X),  ant1-!2-hydroxyendr1n
(83X),  iyji-12-hydroxyendrln  (<0.01X), 3-hydroxyendrln   (5X),  12-ketoendrln
(IX)   and  delta-ketoendMn   (<0.01X).    Day   1  urine   samples   contained
17:2:0:1:10:0 proportions  for  males, while  those from females contained  1-2%
endrln  but  no  12-ketoendMn,  the major  component   being  12-hydroxyendMn-
0-sulfate.

    Only  traces  of  12-ketoendMn were  found In  male  rabbit  urine 6  days
after  oral  dosing and none In rabbit feces  (Bedford,  et al.,  1975b),  even
though  SOX  of  "C-label  was  excreted  In  the urine.   Nearly  all (>99.5X)  of
the  14C-label   In  feces   within  24  hours  was  endrln   Itself,  and endrln
metabolites were excreted  slowly  over  several  days.   Excretion of  the label
was  87X completed within  13  days.   The  following compounds were  found  In
urine  up  to 24 hours:   12-ketoendMn  (7X),  the glucuronlde  of antj.-12-hy-
droxyendrln  (21X), ant1-!2-hydroxyendr1n sulfate  (53X),  syn-12-hydroxvendrln
sulfate  and 3-hydroxyendrln  sulfate  (14X);  the  glucuronlde of trans-4.5-
d1hydro-1sodr1n-4,5-d1ol   glucuronlde  (2X),   and  other   minor   glucuronldes
(3X).   These components  accounted  for  40X  of  the  single   oral  Intake  of
l4C-endr1n.  While  the bulk of endrln metabolites are  excreted directly  by
the  rat  1n  the  bile  (Hutson et  al., 1975),  mostly as glucuronldes,  the
rabbit  excretes  then directly as  sulfates  In  the  urine (Bedford  et  al.,
1975b).   This  behavior  1s  consistent  with  Molecular weight  thresholds  for
biliary excretion,  which   are  32S±50  1n the rat  and 475+50   In  the rabbit
(H1rom et al.,  1972).
00650                                II1-29

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    The  molecular  weight  threshold  for  biliary excrtlU"'   n man lies between
those  of the rat and  the  rabbit but  1s  closer to that or the rabbit.  While
metabolism of  endrln  1n  humans  has  not  been studied systematically, antl-12-
hydroxyendrln  as  the glucuronlde has been  found 1n boil   feces  and urine of
endrln workers (Baldwin  and Hutson,  1980)  (Table 111-8}.   12-Ketoendrln was
not  detected  (Hutson,  1981).   Thus,  available  Information  suggests  that
endrln 1s  probably metabolized  similarly In humans and  1n rats and rabbits.
though the proportion and the type of conjugation  products  differ.  Baldwin
et al. (1976)  showed  that  the sulfate conjugate of ant1-12-hydroxyendr1n was
the major  metabolite In hens.   Endrln  was  the  only other excretion product
In  feces,  generally  at   levels  25-35%  less  than  the sulfate  conjugate  of
ant1-l2-hvdroxyendr1n. which  generally  was at levels  of  4-20 mg  of  endrln
equivalents/kg  (Baldwin  et al., 1976).   Cows  probably excrete the  glucuron-
lde In the bile,  but after enterohepatlc circulation  the  free metabolite 1s
excreted 1n  the urine and feces (see  Table  III-7).   12-Ketoendrln  Is  also
excreted 1n  the urine of  cows  to the extent  of 2-26% of  the  total  adminis-
tered  "C-endrln  (Baldwin  et al.,  1976).   During dally  treatment  a  steady-
state of "C-label In the urine  of cows  1s  attained at  about  day 9.

    A  brief  half-life on  the order  of  a day  for humans   Is .consistent  with
the lack of  persistence of  endrln In  human  tissues  (Coble et al., 1967),  and
with  the rapidity with  which  plateau  concentrations  are  reached  In other
mammals  on chronic exposure,  I.e.,  <1 week for blood endrln  (Richardson  et
al.,  1967).    This  observation   suggests  that  the biological  half-life  of
endrln In the dog 1s also on the order of 1-2  days.
00650                                II1-30

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                                 TABLE III-8
            Analysis  of Urine  fron EndMn Plant Workers 1n England3
Worker Concentration of Total .12-KetoendMnc
ant1-!2-hydroxyendr1nb (vq/mi)
Ug/mi)
1
2
3
4
5
6
7
0.010
0.14
0.098
0.040
0.021
0.098
0.011
NR
0.13
NR
NR
NR
0.075
0.015
antl-12-Acetoxyendrln
after Acetylatlon
Expressed as Alcohol
tug/mi)
NR
0.13
NR
0.037
0.024
NR
NR
aSource: Baldwin and Hutson,  1980
Measured after  8-glucuron1dase cleavage
cProduced after  oxidation
NR . Not reported
00650
111-31

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    Two  cows  given  0.1  ng  **C-endr1n/kg  diet  twice  dally  for  21  days
excreted the  label  1n the milk  and  a  steady-state was attained In 4-6 days,
mostly  as  free endrln.   The antl- and s_£n-12-hydroxyendMn, 3-hydroxyendr1n
and  !2-ketoendr1n  were below  detection  limits (Baldwin et  al.t  1976).   The
estimated half-life Is 2-3 days.

    In  August,  1976,  a  Canadian  dairy  herd  was treated  with  endrln  for
control  of  files;  25 animals  developed  poisoning symptoms,  and  one  cow and
one  calf died  (Frank  et  al., 1979).  The  next  day  after  the  poisoning  a
composite milk sample contained  0.40  ppra endrln  (8.7 ppm  1n  the mllkfat).
After 34 days  the  levels were 0.0026  ppm  (0.056  ppm  in the milk fat).  M11k
from  Individual  cows  on  day  13  contained  endrln  levels  ranging  from
0.031-0.16  ppm In  whole  milk.  The residues  were analyzed by  EC/GC  and  by
TLC, or by two column EC/GC.

    Estimations  of  the  50% disappearance time of endrln  are  presented  1n
Table III-9 for a variety of animal  species.   These data have been estimated
from the data  presented  In  the cited references.   Endrln 1n sheep and  cattle
appears to have a longer half-life than 1n the rest of the species.

    Another study Involved 50  mallard  drakes  (960-1360 g; 1  year  old)  fed 20
ppm endrln for 13 days  (Heinz  and  Johnson, 1979).   Groups  of five ducks  each
were sacrificed at  2,  4, 6, 8,  16,  32 and 64 days after the  end  of  dosing.
Endrln  was  monitored  1n  the blood and carcasses.  The carcass lost  50% of
Its endrln  In  3  days;  the second  half-life required an additional  8.9 days,
and 1t  took 32.9 days  to  lose  90X of the  original amount administered.  On  a
11pld-welght  basis  the  first  half-life  of  elimination  was  2.2  days;  the


00650                                111-32

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                                  TABLE  II1-9
            Estimated  Half-Lives  in  Various Species for Elimination
                   of  EndMn  Administered by the Oral Route*
   Species
    Estimated Half-Life (dose)
       Reference
Rat (H or F)
Rat (M) (1.v.)
    (F) d.v.)
Rat (M)
    (F)
Rabbit (M)
Dog (M)
Man
Sheep
Cattle
Mallard duck
Hen
Cow
2 days (16 vg/kg)
6 days (128 tig/kg)
2-3 days (200 vg/kg)
3-4 days (200 wg/kg)
2-3 days (2.5 mg/kg)
  4 days (2.5 mg/kg)
<1 day (2.12 mg/kg)
T3 days 1n feces alone (2.12 mg/kg)
49 days 1n urine alone (2.12 mg/kg)
1-2 days (0.1 mg/kg/day)
1-2 days 1n blood serum
1.8-8.2 weeks
1.8-8.2 weeks
3 days (subchronk feeding)
1 month from fat (chronic  feeding)
2-3 days
Korte, 1967;
Korte et al.. 1970
Korte, 1967;
Korte et al.. 1970
Hutson et al., 1975
Bedford et al., 19755

Richardson et al.,  1967
Coble et al., 1967
Robinson, 1962
Robinson, 1962
Heinz and Johnson,. 1979
Cunwlngs et al.,  1966
Baldwin et al., 1976
*These half-lives are based on  the  1nU1al  quick excretion.
 tratlon was performed unless  otherwise  Indicated.
M » male; F • female
                                              Acute admlnls-
00650
                     111-33

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second  took  an  additional  6.7 days and a 90% loss of  the administered amount
took  24.8  days.   For blood the  first  and  second half-times and the 90% loss
time  on a  wet weight basis were 1.7,  5.2  and 19.1 days, whereas  on  a llpld
basis,  these values were 1.4, 4.3 and 15.9 days, respectively.

    Cunnings  et  al.  (1966) fed  egg laying White  Leghorn hens a combination
of endrln,  Undane,  dleldrln, DDT and heptachlor  epoxlde at levels of 0.05,
0.15  or 0.45 ppm  of each  compound  In  the  feed.   After 14  weeks  the birds
were  returned  to  the  basal diet  for  32 days.   Hens  1n the  0.45  ppm group
accumulated  -3.4 ppm endrln In  the fat  and  required  about  a month to reduce
the  level  to 50%.   This  Increase In  half-life  may reflect  the  presence  of
the other  pesticides.   However, Baldwin et  al.  (1976)  showed  that hen  eggs
concentrated  J4C-endr1n  during  a  dosing program  of  0.13 mg  endrln/kg.diet
over a  period of 148 days  to  the extent  of 0.11-0.18 mg endrln equivalent/kg
yolk.   The label was  Identified  entirely as  free endrln. Thus, accumulation
In eggs 1s a major pathway of elimination for hens.

Summary
    The  major  route  of  absorption for  humans  appears  to  be  through  food.
The average  dietary  Intake  1n 1973 was  0.5  ng/kg  bw/day.   Special  groups  at
risk  appear  to  be occupational  workers  1n  the  pesticide manufacturing and
formulating  Industries.  Industrial and  field workers  may be exposed  by  both
dermal  and  respiratory  routes.   Several  episodes  of accidental  and suicidal
endrln  poisoning 1n humans  have  occurred.  Poisoning has been caused  by  oral
doses of  endrln  as  low as  0.2 mg/kg.   Endrln  levels  In drinking  water are
usually  <100  ng/i.   Endrln  poisoning  may  occur  In  humans   at  blood
00650                                111-34

-------
 levels  of  50-100  ng  endMn/mi blood.   These data  Indicate endrln  can  be
 absorbed  In  humans.   Quantitative  absorption  rate data are not available for
 mammals.

    Fat  appears to  be  the  major  storage tissue  for  endrln In  lambs  and
 birds.  The  weighted  average  BCF  In the edible portion of all freshwater and
 estuarlne aquatic organisms 1s 3970.

    The  unsubstltuted  methylene  group  of  endrln  Is  preferentially  and
 quickly attacked  to  form mostly antl- and  lesser  amounts of syn-12-hydroxy-
 endrln.   The latter  Is  rapidly  oxidized  by  mlcrosomal  mono-oxygenases  to
 produce !2-ketoendr1n.   Hydroxylatlon at  the  3 position  and  epoxlde  hydra-
 tlon may occur  to a  small  extent.   Syn- and ant1-!2-hydroxyendr1n are  likely
 to  be   Interconvertible  ,1^  vivo,  with   12-ketoendrln  as   a   possible
 Intermediary metabolite.

    Endrln residues  have been found  In  such  organs as  the  liver,  brain and
 kidneys and  In  the fat  of  birds,  dogs,  cows,  rats,  mice and hamsters.  No
 12-ketoendrln  has   been  found  1n   tissues  of  birds.   Endrln  appears  to
penetrate the blood-brain  barrier  1n rats  and hens but  less  readily  In the
cow,  and  the placental  barrier In  rats, mice and hamsters, although much
 less  efficiently  for  rats.   12-Ketoendrln  may also penetrate the  placental
barrier of these three species.

    In rats  >50% of the  endrln  metabolites  are eliminated In the  bile  within
 1   day   as  glucuronldes   that,  after   enterobacterlal  degradation  and
entherohepatlc   circulation,   are  eliminated   as  aglycones  1n  the feces.


 00650                                111-35

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12-KetoendMn  1s  the  major   urinary  metabolite.   Females  excrete  endrln
metabolites  more  slowly   than  males.    Cows  excrete  free  12-hydroxyendrln
after  enterohepatk  circulation.   !2-Ketoendr1n  Is  the  only  other  major
metabolite In cow urine.

    Though  the  major  metabolite   1s  still  arvU-12-hydroxyendMn  1n male
rabbits, 1t Is conjugated  as  the sulfate and excreted  directly  In  the  urine.
This also occurs 1n hens.

    The  ant1-12-hydroxvendr1n  has  been  detected  as Us  glucuronlde In the
urine and feces of humans.

    Hens  appear   to  eliminate  endrln  faster  than most  other  birds.   The
sulfate  conjugate  of anU.-12-hydroxyendrln  1s  the major  metabolite In hen
feces.   The only  other  metabolite  1s endrln  Itself.   Endrln does  appear  to
accumulate more In birds than  1n mammals.
00650                                111-36

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                             IV.  HUMAN EXPOSURE

    This chapter  will  be  submitted by  the  Science  and Technology  Branch,
Criteria and Standards Division, Office of Drinking Water.
00660                                IV-1

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                              IV.   HUMAN  EXPOSURE

     Humans  nay  be  exposed  to  chemicals  such  as  endrln  from  a  variety  of
 sources,  Including  drinking water,  food,  ambient air, occupational  settings
 and  consumer  products.   This analysis of human exposure to  endrln  Is  limited
 to  drinking water,  food  and ambient air  because those media are  considered
 to  be sources common  to  all Individuals.  Even  1n limiting the analysis  to
 these three  sources,  1t must  be recognized  that  Individual  exposure will
 vary  widely based on  many personal chokes and on  several factors  over which
 there 1s  little  control.   Where one  lives, works and travels, what one eats,
 and  physiologic  characteristics  related  to age,  sex and health  status  can
 all  profoundly affect dally exposure and  Intake.   Individuals  living in the
 same  neighborhood  or  even  1n   the  same  household  can  experience  vastly
 different exposure patterns.

    Detailed  Information  concerning  the  occurrence of and  exposure to endrln
 1n  the  environment  1s presented  1n another document  entitled "Occurrence  of
 Pesticides  1n  Drinking  Water,  Food,  and Air1 (Johnston et  al.,  1984).  This
 chapter  summarizes  the pertinent  Information  presented 1n  that document  In
 order  to  assess  the  relative source  contribution from drinking water,  food
 and air.

    In  the  Exposure  Estimation  section  of this  chapter, available Informa-
 tion  1s  presented on  the range of human exposure and Intake for endrln  from
 drinking water,  food  and ambient  air  for  the  70-kg  adult  male..   It  1s  not
 possible  to provide an  estimate  of   the  number of  Individuals  experiencing
 specific combined exposures from those three sources.  However, the  Summary


00660                                IV-1

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 section of  this  chapter provides  some  Insight  Into  the relative  contribu-
 tions  of  the  three  sources,  especially  drinking water,  to  the  range  of
 Intake values  suggested  by  the  available  data.

 Exposure Estimation
     Drinking Mater.   Levels  of  endrln   1n  drinking  water  vary  from  one
 location to  another.  The highest level  of endrln monitored 1n  the available
 studies  was  0.008  wg/l  1n  New  Orleans  (U.S.  EPA,   1975,   as  dted  1n
 PelUzzaM,  1978),  well  below  the  Maximum Contaminant  Level  (NCL)  of  0.2
 yg/l.   Analysis of  the  National  Screening Program  for  Organlcs  In  Drink-
 ing  Water  (NSP)   (Boland,  1981} suggests  that median  levels  of  endrln  In
 drinking water  would  be   below  0.1   vg/l,   since  none  of  116  systems
 sampled  contained  a  level  of  endrln  above 0.1  vg/l.    In  addition,  analy-
 sis  of  the  Rural  Hater  Survey  (RWS)  (U.S.  EPA, 1984) suggests that  median
 levels  of  endrln  1n  drinking  water  systems  would  be  <0.008 vg/l,  since
 none   of  92  systems  sampled  contained   a  level  of  endrln  >0.008  vg/l-
 Endrln  may  not be present  1n drinking water  In some areas.   The  available
 monitoring  data  are  not  sufficient  to  determine  regional  variations   1n
 levels of exposure to endrln.

    The  dally  Intake of  endrln  from drinking  water was  estimated  using  the
assumptions  presented  In Table  IV-1 and  the   values  presented above.  The
 estimates 1n Table IV-1  Indicate  that  the  dally Intake  of endrln from  drink-
 Ing  water  ranges   from 0.0-0.0028  vg/kg/day.   However,  the  values  presented
do not  account  for variances In Individual exposure or uncertainties  In the
assumptions used to estimate exposure.
00660                                IV-2

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                                  TABLE  IV-I
            Estimated  Dally  Intake of Endrln from Drinking Hater*


Drinking water concentration  (v9/i)                     Intake (vg/kg/day)

              0.0                                               0.0
              0.008                                             0.0002
              0.1                                               0.0028

•Assumptions: 70-kg man consuming 2 i of water/day.
00660                                IV-3

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     Diet.   Data are  limited on  the  dietary Intake of  endrln In the  United
 States.   For  fiscal year  1979,  the  only positive value for endrln  In  an  FOA
 market  basket  study on toddlers (FOA, 1982a,b).  In this  study,  an  estimated
 dietary  Intake  of  0.0001  yg/kg/day  was calculated  based  on endrln  levels
 1n  an oil  and  fat composite (FOA,  1982b).

     Additional  data were  obtained on the estimated total  dietary Intake of
 endrln  for  adults  1n  the years  1974-1979 and for Infants and  toddlers  In  the
 years 1975-1979  (Table IV-2).   The average  total Intakes for  adults, Infants
 and  toddlers  over  the years studied  was  0.000008, 0.00004  and  0.00016 vg/
 kg/day, respectively.

     Using  the  above data,  the  dally  adult  Intake of  endrln  1s estimated to
 be  0.000008  yg/kg/day.   This   value does   not account   for  variances  1n
 Individual exposure.

     It  1s  expected  that  dietary  levels of  endrln  vary somewhat with geo-
 graphical  location,  with  higher  levels  occurring  1n  foods from  areas  near
 the  sources of endrln  exposure.   However,  because  of Insufficient  data,  no
estimates could be made of variations 1n  Intake by geographical region.

    EPA has established  a  tolerance of zero  for endrln In  and on  the follow-
 ing  raw  agricultural   commodities:  sugar beets, sugar beet  tops,  broccoli,
Brussel   sprouts, cabbage, cauliflower,   cotton  seed,  cucumbers,  eggplant,
peppers, potatoes,  summer squash and  tomatoes (40 CFR 180.131,  July 1, 1981).
00660                                IV-4

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                                TABLE  IV-2
              Estimated  Total  Dally  Dietary  Intake of EndMn
                   for Adult Hale, Infant, and  Toddler
Year
1974
1975
1976
1977
1978
1979
Average*

Adult
male*
NO
Tracec
NO
0.00004C
NO
NO
0.000008
Intake (vg/kg/day)
Infant5
(6 months)
NO
N0<*
NO
0.0002
NO
0.00004

Toddlerb
(2 years)
NO
0.0007
NO
NO
0.0001
0.00016
    aFrom FDA 1981, except as noted.
    bFrom FDA 1980b, 1982b.
    Calculated based on Information 1n Johnson and Manske 1977  and
     FDA 1980a.
    ^Appears to be an error since a positive value was reported  1n
     Johnson et al. 1981.
    eTrace values were not Included 1n the calculation;  nondetected
     values were assumed to be equal to zero.
    NO > None detected.
00660
IV-5

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     Air.   Levels  of endrln  1n the  atmosphere also  vary  from one  loca:lon
 to another.   The highest  level  of  endrln  reported  was  39.3 ng/m»  (0.0393
 wg/m»)  In  the-Mississippi  Delta  1n 1972-1974  (Arthur  et  al.,  1976)..   In
 a   national  study   the  highest  level   of  endrln  reported  was  19.2  ng/m1
 (0.0192  vg/m»)  1n  Tennessee  1n   1971   (Kutz  et  al.,   1976).    Typical
 levels, however,  are somewhat  lower.  An estimated  mean  level of endrln  1n
 ambient air, based  on  the Information  In Kutz et al.  (1976),  1s 0.2  ng/ra»
 (0.0002 wg/m»).  (However,  this  estimate 1s  based  on  data  from 1970-1972
 and  obtained 1n  sampling  locations with potentially high concentrations  of
 pesticides   1n  ambient  air.)   Additionally,  concentrations  of  endrln are
 below   the  limits  of  detection  in  some  areas  and  may  be  as   low  as 0.0
 ng/m3.   The  available  monitoring  data  are  not  sufficient  to determine
 regional variations  1n levels of exposure to endrln.

    The dally respiratory  Intake for  endrln  from air was estimated using the
 assumptions  presented  In  Table IV-3 and  the  values presented above.   The
 estimates  1n Table  IV-3  Indicate  that  dally  endrln  Intake  from  air  ranges
 from  0.0-0.013 vg/kg/day.   These   values  do  not account  for variances  1n
 Individual  exposure or  uncertainties  1n  the  assumptions  used to  estimate
exposure.

Summary
    This section  considers  the  relative  contribution of  drinking water,  food
and ambient  air to  the  total  human exposure from these three sources.   The
data  presented  here Indicate  the   potential  total  exposure  to endrln  that
could occur  1f  a population was exposed to specific  combinations of  endrln
concentrations  1n drinking water,  food and ambient air.


00660                                IV-6

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                                   TABLE IV-3

                 Estimated Dally Respiratory  Intake  of Endrln*
 A1r concentration Ug/m*)                               Intake Ug/kg/day)


               0.0                                              0.0
               0.0002                                            0.00007
               0.0192                                            0.0063
               0.0393                                            0.013


 •Assumptions:  70-kg man Inhaling 23 m» of air/day (ICRP, 1975).
00660                                IY-7

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     Table  IV-4 presents  a general  view  of  the  total  amount  of endMn  that
may  be received  by  an adult male  from air, food  and  drinking water.   Four
separate  exposure levels  In  air,  three  exposure  levels  1n  drinking water,
and  one exposure  level  from foods are  shown  In  the  table.

     The  data  1n  Table IV-4  have  been selected  from an  Infinite  number of
possible  combinations  of  concentrations for  the  three  sources.   Whether
exposure occurs  at any specific  combination of  levels  Is  not  known; nor 1s
It  possible to  determine the  number  of  persons  that  would  be exposed to
endrln at  any  of  the combined  exposure  levels.   The data represent possible
exposures based on the occurrence data and the estimated Intake data.

    A  mean  level for  endrln  In  ambient  air   of  0.0002  vg/m*  was  esti-
mated.   Assuming   a  level  of  0.0002  yg/m»  In  ambient air  and  the  esti-
mated  endrln  Intake  of 0.000008  yg/kg/day from  foods,  drinking water  would
be the predominant source  of  exposure  to  endrln for the adult male  at drink-
Ing water levels >0.003 yg/l.

    The total  estimated Intake  of  endrln 1s  <0.020 yg/kg/day.  This  value
Is much  lower  than the FAO/HHO and EPA  acceptable dally  Intake of  0.2  yg/
kg/day (FDA,  1981),  but  approaches a maximum  safe level  of 0.04  yg/kg/day
calculated by EPA (U.S. EPA, 1976).

    The relative  source contribution data are based on  estimated Intake  and
do not account for  a  possible differential absorption rate  for  endrln by
route of exposure.  The relative dose  received  may  vary with  the Intake.  In
addition,  the  effects  of  endrln on  the body may  vary by different routes of
exposure.
00660                                IV-8

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                                  TABLE IV-4

            Estimated  Daily  Intake of Endrln from  the Environment
                                by Adult Males
                      Estimated Total Intake 1n yg/kg/day (X From Drinking
                      Water) Based on a Concentration 1n A1r (yg/m1) of:
Concentration
 1n Drinking
Mater  (Hg/i
     Low
    (0.0)
Intermediate
  (0.0002}
  High
(0.0192)
  High
(0.0393)
Low  (0.0)
0.000008 (0%)   0,00008 (OX)   0.0063 (OX)     0.013 (OX)
Intermediate      0.0002 (100X)   0.0003 (67X)   0.0065 (3.IX)  0.013 (1.5X)

(0.008)
High (0.1)
0.0028 (100X)   0.0029 (97X)    0.0091  (31X)    0.016  (17.5X)
Intake from each source:

    Drinking water:   0.0 yg/i:
                      0.008 yg/l:
                      0.1 yg/i:
    A1r:
    Food:
    0.0 yg/ma:
    0.0002 yg/m»:
    0.0192 yg/m>:
    0.0393 yg/m»:

    0.000008 yg/kg/day
       0.0  yg/kg/day
       0.0002  yg/kg/day
       0.0028  yg/kg/day

       0.0  yg/kg/day
       0.00007  yg/kg/day
       0.0063  yg/kg/day
       0.013 yg/kg/day
00660
                   IV-9

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 References

 Arthur,  R.O.,  J.O. Cain  and B.F. Barrentlne.   1976.   Atmospheric levels of
 pesticides   1n   the   Mississippi   Delta.    Bull.   Environ.  Contain.  Toxlcol.
 15(2):  129-134.

 Boland,  P.A.   1981.   National  screening  program for organlcs  In drinking
 water.   Part II. Data.   Prepared by SRI  International,  Menlo Park,  CA, for
 Office  of  Drinking  Water,  U.S.  EPA,  Washington,  DC.    EPA Contract  No.
 68-01-4666.

 FDA  (Food and  Drug  Administration).   1980a.   Compliance program  report  of
 findings.   FY   77  total  diet  studies  —  Adult  (7320.73).   Food and  Drug
 Administration,  U.S.  Department  of  Health. Education and  Welfare,  Washing-
 ton, DC.

 FDA  (Food and  Drug  Administration).   1980b.   Compliance program  report  of
 findings.  FY 77 total diet  studies  --  Infants  and toddlers  (7320.74).   Food
 and  Drug  Administration,  U.S.  Department  of Health,  Education and  Welfare,
 Washington,  DC.

 FDA  (Food and  Drug  Administration).   1981.   The  FDA   surveillance  Index.
 Bureau of Foods, Food and Drug Administration,  Washington, DC.

 FDA  (Food and   Drug  Administration).   1982a.   Compliance program report of
 findings.  FY  79  total   diet  studies   ~  Adult  (7305.002).   Food and  Drug
Administration,  U.S.  Department  of  Health  and  Human Services,  Washington,
DC.  FDA/BF-82/98.

00660                                IV-10

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 PDA  (Food  and  Drug Administration).   1982b.   Compliance  program  report  of
 findings.   FY  79  total  diet  studies  ~  Infants  and  toddlers  (7305.002).
 Food  and Drug Administration, U.S. Department of  Health and Human Services,
 Washington, DC.  FDA/BF-82/97.

 Johnson,  R.D. and  0.0. Hanske.   1977.   Pesticide and other chemical residues
 1n total  diet samples (XI).   Pestle. HonH. J.  11(3): 116-131.

 Johnson,  R.O.,  0.0.  Hanske,  D.H.  New  and  D.S.  Podrebarac.  1981.   Pesticide,
 heavy  metal,  and  other  chemical residues  In  Infant  and  toddler.   Total  diet
 samples  -  (II) -- August 1975-July 1976.  Pestle. HonH. J.  15(1): 39-50.

 Johnston,  P.,  F.  Letk1ew1cz, 0.  Borum,  N. Samba 1, G. Gerner, et al.   1984.
 Occurrence  of pesticides  1n drinking water,  food and  air.  Interim  draft
 report.   Prepared  by  JR8 Associates,  McLean,  VA,  for  Office  of  Drinking
 Water, U.S. EPA, Washington,  DC.

 Kutz,  F.W., A.R. Yobs and  H.S.C.  Yang.   1976.  National  pesticide monitoring
 programs,  in: A1r Pollution  from  Pesticides and  Agriculture  Processes,  R.E.
 Lee,  Ed.  CRC Press,  Cleveland,  OH.  p.  95-136.

 PelUzzaM, E.D.   1978.   Preliminary  assessment  of halogenated organic  con-
 pounds  1n man  and  environmental  media.   Monthly  Technical  Progress Report
 No.  5, April 1-Apr 11  30, 1978.   Prepared by Research  Triangle Institute.
 Research  Triangle  Park,  NC,  for  Office  of  Toxic  Substances,  U.S.   EPA,
Washington, DC.   EPA Contract No.  68-01-4731.
00660                                IV-11

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U.S.  EPA.   1975.   Analytical  report: New  Orleans  water  supply  study.   Region
VI, U.S. EPA.  EPA 906/9-75-003.  (CHed In Pelllzzarl,  1978)

U.S.  EPA.   1976.   National   Interim   primary  drinking  water  regulations.
Office of Hater Supply, U.S. EPA, Washington,  DC.   EPA-570/9-76-003.

