Co-f
fi>EF'A
          United States
          Environmental Protection
          Agency
                                                           FINAL DRAFT
                                                           ECAO-CIN-G066
                                                           September, 1989
          Research  and
          Development
           HEALTH AND ENVIRONMENTAL  EFFECTS  DOCUMENT
           FOR POLYBROMINATED BIPHENYLS (PBBS)
          Prepared  for
          OFFICE OF SOLID WASTE AND
          EMERGENCY RESPONSE
          Prepared  by
          Environmental Criteria and  Assessment Office
          Office of Health and  Environmental Assessment
          U.S. Environmental Protection  Agency
          Cincinnati, OH  45268


                      DRAFT: DO NOT CITE OR  QUOTE
8
o>
                                   NOTICE

           This document Is a preliminary draft.  It has not been formally released
         by the U.S. Environmental Protection Agency and should not at this stage be
         construed to represent Agency policy.  It  Is being circulated for comments
         on Its technical accuracy and policy Implications.


                           HEADQUARTERS LIBRARY
                           ENVIRONMENTAL PROTECTION AGENCY
                           WASHINGTON, D.C. 20460

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                                  DISCLAIMER

    This report  Is  an external draft  for  review purposes only and  does  not
constitute Agency  policy.   Hentlon  of  trade names  or commercial  products
does not constitute endorsement or recommendation for  use.
                                      11

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                                    PREFACE


    Health and  Environmental  Effects Documents  (HEEOs)  are  prepared for the
Office of  Solid  Haste and Emergency Response  (OSHER).   This document series
Is Intended to support  listings  under  the Resource Conservation and Recovery
Act  (RCRA) as  well as  to provide health-related  limits and goals  for emer-
gency  and  remedial actions  under the  Comprehensive  Environmental  Response,
Compensation  and  Liability   Act  (CERCLA).   Both  published  literature  and
Information obtained  for  Agency  Program  Office  files are evaluated  as  they
pertain to potential  human health,  aquatic  life  and environmental  effects of
hazardous waste  constituents.   The  literature searched  for  1n this document
and  the  dates  searched  are  Included  In "Appendix: Literature  Searched."
Literature search  material  Is current  up to 8 months previous  to  the final
draft  date listed  on the front  cover.  Final  draft document  dates  (front
cover) reflect the date the document 1s sent to the Program Officer  (OSWER).

    Several  quantitative  estimates  are  presented  provided   sufficient  data
are available.   For systemic  toxicants,  these  Include Reference doses (RfDs)
for  chronic   and  subchronlc  exposures  for  both  the   Inhalation  and  oral
exposures.   The  subchronlc  or  partial  lifetime  RfD Is an estimate of  an
exposure  level   that  would  not  be  expected  to  cause  adverse effects  when
exposure occurs  during a limited time  Interval  I.e.,  for  an  Interval  that
does  not  constitute  a  significant  portion  of  the  Hfespan.  This  type  of
exposure estimate  has not been  extensively used,  or rigorously defined  as
previous risk assessment  efforts  have  focused  primarily  on  lifetime exposure
scenarios.   Animal data  used  for  subchronlc  estimates  generally  reflect
exposure  durations of  30-90  days.   The  general methodology  for  estimating
subchronlc RfOs  Is  the  same as  traditionally  employed for  chronic  estimates,
except that subchronlc data  are utilized when available.

    In the case  of suspected  carcinogens, RfDs  are  not  estimated.   Instead,
a  carcinogenic  potency  factor,  or  q-|*  (U.S.  EPA,  I960),  Is   provided.
These  potency  estimates  are  derived for  both  oral and  Inhalation  exposures
where  possible.  In addition, unit  risk  estimates for air  and drinking water
are presented based on Inhalation and oral data,  respectively.

    Reportable quantities (RQs)  based  on both chronic toxlclty  and carclno-
genlclty are derived.   The RQ 1s  used  to determine the  quantity of  a hazard-
ous substance  for  which notification  Is  required In the event of  a  release
as  specified  under the  Comprehensive  Environmental Response,  Compensation
and Liability  Act  (CERCLA).   These  two  RQs  (chronic toxlclty and cardno-
genlclty) represent two of six  scores  developed  (the remaining  four  reflect
IgnltabHlty,  reactivity,  aquatic toxlclty,  and acute   mammalian  toxlclty}.
Chemical-specific RQs  reflect the lowest  of these six primary criteria.   The
methodology for  chronic toxlclty and  cancer based  RQs  are   defined  In  U.S.
EPA, 1984 and 1986b, respectively.
                                      111

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                               EXECUTIVE  SUMMARY

    The  polybromlnated  blphenyl  chemical  class  1s  commonly  knoyn by  the
synonym PBB.   There  are 209 possible structural  congeners  of  the bromlnated
blphenyl  structure  containing  two or more  bromines (IARC, 1986).   The  PBBs
are chemically  unreactlve  (IARC,  1986);  however, hexa-,  octa- and decabromo-
blphenyl  have  been  reported to photodegrade by  reductive  debromlnatlon  upon
exposure  to  UV  (IARC,  1978).   Commercial production  of PBBs  In  the  United
States began  1n 1970 and  was  discontinued  1n early 1977.  Between  1970  and
1976, ~13.3  million  pounds of  PBBs  was  produced,  with  -11.8  million  pounds
being  hexabromoblphenyl.   The  PBBs were  commercially produced  by  three
manufacturers  operating three  production  sites (Griffin  and Chou,  1981).
The  PBBs  were  used as  flame  retardants  for synthetic  fibers,   resins  and
plastics  (IARC, 1986; Griffin and Chou,  1981).
    PBBs  are  extremely  persistent  1n   soil  (Jacobs  et a!..  1976,  1978).
Incubation   of  14C-labeled   Flremaster   BP-6   (predominantly   hexabromo-
blphenyl)  1n  a Michigan soil  for 1 year  showed no evidence  of  significant
degradation  (Jacobs  et  al., 1978).  No  difference  1n degradation was  found
1n  control  experiments using  sterile   versus   nonsterlle  soil.   A  minor
degradation  of  -3% was  attributed  to   photodegradatlon.   The  results  of
laboratory   leaching   experiments   have   shown   that   Flremaster    BP-6
(predominantly  hexabromoblphenyl)  and   2,2',4,4',5,5'-hexabromob1phenyl   do
not  leach significantly In  soil  (Griff1n  and  Chou,  1981;  Fllonow et  al.,
1976).  Photolysis may  be  a viable  process  resulting In PBB  degradation  In
water.    The   PBBs   have   been   shown   to   be   readily   susceptible   to
photodegradatlon  when   exposed   to   Irradiation wavelengths   occurring   In
sunlight  (EpHng et  al., 1987; Ruzo et  al., 1976;  Robertson  et al.,  1983).
                                      1v

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The photolysis  occurs  through  a  reductive debromlnatlon process In which the
Irradiated  PBB  Isomer  yields  a  PBB  product   containing   fewer  bromines.
Significant  partitioning  from the  water column  to sediment  and suspended
material  1s  likely  to  occur.   If  released  to the  atmosphere,  the  PBBs may
exist  1n both  partlculate and  vapor  phases.   Vapor-phase  PBB  1s  probably
susceptible  to significant  degradation   from  photolysis.   Partlculate-phase
PBB  1s  susceptible  to  physical  removal by  dry  deposition  and,  perhaps,
degradation  from  photolysis.   A BCF of  18,200 was experimentally determined
for  hexabromoblphenyl   In  fathead   minnows  over  a  32-day   exposure  period
(Velth  et a!.,  1979),  suggesting a  significant potential for bloaccumulatlon
In aquatic organisms.
    The  PBBs  are  not   known   to  occur  naturally  (IARC,  1986).   Therefore,
their detection 1n environmental  media Is a  result of anthropogenic  release.
Air samples  collected downwind of a manufacturing facility (Bayonne,  NJ) and
use  facility  (Staten  Island,  NY)   In April  1977  contained  PBB levels  of
60-100  ng/m3  (Whltlock  and Stratton,  1979).   PBBs have  been detected  In
wastewater effluents from  manufacturing  and  use  facilities and 1n associated
river water  and sediments  (IARC, 1978;  Whltlock and Stratton,  1979).   PBBs
accidentally entered the  food  supply when animal  feed  contaminated with PBB
(Flremaster  BP-6) was  used by  farmers In Michigan  between July 1973  and May
1974  until  the PBBs  were  Identified  as  the  contaminating  substance.   PBB
levels  as high as 595 mg/l and  59.7  mg/kg  were detected In  milk and  eggs,
respectively {IARC,  1978).  PPBs concentrations   from 15-15000  ng/g fish fat
were detected  In  fish  (carp,  hogsucker)  collected  from tributaries  of  Lake
Michigan 1n 1983 (Jaffe et al.. 1985).
    Information  on  the  hazards  posed   to  fish  and  wildlife by  PBBs  Is
limited.  There are no  toxldty  data  available relative  to exposures  of

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aquatic organisms  to  PBBs.   ToxicHy data  collected In the  laboratory have
demonstrated that  PBBs  can  Induce several hepatic mlcrosomal  enzyme systems
In several species of fish.  Data collected  In  the laboratory and field have
demonstrated a high propensity for PBBs  to accumulate  In  the  tissues of fish
and wildlife.  While the propensity for  bloaccumulatlon of  PBBs  by fish Is  a
cause  for  concern,  the  cessation of  the mass manufacture  of  PBB-contalnlng
products  and  their subsequent entry  Into the  environment  lessens  the  need
for definitive toxlclty  data.
    PBBs are rapidly and extensively  absorbed following oral  administration.
Studies with  rats Indicate that  GI  absorption  of  2,2',4,4',5,5'-hexabromo-
blphenyl  and  octabromoblphenyl was  -90 and  70%,  respectively  (Matthews et
al.,  1977;  Morris et  al.,  1975).   Following absorption,  PBBs  are  rapidly
removed  from  the  blood and  stored   Initially  In highly  perfused  tissues.
Subsequently, they are  redistributed  to adipose and other  tissues  with  high
llpld content, where they accumulate and persist  (Domino et al.. 1980,  1982;
Klmbrough  et  al.. 1981; Morris  et  al.,  1975;  Lee  et  al., 1975;  Warltz et
al.,  1977).   Llpld/blood   ratios  from  140-363  have been   determined In
Michigan  residents several  years following PBB  exposure (Cordle et  al..
1978; Wolff  et  al.,  1979;  Tuey  and  Matthews, 1980;  Landrlgan et  al.,  1979;
Eyster et  al.,  1983).   PBBs  are  distributed  to  the  placenta  and breast  milk
(Fries, 1985; Eyster  et al.,   1983).  Limited metabolism  data for  PBBs,  the
documented  persistence  of   PBBs  In   biological  systems   and   extensive
Information for  analogous  PCBs Indicate that metabolism  of the more  highly
bromlnated and  abundant PBB congeners  Is not  significant  (KohH  and  Safe,
1976; Dannan et al., 1978; Fries, 1985).  Excretion  of  PBBs 1s predominantly
through  the  feces, largely  from the  bile.   Studies with  rats  showed  that
~12%  of  oral  doses of  2,2',4,4',5,5'-hexabromob1phenyl was excreted  In  the
                                      v1

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feces  In  the  following 24  hours  (Matthews et al., 1977;  Tuey  and Matthews,
1980).  Monkeys  given  oral  doses of  hexabromoblphenyl  excreted  -38-60% of
the  administered  dose  In  the  following  5-17  days  (Rozman  et al.,  1982).
Approximately 74%  of  a single  oral  dose of  octabromoblphenyl  was recovered
1n the feces of rats by day 16 (Norrls et al., 1975).
    Subchronlc  oral  studies  with rodents  and other  animals  Indicate  that
pathological  changes   In  the  liver   are  the  most prominent  and  sensitive
effect  of P8B  exposure.    Hepatic  effects  Including  liver enlargement  and
hepatocellular degeneration have been observed at  gavage or  dietary doses of
Mremaster PBBs as  low as  0.07-0.2  mg/kg bw/day  (Sleight and  Sanger,  1976;
Akoso  et  al., 1982a;  NTP,  1983).   Oose-related  alterations  1n the  thyroid
and adrenal glands  occurred In  rats  at sufachronlc  oral  PBB doses  comparable
to those  that produced hepatotoxlc  effects  (Sleight  et al., 1978;  Kasza et
al.,   1978;  Allen-Rowlands  et al.,  1981; Akoso  et al.,  1982b;   NTP,  1983;
Byrne  et  al.,  1987,  1988).   PBB (Flremaster  FF-1)  doses of  0.2 mg/kg/day by
gavage for 5  months decreased longevity  In rats  (NTP,  1983).   Immunosuppres-
slve  effects  have  been  reported  In animals  at  subchronlc  oral   PBB  doses
higher  (>0.5-1  mg/kg/day)  than  those eliciting hepatic, thyroid and  adrenal
effects (Farber et al., 1978; Fraker,  1980;  Luster et  al., 1978,  1980;  Loose
et al.,  1981).  Chronic  oral  toxlclty  studies  of PBBs have  not  been  con-
ducted.  The  only  nonacute  Inhalation studies of  PBBs Involved rats  exposed
to 3.5 yg/m3  octabromoblphenyl  vapor  for  23  hours/day, 7  days/week  for
<15 weeks  (Warltz  et al.,  1977}  and to 50 mg/m3  decabromoblphenyl  dust  for
6 hours/day,  5  days/week  for  4 weeks (Mllllscher  et al.,  1979).   Results of
octabromoblphenyl  exposure  were  unremarkable.   The decabromoblphenyl  study
showed  Increased   liver  weights   but  no  hlstologlcal  alterations  In  any
tissues.
                                      vll

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    PBBs  are  liver  tumorlgens  In  rats  and mice,  but  apparently  only  at
dosages  associated  with  hepatotoxldty.    Hepatocellular   carcinomas   and
neoplastlc nodules were  reported 1n male  and female rats treated by  gavage
with Flremaster FF-1 for  6 months followed by a  23-month observation  period
(NTP.  1983; Gupta  et al., 1983b).   Dosages  ranged from  0.1-10 mg/kg/day,  5
days/week.  In  mice  treated  similarly,  an   Increased  Incidence  of hepato-
cellular carcinomas was reported only In males at  10 mg/kg.   A  single  gavage
dose  of  1000  mg/kg  Flremaster  FF-1  markedly  Increased the  Incidence  of
hepatocellular  carcinomas  and  neoplastlc nodules  In  female  rats  after  a
23-month  observation period  (Klmbrough  et al., 1981).   Similar treatment  at
200 mg/kg Increased the Incidence of neoplastlc nodules but  not hepatocellu-
lar  carcinomas.    Flremaster  8P-6 and  three  hexabromlnated  congeners  were
promoters In the two-stage hepatocardnogenlclty assay  1n hepatectomlzed and
DEN-1n1t1ated  female rats  (Jensen, 1983; Jensen et al., 1982, 1983;  Sleight,
1985;  Dlxon et  al., 1988),  but Flremaster  BP-6  was not  a  promoter  In  the
two-stage mouse skin assay (Berry et  al.,  1978).
    Teratogenlclty, fetotoxUHy, delayed  development  and reduced reproduc-
tive  success  were  observed In  rats  (Beaudoln, 1977,  1979;  Corbett  et  al.,
1975; McCormack et al., 1982; Harris et al.,  1978) and  mice  (Corbett et  al.,
1975)  orally exposed  to  Flremaster  BP-6  or  2,4,5,2',4'.B'-hexabromoblphenyl
(Helsch and Morgan,  1985} at  dosages  associated with  maternal toxldty  or
adverse effects on the liver  1n  subchronlc  oral  studies.  Reduced fetal  bw
were  reported  In  rats  at  2.5  mg/kg/day In some  (Corbett et al.,  1975)  but
not all  (Cagen  and Gibson, 1978; Cagen et al., 1979) studies.  The critical
effect  on  the  offspring   In  the  developmental  and   reproductive  studies
appears  to  be  on  the liver.   Hlstopathologlc  lesions  In   the  liver  were
reported  1n the offspring  of dams fed diets  containing  Flremaster  BP-6 at 10
ppm (0.5 mg/kg/day).

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    PBBs are classified In EPA Group  B2,  probable  human  carcinogens,  because
of  the  sufficient evidence  for  carclnogenldty In  oral  studies  In  animals
(NTP, 1983;  Gupta et  a!.,  1983b; Klmbrough et  al.,  1981).  A  slope  factor
(q *)  of  8.87  (mg/kg/day)"1  was derived  for  oral  exposure  based  on  the
Incidence of hepatocellular  carcinomas and  neoplastlc  nodules  1n female  rats
1n  the  NTP  (1983) and Gupta  et  al.  (1983b) studies.  The  oral  slope  factor
was  not  adopted  as the slope factor  for Inhalation  exposure.   An RQ of  10
for  cardnogenlclty  was  also  based  on  the  NTP   (1983)  and  Gupta  et  al.
(1983b) studies.
    Data  were  not  sufficient   for   derivation  of  an  RfD  for  Inhalation
exposure  to PBBs.   An RfD   of  0.07  ug/kg/day  was  derived  for  subchronlc
oral  exposure  to  PBBs,   based  on a  LOAEL  for  subtle  liver  effects  In  a
25-week gavage study using rats  (NTP, 1983;  Gupta  et  al..  1983b).   An  RfD of
0.007 pg/kg/day was  derived   for  chronic  exposure  by applying an  additional
uncertainty factor of  10  to  expand from  subchronlc  to chronic  exposure.   An
RQ of  10  for  chronic toxldty was based  on mortality 1n rats at  a slightly
higher dosage 1n the same  study.
                                      1x

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                              TABLE  OF  CONTENTS
1.  INTRODUCTION	    1

    1.1.   STRUCTURE AND CAS NUMBER	    1
    1.2.   PHYSICAL AND CHEMICAL PROPERTIES 	    1
    1.3.   PRODUCTION DATA	    3
    1.4.   USE DATA	    4
    1.5.   SUMMARY	    4

2.  ENVIRONMENTAL FATE AND TRANSPORT	    5

    2.1.   AIR	    5
    2.2.   WATER	    5

           2.2.1.   Hydrolysis	    5
           2.2.2.   Photolysis	    5
           2.2.3.   Mlcroblal Degradation 	    6
           2.2.4.   Volatilization	    6
           2.2.5.   Adsorption	    6
           2.2.6.   Bloconcentratlon	    7

    2.3.   SOIL	    7

           2.3.1.   Adsorption/Leaching 	    7
           2.3.2.   Degradation 	    8

    2.4.   SUMMARY	    8

3.  EXPOSURE	   10

    3.1.   WATER	   10
    3.2.   FOOD	   11
    3.3.   INHALATION	   11
    3.4.   DERMAL	   11
    3.5.   SUMMARY	   12

4.  ENVIRONMENTAL TOXICOLOGY	   13

    4.1.   AQUATIC TOXICOLOGY 	   13

           4.1.1.   Acute Toxic  Effects on Fauna	   13
           4.1.2.   Chronic  Effects  on Fauna	   13
           4.1.3.   Effects  on Flora	   15
           4.1.4.   Effects  on Bacteria 	   16

    4.2.   TERRESTRIAL TOXICOLOGY 	   16

           4.2.1.   Effects  on Fauna	   16
           4.2.2.   Effects  on Flora	   16

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                          TABLE  OF  CONTENTS  (cent.)
    4.3.   FIELD STUDIES	   16
    4.4.   AQUATIC RISK ASSESSMENT	   17
    4.5.   SUMMARY	   18

5.  PHARMACOKINETCS	   19

    5.1.   ABSORPTION	   19
    5.2.   DISTRIBUTION	   19
    5.3.   METABOLISM	   22
    5.4.   EXCRETION	   23
    5.5.   SUMMARY	   25

6.  EFFECTS	   27

    6.1.   SYSTEMIC TOXICITY	   27

           6.1.1.   Inhalation Exposure 	   27
           6.1.2.   Oral Exposure	   28
           6.1.3.   Other Relevant Information	   37

    6.2.   CARCINOGENICITY	   39

           6.2.1.   Inhalation	   39
           6.2.2.   Oral	   39
           6.2.3.   Other Relevant Information	   44

    6.3.   MUTAGENICITY	   46
    6.4.   TERATOGENICITY	   46
    6.5.   OTHER REPRODUCTIVE EFFECTS 	   53
    6.6.   SUMMARY	   54

7.  EXISTING GUIDELINES AND STANDARDS 	   57

    7.1.   HUMAN	   57
    7.2.   AQUATIC	   57

8.  RISK ASSESSMENT	   58

    8.1.   CARCINOGENICITY	   58

           8.1.1.   Inhalation	   58
           8.1.2.   Oral	   58
           8.1.3.   Other Routes	   59
           8.1.4.   Weight of Evidence	   59
           8.1.5.   Quantitative Risk Estimates  	   59

    8.2.   SYSTEMIC TOXICITY	   62

           8.2.1.   Inhalation Exposure 	   62
           8.2.2.   Oral Exposure	   63
                                     xl

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                          TABLE  OF  CONTENTS  (cont.)
 9.  REPORTA8LE QUANTITIES
     9.1.   BASED ON SYSTEMIC TOXICITY 	    67
     9.2.   BASED ON CARCINOGENICITY	    71

10.  REFERENCES	    76

APPENDIX A: LITERATURE SEARCHED	    96
APPENDIX B; CANCER DATA SHEETS FOR DERIVATION OF  A qi* FOR ORAL
            EXPOSURE	    99
APPENDIX C: SUMMARY TABLE FOR PBBs	101
APPENDIX D: DOSE/DURATION RESPONSE GRAPH(S)  FOR EXPOSURE  TO
            POLYBROMINATED BIPHENYLS 	   102

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                               LIST OF TABLES
No.                               Title                                page
1-1     Synonyms, Molecular Weights, Empirical Formulas, CAS
        Numbers and Structures of Selected Polybromlnated
        Blphenyls	.	    2
6-1     Subchronlc Oral Toxldty Summary for PBBs	   29
6-2     Incidence of Liver Tumors In Rats and Mice Treated by
        Gavage with Flremaster FF-1  1n Corn 011 for 6 Months and
        Observed for an Additional 23 (Rats) or 24 (Mice) Months.  .  .   41
6-3     MutagenlcUy Data for PBBs	   47
6-4     Developmental Effects of PBBs	   49
9-1     Oral Toxlclty Summary for PBBs	   68
9-2     Oral Composite Scores for PBBs Using the Rat	   72
9-3     PBBs: Minimum Effective Dose (MED) and Reportable
        Quantity (RQ)	   73
9-4     Derivation of Potency Factor (F) for PBBs	   75