U.S.  EPA.   1984.   Rural  water survey.   Computer data provided by  Department
of Sociology, Cornell University, Ithaca,  NY.
00660                                IV-12

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                         V.  HEALTH EFFECTS IN ANIMALS
Acute Toxldtv
    Experimental  Lethality  Studies.   EndMn  1s  acutely  toxic  to  a  number
of  species  when administered  by  oral  gavage  1n  a  solvent, In  the  diet,  or
applied  to  the  skin  (Table V-1).   The  LD5Q  varies with the  species  and
strain  of  animal used.   An early  comprehensive  study of  acute  toxlclty  In
mammals  Included  Carworth rats (male  and  female of  two ages),  4 rabbits,  4
guinea  pigs,  1  cat  and  2 monkeys  (Treon  and  Cleveland, 1955).   Minimum
lethal  oral  doses  were:   monkeys, 1-3  ng/kg bw;  cats  and female  rats,  <5
mg/kg; male  rats. 5-7  ag/kg;  rabbits,  5-7  mg/kg;  and male  guinea pigs, 24-36
mg/kg.   These  data suggest  that  primates  are  one of  the most  sensitive
groups.  Signs  of   Intoxication Included ataxla,  tremors,  labored breathing,
diarrhea and tonlc-clonlc convulsions.

    The  oral LD..  of  endrln  for  6-month-old male Sprague-Dawley rats was
reported to  be  40  mg/kg bw by Speck and Maaske  (1958).  Groups  of 8-12  rats
were given single  doses  of endrln  (20-80  mg/kg bw)  In peanut oil  by  gastric
Intubation.  There  was a  latent  period of 45-60  minutes before  the  onset of
convulsions,   regardless  of  the  dose.   Deaths occurred  within  24-72  hours.
Gross examination  at autopsy  revealed  contracted  spleens,  congested  lungs,
and bright red blood,  along  with  reddened  livers  and viscera.  No hlstologk
changes  were apparent  In  sections  of  liver  tissue.   Electroencephalogram
recordings after acute doses  showed Irregular  slowing, Irregular  spikes, and
convulsive discharges.  The  righting reflex was not abolished during convul-
sions unless the attack was  terminal.  PentobarbUal  stopped convulsions but
did not  prevent  death.  Trypan blue (2 mt of  IX solution) given with 50 mg
endr1n/kg bw to  30  rats  prevented convulsions and  lowered  the death rate up


00670                               V-1

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                                  TABLE V-l
               Acute  Lethality of EndMn in Experimental Animals
LD5Q In mg/kg bw
Animal
Species

Rat, young3
Rat. adu1ta
Rat, adulta
Rata
Rata
Rata
Rata
Rat
Rata
Rata
House6
Mousef
House
Hamster
Hamster
Route of
Administration

oral
oral
oral
oral
oral
dermal
dermal
dermal
oral
oral
l.v.
l.p.
1.p.
oral
oral
Formulation
MAMMALS
peanut oil
peanut oil
peanut oil
20% e.c.b
2% f.s.d.c
20X e.c.b
W f.s.d.c

OHSOd
arachls oil
DHSOd
corn oil
methoxytrl-
glycol
corn oil
corn oil
Male

28.8
43.4
40.0
6.6
2.5
10.9
31.5
15-18
5.6
NR
2.3
5.6
8
12
NR
Female

16.8
7.3
NR
3.4
6.6
NR
92

5.3
5.3
NR
NR
NR
17.0
18.6
Reference

Treon et al.,
1955
Treon et al.,
1955
Speck and
Maaske, 1958
Mulr, 1968
Hulr, 1968
Mulr, 1968
Hulr, 1968
Galnes, 1969
Bedford
et al., 1975a
Bedford
et al., 1975b
Walsh and
Fink, 1972
Graves and
Bradley, 1965
Cole and
Caslda, 1986
Cabral
et al., 1979
Chernoff
et al., 1979
00670
V-2

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                              TABLE V-1 (cont.)
Animal
Species
Rabbit
Rabbit
Guinea pig
Dog
(mongrel)
Cat
Monkey

Pigeon
Mallard
Mallard
Route of
Administration
oral
dermal for 24
hours
oral
1.V.
oral
oral

1.V.
oral
percutaneous
Formulation
peanut oil
dry, 100 -mesh
powder
peanut oil
95X ethanol
peanut oil
peanut oil
BIROS
NR
corn oil
corn oil
1050 In mg/kg bw
Reference
Male Female
7-10 NR Treon et al.,
1955
NR 130-160 Treon et al.,
1955
369 169 Treon et al.,
1955
2-39 NR Reins et al.,
1966
5n NR Treon et al.,
1955
39 39 Treon et al.,
1955

1.2-2.0 1.2-2.0 Revzln, 1966
NR 5.64 Hudson
et al., 1979
>140 NR Hudson
et al., 1979
"CFE
 Emulsion concentration
cMeld strength dust
dD1methy1su1fox1de
eCarworth Farms No.  1  strain
 Swiss-Webster and ICR strains of Swiss albino mice
Estimated
 Minimum lethal dosage
NR - Not reported
00670
V-3

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 to 80 hours post -treatment.  All animals  given  endMn alone were dead at 200
 hours after  dosing and  -7% of  the trypan  blue-treated rats  survived.   No
 convulsions were seen In animals with  the chorold  plexus stained blue by the
 dye.   These observations  suggested  that  the   acute  reaction  may  Involve
 Increased  blood-brain  barrier  permeability and  that  the  concentration  of
 endrln had  to  reach a critical  level  In either the  blood or brain  tissues
 before convulsions  occurred.

    Graves   and Bradley  (1965)  calculated  an   10..  of 5.6  mg/kg  bw  for
 endrln In corn oil  Injected  Into the peritoneal cavity  of Swiss-Webster  and
 ICR  strains of Swiss albino mice.   No mortality  was  seen  In controls  (13
 mice)  or at dosages of  1 mg/kg (8 mice)  or  2 mg/kg  (8  mice).  Complete
 mortality was  obtained  with dosages  >10 mg/kg (8 mice).   Observations of
 survivors during an  additional  6-day period revealed no further mortality.
 Similar  observations have been  reported for humans when  Individuals survived
 the symptomatic stage (Curley et  al., 1970).
    Acute  l.v.  LOrQ  values and  median survival  times  (ST^) of  male  mice
(IQ/group)  exposed to endrln  were determined  to be 2.3 mg/kg  bw (2.0-2.6,
95X  confidence  limits), and 17.5 minutes (15.2-20.1, 95%  confidence  limits
at  a dose  of  3  mg/kg),  respectively  (Walsh  and  Fink,  1972).   Endrln  was
administered  In  OHSO.   At  an L09Q  (5  mg/kg),  the ST5_  was  11  minutes.
In  adult male mice (Cfl  strain), a latent period of no activity  that  fol-
lowed Injection ended abruptly with a  first  clonlc convulsion.  Intermittent
clonlc seizures ended with  the beginning of hind leg tonic activity.  Post-
tonic activity  Involved  continual clonlc seizures, which terminated In  some
00670                               V -4

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cases  in  death.  The dose  that  produced  ataxla 1n 50% of  the  mice  was 0.75
mg/kg  (0.59-0.98,  95%  confidence  limits).   The  authors   stated  that  the
mechanism of  tpxldty may  be  due to effects on plasma membranes or  mitochon-
dria! ATPases 1n the brain or both.

    When  endrln was  applied as  a 20%  emulsion,  acute  dermal LD5Q  values
for rats  were about twice  the  size of acute oral  ID,- values  (Nu1r,  1968).
When  endrln  was  applied as  a  field  strength  dust,   the  acute dermal  LD5Q
value was more  than an  order  of magnitude greater.   However,  both of  these
endrln preparations were more toxic than endrln administered In peanut oil,
showing  that  LD.g  values  are  vehicle  dependent.   Dermal  administration  of
endrln as  a  dry 100-nesh  powder  1n  contact  for  24 hours  under  a  rubber
sleeve  with  the  Intact  skin   of  female  rabbits  yielded  an acute  LO,Q
between 130 and  160 mg endrIn/kg  bw and  a minimum lethal  dose between  66 and
94  mg/kg  bw  (Treon  and   Cleveland,  1955).   Table  V-l  summarizes   these
toxldty data.

    Bedford et  al.  (1975a) determined the  acute  oral LD,Q values  (based  on
10-day mortality) for three  metabolites  of endrln  that have  been Identified
1n mammals  (Baldwin et  al..  1970;  Bedford et al., 1975a).   Each metabolite
was more  acutely toxic  than  the parent  pesticide  (Table  V-2).  Svn-12-hy-
droxyendMn and  !2-ketoendr1n were  about  5 times more toxic  than the parent
compound In male  rats;  1n  females,  12-ketoendrln was  5 times and syn-12-hy-
droxyendrln  2 times  more  toxic  than endrln.   AnU.-12-hydroxyendrln  was 2
times more toxic  In male rats and  equltoxlc  to endrln 1n females.   The  most
rapidly lethal  compound  was  12-ketoendrln; mortality  was observed  within  20
hours  of  administration  for  both  male  and female  rats.    Endrln  and  the
Isomers of !2-hydroxyendr1n produced mortality  In 4-6  days  In male rats,  and

00670                               V-5

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                                  TABLE V-2
            Median Lethal Doses 10 Days After Oral Administration
                    of EndMn and Its Metabolites to Rats*
                                     	L050	
          Compound
                                          Male                Female
    Endrln                           5.6 (3.0-7.9)          5.3  (3.6-7.4)
    antl-12-HydroxyendMn            2.4 (2.0-3.0)          5.5  (4.2-7.2)
    sj£-12-Hydroxyendr1n             1.2 (0.6-1.7)          2.8  (0.8-4.0)
    12-KetoendMn                    1.1  (0.7-1.5)          0.8  (0.5-1.2)

aSource: Bedford et al., 1975a
^Administered  by  gavage 1n  OMSO  to  CFE  strain rats,  12-14 weeks of  age,
 divided Into groups of either 4 or  8 rats  of  each sex
cNumbers 1n parentheses are 95X confidence  Units
00670                              V-6

-------
 5-8  days  1n female  rats.   The authors concluded  that  even though oxIdatWe
 metabolism  of  endrln  1s  responsible for the  observed  efficient elimination
 from  rats  of   subacute doses,  oxldatlve  products  of  endrln  may  also  be
 responsible for Us acute toxlcUy.

    LCSQs,  defined  as  the  dietary dosage  (dw)  required  to kill  50%  of  the
 test  animals  1n  a  specified  period  of  time,  have  been  reported  for
 short-tall shrews and Ulster rats (Table V-3).

    Environmental  and  Accidental  Poisoning.   The  meadow  vole  (Mlcrotus
 pennsylvanlcus)  1s   known  to  be  sensitive  to  endrln  as  evidenced  by  the
 virtual disappearance  of the  rodent population after  Us  habitat and  food
 supply  were sprayed  once with  endrln  (Wolfe et al.,  1963).  Panlcum  and
 canary  seed contaminated with  2.20-4.80 ppm endrln  caused  the  deaths  of  -320
 cageblrds (finches,  doves,  quails)  1n an  aviary.   Birds  began  dying  2  days
 after  Introduction  of  the  contaminated feed,  with the  greatest  number  of
mortalities occurring  after 5 days of  exposure.   No  gross   or  microscopic
 lesions were found  1n  12 necropsled birds  (Main, 1978).  Wild birds  such  as
 grackles, mallards and  white  pelicans  have also died of endrln Intoxication
 (Peterson and  Ellarson,  1978).   Two  bald  eagles  possibly died  of  endrln
 poisoning (Kaiser  et al.,  1980).   Brains  of  the  eagles  contained 0.71 and
 1.2 mg  endr1n/kg ww;  the known lethal range begins at -0.6 mg endr1n/kg ww.
Misuse  of endrln  In India was responsible  for the death  of one bullock and
 symptoms  of  acute  poisoning   In  three other  anlaals  (Pandey,  1978).  The
 bullocks were  treated  for  tick  Infestation with "concentrated1 endrln over
 their entire bodies.  Signs of  poisoning occurred after  6 hours.
00670                               V-7

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o
o
                TABLE V-3


Cndrln Short-Terra Oral Dietary
                                                                         Values
Species
Short-tailed
shrew




Rat. Ulstar
Rat. Ulstar
Sex/Age
F/180 days
N/105-150 days
F/105-150 days
M/30-75 days
F/30-75 days
N. F/1mmature
H. F/1mma.ture
Duration Number of
Animals
14 days 5
14 days 5
14 days 5
14 days 5
14 days 5
5 days 50°
5 days 50°
(ppm endrln In the diet]
174
87
152
87
152
60.1 (43-83)c
62.3 (45-85)c
Reference
!
Blus. 1978
Blus. 1978
Blus. 1978
Blus. 1978
Blus. 1978
HcCann et al. .
1981
HcCann et al. .
1981
             Dietary  dosage  (dw) required to kill SOX of test animals In a specified period of  time


     D5 male and  5  female/group/concentratlon; five concentrations


     C95* - Confidence  limit

-------
     EndMn  poisoning  was  reported 1n 15 of a herd of  70 Sa'anen adult  female
goats  after  they  had been  grazing  In an  uncultivated area  of  weeds later
found  to contain  endrIn-contaminated  boxes (Rapaport  et  a!., 1979).  Signs
Included  fits of  trembling affecting  the whole  body,  convulsions,  profuse
salivation  and  collapse  with  an Inability  to rise.   In most  cases  signs
subsided  within  a few Minutes  but resumed within an  hour or so.  Treatment
with   atroplne,   proplonyl   promazlne,   fluid   (saline   and   Ringers).
cortlcosterold   (prednlsone)  and  carbachol  was  not  effective.   Within  16
hours, 8/15 goats  died,  with 2 more dying In  the  next 24 hours.   Postmortem
examination  revealed  profuse  blood-stained  froth in  the  trachea,  diffuse
hemorrhaglc  enteritis,  some petcchlae  on the  eplcardlum,  adhesions  between
the  parietal  and pulmonary  pleurae and  Cysterlcerus  tenulcolUs  cysts In  the
abdomen,  with fluid  and  pale  Intestinal  contents.   Quantities  of  endr In
consistent  with  those found In poisoning cases were  found In the  content of
the rumen.

    Central  Nervous  System  and  Behavioral  Effects.   Sprague-Oawley rats
administered  single,  oral  endrIn doses  ranging  from 20-80  mg/kg  bw were
susceptible  to  convulsions,  which  were  sometimes   followed  by  catatonic
behavior  (Speck  and Naaske.  1958).  In  addition,  electroencephalograph  (EEG)
patterns  following endrln exposure  exhibited  Irregular slowing and  spikes,
and frequent convulsive discharges.

    EEG  patterns In  squirrel  monkeys  were examined  following Intramuscular
endrln exposures of  0.2 mg/kg  bw/day or  higher for  7 days,  and  the  results
were  summarized  In  an abstract   (Revzln,  1968).   Increased  amplitudes and
splklngs  In EEG recordings  were  observed  after  7 days of  exposure  at 0.2
mg/kg/day,  and  were  reportedly  more  narked  at   high   total   dosages.

00670                               V-9

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Following cessation of dosing,  EEG  patterns  remained abnormal  for  at least 1
month.

    Locomotor activities  were measured  1n  nonpregnant female CD-I  nice  and
CO  rats  2-4  hours  after a  single  endrln  exposure  by  gastric  Intubation
(Kavlock  et  al.,  1981).   Mice and  rats  were exposed to 0, 0.5, 1.5  or  4.5,
and 0,  0.5,  1.0  or  2.0  rag/kg  bw,  respectively.  Locomotor activities  were
significantly reduced at  the  two  highest  dose  levels In both  species, and at
0.5 rag/kg bw 1n rats, but not nice.

    Cardiovascular  Effects.    In  the  early  1960s,  little   was   known   of
cardiovascular changes following  acute exposure  to lethal amounts  of endrln.
Experiments with  male and female dogs to  Investigate  these   phenomena were
conducted on  30 dogs weighing  from 10-19 kg  (Emerson  et  al., 1964)  Anes-
thesia was Induced with  sodium  pentobarbltal (30 mg/kg) and,  In some cases,
sucdnylchollne was  given to prevent  convulsions.   Endrln (10  mg/kg bw  In
95% ethanol) was administered by  1.v.  Infusion.  Control animals received  an
equivalent amount of ethanol.  Convulsions started within 5-10 minutes after
the beginning of  endrln  Infusion  1n dogs not given  sucdnylchollne.   Obser-
vations  Included  bradycardla, an  Initial drop  In  arterial  blood  pressure,
Increased body  temperature,   hemoconcentratlon,  decreased  venous  blood   pH,
and  Increased  leukocyte  counts.   Hemolysls was seen  In  every post-endrln
hematocrU.    Cerebral  venous  pressure   and  cerebrosplnal  fluid   pressure
elevations were also prominent features of endrln poisoning.   Uhen  sucdnyl-
chollne was  given,  the results  were similar except that  arterial  pressure
Increased Initially  but   later  fell to  hypotenslve  levels.    Blood  pH also
00670                               V-10

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 decreased  more  and  hemoconeentration  was  more  pronounced.   In  controls,
 succlnylchoHne-lnduced  bradycardla  was  replaced  by  tachycardia   In  some
 animals.   The  heart  rate would then oscillate between bradycardla and tachy-
 cardia.  These authors concluded that most  of  the observed effects  appeared
 to  be caused by endMn  acting  directly  on the CNS, although some might have
 resulted secondarily from  altered cerebral hemodynamlcs.

    Endr1n-1nduced  convulsions  terminating  In  death  are  accompanied 'by
 marked  changed 1n  blood  pressure  and heart  rate.   Using SO  mongrel  dogs,
 Reins  et  al.   (1966)   determined   the  relationship   between   venous  return
 (cardiac  output),  total  peripheral   vascular   resistance  and  hypertension
 after a  lethal dose of  endrln.  All  animals were  treated  with sucdnylcho-
 Une  to  prevent  convulsions.   Endrln  (10 mg/kg  bw  In ethyl alcohol)  Induced
 a  rise   1n  systemic arterial  blood  pressure,  which  depended primarily  on
 Increased  cardiac output  caused by  an  elevated  venous return.   Increased
 levels  of  eplnephrlne  and  noreplnephrlne In blood  plasma, rather than CNS
 stimulation, may  be  the explanation  for  the narked  alterations  In  systemic
 hemodynamlcs.  Total  peripheral resistance  did  not  change  significantly  1n
 either  endr1n-1nfused  dogs  or  control,  animals  Infused with the  solvent.
 ethyl alcohol.   In a  similar  study  with dogs,  Hlnshaw  et al.  (1966)  also
 reported  large  Increases   1n  blood  catecholamlne concentrations,  and In-
creased  cardiac  output.    In  contrast to  the  Reins et al.  (1966) findings,
 these Investigators  reported  that  total  peripheral resistance  fell  signifi-
cantly and  that cardiovascular  alterations were  not significantly correlated
with  blood  catecholamlnes  after endrln  Intoxication.  One major  difference
00670                               V-ll

-------
between  the  two  studies  was that Reins et al.  (1966) used  sucdnylchollne to
prevent  convulsions;  anesthesia  was  achieved  with  sodium pentobarbltal  (30
mg/kg bw) 1n both studies.

    Renal  Effects.    Renal  function  and  hemodynaralcs  were  examined  In
mongrel  dogs  following acute and chronic exposure  to  endrln  (Reins  et al.,
1964).   In the acute  studies,  eight dogs  were exposed to lethal endrln doses
(10 ng/kg)  by Intravenous  Infusion  via the  femoral  vein,  and an additional
four  dogs  received  the  same  endrln  dose  by Injection  Into  the Intestinal
lumen.   Following  a  2-4  hour  examination  period,  Mstologlcal examinations
were   conducted.   Endrln   exposure   elicited  Increased  renal   vascular
resistance, decreased renal blood flow and  glomerular  filtration rate (GFR)
within  1-2  hours   of exposure,  although  marked  Individual   variation  was
noted.   Since  these  renal  alterations  could be  reversed by  treatment  with
phentolamlne, they  were  considered  to  result  secondarily  to  endrln-Induced
systemic hypertension and effects on  circulating  humoral  agents,  rather  than
from  a  direct   toxic effect  of  endrln   on the  kidney.   An Influence  of
exposure route on these renal effects was not stated.  However, convulsions,
hypertension and bradycandla,  which  developed  1n the  Intravenously  Infused
dogs,  did  not  occur   In  those  receiving endrln via  the  Intestinal   lumen.
Hlstologkally,   the  dogs  exhibited protein  precipitation  In  Bowman's  space
and  the renal   tubules,   and 1/12  dogs  developed   renal  tubular  necrosis.
Congestion, degeneration  and/or  swelling  were reported In  the spleen,  liver
and lungs,  whereas the heart, pancreas and Intestine appeared normal.

    Heoatlc Effects.   Oral  administration  of  endrln  (15  wg/kg/day)  for 3
successive   days  elicited   significant  (p<0.05)  elevations of  liver  total
llplds.  liver  trlglycerldes  and  serum cholesterol  In male  Sprague-Dawley

00670                               V-12

-------
 rats.  SGOT  but not SGPT  activities  were also  sightly elevated following
 endMn exposure tBorady et al.,  1983).

     Significant   elevations   In   hepatic   oxldatlve   demethylatlon   of
 dimethylnltrosaralne were elicited \r\ male Swiss  albino mice exposed  by oral
 gavage to  endrln  (2 mg/kg/day)  for  3  consecutive  days  (Hostafa  et  al.,
 1983).  The  effects  of  oral  endMn  exposure  on  IWer  mlcrosomal  P-450
 content,  ethylmorphlne  demethylase and  aniline  hydroxylase activities  In
 pine voles and ICR white  mice  have also been  reported (Hartgrove  et  al.,
 1977).  A  single dose of O.S or  2.0 mq/kg bw was administered to pine voles,
 whereas mice  received a single dose of 4.0 or 10.0 mg/kg bw.  The period of
 time between dosing and  sacrifice  was  not  reported.   Aniline  hydroxylase
 activities  were  elevated  In both  pine  voles   and mice  following   endMn
 exposure.   EndMn elicited a decrease In  ethylmorphlne demethylase activity
 1n  pine  voles,  but  an  Increase  In this  activity In  the  mice.  An elevation
 In  total cytochrorae P-450 content was elicited In mice, but not pine voles.

     Female  guinea pigs  were chosen for a  study  of the effects of  endMn on
 hepatic and renal mlcrosomal  electron transport because of their  sensitivity
 to  the  toxic  effects  of  the  pesticide  (Pawar  and Kachole,  1978).   Six
animals (600-650 g) were Injected  1.p. with endMn  (3 mg/kg bw/day  In safola
oil)  for  3  successive  days; six control  animals  were Injected with  an
equivalent  amount of oil.  Hlcrosomes were  prepared from liver  and  kidney
tissue 24  hours  after  the third  Injection.   The  liver  weights  of endrln-
treated  animals   were  Increased   and   mlcrosomal  protein  content  was
decreased.   Kidney weight was elevated,  but renal mlcrosomal  protein was not
affected.      Decreased    hepatic   mlcrosomal    HAOPH-llnked   amlnopyrlne


00670                              Y.-13

-------
N-demethylatlon  was  attributed  to  decreased  levels  of  cytochrome  P-450.
Endrln    treatment    Increased   Vn    vitro    NADH-med1ated    amlnopyMne
N-demethylat1on  In  renal  mlcrosomes.   A  significant  Increase  In  I1p1d
peroxldatlon  1n  hepatic mlcrosomes was  evident  when NADPH or  ascorbate  was
the electron donor.

    Four  chlorinated  hydrocarbons  Including  endrln were  tested for  their
possible  Interference  with  heme  synthesis  In  Japanese  quail,  a  species
chosen because of  high sensitivity to chlorinated organic: as  determined  by
urinary  porphyMn  concentrations  (NagelsmU et  al.t  1979).   There was  no
Indication that endrln  was  porphyrlnogenlc  (1-3  or 5 mg/kg  bw/day for 3 days
given orally  In a  capsule), which  suggested  that  urinary porphyMn would  not
reflect endrln exposure In exposed humans.

    Effects of acute endrln exposure are summarized  1n Table V-4.

Subchronlc Effects  of Endrln
    Maternal   body-weight  and I1ver-to-body  weight   ratios were measured  In
two  studies   concerning perinatal  endrln  toxlclty   In hamsters,  rats and
mice.  Endrln was  administered  orally  to golden  Syrian  hamsters on days 4-15
of pregnancy,  1n  single dally  doses  of 0,  0.75, 1.5,  2.5  or  3.5 mg/kg/day
(Chernoff et  al.,  1979).   Doses >1.5 mg/kg/day produced maternal  lethality,
which  was preceded  by significant  weight  loss.    Neither   lethality nor
effects on maternal weight  were  elicited at 0.75 mg/kg/day.

    Endrln was administered orally  1n  single dally  doses  to CD rats  on days
7-20  of  gestation, and to  CD-I  mice on days  7-17 of gestation  (Kavlock et
al.,  1981).    Doses  of 0,  0.075,  0.150,  0.300 or  0.450  mg/kg/day  were
00670                               V-14

-------
                                                                  1AIII «-«

                                                       iffectt of  Acute fndrln tiposure
o
0
-J
o















1

I/I













Species/
Strain
Bogs/mongrel


Bogs/mongrel


Bogs/mongrel





Rat Spraguo-
Bawloy

Nice/Swiss
albino

NIce/ICR iditte


Voles/pine



Guinea pigs/
strain not
stated
Ntce/CB-1


Se«/
Mumber
male, female


gender not
stated/50 dogs

gender not
stated/S-7
experiments:
number of dog*
not clearly
stated
mile


•lie


gender not stated/
4-11 mice per
treatment group
gender not stated/
14-18 per treat-
ment group

feMle/i group


female


Dose/
Route I xposure
t.v. Infusion 10 mg/kg


t.v. Infusion 10 mg/kg. In
presence of
succlnylchollne
t.v. Infusion 3 mg/kg





oral IS mg/kg/day for
3 successive
days
oral ? mg/kg/day for
3 successive
days
oral 4.0 and 10 mg/kg/
bw. single dose;
tin* until sacrl-
oral O.S or 2.0 mg/kg
bw single dose;
tin* until sacri-
fice not reported
I. p. 3 mg/kg/day for
3 successive days

oral Intubation 0. O.S. l.S or
4.S mg/kg bw.
single dose
Comments
Convulsions, bradycardta. arterial blood
pressure fall, elevated body temperature.
hemolysts and other hemotologtcal changes
Arterial blood pressure Increase.
decreased heart rate

Increased cardiac output and Increased
blood catecholamlnes. fall In total.
perlpheal vascular resistance



ilevated total liver llplds. liver
trlglycerldes. serum cholesterol and
slightly elevated SG01
Increased oildattve demethy lat Ion of
dtmethylnttrosamlne

Increased hepatic cylochrome f-450
content, aniline hydroxylase and
ethylmorphlne demethylase actlvtles
Increased hepatic aniline hydreiylase
activity, decreased ethylmorphtne
demethylase activity

••created hepatic cytochrome P-450
and amlnopyrlne H-demethylatlon.
Increased liver weight
Reduced locomotor activity at l.S and 4.S
mg/kg bw

Reference
Emerson et al.. 19M


Reins et al.. 19M


Htnshaw et al.. 1944





•orady et al.. 1983


ftostafa et al.. 1983


Hartgrove et al.. 1977


Hart grove et al.. 1977



Pawar and Kachole. 1978


Kavlock et al.. 1981


Rats/Ct
Monkeys/Squirrel
                  fenale
                  3. gender  not
                  stated
oral Intubation
Intramuscular
0. O.S. 1.0 or
7.0 or 4.0
•g/kg bw. single
dose

0.? mg/kg/day for
7 days
Reduced loconotor activity at all
exposure levels
                                    Increased amplitudes  and spiking In  lit
                                    recordings
                                                                                                                      Kavlock  et  al..  1981
                                            Rev*tn. 1968

-------
administered  to  rats;  doses of 0,  0.5,  1.0,  1.5  or 2.0 mg/kg/day were given
to  nice.   Results  from  the range  finding  study  are reported  In  Table  V-4.
Mice  and  rats  were killed  on days  18  and  21  of  gestation,  respectively.
Fetal  mortality, weight,  degree  of  skeletal and  visceral maturation,  and
Incidence  of   skeletal   and  visceral  anomalies   showed   no  dose-related
effects.  Maternal  weight  gain was significantly reduced In rats  exposed  to
0.300  mg/kg/day  (p<0.01) and  markedly  reduced at  0.450 mg/kg/day, but  did
not  differ   from controls  at 0.75 or  0.150 mg/kg/day.   Neither  maternal
deaths  nor   elevations  1n  Hver-to-body  weight  ratios  occurred  1n  exposed
rats.  Elevated  I1ver-to-body  weight ratios were  reported  In  the mice  at  all
exposure levels, and maternal  lethality occurred at doses >1.5  mg/kg/day.

    HepatoblHary  function  and  hepatotox1c1ty have  been  assessed In rats
d1etar11y exposed  to endrln  (Young and  Mehendale, 1986).  Treatment  groups
of  six male  and  six female Sprague-Dawley rats  were  given a  powdered chow
diet  containing  0,  5 or  10  ppra  endrln for  15 days.  The total  endrln doses
for  the  15   days   of  exposure  (and  the  corresponding  dose  expressed  as
mg/kg/day)  were  7.4*1.1  mg/kg   (0.5  mg/kg/day)  and  14.2^0.9  mg/kg (0.9
mg/kg/day)  for  males;   the  female  endrln  doses  were  7.4*0.4  mg/kg (0.5
mg/kg/day) and 12.8+J.8  mg/kg  (0.9  mg/kg/day)  for  5  and  10 ppm, respec-
tively.   On  day 16,  heptatotoxldty 1n  all  animals was  assessed by serum
enzymology,   and  hepatoblHary function  was  assessed  by  measuring biliary
flow rates and excretion  rates of phenolphthaleln  glucuronld*  (PG).

    Serum  enzyme  levels  were  not significantly  elevated  In  the  endrln
exposure groups.   In males  exposed to  5 ppm  endrln,  PG excretion and bile
flow  rates were  reduced  to  66 and 68% of control levels,  respectively.  At


00670                               V-16

-------
10  ppm,  PG  excretion  was  reduced  to  75X  of  control,  but  no  significant
change  1n bile flow rate was  observed.   In  females exposed to 5 ppm endrln,
the  rate of PG  excretion  was 10% higher  than control, whereas  the  rate of
bile  flow was  not  significantly  different  than control.  At 10 ppm, rates of
PG  excretion  and  bile  flow  were  elevated  to  30% and  25X  above  control
levels,  respectively.    It  was  concluded  that endrln  had a  sex-dependent
effect on  hepatoblHary function.

    In  the only  reported subacute study Involving  dermal  exposure  (Treon et
al.,  1955),  three  female rabbits/group were exposed  to  100-mesh,  dry endrln
powder  75 or 150 rag (equivalent  to  67-91  rag/kg bw/day at  the  high-dose  and
20-42 mg/kg  bw/day at  the  low-dose)  under  a rubber  sleeve 2 hours  dally,  5
days/week.   In the  high-dose group  the rabbits died  after  19,  19 and  25
applications.  At the low-dose 1  of 3 died after the 40th application.

    Subchronlc and  chronic  endrln toxldty were evaluated  1n Carworth  rats,
beagle dogs  and an unspecified species  of  rabbit (Treon et  al., 1955).  Four
of  five  female rabbits  that  were orally  administered  1 mg/kg/day endrln  5
days/week  died during  the  10-week exposure  period.   Mortality occurred  1n
3/3 male  rats  after  oral administration  of endrln at  5  mg/kg/day.   Mortality
occurred  In  2/5  females but  no  deaths  occurred 1n  males at the  2  mg/kg/day
dose  level.   All treated animals  developed  hypersens1t1v1ty  to  stimuli  and
weight  loss  but generally  male   rats  were less affected  than female  rats.
Height gains 1n  groups of 20 male and  20  female rats (Initial age 28  days)
given diets  containing 0, 1,  5,  25,  50  or  100 pom endrln for  20 and  40  weeks
were  also  reported.   In 5  ppm males,  weight gain  was  significantly  reduced
at  20 but  not 40 weeks  of  exposure.   At 25  ppm, significant weight gain


00670                               V-17

-------
 reduction  was  observed at both 20  and  40  weeks.  In contrast, female weight
 gain  was  significantly elevated at >5  ppm  following both  20 and 40 weeks of
 exposure.

    Beagle  dogs  were  administered diets  containing  4-50  ppm endrln  for
 periods  ranging  from -1-10 months.  Mortality occurred at  exposure  >5  ppm.
 After  -6 months  of  exposure  to  4 ppm, the  I1ver-to-body weight  ratio  was
 elevated,  and  liver-, kidney- and  brain-to-body  weight  ratios were elevated
 In  dogs  exposed to  8  ppm.   Dogs  that  died during  endrln  exposure  exhibited
 degenerative  lesions  In  brain,  heart,  liver  and   kidneys.  In addition  to
 pulmonary  hyperemla  and  edema.  The  renal  damage  was particularly  severe
 (Treon et al., 1955).

    Sprague-Oawley rats  were  fed  diets containing  various  concentrations  of
endrln for  up  to 16  weeks (Nelson  et al.,  1956).  The  endrln concentrations
were 0, 1,  5,  25,  50 and 100  ppm, and  were administered to groups of  10 rats
 (5  of  each  gender).   Mortality occurred within  4 weeks  1n  males and  females
 fed concentrations >5 and 25  ppm,  respectively.   For the 100 ppm group, this
mortality was  100X.  After 16  weeks, some mortality  had  occurred  In all male
exposure groups, but  only 1n female groups  exposed to >25 ppm.

    Dose-related weight  loss   was  reported  1n  animals  exposed  for up to 8
weeks.   Serum  alkaline  phosphatase  was consistently   elevated  froa weeks
10-16 among  survivors  fed  25  or 50 ppm; this  elevation  occurred but was not
persistent  at  the  lower  exposure  levels.    HypersensHlvHy to various
stimuli was  reported at  all   exposure  levels, but  was  most  pronounced and
followed by  convulsions  at the higher  (25-100  ppm) exposures only.   These


00670                               V-18

-------
 animals   also   exhibited   dysenteric   symptoms,   Intermittent   blindness  and
 slight  nasal  bleeding.   The nasal  bleeding  also occurred In the 1 and 5 ppm
 exposure   groups.    The   latency   to  hypersens1t1v1ty,   nasal  bleeding,
 dysenteric symptoms and blindness was  not reported.

    Endrln  (3.5 mg/kg bw/day)  was  administered  to groups  of  male Sprague-
 Dawley  rats  by oral gavage 5 days/week  for  periods ranging from 1 week to 7
 months  (Speck   and  Maaske, 1958).   After  1  week of exposure,  4/30  animals
 died.    Surviving   animals   exhibited   an   elevated   respiration   rate,
 excitability or Irritability,  and  were  predisposed to  convulsions following
 auditory  stimulation.  Irregular  EEG recordings were also observed following
 1 week of exposure.

    EEG changes were  minimal 1n  the chronic  groups.  However,  after 3 months
 of  exposure,  livers  appeared  spotty with zones  of basophlllc  cells  around
 the  central  and  portal  veins.   Furthermore,  plasma  specific  gravity  was
 significantly reduced following 3 months of  endrln  exposure; this effect  was
 reversible upon discontinuation of endrln exposure.

    Cattle and  sheep  were  not  affected by 5  ppm  In  the  feed Ingested  over  a
 112-day period  (Radeleff,  1956).  Chickens (7 days  old)  were not made  excit-
able by a  ration  containing 1.5 and 3 ppm endrln for 42  days.   This was  not
 so  for  concentrations of  6-12 ppm  endrln;  decreased weight gains  were also
 shown at these concentrations (Sherman and Rosenberg, 1954).

    Feeding studies  were  conducted  to estimate the maximum tolerated  doses
of  endrln 1n  Osborne-Hendel  rats  and  B6C3F1   mice for a National   Cancer
00670                               V-19

-------
Institute  study  of cardnogenlclty (NCI, 1979).   EndMn  was  first dissolved
1n acetone  and  then added to  the  feed.   Corn oil was added  to  all  feed (2%
of final weight  of  feed)  as  a dust suppressant.  Five males and five females
were given  food  with or without endrln  for  6 weeks, followed by observation
for 2 weeks.

    For  rats,  endrln was added  to the feed  In 2-fold  Increasing concentra-
tions, ranging from 2.5-80  ppm (NCI, 1979).   There  were  no deaths at  10 ppm
and mean weight  gains  were  not  different  from controls.   At  20  ppm,  one
animal of  each  sex died, but weights of  survivors were  not  significantly
affected.   In  the  same  1979 NCI  subacute  study, mice were  given  feed
containing from  2.5-20  ppm endrln.  At  10 ppm, 3 males  and 4  females died In
the group of 10  mice.   No mortality  occurred In the 5 ppm group; mean  weight
gains were  comparable  with  that of  controls.  In these  subacute  exposures,.
Increased  mortality   was   the  only   toxic  effect  reported  other   than
hyperexc1tab1l1ty In male mice receiving >5 rag/kg diet.

    Effects of subchronlc endrln exposure are summarized  In Table Y-5.

Chronic Effects
    In a series  of  experiments,  Treon et al.  (1955)  explored the  effects of
endrln 1ngest1on 1n a  number  of  species  Including  rats, rabbits and  dogs.
Included 1n  this study was the  only  report found of an  Inhalation  exposure
of animals  to  'vapors'  of  endrln  (Table V-6).   No  convulsions were  reported
among this  group of animals.   Pathological  findings were similar to  those
observed following other routes of  administration.
00670                               V-20

-------
                                                                   UBlf  V-S

                                                     fffects of Subchronlc  fndrln Iipoture
Species/Strain
Rabbit/not
stated
Rat/Carworth
Rat/Carworth
Rogs/beagle
Sex/Nutter
Route
f/S oral
H/t and f/S oral
M/20 and f/20 oral
15 total animals oral
Dose/E xposure
Regimen
1 mg/kg/day. S
days/weeks for
10 weeks
2 mg/kg/day
dteti contained
0. 1. 5. 25. 50
or 100 ppm endrlii
for 20-40 weeks
dtots contained
4-50 DOM endrln
for 1-10 Months
Comments
4/5 rabbits died
2/5 female rats died; no deaths In Mies
Reduced weight gain In rats exposed
at >$ ppm.
Mortality In some animals >5 pom.
Elevated liver -to -body weight ratio
at 4 OP*, elevated liver-, kidney- and
Reference
Ireon ot al.. 1955
Treon et al.. 1955
Ireon et al.. 1955
Treon ot al.. 1955
Rabbits
3f/group
Rats/Sorague-     N/5 and f/5
Oawley
Rats/Sorague-
Rawley
                                    derMl
                   oral
 Rats/Osborne
 Nendel
H/5 and f/5
oer' group
                   oral gavage
oral
                20-4? or  »7-91
                •g/kg/day
                2 hours/day.  5
                days/week for up
                to 0 weeks

                dietary eiposure
                at 0. 1.  5. 25.  50
                or 100 ppni for up
                to It weeks
                3.5
                5 days/week for
                1 week to 1 Months
diets contained
0. 2.5. 5. 10. 20.
40 or RO pp* for
t weeks, followed
by 2 weeks of
observation
                     brain-to-body weight  ratios  at  0 ppe.

                     Mortality In both eiposwo'groups after
                     19-40 applications.
Mortality In SOON Male rats In all
exposure levels and In females exposed
to >25 ppa.  Nasal bleeding In 1 or 5 ppm
exposure groups.  Height loss, elevated
seruo) alkaline photphatase. dysenteric
symptom and Interoilttent blindness.

4/30 died after 1 week of exposure.
abnormal 116 patterns In survivors.
After 3 months exposure, spotty livers
with tones of basophlllc cells, reduced
plasma specific gravity.

No deaths or weight gain effects at
<10 PPM.  Mortality occurred at 20 op*.
weights of survivors were unaffected.
                                            Treon ot al.. 1955
                                                                  Nelson et  al..  1956
                                                                  Speck  and Maaske.
                                                                  195R
NCI. 1919

-------
                                                                        1ARII V-S fcont.)

                                                               fffects of Subchrenlc fndrln Exposure
Species/Strain
Htco/RtC3M
Sex/Number
N/5 and f/5
Route
oral
Pose/E xposure
Regimen
diet contained
Comments
Ho deaths or weight gain effects at
Reference
NCI. 1979
          Hamsters/golden   20-3W  per
          Syrian            exposure group
                  oral
          Rats/CD
15-30* per
exposure group
oral
i
is*
          Mice/CIO
20-MF per
exposure group
oral
          Rats/Sprague-
          Oawley
H/» and F/
per group
oral
0. ?.5. 5. 10 or
20 ppm endrtn for
4 weeks, followed
by 2 weeks of
observation

single dally doses
of 0. 0.75. 1.5.
2.5 or 3.5 mg/kg
bw were adminis-
tered to pregnant
hamsters on days
4-15 of gestation

single dally doses
of 0. 0.075. 0.150.
0.300 or 0.450
mg/kg bw were ad-
ministered to preg-
nant rats on days
7-M of gestation

single dally doses
of 0. 0.5. 1.0. 1.S
or ?.0 mg/kg bw
were administered
to pregnant mice
on days 7-17 of
gestation

diets contained
0. 5 or 10 pom
endrln for 15 days.
Approximate corre-
sponding mg/kg/
day doses were 0.
0.5 and 0.9. res-
pectively
                                                                                    1.5 mg/kg/day.
                                            Chernoff et al.. 1979
Depressed maternal weight gain at 0.300
and 0.450 mg/kg bw.
Kavlock et al.. 1981
Lethality and/or depressed maternal weight
gain at doses >1.0 mg/kg bw/day.  Elevated
liver-to-body weight ratio at all
exposure levels.
Altered hepatoblllary function which
was se«-dependent.
Kavlock et al.. 1901
Young and Nehendale.
198b

-------
                                   TABLE V-6
    Mortality of Animals Exposed to 0.36 ppn (5.62 ng/m»)  Endrln '
Species
Cat
Guinea pig
Hamsters
Rats
Rabbits
Mice
No. of
Exposure
(days)
130
130
101-130
130
118
107
No. Dead/
No. Exposed
0/1
0/2
0/2
0/3
2/4
1/3
Dally Inhalation
Volume
(ii' /day)
0.15
0.074
0.037
0.26
1.6
0.05
vg Endr1nc
(7 -hour day)
0.25
0.12
0.061
0.43
2.6
0.082
aSource: Treon et al., 1955
^Exposed by Inhalation 7 hours/day, 5 days/week for 185 days
cThe original  paper does  not  provide any weight  data for these  species  In
 these experiments.
00670
V-23

-------
    Treon  et  al.  (1955)  fed  groups of 20  male and 20  female  Carworth rats
diets  containing  0,  1,  5,  25,  50 or  100  ppm endrln  for  2  years.   Rats
receiving  50  or  100  ppn  exhibited hypersensUWHy  to  external  stimuli,
occasional convulsions  and liver degeneration.   In  addition,  after  80 weeks
of  treatment,  Increased mortality  1n rats  was noted at 25, 50 and 100 ppm in
males  and at  50  and  100 ppm  1n  females.    Effects  on  body weight  were
reported  at  20 and  40 weeks.   Females at 5 and  25 ppm appeared to  have  a
greater rate of body weight gain than controls,  while  body weights  In males
appeared  to be slightly depressed  at these levels.   At >50 ppm, rats of both
sexes  appeared  to have a slightly  Increased  rate  of body weight gain,  but
since  mortality was high  In  these  groups,  the survivors may  have  been  the
larger  rats.   Hales at  5 and  25  pom had  Increased relative  liver  weights
compared with controls, while rats at 1 ppm were not different from controls.

    Treon  et  al.  (1955)  also conducted a  study with  beagle dogs  1n  which
groups  of 1-4  were  fed   diets  containing  0-50  ppm  endrln  for  up  to  18
months.   All  dogs  fed 10-50  ppm  (0.49-4.00  mg/kg/day) died,  and  >50*  of
those  fed 5-8  ppm  (0.20-0.65  mg/kg/day)  died.   Actual  endrln  Intakes were
reported  by  the  authors.    All  dogs receiving  <4 ppm  (0.15-0.21  mg/kg/day)
survived, but growth was  affected  1n the 4 ppm groups.   The 3 ppm (0.12-0.25
mg/kg/day) group  had significantly higher  relative  kidney  and  heart  weights
than  controls.   Dogs  fed  1  ppm  endrln  were  similar  to  controls  1n  all
parameters, Including  gross  pathology and hlstopatholoqy.  According  to  the
authors,  the  dogs  (two males  and  two  females) on  the  1  ppa  diet  actually
consumed 0.045-0.120 mg/kg/day.

    In  a  2-year  dog  study,   beagle  dogs   (7/sex/group)  received   diets
containing 0,  0.1,  0.5,  1.0,  2.0 or 4.0 ppm endrln for >2 years  (U.S. EPA,

00670                               V-24

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 1987).   Interim  sacrifices  (2  dog/sex/group)  were  performed at  6 and  12
 months.   Parameters  monitored  Included  growth,  food  consumption,  behavior,
 serum  and urine  chemistry,  organ  weights  and  hlstopathology of all  major
 organs.   Animals  treated  at  the  2 and   4   ppm  dose  levels  experienced
 convulsions,   slight   Increase   1n   relative    liver   weights,   and   mild
 hlstopathologkal  changes  1n liver  cells.   Because of  the  effects  observed
 1n  the  dogs  consuming diets  containing  2 ppm  endrln  (0.05  mg/kg/day),  this
 level was  considered the  LOAEL.   No adverse  effects  were observed  In  dogs
 receiving  diets   containing  <1   ppm  endrln.   Therefore,   1   ppm  (0.025
mg/kg/day) was considered the NOAEL.

    Renal function and  hemodynamlcs were examined  1n  mongrel  dogs  following
acute and chronic exposure to endrln  (Reins et al.,  1964).   In  the  chronic
study,  five  female   dogs  were  given  endrln  (1  mg/kg)  by  Intramuscular
 Injection 5  days/week until  death or sacrifice.   Results concerning renal
function were  reported  as Inconclusive  due  to marked  Individual  variation,
and  hlstologlcal  evaluation  of  the  renal   tubules,  as well  as  the brain,
pancreas, heart  and  Intestines, showed  no  definitive  pathological  changes.
However,  chronic   endrln  exposure   elicited   congestion  and   occasional
hemorrhage In the lungs,  and  adrenal I1p1d depletion and congestion.

    Oelchmann  et   al.  (1970)  conducted   a   chronic  study  for  the   primary
purpose of providing Information  on the  possible carclnogenldty of  endrln.
aldrln  and dleldrln.  Carcinogenic  outcomes  of  chronic studies are  reported
1n  the  Carclnogenldty  section.   Endrln  dissolved  1n  corn oil was added to
ground  Purina rat chow and administered to Osborne-Hendel rats  (SO males and
50  females)  at 1,  3  or 6  ppm for  10 weeks and at 2, 6 or 12 ppm  until death


00670                               V-25

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or  31 months.   There  was  no  significant  effect on mean body weight or weight
gain  In  endrln-treated  rats.   Two hundred rats  (100/sex)  were  fed an uncon-
tamlnated  diet.  No  mention  was  made  whether  corn  oil  was  added  to  the
control  diet.   Signs  of  toxldty  observed  during the course of  the experi-
ment  were  limited  to   episodes   of   tremors  and  clonlc  convulsions  with
•outcries.1  These  signs  were  dose related; however,  the  statement  was  made
1n  general  for all  three Insecticides.   The  mean  survival  rate  for  12  ppm
endrln-treated  male rats was  17.6+6.9 months,  and  for  2 ppm  treated rats,
18.U4.9 months; mean survival for control  rats  was  19.7+4.8 months  (statis-
tical analysis  not reported).  The  mean survival  of  female rats was about
the  same  or  slightly  longer.   Liver-to-body weight ratios were  not  signifi-
cantly different from those observed  1n  control  animals.   H1sto1og1c changes
In  the  livers   of  rats  fed endrln  (2, 6 or  12 ppm)  were similar  to  those
receiving the  control diet with  the exception of a moderate  Increase  In  the
Incidence of  centrllobular  cloudy swelling;  there was also  an  Increase  1n
cloudy swelling of the renal  tubular  epithelium.

    Male and female Osborne-Hendel rats  (24/group) were fed  diets containing
0, 0.1, 1, 5,  10 or 25  ppm endrln  for 2  years  (Reuber, 1978).   Although  this
study  was intended  to  be  a  cardnogenlclty  bloassay,  data on the total
Incidence  and  severity   (none,   mild,   moderate  or  severe)   of   chronic
Interstitial  nephritis  that  developed 1n  both  control and  exposed  groups
were also reported.  There appeared to be a  trend  toward  Increased Incidence
and  severity  of nephritis with Increasing  endrln exposure, particularly  1n
the  males  exposed  to >1  ppm.  The  author  concluded  that  endrln  exposure
Induced  dose-related  Increases  In  the  Incidence  and severity  of  chronic
00670                               V-26

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nepnritls  1n the males.   However,  statistical  evaluation of  these  data was
not  reported,  and such an evaluation  appeared  necessary  In  order to justify
this  conclusion.

    The  NCI  (1979)  conducted  a chronic  study  with Osborne-Mendel  rats and
B6C3F1 mice  to  determine  the  possible  carclnogenldty  of  endrln.  EndMn was
added  to feed as described  1n subacute effects.  Fifty  animals  of  each sex
constituted  a treatment group  of  rats  or  mice.   Ten animals  of each sex were
matched  controls and  data  from 40  or  50 untreated  animals  from  similar
bloassays were pooled for statistical evaluation.

    Groups of  rats  (100 each)  were  administered one of  two  doses  of  endrln
for 80 weeks (NCI,  1979),  and  then observed until  survivors  were sacrificed
at  110-114  weeks.   Hale   rats  received  2.5  or  5  ppm endrln  In the  diet.
There was neither a  significant effect  on  mean  body  weight nor a significant
dose-related  trend   In  mortality.  Clinical  signs  usually  associated  with
aging  were  observed  earlier  In  dosed  rats  than  1n  controls:   alopecia,
diarrhea, eplstaxls, tachypnea, pale mucous membranes, hematurla, rough  hair
coats and dermatitis.  Thyroid  hyperplasla  and  pituitary  cysts  were  observed
1n exposed animals,  but not  In matched controls.  However,  the  spontaneous
occurrence of these lesions In  aged Osborne-Hendel rats was described  as not
uncommon.   Testlcular  atrophy  was  reported  1n  8/42  and  14/45  low-  and
high-dose rats, respectively;  none was  reported  1n matched controls.

    Mice were  administered  endrln  In  the diet  for 80  weeks  and  observed
until sacrifice at 90-91 weeks.  Initial doses  of  2.5 or  5 ppm were  not  well
tolerated by male mice and were reduced to  1.2  and 2.5  ppm (NCI,  1979).   The


00670                               Y-27

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TWA  was  calculated to be 1.6 and 3.2 ppn.   Female mice  were  kept  at  the  2.5
or  5 ppn  level.   Mean body weights  were similar to  corresponding  controls
and  there  was no  dose-related  trend  1n mortality 1r  female  mice.   Survival
was  decreased In high-dose male mice;  a large number of  the low-dose  males
died following the accidental overdose  at  66 weeks and survival  could not be
determined.    Before  the  overdose,   clinical   signs   Included   alopecia,
diarrhea,  eplstaxls,  rough hair coats,  tachypnea,  hematurla  and  discolored
urine.   After about  4  months, all  of  the high-dose  male   group  appeared
hyperexdtable,  and  doses  for  males   were  lowered  as  Indicated   above.
Lowering the  dose  did  not  change the  hyperexdtable  behavior  In  the majority
of  the  group.   In  the  last half  of  the  first year,  clinical signs were
apparent  1n  both  sexes:   abdominal  distension, alopecia   and  rough hair
coats.   Because  of  an  error  at week  66, excessive  amounts  of  endrln were
given  to   the   1.2   ppm  dosed  male  mice  which   caused   animals   to   be
hyperexdtable until  termination.  Researchers determined  that a rather fine
line exists  between  endrln levels  causing CMS  toxldty and  those  virtually
nontoxlc.

    KreHzer  (1980)  determined  whether  behavioral effects would be produced
by endrln  at levels  below those that  produced overt  signs of Intoxication.
Adult male bobwhlte quail, Collnus vlrqlnlanus. were  fed  endrln  dissolved  In
propylene  glycol  and blended Into  feed at  levels  of 0.1 and 1.0 ppm.   An
equal amount  of  propylene glycol was added  to the  feed of controls.  There
were four controls and four birds at each  treatment  level  for all  tests that
measured  performance  on  nonspatlal  discrimination  reversal  tasks.   Birds
were dosed (beginning at the age of 3 days)  for  138,  185 and  240 days before
Tests 1,  2 and  3,  respectively.   The  fourth test  began  after  267 days   of


00670                               V-28

-------
 aoslng  followed  by 25  days  of  untreated feed, and  the  fifth  test  after  278
 days  of  dosing followed by 50 days  of  untreated  feed.   EndMn-treated birds
 made  from 36-139% more errors  than  did controls  (p<0.025).   The  difference
 between  acquisition  error  scores of  controls and  treated birds  Increased
 exponentially  over  the  first four tests.  The 0.1 ppm  diet  dosed  birds made
 significantly  more  errors  than the 1.0  ppm  birds  after  reversal  of black  and
 white  patterns used  for  discrimination to receive  a  reward.   There  was  no
 explanation for  this  effect.   Endrln effects  were reversed  after  50 days  of
 untreated  feed.   The principal  effects of endrln was  to Impair  the  birds'
 ability  to solve  a novel problem.   Mean brain  residues In  endrln-treated
 birds were  0.075  mg endMn/kg ww for the 0.1   ppm  dose  and 0.35  mg  endrIn/kg
 ww for the 1.0 ppm dose.

    Jager  (1970)  published   an  extensive  review of   the  epidemiology  and
 toxicology  of  long-term exposure to aldMn,  dleldrln,  endrln  and  telodMn.
 In  a  discussion  of endrln  toxldty  1n animals,  Jager  concluded  that even
 though endrln  1s  a  stereolsomer  of dleldrln,  1t differs  from dleldrln  In the
 following  respects:   higher  acute toxkHy, more rapid  metabolism, and less
 persistence 1n vertebrates.   The  endrln LD5Q varied  with  the  vehicle  and
 experimental species  used,  endrln being  4-5  times  more  acutely toxic than
dleldrln.  The dietary NOEL for  endrln  In chronic  feeding studies  In the rat
and the dog was 1 ppm endrln  1n  the diet.

The effects of chronic endrln exposure are summarized 1n Table  V-7.

Teratoqenldty and Reproductive  Effects
    Mammals.   Two  studies  of endrln  toxldty 1n  rodents were conducted  1n
 the 1960s  at  doses  that were toxic to  the mother.   Endrln  was added  to the

 00670                              V-29

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                                                                             IARIE v-?

                                                        Summary of  Oral Chronic Effects  After fndrln (xpoture
o
o
Species/Strain
Rats/Carworth
Sex/Hunter
MU/S-20
per group
Dote/I iposure
Regimen
diets contained 0,
1. 5. 2S. SO or 100
ppm endrln for 2 years
Comments
Mortality at >2S ppm. Elevated liver-
to-body weight In males exposed to >S ppm.
lesser but nonsignificant elevations at
1 ppm In males, and 1-5 ppm In females.
Reference
Treon et al.. 19SS
           Dogs/beagle
           Rats/Otborne-
           Hendel
M/50 and f/SO


N/SO and F/50
           Rats/Osborne-
           NeHdel
           Rats/Osborne-
           Mtce/RtOM
            Rats/long-
            Evans
N/24 and f/24
per group


M/50 and f/SO
per group
N/SO and f/SO
per group
N/7 and f/7
per group
diets contained 0-SO
p|M for 1R-19 months

diets contained 2. 4
or 12 ppm endrln
until death or for
31 Months
diets contained 0.
0.1. 1. S. 10 or 24
ppa endrln for 2 years

diets contained IMA
endrln levels of 2.S
or S ppm for males.
and 3 or * ppm for
females for 110-114
weeks

diets contained TIM
endrln dotes of l.t
and 3.2 ppm for
•ales or 2.S and S
ppo) for f MM lei. for
90-91 weeks

diets containing 0. 0.1
O.S. 1.0. 2.0 or 4.0
for >2 years
Enlarged kidneys and hearts at 3
not 1
but
Early mortality In oiposed groups relative
to controls.  Mo effects on body weight gain
or liver-to-body weight ratios.  Moderately In-
creased Incidence of cloudy swelling In
centrllobular liver tones and In renal
tubular epithelium.  Also, moderate
Increases In Incidence of lung congestion
and focal hemorrhages.

Chronic Interstitial nephritis, tending
toward Increased Incidence and severity
with Increasing dose.

Clinical signs associated with aging
appeared earlier In dosed rats than In
controls.  Testlcular atrophy was reported
In exposed males, but not In matched
controls.
Recreated survival In high-dose males.
Mypereicltablltty In high-dose males.
Clinical signs Including alopecia.
abdominal distension and rough hair coats
were reported In dosed groups prior to
controls.

Convulsions, slight Increase In relative
liver weight and mild htstopathologtcal
changes In liver cells at 2 and 4 ppm.
Ho adverse effects at 1 ppm.
Treon et al.. 19SS
            Oelchmann et al.. 1970
            Reuber. 1970
            NCI. 1979
            NCI. 1979
            U.S. EPA. 19876

-------
 feed  of Sprague-Dawley  rats  (Green,  1969) and  of  CFW Swiss mice  (Good  and
 Uare,  1969) at  5 ppm  and fed  to the animals  before and  during  gestation
 (Table  V-8).  .Green  (1969)  reported  Increased  early resorptlon of  embryos
 and  Good  and  Uare (1969) reported  Increased maternal  mortality  and signifi-
 cantly  smaller Utter size, also Indicating Increased resorptlon.

    At  about  the  same  time,  Morris  (1968)  studied  the  effects  of  endrln
 feeding  on field-captured  deer mice  (Peromyscus  manlculatus  osgoodD  for
 parental  survival,  fertility,  Utter size and  survival  of young to  weaning
 (see Table  V-8).   Reproductive  performance was  recorded for 6 months  before
 a 7-month  feeding  program was  Initiated (0, 1,  2, 4 and 7  ppm endrln  In  the
 diet).  Postnatal mortality of  the young  appeared to  be the major  effect  of
 endrln  on  the offspring of deer  nice;  however,  soft and skeletal  tissues
were not  examined  for the Incidence of nalformations.  Survival of  parents
was significantly decreased at  endrln levels >2  ppm.