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4
                             LIST OF  ABBREVIATIONS
ABS                     Acrylonltrlle-butadlene styrene
AHH                     Arylhydrocarbon hydroxylase
AP                      Alleallne phosphatase
BCF                     Bloconcentratlon factor
BOO                     Biological oxygen demand
bu                      Body weight
CAS                     Chemical abstract service
CS                      Composite score
DEN                     D1methyln1trosam1ne
ONA                     Deoxyrlbonuclelc acid
EO]Q                    Effective dose to 10% of recipients
F                       Potency factor
GGTP                    Gamma glutamyl transpeptldase
GI                      Gastrointestinal
HPC                     Hepatocyte primary cell
l.p.                    IntraperUoneal
l.v.                    Intravenous
Koc                     Soil sorptlon coefficient
Kow                     Octanol/water partition coefficient
1050                    Dose lethal to 50% of recipients
LH                      Leutelnlzlng hormone
MED                     Minimum effective dose
MFO                     Mixed-function oxldase
NOAEL                   No-observed-adverse-effect  level
NOEL                    No-observed-effect level
                                                  x1v

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                         LIST OF  ABBREVIATIONS (cont.)
PBB                     Polybromlnated blphenyl
PCB                     Polychlorlnated blphenyl
ppb                     Parts per billion
Rf                      Degree of retention of chemical In soil TLC tests
RfO                     Reference dose
RQ                      Reportable quantity
RV,j                     Dose-rating value
RVe                     Effect-rating value
SGOT                    Serum glutamlc oxaloacetlc transamlnase
SGPT                    Serum glutamlc pyruvlc transamlnase
TLC                     Thin layer chromatography
TSH                     Thyroid-stimulating hormone
TWA                     Time-weighted average
UV                      Ultraviolet
MBC                     White blood cell
                                      XV

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                               1.  INTRODUCTION
1.1.   STRUCTURE AND CAS NUMBER
    The  synonyms,  molecular   weights,   empirical   formulas,  CAS  Registry
numbers  and   structures   of  the   selected   polybromlnated  blphenyls  are
presented  In  Table  1-1.   The  polybromlnated  blphenyl   chemical  class  1s
commonly known  as  PBB.  There are  209 possible  structural  congeners  of the
bromlnated blphenyl structure containing two or more bromines (IARC, 1986).
1.2.   PHYSICAL AND CHEMICAL PROPERTIES
    PBBs containing three  or more  bromines  are solids.   Volatility generally
decreases as  the  number of  bromines  Increase.  PBBs are  slightly  to  highly
soluble In various organic  solvents  with  solubility  decreasing  as  the  number
of  bromines   Increase  (IARC, 1986).   Available  physical  properties   of  the
selected polybromlnated blphenyls are as follows:
    Hexabromoblphenyl:
    Melting point:
    Water solubility:
      no temperature given
      at 28°C
    Vapor pressure:
      at 25°C
    Log Kow:
Octabromoblphenyl;
    Melting point:
    Vapor pressure:
      at 29°C
    Water solubility:
      no temperature given
72°C
11 pg/kg
10-20
5.2x10"" mm Hg
(estimated)
7.80
200-250°C
IARC, 1978
IARC, 1978
Jacobs et a!., 1978
Jacobs et al., 1976
Garst, 1984
IARC, 1978
3.7xlO~7 mm Hg     Burkhard et al.,  1984
20-30
IARC, 1978
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Decabroiiioblphenyl;
    Melting point:              380-386°C          IARC, 1978
    Hater solubility:           Insoluble          IARC, 1978
    Vapor pressure
      at 50.7'C:                2.0xlO"8 mm Hg     Burkhard et al., 1984
    Log Kow:                    8.58               Doucette and Andren,
                                                   1989
The  polybromlnated  blphenyls  are chemically  unreactlve  (IARC,  1986);  how-
ever, hexa-,  octa-  and decabromoblphenyl have been  reported  to photodegrade
by reductive debromlnatlon upon exposure to UV (IARC, 1978).
1.3.   PRODUCTION DATA
    Commercial  production  of  polybromlnated  blphenyls  In  the  United  States
began  In  1970  and  was discontinued  1n early 1977.  Between  1970  and 1976,
-13.3 million  pounds  of PBBs  was produced,  with -11.8 million pounds being
hexabromoblphenyl.  The  remaining 1.5 million pounds consisted of octa- and
decabromoblphenyl.   The  hexabromoblphenyl  was  marketed  under  the  names
Flremaster BP-6 or Flremaster FF-1 (Griffin and Chou, 1981).
    Michigan  Chemical  Corporation  (St. Louis,  MI) manufactured  Flremaster
BP-6 and  FF-1,  and  White Chemical Company (Bayonne, NJ)  and  Hexcel Corpora-
tion (Sayrevllle, NJ)  manufactured octa- and  decabromoblphenyl  (Griffin and
Chou,  1981).   Michigan  Chemical  Corporation  discontinued   production  In
November  1974.   This  discontinuation  was precipitated  by  an Incident  In
1973-1974  In  which  Flremaster  FF-1  was  added to  animal   feed  In Michigan,
resulting  In contamination  and  destruction   of  thousands of   farm  animals
(IARC,   1978.  1986).   White  Chemical  and Hexcel Corporation  stopped  produc-
tion of octa- and decabromoblphenyl  1n early 1977  (Griffin and Chou,  1981).
PBBs were manufactured by the bromlnation of  blphenyl (IARC, 1986).
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    Under  the Federal Toxic  Substances Control  Act,  the U.S.  EPA requires
that any persons  who  Intend  to manufacture,  Import or process polybromlnated
blphenyls  for any use  must  notify the EPA at least 90 days before commencing
(U.S. EPA, 1987).
1.4.   USE DATA
    The polybromlnated blphenyls  were used as  flame retardants for synthetic
fibers, resins  and plastics  (IARC, 1986; Griffin  and  Chou,  1981).  In 1974,
-55X of  the  total  hexabromoblphenyl  produced  was used  In ABS resins  (IARC,
1986).  These plastics, which  had a  P8B content of -10%, were used primarily
for small  appliance and  automotive applications.   Hexabromoblphenyl  was used
In  housings   and  cases   for   typewriters,   calculators,  microfilm  readers,
business   machines,   projectors,   film  equipment,  motors   and  Industrial
equipment and In  coatings for electrical wire and cables (IARC, 1986).
1.5.   SUMMARY
    The  polybromlnated blphenyl  chemical class   Is  commonly  known by  the
synonym PBB.  There are  209 possible structural  congeners of  the bromlnated
blphenyl structure containing  two or more bromines (IARC, 1986).   The PBBs
are chemically  unreactlve  (IARC,  1986);  however,  hexa-,  octa- and decabromo-
blphenyl have been reported to photodegrade by reductive  denomination upon
exposure to  UV  (IARC. 1978).   Commercial production  of PBBs In  the  United
States began  In 1970  and was  discontinued  In early 1977.  Between  1970  and
1976, -13.3  million pounds of  PBBs  was produced, with  -11.8  million  pounds
being  hexabromoblphenyl.    The  PBBs  were   commercially  produced  by  three
manufacturers operating  three  production sites   (Griffin and Chou,  1981).
The  PBBs  were  used as  flame  retardants  for   synthetic  fibers,  resins  and
plastics (IARC,  1986;  Griffin and Chou,  1981).
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                     2.   ENVIRONMENTAL FATE AND TRANSPORT
2.1.   AIR
    The environmental fate  of PBBs  1n  the atmosphere are not  well  defined.
Based upon the limited vapor  pressure data  presented  1n  Section 1.2.,  hexa-,
octa- and  decabromoblphenyl   may  exist   1n  the  ambient  atmosphere  In  both
partlculate and  vapor  phases  {Elsenrelch  et al.,  1981).   As  the number  of
bromines  Increase,  association  with atmospheric partlculates 1s  also  likely
to  Increase.   Based upon the photolysis data  presented In  Section  2.2.2.,
vapor-phase PBB  Is  likely to photodegrade relatively rapidly In  sunlit  air.
Partlculate-phase PBB may  also  be  susceptible to  significant  photodegrada-
tlon; however, the  nature  of an  adsorbing substrate may attenuate  the  rate
of  photodegradatlon.   Experimental  data  are  required  to ascertain   the
Importance of photodegradatlon In air.
    Partlculate-phase  PBB   1s   susceptible  to  physical   removal  by   dry
deposition.
2.2.   WATER
2.2.1.   Hydrolysis.  Experimental  hydrolysis  data regarding the PBBs  were
not  located.   However,  halogenated  aromatlcs  such  as  PBBs  are  generally
resistant  to  environmental  hydrolysis {Harris, 1982);  therefore,  hydrolysis
of PBBs In the aquatic  environment Is not expected to  be Important.
2.2.2.   Photolysis.  The PBBs  have been shown to be readily susceptible  to
photodegradatlon   when  exposed   to  Irradiation   wavelengths  occurring  In
sunlight  (EpUng  et al..  1987;  Ruzo  et  al., 1976; Robertson et  al.,  1983).
The photolysis occurs through a  reductive  debromlnatlon  process In which the
Irradiated PBB Isomer  yields a  PBB product containing  fewer bromines.   For
example,  photolysis of  F1remaster  BP-6  (which  consists primarily of  hexa-
bromoblphenyl) In a 90%  acetonltrlle-water solution has been shown  to  yield
penta-, tetra-, tr1-, dl- and monobromoblphenyls {Epllng et  al., 1987).
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    The rate  of  photolysis has also  been  shown to be relatively rapid  under
laboratory  conditions using  artificial  Irradiation  sources.   Robertson et
al. (1983)  noted  a  reduction  from 78.22% hexabromoblphenyl before photolysis
to  30.60X  after  12 hours  of  Irradiation  1n  cyclohexane  solution with  light
wavelengths   >290   nm.   Ruzo   et  al.   (1976)   found  a  55%  reduction  of
2,2',4.4',5,5'-hexabromoblphenyl  and  a  9454 reduction of 2,2',3,3',5,5',6,6'-
octabromoblphenyl using  a  "merry-go-round"  apparatus and  hexane solvent at
wavelengths >290 nm.
2.2.3.   M1crob1al  Degradation.    Very  limited  blodegradatlon  data   are
available  for PBBs  In  water.    Results  using   Japanese  MITI   protocol  have
Indicated  that decabromoblphenyl  is resistant to blodegradatlon  (theoretical
BOD was  <30X after  a  14-day  Incubation using  activated  sludge as  Inoculum)
{Sasaki, 1978; Kawasaki, 1980).
2.2.4.   Volatilization.   Using  the  group  estimation  method  of  Hlne  and
Mookerjee  (1975), the Henry's  Law  constants  for  hexa-,  octa-  and decabromo-
blphenyl  at  25°C  can   be ~2.23xlO~6,   3.88x10""'   and  6.74xlO~«*   atm-mV
mol,  respectively.    The  estimated  values  for  octa- and  decabromoblphenyl
Indicate  very slow  to  essential nonvolatmty  from water (Thomas,  1982).
The value  for hexabromoblphenyl  Indicates  slow volatilization.  Considering
that significant  adsorption of PBBs  to sediment and suspended material may
occur  1n  natural  waters  (Sections  2.2.5.  and  2.3.1.),  which  will  decrease
the rate of  volatilization, volatilization may not be an  Important  environ-
mental  fate process  for hexa-,  octa-  and  decabromoblphenyl  1n  the  aquatic
environment.
2.2.5.   Adsorption.   Based upon  the  soil  adsorption  data   presented  In
Section  2.3.1.,   significant   partitioning  of   PBBs  from  water  column  to
sediment and  suspended material 1s  likely.   In  one monitoring  study  of river


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water  and  associated  sediment (IARC, 1986), the PBB level of  the  river water
32.2 km  downstream from a contaminating outfall was <0.01 ppb, while  the PBB
concentration  In sediments 38.4 km downstream was 0.1 mg/kg.
2.2.6.   B1oconcentrat1on.   A BCF  of  18,200  was   experimentally  determined
for  hexabromoblphenyl  1n  fathead   minnows  over  a  32-day  exposure  period
(Ve1th  et  al.,  1979).   A fish  BCF  of  100,000  has been  reported for deca-
bromoblphenyl  (Anllker  et al., 1987).  These BCF  values  Indicate a signifi-
cant potential for bloaccumulatlon In aquatic organisms.
2.3.   SOIL
2.3.1.   Adsorption/Leaching.   The   results  of  laboratory leaching  experi-
ments  have shown that  Flremaster BP-6  (predominantly  hexabromoblphenyl)  and
2,2',4,4',5,5'-hexabromoblphenyl do  not leach  significantly 1n soil (Griffin
and Chou,  1981;  Fllonow et  al.,  1976).   Griffin and Chou  (1981) determined a
soil  Rf  value  of  0.00  for   Flremaster  BP-6  In three  different  soil  types
(silt  loam,  sllty clay  loam and sand)  using  soil TLC measurements.   An  Rf
value  of  0.00  Indicates  soil   Immobility and   tight  adsorption  to  soil
materials.   When  the  experiments were repeated  using  a  landfill  leachate
Instead  of  water   as   the   leaching  media,  the  Rf  values  remained  0.00.
However, when  organic  solvents  such as methanol,  acetone and  dloxane  were
used as the leaching media, the PBBs were readily leached.
    Fllonow et  al.  (1976) studied the  leaching of 2,2',4,4',5,5'-hexabromo-
blphenyl   In  four   agricultural   soils   from  H1ch1gan  using  soil  leaching
columns.   Less than 0.6X of  applied  hexabromoblphenyl   (100  ppm) was  lost
from the soils  using  leachate quantities equivalent to  20 times  the average
annual rainfall  1n Michigan.  Based  upon  the  results of  their  experiments,
the authors suggested  that  PBBs  released to Michigan farm soils  by contami-
nated manure should not leach below the depth of Incorporation.
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2.3.2.   Degradation.   PBBs  have been  found to  be  extremely  persistent  In
soil  (Jacobs et al.,  1976,  1978).   Jacobs  et al.  (1976) Incubated Flremaster
BP-6  1n  flasks  containing two different Michigan  soils  for  a 24-week period
and  found  no significant degradation  with  the exception  of  a  single penta-
bromoblphenyl  Isomer.   Jacobs  et  al.  (1978)  examined  the degradation  of
"C-labeled  P8B  (Flremaster  BP-6)   In  a  Michigan soil  over  an  Incubation
period  of  1  year.   No  evidence  of significant  degradation was  found.   No
difference  1n  degradation  was found  1n  control  experiments  using  sterile
versus nonsterlle soil.   A minor  degradation of -3X  was attributed to photo-
degradation.   Less   than  0.2%  of  the  14C  was volatilized  over  the  1-year
period.  Based  upon  the results of  their  Incubation  studies  and field moni-
toring  of  contaminated farm  soils  1n  Michigan,  the authors  (Jacobs  et al.,
1978) "expect PBB to be a rather permanent component  of contaminated soils."
    H111 et  al.  (1982) examined soil  samples taken  from the  former  Fire-
master  BP-6  manufacturing  site  1n Michigan and  compared  the  PBB  Isomer
content  of  the soils  to the known  Isomer  content of  Flremaster  BP-6.   The
soil  samples  were apparently  collected at least  several  years  after  produc-
tion  had stopped.  The comparison  suggested that some degradation may have
occurred by  photodegradatlon.  As noted  above,  Jacobs  et  al.  (1978)  observed
minor  photodegradatlon of  Flremaster  BP-6  during  soil  Incubation  studies.
However,  photodegradatlon  1s  only  viable  on  soil  surfaces  exposed  to
sunlight.  If a PBB  substrate Is  Incorporated within  the  soil,  sunlight will
not be able to reach 1t.
2.4.   SUMMARY
    When  PBBs  are   released  to  soil,  they are  expected  to   be extremely
persistent   (Jacobs  et  al.,   1976,  1978).   Incubation of  14C-labeled  Fire-
master BP-6  (predominantly  hexabromoblphenyl) In  a Michigan  soil  for  1  year


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showed  no  evidence of  significant degradation  (Jacobs et  al., 1978).   No
difference  1n  degradation  was  found  In control  experiments using  sterile
versus nonsterlle soil.  A minor degradation  of  ~3X was attributed  to photo-
degradation.  The results of  laboratory  leaching experiments  have  shown that
Flremaster  BP-6  (predominantly  hexabromoblphenyl)  and  2,2',4,4',5,5'-hexa-
bromoblphenyl do  not  leach  significantly  In soil  (Griffin  and Chou,  1981;
Fllonow et  al.,  1976).   Photolysis may be a  viable  process  resulting In  PBB
degradation In water.  The PBBs have been shown  to  be readily susceptible to
photodegradatlon  when  exposed  to  Irradiation wavelengths  occurring   In
sunlight (EpHng et  al.,  1987; Ruzo et  al., 1976;  Robertson et al.,  1983).
The photolysis occurs through a reductive debromlnatlon  process  1n which  the
Irradiated  PBB  Isomer   yields  a  PBB  product  containing  fewer  bromines.
Significant  partitioning  from  the water  column to  sediment and suspended
material 1s  likely  to occur.   If  released  to  the  atmosphere,  the PBBs  may
exist  In  both partlculate  and vapor  phases.   Vapor-phase  PBB  1s probably
susceptible to significant  degradation by photolysis.   Partlculate-phase  PBB
Is  susceptible  to   physical  removal  by   dry  deposition  and,  perhaps,
degradation  by  photolysis.    A  BCF of 18,200 was experimentally determined
for  hexabromoblphenyl In  fathead  minnows   over a   32-day  exposure   period
(VeHh et al., 1979), suggesting a  significant  potential for  bloaccumulatlon
In aquatic organisms.
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                                 3.  EXPOSURE

    PBBs  are  not  known  to  occur  naturally  (IARC,  1986).  Therefore,  their
detection 1n environmental media results from anthropogenic release.
3.1.   HATER
    Wastewater  effluents  from  a  plant  manufacturing  PBBs  were found  to
contain PBB levels as  high  as  104  ppb,  which resulted In a discharge of -122
g/day.   PBB  concentrations  In the  river  water receiving  discharges  ranged
from  3.2  ppb  at a point 69 meters downstream of  the  plant  to 0.01 ppb about
12.8  km  downstream.   PBB levels  In  river  water 19.3  and  32.2 km downstream
were  below the  monitoring detection limit of 0.01  ppb.   Sediment concentra-
tions  ranged  from  77 mg/kg  near  the  plant outfall  to 0.1  mg/kg 38.4  km
downstream {IARC, 1986).
    Water samples  collected  In April 1977 from a  wastewater  basin receiving
discharges from White Chemical  Corporation contained  PBB  levels  of  9.8-46
ppb.   Decabromoblphenyl  was Identified  as  the primary  Isomer (76X)  of  the
PBB  detections, with  smaller  amounts  of  nonabromoblphenyl  (15%)  and  other
PBBs.  Sediment  samples  collected  In April 1977 from  a  discharge canal at a
Staten  Island,   NY  factory  that  used  PBBs  contained 40  ppb  of  hexabromo-
blphenyl  and  20  ppb  of  heptabromoblphenyl.   Swamp water  samples collected
near  the  Hexcel Organlcs manufacturing facility  (Sayrevllle,  NJ) contained
210  ppb   PBB,  while  storm  sewer  water  contained  138  ppb PBB.   Decabromo-
blphenyl  was  the  dominant  Isomer  Identified.   Analysis  of  artesian  well
water  (used by  local  people for potable water) -1000  m  from the  Hexcel site
failed  to detect any  PBB  (detection  limit   not  reported)   (Whltlock  and
Stratton, 1979).
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    Hexabromoblphenyl  has  been qualitatively detected  In  water samples from
Lake  Ontario  (open water)  and the  Pickerel  River, which  empties  Into Lake
Huron (Great Lakes Water Quality Board, 1983).
    The  U.S.  EPA  STORET  data  base  contained  no  postings for  the  selected
PBBs.
3.2.   FOOD
    Animal feed contaminated  by PBB  (Flremaster  BP-6)  was  used by farmers  1n
Michigan  between  July 1973  and May 1974  until  the PBBs  were  Identified  as
the contaminating  substance.   In  1974,  measurements at 22  contaminated farms
found maximum  PBB  levels  of 595 mg/l  In  milk and 59.7 mg/kg  In  eggs.   In a
survey of dairy cattle In  March,  1975,  the FDA found milk  fat levels of 1-13
mg/kg (IARC, 1978).
    Average PBB  levels of 2.78-3.39 mg/kg were detected  1n  the  milk  fat  of
four  Holsteln  cows  that  had  consumed  10 mg/day  PBB  (Flremaster 8P-6)  for
30-60 days.   These levels  dropped  by  65-77X  15  days  after  feeding of  PBBs
had stopped {IARC, 1986).
    PPB  concentrations from 15-15,000  ng/g  fish  fat  were detected 1n  carp
and hogsucker  collected from tributaries  of Lake  Michigan  In 1983  (Jaffe  et
al, 1985).
3.3.   INHALATION
    An  air  sample collected  downwind  of  the White  Chemical  Corporation
manufacturing  facility (Bayonne,  NJ)  1n  April  1977 contained a  hexabromo-
blphenyl  level  of 60  ng/m3.  An air  sample collected  downwind  from a PBB
use  facility   1n   Staten   Island,  NY,   1n  April   1977  contained  100  ng/m3
hexabromoblphenyl  (WhHlock and Stratton,  1979).
3.4.   DERMAL
    Pertinent  monitoring data  regarding the dermal  exposure of  PBBs  were not
located 1n the available literature  as  cited In Appendix A.