    A  single  oral dose  of endrln, 5  mg/kg bw  (1/2  L05Q), administered  by
 Intubation  to pregnant  Syrian  golden hamsters,   caused a  marked  and  statis-
 tically significant Increase In  fetal  deaths  In animals treated on day 7  or
8 of gestation (Ottolenghl et al.,  1974).   In these  studies  (Table  V-9), two
control groups  were  used, one  group receiving  the  corn oil  vehicle and a
second  group  receiving  no treatment.   Comparisons of  litters from  pesticide
 treated hamsters were made with  the corn oil-treated group  for evaluation  of
 the  Incidence of embryoddal  and  teratologlcal  effects by  using the Hann-
Uhltney U-test.   Ounnett's multiple comparisons test was  used  to evaluate
differences 1n  fetal  weight.   A statistically   significant  Increase  In the
 Incidence of  fused  Mb  and cleft  palate  (p<0.01)  occurred In Utters from


00670                               V-31                              'VI*  u:

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g
o»
-J .
o


TABLE V-8

Teratogentctty and Reproductive Studies PerforMed with Endrln In the 1960s
Species
< Sprague-Dawley
w rats
CfW Swiss Mice
Deer Mice
(PeroMyscus
Manlculatus
Sex
females
Males and
females
14 parental
pairs/dose
Dose
(PP-)
5
5
2
4
7
Feeding Procedure
60 days before and
during gestation
4 Months before and
during gestation
At Intervals over
7 -Month period
Effects Reference
Increase In fesorptlons Green. 1969
Parental Mortality (1/3) Good and Ware.
Significantly smaller 1969
litter size
Parental Mortality Morris. 1968
Significant decrease
In survival of off-
osqoodl)
spring at 21 days

-------
dams  treated  on day  7, 8  or  9 and  sacrificed on  day  14 of  gestation.   A
significant  Increase  1n open  eye  and webbed  foot occurred only  1n Utters
from  dams  treated on  day  8.   Fetal weight  was  reduced  1n all  treated
Utters.  The association  of  webbed foot and open  eye with low fetal  weight
suggests  that  these  effects  may   be  an  expression of  growth  retardation
(Ottolenghl et al.. 1974).

    OttolengM  et  al.   (1974)  also  examined the  effects  of orally  adminis-
tered endrln  1n corn oil  (day  7, 8  or  9  of gestation) on  the fetuses of CD-I
mice  (see Table V-9).  The  frequency  and  gravity  of defects  produced  by  a
single  dose  of 2.5  mg/kg bw  (1/2  LD5Q) administered  to mice  on  day  9  of
gestation  were  less  pronounced  than  those  seen  In  hamsters  at  5  mg/kg.
Abnormalities Included  an  Increased Incidence  of  eye opening  (p<0.5)  and  a
low  occurrence  of  cleft  palate.   No  significant  effects were found. with
regard to fetal  survival or fetal  weight.
                   «
    A  single dose of  endrln  1n  corn  oil administered  to  Syrian  golden
hamsters by oral gavage on day  8 of  gestation produced menlngoencephaloceles
at  doses  above  1.5 mg/kg  bw and fused  ribs at  doses above  5.0 mg/kg  (see
Table V-9).   Open  eyes, cleft  palate and webbed  foot were  not  observed.  No
significant effects were noted  1n either  maternal mortality and weight  gain
or  fetal  mortality and  weight  gain.   In  a  multiple dose  study,  the  adminis-
tration of endrln  on  days 5-14 of  gestation produced maternal  lethality at
doses  >1.5  mg/kg  bw/day.   Fetal  toxldty  (Including  Increased mortality,
reduced fetal  weight  and  reduced  skeletal  ossification)  resulted  at  doses
above 0.75 mg/kg/day  (see  Table V-9).  Endrln  crossed  the placenta and was
Identified 1n the  fetus.   12-KetoendMn  was found  1n both mother and  fetus
but not quantified  (Chernoff et al.,  1979).

00670                               V-33

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                           1AMI  V-9
Reproductive Iffects of fndrtn for Studies Perforated Sine* 1910
0
Species
•olden syrlan
hamsters

•olden syrlan
hamsters
(LV6 strain)
•olden syrlan
hamsters
-e flV6 strain)
£ •olden syrlan
hamsters
•olden syrlan
hamsters
ۥ rats
C» rats
ۥ rats
C» rats
Route of
Adnlnls- nose
tratton |mg/kg/day)
oral S
gavage

•ral >«.7S
•ral >1.5
gavage
•ral >*.•
gavage
•ral 1.5
gavage
gastric •••75
gastric •.!$
Intubation
gastric 9.3
Intubation
gastric 0.450
Vehicle toy of Mo. of
Gestation titters
corn oil 7 7

corn oil 5-14 19
corn oil 5-14 71
corn oil • 50
34
74
corn oil 5-14 13
corn oil 7-70 14
corn oil 7-70 77
corn oil 7-70 79
corn oil 7-70 17
Iffects
fetal death (37X of Implantations).
growth retardation, congenital abnor-
Mlltles In ?W of fetuses treated on
day •: open eye. 77k; webbed foot.
1M; cleft pal'te. 5*; cleft lip. 1«;
fused ribs. M
Harked Mternal toitctty; bypeacttv-
tty. tremors, reduced weight gain.
lethality; fetal toitctty; In-
creased mortality, reduced fetal
weight, reduced skeletal ossification
Significant Mternal lethality and
weight reductions, mentngoencephale-
celes In fetuses of two Utters
fused ribs and menlngoencephaloceles;
no overt embryolethal or maternotoilc
effects
Persistent elevation of locomator
activity In offspring; nonlocomotor
behavior of offspring unaffected;
SIX of dams died during dosing period.
Mo effect on Mternal weight gain or
fetus
Mo effect on Mternal weight gain or
fetus
Significant decrease In Mternal
weight. Mo effect on fetus.
•TV decrease In Mternal weight gain.
no apparent effect on the fetus
Reference
•ttolenghl
et at.. 1974

Chernoff
et al.. 1979
Chernoff
et al.. 1979
Chernoff
et al.. 1979
•ray et al..
1901
Kavlock
et al.. 19«1
Kavlock
et al., 19fl
Kavlock
et al.. 1981
Kavlock
et al.. 1981

-------
                                                                           1ABII  V-9  (cont.)
in
Spec tes
» rats




«-l mice

CO-1 ate*

Cl-l mice


CI-1 mice





C8-1 mice

C8-1 mice

Ci-1 mice




M.I mice
'v
1CR/SIN ale*

Route of
Adminis-
tration
oral
»*•'«•



oral
gavage
gastric
Intubation
gastric
Intubation

gastric
Intubation




gastric
Intubation
gastric
Intubation
gastric
Intubation



gastric
Intubation
tailrlc
Intubation
Dose Vehicle Day of
(•g/kg/tfay) Gestation
0.07S corn oil 1 tnrougb
0.1S day IS
0.30


2.5 corn oil 9

O.S corn oil 1-17

1.0 corn oil 1-1?


l.S corn oil 1-11





7.0 corn oil 1-11
single oose
2 corn oil •-!?
•
1 corn oil •
*



2 MS 14-11

2.2 corn oil 8-1?

Ho. of
litters
13
13
S


10

31

32


12





2

11

14
U



MS

24

iffeett
Pupi 30X «oro active In the Mies than
controls or 0.01S Mg/kg endrln dose
groups; at 90 days of age. no endr In-
Induced differences were apparent;
did not affect pup survival or growth.
Congenital abnormalities: open eye;
cleft palate
Maternal liver enlargement

•educed maternal weight gain; decrease
In fetal weight and skeletal and vis-
ceral maturation
Maternal lethality; no teratogenlc
effect or embryo lethality; decreased
locomotor activity, reduced weight
gain In pups; activity levels depressed
after first and third doses but no sig-
nificant difference after tenth dose.
No dose-related evidence of open eyes
and cleft palate
Reduced maternal weight, reduced
fetal weight
Reduced maternal weight gain, fetal
weight, percent of supernumary
ribs, sternal and caudal ossifications.
Eiencephaly and fused ribs were observed
In a few offspring.
Reduced locomotor activity In figure
eight mates.
Reduced neonatal weight

Reference
Cray et al..
1981



Ottolenghl
et al.. 1914
Kavlock
et al.. 1901
Kavlock
et al.. 1981

Kavlock
et al.. 1981




Kavlock
et al.. 1981
Cher no ff and
Kavlock. 1982
Kavlock
et al.. 198S



Gray et al..
1981
Setdenberg et
al.. 1986
            MS • Mot stated

-------
    In  the  hamster, exposure  to  endMn  1n corn  oil  at 1.5 nxj/kg  bw/day  on
days  5-14 of  gestation produced a significant  elevation  1n  locomotor  activ-
ity of  offspring  that  was still present at 125 days  of age  (see  Table V-9).
Nonlocomotor behavior  of  the offspring (Including rearing  In  the  open  field,
running  wheel  activity and mounting)  were not altered by treatment.   Dams
were markedly hypoactlve  using  the same  testing conditions  1n  which the pups
were hyperactive.  More than half of the group receiving 1.5  mg/kg/day died.
Rats  exposed  on days  7  through 15  of  gestation  to  endrln  at 0.15 or  0.30
mg/kg/day were  30% more  active than  controls  before weaning  but  not  as
adults.   These  doses  did  not  kill  the  dams or  affect  pup  survival  or
growth.  In this study, a dose  of 0.075  mg/kg/day appeared  to  have  no  effect
on  behavior.   Behavioral  effects may  be of special  concern  In view of the
persistence of  endrln  In  the environment  and   Us capability  for magnifica-
tion 1n the food chain  (Gray et al.,  1981).

    Kavlock  et  al.  (1981) found that endrln  was  not teratogenk or embryo-
lethal  In the  CO  rat  or  CD-I  mouse  when administered  by gastric Intubation
at maternally-toxic  dose  levels throughout the period  of organogenesls  (see
Table V-9).   However,  evidence  of fetal  toxldty  (depressed fetal weight and
caudal  vertebrae  number;  elevated supraocdpUal  score)  was  reported among
offspring of mice exposed to 1.0 or  1.5  mg endrIn/kg/day.  Adult  female  rats
tolerated 2-3 times  less endrln than did adult  mice or  hamsters,  but the rat
1s  the  only  one  of  the  three  species  In  which   endrln  did  not   Induce
fetotoxkHy.   The  difference  In fetal  sensitivity  was attributed  to lower
levels  of   12-ketoendrln  present  1n the  rat  fetus  than  observed  In  the
hamster  fetus.  More recently, fetal outcomes  were  examined  following oral
exposure of CD-I  mice  to a low (7  mg/kg) or  moderate  (9 mq/kg) maternally
toxic  dose  of  endrln on  day  8 of  gestation   (Kavlock  et   al.,  1985).

00670                              V-36

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Statistically  significant  (p<0.05) reductions  In  fetal  weight  and number of
sternal  and  caudal ossifications  were  reported at 7 mg/kg,  but  not 9 mg/kg
endrln.   Significant  reductions 1n the percent of supernumary  ribs (p<0.05)
were  reported  for both doses.   Exencephaly and fused  ribs  were  observed In
2/157 and  3/184  fetuses examined.   These  data were Interpreted  as Indicative
of  a low  but  significantly  elevated Incidence  of  terata  following  endrln
exposure.

    Chernoff and Kavlock  (1982)  assayed  28  compounds   of  known  teratogenlc
potential  by an  In  vivo  teratology  screening procedure  (see  Table  V-9).
Endrln was administered  by oral gavage  (2 mg/kg bw) to 25  gravid  CD-I  mice
on days  8-12 of  gestation.  Dams were allowed to give birth, and  Utter  size
and  weight  on  postpartum days   1   and   3 were  compared  with   concurrent
controls.   Results  Indicated  significantly  reduced  maternal  weight   and
reduced  fetal  weight  on  postpartum  day  1.   In  a similar  screening  study,
reduced  neonatal  weight,  but  not viability, was  reported  following  exposure
of ICR/SIM mice  to  endrln  (2.2  mg/kg/day)  by  oral  Intubation on days 8-12 of
gestation (Seldenberg et al.,  1986).

    Behavioral   development of  CD-I  mouse offspring prenatally  exposed  to
endrln  has also  been  evaluated   by  measuring  figure   eight  maze  reactive
locomotor  activity   (Gray  et   al.,  1986).    Endrln   (2  mg/kg   bw)   was
administered by  oral  gavage  to  pregnant  females on days 14-18  of gestation,
and  locomotor  activities  were  measured  In offspring  22,  58  and  200  days
after birth.   Locomotor  activity  was less than the  control  at days 58  and
200; this effect was statistically  significant (p<0.05)  at  day 58  only.
00670                               V-37                             03/1 i:/

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    Birds.   A  disastrous  die-off  of  brown  pelicans,   which   reduced  the
population  from 400  to 250  birds,  occurred  In Louisiana  In May  and  June
1975.   Several  months  earlier,  a  die-off  of  -100 white  pelicans  occurred
near  the  same  area.   Shell thickness  of  pelican eggs  from 1971  through 1976
averaged  6.7-13.5X less than  the mean  thickness  for  eggs  collected  before
1947.  Statistical analysis of data  on residues 1n eggs Indicated that there
were  significant differences  In  DOT and  DOE  mean  concentrations  for several
years but  no  pronounced trend.   PC6 residues  remained  essentially the same.
DleldMn  residues  Increased  significantly during  the  study;  endrln  residues
increased  significantly through  1975,  and  then  dropped  sharply  In  1976.
Endrln has  been considered the major  factor   In the d1e-offs  because  endrln
residues were detected  In  brains  of  several pelicans and  because  the die-off
In  1975  coincided with  the  peak  1n endrln  residues  In  pelican  eggs.   The
effect of  endrln  on  reproductive success 1s  unknown,  but the egg  with  the
highest residues (1.47 mg/kg ww)  contained  an embryo that  died while pipping
(Blus et al.,  1979).

    On the  basis  of  further studies,  the critical level  of endrln  In  brown
pelican eggs was  roughly estimated  at  >0.5 wg/g.   More exact  determination
was  not  possible  because  of  the small  population.   Of  the  avlan  species
studied,  the   brown  pelican  was   the   most  sensitive   to   organochloMne
contaminants,  particularly  DOE  and  endrln  (Blus,  1982).   In mallard  ducks
dletarlly exposed  to 0.5  or  3.0  ppm  endrln, egg production, fertility  and
hatchabllUy were  not  affected,  but embryo survival was  reduced  In the  3.0
ppm  treatment  group  (Roylance et  al., 1985).   A  similar  study  reported no
adverse  reproductive  outcomes  for  mallards  dletarlly  exposed  to  1   ppm
endrln,  but equivocal evidence of poor reproduction at  3 ppm exposure  (Spann


00670                               V-38

-------
et  al.,  1986).  However,  application  of  endrln directly  to  mallard  eggs  at
doses   greater  or   less   than  the   1C     elicited  reduced   growth   and
malformations  In surviving embryos (Hoffman and Albers, 1984).

HutaqenlcUy
    Endrln was one  of  228  pesticides  tested  for mutagenlcHy  1n a Salmonella
typhlmurlum  reverse  mutation  assay  using strains  TA1536,  TA1537,  TA1538,
TA98 and TA100 (Ames  et  al.,  1975).   Endrln  was not mutagenlc for any of  the
above  bacterial  strains, nor for Escherlchla  coll  HP2 her.  These in  vitro
assays were  done both with  and without addition of  rat  hepatic  homogenates
(S9)  to supply  mammalian  metabolic   enzymes   (HoMya  et al.,  1983).   The
National Toxicology Program  (U.S.  DHHS,   1982)  also  reported  endrln to  be
nonmutagenlc for  Salmonella,  although no  details of  testing  procedures were
given.   A   third study  utilized  a  modification   of  the  standard  reverse
mutation assay wherein the Salmonella  strains  were streaked  on agar plates
poured  so   as  to  obtain  a  concentration  gradient  of   the  test  compound.
Endrln was not mutagenlc for any  of the above  strains nor for  the following:
his G46. his  C3076. or  his  D3052 (Probst  et al.,  1981).  Similarly, endrln
was not  mutagenlc  In  the absence  of  S-9  1n   S.  typhlmulrum strains TA98,
TA100, TA1535  or TA1537.   Further,  mutagenlcUy was not  observed  In  TA98  or
TA100  1n  the  presence of S-9,  nor  1n TA98  plus  S-9 and  TCPO,  an  epoxlde
hydratase Inhibitor  (Glatt et al., 1983).

    Endrln  exposure of primary  rat  or hamster  hepatocytes did not result  1n
Increased unscheduled  DNA  synthesis  (Probst et al.,  1981; Williams,  1980).
This nonrepllcatlve ONA  synthesis 1s   regarded  as  an  Indicator  of repair  of
ONA damage.   Endrln  (as  well  as DOT, rnUex.   kepone, hexachlorocyclopenta-
dlene, heptachlor and  chlordane)  produced  no Increases over control  numbers

00670                               V-39

-------
of  mutants at  the  hypoxanthlne-guanlne  phosphorlbosyl  transferase  (HGPRT)
locus  when tested   In  adult  rat  liver  epithelial  cells  (Williams,  1980;
Telang  et  al.,  1981).   Genotoxlclty  was  not  elicited  by  a  variety  of
organochlorlne  pesticides  Including  endrln  tested  Jhi vitro 1n a  hepatocyte
primary  culture ONA repair  assay  using hepatocytes  from male Fischer  F344
rats  (300-375  g),   CD-I  mice  (25-35  g)   and  Syrian  hamsters  (85-130  g)
(Maslansky  and  Williams,   1981).    The   potent   procarclnogen,   dlmethyl-
benzanthracene, was  the  positive control and  OMSO  was the solvent  control.
The   lack  of   endr1n-1nduced  genotoxldty   agrees  with   the   negative
mutagenldty 1n sensitive mlcroblal  assays.

    Adult  DrosophUa were exposed  to  endrln by abdominal Injection, and  the
Muller-5  test  for recessive  lethal mutation on  the  X-chromosome  was  done.
The authors noted no positive responses for endrln or  any  other chlorinated
pesticide tested (Benes,  1969).

    In  an abstract, Grant  (1973)  reported  that among a  number  of organo-
chlorlne  pesticides,  endrln,  aldrln,  chlordane, dleldrln,  DDT,  heptachlor
and  llndane,   all  caused  chromosome   breakage.   The  organisms and dosage
routes were not described.   01ksh1th  and Oatta  (1973)  reported the effects
of  endrln  on  rat   chromosomes.   Male albino   rats   (200-250 g),  treated
Intratestkularly with 0.25 mg  endrln  (In  saline) per testls and sacrificed
10 days  after  dosing,  exhibited chromosomal aberrations In germinal tissue.
Abnormalities   Included  breaks,  fragments,   ring formation,  stickiness  and
chromatln bridges.

    Endrln,   10~«,   10~»   and   10'* H,    did   not   significantly   affect
s1ster-chromat1d  exchange  frequencies  1n   both  activated  and  nonactlvated

00670                              V-40

-------
 human  lymphold  cells of  the  LA2-007  cell  line over 48 hours  (Sobtl  et al.,
 1983).   However,  slster-chroraatld  exchange  frequencies  were  significantly
 elevated  In  15  central  mud  minnows  per  exposure  following  exposure  of
 5.4x10""  to 5.4x10'*  M  endrln  1n  aquaria  water  for   2  weeks  (Vlgfusson
 et al., 1983).

 Carc1noqen1c1ty
    Endrln has  been examined for carc1nogen1c1ty 1n mice  (B6C3F1,  C57B1/6J,
 C3D2F1/J and  C3HF strains), rats (Os borne-Mendel,  Sprague-Oawley). and  dogs
 (beagle  and   mixed  breeds).   Reuber   (1979)  has  strongly  claimed cardno-
 genlclty  for  rats,  and  less   strongly  for  other  animal  species;  however
 evidence accumulated to date remains  somewhat  conflicting since  results  have
 been negative for most studies.   In  studying mice and  dogs, clear  conclu-
 sions have been much more difficult to reach,  owing to toxldty  problems and
 the  Inadequate  numbers  In  most Investigations.   The  following  studies are
 summarized 1n Table V-10.

    The first study  of  endrln  cardnogenldty was conducted by Treon et al.
 (1955).   Endrln  was administered  to  28-day-old  rats,   20   males   and  20
 females/group, In doses  of 0, 1, 5, 25, 50  or  100 ppm endrln  In  the feed for
 106 weeks.   The 100 ppm  dose  approximated 10 mg/kg bw/day.   Doses  >25 ppm
 for females and  >50 ppm for males  resulted In significant  mortality  by 106
*eeks  so  that few  animals  remained at these  higher doses  for pathological
 examination.   Signs of overt toxldty  (hypersensltlvUy to external stimuli.
 or occurrence of convulsions) were not evoked at  doses <25 ppm.  The authors
 reported that the  Incidence of neoplasla was  no  greater  among experimental
animals than  among  controls In  the tissues  studied (liver,  kidney,  brain,
00670                               V-41                             08/1 3/3

-------
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-------
heart,  adrenal  gland,  spleen,  skin.  lung, and  other  unidentified tissues).
No  primary  data  were presented.   Subsequent Independent assessment of hlsto-
loglcal specimens led  to  the  report (Reuber,  1979) that one animal Ingesting
25  ppm  had  a carcinoma of the pituitary and  one Ingesting 50 ppro a broncho-
genie carcinoma.  No malignancies  were  originally reported In untreated rats
although  these  (and  endMn-treated  animals)  were later  reported  to  have
developed benign tumors of the breast and retlculum sarcomas.

    In  addition  to  the above, three Independent  studies  were conducted with
the same  species  (rats.  Osborne-Mendel)  under similar  conditions.  Delchmann
et  al.  (1970)  found that animals  Ingesting endrln  dissolved In  corn  oil  and
admixed with ground  Purina chow  developed  malignant tumors;  however,  similar
Incidences  occurred  In  control animals.  In this study, Osborne-Mendel  wean-
ling  rats,  50  male  and 50 female  per  treatment and 100 male  and 100 female
per control  group were administered 1,  3 or 6  ppm  endrln  In the feed for  10
weeks and then twice  those concentrations  until  sacrifice,  the tlae of  which
varied  considerably  (5-29 months).  Hale animals  treated  with final doses  of
2,  6  or 12 ppm  showed  15, 9  and  24% Incidences,  respectively,  of malignant
tumors, compared  with 18% 1n controls.  In females the  corresponding  Inci-
dence of  malignancies  was  21, 11  and 22%,  with  24% 1n  control animals.  The
predominant  tumor type In both  sexes  In  all groups was  malignant lymphoma.
In  this study  excess  cancer  Incidence In  animals  Ingesting  endrln  was not
reported  1n the  liver, endocrine organs   or  reproductive  tissues,  as was
observed  1n the previous studies.   The authors  concluded  that endrln  fed for
a lifetime to albino rats was  neither  tumoMgenie nor carcinogenic.

    In  a  second  Osborne-Mendel  rat study reported  by Reuber  (1978),  22-day-
old male  and female rats,  24/group, were fed 0,  0.1,  1.0, 5, 10  and 25 ppm

00670                               V-43                            -•- -   '

-------
endrln admixed  In  corn oil wUh the diet  (IX)  for  104  weeks.   Owing to high
and early mortality  1n  the highest  concentration group, additional  groups of
animals  Ingesting  this  concentration were  subsequently  established.   Some of
the  tissues  studied on  sacrifice  were  lung,  spleen,   kidney,  heart,  liver,
pancreas, stomach,  small  Intestine, colon,  kidney,  adrenals,  thyroid,  ovary,
leg  muscle,  leg  bone,  bone  marrow,   bladder  and  prostate.   In male  rats,
endHn  Induced  hyperplastlc  nodules   1n  the  liver.    For  both nodules  and
•malignant lesions"  (defined  as  the sum of carcinomas  and  sarcomas),  endrln
appeared most active at a  dose  of  0.1  ppm.   The tabulated data were  often
confusing.   The  Incidence  of   malignant   hepatic  neoplasla   1n  males  and
females  was  relatively  low (Tables V-11 and  V-12).  No malignant  tumors  In
the  liver  were  observed  1n control animals of  either  sex.  In addition  to
developing  liver  lesions,  endrln-treated  rats  of   both   sexes   developed
neoplasms at  a  number  of  other  sites.  In males  these Included  retkulum
cell  sarcomas of  the lungs and  lymph  nodes and some rare  malignant  tumors,
as  well  as  carcinomas  of  the  thyroid and  renal  cortex.   The  observations
showed  no  preferred  cancer  site  (greater  than  two  Instances)   although
frequencies  never  exceeded 13%  for a  spedf'.c site  at a  given  dose.   In
females, carcinomas  and lelomyosarcomas of  the mammary gland,  stromal  cell
sarcomas of  the uterine  endometrlum,  retlculum cell sarcoma of  the  lung  and
hepatic  Kupffer  cell sarcoma  were  observed (see Table  V-12).   The  preferred
cancer  sites  1n  this  study  were   the  mammary  gland,  the  thyroid  and  the
uterus,  In  that  order.    On  the basis  of  the above  findings, the author
concluded that endrln was  a carcinogen.  The data appear more  conclusive  for
female rats than for male rats.   Doses below 5  mg/kg appeared  to elicit  few
overt signs  of  toxUHy In the  animals.   Inherent  difficulties are encoun-
tered when  Interpreting Reuben's  (1978) report.   Statistics  were  based  on

00670                               V-44                             'JfiVi*.

-------
o
o
                        TABLE ¥-11
Incidence  of Malignant Tutors In Hale Rats  Ingesting Endrln*
Endrln
Concentration
(p|M feed)
0
0.1
1
5
10
25

No. AnlMls
Examined
15
16
10
10
20
19
Liver

Carclnou
0
2
0
0
1
1


SarcoM
0
0
0
0
1
0

Lung
SarcoM
0
1
0
0
0
1
HaMUry

Carclnou
0
0
0
1
0
0
Gland

SarcoM
0
1
1
0
1
0
Other

CarctnoM SarcoM
0 0
4° 3C
id }9
0 0
0 if
ig 2"
Total
Malignant
Twwrs
0
11
3
1
4
5
         'Source: Reuber. 1970
         ^wo thyroid, adenocarc InoM  (site unknown) and adrenal  cortex
         cTwo In lyaph nodes and  one In the stoMch
         dStOMCh
         eKtdney
         rHeMngtoendothel1al
         flThyrold
           Lynph node and osteogenlc

-------
                                                TABLE V-12

                       Incidence  of Malignant Tumors  In female Rats  Ingesting Endrln*
Endrln
Concentration
(ppm feed)
0
0.1
1
5
10
25
Liver
No. Animals
Examined
23
23
23
20
18
19
Carcinoma
0
0
0
1
0
1
Sarcoma
0
1
0
0
1
0
Lung
Sarcoma
0
0
1
1
0
0
Mammary
Carcinoma
6
10
14
13
8
1
Gland
Sarcoma
1
2
0
0
1
2
Other Total
Carcinoma
2b
0
2d
0
>
5'
Malignant
Sarcoma Tumors
0 9
le 14
1C 18
0 15
0 11
lc 10
'Source: Reuber. 1978
 Papillary adenocarclnoma. site unknown
cUterus
 Thyroid and colon
'Adrenal cortex
 four In thyroid and one In the adrenal  cortex

-------
 the  number  of  animals  with malignant  tumors.   From  the data,  the reader
 cannot  Justify  the  numbers  reported In the text; also one animal may develop
 more  than  one lesion.

    In  a  study  by  NCI  (1979),  35-day-old male Osborne-Hendel  rats were, fed a
 diet  Incorporating  endrln Initially dissolved  1n acetone to a  level of 2.5
 or 5.0  ppm diet.   Females (50) were fed  a  diet containing 0,  3.0 or 6.0 ppm
 technical  grade endrln  for  80  weeks and surviving animals were sacrificed at
 111-114  weeks.   There  were  10  control  rats  of  each  sex.    The  tissues
 utilized  for hlstopathology were  the  following:   skin,  lungs  and  bronchi,
 trachea,  bone  and  bone marrow,  spleen,  lymph  nodes, heart,  salivary gland,
 liver,  pancreas,  stomach, Intestines,  kidneys,  bladder,  pituitary,  adrenal,
 thyroid, parathyroid, mammary gland, prostate  or uterus,  testls  or  ovary and
 brain.   Comparing  Incidences   of  malignant  tumor  formation  1n  Individual
 tissues between  control and treated animals,  the authors of the study  con-
 cluded  that  endrln  was not carcinogenic  1n  either  sex.  Malignant  tumors
 that  were  observed 1n  two  or  more male  animals per  group (4X  Incidence  In
 treated animals) were  hematoma  of  the kidney  (4% at  the high  dose),  adrenal
 carcinoma  (4% at  the low dose),  Islet cell carcinoma of  the  pancreas (6X  at
 the high dose) and  fibrous  hlstocytoma  (4X at  the high  dose).   The  Increased
 Incidence  of Islet  cell carcinomas  1n  the high  dose  group was  statistically
 significant  compared  with  controls applying  the Cochran-Armltage,   but not
 the   Fisher   exact  test.   Cancer  Incidence   at   other  sites  was  not
 statistically  significant.   In  female  animals,  two  or more  animals  had
malignancies 1n  the pituitary   (4X  at  the  low dose) and  adrenal  (14% at the
 low and 6X at  the high dose but  11X 1n controls).  None  of  these  Increased
 Incidences were  statistically   significant,  but  the  Increases  of  pituitary


 00670                               V-47

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adenomas,  and combined  Increased Incidences  of adenomas  and  carcinomas  of
the  adrenal  were   significant.   Data  Interpretation  in  this  study  was
complicated by the use of only 10 matched controls per gender.

    The opposite  conclusions  to  those  made  above were reached,  however, by a
later  reviewer  of  this  study  (Reuber,  1979)  after  re-examination of  the
pathology  slides, and based on  comparisons  of  cumulated cancer  Incidences  at
different  sites,  I.e.,  endocrine and  reproductive  tissues, or  control  vs.
treated groups.   In males  and  females, Increased cancer  Incidence  compared
with  controls  was thereby  observed  for both  doses  of  endMn  for endocrine
organs  (pituitary and  adrenal glands)  and  the  liver.   In  addition,  females
showed an  Increase In Incidence  of malignant  tumors  of the ovary, uterus.and
mammary  gland.    In  males,  the  numbers  of  animals  with  malignant  tumors
(carcinomas  and  sarcomas)  were  67X  and  64X  at  the  low and  high  dose,
respectively,  compared  with  10% 1n  the control  groups.   In  females,  the
corresponding  values were  74  and  82% compared  with  40% In  the  control
groups.   In  female  rats, 74  and  67% of animals Ingesting  the low and  high
dose,  respectively,  had  carcinomas  of the  endocrine organs,  compared  with
10% of  untreated  animals.  In male  rats,  the corresponding Incidences  were
36 and 42% 1n treated and 10% 1n  control  animals.   Statistically significant
Increases   1n  carcinoma  Incidence In the  pituitary  (43% low-dose, 30%  high-
dose,  0%   control)  and  adrenal  glands (33,  31  and  0%, respectively)  were
observed  In female rats  at  both endrln doses  (Table  V-13),  and  1,< the  pitu-
itary  gland  of  males at  the  lower  dose (29%  coapared with 0%  In controls)
(Table V-14).  In female  rats,  40 and  28%  developed  malignant tumors of the
reproductive system at the  low and high endrln doses,  respectively,  compared
with  10%   of  control animals  (see  Table  V-13).   Hepatocellular carcinoma


00670                               V-48

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o
o
                     TABLE V-13
Nunber of Osborne-Hendel Feoale Rats with Carcinomas*
Oose
(pp» endrln In the diet)
0 Matched
Pooled
2.78
5.56
Low » high dose
Number
Examined
10
49
46
46
92
Endocrine
1
11
34
31
65
(10X)b
(23X)
<74X)C
(67X)h
(71X)"
Pituitary
0
6
20
14
34

(12X)
(43X)d
(30X)1
(37X)n
Adrenal
0
0
15
14
29

<33X)e
(31X)J
<32X)J
Reproductive
System
1 (10X)
3 (6X)
17 <40X)f
13 (28X)k
30 (33X)f
L
0
0
1
4
5
Iver

(W)
<9X)
(5X)
Total No. with
Carcinomas
1 <10X)
5 (JOX)
29 (63X)g
35 (76X)1
64 (10%)
    'Sources:  NCI.  1979;  Reuber.  1979
     Percentage of  anlaals examined with  tiwor  of  tissue  specified
    cp<10~», one-sided test
    dp<10~*. one-sided test
    ep<5x!0~*. one-sided  test
     p<3xlO~*. one-sided  test
    9p . 2x10"». one-sided test
    hp<)0~». one-sided test
    V . 2.7xlO~».  one-sided test
    Jp<1.2xlO"». one-sided test
    kp - 3.4xlO~*.  one-sided test
     p - 1.8xlO~»,  one-sided test
    "p<10~».  one-sided test
    np = 7xlO~«. one-sided test

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o
o
                                                     TABLE  V-14
                                Number of Osborne-Mendel Hale Rats with Carcinomas*
I
in
O
Dose
(ppm endrln In the diet)
0 matched
Pooled
2.5
5.0
Low * high dose
Number
Examined0
10
49
45
45
90
Endocrine
1 (10X)
5 (10*)
17 (36*)
19 (42*)
36 (40*)
Pituitary
0
3 (6*)
13 (29*)c
7 (16X)
30 (22*)«
Adrenal
1 (10*)
1 (2*)
1 (2*)
« (9*)
5 (6X)
Liver
0
0
1 (2*)
2 (4*)
3 <3*)
Total No. with
Carcinomas
1 (10*)
4 (6*)
24 (53X)d
22 (49X)d
44 (49X)d
    'Sources:  NCI.  1979;  Reuber.  1979
    Percentage of  number examined
    cp • 0.003, one-sided test
    VO.000.009) one-sided test
    ep • 0.001. one-sided test

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Incidences  observed  In  low and  high-dose  endrln-treated female  rats,  com-
pared with  controls,  were 2, 9 and  OX,  respectively,  but were not statisti-
cally  significant.   The  corresponding  figures  for male  rats were 2,  4 and
OX,  respectively  and also  not  significant.  Female rats  therefore appeared
to be  more  susceptible  than male rats at  the various  target sites mentioned
above.   The Incidences  of  benign  tumors   In male or  female rats were  not
reported to be  significantly different  from values In  controls or  any endrln
dose (Tables V-15 and V-16).

    Re-evaluation of  the  tissue sections by  Reuber (1979)  thus  has resulted
In  dramatically  Increased   tumor  Incidences  In  both control  and  exposed
groups.  Reuben's  criteria  for  classifying tissues as  tumorlgenlc  appear  to
differ   from   those   of   other   Investigators.    Until  differences  between
Reuber's criteria  and those of others  1s  resolved  It will  be  difficult  to
draw conclusions from his findings.

    In a study with mice (WUherup  et  al., 1970), males and  females  of  the
C57B1/6J and C302F1/J strains Ingested Purina mouse chow  admixed with  endrln
dissolved 1n 95X  ethanol  to give concentrations of 0, 0.3 or  3.0  ppm  1n  the
diet.  For  both strains, 100 males  and  100  females constituted each  treat-
ment  group  and two  control  groups.   Tissues  analyzed  histopathologlcally
were  the following:   heart, lungs,  liver,  spleen, kidneys,   GI  tract,  lymph
nodes, urinary  bladder,  gonads, pancreas,  thyroid, thymus,  adrenals,  brain,
pituitary,  spinal cord,  eyes,  bone  marrow, nasal  passages,  skin and  periph-
eral  blood  smears.   In  this lifetime study  (up  to  119  weeks) the  overall
Incidence of  neoplasms  found  In  each strain and  diet group was  not  Influ-
enced  by the  content  of endrln  In  the dally  diet.   The authors  concluded

00670                               V-51                              lG/':/38

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I
w«
IVJ
                                                         TABLE  V 15


                                  NiMber of Osborne-Nendel Female Rats with Benign Tuw>rsa
Dose
(ppa endrln In the diet)
0 Matched
Pooled
2.78
5.56
Low *• high dose
NiMber
Examined
10
49
46
46
92
Endocrine
4 (40X)
14 (30X)
6 (13X)
10 (22%)
16 (17X)
Pituitary
1 <10X)
6 (12X)
3 (7%)
7 |15X)
10 HIX)
Adrenal
2 (20X)
3 <6X)
8 (18X)
13 (28X)
21 (23X)
Reproductive
Syste*
0
4 (W)
9 (20X)
3 (7X)
12 (13X)
Liver
0
1 (»)
9 (20X)
14 (30X)
23 (25X)
lotalb
3 (30X)
14 (29X)
2 (4X)
5 (11X)
7 (8X)
         'Sources: NCI. 1979; Reuber. 1979


         bTotal  nunber of anlMls bearing benign tuaors

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c*
                                                     TABLE V-16
                        NiMber  of Osborne-Mendel Male Rats Ingesting Endrln with Benign Tuw>rsa
Dose
(ppa endrln In the diet)
0 Mtched
Pooled
2.5
5
Low * high dose
NiMfcer
Examined
10
49
45
45
90
Endocrine11
2 (20X)«
14 (49X)
19 (49X)
16 (36*)
35 (39X)
Pituitary0
1 (10X)
8 (16X)
5 (W)
10 (2?X)
15 (17X)
Adrenal*
2 (20X)
3 (**)
12 (27X)
3 (11*)
15 (17X)
Llverc
1 (Itt)
4 (8X)
13 (29X)
6 (1W)
19 (21X)
Total*
5 (50X)
17 (49X)
10 (22%)
9 (20X)
19 (21X)
      'Sources: NCI, 1979; ReiK«r. 1979
      bAdenoMS
      cHyperplast1c nodules
      ^Total nunber of anlMls bearing benign tuwtrs
      •Statistical  analysis  (one-sided t test) revealed no  statistical  significance for any experimental  group
       compared with controls

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 that  wnen endrln  was  added  to  the dally diet  of C5781/6J  Inbred  mice and
 C302F1/J  hybrid nice  1n  the amounts of  3.0  and 0.3 pom.  the pesticide was
 not  carcinogenic  to the animals.   Reuber  1n  his Independent analysis of the
 slides  of this study  came  to the  opposite  conclusion  for  the  0.3  ppra dose
 (Reuber.  1979).
   •
    In  an NCI  study  (1979), female  B6C3F1  mice  35  days  of  age  Ingested
 endrln admixed  with  the  diet for 80 weeks at concentrations of 0, 2.5 or 5.0
 ppm and  0,  1.6 and 3.2 pom  for  aales.  All  surviving nice were killed at 90
 or 91 weeks.   Each treated  group contained 50 animals and each control group
 10 animals.   In male nice,  two or more animals per treated group had hepato-
 cellular  carcinoma (16X  at  the  high  dose)  compared with one  (10X)  1n  the
 control  group.   A  corresponding number  of  mice  with  malignancies  was  not
 observed  1n females.   Significant Incidences  for any  site In either  sex were
 not observed.   Because of the  high mortality In  the treated  groups,  hlsto-
 loglcal  examination  was  limited  to  only  one section of  the  liver and since
 the numbers of  control animals were only  10,  an Independent reviewer  stated
 (Reuber,  1979)  that no conclusions could be reached from this study.

    Four  bloassays  for cardnogenldty were  done 1n  rats and  three were  on
mice.  These  bloassays were  done at different Institutions, namely  Food  and
 Drug Administration  (FOA) during 1955-1957 as Devaluated by  Reuber  (1978).
 the  National   Cancer   Institute  (NCI,   1979).  the  University  of  Cincinnati
 (Ketterlng Laboratory) (Ultherup et al..  1970),  and  the  University  of H1am1
 (Oelchmann et  al..  1970).  All the bloassays on rats and mice were  reported
 as  negative   by those authors.   There were,  however,   deficiencies   1n  the
 studies  which 1s   explained  below,  which  render the  findings  Inadequate  to
 properly  assess the carcinogenic potential 1n animal test systems.

 00670                               V-54

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     In  the FDA  rat  (Osborne-Hendel)  study  the  animals  at highest dose  (25
 ppm)  did  not  survive well and additional  animals  were  started  In  that  dose.
 The  remainder of  the groups lived  for  the  programmed  two year  study.   It
 also  appeared that  every  animal  came to  autopsy  and not  all  sections  from
 grossly  observed  animals  were studied  microscopically.   In  spite of  some
 deficiencies  there  were  a  sufficient  number  of  animals In  the  studies
 particularly  1n  the aspect of  liver and kidney,  In  all experimental  and
 control  groups  (Reuber,  1978).    This   study  was  originally  reported  as
 negative.   It was  reevaluated  by-  a  panel  of pathologist whose  report  was
 referenced  In a CAG  document  (U.S.  EPA.  1978).   One  pathologist  considered
 the  finding  positive  (Table V-ll  and  V-12)  but  did not provide slide  by
 slide  tabulation  of  his findings  and  did  not  distinguish between  primary
 and/or metastatlc  tumors In  the liver.   A  second  pathologist  whose original
 finding  Indicated  that  the  study was  negative,  provided slide by  slide
 tabulation of diagnosis  which was confirmed by the panel review.  In  the FDA
 mice  (C3HF1)  study  the  survival   was   very  poor  In  both  control   and
 experimental  group.

    The KetteMng  study used  two  strains  of  mice  (C5781/6J  and  C3D2F1/J).
 The  C57B1/6J  strain  exhibited mainly  leukemia  and liver  tumors with  low
 Incidence.  These  tumors  appeared  equally  1n the  experimental and  control
groups and the  latent  period  of  tumor  formation was  similar.   But  In  the
C302F1/J strain, the Incidence of  liver  tumors 1n the dose group  (3 ppm) was
 slightly  higher  In  the  female than  In  controls  and  the latent   period  of
 tumor formation was decreased than other groups  (HUherup et al.,  1970).
00670                               V-55

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    The NCI bloassay was done  In  Osborne-Hendel  rats and B6C3F1 mice.  These
studies were  reported as  negative.   A primary  reviewer for  NCI  noted that
the negative  findings  could  be a reflection  of  the high toxlclty of endrln,
which  only  permitted  the  administration  of relatively  low  chronic dosages.
Furthermore,  the reviewer  observed  that  an  accidental  overdose  among  low
dose male mice  resulted  In early death of  several  animals  1n this treatment
group and the study was marred  by a  small  (10) If matched controls; however,
this  deficiency was compensated  by  the  use  of  pooled controls  (see  Table
V-17).  There were  significant  Increases  In hemangloma  In  low  dose  male
rats,  adrenal adenoma  and/or   carcinoma  In  high dose  1n  males,  pituitary
adenomas  In  the high  dose female, adrenal  adenoma and/or  carcinoma  1n  low
dose  female  rats  as  compared  to  the   pooled  controls.    Although,  the
islet-cell  carcinoma  In  male  rats  had  a  significant   trend    but   no
statistical  significance at  either  dose group, the  NCI  concluded  that  these
tumors  could  not  be  clearly   considered  related  to  the  admlnstratlon  of
endrln  (NCI,  1979).   Although  NCI concluded  that  the  bloassays  of  endrln
were not carcinogenic,  the responses noted  above  can not be  totally Ignored.

    Endrln  was  not   mutagenlc   1n   any   bacterial   strains   but   exhibited
chromosomal  aberration 1n  germinal  tissues.   Endrln  1s  also  structurally
related to aldrln, dleldHn, chlordane, chlorendlc  acid  and  heptachlor  which
                  t
are known  to  carcinogenic  1n   animals.  The available  cancer  epldemlologtc
data  Involving   several  studies  1s  Inadequate  to  demonstrate  or  refut, a
carcinogenic  hazard   because   of  study   design   limitations  and/or   mixed
exposures.  Using  the criteria   1n  the  U.S.   EPA  (1986)  guidelines  for
classification  of  carcinogens, endrln  1s  most  appropriately classified  In
Group  0;  I.e. a  chemical  for  which  there  1s Inadequate evidence  to  assess
the potential  carclnogenlclty   for humans.   This  classification Is based  on

00670                               V-56                                 - :

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                                  TABLE  V-17

           Analysis  of  Incidence of Primary  Tumors  In Osborne-Hendel
                         rats  fed EndMn In the diet
Sex Site
Hale Hemangloraa
P Values*
Adrenal
Carcinoma
P Values*
Adrenal-
Adenoma or
Carcinoma
P Values*
Pancreatic
Islet Cell
Carcinoma
Female Pituitary-
Adenoma
P Values*
Adrenal-
Carcinoma
P Values*
Adrenal:
Adenoma or
Carcinoma
P Values
Pooled
Control
0/49(0)
NS
0/44(0)
NS
2/44(5)
P.O. 028
0/46(0)
P.Values
0.039
4/44(9)
P.O. 01 5
2/46(4)
NS
4/46/(9)
NS
Matched
Control
0/10(0)
NS
0/9(0)
NS
2/9(22)
NS
0/10
2/7(29)
NS
1/9(11)
NS
3/9(33)
P.O. 041
Low
Oose
5/46(11)
P.O. 024*
2/46(4)
NS
4/46(9)
NS
0/45
11/47(23)
NS
7/49(14)
NS
14/49(33)
P.O. 004*
High
Oose
3/47(6)
NS
0/44(0)
NS
8/44(18)
P.O. 045*
3/47(6)
13/45(29)
P.O. 016*
3/47(6)
NS
7/47(15)
NS
Source: NCI, 1979

NS » Non significant
 * - Significant  with  respect  to  pooled control
 * » Beneath the  Incidence  of  tumors  In the control groups Is the
     probability  level  for  the Cochran ArmHage  test when P <0.05, otherwise
     not significant  (NS)  Is  Indicated.
00670
V-57

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the  nonposUlve  but  suggestive results  In  some of the animal  studies.   The
negative conclusions as  reported  by the study  authors of  the  four  bloassays
do not  support  a Group E classification, because  of  the  Inadequacies of  the
studies.  A  Group 0 we1ght-of-ev1dence  1s  thought to be  the  best  classifi-
cation until additional studies can be done to clarify the situation.

    Later studies  suggested  that  endrln or  Us rapidly-produced  metabolites
might  act  as promoters,  although  some  have produced conflicting  evidence.
Ito et  al.  (1980)  showed that endrln (25 ppm  1n diet) promotes  the develop-
ment of  preneoplastlc  changes  1n  rat liver  after  Initiation with N-nHroso-
dlethylamlne  or   N-2-fluorenylacetam1de.    Maslansky  and Williams  (1981)
showed  that  endrln  (10"» to  10"* M) was  not genotoxk  In  the hepatocyte
primary  culture  (HPCJ/DNA   repair   assay  utilizing  hepatocytes  from  male
Fischer  F344 rats, male  CO-1  mice and male  Syrian hamsters.  ONA repair was
observed 1n  response to  a positive control  1n  all three  systems.   Thus, the
mechanism of  the weak hepatocardnogenldty of endrln may  reflect an  epl-
genetlc  mechanism, probably  Involving a promotional  rather than a  genotoxk
effect.  Kurata  et al. (1982) demonstrated  that endrln  above  5 mg/i 1n the
HGPRT  system using  wild-type  6-th1oguan1ne-sens1t1ve  V79  Chinese hamster
cells and mutant 6-th1oguan1ne-res1stant cells Inhibited  metabolic coopera-
tion  (reciprocal  exchange  of  material  between  cells   In contact), as  do
recognized '.uraor  promoters.   A concentration  of  20 mg  endr1n/i caused 80%
Inhibition whereas  10  mg endMn/l  elicited -25%  Inhibition.   On the other
hand, Miller et  al.  (1981),  1n an  abstract, reported that endrln  (0-40 u«)
did  not  change   the  frequency of   transformation  of C3H lOTl/2  cells  by
3-methylcholanthrene or   benzo(a)pyrene  (0-10  mg/1)  after  a  3-hour  Incu-
bation.


00670                               V-58

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Summary
    The  acute  oral  LO,Q  of endMn  given  to mammals  by oral  gavage  ranged
from  2.3  mg/kg  to  43.4  mg/kg  bw  (see  Table  V-l).   The  L05Q  following
dermal exposures  ranged  from 10.9-92 mg/kg bw  and  was vehicle-dependent.   A
lone  Inhalation  study Indicated  that 130 seven-hour  exposures to 0.36  ppm
endrln  "vapor*  were not  fatal  to rats,  hamsters and guinea pigs;  however,
two  of   four rabbits died  after  188 exposures and one  of three mice  died
after  107 exposures  (see  Table  V-5).   Young  animals appeared  to  be  more
sensitive  to dietary endrln  than  older animals  (see Table V-3).  Metabolites
of  endrln were  more acutely  toxic  In  rats  than  the parent  compound  (see
Table V-2), with  !2-ketoendr1n  being the  most  toxic  1n  both  male  and  female
rats  and having  acute  oral LO,Qs  of 1.1  and 0.8 mg/kg  bw,  respectively.
The  acute oral  LO.. values for  endrln  Itself were  5.6  and 5.3 mg/kg  bw,
respectively,  In this same study.

    Short-term  endrln exposures  reportedly  elicit CMS  effects,  Including
convulsions (Emerson  et  al., 1964),  reduced  locomotor activity (Kavlock  et
al.,  1981),  and  altered EEG  recordings   (Revzln,  1968).  Reported hepatic
effects  Include  elevated  liver  weight,  Uplds  and  tMgycerldes, and changes
In  cytochrome  P-450  content and  P-450-med1ated enzyme activities  (Hartgrove
et al.,  1977;  Pawar  and  Kachole,  1978;  Borady  et al., 1983;  Nostafa et al.,
1983).   Endrln  also elicits  changes  1n  cardiac  output,  blood pressure,
hemolysls  and  other  hematologlcal parameters  (Emerson et al.,  1964; Hlnshaw
et al., 1966;  Reins et al.,  1966).

    Longer exposure  to endrln  elicits  mortality,  depressed  weight  gain  or
weight loss, and  elevated organ-to-body  weight ratios (Treon et al., 1955;
Nelson et al., 1956; Chernoff et  al., 1979; Kavlock et al., 1981).  Abnormal
00670                               V-59

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EEG  patterns,  elevated serum  alkaline  phosphatase, reduced plasma  specific
gravity  and  Intermittent  blindness  have also  been  reported,  as  well  as
altered  hepatoblHary  function,  following  endrln  exposure ranging  from  2
weeks  to  several  months (Nelson et al.,  1956; Speck and Maaske,  1958;  Young
and Nehendale, 1986).

    Chronic endrln exposure causes mortality or  early  appearance  of  clinical
signs  associated  with  aging  (Treon et  al., 1955;  Oelchmann  et  al.,  1970;
NCI,  1979).   Organ-specific  effects reported Include  elevated  organ-to-body
weight  ratios,  lung  congestion  and hemmorhage,  swelling  of renal  tubules,
and  chronic  Interstitial  nephritis  (Treon  et  al..  1955;  Dlechmann  et  al.,
1970;  Reuber, 1978).   Prenatal exposure  to endrln  elicited  terata, mortality
and/or  reduced  neonatal weight or weight  gain  1n offspring of hamsters and
mice.   These  outcomes  were  not  consistently  observed In  rats.  However,
evidence  of  altered  behavioral  development,  measured  by maze locomotor
activity,  was  observed  In  offspring of  rats,  mice and  hamsters following
prenatal endrln exposure.

    Endrln was not mutagenlc  In  mlcroblal systems with or without metabolic
activation,   and    endrln   exposure    did    not    significantly   affect
slster-chromatld  exchange  frequencies   1n  a   human   lymphold  cell   line.
However, a  significant elevation  of slster-chromatld  exchange frequency was
observed In minnows following endrln exposure.

    Conclusions  concerning endrln  cardnogenlcUy  have  not  been  entirely
consistent.  Endrln was determined  to lack cardnogenkHy  1n Osborne-Mendel
rats  and  86C3F1  mice under the conditions  of  an NCI  (1979) bloassay.  This
conclusion  Is  consistent  with those  of three  previously  reported  studies

00670                               V-60                            "Vi 7/88

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concerning  endrln  carclnogenlcHy  In  rats  and mice.   In  contrast,  Reuber
(1979)  has  concluded  that  an  Increased   tumor  Incidence  Is  elicited  by
chronic  endrln  exposure,  based  on  his  Independent  evaluation  of  the  NCI
(1979) bloassay tissue sections,  and on a separate study  (Reuber, 1978).
00670                               V-61

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                         VI.  HEALTH EFFECTS IN HUMANS
Acute Toxldty
    In  September  1978,  the  U.S.   Department  of  Health  and  Human Services
Issued  an  occupational  health  guideline  for  endrln  (U.S.   OHHS,  1978).
Symptoms of overexposure were described as follows:
    Exposure  to  endrln  may  cause sudden  convulsions which  may  occur
    from  30 minutes  to  10 hours  after  exposure.   Headache, dizziness,
    sleepiness,  weakness  and loss of appetite  may be present  for 2-4
    weeks  following  this  exposure.  A  number  of  deaths  have occurred
    from  swallowing endrln.  In less severe  cases of endrln poisoning,
    the  complaints Include  headache,  dizziness,  abdominal  discomfort,
    nausea, vomiting, Insomnia, agitation and mental confusion.
    Electroencephalograms may show dysrhythmlc  changes which frequently
    precede convulsions;  withdrawal from exposure usually  results 1n a
    normal, electroencephalogram  within  1-6 months.   In  most  cases,
    recovery  1s  rapid,  but headache, dizziness,  lethargy,  weakness and
    anorexia may persist for 2-4 weeks.
    Accidental  and  Intentional  Poisonings.    Several   Incidents  of  endrln
poisoning  from contaminated  flour have been reported In  the  literature.   In
Hales,  bread  made from flour  contaminated  with endrln during  shipment  In  a
railway  car  resulted  In  59  poisoning cases with  no deaths  In 1956.   The
bread  contained  up to 150 mg endr1n/kg bread and  the smallest  acute  dosage
to  elicit  serious  effects  was  calculated  to  be  0.2 mg/kg  bw (Davles  and
Lewis, 1956).

    In 1967, explosive outbreaks  of acute endrln  poisoning  occurred  In Doha,
Qatar  and  Hofuf  In  Saudi a  Arabia  as a  result of  the  tngestlon  of  food
prepared with endrln-contamlnated flour (Weeks, 1967; Curley et al.,  1970).
Twenty-six persons  died  and  874  were  hospitalized.  Many others were  prob-
ably poisoned to  a lesser degree but  did not seek  medical  aid.  The concen-
tration  of endrln  1n  bread  eaten  by patients  ranged  from  48-1807   mg/kg


00680                               VI-1                             JCv'22/;"

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bread.  Flour used  to  made  the  bread  contained 2153-3367 mg endrIn/kg flour.
Coble et al.  41967} reported acute endrIn  poisoning  with  sudden convulsions
In  three  Egyptians,   following  1ngest1on  of'bread  made  with  contaminated
flour.  In these cases,  recovery was  spontaneous.   A  serum endrIn concentra-
tion  of 0.053 ppm was reported for one  of these patients 5  hours  after  Us
apparent consumption  1n  contaminated  bread, and  30 minutes after  a  convul-
sion was observed.

    In  the  Punjab  province  of Pakistan  between July  14  and  September  26,
1984  there  were  194  cases  of  probable  endrIn  poisoning  (Anonymous,  1984;
Rowley  et  al.,  1987).  Of  the  194  cases,  19 (70%)  deaths occurred  among
persons between 1  and  9 years  of  age.  Males  and  females  were  equally
affected.    Symptoms  Included  sudden  collapse,  'bilateral  jerking  of  the
upper  extremities  followed  by  general   tonic,   clonlc   contractions   and
frothing and  vomiting1.   Older patients reported headaches and/or  nausea  and
minor  muscular  spasms  about  one-half   hour  before  collapsing.  Repeated
attacks were  associated  with hypoxla, pulmonary congestion and  death.   Serum
levels  from   12  of  18 patients  with  convulsions  had  measurable levels of
endMn.  Values  from  the 12  patients  ranged from 0.3-254 ppb with a  mean of
30.10 ppb.   No  endrln  was detected  1n the urine  of  these 12  patients  (Rowley
et  al.,  1987).  A  case-control  study  did not  Implicate  causative food or
environmental factors.  However, a common  food product,  sugar, may have been
contaminated.   One  composite  sugar  sample  taken  from  the hoaes  of  three
patients had  endrln levels  of  0.04 ppn (Rowley et al.,  1987).   The presence
of  endrln In  57X of patients with seizures tested  1n  Pakistan  suggests that
endrln was  the cause of this  outbreak  (Anonymous.  1984; Rowley et al.,  1987).
00680                               VI-2

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     Cases  of  fatal   endrln  poisoning  have  been  reported  from Intentional
 1ngest1on  and accidental  Ingest!on.   TewaM  and  Sharma  (1978)  reported  11
 fatal  poisonings;  the  time  periods  from  administration  of  the  pesticide
 (route  not known  1n seven cases)  to death  ranged  from  1-6  hours.   Endrln
 Ingestlon  with  milk  or  alcohol  appeared  to  Increase  toxldty  as  death
 occurred  within  an  hour or  two.   Increased toxldty was attributed  by  the
 authors to more rapid absorption through the GI tract.

     A  pedlatrlc  hospital  In  Mexico-  reported  endrln  Intoxication  1n  33
 patients  ranging  1n  age  from  1-16  years   (Hontoya  Cabrera  et  al.,  1982).
 Accidental  Ingestlon accounted  for  22  cases, 7  were  suicides  and 4 were
 attributed  to  criminal  Intent.   The  accidental poisonings resulted  from  the
 uncontrolled use of endrln In the home as a rodentldde.

     A 19-year-old  male who attempted  suicide  by  Ingestlon of  endrln  devel-
 oped severe pulmonary edema as  well as CMS  Involvement.   Pulmonary  edema was
 thought  to be due to  chemical  pneumonltls and  aspiration  pneumonia.  The
 authors believed  that  the use of PEEP  (positive end-expiratory  pressure)  up
 to   28  cm  H.O  In  treatment  of  the  pulmonary  edema  contributed  to  the
 patient's complete recovery (Jedelkln et al., 1979).