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3.5.   SUMMARY
    The  PBBs are  not  known  to  occur  naturally  (IARC,  1986).  Therefore,
their  detection  1n  environmental  media 1s a result of anthropogenic  release.
Air samples  collected  downwind of a manufacturing facility {Bayonne. NJ) and
use  facility  (Staten   Island,  NY)  In April  1977 contained  PBB  levels  of
60-100 ng/m3  (Whltlock and  Stratton, 1979).   PBBs   have  been  detected  1n
wastewater effluents  from  manufacturing and use facilities and  In associated
river  water  and sediments  (IARC,  1978; Whltlock and  Stratton,  1979).   PBBs
accidentally  entered  the food supply  when  animal  feed contaminated  with PBB
(Flremaster  BP-6)  was  used by farmers  In  Michigan  between July 1973 and Hay
1974  until  the  PBBs  were  Identified as  the  contaminating  substance.   PBB
levels as  high as  595  mg/l and  59.7  mg/kg were detected  1n  milk  and  eggs,
respectively  (IARC, 1978).   PPBs  concentrations  from  15-15,000 ng/g  fish fat
were  detected In fish  (carp,  hogsucker)  collected from  tributaries  of  Lake
Michigan In 1983 (Jaffe et al., 1985).
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                         4.  ENVIRONMENTAL TOXICOLOGY
4.1.   AQUATIC TOXICOLOGY
4.1.1.   Acute  Toxic  Effects  on Fauna.   Applegate et  al.  (195?)  assessed
the toxlclty of  hexabromoblphenyl  to larval  sea lamprey, Petromyzon marlnus.
Larvae  were exposed  to  a  maximum concentration  of  5  ppm for 24  hours  at
55°F.   No  effects  from  exposure  to  hexabromoblphenyl  were  observed  under
these conditions.
    James  and  Little (1981)  reported that  an  1.p. Injection  of  sheepshead
minnow,  Archosarqus  probatocephalus.  with 50  mg/kg  of  Flremaster  FF1  (PBB
mixture)  resulted  In  the deaths of  2/5 minnows after 4 days;  the remaining
three  fish were moribund  on  the   following  day.  The Investigators  also
reported  that  the  PBB-treated  minnows exhibited Increased hepatic  mlcrosomal
benzo[a]pyrene  hydroxylase  (AHH)  and  7-ethoxycoumarln-O-deethylase  (7-EC)
activities and elevated P-450 contents compared with control minnows.
4.1.2.   Chronic Effects on Fauna.
    4.1.2.1.   TOXICITY — Elcombe  and  Lech   (1978)  and   Elcombe   et  al.
(1979)  assessed the  effect of  1.p.  Injections  of Flremaster  BP-6 on  the
hepatic  mlcrosomal  P-450 and  monooxygenase  systems of  rainbow  trout,  Sal mo
galrdnerl.  Fish were Injected with  a  1 ml/kg  dose of  BP-6  1n  corn oil  and
maintained  1n  50 i  tanks  for  <20  days.    Activity  of  the  enzymes   of
Interest peaked 4-8 days  after  treatment and declined  through the  end of  the
study.
    James  and  Little (1981)  reported  that  l.p.  Injection of  sheepshead
minnow,  A.  probatocephalus. with  15 mg/kg  of  Flremaster FF1  (PBB  mixture)
produced  no  mortalities  among  treated  minnows.    The  PBB-treated  minnows
exhibited  Increased hepatic mlcrosomal AHH and 7-EC activities  and  elevated
0176d                               -13-                             06/07/89

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P-450  contents  compared with control  minnows.   The extent of  the Induction
was  greater  when  experiments  were  carried  out  at  summer  temperatures
(25i4°C) as compared with winter temperatures (1U3°C).
    Law  and  Addlson  (1981)  assessed the effects  of Mremaster BP-6  on  AHH
and  7-EC  activities  of  brook  trout,  Salvellnus  fontlnalls.   F1sh  were
offered  gelatin capsules  containing 200 vq  contam1nant/g fish three times
at 2-day  Intervals.   The study was  conducted at  10°C  for  18  days.  Investi-
gators  reported a  significant  Increase In  the  AHH activity among  treated
fish but  no  change In 7-EC activity  for treated  fish.   Induction  of  hepatic
NFO activity  1n fish  exposed  to  PBBs  has  also  been  reported by  James  and
Bend (1978) and Franklin et al. (1981).
    4.1.2.2.   BIOACCUMULATION/BIOCONCENTRATION — Zltko    and    Huntzlnger
(1976) assessed  the accumulation  of  six different PBB congeners  from water
and food  by  Juvenile Atlantic  salmon,  Salmo salar.  Salmon  were  exposed  to
PBB  solutions  with   Initial   concentrations   of   46.0-57.6   vg/im  for   96
hours  under  static conditions  at  15°C.  In  separate experiments,  fish  were
offered  dry  fish  food  contaminated  with 7.75  vg Br/g food  for  40 days  at
15°C.   The Investigators  reported accumulation coefficients  (equivalent  to
BCFs) of 63-1343 for  PBBs  by salmon  from water  and 0.179-0.587 for PBBs  from
contaminated  food.   In general,  the dlbromoblphenyls  exlblted the greatest
propensity for  accumulation by  salmon  (except  for  the 3,4-congener,  which
had the  lowest  accumulation coefficient),  followed  by  the trlbromoblphenyls
and  the  tetrabromoblphenyls.   Hexabromoblphenyl   could  not  be  detected  In
tissue samples In either series of experiments.
    Subsequently,  ZUko  (1977a,b) assessed  the uptake of PBBs by  Atlantic
salmon, S. salar.  from  two  commercial  preparations,  Flremaster  BP-6 and  OBB,
under  the conditions  described  above  (ZUko  and  Hutzlnger,  1976).   The

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patterns of  BCFs  reflected those obtained  In  the  earlier study.  Penta- and
hexabromoblphenyl concentrations  In  fish  were  low with consequently low BCFs
(48  and  54).  The heptacongener  was not evident  In  tissue samples.  Uptake
of PBBs from food was Insignificant with BCFs <1.0.
     Suglura  et al. (1978)  assessed  the  accumulation of three different PBBs,
3,5-d1bromob1phenyl,   3,5,4'-tr1bromob1phenyl   and   3,5,3',-5'-tetrabromo-
blphenyl,  by  the  kllUflsh,  Oryzlas  latlpes.  Fish  were  exposed  to  0.05,
0.005 and  0.0005  ppm solutions of each of  these compounds  for  20 days under
flowthrough  conditions  at  25i2°C.   The  Investigators  reported  estimated BCF
values of  340-1280,  7340-16,760  and  2840-5300  for the d1-,  trl- and  tetra-
bromoblphenyls, respectively.
     Velth  et al.  (1979) assessed the bloconcentration of  hexabromoblphenyl
by   fathead  minnow,  Plmephales  promelas.    Minnows  were  exposed  to  5.3
jig/mi  hexabromoblphenyl   for   32   days  under   flowthrough  conditions   at
25°C.  Concentrations of hexabromoblphenyl  were  analytically verified  dally.
Investigators  reported  a  BCF  of  18,100   for  hexabromoblphenyl  1n  fathead
minnows.
     Sabljlc  (1987) reported  the  results of  a  bloconcentration  study  In which
the  original  Investigators obtained a BCF  of  2.69 for decabromoblphenyl  1n
fish.
4.1.3.   Effects on Flora.
    4.1.3.1.   TOXICITY --  Pertinent  data  regarding  the  toxic  effects  of
exposure of  aquatic  flora  to  polybromlnated blphenyls were not  located  1n
the available literature cited In Appendix A.
    4.1.3.2.   BIOCONCENTRATION — Pertinent data   regarding  the  bloconcen-
tration  potential  of  polybromlnated  blphenyls   in aquatic  flora were  not
located In the available literature cited In Appendix A.


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4.1.4.   Effects  on  Bacteria.    Pertinent  data  regarding  the  effects  of
exposure of aquatic bacteria  to  polybromlnated  blphenyls  were not located In
the available literature cited In Appendix A.
4.2.   TERRESTRIAL TOXICOLOGY
4.2.1.   Effects  on  Fauna.   Burslan  et  al.   (1983)  assessed  the effects  of
PBBs  1n  the  diet  of  Japanese  quail,  Cpturnlx coturnlx.  on  reproductive
function  and  MFO.  Birds were  offered feed  contaminated  with  40 or 80 ppm
PBB  for  5  weeks.   PBBs  Induced MFOs In  quail at  40 ppm  and  reduced  egg
production  at  80  ppm.   Strlk  (1973)  reported  that  oral administration  of
hexabromoblphenyl  1n   gelatin   capsules   to   Japanese  quail  significantly
Increased amlno-levuHnlc add synthetase activity.
    Cottrell et  al.  (1984)  assessed  the  oral   toxlclty  of  dietary PBBs  In
bobwhlte quail, Collnus  vlrqlnlanus.   Quail were 13-14  days old at  the  start
of  the  study.    Investigators  estimated  an  8-day  LC™  (and  95% confidence
Intervals)  of  428  ppm  (253-577).   There were no  mortalities  among  quail
offered food containing 100 ppm  PBBs.   All  birds  receiving 600  ppm PBBs  1n
their diets died after -5 days of treatment.
4.2.2.   Effects  on  Flora.    Pertinent   data   regarding  the   effects   of
exposure  of  terrestrial flora  to  polybromlnated blphenyls were  not  located
In the available literature cited 1n Appendix  A.
4.3.   FIELD STUDIES
    Hesse and Powers  (1978) assessed  the ability of  caged fathead minnow,  £.
promelas.  to accumulate  PBBs  \n_  situ.  Minnows  were  placed 1n the Pine  River
below a Flremaster  BP-6 manufacturing plant  for 2 weeks.  The  Investigators
reported a  BCF  of  >10,000.   Hesse and Powers (1978)  also examined  fish from
the  P1ne  River  and wild ducks  collected  In  the vicinity of the Flremaster
manufacturing plant.  The Investigators found levels  of PBBs  as high as 1.33
0176d
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rag/kg  In  skinless filets of  carp,  Cyprlnus carplo.   They also found levels
1n  ducks  ranging  from 80-290  tig/kg  In  skinless  breast  muscle  and  from
230-2700 pg/kg 1n breast muscle with the  skin attached.
    DICarlo  et  al.  (1978)  cited studies  reporting  the presence  of PBBs  In
fat of  deer, rabbits,  coyote, ravens and ducks,  and 1n herring gull eggs  at
six different locations on the Great Lakes.
    Stratton and  Hhltlock (1979)  measured PBBs  In fish and algae from rivers
near  three PBB-manufacturlng sites.   PBBs were  not  detected  In  samples  of
planktonlc  algae  from  any  of the  sites,  but  fish from two  sites contained
220  and 230  yg   PBBs/kg  tissue.   Stratton  et  al.  (1979)  measured  PBBs  1n
fish  collected  In  New Jersey.   Concentrations  of  hexabromoblphenyl  ranged
from  below detection  to  3.4  ng/g.   Concentrations  of  hepta- and  octabromo-
blphenyl were <1.8 ng/g.  Nona- and decabromoblphenyls were not detected.
    Kaiser  et  al.  (1980) analyzed  dead  or  moribund bald  eagles,  Hallaetus
leucocephalus.  from  29  states   between  1975  and  1977   for   PBB  residues.
Residue  levels   ranged  from  30-270  pg/kg  In  11  eagles   from six  states.
Jaffe et al.  (1985)  analyzed  the  fat  of sedentary fish collected from tribu-
taries and embayments  of Lakes Huron  and  Superior.  PBB levels 1n  the fat  of
these  fish ranged  from 15-15,000 ng  PBBs/g of  fish  fat.  Watanabe et al.
(1987)  analyzed  unidentified mussels  and  several  species of  fish  (mullet,
goby,  sardine,  sea  bass,  mackerel  and  halrtall)  collected  from  different
seashores  in  Japan  for PBBs.  Investigators  reported  concentrations ranging
from  below detection  In  the  majority of  samples  to 14.6 vg/kg (wet  weight
basis) for tetrabromoblphenyl.
4.4.   AQUATIC RISK ASSESSMENT
    The lack of pertinent data  regarding the effects  of exposure  of aquatic
fauna  and  flora  to polybromlnated  blphenyls precluded  the  development  of
freshwater and saltwater criteria by the method of U.S. EPA/OMRS (1986).

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                             5.  PHARMACOKIKETICS
5.1.   ABSORPTION
    PBBs  are readily  absorbed  by  various  species  following  oral  exposure
(OlCarlo  et  a!.,  1978; Oamstra  et  al., 1982; Fries,  1985).   In general, GI
absorption of PBBs decreases with Increasing bromine content.
    Rats  that  were  administered a  single  1  mg/kg  dose  of  2,2',4,4',5,5'-
[14C]hexabromob1phenyl  In  Emulphor:ethanol-.water  (1:1:8)  vehicle by  gavage
eliminated 7.9% of the  radioactivity  1n the  feces  during the first 24 hours.
Urinary excretion of  radioactivity was  negligible, and l.v.  Injection  of  the
same dose  In rats resulted  in  fecal  elimination  of 0.96% of the administered
radioactivity during  the  first  24 hours;  thus,  It appears that  ~93X  of  the
oral  dose was  absorbed  from   the  gut.   Fecal  radioactivity  measurements
during  the 3 days following gavage  administration of 4 consecutive dally  1
mg/kg  doses  of   2,2',4,4',5,5'-[14C]hexabromob1phenyl  1n  Emulphor:ethanol:
water Indicated GI absorption  by rats of  >85X.  When administered to rats In
corn  oil,   4  consecutive   dally   gavage  doses  of  3,   10   or  30   mg/kg
2,2',4,4l,5,5'-[l4C]hexabromob1phenyl were  absorbed >90%  from the GI  tract
(Matthews et  al., 1977).
    Fecal  radioactivity  measurements   during the   16 days  following  oral
administration  of  a   single  1  mg/kg  dose  of  [l4C]octabromob1phenyl  1n  corn
oil Indicated GI  absorption  by  rats of >73X (Norrls et al., 1975).
5.2.   DISTRIBUTION
    PBBs  are distributed  similarly   1n  various  species  (Matthews  et  al.,
1977; Tuey and Matthews,  1980;  DICarlo et  al.,  1978; Damstra  et  al.,  1982;
Fries, 1985).  Following absorption,  PBBs are  rapidly  removed  from the blood
and stored Initially In highly  perfused  tissues  (e.g.,  liver  and muscle).
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Because of  their  llpophlllclty,  PBBs  are (with time) redistributed primarily
to  adipose  and other  tissues  with high I1p1d content  (e.g.,  skin,  mammary
and brain) where they accumulate.
    Levels  of  2,2',4,4',5,5'-hexabromob1phenyl In  the  blood of  rats  peaked
within 4  hours of a single  10  mg/kg  gavage dose of  Flremaster  FF-1  In corn
oil  (Domino et  al.,  1980,  1982).   Concentrations   In  most tissues  peaked
within 12 hours, with  the  highest  levels occurring  In the liver.  The lowest
concentrations,  generally  an   order   of magnitude   lower   than  the  liver,
occurred  In  the  blood, brain and  testes.   Concentrations  In Inguinal  subcu-
taneous fat  peaked  twice,  first after 8  hours and again  after  2-4 days,  and
slowly  plateaued  during  the following  108 days.   Based on  concentrations
during   the   first    112   days,   the   half-time    for   disappearance   of
2,2',4,4',5,5'-hexabromob1phenyl from  the blood was  145  days (Domino  et al.,
1982).  Tissue levels  showed  that the  tissues  could be grouped  Into  three
compartments:  Compartment  1  Included  heart, kidney,  spleen  and  whole  blood,
Compartment  2  Included  liver,   lung,  brain and  testes,  and  Compartment  3
Included  subcutaneous  fat.  Tissue half-times  for   Compartments  1,  2  and  3
were 26.5-37.8 minutes, 18.1-23,1 hours and 36.9 days, respectively.
    Rats  given single  oral doses  (200 or 1000 mg/kg) or  divided  doses (100
mg/kg  twice  a  week  every  3  weeks  for 12  doses)  of   Flremaster  FF-1  In corn
oil by gavage  still  contained  PBBs In the  liver  after  2  years  (Klmbrough et
al., 1981).
    Domino et  al. (1980) measured  concentrations  of  the  major  PBB components
In  the liver,  lung,  testes  and  fat  of rats  following a  single 10  mg/kg
gavage dose of  Flremaster  FF-1.   Levels  of  2,2',4,5,5'-pentabromob1phenyl
diminished  more  rapidly   than  2,2',4,4',5,5'-hexabromob1phenyl   1n   these
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tUsues,   indicating   preferential   clearance  of  2,2',4,5,5'-pentabromobl-
phenyl.  The uptake and  clearance  of the other PBB components {various hexa-
and  heptabromoblphenyls) were  similar  to  2,2',4,4',5,5'-hexabromob1phenyl.
Mlllis  et  al.  (1985)  administered single equlmolar  doses  of 3,4,5,3',4',5'-
hexabromoblphenyl  (13.3  mg/kg)  or  3,4,3' ,4'-tetrabromob1phenyl  (10 mg/kg)  1n
corn  oil  by gavage  to  rats.   Liver  and  fat concentrations  of  tetrabromo-
blphenyl decreased  In  a time-dependent  manner  during  the 10  days following
treatment, but tissue levels of hexabromoblphenyl  did not change.
    Rats fed diets containing 1, 10,  100 or  1000  ppm octabromoblphenyl for  2
or 4 weeks showed  dose-related  accumulation  of  bromine  In  the fat, liver and
muscle  at  levels >10 ppm (Lee et al.,  1975;  WaMtz et  al., 1977).  Levels  1n
the  muscle were  -3-4   times  lower  than In  the   fat  and  liver.   Following
treatment,  bromine decreased  progressively  in   the  liver  and  muscle, but
continued  to  accumulate In  the fat.   At  18 weeks  after  treatment with  10
ppm, bromine levels In  the  fat,  liver  and muscle  were  -11, 1.5 and 2.4 times
higher, respectively,  than levels of bromine  In these  tissues  from controls.
At 18  weeks after  treatment  with 1000  ppm,  bromine  levels 1n  the fat,  liver
and  muscle were -800,  9 and 27  times  higher  than  control   levels,  respec-
tively.  When rats were  fed 0.1 mg octabromob1phenyl/kg  bw/day  for 180 days,
the concentrations of  bromine  1n  the  IWer  and  fat Increased  steadily with
no attainment of a  plateau  (Norrls et  al.,  19/5).   Rats fed 1 mg octabromo-
blphenyl/kg bw/day for  90  days  showed  reduced  bromine levels In  the  liver,
but not In fat,  during  90 days  following treatment.
    Analyses of  Michigan  residents  several  years after  PBB exposure have
determined llpld/blood  ratios  of  175  (Cordle et  al..  1978),  320  (Wolff et
al., 1979), 358  (Tuey  and  Matthews,  I960),  363 (LandMgan et al.,  1979) and
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o
140-329  (Eyster  et  al.,  1983).  A  survey of  27  Michigan women  showed PBB
levels  1n  breast milk 107-119  times  higher than  levels  1n  serum (Eyster et
al., 1983).
    PBBs can  cross  the  placenta  Into  fetuses.   Transplacental  distribution
of  PBBs  1s Indicated by  developmental  and toxic  effects  (Section  6.4.) and
the  presence  of PBBs  In  tissues  (Beaudoln,  1977;  Corbett  et al.,  1978;
McCormack  et   al.,  1981; Harltz  et  al.,   1977)  In  fetuses  and progeny  of
orally  exposed animals.   A survey  of 60 parturient  Michigan  women  that had
varying  exposure  to  PBBs  showed  that  cord  blood contained  ~7 to  10-fold
higher  PBB concentrations than maternal serum,  Indicating  partial  placenta!
passage  (Eyster  et  al.,  1983).  Ratios of PBB  levels  In maternal  serum to
placenta!  levels were similar.
5.3.   METABOLISM
    Limited Information  Is available  on  the metabolism  of  PBBs.   The limited
data  for  PBBs,  documented  persistence  of PBBs   In  biological  systems  and
extensive  Information for analogous PCBs suggest  that metabolism of  the more
highly  bromlnated and  abundant  PBB  congeners  Is not significant  (Fries,
1985).
    Mass spectrometMc analysis showed  that ~1X of a 100  mg/kg  Intraperlto-
neal dose  of  Flremaster  BP-6  was  excreted  as  a monohydroxypentabromoblphenyl
In  the  feces  and urine  of  a  pig over  7  days (KohH  and Safe,  1976).   This
metabolite  could  have  been  formed  from  hexabromoblphenyl   by  reductive
debromlnatlon  followed by hydroxylatlon, or directly  from pentabromoblphenyl
by hydroxylatlon.
    The  results  of   Vn   vitro  studies  with  Flremaster  BP-6  and  various
constituent  congeners,   using  liver  mlcrosomes  from phenobarbltal  or  PBB-
pretreated   rats   In  the  presence  of NADPH  and   atmospheric  Op,  suggested


0176d                               -22-                             04/24/89

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that  the presence  of  a  free para  position 1s  required for  metabolism of
bromlnated  blphenyls.   Brom1nat1on  of  both para positions  seemed  to render
PBB molecules resistant  to mlcrosomal  metabolism regardless  of the number of
bromines, their  distribution  on  the blphenyl nucleus  or  the presence of two
adjacent  unsubstHuted  carbons.   Binding  of  radioactivity  to DNA  was  not
detected  when   a   mixture   of   2,2',4,4',5,5'-[14C]hexabromob1phenyl   and
2,2',3,4,4',5,5'-[14C]heptabromob1phenyl  was Incubated  with  denatured  DNA,
suggesting  that  these  PBBs were  not metabollcally activated  to electrophlllc
DNA-b1nd1ng metabolites  (Dannan et al., 1978).
5.4.   EXCRETION
    Rats  that  received  a  single  1  mg/kg dose  of  2,2',4,4',5,5'-[14C]hexa-
bromoblphenyl Emulprior :ethanol iwater  (1:1:8) by gavage excreted  7.9X of  the
dose  In  the  feces within   the  first  24  hours.   When  administered  four
consecutive  dally  1  mg/kg   doses  of  2,2',4,4',5,5'-[14C]hexabromob1phenyl
In Emulphor:ethanol:water by  gavage,  rats  eliminated -12X of each dally dose
In the  feces within the following  24  hours  (Matthews  et  al.,  1977;  Tuey and
Matthews, 1980).  Rats  excreted  similar  percentages  of the administered dose
1n  the   feces  following each of  22 oral  doses  (0.5   mg/kg)  over a  30-day
period (Tuey and Matthews, 1980).
    Two  monkeys  given  50  mg/kg   of   [l4C]hexabromob1phenyl   In  1%  methyl
cellulose suspension by  gavage,  followed  by a  second  dose  5  days  later,
excreted  -60%  of the  radioactivity 1n  the  feces In  10  days  following  the
Initial   dose.   Approximately   0.05X of  the  total dose was  excreted  In  the
feces during days  11-17, and  -0.06X of the  total dose was  excreted  1n  the
urine during days   1-17.  A  monkey  given  2 mg/kg of  [14C]hexabromob1phenyl
In mineral  oil  by  gavage excreted ~38X of  the radioactivity In the  feces In
the  following   5 days   (Rozman  et  al.,   1982).   This monkey was  given  a


0176d                               -23-                             04/24/89

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complete  biliary  bypass on day  6.   Additional doses of  2  mg/kg were admin-
istered on  days  6-9.   Measurements on days  6-11  showed that fecal excretion
of  radioactivity  diminished  -70%  compared  with  pre-bypass   levels,  with
biliary excretion accounting for the difference.
    Elimination of radioactivity  In  the  feces  was  blphaslc  after 1.v. Injec-
tion  of  a  single 1  mg/kg  dose of  2,2',4,4',5,5'-[l*C]hexabromob1phenyl  to
rats  (Matthews et al..  1977;  Tuey  and  Matthews, 1980).   By days 1, 7 and 42,
0.96,  3.3  and  6.6X,  respectively,  of  the  administered  radioactivity  was
passed to  the feces.    Extrapolation of  these data  Indicated  that  only  9.5X
of  the  total  dose  would  ever  be  excreted.   Excretion  In  the  urine  was
negligible, as cumulative  urinary  excretion accounted  for  <0.1% of the  dose
In  7  days, and  little  or  no  radioactivity  was  detected  thereafter.   Rats
that  were  bile  duct-cannulated 4  or  24  hours after dosing excreted  0.68  or
Q.Q32X of  the total  dose,  respectively.  In bile  In 1  hour.   Animals cannu-
lated  7  or 42  days  after  dosing  excreted  too  little  radioactivity  In  the
bile  to be accurately measured.
    Rats given a  single 1  mg/kg  dose  of  [14C]octabromob1phenyl  In corn  oil
by  gavage  eliminated  ~62X  and 7X of  the  administered radioactivity  1n  the
feces  1n  the  first  and second 24  hours, respectively  {NorMs  et al., 1975).
Approximately 26X of  the radioactivity In  the  dose had  not  been recovered  In
the feces by  day  16,  at the end of the  study.   Less than 1% of the adminis-
tered  radioactivity  appeared  In  the urine  or expired air over  the  16-day
period.
    As discussed  In  Section   5.2.,  PBBs  are  passed Into  the  breast milk.
Quantitative  studies  of cows,  of  PB8  concentrations  1n  the milk  of  humans
and other species and of PBB  accumulation  In nursing offspring Indicate  that
milk  1s   the  most  Important   route  of  elimination 1n  lactatlng  females.