     Effects  of   Occupational   Exposures.   No   Illnesses  were  noted   In
 seasonal workers dusting  potatoes with  1% endrln dust  at a calculated dermal
 exposure  of  2.0  rag/kg  bw/day  In combination  with  a  calculated  respiratory
 exposure  of  0.044 mg/kg bw/day  (Wolfe  et  al., 1963).   Also, no  Illnesses
were noted when  endrln was  applied  at 544-634 kg/acre as  an  emulslflable
00680                               VI-3

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concentrate  for  nice control at  a calculated dermal  dose of 0.28 mg/kg/day
1n combination with  a  calculated  respiratory exposure of 0.0011 mg/kg bw/day
(Wolfe et al., 1963).

    Immunology.   Thirteen   pesticides   Including  endrln  were  tested  for
their  jjn vitro  effects  on  human lymphocyte  mltogenlc  responses  to  phyto-
hemaglutlnln  and neutrophll  chemotaxls  (Lee  et  al.,  1979;  Park and  Lee,
1980).   This  study was undertaken 1n  an effort to clarify the Imunosuppres-
slve  effects of many  pesticides.  Endrln Inhibited  the lymphocyte response
In whole blood  11.5X and 14.2% 1n mononuclear cells.  Neutrophll chemotaxls
was  Inhibited 21%  (77*4  vs. 105*10  cells  per  high  power field  In  control
cultures).   In  each case,  Inhibition was not reported to  be statistically
significant.  All  pesticides tested  Inhibited lymphocyte responses  to  some
degree,  and  the authors  suggested  that  the  Inmunosuppresslve effect  of
pesticides could be a direct effect of those chemicals on leukocytes.

    Epldemloloqlcal  Studies.   Jager   (1970)   reported  an  epldemlologlcal
study conducted  on 826 male  workers at  the  Insecticide plant of Shell  Neder-
land  Chemle  located at  Pernls,  Netherlands.  A  unit for the  production  of
endrln was begun 1n  February 1957.  During  the first  2 years of plant  opera-
tion  seven cases of  endrln  Intoxication  had  occurred  and were accompanied  by
convulsive seizures.  All were due to acute  overexposure either  following  an
accident  or  to  obvious neglect of  precautions.   Normal recovery  was  rapid,
usually within 1-3 days.

    Concentrations of  endrln In  the  blood  of 45 operators  from  the  endrln
plant were  determined at  least  once a  year  from 1964-1968.  The threshold

00680                               VI-4                             ""•'": '*'••

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 level  of  endrln  In the blood below which no sign  or  symptoms of  Intoxication
 were  seen  was  0.050-0.100  vg/rai.   The  half-life of  endrln  In  the blood,
 and  thus  1n  the  body,  was estimated  to be  -24 hours.  Medical  files and
 routine  medical  examinations  revealed  no abnormalities other than those that
 would  be  expected  1n any group  of  233 long-term workers (4-13.3 years expo-
 sure).   Results  of  determination  of alkaline phosphatase,  SGOT,  SGPT,  LDH,
 total  serum proteins,  and  the  spectra  of serum  proteins  did not  show any
 changes  that  could be  correlated  with the Influence  of  the degree or dura-
 tion of  exposure to  these  Insecticides on these parameters.   In all cases of
 Intoxication characterized  by typical  EE6 changes, EEG patterns  returned to
 normal.   In the  study  of  the  parameters  of enzyme Induction, the data showed
 that occupational  exposure 1n  endrln  manufacturing may  cause  enzyme Induc-
 tion In  hydroxylatlng  enzyme  systems although this response appeared not  to
 affect  the health  of  the workers.   It was not  known whether  endrln  or  Its
 manufacturing precursors were the causative agents (Jager, 1970).

    A  follow-up  mortality  study  on 233 of these  workers having at  least  4
 years  of  exposure  by  1970  has  recently  been  reported  (Rlbbens, 1965).   Of
 these  233  workers  who were  occupationally   exposed  to aldrln,  dleldrln,
 endrln and/or TelodMn, 232 were accounted for.   The  mean and range of expo-
 sure durations were  11  and  4-27  years,  respectively.   These  periods,  as  well
as the  exposure  levels, were considered  sufficient for  meaningful  mortality
 evaluation.  The   total mortality  of  this population was 25,  significantly
 lower  than  the  expected mortality  of  38 based on death  statistics of Dutch
men.   Nine  of 25 deaths were caused by  neoplasms,  versus 12 expected cancer
 deaths;  3/9 neoplasms were  lung  tumors.  The  remaining  six  cases  were
 comprised  of  six  different neoplasms,  none   of  which  were liver  tumors.

 00680                               VI-5

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These  results  were concluded to reveal no evidence  for  specific cardnogen-
1c1ty  of endrln, aldrln or dleldMn In this exposed population.

    Hoogendara  et  al.  (1962, 1965) conducted  a  parallel  study at  the  same
plant.   Of  the 122  men  exposed to all pesticides  at the plant,  25 workers
had  EEG abnormalities (Hoogendam et  al.,  1962).   A  worker  was accidentally
covered with a  50% Isodrln  solution  1n xylene.   He experienced dizziness  and
headache  and  profusely  perspired 2  hours  later.   This  worker suffered  a
typical  eplleptlforra convulsion  6  hours  after  the  exposure,  regained  con-
sciousness within  10 minutes and rapidly  recovered.  There  1s  some  evidence
to  suggest  that Isodrln  was partially converted  to  endrln  1n  the  liver  of
this patient (Brooks,  1969).  The EEGs of patients with  endrln Intoxication
showed  paroxysms of  predominantly bilateral  synchronous  theta-waves.   In  the
other  report (Hoogendam  et  al., 1965) three endrln workers  suffered convul-
sive Intoxications,  two  being examined for  recovery  of  abnormal EEGs.   One
was  exposed  for 1.5  years  and  the  other  for 3  years.   One recovered 1n  1
month,   and the  other In  <6 months.  The authors  suggested that the  prevail-
ing  exposure   1n  the  manufacture of  aldrln,  dleldrln  and   endrln  did  not
disturb liver  function since the levels of SGOT  and  SGPT  returned to  normal
In the  four workers who Initially showed Increases.

    Ottevanger  and Van SUtert  (1979)  continued the enzyme Induction studies
of  Jager  (1970) on  29  endrln workers at  the  endrln  manufacturing  plant  in
Pernls.  The D-glucarlc  add concentration 1n urine  was  considered  to be a
useful   test for  enzyme Induction.  After  7  days  of  exposure,  levels  of  the
metabolite, antl.-12-hydroxyendrln.  Increased  (up  to  0.360 mg/g creatlnlne)
accompanied by  a sharp rise  In  D-glucarlc acid levels.  After  the  long week-
end, the anU.-12-hydroxyendrln  levels decreased,  but 0-glucar1c add  levels
00680                               VI-6

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remained  above  normal.   The normal  values  obtained after a  6-week  shutdown
and maintenance  period  Indicated that enzyme Induction  1n endrln  workers  is
reversible.  A  urinary  ant1-12-hydroxvendr1n level of  0.130  mg/g  creatlnlne
was  considered  the  threshold  level  below  which  enzyme  Inductlo- does  not
occur, although exceptions were noted.

    VMJ-Standhardt  et  al.  (1979)  examined  urinary excretion  of  D-glucar1c
add  and  total  porphyrln  1n  endrln  workers.  The  excretion  of  D-glucarlc
add  after working was  significantly  Increased  compared with  excretion  after
a  long  weekend  and with  a  control  group.  The  results  Indicated   that
D-glucarlc add was  a  useful  test  for  exposure to  endrln,  but  porphyrln
excretion was not.

    An ep1dem1olog1cal  study was  made of 216 patients  with contact dermatl-
t1s In rural regions  of Japan  from  1968-1970  (Matsushita  et al., 1980).  All
participants   except   three  were farmers.    Exposure  occurred  mainly   from
spraying  operations.   Chlorinated hydrocarbons  (BHC and endrln) were  thought
to be responsible for 9.7% of  the cases.  Inaoequate  protection of the  spray
personnel, poor  health  conditions and carelessness were  largely responsible
for the dermatitis.

    Wang  and Grufferman (1981) performed a case control  study of the  associ-
ation  between   fatal aplastlc  anemia  and  occupations  entailing   pesticide
exposure.  They  found no  correlation between use  of chlorinated hydrocarbon
pesticides,  Including endrln,  and  aplastlc  anemia mortality in   the United
States from 1950 through 1975.
00680                               VI-7

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    OUraglla  et  al.  (1981)  conducted  a   retrospective   cohort  study  to
examine  the  mortality of workers  employed In the  manufacture  of chlordane,
heptachlor,  DOT  and  aTdrln/dleldrln/endrln.   The  four  plants  selected  for
study are  described  1n Table VI-1.  Workers  '.elected  for  the study had been
employed  at  least  6 months;  the  personnel  1n  contact  with  endrln  were
located at plants 2 and 3, and numbered 30S and 1155, respectively.

    The only major category  where  observed deaths  were greater  than expected
was  'nonmallgnant  respiratory system  disease1  at  Plant  3   (22  observed  vs.
10.4  expected:  SMR-212)  and for  'other  respiratory diseases'  (11  observed
vs.  5.2  expected:  SHR-213,  p<0.05).   No  statistically  significant  excesses
or deficits  In mortality  for any  specific cancer  site were noted.   In  Plant
3  there was  a  slight excess of cancer of  the esophagus  (2  observed  vs.  0.85
expected), cancer  of the  rectum   (3 observed  vs.  1.24 expected), cancer  of
the  liver  (2 observed, vs.  0.57  expected),  and  cancer of  the  lymphatic  and
hematopoletlc system (6 observed  vs.  4.09 expected).   There was a  deficit
for  respiratory  cancer (7  observed  vs.  12.64 expected)  at  Plant 3.   Addi-
tional  analyses  are  necessary to determine 1f  an  excess  1n  nonmallgnant
respiratory disease observed at Plant  3 was associated with specific  occupa-
tional  exposure.   Since malignant respiratory disease  was not  reported  at
Plant  2,   which  also  manufactured endrln,  endrln  alone   probably  did.  not
Induce the  lethal  respiratory disease reported at  Plant 3  unless  exposures
were much  higher  than  those at  Plant 2.  However,  OUraglla et al.  (1981)
did not report exposure data.
00680                               VI-8                             Cc. :

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                                  TABLE VI-1

         Description of Plants Included In the Study of Manufacturers
                      of Organochlorlne (OC) Pesticides*
                       Plant 1
 Plant 2
Plant 3
Plant 4
Starting date for OC
pesticide production
OC pesticides
produced
Other pesticides
produced
Other chemicals
at plant
Location
*Source: Dltraglla et
1946
Chlordane
None
Chlorine,
dlcyclo-
pentadlene
Illinois
al., 1981
1951
Heptachlor,
endrln
None
Chlorine,
chlorendlc
anhydride.
hexachloro-
cyclopenta-
dlene, vinyl
chloride
Tennessee

1946
Aldrln,
dleldrln,
endrln
Organo-
bromlnes;
organo-
phosphates
Numerous
precursors
Colorado

1947
Dlchloro-
d1phenyl-tr1-
chloroethane
(DDT)
None
Tr1-chloro-
acetaldehyde,
sulfurlc add,
nonochloro-
benzene
California

00680
VI-9

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Suarnary
    Exposure  to endrln  1s  reported  to cause  CNS effects,  convulsions  and
death.   In  less  severe  poisoning,  recovery Is usually rapid and there are no
permanent effects.

    A number  of  cases of  acute poisoning resulting from accidental or Inten-
tional  Ingestlon of endMn  have been  reported.   The approximate  oral  dose
producing convulsions Is between 0.2 and 0.25 mg/kg bw.

    No  potential  hazard existed  during typical dermal  or  respiratory expo-
sures encountered by seasonal  agricultural  workers exposed  to endrln through
dusting and spraying operations.

    No  fatalities or permanent abnormalities were recorded  1n  a  1970 eplde-
m1olog1cal  study  of 233  workers  engaged  In  the manufacture  of  chlorinated
hydrocarbon  Insecticides  Including  endrln  for more  than 4  years.   Convul-
sions  and  CNS  effects  were  observed  In  some workers.   Exposure did  not
elicit  an  elevation  In  total  mortality  of  these  workers  through  1985.
Occupational  exposure  In  endrln manufacturing may cause  enzyme  Induction  In
hydroxylatlng enzyme  systems,  but  this response  appeared  to  be  reversible
and  to   have  no  effect  on  the  health of  workers.   Antl-12-hydroxyendrln
levels  excreted  1n  the  urine of endrIn-exposed workers  were  correlated with
excretion of D-glucar1c add.

    No  correlation was  found  between mortality from aplastlc anemia  and  the
use of  chlorinated pesticides  Including  endrln  In the  United States from
1950 through  1975,  although  no exposure data were provided  to  allow assess-
ment of the Importance  of endrln 1n this study.
00680                               VI-10                            v«

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    A  mortality  study of workers  engaged  1n the  manufacture of organochlo-
rlne pesticides  did  not  Identify a specific  cancer  risk but further studies
were recommended.
00660                               VI-11

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                         VII.  MECHANISMS OF TOXICITY
Acute Toxlclty
    The order of acute  oral  toxldty  to  endrln 1n various adult male species
1s monkey  >  rabbit > pheasant •  quail > chicken » cattle «  dog  > hamster  >
guinea  pig -  rat.  Young  animals  and  female animals are more  susceptible
than adult males,  at least 1n rats (Treon  and Cleveland,  1955).   Endrln  and
Us metabolites are  quickly eliminated except  at grossly  high doses,  and  the
total half life varies  between 1  and  4 days (see Chapter  IV).  Doses  of >0.2
mg endr1n/kg bw can  cause  convulsions  (Jager,  1970);  lethality to humans  may
occur at doses >6 g/person (Reddy et al., 1966).

    The  unsubstltuted  methylene  group  1n  endrln  1s rapidly  attacked  to
produce mostly  antl- and  some s^n-12-hydroxyendrln, the former being  elimi-
nated as  the  sulfate in the  urine  of  rabbits, female rats and hens,  as  the
aglycone 1n the  feces  of  male rats, as  the glucuronlde 1n the urine and  the
feces of  humans,  and as  the free  metabolite  1n the  urine  of the cow (see
Chapter IV).  The  s^n-alcohol Is  quickly transformed  to !2-ketoendr1n, which
Is the most acutely  toxic  to  rats of  all endrln derivatives  Including  endrln
Uself (Bedford et al., 1975a).   In fact, associations between lethality  and
the presence of  !2-ketoendr1n residues  In the brain have been made for rats
(Hutson  et al.,   1975),  rat fetuses  (Kavlock  et al.,  1981)  and hamster
fetuses (Chernoff et al.. 1979) but not  for birds  (SUckel et al.,  197°a,b);
12-ketoendrln has been postulated as the ultimate toxicant, at lease  In rats
(Bedford et  al.,   1975a).  hamster  fetuses  (Chernoff  et  al..  1979)  and   rat
fetuses (Kavlock et al., 1981).
00690                               VII-1

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     The  CMS  Is  the  major  target  system  for  acutely  administered  endrln.
 Emerson  et al.  (1964)  suggested  that endrIn-Induced  hyperexcUablllty and
 convulsions  were caused  by a  direct  action  of  endrln on  the  motor cortex
 and/or  spinal  cord.   It was further suggested  that endrln acted directly on
 the  medulla  since  the  bradycardla  that  followed endrln  exposure  preceded
 pressure  Increases  In  the  cerebrosplnal  fluid   and  sagltal venous  sinus,
 which were  also  elicited  by endrln  exposure.  Walsh and Fink  (1972) suggested
 that  the mechanism  of acute  endrln  toxldty  Involved Induction of a  bio-
 chemical lesion  In the CMS,  followed by a time-dependent process culminating
 In  toxic manifestations.   It  was postulated  that Interference  with  plasma
 membrane or mitochondria!  ATPase may be Involved  In the mechanism.  However,
 Nehrotra et al.  (1982) reported that although  some ATPase activities of rat
 brain  and   beef  heart  were  Inhibited  by  cyclodlene  pesticides  (Including
 endrln)  Jjn vitro,  these  Inhibitions   could  not  be  easily  related  to  the
 toxldty of the  compounds.  For example, endrln was  more  toxic  to rats  than
 aldrln,  but ATPase  activities were Inhibited  to  a greater  extent by aldrln
 relative to endrln.

    A series  of  more  recent studies  suggests that  mechanism of  CNS disturb-
ance and toxldty  for endrln  are  related to Interference with  gamma-ami no-
butyric  acid  (GABA)-medlated functions.  The toxic and  convulsant potencies
 In  mice  of  a  series  of  14  polychlorocycloalkane  (PCAA)  Insecticides,
 Including endrln, were determined and related to  their  .In.  vivo potencies for
 Inhibiting  the  mouse  brain  t-butylblcyclophosphorothlonate  (TBPS)   binding
 site, which  Is  associated  with  GABA-regulated  chloride transport (Cole  and
Caslda,  1986).   Following LD5Q estimations,  male Swlss-Uebster  mice   were
administered  LD5Q,   L05Q/2  or LD50/*  doses  of  each  compound  by  Intra-
perltoneal   Injection.   Mice were  sacrificed  30  Minutes  later,  brains   were
00690                               VII-2

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removed  and binding  of [>$S]TBPS  to brain  membranes  was  determined.   For
endrln  specifically,  the  LD50  was 8  mg/kg  bw, and  the  percent Inhibitions
for  LDjQ,  LDjQ/2  and LD5Q/*  doscs  were  77±7»  39±6  and  °*,  respec-
tively.   These data  were  consistent with  two previous  reports  suggesting
binding  of  cyclodlene  Insecticides  (Including endrln)  to  the GABA receptor
(Lawrence and  Caslda, 1984; Tanaka  et al.,  1984;  Aballs  et  al.,  1985).  It
was   concluded  that   the  toxldty  or   convulsant  activities   of   PCAA
Insecticides were correlated with  in  vivo  disruption  of the mouse brain TBPS
binding site.

    Aballs  et  al.  (1986)  also  reported that  a  GABA-Indue ted  "Cl~  Influx
Into  rat brain  mlcrosacs  Is   reduced by  Uj,  vitro  exposure  to  cyclodlene
Insecticides.  Mlcrosacs  exposed  to  endrln  (1 jifl)  exhibited an 82%  reduc-
tion  1n  "Cl~ Influx  relative  to  control.   These data were  Interpreted
as  supportive  of  previous  suggestions that  cyclodlene  Insecticides  (Includ-
ing endrln) Inhibit functions mediated by the GABA receptor.

    Peripheral  vascular  effects  of  acute endrln  exposure were examined  In
partially Isolated forellmbs of  10 mongrel dogs (Emerson  and  H1nshawt  1965).
Following the  surgical  forel 1mb  separation and,  In  5/10 dogs,  denervatlon  of
the forellmb,  endrln  (10 mg/kg) was  Intravenously Infused.  After  about  10
minutes  of   Infusion,  Innervated  11mb vascular  resistance Increased  -80%;
this Increased resistance  was  accompanied  by a decrease  In  limb  blood  flow.
S1m41ar  results  were observed  In the denervated  forellmbs  after   about  10
minutes of  Infusion.  However,  In  contrast to  the  Innervated  limbs,  vascular
resistance  subsequently Increased  steeply  to  high  levels,  and 11mb  blood
flow  virtually ceased.   It  was concluded  that sympathetic  1nnervat1on was
not necessary  for vascular resistance Increases following endrln  exposure,

00690                               VII-3

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and  U  was  suggested  that  the  vascular  effects  of  endMn  may be  due to
circulating catecholamlnes.

    Endrln  toxldty  may  also   be  mediated  through  effects   on  membranee
permeability,  since  heraolysls  has been  observed  for postendrln hematocrlts
In dogs  (Emerson  et al.,  1964),  and  "hemorrhaglc  enteritis1  has been noted
In rats and birds (Stlckel et al., 1979b).

    Subchronk  studies  In  human workers  are  consistent with  a reversible
Induction  of   liver  nlcrosomal  activity,  as  denoted  by urinary levels  of
D-g1ucar1c  add,   which  Is  dependent  on  the  level  of  cytochrome  P-450
(Ottevanger and  Van Slttert, 1979).   0-glucarlc add was  not  detected  In
urine when ant1-!2-hydroxyendr1n urine  levels were <0.13 mg/g of creatlnlne.

    In rats (Treon et al., 1955), the only long-term degenerative changes In
the organs  from  fatally-poisoned animals studied occurred 1n  the liver  and
kidneys.  The mechanisms responsible for  such changes are not known.

    Endrln was reported to lack  cardnogenldty In  several  studies  (Treon et
al..  1955;  Oelchmann et al., 1970; Ultherup  et al., 1970; NCI, 1979),  but
Reuber (1978,  1979)  has concluded that endMn  Is a  carcinogen.   It  Is  note-
worthy  that  endrln  lacks  genotoxldty  1n  bacterial assays  (Ames  et al.,
1975;   Horlya  et al.,  1983),  and like other  organochlorlne pesticides.   In
rat,  mouse and hamster  hepatocytes (Maslansky and UllHams, 1981).  In view
of these  results,  Haslansky  and Williams (1981) proposed that  the  cardno-
genldty of  organochlorlne  pesticides  reflects  an  eplgenetlc  rather than a
genotoxlc mechanism.  This  proposal  Is consistent  with  the observations  of


00690                              VII-4

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Kurata   et   al.   (1982),  which  Indicated  that  organochlorlne  pesticides
(Including   endrln)   Inhibited  metabolic  cooperation  1n  Chinese  hamster
cells.   It  was  suggested  that  the  pesticides  that   Inhibited  metabolic
cooperation  might  be tumor  promotors.   Further, Ito  et  al.  (1980)  reported
that  dietary endrln  exposure  (25  ppm  for  6 weeks) elicited  an Increase In
the  area of hyperplastlc  liver  nodules In hepatectomlzed  Fischer  F344 rats
previously  treated  with  d1ethyln1trosam1ne,  although  the  number  of  nodules
was  not affected  by  endrln.   A  classification system  was  also  proposed;
endrln would be classified by  this system as a weak promoter.

    It  Is  emphasized that the discussion In the above  paragraph  should not
be construed as  positive evidence  for  endrln tumor 1 gene11ty,  but  rather,  as
evidence of  a  possible eplgenetk  action of  endrln.   Conclusions  concerning
endrln carclnogenldty are presented 1n the following chapter.

Interactions
    Ludke  (1976)  demonstrated  that  prior  treatment  with  a  closely-related
Insecticide  can  Increase bird mortality.   Fourteen-week-old male and  female
white quail  (Collnus  v1rq1n1anusl  were divided   Into four groups; four  birds
constituted  the control  group.  All  groups were  fed turkey maintenance mash
with IX  (w/w) propylene  glycol  mixed  In the diet.  Pesticides  were  dissolved
In propylene glycol and mixed  Into the diet.  Twenty-eight  birds received 10
ppm  technical chlordane  In the diet for  10 weeks and  20 of these were Inert
fed 10 ppm 98% pure  endrln  In  the  diet for  6-10 days.   A fourth group  (N-20)
was  fed  10 ppm endrln  In the diet.   No mortality  occurred 1n the control
group nor In the group fed chlordane alone.   For endrIn-fed birds, mortality
occurred on  days  1  (1 bird),  6 (7),  9  (5)  and 10 (2).  For  the chlordane-
endrIn-treated groups, mortality occurred on days  3  and 6-10  (14 birds)  of
00690                               VII-5

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endMn  exposure,  and  survivors  were sacrificed on  days  9 and 10  of  endrln
exposure.  All  surviving  birds  treated  with  endrln alone  or chlordane-endrln
lost  weight  and   showed  depleted  llpld  content   In  the  carcasses  (Table
VII-1).    Control   and   chlordane-treated  birds   showed  no   significant
decreases.  Birds  that  survived  exposure  to  chlordane-endrln  or  endrln  alone
had  lower brain residues of endrln  than the  dead birds.   Birds  dying  of
endrln  poisoning  alone  had  brain  residues   ranging   from  0.34-1.84   rag
endrIn/kg  ww  (survivors  • 0.28-0.62 rag endMn/kg  ww).  In chlordane-endrln-
treated  birds,  the  dead  birds contained  0.17-1.25  rag  endrln/kg  brain,
whereas  the  survivors  had  0.14-0.56  rag/kg  brain.   The  latter  two  groups
differed  at p<0.10.   Dead or  moribund birds  treated with  the  two pesticides
contained  significantly  lower   (p<0.025)  endrln  brain  residues  than  the
corresponding  birds  treated  with  endrln  alone.  Thus,  birds nay  be more
vulnerable to a toxicant  if the  bird  already carries a  body burden  of one  or
more closely related  chemicals.   In this  study, Mortality  from endrln  alone
was associated with as little as 0.34 rag endMn/kg  brain.

    Neena  et al.  (1978)  Investigated endrln-lnduced toxldty   In normal rats
and rats  Irradiated  with gamma  radiation by dividing  128 male  albino rats
(150-200 g) Into  four equal  groups.   The control  group  received  groundnut
oil 1.p.;  group 2  received  a  single 1.p. Injection of 10 ag endrln/kg bw  In
groundnut  oil;  group  3  served   as  Irradiated  controls (900  rads);  group 4
received 10 rag endrln/kg  bw 0.5  hours after  Irradiation.   In both normal and
irradiated rats,  endrln  caused  a  significant   Increase  In SGOT,  SGPT and
ATPase; add and alkaline phosphatase,  sucdnlc  dehydrogenase  and glucose-6-
phosphatase decreased  significantly  during  varying periods   of  2-48  hours
after   treatment.   In  Irradiated rats  given  endrln,  the  changes  appeared
earlier and  were  more  pronounced  than  In normal  rats given  endrln alone,

00690                               VII-6

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                                 TABLE  VII-1

    Weight Loss and Llpld Content (Mean X + S.E.)  of  Quail Carcasses After
    Technical Chlordane, 98%-Pure Endrln,  and  Chlordane-EndMn Treatments*
        Treatment
Chlordane
Endrln
                               Condition     No.     X Llpld     % Weight Loss
None
10 ppm diet:
10 weeks
None


10 ppm diet:
10+ weeks

none
none

10 ppm diet:
6-10 days

10 ppm diet:
6-10 days

S
S

0
M
S
D
H
S
4
4

13
1
3
12
3
3
4.69+0.77
3.45+0.56

0.43+0.14
0.73"
2.73+0.97
0.39+0.06
0.2770.04
2.78+"l.29
0
0

32.2+2.4
68.6"
14.7+1.1
31.4+3.0
37.2711.7
19.U3.5
•Source: Ludke, 1976

S > Sacrificed, no apparent signs  of  toxldty; 0
(reduced activity and lowered appetite)
                                dead; M * moribund or sick
00690
                  VII-7

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except  1n  the  case of ATPase where  endrln  appeared to neutralize the effect
of radiation on  the  mitochondria!  membrane.   The study indicated that endrln
leads to  Injury  of liver and kidney  tissues,  and  that this  may occur sooner
after gamma Irradiation of rats.

    Following  2  weeks of dietary  exposure  to 0,  5 or 100 ppm endrln,  rats
were  administered a  single  dose of  CC1.  (0.1  ml/kg)  by  Intraperltoneal
Injection, and  hepatotoxldty was assessed  the following day  by determina-
tion  of  serum enzyme  activities  (Young and  Hehendale,  1986).   No  signifi-
cant  elevations  In  enzyme  activities were  observed following   exposure  to
endrln  alone.    Following  exposure  to CC1.  alone,  modest  but  significant
elevations 1n  serum  of  male rats  was  reported  for  SGPT,  SGOT  and Isodtrate
dehydrogerase   (ICO)   activities.   In   females,   CC1.  exposure   elicited
significant  but  modest  elevations  In  SGOT and  ICO activities  and a  more
substantial  elevation  1n  ornlthlne-carbanyl   transferase   (OCT) activity.
However,  exposure  to  CC1.  plus  endrln elicited  marked elevation  In  SGPT
and ICO activities 1n females relative to the  untreated  controls.   Further,
these  activities  were  statistically   significantly  higher  than those of
animals  exposed  to   CC1.   alone.    It  was  concluded  that   dietary  endrln
pretreatment  potentiated CC1.  hepatotoxldty.

Summary
    Acute exposure to  endrln  causes  death,  which Is preceded by  convulsions
and other  CMS  disturbances.   Acute toxlclty Is associated with  the  presence
of 12-ketoendMn, and this metabolite  has been  postulated to be the  ultimate
toxicant.   Evidence  suggests  that endrln  (and other  polychlorocycloalkene
Insecticides)  may  Induce convulsions  and  death by  Interfering with GABA-
regulated  functions  1n  the  CMS, particularly chloride  transport.  Increased
00690                               VII-8                             '••••'•••.-._

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vascular  resistance that  follows endrln  exposure may  be Mediated  through
effects  of  circulating  catecholamlnes.   Studies  of  human  workers  exposed
subchronlcally  to  endrln   suggest  Induction  of  liver  nlcrosomal  enzymes.
Mechanisms of chronic endrln toxldty are not known.

    As  with  other  organochloMne pesticides, endrln  lacks  genotoxlclty  In
bacterial  systems  and   1n  rodent  hepatocytes,   but  can  Inhibit  metabolic
cooperation  1n Chinese  hamster  cells.   These  observations  are  consistent
with,  but  do not  necessarily  Indicate,  a  capability of endrln  to  Influence
tumor development  by eplgenetlc mechanisms.

    Evidence  for  Interactions  augmenting  endrln  toxldty exists  for birds
carrying a body burden of closely related  chemicals, and for rats  pretreated
with  gamma Irradiation.   Pretreatment  with  endrln potentiated  CC1.-Induced
hepatic Injury In  rats.
00690                               VII-9

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                VIII.  QUANTIFICATION OF TOXICOL06ICAL EFFECTS

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

    In  the  quantification  of  noncarclnogenlc   effects,  a  Reference  Dose
(RfD),  [formerly  termed  the  Acceptable Dally  Intake (ADI)]  1s  calculated.
The RfD  Is an estimate  (with uncertainty  spanning perhaps an order  magni-
tude)  of  a  dally  exposure to  the  human  population (Including  sensitive
subgroups) that  Is  likely to  be  without  an  appreciable risk  of  deleterious
health  effects  during  a  lifetime.   The RfD  Is  derived from  a  no-observed-
adverse-effect   level   (NOAEL),   or    lowest-observed-adverse-effect   level
(LOAEL),  Identified  from a  subchronk  or  chronic  study,  and  divided by  an
uncertainty factor(s)  times  a modifying  factor.  The  RfD  Is  calculated  as
follows:
     RfD - 	(NOAEL or LOAEL)	,
           [Uncertainty Factor(s) x Modifying Factor]   	
    Selection of the uncertainty factor to be  employed  1n  the calculation  of
the RfD  1s based  upon  professional judgment,  while considering the  entire
data  base  of lexicological  effects for  the chemical.  In  order to  ensure
that  uncertainty  factors  are  selected  and applied  In  a  consistent  manner,
00700                              VIII-1

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 the  U.S. EPA  (1988a)  employs a  modlfIcatlon  to  the guidelines proposed by

 the  National Academy of Sciences  (HAS, 1977,  1980) "as  follows:


 Standard Uncertainty Factors  (UFs)

         Use a  10-fold  factor  when extrapolating from  valid experimental
         results from studies  using prolonged  exposure  to average healthy
         humans.   This  factor  1s  Intended to  account  for  the variation
         1n sensitivity among  the members of the human  population.  [10H]

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

     •    Use an additional  10-fold  factor  when extrapolating  from less
         than chronic  results on  experimental animals when there  Is no
         useful  long-term  human  data.   This  factor  Is  Intended  to
         account  for the  uncertainty  1n extrapolating  from  less  than
         chronic NOAELs to chronic NOAELs.  [10S]

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

Modifying Factor (MF)

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

principally  i^on  scientific  judgment   rather   than  scientific   fact  and

accounts  fur  possible   Intra-  and   Interspedes   differences.   Additional

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

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

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

counterbalancing of beneficial effects.



00700                              VII1-2

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    From  the RfD,  a Drinking  Hater Equivalent  Level  (DUEL) can  be calcu-
lated.   The  DUEL  represents  a  medium  specific  (I.e.,  drinking  water)
lifetime  exposure  at which  adverse, noncarclnogenlc health  effects  are not
anticipated  to  occur.   The DUEL  assumes  100% exposure from  drinking water.
The DUEL  provides  the noncarclnogenlc health effects basis  for  establishing
a  drinking  water  standard.   For  Ingest!on  data,  the  DUEL  Is derived  as
follows:
               DUEL  .   («")  *  (Body weight  In  kg)    m
                      Drinking  Uater Volume  in  i/day   	
where:
        Body weight « assumed to be 70 kg for an adult
        Drinking water volume - assumed to be 2 i/day for an adult
    In addition  to the RfD  and  the DUEL, Health Advisories  (HAs)  for  expo-
sures  of  shorter  duration  (1-day, 10-day  and longer-term)  are  determined.
The  HA values  are used  as  Informal  guidance to  municipalities and  other
organizations when  emergency spills or contamination situations  occur.   The
HAs are  calculated using an  equation  similar  to  the RfD and  DUEL;  however,
the NOAELs  or  LOAELs  are Identified  from acute or  subchronlc  studies.   The
HAs are derived as follows:
                        (MOAEL or LOAEL) x (bw)           ,.
                        *-~———~-~~~~~~~*~~l~~  • 	mg/i
                          (UF) x (	I/day)      	
    Using the above equation, the  following drinking water HAs  are  developed
for noncarclnogenlc effects:
    1.  1-day HA for a 10 kg child Ingesting 1  i water  per  day.
    2.  10-day HA for a 10 kg child Ingesting 1 i water per day.
    3.  Longer-term HA for a 10 kg child Ingesting 1  i  water  per day.
    4.  Longer-term HA for a 70 kg adult Ingesting 2  i  water  per day.
00700                              VIII-3

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

    The U.S. EPA categorizes the  carcinogenic potential of a chemical,  based
on  the overall we1ght-of-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.
        Group   B: Probable  Human  Carcinogen.    Sufficient  evidence  of
        cardnogenlclty  In  animals with  limited  (Group  Bl) or  Inade-
        quate  (Group 82} evidence 1n humans.
        Group   C:   Possible  Human  Carcinogen.    Limited   evidence   of
        cardnogenlclty 1n animals In  the absence of human  data.
        Group   D:  Not  Classified  as to  Human  Cardnogenlclty.   Inade-
        quate  human and animal evidence  of  cardnogenlclty  or  for which
        no data are available.
        Group   E:   Evidence  of   Noncarclnogenldty  for   Humans.    Mo
        evidence  of cardnogenldty  1n at  least  two  adequate  animal
        tests   In  different species or   In  both adequate  ep 1 dentlologle
        and animal studies.
    If toxlcologlcal 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
Ingestlon  of  the contaminant  In  drinking water.   The  data used  In these
00700                              VIII-4

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estimates  usually  come from  lifetime  exposure  studies  using  animals.   In
order  to predict the risk for  humans  from animal data, animal doses must  be
converted  to equivalent  human doses.   This conversion  Includes correction
for  noncontlnuous exposure,  less  than lifetime  studies  and for differences
1n  size.  The  factor  that compensates  for  the  size  difference  Is  the cube
root of  the  ratio of the  animal and  human body weights.  It Is assumed that
the  average  adult  human   body  weight Is  70 kg  and that  the  average water
consumption of an adult human 1s 2 l of water per day.

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

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

00700                              VIII-5                            •--•/,"

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uncertainty  when  the  data  are  extrapolated  to  humans.   When  developing
cancer  risk  rate levels,  several  other areas  of  uncertainty exist, such as
the  Incomplete knowledge  concerning the  health  effects  of  contaminants In
drinking  wa*er,  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  1n experimental animals or humans.
Dose-response  data  usually  are  available  only  for  high  levels  of exposure
and  not for  the lower  levels of  exposure  closer to  where  a  standard may be
set.   Uhen  there  1s exposure  to  more  than one   contaminant,  additional
uncertainty  results from a lack of  Information about possible synerglstlc or
antagonistic effects.

Moncardnoqenlc Effects
    Although the  acute LD5Q  for  endrln has been determined  for  a  number of
species,  the available data  for defining  short-term  health advisories  (HAs)
1s more limited.   In  an abstract, Revzln  (1966)  reported an  Increase 1n  the
amplitude of the  EEG and  a tendency toward spiking  after  seven  dally  doses
of 0.2  mg/kg bw endrln 1n  rats.  No  effects w«re  noted,  however, after 1 or
                                                                 t
2  days  exposure to  the  same dose level.   Speck  and Haaske  (1958)  reported
EEG  changes  and occasional  convulsions  after  1 week using dally oral  doses
of 3.5  mg/kg bw 1n  rats.   It was not  reported whether  effects  occurred at
lower doses  (0.8 and 1.7 mg/kg bw),  which were also employed.

    Information  on  acute   and subchronlc  effects   of   endrln  exposure   1s
available from  perinatal  toxlclty studies.  Chernoff et  al.  (1979)  reported
marked  maternal toxlclty   In  Syrian golden  hamsters  at  doses  >1.5  mg/kg
                                         •»*•
bw/day  for   10  days.   Kavlock  et al.   (1981)  reported  decreased  locomotor

00700                              VII1-6

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activities  In adult female  CD-I  mice after single  oral  exposures  to 1.5 or
4.5  mg/kg endMn,  but not  to 0.5  mg/kg endMn.   In CD  rats,  single oral
endrln  doses  of  0.5,  1.0  or  2.0 mg/kg bw elicited a dose-related decrease 1n
locomotor activity.  Pregnant  CO-1  mice  exposed to endrln doses of 0.5, 1.0,
1.5  or  2.0 mg/kg  bw/day  by  oral  gavage on days  7-17  of  gestation exhibited
reduced weight gain at the three  highest exposure levels  and elevated llver-
to-body weight  ratios  at  all  exposure levels.  Pregnant  CD  rats  exposed to
endrln  doses  of  0.075,  0.150, 0.300  or 0.450 mg/kg/day by oral  gavage  on
days  7-20 of gestation  exhibited decreased weight  gain  at  the  two  highest
doses  only;   llver-to-body weight  ratios were unaffected  1n all  exposure
groups.   Thus,  0.150  mg/kg/day  may be  considered as a  NOAEL for a 14-day
oral endrln exposure.
                     s
    Nelson et al.  (1956)  exposed  Sprague-Dawley rats  to 1, 5, 25,  50  and 100.
ppra endrln 1n the diet for up to 16 weeks.  Body  weights and serum alkaline
phosphatase,   an  Index  of  liver  damage,  were  measured weekly.  Following  4
weeks of  exposure, 40% mortality had  occurred at exposure levels >5 ppm  1n
males,  and  hypersens1t1v1ty  to  various  stimuli  and  nasal  bleeding  had
occurred  at   the  1  and  5  ppm  exposure  levels.   Body   weight  losses  and
elevated  serum alkaline phosphatase  occurred  at all exposure levels.    By  10
weeks of  exposure, mortality  had occurred at  all exposure  levels In  males
and to  females at levels  >25 ppm.  Mortality  within  the  groups remained the
same at week 16.
           /-
    NCI  (1979)   In a  cancer  range-finding  study  found   decreases   In  body
weight  gain  1n  rats administered 20  ppm,  but   not  10  ppm In the diet  for 6
weeks.  In the same  study decreased body weight gains were also reported  In
mice administered 10 ppm,  but not  5  ppm In the  diet.
00700                              VIII-7                           •:•:.. ••j/cr-

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     Treon  et  al.  (1955)  conducted subchronlc and chronic exposure studies on
both rats and  dogs.  Groups  of 20  male and  20 female Carworth  rats were
given  diets  containing 0, 1, 5,  25,  50 or 100  ppm endrln for up to 2 years.
Mortality  was high at the  50  and 100 ppm exposure  levels.   Height  gain was
decreased  in  the  males exposed  to 5 and 25 ppm, but not  1 ppm, for 20 weeks.
Liver-to-body weight  ratios  were Increased 1n  male  rats  1n  the 5 and 25 ppm
groups,  but  not  the  1 ppm  group, after  2 years  of exposure.  Liver-to-body
weight  ratios In  the  female rats exposed to 1 or 5 ppm endrln  for  2 years
did  not differ significantly from controls.

                    s
     Treon  et  al.   (1955)  also  conducted  a  study  with  beagle dogs  In which
groups of  1-4 were  fed diets containing 0-50 ppm endrln  for up to 18 months.
All  dogs  fed  10-50  ppm (0.49-4.00 mg/kg/day)  died, and  >50% of those fed 5-8
ppm  (0.20-0.65  mg/kg/day) died.   Actual endrln Intakes were  reported  by the.
authors.   All dogs receiving <4 ppm  (0.18  mg/kg/day)  survived, but  growth
was  affected  1n  the  4  ppm  groups.   The 3 ppm  (0.19  mg/kg/day) group  had
significantly higher  relative  kidney and heart weights  than  controls.   Dogs
fed  1  ppm  endrln  were  similar to controls 1n all  parameters.  Including gross
pathology and hlstopathology.  According  to  the authors,  the  dogs (two males
and  two females) on the 1 ppm diet actually consumed 0.083 mg/kg/day.

    Unite other chronic  studies  have been conducted with the  primary  Intent
of  evaluating  carcinogenic  response,  some  toxldty  data  have also  been
                              s-
reported.  Oelchmann et al. (1970) administered endrln  to rats  at concentra-
tions  of  2,  6  and  12 ppm In  the  diet  for up  to 37  months.   A moderate
Increase 1n cloudy  swelling  of  the  liver and renal  tubular epithelium along
00700                              VIII-8

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with  a  moderate  Increase  1n  the  Incidence  of  lung  congestion  and focal
hemorrhage was  reported.   Since the authors  stated that the effects were not
dose-related,  H  Is  assumed they  occurred at  the 2 ppm level as well as the
higher doses.

    In an  NCI  (1979)  study both  mice  and  rats  were chronically exposed to
endrln.  The  mice were administered a time-weighted-average (TWA) concentra-
tion  1n  the  diet  of  1.6  and 3.2  ppm,  while the rats  received  3 and 6 ppm.
Neither mortality  nor  body  weights were affected by either dose.  However,  a
variety  of  clinical  signs  usually associated with  aging  were  observed
earlier  1n the  exposed mice and rats.   Although a  NOAEL  was not observed In
the Oelchmann  et  al.  (1970) or  the  NCI  (1979)  studies, the results of these
Investigations provide  strong support for a  NOAEL no greater than 0.05 mg/kg
bw in rats and 0.13 mg/kg bw 1n mice (1  ppm 1n the diet).

    In  a  2-year  dog study,   beagle   dogs   (7/sex/group)  received  diets
containing 0,  0.1, 0.5, 1.0, 2.0  or  4.0 ppm endrln for >2  years (U.S.  EPA,
1987).   Interim sacrifices  (2  dogs/sex/group)  were  performed  at  6 and 12
months.  Parameters  monitored  Included  growth,   food consumption,  behavior,
serum  and  urine  chemistry,  organ  weights  and  hlstopathology  of all  major
organs.  Animals  treated  at the 2 and  4 ppm  dose levels  experienced convul-
sions, slight Increase  1n  relative liver weights, and mild hlstopathologlcal
changes  1n  liver cells.   Because  of  the  effects  observed   1n  the dogs
consuming  diets  containing 2  ppm  endrln  (0.05  •g/kg/day),  this level  was
considered the  LOAEL.   No  adverse effects  were observed  1n dogs  receiving
diets  containing  <1  ppm  endrln.   Therefore.  1 ppm (0.025 mg/kg/day)  was
considered the NOAEL.

00700                              VIII-9

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    Only  one  chronic nonmaramallan  study  appears  to  have been  conducted  to
                     u--
date.   KreUzer  (1980)  measured  behavioral   effects  of  endrln  In  adult
bobwhlte   quail   (Collnus   v1rq1n1anus)   using   nonspatlal   discrimination
reversal  tasks.  The birds were  fed 0.1 and  1.0 ppm endrln In the diet (0.01
and 0.10  rag/leg bw If  H Is assumed  the birds eat an amount equivalent to 10%
of  bw/day)  for  up  to  240  days.   Significantly  Increased error  rates  were
detected  at  both   levels  of  exposure.   While the  results   of  this  study
suggest a NOAEL  lower  than  values determined from other  chronic  studies,  It
1s  uncertain  how they  relate  to those of  mammalian exposures.   Acute  ID,.
studies on  pigeons  (Revzln,  1966) suggest that some  species  of  birds may  be
more sensitive to endrln exposure than mammals.

Quantification of Noncardnoqenlc Effects
                                                                 t
    Derivation  of   1-Oav  HA.   Previously the  study  by   Revsln  (1968) was
selected  as the basis  for   the  1-day HA.   In  this  study,   Revsln  reported
alterations 1n the  EEG  of squirrel  monkeys after  7 dally  doses  of  0.2 mg/kg
endrln.   Results of this study  were  provided  as  an  abstract.   Recently the
Science Advisory Board  of the U.S.  EPA  (1988c) In their  meeting  discourage
the use  of data  from an abstract for  the derivation  of an HA level.   Under
the  circumstances,  the  Kavlock  et  al.  (1981)  study  1s  considered  for the
1-day  HA.  In  a preliminary  range  finding study,  Kavlock   et  al.  (1981)
reported  decreased  locomotor activities  1n  adult  female CD-I  mice  following
single oral endrln  doses of  1.5  or  4.5, but  not 0.5 mg/kg bw. The 0.5 o^/kg
dose can  be considered  a NOAEL.   The 1-day HA  for a  10 kg child  1s  derived
as follows:
                   i j   u.    O.S mq/kg x  10  kg    n n, ...
                   1-day HA  -     ^  ^	... ^  • 0.05 mg/l
                                1 t/day x  100
00700                              VIII-10

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where:
        0.5 mg/kg • NOAEL, based on locomotor activities 1n mice
                    (Kavlock et al., 1981)
        10 kg     . weight of protected Individual (child)
        1 i/day   • assumed water consumption by a child
        100       « uncertainty   factor,   chosen  In   accordance   with
                    NAS/OOW and  Agency guidelines for  use  with a  NOAEL
                    from a study In animals

    Derivation  of  10-Oav HA.   Formerly the  10-day  HA value  was  calculated
based  on  the results  of  the  Nelson et al.  (1956) study on  rats.   However,
revaluation of  the  study Indicated certain  observations that  should  not  be
Ignored.  These observations  Included body weight  losses,  hypersensUlvlty
to  various  stimuli,  nasal  bleeding  and  Increased  alkaline  phosphatase
activity  at  the  lowest  endrln   level   tested.    In  view  of  the   noted
observations, It 1s  prudent  to consider the  Kavlock  et al.  (1981)  study  for
                                                     *•
derivation  of   the  10-day  HA.   Kavlock  et  al.  (1981)  reported  depressed
maternal  weight  gain   1n CD rats  exposed  to  endrln  doses  of 0.300 or  0.450
but not  0.150  or  0.075  mg/kg/day  for  14  consecutive  days;  0.150  mg/kg/day
can be  considered  a  NOAEL for a 10-day exposure.  The  10-day HA for a  10  kg
child 1s derived as follows:
                10-day HA  -  0.150 mq/kq/day  x  10  kq m    Q2
                    *          1  I/day x  100
where:
        0.150 mg/kg/day - NOAEL, based on  weight gain changes In rats
                          (Kavlock et al.,  1981)
        10 kg           . weight of protected Individual (child)
        1 i/day         • assumed water consumption by a child
        100             « uncertainty factor, chosen  1n accordance  with
                          NAS/OOW and  Agency  guidelines for use with a
                          NOAEL from a study In animals
00700                              VIII-11

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    Derivation  of  Longer-Tern  HA.   Subchronlc  exposure  data  appropriate
for  deriving  longer-term HAs  are extremely  limited.   Nelson et  al.  (1956)
reported  body  weight  losses,  hypersensltlvHy  to  various   stimuli,  nasal
bleeding and  Increased  alkaline phosphatase activity to  levels  of endrln >1
ppm  In  Sprague-Qawley rats.   The reported LOAEL  of  1 ppm endrln In the diet
corresponds to  a  dose of 0.05  rag/kg/day (assuming  an  average dally dietary
consumption of  5X  of body  weight  for  Sprague-Dawley  rats  In  a  subchronlc
study;  U.S. EPA,  1*87).   By 10 weeks  of exposure,  Mortality  had occurred at
all exposure levels 1n males and to females at levels >25 ppm.

    Treon  et  al.   (1955)  reported  elevated  kidney  and  heart-to-body  weight
ratios  1n beagle dogs exposed for  up  to 18 months to diets containing 3 ppm,
but not 1 ppm endrln.   At both  doses,  organ-to-body weight ratios  for liver,
brain  and   spleen  did  not   differ  significantly  from   controls.   Based  on
measured food  Intake, the dally  dose  for the 1  ppm dose group varied  from
0.045-0.12 mg/kg  bw.   However,  the dally  Intake of 1 ppm  endrln  appears  to
be  suspect  since  this  range overlaps with  the  3 ppm  range  of exposure  as
given  In  the  published report.   It  1s therefore recommended  that  the  DUEL,
which 1s based on lifetime exposure (see Assessment  of  Lifetime  Exposure  and
Derivation  of  a  DUEL Section),  be used  as  a  conservative  basis  for  the
longer-term HA.  This value  1s  based  on a chronic NOAEL  of 0.025  mg/kg/day.
                    *•
The Nelson  et  al.  (1956)  study  1s precluded for use  since  a high rate  of
mortality occurred In  male rats  at >0.05 mg/kg/day after  10 weeks.

    The  DUEL   of   0.009  mg/i   Is   based on  adult  body  weight  and  water
consumption and   therefore   1s  used  directly for   the  longer-term  HA   for
adults.  For the  10 kg  child,  the RfO  upon  which  the DUEL Is based Is used
1n the following derivation.

00700                              VIII-12

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            longer -Term HA   RfD x 10 **   °-0003
                 (child)       1 i/day           1 i/day
                                 • 0.003 mg/i

where:
        RfO             . 0.0003 rog/kg/day
        10 kg           - assumed weight of exposed Individual (child)
        1 i/day         • assumed volume of  water  consumed/day by a  10
                          kg child

    Assessment of  Lifetime  Exposure and Derivation  of a DUEL.   A  review of
the literature,  Including an unpublished study  from  the CBI files concerning
endMn  and  the  various  RfD   values   that  have  been  promulgated  by  the
different branches  of the  Agency,  has Indicated that  the  CBI study  1s  the
most  appropriate basis  for  an RfD  (U.S.  EPA, 1988b).   In this 2-year  dog
study, beagle dogs  (7/sex/group) received diets containing  0,  0.1,  0.5,  1.0,
2.0 or 4.0 ppm endrln  for >2 years.   Animals treated at the 2 and 4 ppm dose
levels experienced  convulsions, slight Increase  1n  relative  liver  weights.
and mild  histopathologlcal  changes  In  liver  cells.   No adverse effects  were
observed  at <1 ppm endrln,  therefore 1 ppm  (0.025 mg/kg/day)  was considered
the NOAEL.  Using the above study,  the derivation  of  the DUEL 1s as  follows:
       Step 1  - RfD Derivation
                   Rf0 . 0.025 mq/kq/day m

where:
        0.025 mg/kg/day « NOAEL   for   oral  exposure   fn  dogs   (U.S.
                          EPA.1987)
        100             • uncertainty factor appropriate for use with a
                          NOAEL   (from   animal   data  and  to   protect
                          sensitive members of  the human population
00700                              VIII-13

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       Step 2 - DUEL Derivation

         nun    RfD x 70 fco   0.00025 roo/ko/day x 70 kg
         DWcL • 	* • 	a—*——'	•  . 0.009 mg/l
                   2 I/day            2 l/day                    ^
where:
        RfD     . 0.00025 mg/kg/day
  •
        70 kg   • assumed weight of protected Individual  (adult)
        2 i/day • assumed volume of water consumed by a 70 kg adult
    The recommended  lifetime DUEL  for  a 70 kg  adult  Is 0.009 mg/i  endMn.
A summary  of  the  data  used to  calculate  the HAs  and the lifetime  DUEL  Is
provided 1n Table VIII-1.  The values derived  for  the  HAs and DUEL represent
estimates  of  the concentration  of endrln  In drinking  water  that will not
cause adverse effects after 1-day, 10-day,  longer-term or lifetime  exposures.

Carcinogenic Effects
    There  are  no  clinical  reports available  relating   endrln  exposure  to
induction of cancer  In  humans.   DUraglla et  al.  (1981) conducted a retro-
spective cohort  study to  examine the  mortality of  workers  employed In the
manufacture of  chlordane,  heptachlor,  DOT  and  aldrln/dleldrln/endrln.  No
statistically significant  excess  for  any  specific cancer  site  was noted.
However, since no exposure  data  are reported, the results of  this  study are
Inconclusive.   While there Is no  evidence Unking endrln  to cancer  Induction
In humans,  the  amount of  data available 1s  Insufficient to allow definite
conclusions to be drawn.

    Four bloassays  for  carclnogenlcUy  were done  1n  rats and three were on
mice.  These bloassays were  done at different Institutions,  namely Food and
Drug Administration  (FOA)  during 1955-1957  as Devaluated by Reuber  (1978).

00700                              ¥111-14

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o
o
o
o
                                                          TABLE VI11-1



                                           Summary of Data Used to Derive HAs or DUEL


1
en




Criteria Dose Duration Effect
(•g/kg bw/day)
1-Day HA 0.5 1 day NOAEL: locomotor
activities In mice
10-Day HA 0.15 14 days NOAEL: decreases In
maternal weights In
rats
Longer-term HA 0.025 2 years NOAEL: htstologtcal
liver lesions and
occasional convulsions
DUEL 0.025 2 years NOAEL: hlstologlcal
liver lesions and
occasional convulsions
Value of HA or DUEL

Child Adult
(mg/t) (mg/t)
0.05 NC
0.02 NC
0.003 0.009

NC 0.009

Reference

Kavlock
et al.. 1981
Kavlock
et al.. 1981
U.S. EPA.
1987b

U.S. EPA.
1987b

           NC  .  Not  calculated

-------
the  National  Cancer  Institute  (NCI,  1979),  the  University of  Cincinnati
(KetteMng Laboratory)  (HHherup  et  al.. 1970), and  the  University  of  «1am1
(Dekhmann et  al.,  1970).   All the bloassays on  rats and nice were  reported
as  negative  by  those  authors.   There  were,  however,  deficiencies  1n  the
studies  which  1s explained  below,  which render  the findings Inadequate  to
properly assess the carcinogenic potential 1n animal test systens.

    In  the  FOA rat  (Osborne-Hendel)  study  the  animals  at highest dose  (25
pp(n) did  not survive  well  and additional animals were started In  that  dose.
The  remainder  of the  groups  lived  for  the programmed  two year  study.   It
also appeared  that  every  animal  came to autopsy and not all sections  from
grossly  observed  animals  were studied  Microscopically.    In  spite  of  some
deficiencies  there  were   a  sufficient  nunber   of   animals  1n  the   studies
particularly  In  the  aspect of  liver and  kidney,   In all experimental  and
control  groups  (Reuber,   1978).   This   study  was  originally  reported  as
negative.  It  was  reevaluated by a  panel   of  pathologist whose  report  was
referenced 1n  a  CAG document  (U.S.  EPA, 1978).  One pathologist  considered
the  finding  positive  (Table  V-11 and  V-12) but did not  provide slide  by
slide  tabulation  of his  findings and  did   not  distinguish between   primary
and/or metastatlc tumors 1n  the liver.   A second pathologist  whose original
finding  Indicated   that  the  study  was  negative,  provided slide by  slide
tabulation of diagnosis which  was confirmed  by  the  panel  review.   In  the  FOA
mice  (C3HF1)  study  the  survival  was  very  poor   In   both  control   and
experimental group.

    The  KetteMng  study used  two strains of mice  (C5781/6J  and  C302F1/J).
The  C57B1/6J strain  exhibited mainly  leukemia and  liver  tumors with  low
Incidence.   These  tumors   appeared  equally   In  the  experimental  and   control
00700                              VIII-16

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groups  and the  latent  period  of  tumor formation  was  similar.  But  1n  the
C302F1/J  strain,  the  Incidence  of  liver tumors  1n the dose group (3 ppm)  was
slightly  higher   In  the  female  than  in controls and  the  latent  period  of
tumor formation was decreased than other groups (WUherup et a!., 1970).

    The NCI bloassay  was done  In Osborne-Mendel  rats  and B6C3F1 nice.   These
studies were  reported as  negative.   A primary  reviewer for MCI noted that
the negative  findings could  be a reflection of  the high toxldty of  endrln.
which  only permitted the  administration  of relatively  low  chronic dosages.
Furthermore,  the reviewer  observed  that  an accidental  overdose  among  low
dose male  mice  resulted  In early death of  several  animals  In  this  treatment
group and  the study was marred  by  a small  (10)  1f matched controls; however,
this  deficiency  was  compensated by  the  use of  pooled controls (see  Table
V-17).   There were  significant Increases  1n hemangloraa  In  low dose male
rats,  adrenal  adenoma  and/or   carcinoma  In high dose  In  males,  pituitary
adenomas  In  the  high dose female, adrenal  adenoma and/or  carcinoma  In  low
dose  female  rats  as  compared  to  the  pooled  controls.    Although,  the
Islet-cell  carcinoma  In  male  rats  had  a  significant  trend   but  no
statistical significance at  either  dose group,  the NCI  concluded that  these
tumors  could  not be clearly   considered  related  to  the  admlnstratlon  of
endrln  (NCI,  1979).  Although  NCI concluded  that the  bloassays of  endrln
were not carcinogenic, the responses noted  above  can not be  totally  Ignored.

    Endrln  was   not  nutagenlc  1n   any   bacterial   strains   but  exhibited
chromosomal aberration  1n  germinal  tissues.   Endrln  Is  also  structurally
related to aldMn, dleldrln, chlordane, chlorendlc  acid and  heptachlor  which
are  known to carcinogenic  1n  animals.  The available  cancer  epldemlologlc


00700                              VIII-17

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data  Involving  several  studies  1s  Inadequate  to demonstrate  or  refute  a
carcinogenic  hazard   because   of  study   design  limitations  and/or   mixed
exposures.   Using  the  criteria  1n   the  U.S.  EPA  (198?)  guidelines  for
classification  of  carcinogens,  endrln 1s most  appropriately  classified  In
Group  0;  I.e. a  chemical  for which there  Is Inadequate evidence  to  assess
the  potential  cardnogenlclty for  humans.   This classification 1s based  on
the  nonposltlve but  suggestive results In  some  of the  animal  studies.   The
negative conclusions as  reported by the study authors of  the four  bloassays
do not  support  a  Group E classification,  because  of  the Inadequacies  of  the
studies.  A  Group  D we1ght-of-ev1dence 1s  thought to be  the best  classifi-
cation until additional studies can be  done to clarify the situation.