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Clearance of PBBs  from  milk  depends  on  the ratio of the PBB concentration 1n
milk fat  to  body fat, and the quantity of  milk  fat  produced relative to the
quantity  of  body fat.  Although  milk  Is  the most  Important  route  of excre-
tion  In  lactatlng animals,  the  quantitative  significance of  this  route has
only been determined  In cows, a  species which has  been genetically selected
for high milk production.  The amount of  PBBs  eliminated In the milk of cows
at  steady state  Is  -20-25X  of  the  dally  Intake,  but  a  high-producing cow
will excrete <1X of the body burden In milk/day (Fries,  1985).
5.5.   SUMMARY
    PBBs are rapidly  and  extensively  absorbed  following oral administration.
Studies with  rats Indicate  that GI absorption  of  2,2',4,4',5,5'-hexabromo-
blphenyl  and  octabromoblphenyl  was  -90 and  70%,  respectively  (Matthews  et
al.,  1977;  NorMs et al.f  1975).   Following absorption,  PBBs are  rapidly
removed  from the  blood  and stored  Initially  In  highly perfused  tissues.
Subsequently, they are  redistributed  to adipose  and other  tissues  with high
Upld content, where  they  accumulate and persist  (Domino et al., 1980,  1982;
Klmbrough et  al., 1981;  Morris  et al.,  1975;  Lee  et  al.,  1975;  WarHz  et
al.,  1977).   Upld/blood  ratios  from  140-363  have   been  determined  1n
Michigan  residents several  years  following  PBB  exposure  (Cordle et  al.,
1978; Wolff  et  al.,   1979; Tuey  and Matthews,  1980; LandMgan  et al.,  1979;
Eyster et al.,  1983).  PBBs  are distributed to  the  placenta  and breast milk
(Fries, 1985; Eyster  et al.,  1983).  Limited  metabolism data  for  PBBs, the
docu-  mented  persistence  of  PBBs  In  biological  systems  and  extensive
Information for  analogous  PCBs  Indicate that  metabolism of  the more  highly
bromlnated and  abundant PBB  congeners  1s   not significant  (Kohll  and  Safe,
1976; Oannan et al.,  1978; Fries,  1985).   Excretion  of  PBBs 1s predominantly
from the  feces,  largely from  the  bile.   Studies with  rats  showed  that ~12X

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of  oral  doses  of 2,2',4,4',5,5'-hexabromob1phenyl  were excreted 1n the feces
In  the  following 24 hours (Matthews et  al.,  1977; Tuey and Matthews, 1980).
Monkeys  given  oral  doses   of  hexabromoblphenyl   excreted ~38-60X  of  the
administered  dose  1n  the  following  5-17  days  (Rozman  et  al.,  1982).
Approximately  74% of  a single  oral  dose of  octabromoblphenyl  was recovered
In  the feces of  rats by day 16  (Morris et al., 1975).
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                                  6.   EFFECTS
6.1.   SYSTEMIC TOXICITY
6.1.1.   Inhalation Exposure.
    6.1.1.1.   SUBCHRONIC — Groups  of  six  young  adult  Manor  Farm  rats
{45-55  days  old,  220-250 g)  of  unspecified  sex were  exposed  to  0 or  3.5
pg/l  (3.5  pg/m3)  of   commercial  octabromoblphenyl  vapor  1n  air  for  23
hours/day, 7  days/week for  2,  4, 7,  9,  11,  13 or  15  weeks.   The  3.5  pg/8,
level was  the  calculated equilibrium concentration  of  volatilized  octabromo-
blphenyl  1n  air  at 28°C.   Clinical  signs  of  toxldty  were  not  observed.
There were  no  effects  on relative  liver  weight or gross  liver  pathology  In
any  of  the  sacrificed rats.   Gross  pathology  and weights of  kidneys  and
thyroid, conducted  only at  15 weeks,  were  unremarkable.   Hlstologlcal  exami-
nations were not conducted.  Analyses at  15  weeks showed  Increased  bromide
concentrations  1n the liver  and  fat but not In muscle (WarUz et  al.,  1977).
    Groups of  10 Sprague-Dawley CFY  rats  of  each  sex were exposed  to  deca-
bromoblphenyl  dust  concentrations of  0,  0.005 (females only),  0.009  (males
only),  0.05,   0.5  or  5 mg/l  for  6  hours/day,  5  days/week  for  4  weeks.
Ocular  Irritation  and  slight  dyspnea were  observed at  5 mg/i  (5  g/m3).
Clinical chemistry  evaluations  showed decreases  In SGOT  at >0.5  mg/l  (500
mg/m3),  which  were  not  clearly  related  to  treatment.  Relative  liver
weights  Increased ~25X  at  >0.5  mg/i 1n  males and  >0.05 mg/l {50  mg/m3}
In  females,  but  hlstologlcal  examinations of  the liver  and  other  tissues
were  unremarkable.   There  were  no  treatment-related  effects  on  survival,
body weight gain, hematology or  urlnalysls (Mllllscher  et  al.,  1979).
    6.1.1.2.   CHRONIC  — Pertinent  data  regarding the  chronic  toxldty  of
Inhaled  PBBs  were  not  located  In  the available   literature   cited  In
Appendix A.
0176d
-27-
06/07/89

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6.1.2.   Oral Exposure.
    6.1.2.1.   SUBCHRONIC — Most  of  the  studies   tested  commercial  hexa-
bromoblphenyl  formulations  (F1remaster  FF-1  or  BP-6);  few  lexicological
evaluations   of   octabromoblphenyl,   decabromoblphenyl   or   specific   PBB
congeners were  available.   Because of  the  number of  studies and variety of
endpolnts examined,  this  section  will  concentrate on those studies Identify-
ing effects  at  low doses, particularly those  1n  the threshold  region of the
dose-response curve.  These studies are summarized 1n Table 6-1.
    It  1s  well  established  that  pathological  changes  In the  liver  are the
most  prominent  systemic  effects of subchronlc  oral  PBB  exposure  (DICarlo et
al..  1978;  Damstra et al.,  1982; Safe, 1984;  Fries,  1985).   Hepatic effects
of PBBs are  similar  among  species,  but  rodents, particularly rats, appear to
be  more sensitive than  other  species.  Effects  typically  observed  Include
Increased liver weight,  enlargement of  hepatocytes, hepatocellular degenera-
tion  characterized by vacuoles  containing Hplds, hepatocellular  necrosis or
formation of necrotlc areas,  and fatty  Infiltration  {see Table  6-1).   The
hepatomegaly  Is  generally associated with  Induction of  mlcrosomal  enzymes.
Limited  Information  Is  available  on  hepatic  effects  of  extended  (>2-6
months) exposure,  but  severity  1s  related to  dose,  duration  of  treatment and
duration  of  posttreatment   observation.    Extended observation  of  rodents
following higher   doses  for  shorter  durations or  lower doses  for  longer
durations showed  progesslon of the degenerative  effects.   As Indicated In
Table 6-1,  liver  hypertrophy and hlstopathologlc changes  have  been  observed
In rats  following subchronlc administration  of Flremaster  PBB doses as  low
as 0.07-0.2  mg/kg  bw/day  by gavage or  1n  diet  (Sleight and  Sanger,  1976;
Akoso et al., 1982a; Gupta et al., 1983a;  NTP, 1983).
0176d                               -28-                             06/07/89

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    Dose-related alterations  In the  thyroid  have been  observed In  rats  at
PBB doses comparable with  those  that  produced  hepatotoxlc  effects  (Norrls  et
al.. 1975;  Sleight  et  al., 1978; Kasza et  al..  1978;  Allen-Rowlands et al.,
1981;  Akoso et  al.,  1982b;  Gupta  et al.,  1983a; NTP,  1983;  Sepkovlc  and
Byrne, 1984; Byrne  et  al.,  1987).   Effects  Include enlargement,  hlstologlcal
changes  characterized  by hyperplasla and ultrastructural  alterations  of  the
follkular  cells, and  functional changes  Including decreased  levels  of serum
thyroid  hormones.   As  Indicated In  Table 6-1,  thyroid  hlstologlcal  altera-
tions  and  decreases  In  serum trllodothyronlne  (T.)  and  thyroxlne  (T )
occurred at doses as low as  0.1-0.25  mg/kg/day after  1-7 months  of  treatment
(Kasza et  al.,  1978;  Akoso  et  al..  1982b; Gupta  et  al.,  1983a; NTP,  1983;
Byrne et al., 1987).
    Effects on the  adrenal also  have  been  described at  doses  comparable with
those  that  produce hepatic alterations.   Byrne  et  al.  (1988)   observed
decreased adrenal weight and serum cortlcosterone In rats  following dietary
exposure  to >0.05  mg/kg/day of Flremaster  BP-6  for  5-7  months (see  Table
6-1).
    Immunosuppresslve  effects  have  been  reported In  mice,   rats  and dogs
following  subchronlc  exposure  to  Flremaster  PBBs at  doses  higher  (>0.5-1
mg/kg/day)  than  those  eliciting  hepatic,  thyroid and  adrenal  effects (Farber
et al.,  1978;  Fraker,  1980;  Luster et al., 1978,  1980;  Loose  et al.,  1981).
Reduced  performance of  rats  and mice  \n behavioral  and  neurophyslologlcal
tests  has  been  attributed   to  subchronlc exposure  to  3-30  mg/kg/day   of
Flremaster  (Tllson et al.,  1978; Tllson and Cabe, 1979).
    6.1.2.2.   CHRONIC  — Pertinent   data   regarding   the   chronic  oral
toxlclty  of PBBs  were  not   located  In   the  available  literature  cited  In
Appendix A.
0176d
-36-
06/07/89

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6.1.3.   Other  Relevant   Information.    Acute   oral   toxUHy  of  PBBs  as
measured  by  classical  LD5Q  techniques  Is   very  low.   A  single-dose  oral
L050  of   21.5  g/kg   for   Flremaster   BP-6   has  been  determined  In  rats
(Michigan  Chemical  Corp.,  1971.)   Additional  Information  regarding  the
determination of  this  value, such  as  method of oral  treatment  and observa-
tion  period,  was  not  reported.   Single gavage  doses  as  high as  17 g/kg  of
technical  octabromoblphenyl were  not  lethal  In  rats  observed for 7 days, but
doses from 3.4-17 g/kg produced  liver  enlargement  but no  clinical  signs  or
other gross  pathologic effects (Warltz  et  al., 1977).   Single  gavage doses
of  technical  octabromoblphenyl as  high  as 2  g/kg caused no signs of toxlclty
in  rats  during  a  14-day observation period  (Morris et al.,  1975).  A  5  g/kg
dose  of  decabromoblphenyl  was not  lethal or grossly  pathologic  for 10  rats
during  a  14-day  observation period  (Mllllscher et  al.,  1979).   Classical
L050  values  are not good  Indicators  of  PBB  toxlclty,  however,  because  they
do  not  reflect  effects   that  become   apparent during  longer  observation
periods  (Fries,  1985).   Gupta and  Moore (1979) found  that  oral  LD5Q  values
are lower  when  observation periods are  longer.  When  rats  were  administered
dally oral  doses  of 30-1000 mg/kg of Flremaster FF-1  on  5  days/week for 4.5
weeks  (22  doses)  and  observed  for  30  days,  the  estimated  L05Q for  both
sexes was  200  mg/kg/day.   When  observed for  90 days,  the  estimated  LD5Q
values were 65 mg/kg/day for males and 149 mg/kg/day for females.
    Eighty weanling rats of each  sex were given a  single 1000 mg/kg dose  of
Flremaster FF-1 by  gavage   and killed after  2,  6,  10  and 14 months  (20/sex/
sacrifice) for  pathologic  evaluation (Klmbrough et al.,  1978).   Alterations
occurred only  1n  the  liver In all  sacrifices.  Effects  Included Increased
relative  liver  weight,  fatty gross  appearance, porphyMa and  hepatocytes
that  were  enlarged,   vacuolated,  foamy   or   occasionally  flbrotlc,   and
necrotlc.  Neoplastlc nodules were observed after 10 months.

0176d                               -37-                             06/07/89

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    Immature  male  rats  were  administered   a   single  13.3  mg/kg  dose  of
3,3',4,4',5,5'-hexabromob1phenyl  by gavage  and  sacrificed  after  1-14  days
(eight  sacrifices,   three  rats/sacrifice)  (mills  et  al.,  1985).   Effects
Included significantly  Increased  liver  weight  after  3 days and  character-
istic hlstologlcal alterations In the liver.
    Relative  liver  weights Increased  In  8-week-old male mice  (3/group)  fed
1000 ppm Mremaster  BP-6  In the  diet  {130 mg/kg bw, calculated  assuming food
factor  = 0.13}  for  4,  8,  11  or  14 days  (Corbett et al.. 1978).   Light  and
electron microscopy  studies of  the  liver  showed progressive  changes.  Includ-
ing Increased hepatocyte  size from day 4 and decreased glycogen  content  and
mitochondria! degeneration from  day 8.  Results of  the  hlstologlcal examina-
tions were Incompletely reported.
    Groups of  six male rats were fed  diets  containing  0,  0.1,  1,  10  or  100
ppm  Mremaster  8P-6,  2,2',4,4',5,5'-hexabromob1phenyl  or   3,3',4,4',5,5'-
hexabromoblphenyl  for  9 days  (Render  et  al.,  1982).   Effects  on  the liver
occurred at  levels  as  low as  1  ppm of  3,3',4,4',5,5'-hexabromob1phenyl  (0.3
mg/kg/day,  calculated  from reported  food consumption  and  bw  data).   These
effects  Included  Increased cytochrome  P-450,  Increased  benzopyrene  hydroxyl-
ase  activity   and  perlportal   hepatocellular   enlargement.    Dose-related
characteristic  hlstologlcal  alterations  In  the  liver  occurred In rats  fed
all three compounds  at >10 ppm.   Effects  at  10  ppm Included  enlarged  hepato-
cytes  with  F1remaster  BP-6   (2.5  mg/kg/day) and  enlarged  hepatocytes with
llpld  vacuolatlon  with  3,3',4,4',5,5'-hexabromob1phenyl   (2.8  mg/kg/day).
Thymus and spleen  weights  decreased and thymus  histology was altered  at  >10
ppm  3,3',4,4',5,5'-hexabromob1phenyl.    Hlstologlc   effects   In  the   thymus
Included  decreased  ratio  of   cortical:medullary   lymphocytlc  depletion.
0176d
-38-
04/24/89

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Overall,   more  severe   pathologic   effects   resulted   from   exposure  to
3,3',4,4',5,5'-hexabromob1phenyl  than  to Flremaster  8P-6  or 2,2' ,4,4', 5,5'-
hexabromoblphenyl.
    Rats  did  not  die  from  1-hour  Inhalation  exposure  to  71.1 mg/i {71.1
g/m3)   Flremaster   BP-6   dust   or   200   mg/t  (200  g/m3)  decabromoblphenyl
dust  (Consumer Product Testing  Co.,  Inc.,  1977).   The only other Information
reported was  that  rats  became emaciated after  "four  such  exposures" to BP-6
dust.   Six male  rats  {50-60  days old) were  exposed  to commercial octabromo-
biphenyl  dust at  a TWA  concentration  of 0.96  mg/i  (96  g/m3)  for  4 hours
and  observed  for   7  days  (WaMtz  et  al.,  1977).    Relative  liver  weight
Increased  Insignificantly,  but  no  mortality or hlstologlcal alterations  In
the  liver  were  reported.  Other  tissues were  not examined, and  additional
relevant Information was not  reported.
6.2.   CARCINOGENICITY
6.2.1.   Inhalation.   Pertinent   data   regarding   the  cardnogenlclty   of
Inhalation exposure to  PBBs  were  not  located In  the available  literature
cited In Appendix A.
6.2.2.   Oral.   NTP (1983)  and  Gupta  et al.  (1983b) treated  groups of  51
male  and  51   female F344N rats  and  50  male and 50  female B6C3F1  mice  with
Flremaster FF-1  In  corn  oil  by  gavage at doses of 0, 0.1, 0.3,  1.0,  3.0  or
10.0  mg/kg/day,  5  days/week,   for  25  consecutive  weeks.   Subgroups of  10
males and  10 females  of  each species  from each treatment level  were sacri-
ficed  at   the end  of  the  exposure  period  for   clinical  pathological  and
histopathologlcal evaluation.   In addition,  20 or  21  female  rats  and 11  male
mice  and  20   or  21  female mice  from each treatment  level were  removed  for
evaluation of  Immune function.  Removed for  behavioral testing were 0-8  rats
of  either  sex from the  control  and the  1.0,  3.0  and  10.0 mg/kg groups.
0176d
-39-
04/24/89

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Other  rats  and subgroups  of  8-15 mice  were removed  for  behavioral  testing
but  returned  to the  study after  testing.   The remaining animals  and  those
returned  after  behavioral  testing were  maintained on  control  diets for  an
additional  23-month  (rats)   or  24-month  (mice)  observation  period,  after
which about 10X of  the  surviving  rats  and mice 1n each group were killed and
examined.  The remaining animals were allowed to finish their llfespans.
    Hale  rats  exhibited a dose-related, statistically  significant  decrease
In  longevity  at  0.3 mg/kg/day.   Treatment  had  no effect  on  longevity  of
female  rats.    A  dose-related  decrease  In  body  weights   that  persisted
throughout  the  observation period  occurred  In  rats  of  both  sexes at  >0.3
mg/kg/day.  A  statistically  significant Increased  Incidence  of  neoplastlc
nodules  and  hepatocellular carcinomas  was  observed  1n rats of  both  sexes
(Table 6-2).  In addition, treated rats  of  both  sexes  at  10.0 mg/kg/day had
Increased Incidences of cholanglocardnomas  of  the  liver.  The  Incidences  of
cholanglocardnomas were significantly Increased  (p<0.01)  In the  females and
marginally  Increased  (p=0.06)  1n  the  males.   Cholanglocardnomas  typically
develop as a reaction to severe hepatic necrosis {Bannasch et al., 1985).
    Decreased longevity and slight bw  reductions were  reported In  male mice
at 10.0 mg/kg/day.  There  were  no  effects  on longevity or  bw of  female  mice.
A statistically significant Increased  Incidence of  hepatocellular carcinomas
was  reported  In male  mice (see  Table  6-2).   Treatment was not  associated
with Increased Incidence of any tumor  type  1n female mice.   NTP  (1983)  noted
that an Increased Incidence of  liver tumors  occurred only  1n those  groups  of
animals that exhibited marked  liver toxldty.
    Klmbrough  et  al. (1981)  performed  a  series of  three  experiments  with
single large  doses  of  Flremaster  FF-1.   In  the first experiment, a single
gavage dose of  Flremaster  FF-1  In corn  oil  was  administered to groups  of  65


0176d                               -40-                              09/29/89

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    0176d
                                    -43-
                                                                    09/29/89

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female, 2-month-old  Sherman  rats at  dosages  of 0  (vehicle  control)  or 1000
mg/kg  to study  the development of liver  tumors.   The  observation period was
terminated when the  rats were  25  months  old.   Complete necropsy examinations
were  performed  on decedents and  those  sacrificed  at  termination.   In rats
treated with  the  single 1000 mg/kg dose,  hepatocellular  carcinomas occurred
In  24/58  and neoplastlc  nodules  occurred  In  42/58;  these  lesions were not
observed 1n 53 controls.
    In the second  study, groups of  30 two-month-old female Sherman rats were
similarly treated  at dosages of 0 or  100 mg/kg twice weekly every third week
for  a  total  of   12 doses.   Survivors  were  killed  when  26  months  old.
Hepatocellular carcinomas were reported  1n  17/28  and  neoplastlc  nodules were
reported In  24/28 of the treated rats.   Hepatocellular  carcinomas were not
observed  In  25  controls;   however,   one   control  had  a  liver  containing
neoplastlc nodules.
    In  the  third study,  a  group of   16  four-month-old  female  rats  were
similarly  treated  with  single doses  of  200 mg/kg.  A vehicle  control  group
of  19  rats was maintained.  The  study was terminated when  the  rats  reached
26  months   of age.   Hepatocellular  carcinomas  were  not  observed  In  the
treated rats.   Neoplastlc nodules,  however,  were  reported In  5/16  treated
rats and 1n 0/19 controls.
    These  three studies (Klmbrough et al.,  1981} suggest  that  single  large
doses  of  F1 remaster  FF-1  may  Increase  the  risk  of  late-developing  liver
tumors.
6.2.3.   Other  Relevant Information.   Several  PBBs  have  been  tested  for
hepatic tumor-promoting ability  In  the two-stage  hepatocarclnogenlcUy  assay
In  female  Sprague-Dawley  rats.   Initiation consisted of  70% hepatectomy and
administration of  a  single   l.p.  10 mg/kg dose of  DEN (Jensen,  1983;  Jensen


0176d                               -44-                             09/29/89

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et  al.,  1982, 1983;  Sleight,  1985; Olxon  et  al., 1988).   Starting  30 days
after treatment with  DEN,  rats  were fed  diets  containing F1remaster BP-6 (10
or  100  ppm)  or  the  pure PBB congeners  2,4,5,2',4',5'-hexabromob1phenyl  (10
or  100  ppm),  3,4,5,3',4',5'-hexabromob1phenyl  (0.01, 0.1  or 1.0  ppm) (the
latter apparently  not present  In Flremaster BP-6)  or  3.4,3',4'-tetrabromo-
blphenyl  (0.1,  1  or  5 ppm) for  140-180 days.   At  the  end  of  the exposure
period, the  rats  were sacrificed.   The  development  In  the  liver  of  enzyme-
altered  foci manifesting  gamma  glutamyl  transpeptldase activity  Indicated
tumor-promoting activity.
    Flremaster    BP-6    and   2,4,5,2',4',5'-hexabromoblphenyl    exhibited
tumor-promoting  ability   at  both  dietary  concentrations  (10  or   100  ppm);
3,4,5,3',4',5'-hexabromob1phenyl  exhibited   tumor-promoting   ability  at  1.0
but  not   at   0.1  or  0.01  ppm;  and 3,4,3' ,4( -tetrabromoblphenyl  exhibited
promotion  at 5 but  not  at 0.1 or  1.0  ppm.  Promotion  with 2,4,5,2',4',5'-
hexa- and  3,4,3',4'-tetrabromoblphenyl   occurred  at  dosages  that  were  not
hepatotoxlc,  but  promotion  with  3,4,5,3',4',5'-hexabromob1phenyl  occurred
only  at   doses  that  were hepatotoxlc.   The  Investigators   speculated  that
different  mechanisms   of  promotion  were  Involved  with   the   different
congeners.   A synerglstlc effect  was  produced by  combining a  nontoxlc  and
nonpromotlng  dietary  concentration  of 3,4,5,3',4',5'-hexabromob1phenyl  (0.1
ppm) with  a  promoting concentration of  2,4,5,2',4',5'-hexabromob1phenyl  (10
ppm).  Single oral doses  of  1,  5  or 10  mg/kg of 3,4,3',4'-tetrabromoblphenyl
given  to  partially   hepatectomlzed  rats  acted  as   Initiators  when  pheno-
barbltal   In  the  diet  (500 ppm for  180 days) was  used as  the promoting agent
(Olxon et al., 1988).
    Flremaster BP-6 did not  premote  tumors  In  the two-stage mouse  skin assay
(Berry et al., 1978).   In this  test,  groups  of  30 pre-shaven female CD-I
mice were  Initiated with  a single dose of dlnethylbenzanthradne In acetone.
0176d                                -45-                             09/29/89

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F1 remaster  BP-6  1n acetone  was  applied  twice  weekly  at a  dose of  100 vg
for  30 weeks.   Mice  promoted  with  tetradecanoylphorbol acetate  (positive
control) responded appropriately.
    Hong et al.  (1984) performed  a  prospective  mortality  study on white male
workers  occupatlonally  exposed  to  PBBs.    Worker  exposure  to  PBBs  was
categorized as routine or nonroutlne.  Of 91  routinely  exposed workers, none
died;  therefore,  no  data  were available  from  this  group.   Of  237  workers
exposed nonroutlnely,  two died,  one  from  cancer of  the large  bowel.   The
data, however, were too limited for meaningful statistical analysis.
6.3.   MUTAGENICITY
    Limited  data,  summarized  In  Table  6-3,   suggest   that  PBBs  are  not
mutagenlc  or  clastogenlc.  Oecabromoblphenyl  and an unspecified  hexabromo-
blphenyl  congener  were tested  In the reverse  mutation assay  1n  Salmonella
typhlmurlum  (Nllllscher  et  al.,  1979;  Haworth  et  al.,  1983).   3,3',4,4'-
Tetrabromoblphenyl,    3,3',4,4',5,5'-  and    2,2',4,4',5,5'-hexabromob1phenyl
(Kavanagh  et  al.,  1985),  F1remaster BP6 (Kavanagh et al..  1985;  Garthoff et
al., 1977)  and unspecified PBBs  (Hertz  and Flcsor,  1978; Fksor  and Hertz,
1976}  were  tested  for   forward  mutation  and  chromosomal  aberrations  In
mammalian systems.  All results were unequivocally negative.
6.4.   TERATOGENICITY
    Many  studies  were located   regarding  the  developmental  and  perinatal
toxlclty  of PBBs  1n  rats and  mice.  Those  studies reported  In  sufficient
detail   for  Independent evaluation  are summarized  In  Table  6-4.  Host were
performed with F1remaster BP-6, a commercial  preparation  consisting  of 62.B%
hexabromoblphenyl,  13.8%  heptabromoblphenyl,  10.6X  pentabromoblphenyls  and
smaller amounts of other  polybromlnated blphenyls  (Harris et  al.,  1978).   In
rats,   teratogenlc  effects   (Increased   Incidence   of   cleft   palates  and

0176d                               -46-                             09/29/89

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diaphragmatic  hernias)  were reported  at  dosages >400  mg/kg/day but  not  at
200  mg/kg/day  (Beaudoln,  1977,   1979).   Evidence of  severe  fetal  toxldty
Included  Indications  of late  fetal  death at  50 mg/kg/day  (Corbett  et  al.,
1975)  and  Increased  fetal  resorptlon  at  400  mg/kg/day   (Beaudoln,  1977,
1979).   Reduced  fetal  bw  were  reported  1n  rats  at dosages  as low  as  2.5
mg/kg/day  (Corbett  et  al.,  1975; McCormack  et  al.,  1982),  although  other
studies reported no effects  on bw at  2.5  mg/kg/day  (Dent et al.. 1978; Cagen
and  Gibson,  1978; Cagen  et  al.,  1979)  or  10 mg/kg/day (Harris et al., 1978).
There  Is  no apparent  reason  for  these  differences  In  fetal  body  weight
effects.
     Effects  In  rats  exposed  both pre- and  postnatally Included  Increased
relative  liver weight and  drug metabolizing enzyme activities (Dent  et  al..
1978)  and  Increased  hepatic  excretory  function  (Cagen  and Gibson,  1978;
Cagen  et  al.,  1979)  at 2.5 mg/kg/day,  decreased bw gain,  decreased  liver
content of  vitamin  A and  Increased  urinary excretion of  uro- and  copropor-
phyrlns at  5 mg/kg/day   (Johnston  et  al., 1980; HcCormack et  al.,  1982} and
delayed vaginal opening  1n females at 10 mg/kg/day (Harris et al.,  1978).
     In mice  treated with F1remaster  BP-6 during organogenesls at 6.5,  13  or
130  mg/kg/day, significant  reductions  In  fetal bw were  reported  (Corbett  et
al..  1975).   A  nonsignificant  Increase  In  exencephaly was  reported at  13
mg/kg/day and  In cleft  palate and  hydronephrosls  at  130  mg/kg/day.   Markedly
elevated  liver weight and  Increased  hepatic ouabaln excretion were  reported
In mice from dams exposed  to 6.5  mg/kg/day  on  lactation  days 1-15 (Cagen and
Gibson, 1978).
    Moore  et al. (1978)  exposed  rat  dams to  Flremaster  FF-1  on  lactation
days 1-18 at dosages of  0.005, 0.05 or  0.5 mg/kg/day to determine effects  on
the  livers  of  the  nursing offspring.   (Flremaster FF-1  1s a mixture  of

0176d                               -52-                             09/29/89

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polybromlnated  blphenyls,  predominantly 2,4,5,2',4',5'-hexabromob1phenyl and
2,3.4,5,2',4',5'-heptabromob1phenyl)  (Luster  et   al.,  1980).   Dose-related
Increases  were  reported  In  relative  liver  weight  (significant  at  0.5
mg/kg/day),  liver  mlcrosomal  protein  content  and  drug-metabolizing  enzyme
activities  (significant at 0.05  mg/kg/day).   The  authors  concluded that PBBs
or  components  of  PBBs  could be  transmitted to  the  young through  milk and
that  nursing  offspring  are more  sensitive  to the Inductive  effects  of PBBs
than  lactaUng mothers.  Luster  et al.  (1980)  treated mice dams  by  gavage
with  Flremaster  FF-1 every  other day  at  0.3,  1.0,  3.0  or  10.0  mg/kg from
gestation  day  0  throughout  lactation.  Treatment had no  effect  on reproduc-
tion,  offspring  mortality,   bw  gain  or  hematology.   A  dose-related  but
nonsignificant  Increased  sensitivity  to  Injected   E_.  coll  endotoxln  was
observed.   The  Investigators  concluded  that  treatment-related  effects  on
Immune function were equivocal.
    Few  studies  were performed  with  purified PBB congeners.  MUllscher  et
al.  (1979) reported  no evidence  of  maternal or  fetal  toxlclty  or  terato-
genlclty  In  rats  treated by gavage  with  decabromoblphenyl at dosages  <1000
mg/kg/day  on days  6-15  of gestation.   Luder  et  al.  (1978) reported no feto-
toxlclty  or  teratogenldty  In  mice  treated  by  gavage with  2,4,5,2',4',5'-
hexabromoblphenyl  on  days  10-16 of gestation.  Apparently, 40 mg/kg/day was
the  highest  dose   tested.   Uelsch   and  Morgan   (1985),  however,  reported
maternal  toxlclty,  reduced  pregnancy  success  rate,  reduced fetal  bw  and
Increased  Incidence of  cleft palate and a cystic  defect  In the cerebellum In
mice  exposed  to   2,4,5,2',4',5'-hexabromob1phenyl  at >63.0  mg/kg/day.   No
effects were observed at 21.0 mg/kg/day.
6.5.   OTHER REPRODUCTIVE EFFECTS
    NcCormack et al.  (1981)  fed  diets containing Flremaster  BP-6  to  rats  at
0, 10 or  100 ppm (0,  0.5  or  5 mg/kg/day assuming a food factor of  0.05) In a
0176d
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09/29/89

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multlgeneratlon  study of  effects on  the offspring.   Exposure to  the test
material  was confined to  the FQ  generation,  with exposure  starting on day
8  of gestation and  continuing  to postpartum  day  28.   At that  time, the F,
offspring  were weaned  to  control  diet.   Diets  containing  Flremaster BP-6
were  not  fed  to  rats  1n  later generations.   Subsequent generations were
obtained  by mating  rats  at  10-16 weeks  of age.   F..  pups from dams In the
100  ppm  group  had  reduced  survival  and delayed growth and maturation.  These
effects  were  not  seen  In F,  rats  at  10  ppm  or  In  F? rats  at  100 ppm.
Increased   relative  liver  weights,   Mstopathologlc   lesions   In  the  liver
(vacuollzatlon,   necrosis,  pyknotlc  nuclei),  decreased  anesthesia  time
Induced  by pentobarbltal  or  progesterone  and  Increased hepatic drug-metabo-
lizing  enzyme  activity were  reported  1n  F,  rats  at  10  and  100  ppm and  In
F- rats at  100 ppm, but not In F_ rats at 100 ppm.
6.6.   SUMMARY
    Subchronlc  oral   studies  with rodents  and other  animals  Indicate that
pathological  changes  In   the  liver  are  the  most  prominent  and  sensitive
effect  of  PUB  exposure.    Hepatic  effects  Including  liver  enlargement  and
hepatocellular degeneration have  been  observed at  gavage  or dietary  doses  of
Flremaster  PBBs  as low as  0.07-0.2  mg/kg bw/day  (Sleight and  Sanger, 1976;
Akoso  et  al.,  1982a;  NTP, 1983).   Dose-related alterations  In the thyroid
and adrenal  glands occurred In rats at subchronlc  oral  PBB doses  comparable
with those  that produced hepatotoxlc effects  (Sleight  et  al..  1978;  Kasza et
al.,  1978;  Allen-Rowlands  et al.,  1981; Akoso  et al.,  1982b;  NTP,  1983;
Byrne et  al.,  1987,  1988).  PBB  (Flremaster FF-1)  doses  of 0.2 mg/kg/day  by
gavage for  5 months decreased longevity  In  rats  (NTP,  1983).   Immunosuppres-
slve  effects have  been  reported  1n  animals  at   subchronlc  oral  PBB doses
higher (>0.5-1 mg/kg/day)  than those eliciting hepatic,  thyroid and adrenal
0176d
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09/29/89

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effects  (Farber  et  al.,  1978;  Fraker,  1980;  Luster et al., 1978, 1980; Loose
et  al.,  1981).   Chronic oral  toxldty  studies of  PBBs  have not  been  con-
ducted.  The  only nonacute Inhalation studies  of  PBBs  Involved  rats exposed
to  3.5  yg/m3 octabromoblphenyl  vapor  for  23  hours/day,  7 days/week  for
<15  weeks  (HaMtz et al.,  1977}  and to 50  mg/m3  decabromoblphenyl  dust  for
6  hours/day,  5 days/week for 4 weeks  (Mllllscher  et al.,  1979).  Results of
octabromoblphenyl  exposure were  unremarkable.   The  decabromoblphenyl  study
showed   Increased  liver  weights   but   no  hlstologlcal  alterations  1n  any
tissues.
    PBBs  are  liver  tumorIgens  In  rats  and  mice,  but  apparently only  at
dosages  associated  with   hepatotoxlclty.    Hepatocellular   carcinomas   and
neoplastlc  nodules  were reported  In male  and  female rats treated  by  gavage
with  Flremaster  FF-1  for 6 months followed  by  a  23-month  observation  period
(NTP,  1983;  Gupta et al.,  1983b).   Dosages  ranged  from 0.1-10  mg/kg/day,  5
days/week.   In  mice  treated  similarly,  an Increased  Incidence of  hepato-
cellular carcinomas was  reported  only  1n males  at  10 mg/kg.   A single  gavage
dose  of  1000 mg/kg  Flremaster  FF-1  markedly  Increased  the   Incidence  of
hepatocellular  carcinomas   and  neoplastlc  nodules  In  female rats  after  a
23-month observation period (Klmbrough et  al., 1981).  Similar  treatment  at
200 mg/kg  Increased the  Incidence  of neoplastlc nodules but  not  hepatocellu-
lar  carcinomas.    Flremaster  BP-6 and  three  hexabromlnated  congeners were
promoters  1n  the two-stage hepatocarclnogenlclty assay  In  hepatectomlzed  and
DEN-1n1t1ated  female rats  (Jensen, 1983; Jensen et al., 1982, 1983;  Sleight,
1985;  Dlxon  et  al., 1988), but  Flremaster  BP-6  was not  a   promoter  1n  the
two-stage mouse skin assay  (Berry et  al.,  1984).
    TeratogenlcUy, fetotoxlclty,  delayed  development and reduced  reproduc-
tive  success  were observed  In  rats  (Beaudotn. 1977,  1979;   Corbett et al..
0176d
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09/29/89

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1975; McCormack  et  al.,  1982;  Harris et al., 1978) and mice  (Corbett et al.,
1975) orally  exposed to  Flremaster  BP-6 or 2,4,5,2',4',5'-hexabromob1phenyl
(Uelsch  and Morgan,  1985)  at  dosages  associated  with maternal  toxlclty  or
adverse  effects  on the  liver  1n subchronlc oral  studies.   Reduced fetal  bw
were  reported In rats at 2.5  mg/kg/day  In  some (Corbett et  al.,  1975)  but
not all  (Cagen and Gibson, 1978; Cagen  et  al.,  1979) studies.  The critical
effect  on  the  offspring  In   the   developmental  and  reproductive  studies
appears  to be  on  the  liver.   Hlstopathologlc  lesions  In  the  liver  were
reported  In the  offspring of dams  fed diets containing Flremaster BP-6 at  10
ppm (0.5 mg/kg/day).
0176d                               -56-                             09/29/89

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                     7.   EXISTING GUIDELINES AND STANDARDS
7.1.   HUNAN
    In Nay  1974,  the FDA set guidelines for PBBs of  1.0  mg/kg in the fat of
milk,  meat  and  poultry,  0.1 mg/kg  1n  whole  eggs and  0.3 mg/kg  1n animal
feeds  (IARC,  1986). These  guidelines  were  reduced  In November  1974 to 0.3
mg/kg  In  the  fat  of  milk,  meat,  and  poultry and 0.05 mg/kg In whole eggs and
animal  feed.   The FDA  regulates PBBs  as  Inadvertent  environmental  contami-
nants under the Food, Drug and Cosmetic Act.
7.2.   AQUATIC
    Guidelines  and  standards   for  the  protection  of  aquatic  life  from
exposure  to  polybromlnated  blphenyls  were  not  located  In  the  available
literature cited  1n Appendix A.
0176d                               -57-                             06/01/89

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                              8.   RISK  ASSESSMENT
    Statements  concerning  available  literature  In  this  document  refer  to
published, quotable  sources  and are In no way  meant  to Imply that confiden-
tial business  Information  (CBI),  which this document could  not  address,  are
not  In  existence.   From examination of  the bibliographies  of  the CBI  data,
however,  It  was determined  that  CBI  data  that  would  alter  the  approach  to
risk assessment or the risk assessment values presented herein do not exist.
8.1.   CARCINOGENICITY
8.1.1.   Inhalation.   Pertinent   data   regarding  the  cardnogenldty   of
Inhalation exposure  to  PBBs  were  not  located  1n  the available  literature
cited In Appendix A.
8.1.2.   Oral.   Hepatocellular   carcinomas   and  neoplastlc  nodules  were
reported  In  male  and female rats treated by  gavage with  Flremaster  FF-1  for
25 weeks  followed by a 23-month observation  period  (NTP,  1983;  Gupta et al.,
1983b).   Dosages  ranged  from  0.1-10  mg/kg/day,  5  days/week.   Statistical
analysis  revealed  significant  overall  dose-response  trends 1n  males  for
hepatocellular  carcinomas  and  In females for neoplastlc nodules  and hepato-
cellular  carcinomas.    In   males,  significantly  Increased  Incidences   of
hepatocellular  carcinomas were  reported  at  1.0, 3.0 and 10.0 mg/kg/day.   In
females,  significantly  Increased  Incidences  of neoplastlc  nodules  occurred
at  3.0  and   10.0  mg/kg/day,  and  a   significantly  Increased  Incidence   of
hepatocellular  carcinoma  occurred  at  10.0  mg/kg/day.    In  mice  treated
similarly, an  Increased  Incidence of hepatocellular carcinomas  was  reported
only In males at 10 mg/kg/day.
    In  other  studies,   single   gavage  doses  of  Flremaster  FF-1  In  rats
examined 23-24  months later  significantly Increased the Incidence  of hepato-
cellular  carcinomas  (at  1000 mg/kg)  and neoplastlc nodules (at  200 mg/kg)
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(Klmbrough   et   al.,   1981).   Flremaster  BP-6   and   three  hexabromlnated
congeners  were  promoters  In  the two-stage  hepatocardnogenldty assay  In
hepatectomlzed  and  DEN-lnltlated female  rats  (Jensen,  1983;  Jensen  et  al.,
1982, 1983; Sleight, 1985; Dlxon et al., 1988).
8.1.3.   Other  Routes.   Flremaster BP-6  was not a promoter  1n the two-stage
mouse skin assay (Berry et al., 1984).
    The  only cancer  study  with  humans  was  a  prospective mortality  study
using  workers  exposed  routinely  or  nonroutlnely  to  PBBs   (Hong  et  al.,
1984).  The  number  of  exposed  workers that  died (thereby  providing data) was
too small for meaningful analysis.
8.1.4.   Weight  of  Evidence.  Hong et al.  (1984)  lacked  sufficient  numbers
of  workers  for meaningful  evaluation   of  the  cardnogenlclty of  PBBs  to
humans; therefore,  there are no  data  for  cancer risk  In humans.  Animal  data
consist  of  the  positive NTP  (1983)  study 1n  rats  and  mice  treated for  6
months by gavage and  the  positive  single-dose  gavage  studies by Klmbrough et
al. (1981).  The animal  data are  considered sufficient  evidence for cardno-
genlclty.  IARC  (1986)  Judged  the evidence for cardnogenlclty  In humans  to
be Insufficient and the  evidence  for  cardnogenlclty  1n animals to be suffi-
cient.  Using  the  U.S. EPA  (1986b)  guidelines  for evaluating  the weight  of
evidence  for  cardnogenlclty  for  huraans,  PBBs  are  best  classified  1n  EPA
Group B2: probable human carcinogens.
8.1.5.   Quantitative Risk Estimates.
    8.1.5.1.   INHALATION — Data were  not located  regarding  the cardno-
genlclty of  Inhalation  exposure  to  PBBs.  Data were sufficient, however,  to
estimate cancer  potencies  for oral  exposure  to PBBs  (see below).   In  such
cases,  H  has  sometimes  been the  policy  of  the  Agency  to  adopt the  oral
potency  estimate as  the  Inhalation  potency  estimate  and apply  adjustment
0176d
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             factors to  correct  for route-specific  differences  In absorption or  metabo-
             lism when  estimating  risk-specific  concentrations  In  air.   This policy  Is
Mfc         appropriate when  sufficient  pharmacoklnetlc and  effects  data are  available
             to  suggest  a similar  response  across  routes  of  exposure.   In  the case  of
             PBBs, however,  Inhalation  pharmacoklnetlc  and  effects data are  lacking,  and
             1t would be  Inappropriate  to  adopt the oral potency  estimate as  the  Inhala-
             tion potency estimate.  Therefore,  no potency  estimate has been  derived  for
             Inhalation  exposure  to PBBs.
                 8.1.5.2.   ORAL  ~ The only  oral  studies  suitable  for  estimation  of
             potency values  were  NTP  (1983)  and Gupta  et al.  (1983b), In which rats  and
             mice were  treated with Flremaster  FF-1 by  gavage for 25  weeks  and held  for
             an  additional   23-24  months  before  termination.   Increased  Incidences  of
             hepatocellular   carcinomas,  neoplastlc nodules  and  cholang1ocarc1nomas were
             reported In rats of both sexes, and an  Increased  Incidence  of hepatocellular
             carcinomas  was reported In male mice.  The  Incidences  of  cholanglocardnomas
             are not considered  1n potency value  estimation because response appears  to
             be  due  to  an  Indirect mechanism  (I.e.,  reaction to  severe necrosis) that
             occurs  only  at  high  doses.   The   Incidence of  hepatocellular  carcinomas  In
             male mice  Is  not considered  In  the estimation of a  potency value, because
             these tumors are  a  common,  spontaneously  occurring   tumor  In this species.
             In NTP  (1983) and  Gupta  et al.  (1983b),  hepatocellular carcinomas occurred
             1n 12/25 males  1n  the control  group.
                 Since  liver  tumors are not a  common,  spontaneously occurring tumor type
             In  F344/N  rats, the  Increased  Incidence  of  hepatocellular  carcinomas  and
             neoplastlc  nodules  In rats 1s chosen as the basis for  cancer  risk estimates.
             Using the multistage model by Howe and Crump (1982),   potency  values for both
             male and female rats  are  calculated  1n Appendix  8.   Slope factors (q *) of
             2.94   (mg/kg/dayr1   and   8.87    (mg/kg/day)"1   were   derived   from   the