Existing Guidelines. Recommendations and Standards
    The U.S.  EPA  (1975)  has  set  an Interim standard for endrln  In finished
                                             w
water  of  0.0002  mg/i.   The  U.S.  EPA  (1980a)   proposed an ambient  water
criterion  for  endrln  of   0.001  mg/1.   This  value  was  the  same  as  the
maximum  allowable  concentration  recommended  at  that   time  by  the  Public
Health Service.

    The World Health Organization (FAO/WHO,  1973)  established as a  guideline
a  maximum  Intake  of  2  vg/kg/day,  or  138.2  yg/day,  for a  69.1  kg person.
The  proposed  Index  AHmentarlus  Commission's maximum residue limit In  wheat
                            w^"
1s 20 vg/kg (Bailey et  al.,  1982).

    The threshold  limit  value  (8-hour TLV/TWA)  recommended  by the American
Conference  of  Governmental   Industrial  Hyglenlsts  Is  0.10  mg/ra»   (0.10
00700                              VIII-18

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vg/l),  wHh  a  short  time  exposure  limit   {15  minutes)  of  0.30  mg/m»
(ACGIH, 1982).   The  Occupational  Safety and Health Administration limits are
the same, 0.10 mg/m' (29 CFR 1910-1000).

    The  history of  recommendations  concerning  endrln  1s  provided  In  the
Federal Register (1979).   The  U.S.  EPA  Issued a notice  of  rebuttable pre-
sumption  against registration and  continued registration  (RPAR)  of endrln-
contalnlng  products  (e.g.,  R1d-a-B1rd  and  Sorblklll)  on  July  27.  1976.   It
Included  three  supportable  risk presumptions —  risk  of significant popula-
tion  reductions of  nontarget  organisms,  acute  toxlclty  to  wildlife,  and
teratogenldty.  After  review,  the  Agency determined  that  the  offsetting
economic,   social or  environmental  benefits were  still  not  great  enough.
Thus,  endrln  use was  cancelled In  the following areas:   on  cotton  1n  all
areas  east  of  Interstate highway  35;  on  small grains  to  control  all  pests
other  than  army  cutworm, the  pale  western cutworm and grasshoppers; on apple
orchards  1n the  eastern  United States  to  control meadow voles; on sugarcane
to  control  the  sugarcane borer;  and on  ornamentals.    Registration  for  new
uses  of  endrln  was  denied,  as well  as  Us  use In  unenclosed bird  perch
treatments.   Limited use  was  allowed  under  specific  conditions  for  the
following:  on cotton west of  Interstate  35;  on small  grains  to control array
cutworms  and  pale western cutworms;  on apple orchards  In the eastern United
States  to control the  pine  vole and  In the western United States  to control
meadow voles;  on sugarcane to control  the sugarcane beetle; for conifer seed
treatment;  and  use  In enclosed bird  perch treatments.   New  uses  and  regis-
tration of  endrln under  specified  conditions were allowed  as follows:  as a
tree  paint  In Texas; on alfalfa  and clover  seed  crops 1n Colorado; and on
small  grains   to control  grasshoppers  (In  Montana).    These determinations
were originally  Issued on October 20, 1978 by the Agency.

00700                              VIII-19

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    In  response  to  the  endrln RPAR,  the  Agency determined  that  endrln was
unlikely to pose an  oncogenlc  risk  to humans,  and that the risk presumptions
for  acute  dermal  toxldty and  fatalities  to endangered  species had  been
rebutted.

    In  the case of  fish  kills,  signs  stating 'Contaminated:  No Fishing" must
be  posted  for  1  year  after  a  fish kill,  or  for  6  months after  lesser
contamination unless  endrln residues  In  the edible portion  of fish  are <0.3
ppm ww.

    The bird species  deemed potentially at  risk  were  the Arctic and  American
peregrine  falcons,  bald  eagles and brown  pelicans.   A NOEL  of  1.5 mg/kg  bw
was accepted for  teratogenldty  1n  the hamster. The  LOEL  1n the hamster was
5 mg/kg.  However, behavioral  studies  using  quail  have  Indicated that  either
quail are  very sensitive to  the effects of  endrln or the  endpolnts measured
are more sensitive than those  used In the  past.

Special Considerations
    Endrln given to  the  dam at dose  levels  -10-fold  In  excess of the chronic
NOEL  in adult  nonpregnant  animals  has  been  associated  with  reduced  fetal
weight  In  hamsters  and  mice.   At  levels  comparable to  the  chronic  NOEL,
endrln  exposure  resulted  1n   Increased  locomotor activity  of offspring  of
rats and hamsters.   Thus,  unborn children  must  be considered  a  potentially
sensitive group.

    The general public In  the  Missouri and Mississippi  basins  between  March
1964 and June 1967 were  exposed  to  endrln  In drinking water  (Schafer et al.t


00700                              VIII-20

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1969)  and  In 1976  In  Ottawa,  Canada (Williams et  al.,  1978).   These situa-
tions  occurred  1n  agricultural  areas.   Acid drinking waters  are  more likely
                                                       U--
to  contain endrln  ketone  than  endrln  Itself  (ApSlmon  et al.,  1982),  also
keeping  In  mind  that  endrln  cannot  be  analyzed  well   1n  acid water,  In
                                  »
contrast  to  endrln  ketone  (Millar  et  al., 1981).   Thus, people living  In
areas  of  high  endrln use have more  potential  for  risk  than  have  the general
population.

    Farming communities  and workers  near  areas of  endrln  application  may  be
exposed not  only  to endrln  (Wolfe et al.,  1963,  1967;  U.S.  EPA,  1971, 1979;
Arthur  et al.,  1976;   Jeg1er7  1964),   but also   to  the major  product  of
sunlight degradation,  the  half-cage ketone  Identified  also  1n  environmental
samples (Zablk  et  al.,  1971).   Exposure  to this product  may Increase their
risk.

    Workers  exposed  to  endrln  In  occupational environments  have been  known
to  suffer convulsions   (Jager,  1970).    Such  workers  are   the  best  study
populations  for  monitoring signs  of cancer.   Poisoning  episodes have  also
been  reported   for  endrIn-contaminated   flour   (Coble  et  al.,  1967;  Weeks,
1967; Curley et al., 1970).

    Previous  exposure  to related  compounds can  Increase susceptibility  to
the  toxic effects   of   endrln.   Pretreatment  of   quail  with  chlordane  at
dosages less than  the NOAEL  (10 ppm 1n the diet  for 10  weeks)  resulted  In
greater mortality  In birds subsequently  administered 10  ppm endrln  1n the
diet  than  In those  administered endrln alone  (Ludke,  1976).  Of the  birds
that died, the ones  treated with endrln alone  had  lower brain endrln concen-
trations than In those pretreated with  chlordane.

00700                              VIII-21

-------
     Raa'atlon may  increase  the response to endrln.  Irradiation of rats with
gamma  particles  (900  rads)  before  Injection  of  10 mg/lcg  bw  endrln  to rats
resulted  1n  a greater  Increase In SGOT, SGPT, and a greater decrease In add
and  alkaline phosphatase,  sucdnk dehydrogenase  and glucose-6-phosphatase
                                             s-         /'
than  1n rats treated with endrln  alone  (Heena  et al.,  1978).

    Finally, stress may  lower  the threshold for the toxic effects of endrln.
The  survival  tiroes  of  female  field   nice   (Peromyscus  manlculatus)  were
shorter during combined  cold and starvation,  at  doses of  endrln as  low as 1
                                                                        *-
ppm  In the  diet,  than  In  stressed mice   that  received  no endrln  (Morris,
1968).

Summary
    The NOAEL  for acute exposure  to endrln   Is determined  to  be 0.5  Rig/kg
bw/day  based upon locomotor  activities 1n nice.   Based  upon  this NOAEL,  a
1-day HA for a 10 kg child of 0.05 og/i Is  proposed.

    The NOAEL for  14-day exposure to endrln Is determined  to  be 0.150  mg/kg
bw/day  based upon  body  weight  changes  In rats.   Utilizing  this  NOAEL  a
10-day HA Is proposed to be 0.02 rog/i for a 10 kg child.

    The NOAEL  for a  2-year exposure  to endrln  1s determined  to be  0.025
mg/kg bw/day based upon  histologlcal liver lesions In  dogs.   Utilizing  this
NOAEL,  longer-term  HAs   of  0.003  mg/l  for   children and  0.009 mg/i  for
adults are proposed.
00700                              YIII-22

-------
    An  RfO  of  0.00025  mg/kg/day  was  derived  based upon  a  NOAEL of  1  ppm
endrln  In  the diets of  dogs  exposed for 2  years  and mild hlstopathologlcal
liver  changes 1n  exposed  animals.  Based  on this  RfO,  a lifetime  DUEL  of
0.009 mg/l 1s proposed.
00700                              VIII-23

-------
                                IX.   REFERENCES

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00710                               IX-1

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00710                               IX-2                              -

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00710                               IX-3

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00710                               IX-5

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00710                               IX-7                             :

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00710                               IX-8

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00710                               IX-9

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00710                               IX-10

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00710                               IX-11

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00710                               IX-12

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Kutz,  F.H.,  S.C.  Strassman and  J.F.  Sperling.   1979.   Survey  of  selected
organochlorlne  pesticides   In  the general population  of  the United States:
Fiscal years 1970-1975.  Ann. N.Y. Acad. Sd.  320: 60-68.

Lawrence,  L.J.  and  J.E. Caslda.   1984.   Interactions of Undane,  toxaphene
and cyclodlenes with bra1n-spedf1c t.-butylb1cyclophosphoroth1onate  receptor.
Life Sc1.  35: 171-178.

Lee. T.P., R.  Moscatl  and  B.H. Park.  1979.  Effects  of pesticides on human
leukocyte functions.  Res.  Commun. Chew.  Pathol. Pharmacol.   23:  597-609.

Long, U.H.. L.O. Newson and A.M.  HulUns.  1961.   Endrln residues In the fat
of lambs grazed on endrln-treated pasture.  J.  Econ.  Entomol.  54: 605-606.

Ludke, J.L.   1976.  Organochlorlne  pesticide  residues associated  with mor-
tality: Addltlvlty of chlordane and  endrln.  Bull. Environ. Contarn. Toxlcol.
16: 253-260.

MacLeod,  K.E.,  R.C.  Hanlsch and  R.G.  Lewis.   1982.   Evaluation  of  gel per-
meation chromatography for  cleanup of human adipose tissue samples for  GC/MS
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McCann,  J.A.,  U.  Teeters,  D.J.  Urban  and  N.  Cook.   1981.  A short-term
dietary toxldty  test  on  small mammals.  Aa.  Soc. Test.  Mater.  Spec.  Tech.
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Main, D.C.   1978.  Endrln  toxldty In cageblrds.  Aust. Vet. J.  54: 198-199.


00710                               IX-13

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Manganl,  F.,  6.  Crescentlnl  and  F.  Bruner.   1981.   Sample enrichment  for
determination of  chlorinated pesticides In water  and  soil  by chromatographk
extraction.  Anal. Chem.  53: 1627-1632.

Marlon,  W.R.   1976.   Organochlorlne pesticide residues 1n plain chachalacas
from south Texas, 1971-72.  Pestle. Monlt.  J.   10: 84-86.

Maslansky, C.J.  and  6.M.  Williams.  1981.  Evidence  for  an eplgenetlc mode
of action  1n organochlorlne  pesticide hepatocardnogenldty: A lack of geno-
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Matsushita, T.,  S. Nomura  and  T.  Wakatsukl.   1980.  Epidemiology of  contact
dermatitis from pesticides 1n Japan.  Contact  Dermatitis.   6: 255-259.

Meena,  K.,  P.K.  Gupta and  S.R.   Bawa.   1978.    EndMn-lnduced  toxlclty  In
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Mehrotra, B.D.,  S.K.  Bansal  and D. Desalah.   1982.   Comparative  effects  of
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Merck  Index.   1983.    An  Encyclopedia  of  ChetBlcals,  Drugs and B1o1oglca1s,
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Hetcalf. R.L.   1981.   Insect  control technology.   Jn:  Klrk-Othmer  Encyclo-
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00710                               IX-14

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Millar, J.O.,  R.E.  Thomas  and H.J. Schattenberg,  III.  1981.  Determination
of  organochlorlne  pesticides  and  polychloMnated  blphenyls  In water  by gas
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Miller, C., S.  Nesnow and  A.  SarMf.   1981.  Oleldrln and related compounds
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Montoya  Cabrera,  N.A.,  H.  Escartln   Chavez,   H.  Reynoso  Garcia  and  C.G.
Strecker.   1982.   Intoxlcadon por endrln.   Informe  de 33 casos.   Rev.  Ned.
Inst. Hex  Seguro Soc.  (Mexico).   20: 79-84.   (Spa.)

HoMya, M.,  T.  Ohta, K.  Uatanabe,  T.  Nlyazawa,  K.  Kato and Y.  Shlrasu.
1983.   Further   mutagen1c1ty  studies  on  pesticides  In bacterial  reversion
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Morris, R.O.  1968.   Effects  of  endrln  feeding  on survival and reproduction
In the deer mouse,  Peromyscus  manlculatus.   Can.  J. Zool.  46: 951-958.

Mostafa,  M.H.,   E.A.   E1-Bass1oun1,  S.N.  El-Sewedy,  T.   Tawlflc  and  A.M.
El-Sebae.   1983.  Influence of pretreatroent with various Insecticides  on the
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Mu1r, C.M.C.  1968.  No title  provided.   (CUed  In  Oager, 1970)
00710                               IX-15

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NagelsmU, A.,  p.u.  Van VHet,  H.A.M.  Van der  Hlel-Hetzels, ct  al.   1979.
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NCI  (National  Cancer  Institute).   1979.  Bloassay  of  endrln for  possible
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Nelson,  S.C., T.L.  Bahler,  U.V. Hartwell,  O.A. Greenwood  and I.E.  Harris.
1956.   Serum alkaline  phosphatase  levels,  weight  changes,  and  mortality
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Pocket Guide to  Chemical Hazards.   191 p.

Ohlendorf,  H.N.,  D.H.  Swlneford  and  L.N.  Locke.   1981.    OrganochloMne
residues and mortality  of herons.   Pestle. HonH. J.  14: 125-135.
00710
IX-16

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Ottevanger,  C.F.  and  N.J.  Van  SHtert.   1979.   Relation between  antl-12-
hydroxyendrln  excretion and  enzyme  Induction  1n  workers  Involved  1n  the
manufacture of  endrln.   In.:  Chemical  PorphyMa 1n Han,  J.iJ.T.H.A. Strllc  and
J.H.  Koeman,   Ed.    Elsevler/North   Holland   B1omed1ca1   Press,   New   York.
p. 123-129.

Ottolenghl, A.D., J.K.  Haseman  and F. Suggs.  1974.  Teratogenlc  effects  of
aldrln, dleldrln, and endrln In hamsters and nice.   Teratology.   9: 11-16.

Pandey, B.B.   1978.   A  note  on endrln  poisoning  1n bullocks.  Indian Vet.
J.  55: 253.

Park, B.H.  and T.P.  Lee.   1980.  Effects  of  pesticides on human leukocyte
function.   HHS Publ.  (FDA).   FDA-80-1074.  p.  273-274.

Pawar, S.S. and  M.S.  Kachole.   1978.   Hepatic and renal mlcrosomal electron
transport  reactions  In  endrln  treated  female guinea  pigs.   Bull. Environ.
Contain. Toxlcol.  20: 199-205.

Peterson,    S.R.   and  R.S.  Ellerson.    1978.   p.p'-OOE,  polychlorlnated
blphenyls   and  endrln  1n old squaws  In North America,  1969-1973.  Pestle.
Monlt. 0.   11: 170-181.

Phillips,  O.O., G.E.  Pollard and S.B.  Soloway.   1962.  Thermal  1somer1zat1on
of endrln and  Us behavior  In gas  chromatography.  J. AgMc. Food  Chem.  10:
217-221.
00710                               IX-17

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Probst,  G.S., K.E.  HcMahon,  L.E.  Hill, et  al.   1981.   Chemically-Induced
unscheduled  DMA  synthesis 1n  primary  rat hepatocyte cultures:  A  comparison
with  bacterial  mutagenldty  using  218  compounds.  Environ.  Hutagen.   3:
11-32.

Radeleff, R.O.   1956.  Hazards  to  livestock of  Insecticides  used In  mosquito
control.  Mosquito News.   16: 79-80.

Rapaport, E.,  E. Farjoun, S.  Shlosberg  and  H.N. Egyed.  1979.  Endrln  poi-
soning 1n a herd of goats.  Refu. Vet.   36:  142-143.

Reddy, O.B.,  V.O.  Edward, G.J.S. Abraham and  R.K.  Venkallswara.  1966.   No
title provided.  (Cited 1n Jager, 1970)

Rees, 6.A.V.  and L.  Au.   1979.  Use  of  XAO-2  macroretkular  resin  for  the
recovery of ambient trace levels of pesticides  and  Industrial organic pollu-
tants from water.  Bull.  Environ. Contain.  Toxlcol.   22:  561-566.

Relchel,  W.L.,   E.  Cromartle,   T.G.  Lament,  B.H.  Hulhern and  R.H.  Prouty.
1969.  Pesticide residues 1n  eagles.  Pestle. Monlt. J.   3: 142-144.

Reins, O.A., 0.0. Holmes and L.B. Hlnshaw.  1964.   Acute  and chronic effects
of the Insecticide endrln on renal function and  renal henodynamlcs.  Can.  J.
Physio!. Pharaacol.  42:  599-608.

Reins,  O.A.,  J.A.  Rleger,   Jr., W.B.   Stavlnoha and  L.B.   Hlnshaw.   1966.
Effect  of  endrln  on  venous  return  and  catecholamlne  release  In  the  dog.
Can. J.  Physlol.  Pharmacol.   44: 59-67.

00710                              IX-18

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Reuber,  M.D.    1978.   Carcinomas,  sarcomas  and  other  lesions  1n  Osborne-
Mendel rats Ingesting endrln.  Exp.  Cell.  Blol.   46:  129-145.

Reuber,  M.D.   1979.   CardnogenlcHy  of  endrln.  Scl.  Total  Environ.  12:
101-135.

Revzln,  A.M.  1966.   The  effects  of endrln on telencephallc function  In the
pigeon.  Toxlcol. Appl. Pharmacol.  9:  75-83.

Revzln,  A.M.    1968.   Effects  of  chronic  endrln  administration  on  brain
electrical activity In the squirrel  monkey.  Fed.  Proc.   27: 597.

Rlbbens,  P.H.    1985.   Mortality  study  of  Industrial  workers  exposed  to
aldMn, dleldrln and endrln.   Int. Arch. Occup. Environ.  Health.  56: 75-79.

Richardson, L.A.,  J.R.  Lane, U.S.  Gardner,  J.T. Peeler and  J.E.  Campbell.
1967.   Relationship  of  dietary  Intake  to  concentration  of   dleldrln  and
endrln 1n dogs.   Bull. Environ.  Contam.  Toxlcol.   2:  207-219.

Robinson,  J.    1962.   Shell   Research  Ltd.   Private communication  to K.U.
Jager.   (Cited 1n Jager,  1970)

Rowley,  O.L., M.A.  Rab,  U. Hardjotanojo,  et al.   1987.   Convulsions caused
by endrln poisoning In Pakistan.   Pediatrics.  79(6): 928-934.
00710                               IX-19                            08/19/88

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Roylance, K.J.,  C.O.  Jorgenson,  G.M.  Booth and M.H.  Carter.   1985.   Effects
of dietary endMn  on  reproduction of mallard ducks.  Arch.  Environ.  Contain.
Toxlcol.  H: 705-711.

Safe,  S.  and  0.  Hutzlnger.   1973a.   Mass  Spectrometry  of Pesticides and
Pollutants.   CRC Press, Cleveland, OH.   p.  124.

Safe,  S.  and  0.  Hutzlnger.   1973b.   Mass  Spectronetry  of Pesticides and
Pollutants.   CRC Press, Cleveland, OH.   p.  23.

SANSS  Data  Base.  1983.  Endrln  nomenclature,  Indexing terms and  synonyms,
June.

Seldenberg,  J.N., D.G. Anderson and R.A. Becker.  1986.  Validation of an jjt
vivo developmental  toxldty  screen In  the mouse.   Teratog.  Carclnog. Mutagen.
6: 361-374.

Schafer,  M.L.,  J.T.   Peeler,   U.S.   Gardner   and   J.E.  Campbell.   1969.
Pesticides  1n  drinking  water.    Waters  from  the Mississippi  and  Missouri
Rivers.  Environ. Sc1. Techno!.   3:  1261-1269.

Sharma,  R.O.  and  O.P.  Gautam.    1971.    Experimental  endrln  poisoning  1n
calves.  J.  Res. (Punjab AgMc. Univ.)   8:  394-403.

Sherman, M.  and  M.M.  Rosenberg.   1954.   Subchronlc  toxlclty of four chlori-
nated  dlmethanonaphthalene  Insecticides  to chicks.   J.  Econ. Entomol.   47:
1082-1083.
00710                               IX-20

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SUtlg,  M.   1977.  Pesticide  Process  Encyclopedia.   Noyes  Data Corp.. Park
Ridge, NJ.  p. 226-229.

Sobtl, R.C.,  A.  KMshan and J.  Davles.   1983.  Cytoklnetlc and cytogenetlc
effect  of agricultural  chemicals  on  human lymphold  cells in  vitro.  II.
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Spann, J.W.,  6.H.  Heinz and C.S.  Hulse.   1986.  Reproduction and health of
mallards fed endrln.  Environ.  Toxlcol.  Chen.   5:  755-759.

Spauldlng.  J.E.   1972.   Pesticide  and  heavy  metal   residues.   Proc. Heat
Industry Res. Conf., Am. Meat Inst. Foundation, Chicago,  IL.

Speck, L.B. and  C.A.  Maaske.   1958.   The effects of chronic and acute expo-
sure of rats to endrln.  Am.  Hed. Assoc.  Arch.  Ind. Health.  18: 268-272.

SUckel,  W.H.,  T.E.   Kaiser  and  W.I.  Relchel.   1979a.   Endrln   versus
12-keto-endMn  In  birds and rodents.   Am.  Soc.  Test.  Mater. Tech.  Publ.
693: 61-68.

Stlckel,  U.K.,  H.I.  Relchel  and  D.L.  Hughes.   1979b.   Endrln   In   birds:
Lethal  residues  and  secondary  poisoning.   Oev. Toxlcol. Environ.  Sc1.   4:
397-406.

Tanaka,  K.,  J.6.  Scott  and  F. Hatsumura.  1984.   P1crotox1n1n  receptor  1n
the central nervous system of  the  American cockroach:  Its role 1n the  action
of cyclodlene-type Insecticides.  Pest.  Blochem. Physlol.  22: 117-127.


00710                               IX-21

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Taylor, 0.6.   1980.   NIOSH  Manual  of Analytical Methods, U.S.  OHHS,  Vol. 6,
Method S-284.  p. 80-125.

Telang, $.,  C.  long and  6.M.  Williams.   1981.  Induction of mutagenesls by
carcinogenic  polycycllc  aromatic   hydrocarbons  but  not  by organochlorlne
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Mutagen Soc.  Environ. Mutagen.  3: 359.   (Abst.)

TerMere,  L.C.,  U.  KHgemagl  and   O.C.  England.  1958.  Endrln  content of
body  tissues of  steers, lambs,  and hogs  receiving endrln  In their dally
diet.  J. Agrlc.  Food Chem.   6: 516-518.

TerMere, I.C., G.H. Arscott and U.  K11gemag1.   1959.  The endrln  content of
eggs  and  body tissue  of poultry receiving endrln 1n  their  dally diet.   J.
Agrlc. Food Chem.  7: 502-504.

Tessarl,  J.D.,  L.  Griffin  and  H.J.  Aaronson.    1980.   Comparison  of  two
cleanup procedures  (Mills,  Onley,   Gaither  versus  automated  gel permeation)
for  residues  of  organochlorlne  pesticides  and polychlorlnated  blphenyls In
human adipose tissue.  Bull. Environ. Contain.  Toxlcol.  25: 59-64.

TewaM, S.N.  and  I.C.  Sharma.    1978.  Study  of  the  distribution of chlori-
nated  organic  pesticides 1n different autopsy materials  of  human poisoning
cases  using  TLC  and  UV  spectrophotometrlc   techniques.   Chea.   Era.   14:
215-218.
00710                               IX-22

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Treon,  J.F.  and  F.P.  Cleveland.   1955.   ToxIcHy of  certain  chlorinated
hydrocarbon  Insecticides  for  laboratory animals,  with  special  reference to
aldrln and dleldHn.  J. Agrlc.  Food Chem.   3:  402-408.

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U.S.  OHHS  (U.S.  Department of  Health  and  Human  Services).   1978.   Occupa-
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U.S.  EPA.    1975.    National  Interim  primary  drinking water  regulations.
December 24.  Federal Register.   40(248):  59566-59588.

U.S.  EPA.   1978.  Carcinogen Assessment Groups  Risk Assessment  for  Endrln.
June  19.  (Unpublished study)

U.S.  EPA.   1979.   Reviews of the  Environmental  Effects  of  Pollutants:  XIII
Endrln.   Health  Effect  Research  Laboratory,  ORD, Cincinnati,  OH.   EPA
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00710                               IX-23                            "P-

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U.S.  EPA.   1980a.   Ambient Water  Quality Criteria for  Endrln.   Prepared  by
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                                                                      *
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600/8-80-023.  p. 194-195.

U.S.  EPA.    1985.   National  Primary  Drinking  Water   Regulations;  Synthetic
Organic Chemicals,  Inorganic  Chemicals,  and  Microorganisms;  Proposed Rule  40
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U.S.  EPA.    1986.    Guidelines  for  Carcinogen  Risk  Assessment.    Federal
Register.   51(185): 33992-34003.

U.S.  EPA.   1987.   Health  Effects  Assessment  for  Endrln.   Prepared by  the
Office  of  Health  and Environmental Assessment,  Environmental  Criteria and
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U.S.  EPA.  1988a.   Reference  Dose  (RfD): Description  and Use  In  Health  Risk
Assessments.    Integrated   Risk   Information   System   (IRIS).     Online.
Intra-Agency  Reference   Dose  (RfD)  Work  Group,  Office  of   Health  and
Environmental  Assessment,  Environmental  Criteria  and  Assessment   Office,
Cincinnati,  OH.   February.
00710                               IX-24

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U.S.  EPA.   1988b.   Integrated Risk  Information System  (IRIS).   Reference
Dose  (RfO)  for   Oral   Exposure  for  EndMn.   Online.    (Verification  date
04/20/88).    Office of  Health  and  Environmental  Assessment,  Environmental
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U.S.  EPA.   1988c.   Memorandum from  Richard  Cothern (Science Advisory Board)
to  Office  of  Health  and  Environmental  Assessment and  Office of  Drinking
Water participants of  the March 15,  1988  meeting.

Vlgfusson,   N.V.,  E.R.   Vyse,  C.A.  Pernstelner and  R.J.  Dawson.  1983.   In
vivo  Induction of sister-chromatld  exchange  In  Umbra  11m1 by  the  Insecti-
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VMJ-Standhardt,   U.G.,  J.J.T.W.A.  StrU,   C.F.  Ottevanger  and  N.J.   Van
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J.J.T.y.A.   Strlk  and  J.H.  Koeman, Ed.   Elsevler/North  Holland  B1omed1cal
Press, New York,  p. 113-121.

Walsh, G.M. and G.B. Fink.   1972.   Comparative  toxklty  and distribution  of
endrln  and dleldMn  after  Intravenous  administration  1n mice.   Toxlcol.
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Wang,  H.H. and   S.  Grufferman.  1981.   Aplastlc  anemia  and  occupational
pesticide exposure: A case-control study. J.  Occup. Ned.  23: 364-366.
00710                               IX-25

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Weeks,  O.E.    1967.   Endrln  food-poisoning.   A report  on  four  outbreaks
caused  by  two separate shipments  of  endrIn-contaminated  flour.   Bull. WHO.
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Williams, G.M.   1980.  Classification of genotoxlc and eplgenetlc hepatocar-
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Williams,  O.T.,  P.M.  Benolt,  E.E.  McNeil   and R.  Otson.    1978.   Organo-
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WUherup, $., K.L.  Steramer,  P. Taylor  and  P. Bletsch.   1970.  The Incidence
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pesticides.  Arch.  Environ.  Health.   14: 622-633.

Young,  R.A. and  H.H. Hehendale.  1986.  Effect  of  endrln  and endrln  deriva-
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toxldty 1n male and female rats.   Food Chem. Toxlcol.  24: 863-868.


00710                              IX-26

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   Ziblk.  H.J..  R.D.  Schuetz, H.L.  Burton and 8.E.  Pape.   1971.  Photochemistry
   of  bloactlve  compounds: Studies  of a major photolytlc product of endMn.  j.
   Agrlc.  Food Chen.  19: 308-313.
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