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Incidence  data  for  tumors  and neoplasUc  nodules  1n male  and female rats,
respectively.   The  q *  of  8.87  (mg/kg/day}"1  derived  from  the  data  on
female  rats 1s  chosen as  the oral  cancer  potency  estimate  for  Mremaster
FF-1  because  data from female  rats  fit the model better  and  yielded a more
conservative estimate  than  data from the male rats.
    One of  the  reviewers  of the NTP  (1983) study (Dr. Hitchcock) stated that
the  results  from this  study  can  be  applied only to  Flremaster  FF-1  and  not
to  other  mixtures  of PBBs.   In  the  absence  of cancer  data   for  the other
mixtures or Individual  PBB  congeners,  however,  It Is  appropriate to consider
adoption  of the  q^ for  Flremaster  FF-1  to other  PBBs.   NTP  (1983) noted
that  the  difference  between  Flremaster BP-6  and Flremaster  FF-1  consisted
only  of  the addition  of  254 calcium  trlslllcate to the former  to create  the
latter.  NTP  (1983) also noted  that  an Increased Incidence of liver tumors
occurred  only   In   those  groups   that  manifested   marked  hepatotoxlclty.
Comparative toxlclty studies  (see Chapter 6) Indicated  that  Flremaster FF-1
has  greater  hepatotoxlc  potency  than  Us  major component,  2,4,5,2',4',5'-
hexabromoblphenyl (Gupta  et al.,  1981).   Furthermore, synerglsm was reported
when  two  congeners  were  combined  1n  the  two-stage  hepatocarclnogenlclty
assay  In  female  rats  (Jensen,  1983;  Jensen  et al.,  1982,  1983;  Sleight,
1985).  These observations  suggest  that mixtures of  PBBs  such  as Flremaster
FF-1  may  have  greater cancer  potency  than the pure  Isomers.   Therefore,  In
the  absence  of  cancer data  for  other mixtures  or   Individual  congeners  of
PBBs,  It  seems  reasonable  to  adopt  the  q,*  of   8.87  (mg/kg/day)'1  for
exposure to Flremaster FF-1 as  being  sufficiently protective for exposure  to
other  mixtures   and  Individual  congers of  PBBs.   This   potency  factor  Is
equivalent  to   a concentration  of  PBBs   1n  drinking  water   of 0.395  jig/4.
associated with  Increased lifetime cancer risk  of  1x1 CT5  for  a  70 kg human
drinking 2 I of water/day.
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8.2.   SYSTEMIC TOXICITY
8.2.1.   Inhalation Exposure.
    6.2.1.1.   LESS  THAN  LIFETIME  EXPOSURE   (SUBCKRONIC) — Limited  Infor-
mation  Is  available  on the  subchronlc  Inhalation  toxldty of  PBBs.   Rats
exposed  to  a  low concentration  of  octabromoblphenyl  vapor   In  air  (3.5
pg/l)  for  23  hours/day,  7  days/week  for  <15 weeks  did not  show clinical
signs  of toxldty  or  effects on  liver,  thyroid  or  kidney weight or  gross
appearance   (Harltz  et  al.,  1977).   HlstologUal  examinations  were  not
conducted.   In  another  study, relative liver  weights  Increased  ~25X  1n rats
exposed  to  decabromoblphenyl  dust concentrations   of   >0.009  mg/i  for  6
hours/day, 5 days/week  for  4 weeks  (Mllllscher et al.,  1979).   Hlstologlcal
alterations  were  not  observed 1n the  livers or other tissues  of these  rats.
Other  effects  Included  equivocal decreases  1n SGOT  at >0.05 mg/4  and  signs
of ocular Irritation and slight dyspnea at 5 rng/d.
    The  4-week  decabromoblphenyl dust  Inhalation  study  Identifies  an effect
* J+**"'f
and  a no-effect  level  for  liver  enlargement  In   rats  (0.05 mg/i),  but  the
unremarkable  histology  makes   the   adversity   of   this  effect   uncertain
(Mmischer  et  al.,  1979).   As  Indicated  In  Section  6.1.2.1.,  P8B-related
hepatomegaly  1n  oral studies Is  usually  accompanied by  hepatic  hlstologlc
alterations.  The  uncertain  adversity of  the  effect, lack  of  corroborating
Inhalation  data  and  especially  the  short  treatment  duration  makes   H
Inappropriate to use the no-effect  level  from  this  study  as  the basis for  an
RfD for subchronlc Inhalation exposure.
    8.2.1.2.   CHRONIC  EXPOSURE ~ Pertinent  data   regarding   the  chronic
toxldty of  Inhaled PBBs are not available.
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8.2.2.   Oral Exposure.
    8.2.2.1.   LESS  THAN  LIFETIME  EXPOSURE  (SUBCHRONIC) — HepatotoxHHy
Is  the most  prominent  and  best characterized effect of subchronlc oral expo-
sure  to  PBBs.   As discussed  In Section 6.1.2.1.,  effects  Include Increased
liver weight and progressive  hlstologlcal  alterations,  typically hepatocyte
enlargement,   hepatocyte   degeneration  characterized  by   vacuolatlon  and
necrotlc areas  and  Upld  accumulation.   In what  appears to be  the  longest
duration PB6 study  with  rodents, rats  and mice were  treated  with  0,  0.1,
0.3,  1,  3  or 10 mg/kg doses of  Flreniaster  BP-6  by  gavage 5  days/week for 25
weeks (NTP,  1983;  Gupta  et al.,  1983a,b).   When  adjusted for partial weekly
treatment,  the doses were  0, 0.07,  0.2,  0.7, 2 or 7 mg/kg/day,  respectively.
Hepatic  effects,  consisting of  Increased  liver  weight  In  female rats  and
foamy  hepatocytes  In  male  rats,  occurred  at   the  lowest  dose.   Hepatic
effects  at  higher  doses  Included  Increased  liver  weight   (male rats  and
female mice) and slight hepatocyte  swelling  (male  rats) at 0.2  mg/kg/day,
and Increased  liver  weight (male mice) and  slight  hepatocyte swelling  (male
and female rats  and  mice)  at  0.7 mg/kg/day.   In  diet  studies with rats (see
Table 6-1),  mild  hepatocyte  vacuolatlon  resulted  from exposure  to Flremaster
BP-6  at  0.13 mg/kg/day for  30 days  (Akoso  et al.. 1982a) or to  unspecified
PBBs at 1.5  mg/kg/day  for  30 days (Sleight  and Sanger,  1976).  Liver  weights
Increased  from  exposure to  unspecified PBBs  at 0.5 mg/kg/day  for  30  days
(Sleight et  al., 1978),  to Flremaster  BP-6  at  1.3 mg/kg/day  for   30  days
(Akoso et  al.,  1982a)  and to  unspecified PBBs at 1.5 mg/kg/day  for  30 days
(Sleight and Sanger,  1976).   Increased  liver  weights   and  hlstopathologlc
lesions   In  the  liver  (vacuolatlon, necrosis,  pyknotlc  nuclei) occurred  In
the offspring  of  rats  fed diets  providing  0.5 mg/kg/day of  Flremaster  FF-1
during pregnancy and lactation (McCormack  et al., 1981).  Liver  biopsies  of
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three  monkeys exposed  to  0.05  mg/kg/day  of  Flremaster  FF-1  for  38 weeks
showed  enlarged  hepatocytes with  moderate fatty  Infiltration  (Lambrecht et
al., 1978).
    It  1s  evident  from these studies that  subchronlc  oral administration of
PBBs can  produce  hepatic  alterations In rats at  -0.1  mg/kg/day.   Since PBBs
are  unequivocally hepatotoxlc,  and  the  progression  of  hepatic  changes  1s
well characterized,  It Is  appropriate  to  regard liver weight  Increases  and
subtle  hepatocellular  alterations  (e.g.,   foamy  cytoplasm,  slight  vacuola-
tlon)  as  potentially adverse.   The  0.07  mg/kg/day dose  from NTP  (1983)  and
the  0.05  rng/kg/day  dose  from Lambrecht  et al.  (1978),   therefore,  are  the
lowest  subchronlc oral LOAELs  for  hepatic  effects.   Subchronlc  oral  doses at
which  characteristic hepatic alterations  do not occur have  not  been Identi-
fied;  therefore, a NOAEL or NOEL for hepatic effects cannot be Identified.
    Effects  on  the  thyroid and adrenal  glands have  been observed  In  rats
following exposure to  PBBs  (Flremaster  BP-6) at doses  similar  to  those that
produced  hepatic  effects  (see  Table 6-1).   Thyroid effects Include Msto-
loglcal alterations  that occurred when 0.13  mg/kg/day was  administered  In
the diet  for 30 days  (Akoso  et  al., 1982b)  and 0.25 mg/kg/day In  the diet
for  5   weeks (Kasza  et  al.,  1978), decreased  serum  thyroxlne  after  0.25
mg/kg/day  doses   In  the  diet  for  140  days  (Byrne  et  al., 1987)   and  0.2
mg/kg/day  doses   by  gavage for  25  weeks  (NTP,  1983).    Exposure   to  0.05
mg/kg/day  for   175   days  decreased  relative  adrenal   weight   and  serum
cortlcosterone  (Byrne  et  al.,  1988),  but  the  decrease  In adrenal  weight
appeared  to  be  Inversely dose-related and  the  toxlcologlcal  significance of
these  effects on  the adrenal Is unknown.   PBB-1nduced effects on the thyroid
and adrenal  are potentially adverse  because alterations  have been  functional
as well as  hlstologlcal.   These effects are particularly remarkable because

0176d                               -64-                             06/07/89

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they  provide  additional  evidence of  adversity of PBBs  In  the hepatic LOAEL
dose  range.   NTP  (1983)  showed decreased  longevity  In  the  thyroid effects
dose  range  (I.e.,   In  rats  treated  with  0.2  mg/kg/day  for  25  weeks  and
observed  posttreatment).   Teratogenlc and fetotoxlc effects  of  PBBs 1n rats
and mice  occur at doses  higher than the lowest  doses  that produced effects
In  the  liver, thyroid or  adrenal  (Section  6.4.).  Liver  mlcrosomal protein
content  and  drug  metabolizing  activities  Increased  In  nursing  rats  whose
lactatlng  mothers  received 0.05 mg/kg/day  of Flremaster FF-1.   However,  It
Is  not  certain whether the  enzyme  Induction  Is a precursor  to  liver weight
changes observed at  higher  doses or  an  adaptation response to the chemicals.
Also, at  relatively  higher doses compared with  other  toxic effects of PBBs,
reduction  of  fetal   body  weights  In  rats  was  observed  to occur at  2.5
mg/kg/day  (Corbett et al., 1975).   However,  other similar  studies with rats
did not  report a decrease  1n  body  weight (Cagen and Gibson,  1978;  Cagen  et
al., 1979).
    The 0.07  mg/kg/day  hepatic LOAEL 1n  rats  (NTP, 1983)  and 0.05 mg/kg/day
LOAEL  In   monkeys  (Lambrecht  et  al.,  1978)   are  essentially Identical  and
supportive  of  each other, but  the  rat  LOAEL  Is  based  on  a  study that used
much  larger numbers  of animals and  more extensive hlstologlcal examinations.
Application of an uncertainty  factor  of 1000  (10 for  LOAEL-to-NOAEL extrapo-
lation, 10  for Interspecles extrapolation and 10 for  protection  of sensitive
humans) yields a  subchronlc  oral   RfD  of  0.07  yg/kg/day,  or  5  ug/day  for
a 70  kg human.   Although  a NOAEL  for  systemic  effects was  not  Identified,
confidence  In  the  key study and this RfD Is  medium because  the  subtlety  of
the hepatic  effects  1n the critical  study  indicates  proximity  to the NOAEL
region.   Although  numerous systemic  toxicUy and  developmental  studies  of
PBBs are available,  confidence  In the data  base  1s  medium because there were
few low-dose studies  >30-60 days.

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    8.2.2.2.   CHRONIC   EXPOSURE  —  Pertinent   data  regarding  the   chronic
oral  toxlclty  of  PBBs  are  not   available.   A  chronic  oral  RfD  of  0.007
mg/kg/day  or  0.5 ing/day for a 70 kg  human  can be derived  by dividing  the
subchronlc  oral  LOAEL  by an additional  uncertainty  factor of 10 to extrapo-
late from  subchronlc to  chronic exposure.
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                           9.   REPORTABLE  QUANTITIES
9.1.   BASED ON SYSTEMIC TOXICITY
    The toxldty of PBBs was  discussed  In Chapter 6 and oral data useful for
RQ derivation are  summarized  1n  Table 9-1.   Chronic toxlclty studies of PBBs
have not  been  conducted.   The only Inhalation  studies  exposed  rats  to octa-
bromoblphenyl vapor for  15 weeks (Warltz et al.,  1977)  or decabromoblphenyl
dust for  4 weeks  (Mllllscher  et  al..  1979).   The octabromoblphenyl  study was
unremarkable; the  decabromoblphenyl study showed Increased liver  weights but
Is Inappropriate for possible RQ derivation because of Us short duration.
    PBBs    are     unequivocally    hepatotoxlc.    producing    characteristic
dose-related,   treatment/duratlon-related and   observatlon/duratlon-related
effects.  These  Include  Increased liver  weight  and progressive hlstologlcal
alterations,  such  as  hepatocyte   enlargement;   hepatocyte   degeneration
manifested  as  foamy appearance,  vacuolatlon and  necrotlc areas; and  Upld
accumulation.  Hepatic effects occurred at 0.5  mg/kg/day 1n  the offspring of
rats  exposed  during   gestation   and  lactation   (McCormack  et  al..  1981).
Effects  on   the  adrenal  gland  (decreased relative weight,  decreased  serum
cortlcosterone) have been  observed In rats exposed  to 0.05 mg/kg/day for 5-7
months  (Byrne  et  al.,  1988).   The  adversity  of  the  adrenal  effects  1s
uncertain;   however,   the   depression   In adrenal   weight  occurred  In  an
Inversely dose-related manner because toxldty of PBBs  to the  adrenal  Is not
established  and  reversibility   not  determined.   Toxlclty  of  PBBs  to  the
thyroid 1s established; effects  Include  Increased thyroid weight,  folllcular
hlstologlcal  alterations   and  decreased  levels  of  serum thyroid  hormones.
Effects on  the  thyroid have been observed at  doses as  low  as  0.2  mg/kg/day
(reduced  serum thyroxlne 1n rats  treated  for  25  weeks).   Exposure of rats to
5 mg/kg/day  during gestation and  lactation  caused  lengthened  estrus  cycles
0176d
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09/29/89

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(Johnston ei al.,  1980)  and  reduced survival  {MeCormack et al., 1981) In the
offspring.   Exposure  to a  much  higher  dose  of  PBBs  (400  mg/kg/day)  was
embryolethal and teratogenlc to rats (Beaudoln, 1977, 1979).
    Derivations of  CSs  for  PBBs, based on  the  lowest  human equivalent doses
for  the  effects  discussed previously,  are  presented 1n  Table  9-2.   The  most
appropriate  RV    for  all   PBB-related   liver   effects   1s  6  because   the
progression  to  unequivocally toxic alterations 1s  well  characterized  and It
Is  Inappropriate  to consider  these alterations  reversible.   However,  since
the  hepatic  cardnogenlclty  of  PBBs  Is  well  documented (Gupta  et  al.,
1983b),  these early  hepatic  changes will  not  be considered In the derivation
of  the  RQ  based  on chronic  toxlclty.   The RV   for   liver  effects  1n  the
offspring  of  treated  rats   1s  also  6,   because  these  effects  are  more
consistent  with  systemic toxlclty  than  fetotoxlclty.    The  most  appropriate
RV   for  adrenal  effects  (because of uncertain adversity  and  reversibility)
Is 4.  The  lengthened  estrus cycle  Is given  an RV  of  7,  because  this  Is  a
physiological change that does not  necessarily  reduce  reproductive capacity.
Teratogenlclty and  fetolethallty rates an  RV  of  9.    The  chronic  progres-
sive  nephropathy  observed  after a 2-year observation  following a  6-month
treatment period  1n rats (Gupta  et  al.,  1983b) rates  an RVfi  of 9.   This Is
reflected In the highest  calculated CS (57.5)  for Flremaster FF-1  PBBs which
corresponds to an RQ of 10 (Table 9-3).
9.2.   BASED ON CARCINOGENICITY
    The  cardnogenlclty  of PBBs was discussed  1n Chapter  6.   NTP  (1983)  and
Gupta  et   al.   (1983)   reported   Increased   Incidences  of  hepatocellular
carcinomas  and  neoplastU nodules  In  both sexes  of  rats  treated  by  gavage
with Flremaster FF-1 for 25  weeks and maintained  for  an additional  23-month
observation period.  An  Increased Incidence of  hepatocellular  carcinomas  was
0176d
-71-
09/29/89

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                                  TABLE 9-3
                                     P68s
           Minimum  Effective  Dose  (MED) and Reportable Quantity  (RQ)
Route:
Species:
Dose*:
Duration:
Effect:
RVd:
RVe:
CS:
RQ:
Reference:
oral
rat
0.26 mg/day
25 weeks
chronic progressive nephropathy
6.4
9
57.5
10
NTP, 1983
'Equivalent human dose
0176d
            -73-
09/29/89

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reported  In male  but  not female  mice  treated  Identically  except  with  a
24-month  observation  period.   In  other  studies,  single  gavage  treatments
with Flremaster FF-1 Increased the  Incidences of  liver  tumors  1n  female rats
examined  23-24  months  later  (Klmbrough  et  al.,  1981).   Several  PBBs  were
tumor promoters  In  the  two-stage hepatocarclnogenlcUy assay  1n female rats
{Jensen,  1983;   Jensen  et  al.,  1982,  1983; Sleight,  1985;  Dlxon  et  al.,
1985).  Flremaster BP-6 was not  a  tumor  promoter  In the two-stage  mouse skin
assay (Berry et  al.,  1978).  The  only study that attempted to evaluate  the
carclnogenlcUy  of  PBBs  to  humans was  an  Inadequate  prospective mortality
study using workers  from  the manufacturing  plants  (Wong et al.,  1984).   On
the  strength  of  the  data In animals,  PBBs  were assigned  to  EPA Group  B2:
probable human carcinogens.
    An  F  can  be derived  for  exposure  to PBBs from Incidence  data for  liver
tumors  and  neoplastlc nodules 1n  female rats that  served  as  the basis  for
the  q-j* for oral  exposure (NTP,  1983;  Gupta et al.,  1983b).  The  deriva-
tion of an  F  factor  of  54 1s presented  1n  Table 9-4.  An F factor of  54 1s
associated  with  Potency  Group   2.   Chemicals In  EPA  Group B2  and  Potency
Group 2 are assigned  a  hazard ranking of medium, which corresponds to  an RQ
of 10 based on carclnogenlclty.
0176d                               -74-                             10/02/89

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                                   TABLE  9-4
                   Derivation  of  Potency  Factor  (F)  for  PBBs
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:
Ufespan of animal:
Target organ:
Tumor type:
Experimental doses/exposures:
Human equivalent doses:
(mg/kg/day)
Tumor Incidence:
1/ED10:
(F factor)
NTP, 1983; Gupta et al., 1963b
oral (gavage)
rat
F344N
F
corn oil
0.35 kg (reference value)
175 days
865 days
865 days
liver
hepatocellular carcinoma and neoplastlc
nodules
0, 0.1, 0.3, 1.0, 3.0, 10.0 mg/kg,
5 days/week
0, 0.00247, 0.00741, 0.02471, 0.07413,
0.24711
0/20, 2/21, 0/21, 2/11, 7/19, 16/20
54
0176d
  -75-
09/29/89

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                                10.   REFERENCES

Akoso,  B.T.,  S.D.  Sleight,  S.D. Aust  and  H.D.  Stowe.   1982a.   Pathologic
effects of  purified  polybromlnated  blphenyl  congeners  1n  rats.   J.  Am.  Coll.
Toxlcol.  1(3): 1-21.

Akoso,  B.T.,  S.O.  Sleight, R.F.  Nachrelner  and S.D. Aust.   1982b.   Effects
of  purified polybromlnated blphenyl  congeners  on the  thyroid  and  pituitary
glands  In rats.  J. Am. Coll.  Toxlcol.  1(3): 23-36.

Allen-Rowlands, C.F.,  V.D.  Castracane,  M.6.  Hamilton and  J.  Selfter.   1981.
Effects of  polybromlnated blphenyls  (PBB) on  the pituitary-thyroid axis  of
the rat.  Proc. Soc. Exp. B1ol. Med.  166: 506-514.

Anllker, R., P. Moser  and  D.  Popplnger.   1987.   Bloaccumulatlon of  dyestuffs
and  organic pigments  In  fish.   Relationships  to hydrophoblclty and  sterlc
factors.  Ecol. Toxlcol. Assoc. Dyest. Manuf. Ind.  17(8):  1631-1644.

Applegate,  V.C.,   3.H.  Howell,  A.E.  Hall,  Jr.  and  M.A.   Smith.    1957.
Toxldty of 4346 chemicals to  larval  lampreys  and fishes.   Spec.  Sc1.  Rep.  -
F1sh. No.  207, F1sh HUdl Serv., USDI, Washington, DC.   p.  1-9,  36-37.

Bannasch,    P.,  V.   Benner  and   H.   Zerban.    1985.    CholanglofIbroma  and
cholanglocarclnoma,  Hver,  rat.   in: Digestive  System,  T.C.  Jones and  R.B.
Hunt, Ed.   Sprlnger-Verlag, New York.  p.  52-65.
0176d
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09/29/89

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Beaudoln,  A.R.   1977.  Teratogenlclty  of  polybromlnated  blphenyls  In rats.
Environ. Res.  14(1): 81-86.

Beaudoln,  A.R.    1979.   EmbryotoxIcUy  of  polybromlnated blphenyls.   Adv.
Study Birth Defects.  2: 211-222.

Berry, D.L., J. DIGIovannl, M.R.  Juchau, W.M.  Bracken,  G.L.  Gleason  and T.J.
Slaga.   1978.    Lack of  tumor-promoting  ability  of  certain  environmental
chemicals  In a  two-stage mouse  skin  tumorIgenesls  assay.  Res.  Comm.  Chem.
Pathol. Pharmacol.  20(1): 101-108.

Burkhard,  L.P., O.E.  Armstrong and A.M. Andren.  1984.   Vapor  pressures  for
blphenyl,    4-chloroblphenyl,    2,2',3,3',5,5',5,5'-octachloroblphenyl    and
decachloroblphenyl.  J.  Chem.  Eng. Data.  29: 248-250.

Burslan, S.J.,  D.  Polln, B.A.  Olson,  L.R.  Shull,  H.L.  Marks  and H.S.  Slegel.
1983.   Hlcrosomal  enzyme   Induction,  egg  production,  and  reproduction  In
three  lines  of  Japanese quail  fed  polybromlnated  blphenyls.    J.  Toxlcol.
Environ. Health.  12(2-3): 291-307.

Byrne,  J.J.,  J.P.  Carbone and   E.A.  Hanson.   1987.   Hypothyroldlsm  and
abnormalities In  the  kinetics  of  thyroid hormone metabolism 1n  rats  treated
chronically  with   polychlorlnated  blphenyl   and  polybromlnated blphenyl.
Endocrinology (Baltimore}.   121(2): 520-527.
Byrne,  J.J.,   J.P.  Carbone  and  M.G.  Pepe.   1988.   Suppression  of  serum
adrenal cortex hormones by chronic  low  dose  polychloroblphenyl  or  polybromo-
blphenyl treatments.  Arch.  Environ. Contam.  Toxlcol.   17(1):  47-53.
0176d
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organic pollutants  from the molecular connectivity model.  Z. Gesamte.  Hyg.
Ihre. Grenzgeb.  33: 493-496.

Safe,   S.    1984.    Polychlorlnated  blphenyls   (RGBs)  and   polybromlnated
blphenyls  (PBBs):  Biochemistry,  toxicology  and  mechanism of action.   CMt.
Rev. Toxlcol.  13: 319-395.

SANSS  (Structure  and  Nomenclature  Search System).   1989.   Chemical  Informa-
tion System (CIS) computer  data base.

Sasaki, S.  1978.   The  scientific  aspects of  the  chemical  substance  control
law  In   Japan.    IJK   Aquatic  Pollutants:   transformation   and   Biological
Effects, 0. Hutzlnger,  L.H.  Von  Letyoeld and  B.C.J.  Zoeteman, Ed.   Pergamon
Press, Oxford,  p. 283-298.
0176d                               -90-                              09/29/89

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Sepkovlc,  O.W.  and  J.J.  Byrne.   1984.   Kinetic  parameters  of L-[125IJtr1-
lodothyronlne degradation  In rats pretreated with polyhalogenated blphenyls.
Food Chem. Toxlcol.  22(9):  743-747.

Sleight,  S.   1985.   Effects of PCBs and  related compounds on hepatocarclno-
genesls  In rats and mice.   Environ. Health Perspect.  60:  35-39.

Sleight,  S.D. and  V.L.  Sanger.   1976.   Pathologic features of polybromlnated
blphenyl  toxicosis  1n  the  rat and  guinea  pig.   J.  Am.  Veter. Med.  Assoc.
169(11):  1231-1235.

Sleight,  S.D.,  S.  Mangkoewldjojo, B.J. Akoso and  V.L.  Sanger.   1978.   Poly-
bromlnated  blphenyl  toxicosis  In  rats  fed   an  1od1ne-def1c1ent,  Iodine-
adequate  or Iodine-excess diet.  Environ. Health Perspect.  23:  341-346.

Stratton,  C.L.  and  S.A.  Whltlock.   1979.   A  survey  of  polybromlnated
blphenyls  (PBBs)  near  sites  of   manufacture   and  use  In northeastern  New
Jersey.   Spec.  Conf.  Control  Specific   (Toxic)  Pollutants   1979.   p. 1-42,
Appendix  A.

Stratton, C.I., J.J. Mousa  and J.T. Bursey.  1979.   Analysis for  polybroml-
nated  blphenyls  {PBBs) In  environmental  samples.   EPA/560/13-79/001.   NTIS
PB-296466.  79(19): 121 p.

Strlk,   J.J.T.   1973.    Chemical   porphyrla   1n  Japanese  quail   (Coturnlx
coturnlx Japonlca).  Enzyme.  16(1-6):  211-223.
0176d
-91-
09/29/89

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Suglura,  K., N.  Ito,  N.  Matsumoto,  et  al.   1978.   Accumulation  of  poly-
chlorinated  blphenyls and  polybromlnated  blphenyls  1n  fish:  Limitation  of
correlation   between   partition   coefficients   and   accumulation   factors.
Chemosphere.  9: 731-736.

Thomas,  R.G.  1982.   Volatilization from water.   lr±; Handbook  of  Chemical
Property Estimation Methods, W.J.  Lymon, W.F. Reehl  and  D.H.  Rosenblatt,  Ed.
McGraw-Hill  Book Co., NY.  p. 15-1 to 15-34.

Tllson,  H.A.  and P.A. Cabe.   1979.   Studies on the  neurobehavloral  effects
of polybromlnated blphenyls In rats.  Ann.  NY Acad. Sd.   320: 325-336.

Tllson,  H.A.,  P.A.  Cabe and  C.L.  Mitchell.   1978.   Behavioral and  neuro-
logical  toxldty of  polybromlnated  blphenyls  In  rats  and  mice.   Environ.
Health Perspect.  23: 257-263.

Tuey,  D.B.  and  H.B.   Matthews.    1980.    Distribution   and  excretion   of
2,2',4,4',5,5'-hexabromob1phenyl  1n  rats   and   man:   Pharmacoklnetlc   model
predictions.  Toxlcol. Appl. Pharmacol.  53(3):  420-431.

U.S.  EPA.    1980.   Guidelines and  Methodology   Used  1n  the  Preparation  of
Health  Effect  Assessment   Chapters  of  the   Consent   Decree  Water  Criteria
Documents.  Federal Register.  45(231): 79347-79357.

U.S. EPA.   1984.  Methodology  and Guidelines for Ranking  Chemicals  Based  on
Chronic  Toxldty  Data.   Prepared by  the Office of Health  and  Environmental
Assessment,  Environmental Criteria  and  Assessment  Office,  Cincinnati. OH  for
the Office of Emergency and Remedial Response, Washington,  DC.
0176d                               -92-                             09/29/89

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U.S.  EPA.   1986a.   Reference  Values for  Risk  Assessment.   Prepared  by the
Office  of  Health  and Environmental  Assessment,  Environmental  Criteria and
Assessment Office, Cincinnati,  OH  for  the Office of Solid Haste, Washington,
DC.

U.S.  EPA.   1986b.   Guidelines  for  Carcinogen   Risk  Assessment.   Federal
Register.  51(185):  33992-34003.

U.S.  EPA.    1987.    PBBs  and  Trls:  Significant  New Uses  of Chemical  Sub-
stances.  Federal Register.  52(16): 2699-2703.

U.S.  EPA/OWRS.   1986.   Guidelines  for   Deriving   Numerical  Water  Quality
Criteria for  the  Protection of Aquatic Organisms and Their  Uses.   EPA/OWRS,
Washington, DC.  p.  22-58, 98.

VeHh,  G.D.,  D.L.  Delore  and B.V. Bergstedt.   1979.  Measuring  and estimat-
ing  the bloconcentratlon  factor  of  chemicals  1n  fish.   3.  Fish  Res.  Board
Can.  36: 1040-1048.

Warltz, R.S.,  J.G.  Aftosmls,  R. Cullk, et al.   1977.  Tox1colog1cal  evalua-
tions of some bromlnated blphenyls.  Am. Ind. Hyg. Assoc.  J.  38(7): 307-320.

Watanabe, I., T.  Kashlmoto and  R.  Tatsukaua.   1987.   Polybromlnated blphenyl
ethers  In  marine fish,  shellfish  and  river  and marine  sediments  In  Japan.
Chemosphere.   16: 2389-2396.
0176d                               -93-                             09/29/89

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Uelsch,  F.  and  K.T. Morgan.   1985.   Placenta!  transfer and  developmental
toxldty of 2,2',4,4l,5,5'-hexabromob1phenyl  In  B6C3F1  mice.   Toxlcol.  Appl.
Pharmacol.  81(3): 431-442.

Wertz,  G.F.   and  6.  Flcsor.    1978.   Cytogenetlc  and   teratogenlc  test  of
polybromlnated blphenyls 1n rodents.  Environ. Health Perspect.   23:  129-132.

Hhltlock,  S.A.  and  C.I.   Stratton.   1979.    A  survey  of   polybromlnated
blphenyls (PBBs)  near  sites of manufacture and  In northeastern  New  Jersey.
Spec. Conf. Control Specific (Toxic) Pollut.   22: 174-184.

Williams, G.M.,  J.C. long and S.  Telang.   1983.  Polybromlnated  blphenyls
are  non-genotoxlc  and  produce  an  eplgenetlc  membrane  effect   In  cultured
liver cells with cover  letter  & EPA acknowledgement  dated 10-11-83.   EPA/OTS
Document No.  FYI-OTS-0583-0244.

Wolff,  M.S.,  H.A.  Anderson,  K.D.   Rosenman   and   I.J.  Sellkoff.    1979.
Equilibrium of  polybromlnated   blphenyl  (PB8)  residues   In  serum and fat  of
Michigan  residents.   Bull. Environ. Contain.  Toxlcol.   21: 775-781.   (Cited
In Tuey and Matthews, 1980)

Wong,  0., W.  Brocker,  H.V.   Davis and  G.S.  Nagle.   1984.   Mortality  of
workers potentially  exposed to organic  and  Inorganic  bromlnated chemicals,
DBCP, TRIS, PBB and DOT.  Br.  J. Ind. Med.  41:  15-24.

ZUko,  V.   1977a.    Uptake and   excretion  of  chlorinated  and  bromlnated
hydrocarbons  by fish.  Tech. Rep.  - Fish. Mar. Serv.   14 p.


0176d                               -94-                             09/29/89

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ZHko,  V.    1977b.   The accumulation  of polybromlnated  blphenyls  by  fish.
Bull. Environ. Contam. Toxlcol.  17(3): 285-292.

ZHko,  V.  and 0.  Huntzlnger.   1976.   Uptake of chloro- and bromoblphenyls,
hexachloro- and  hexabromobenzene  by fish.   Bull.  Environ.  Contam.  Toxlcol.
16: 665-673.
0176d
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09/29/89

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                                  APPENDIX A

                              LITERATURE  SEARCHED



    This  HEED  Is  based  on  data  Identified  by  computerized  literature

searches of the following:

              CHEMLINE
              TSCATS
              CASR online (U.S. EPA Chemical Activities Status Report)
              TOXLINE
              TOXLIT
              TOXLIT 65
              RTECS
              OHM TADS
              STORET
              SRC Environmental Fate Data Bases
              SANSS
              AQUIRE
              TSCAPP
              NTIS
              Federal Register
              CAS ONLINE (Chemistry and Aquatic)
              HSOB
              SCISEARCH
              Federal Research In Progress


These  searches  were  conducted  In  May,   1988,  and  the following  secondary

sources were reviewed:
    AC6IH  (American  Conference of Governmental  Industrial  Hyg1en1sts).
    1986.   Documentation  of the  Threshold  Limit Values  and  Biological
    Exposure Indices, 5th ed.  Cincinnati, OH.

    ACGIH  (American  Conference of Governmental  Industrial  Hyglenlsts).
    1987.   TLVs:  Threshold  Limit Values for  Chemical  Substances  1n  the
    Work  Environment  adopted   by   ACGIH   with   Intended  Changes  for
    1987-1988.  Cincinnati,  OH.  114 p.

    Clayton,  G.D. and  F.E.  Clayton,  Ed.    1981.   Patty's  Industrial
    Hygiene  and  Toxicology,  3rd rev.  ed.,  Vol.  2A.   John  Wiley  and
    Sons, NY.  2878 p.

    Clayton,  G.D. and  F.E.  Clayton,  Ed.    1981.   Patty's  Industrial
    Hygiene  and  Toxicology,  3rd rev.  ed..  Vol.  2B.   John  M1ley  and
    Sons, NY.  p. 2879-3816.
0176d                               -96-                             09/29/89

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    Clayton,  G.D.  and  F.E.  Clayton,  Ed.   1982.    Patty's  Industrial
    Hygiene  and  Toxicology,  3rd  rev.  ed.,  Vol.  2C.   John Wiley  and
    Sons, NY.  p. 3817-5112.

    Grayson,  H.  and D.  Eckroth, Ed.   1978-1984.   K1rk-0thmer  Encyclo-
    pedia of  Chemical  Technology,  3rd  ed.   John Wiley and Sons, NY.  23
    Volumes.

    Hamilton, A.  and H.L.  Hardy.  1974.  Industrial  Toxicology, 3rd ed.
    Publishing Sciences Group, Inc., Littleton, MA.   575 p.

    IARC  (International  Agency  for  Research  on  Cancer).   IARC  Mono-
    graphs  on  the  Evaluation   of  Carcinogenic  Risk  of Chemicals  to
    Humans.   IARC, WHO, Lyons, France.

    Jaber,  H.M.,  W.R.   Mabey,  A.T.  Lieu,  T.W.  Chou  and  H.L.  Johnson.
    1984.    Data  acquisition   for   environmental   transport  and  fate
    screening for compounds of  Interest  to  the Office of  Solid  Waste.
    EPA  600/6-84-010.    NTIS  PB84-243906.   SRI  International,   Menlo
    Park, CA.

    NTP  (National Toxicology  Program).  1987.   Toxicology  Research  and
    Testing   Program.    Chemicals   on   Standard  Protocol.   Management
    Status.

    Ouellette,  R.P. and  J.A.   King.   1977.   Chemical  Week  Pesticide
    Register.  McGraw-Hill Book Co., NY.

    Sax, I.N.   1984.   Dangerous  Properties of Industrial  Materials,  6th
    ed.  Van Nostrand Relnhold Co., NY.

    SRI  (Stanford Research  Institute).   1987.   Directory  of  Chemical
    Producers.  Nenlo Park, CA.

    U.S.  EPA.  1986.    Report  on  Status  Report In  the  Special  Review
    Program,  Registration  Standards  Program  and   the  Data  Call   1n
    Programs.   Registration Standards  and the  Data  Call  In  Programs.
    Office of Pesticide Programs, Washington, DC.

    USITC  (U.S.  International  Trade  Commission).    1986.   Synthetic
    Organic  Chemicals.   U.S.   Production  and  Sales,  1985,  USITC  Publ.
    1892, Washington,  DC.

    Verschueren,  K.   1983.  Handbook  of  Environmental Data  on Organic
    Chemicals, 2nd ed.   Van Nostrand Relnhold Co.,  NY.

    Hlndholz, M., Ed.    1983.  The Merck Index,  10th  ed.   Merck  and Co.,
    Inc., Rahway, NJ.

    Worthing, C.R.  and S.8. Walker,  Ed.   1983.  The  Pesticide Manual.
    British Crop Protection Council.  695 p.
0176d                               -97-                             09/29/89

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    In  addition,  approximately  30 compendia  of aquatic  tox1c1ty  data were

reviewed, Including the following:


    Battelle's  Columbus  Laboratories.   1971.   Water  Quality Criteria
    Data  Book.   Volume  3.  Effects  of  Chemicals  on  Aquatic  Life.
    Selected  Data from the  Literature  through  1968.   Prepared  for the
    U.S. EPA under Contract No. 68-01-0007.  Washington, DC.

    Johnson,  W.W. and  M.T.  Flnley.   1980.  Handbook of  Acute Toxlclty
    of  Chemicals  to  F1sh  and  Aquatic   Invertebrates.   Summaries  of
    Toxlclty  Tests  Conducted  at  Columbia National  Fisheries Research
    Laboratory.   1965-1978.   U.S. Dept.  Interior,  Fish  and Wildlife
    Serv. Res. Publ. 137, Washington, DC.
    HcKee,  J.E.  and H.W.  Wolf.  1963.  Water
    Prepared  for   the  Resources  Agency  of
    Quality Control Board.  Publ. No. 3-A.
          Quality  Criteria,  2nd ed.
           California,  State  Water
    Plmental,  D.   1971.   Ecological  Effects  of Pesticides on Non-Target
    Species.   Prepared for the U.S. EPA, Washington, DC.  PB-269605.

    Schneider,  B.A.   1979.   Toxicology Handbook.   Mammalian and Aquatic
    Data.   Book  1:  Toxicology  Data.   Office  of Pesticide Programs, U.S.
    EPA, Washington, DC.  EPA 540/9-79-003.  NTIS PB 80-196876.
0176d
-98-
09/29/89

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                                 APPENDIX B-l

         Cancer  Data  Sheets  for  Derivation  of a  qi*  for  Oral  Exposure3
Compound:  Flremaster FF-1

Reference:  NTP, 1983; Gupta et al.f 1983b

Specles/straln/sex:  rat, F344N, male

Body weight = 0.350 kg3 (assumed)
Length of exposure (le) = 175 days

Length of experiment (Le) = 865 days
                                 b
llfespan of animal (L) = 865 days

Tumor site and type:  liver, hepatocellular carcinoma and neoplastlc nodules

Route/vehicle:  oral (gavage) In corn oil 5 days/week
Experimental Doses      Human Equivalent Dosec              Incidence
     (mg/kg)                 (mg/kg/day)            No. Responding/No.  Tested
0
0.1
0.3
1.0
3.0
10.0
0
0.00247
0.00741
0.02471
0.07413
0.24711
0/33
2/39
1/40
5/31
10/33
8/31
Human q^* = 2.94 ( mg/kg/day )~ld

aAlthough  body  weight  data  were  provided  for  the non-exposed  observation
 period,  data were  not  provided   for  the  exposure  period;  therefore  the
 reference body  weight  for rats of 0.350 kg  (U.S.  EPA,  1986a) was  used  In
 the calculations.

bThe  length  of   the experiment   (175  days  of  exposure  and  690  days  of
 observation) was adopted as  the length of Hfespan for this  experiment.

cHuman  equivalent  doses  were  estimated  by  multiplying the  animal   dose  by
 5/7  to adjust  for  treatment  on  5 days/week,  by  175/865  to adjust  for  the
 proportion  of  the  experimental  period  during  which  exposure occurred  and
 by  the cube root  of  the  ratio  of  the  rat  body  weight  (0.35  kg);  human
 reference body weight (70 kg) to extrapolate from animals  to humans.
      calculation  was  based   on   human  equivalent  dosage,  therefore,  the
 slope  factor  generated  by   Global  82  Is  for  exposed  humans;  no  other
 adjustment 1s necessary.


0176d                               -99-                             09/29/89

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                                 APPENDIX B-2

         Cancer  Data  Sheets  for  Derivation  of  a  q-|*  for  Oral  Exposure3
Compound:  Flremaster FF-1

Reference:  NTP, 1983; Gupta et al.t 1983b

Specles/straln/sex:  rat, F344N, female

Body weight = 0.350 kg3 {assumed}
Length of exposure (le) = 175 days

Length of experiment {Le) * 865 days

Llfespan of animal (L) = 865 days

Tumor site and type:  liver, hepatocellular carcinoma and neoplastlc nodules

Route/vehicle:  oral (gavage) In corn oil 5 days/week
Experimental Doses      Human Equivalent Oosec              Incidence
     (mg/kg)                 (mg/kg/day)            No.  Responding/No.  Tested
0
0.1
0.3
1.0
3.0
10.0
0
0.00247
0.00741
0.02471
0.07413
0.24711
0/20
2/21
0/21
2/11
7/19
16/20
Human q-j* = 8.87 (mg/kg/day rid

aAlthough  body  weight  data  were  provided  for  the non-exposed  observation
 period,  data were  not  provided  for  the  exposure  period;  therefore  the
 reference body  weight  for rats  of 0.350 kg  (U.S.  EPA,  1986a) was  used  In
 the calculations.
                                                                           of
bThe  length  of  the  experiment   (175  days  of  exposure and  690  days
 observation) was adopted as the length of Hfespan for this  experiment.

cHuman  equivalent  doses were  estimated  by  multiplying  the  animal  dose  by
 5/7  to  adjust  for  treatment  on  5 days/week,  by  175/865 to adjust for  the
 proportion of the experimental period  during which  exposure  occurred  and  by
 the cube root of the ratio of the rat body weight (0.35 kg);  human reference
 body weight (70 kg)  to extrapolate from animals to humans.

<*The calculation was  based on human equivalent dosage, therefore,  the slope
 factor generated by Global 82  Is  for  exposed  humans; no other  adjustment  1s
 necessary.


0176d                               -100-                            09/29/89

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-------
                                  APPENDIX 0
   DOSE/DURATION RESPONSE GRAPH(S) FOR EXPOSURE TO POLYBROMINATE0 BIPKENYLS
0.1.  DISCUSSION
    Dose/duration-response   graphs   for  oral   exposure   to  polybromlnated
blphenyls generated  by  the Crockett et al.  (1985)  method using the computer
software  by  Durkln  and  HeyIan  (1988)  developed  under  contract   to  ECAO-
ClncInnatl  are presented  In  Figures  D-l  and D-2.   Data used  to generate
these  graphs  are  presented  In  Section  D.2.   In  the  generation   of  these
figures,  all  responses  are  classified  as  adverse  (PEL,  AEL  or  LOAEL)  or
nonadverse  (NOEL  or  NOAEL)  for plotting.   For  oral  exposure,  the ordlnate
expresses dosage  as  human equivalent  dose.   The animal  dosage  1n  mg/kg/day
Is multiplied  by  the cube root of  the  ratio of  the animal:human body weight
to  adjust  for species  differences  1n  basal  metabolic  rate  (Mantel  and
Schnelderman,  1975).  The  result  Is then multiplied by  70 kg,  the  reference
human body  weight,  to express  the  human  equivalent dose as mg/day for  a  70
kg human.
    The  boundary  for adverse  effects  (solid  line)  Is drawn by Identifying
the lowest  adverse effect  dose or concentration at  the  shortest duration  of
exposure at  which an adverse effect occurred.   From this point, an Infinite
line  1s  extended  upward, parallel  to  the dose axis.  The  starting point  1s
then  connected to the  lowest  adverse  effect dose  or concentration at  the
next  longer  duration of  exposure  that has an  adverse  effect  dose or concen-
tration equal  to  or  lower  than the previous  one.   This  process  1s  continued
to the lowest  adverse effect  dose or  concentration.  From this  point, a line
Is extended to the  right,  parallel  to  the duration  axis.   The  region  of
adverse effects lies  above the adverse effects boundary.
0176d
-102-
09/29/89

-------
   f,
   3i
   C
   I

   I


   a
          lee •-
           i --
          e.i
            0.001


   
                                                 F38
                                                 07
                                                           L24


                                                          --W25
                                         L22

     e.ei                   0.1
HUMAN EQUIV DURATION (fp*ction
          ENVELOP METHO»
      Key:   F .  FEL
             A .  AEL
             I .  LOAEL
             N -  NOEL
             Solid  line « Adverse Effects  Boundary
             Dashed line « No Adverse  Effects Boundary
                                    FIGURE D-l

           Dose/Duration - Response Graph  for Oral Exposure  to  PBBs:
                                 Envelope Method
01?6d
         -103-
09/29/89

-------
      •5
      hi
      Its
      I
      t
      a
      z
            e.i
               0.881

     *p*n>
                        CENSORED MTA METHOD
      Key:
F « FEL
A « AEL
L » LOAEL
N - NOEL
Solid line  •
Dashed line
                           Adverse Effects  Boundary
                          • No Adverse Effects Boundary
                                    FIGURE D-2

           Dose/Duration - Response Graph  for Oral Exposure  to PBBs:
                               Censored Data Method
0176d
                         -104-
09/29/89

-------
    Using  the  envelope method,  the  boundary for no  adverse effects (dashed
line)  Is drawn  by  Identifying  the highest no adverse effects dose or concen-
tration.   From  this  point,  a line parallel  to  the  duration axis Is extended
to  the dose or  concentration axis.  The  starting point 1s then connected to
the next  lower  or  equal no  adverse  effect  dose or  concentration at a longer
duration  of exposure.   When  this  process  cannot  be  continued,  a  line Is
dropped, parallel  to the dose  or concentration axis,  to  the duration  axis.
The region  of no adverse  effects lies  below the no adverse effects boundary.
At  either   ends  of  the graph  between the  adverse  effects  and  no  adverse
effects  boundaries  are regions  of  ambiguity.   The  area  (If  any)  resulting
from  Intersection  of the adverse effects and no adverse  effects  boundaries
Is defined  as the region of contradiction.
    In  the  censored  data  method,  all  no adverse effect points located In the
region  of  contradiction are dropped  from consideration, and  the  no  adverse
effect  boundary Is redrawn  so  that  1t  does  not  Intersect the adverse effects
boundary and  no region of  contradiction  Is generated.  This  method  results
In the most conservative definition of the no adverse effects region.
    The  adverse effects boundary In Figure  D-l,  generated by  the  envelope
method,  Is defined  by  LOAEL   values  for  liver effects   1n  rats,  mice  or
monkeys  treated with  octabromoblphenyl  (Warltz et  al.,  1977, Rec.  #26),
Flremaster  FF-1 or  Flremaster   BP-6  (Klmbrough et   al.,   1978,  Rec.   #31;
Corbett et  al., 1978,  Rec.  #32;  Render et  al.,  1982,  Rec.  #33;  Lambrecht et
al.,  1978,  Rec. #15),  and  by  Increased  adrenal weights  In rats  (Byrne et
al.,  1988,  Rec.  #18).   The  latter  data point,  although lower  than  that  for
liver  effects  In  rats  upon  which the  oral  RfO values  are  based (NTP,  1983,
Rec. #1),  Is not considered  for  risk  assessment  because the adversity of the
effect  In  the  absence  of hlstopathologlcal  lesions  Is  unclear.   Several  no
0176d
-105-
09/29/89

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adverse effect  points  He  on  or above  the  adverse effects boundary  1n  the

region  of  contradiction.   These  Include  studies  with  octabromoblphenyl

(NorMs et  al.,  1975,  Recs. #21, 27;  Lee  et al.,  1975, Rec. #23)  and deca-

bromoblphenyl (Hllllscher  et  al., 1979, Recs.  #25,  28), which  suggest  that

these  Isoraers are not as  hepatotoxlc as  the  Flremaster  mixtures.   Figure  D-2

presents  the graph  generated  by  the censored data method so that  the  region

of contradiction Is eliminated.

D.2.  DATA USED TO GENERATE DOSE/DURATION-RESPONSE  GRAPHS

Oral Exposure
Chemical Name:
CAS Number:
Document Title:

Document Number:
Document Date:
Document Type:
Polybromlnated Blphenyls
NA
Health and Environmental Effects  Document  for
Polybromlnated Blphenyls
pending
pending
HEED
RECORD #1:








Species: Rats
Sex: Both
Effect: LOAEL
Route: Gavage
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:




102
NR
DEGEN
LIVER
5
Dose:
Duration Exposure:
Duration Observation:

102
NR
WGTIN
SPLEN
4
0.070
175.0 days
865.0 days






Comment:       0.1 mg/kg, 5 days/week (range:  0.1,  0.3,  1,  3,  10 mg/kg).
               Increased liver weight and mild hlstopathologlcal lesions  In
               females; Increased spleen weight 1n  both  sexes.
               Flremaster FF-1.

Citation:      NTP. 1983; Gupta et al.,  1983a,b
0176d
                  -106-
09/29/89

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RECORD 12:








Comment:
Citation:
RECORD #3:








Species: Rats
Sex: Hale
Effect: PEL
Route: Gavage
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:




51
NR
DEGEN
LIVER
5
Dose:
Duration
Duration

51
NR
WGTIN
SPLEN
4
0.200
Exposure: 175.0
Observation: 865.0

51 51
NR NR
DEGEN DEATH
KIDNY BODY
6 10

days
days






0.3 mg/kg, see previous record.
NTP, 1983; Gupta et
Species: Mice
Sex: Female
Effect: LOAEL
Route: Gavage
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
al..




50
NR
WGTIN
LIVER
4
1983a,b
Dose:
Duration
Duration







0.200
Exposure: 175.0
Observation: 895.0








days
days






Comment:       0.3 mg/kg; same protocol as rats (see Record #1);  elevated
               liver weight In males at 0.7 rag/kg/day; liver lesions In both
               sexes at 0.7 mg/kg/day.

Citation:      NTP, 1983; Gupta et al.. 1983a,b
RECORD #4:



Species:
Sex:
Effect:
Route:
Mice
Male
PEL
Gavage
Dose:
Duration
Duration


Exposure:
Observation:

7.000
175.0 days
895.0 days

Comment:

Citation:
Number Exposed:     50
Number Responses:   NR
Type of Effect:     DEATH
Site of Effect:     BODY
Severity Effect:    10

10 mg/kg (see previous record).

NTP, 1983; Gupta et al.. 1983a,b
0176d
                     -107-
09/29/89

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RECORD #5:
Comment:

Citation:
Species:
Sex:
Effect:
Route:
Mice
Female
NOEL
Gavage
Dose:
Duration Exposure:
Duration Observation:
0.070
175.0 days
895.0 days
Number Exposed:     48
Number Responses:   NR
Type of Effect:     DEGEN
Site of Effect:     LIVER
Severity Effect:    6

0.1 mg/kg {see previous record).

NTP, 1983; Gupta et al., 1983a,b
RECORD #6:



Species:
Sex:
Effect:
Route:
Rats
Both
LOAEL
Gavage
Dose:
Duration
Duration


Exposure:
Observation:

2.000
30.0 days
120.0 days

Comment:
Citation:
Number Exposed:     48
Number Responses:   NR
Type of Effect:     DEGEN
Site of Effect:     LIVER
Severity Effect:    6

3 mg/kg, 5 days/week (range:  0.03,  0.3,  3,  30 mg/kg).
Increased liver weight and hepatocellular  necrosis  1n  males;
Flremaster FF-1.

Gupta et al., 1981
RECORD #7:
Comment :
Citation:
Species: Rats Dose:
Sex: Both Duration Exposure:
Effect: AEL Duration Observation:
Route: Gavage
Number Exposed: 48 48
Number Responses: NR NR
Type of Effect: DEGEN WGTDC
Site of Effect: LIVER BODY
Severity Effect: 6 4
30 mg/kg (see previous record).
Gupta et al., 1981
21.000
30.0 days
120.0 days
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                     -108-
                                           09/29/89

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RECORD #8:

Comment:
Citation:
RECORD #9:
Species: Rats
Sex: Both
Effect: NOEL
Route: Gavage
Number Exposed:
Number Responses:
Type of Effect:
SUe of Effect:
Severity Effect:

48
NR
DEGEN
LIVER
6
Dose:
Duration Exposure:
Duration Observation:
48
NR
WGTDC
BODY
4
0.200
30.0 days
120.0 days

0.3 mg/kg (see previous record).
Gupta et al., 1981
Species: Mice
Sex: Both
Effect: LOAEL
Route: Gavage



Dose:
Duration Exposure:
Duration Observation:

2.000
30.0 days
120.0 days
Comment:
Citation:
Number Exposed:     48
Number Responses:   NR
Type of Effect:     WGTJN
SUe of Effect:     LIVER
Severity Effect:    4

3 mg/kg (protocol Identical  to rats,  see  previous  record);
Increased liver weight.   Lesions  1n  liver  (both  sexes) at
21 mg/kg/day.

Gupta et al., 1981
RECORD #10:



Species:
Sex:
Effect:
Route:
Mice
Both
NOEL
Gavage
Dose:
Duration
Duration


Exposure:
Observation:

0.200
30.0 days
120.0 days

Comment:

Citation:
Number Exposed:      48
Number Responses:    NR
Type of Effect:      DEGEN
SUe of Effect:      LIVER
Severity Effect:     6

0.3 mg/kg (see previous  record).

Gupta et al.. 1981
0176d
                     -109-
09/29/89

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RECORD #11
Comment:
Species:
Sex:
Effect:
Route:
Rats
Male
LOAEL
Food
               Number Exposed:     6
               Number Responses:   NR
               Type of Effect:     OEGEN
               Site of Effect:     LIVER
               Severity Effect:    6
Dose:
Duration Exposure:
Duration Observation:
                             6
                             NR
                             OEGEN
                             THYRD
                             6
0.130
30.0 days
30.0 days
Citation:
1 ppm 1n diet (range 1, 10, 100 ppm), dosage estimated from
food consumption and bw data; mild liver and thyroid lesions.
Flremaster BP-6.  More pronounced lesions with 2,4,5,2',4',5'
HBB.

Akoso et al., 1982a,b
RECORD #12:



Species:
Sex:
Effect:
Route:
Rats
Male
LOAEL
Food
Dose:
Duration
Duration


Exposure:
Observation:

0.150
30.0 days
30.0 days

Comment:
Citation:
Number Exposed:     12
Number Responses:   NR
Type of Effect:     HGTIN
Site of Effect:     LIVER
Severity Effect:    4

1 ppm (range: 1, 10, 100, 500 ppm),  dosage estimated  from food
Intake and body weight data.   Test sample not  characterized;
others exposed for 60 days.

Sleight and Sanger, 1976
RECORD #13:



Species:
Sex:
Effect:
Route:
Rats
Male
AEL
Food
Dose:
Duration
Duration


Exposure:
Observation:

1.500
30.0 days
30.0 days

Comment:


Citation:
Number Exposed:     12
Number Responses:   NR
Type of Effect:     DEGEN
SHe of Effect:     LIVER
Severity Effect:    6

10 ppm (see previous record);  lesions  were more  severe  after
60 days of exposure.

Sleight and Sanger, 1976
0176d
                     -110-
                                          09/29/89

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RECORD #14:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Hale
LOAEL
Food
               Number Exposed:     12
               Number Responses:   NR
               Type of Effect:     WGTIN
               SHe of Effect:     LIVER
               Severity Effect:    4
Dose:
Duration Exposure:
Duration Observation:
                             12
                             NR
                             WGTIN
                             THYRD
                             4
0.500
30.0 days
30.0 days
10 ppm (range 1. 10, 100 ppm for 30 or 60 days),  dose
estimated from reference values; effects on thyroid weight
evident after 60 days; test sample not described.

Sleight et al.. 1978
RECORD #15:








Species: Monkeys
Sex: Female
Effect: LOAEL
Route: Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:




3
NR
DEGEN
LIVER
5
Dose: 0.050
Duration Exposure: 38.0 weeks
Duration Observation: 38.0 weeks






Comment:       1.5 ppm In diet, dosage calculated from food Intake and body
               weight data; enlarged hepatocytes with moderate fatty
               Infiltration, biochemical evidence of altered liver function,
               Flremaster FF-1.

Citation:      Lambrecht et al., 1978
RECORD #16:



Species:
Sex:
Effect:
Route:
Rats
Male
LOAEL
Food
Dose:
Duration
Duration


Exposure:
Observation:

0.250
5.0 weeks
5.0 weeks

Comment:
Citation:
Number Exposed:     9
Number Responses:    NR
Type of Effect:     DEGEN
Site of Effect:     THYRD
Severity Effect:    5

5 ppm (range 5, 50, 500 ppm), food factor 0.05;
ultrastructural changes; hlstopathologlcal changes
at 2.5 mg/kg/day;  Flremaster BP-6.

Kasza et al., 1978
0176d
                     -111-
                                           09/29/89

-------
RECORD #17:
Comment:


Citation:
Species:
Sex:
Effect:
Route:
Rats
Female
LOAEL
Food
Dose:
Duration Exposure:
Duration Observation:
0.250
5.0 months
5.0 months
Number Exposed:     10
Number Responses:   MR
Type of Effect:     FUNS
SHe of Effect:     THYRD
Severity Effect:    7

5 ppm (range 5, 10 ppm) food factor 0.05;  alterations  In
thyroid function but not on thyroid weight;  F1remaster  BP-6.

Byrne et al.. 1987
RECORD #18:



Species:
Sex:
Effect:
Route:
Rats
Female
LOAEL
Food
Dose:
Duration
Duration


Exposure:
Observation:

0.050
5.0 months
5.0 months

Comment:


Citation:
Number Exposed:     10
Number Responses:   NR
Type of Effect:     WGTIN
Site of Effect:     ADRNL
Severity Effect:    4

1 ppm (range 1, 5,  10, 50 ppm),  food factor  0.05;  also  altered
serum cortlcosterone; Flremaster 8P-6.

Byrne et al., 1988
RECORD #19: Species: Rats
Sex: Male
Effect: LOAEL
Route: Food
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:




NR
NR
DEGEN
KIONY
6
Dose:
Duration Exposure:
Duration Observation:

NR NR
NR NR
DEGEN HYPRP
LIVER THYRD
6 4
8.000
30.0 days
30.0 days






Comment:       0.01X (range 0.01, 0.1,  1.0%),dose reported by authors
               No statistical  analysis;  octa-BB.

Citation:      Norrls et al.,  1975
0176d
                     -112-
                                          09/29/89

-------
RECORD #20:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Both
LOAEL
Food
Dose:
Duration Exposure:
Duration Observation:
1.000
8.0 months
8.0 months
Number Exposed:     NR
Number Responses:   NR
Type of Effect:     HGTIN
SHe of Effect:     LIVER
Severity Effect:    4

Range 0.01, 0.1, 1.0 mg/kg/day through diet;  Increased
relative and absolute liver weight;  no mention of
hlstopathologlcal results, no statistical  analysis;  Octa-BB.

Norrls et al., 1975
RECORD #21:

Comment:
Citation:
RECORD #22:
Species: Rats
Sex: Both
Effect: NOEL
Route: Food
Number Exposed: NR
Number Responses: NR
Type of Effect: WGTIN
Site of Effect: LIVER
Severity Effect: 4
See previous record.
Norrls et al., 1975
Species: Rats
Sex: Male
Effect: LOAEL
Route: Food
Dose: 0.100
Duration Exposure: 8.0 months
Duration Observation: 8.0 months



Dose: 5.000
Duration Exposure: 14.0 days
Duration Observation: 28.0 days
Comment:
Citation:
Number Exposed:     40
Number Responses:   NR
Type of Effect:     HYPRP
Site of Effect:     LIVER
Severity Effect:    4

100 ppm (range 1, 10, 100, 1000 ppm) food factor  occurred In
dose and duration related manner (exposed for 2 or  4 weeks,
sacrificed at 4-22 weeks); octa-BB.

Lee et al., 1975; Warltz et al., 1977
0176d
                     -113-
                                           09/29/89

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RECORD #23:
Species
Sex:
Effect:
Route:
: Rats
Male
LOAEL
Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Comment:
Citation:
RECORD #24:
10 ppm
Lee et
Species
Sex:
Effect:
Route:
(see previous

40
NR
HYPRP
LIVER
4
record)
al.. 1975; WarHz et
: Rats
Both
LOAEL
Food

Dose:
Duration Exposure:
Duration Observation:

•
al., 1977
Dose:
Duration Exposure:
Duration Observation:
0.500
14.0 days
28.0 days



100
13.
13.



.000
0 weeks
0 weeks
Comment:
Citation:
Number Exposed:     35
Number Responses:   NR
Type of Effect:     DEBEN
Site of Effect:     LIVER
Severity Effect:    6

2000 ppm (range 1, 10, 100, 500, 2000 ppm), food factor 0.05;
Increased relative liver weight and lesions confined to liver;
deca-BB.

millscher et al., 1979
RECORD #25:



Species:
Sex:
Effect:
Route:
Rats
Both
NOEL
Food
Dose:
Duration
Duration


Exposure:
Observation:

25.000
13.0 weeks
13.0 weeks

Comment:

Citation:
Number Exposed:     35
Number Responses:   NR
Type of Effect:     DEGEN
Site of Effect:     LIVER
Severity Effect:    6

500 ppm (see previous record)

millscher et al., 1979
0176d
                     -114-
09/29/89

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RECORD #26:
Comment:

Citation:
Comment:

Citation:
Comment:

Citation:
Species:
Sex:
Effect:
Route:
Rats
NR
LOAEL
Gavage
Dose:                   3400.000
Duration Exposure:      1.0 days
Duration Observation:   7.0 days
Number Exposed:     NR
Number Responses:   NR
Type of Effect:     WGTIN
Site of Effect:     LIVER
Severity Effect:    4

No clinical or gross pathological  effects;  octa-88.

WarUz et al., 1977
RECORD #27:



Species:
Sex:
Effect:
Route:
Rats
NR
NOEL
Gavage
Dose:
Duration
Duration


Exposure:
Observation:

2000.000
1.0 days
14.0 days

Number Exposed:     NR
Number Responses:   NR
Type of Effect:     PATHO
Site of Effect:     LIVER
Severity Effect:    6

No lethality or gross pathological  effects;  octa-BB.

Norrls et al., 1975
RECORD #28:



Species:
Sex:
Effect:
Route:
Rats
NR
NOEL
Gavage
Dose:
Duration
Duration


Exposure:
Observation:

5000.000
1.0 days
14.0 days

Number Exposed:     10
Number Responses:   NR
Type of Effect:     DEATH
Site of Effect:     BODY
Severity Effect:    10

No lethality or gross pathological  effects;  deca-BB.

millscher et al., 1979
0176d
                     -115-
                                           09/29/89

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RECORD #29:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Male
FEL
Oral (NOS)
Dose:                  65.000
Duration Exposure:     30.0 days
Duration Observation:  30.0 days
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
                                   NR
                                   NR
                                   DEATH
                                   BODY
                                   10
Oral LDso for 4.5 weeks of treatment (5 days/week) and 90
days of observation; LDsg was 200 mg/ kg/day when observation
was reduced to 30 days; Flremaster FF-1.

Gupta and Moore, 1979
RECORD #30:
Species: Rats

Sex: Female







Effect: FEL
Route: Oral
Number Exposed:
Number Responses
Type of Effect:
SHe of Effect:
Severity Effect:

(NOS}
NR
: NR
DEATH
BODY
10
Dose: 149.000
Duration Exposure: 30.0 days
Duration Observation: 30.0 days






Comment:       Oral 1059 treated 4.5 weeks on 5 days/week observation; 1059
               was 200 mg/kg/day with 30 day observation; Flremaster FF-1.

Citation:      Gupta and Moore, 1979
RECORD #31 :



Species:
Sex:
Effect:
Route:
Rats
Both
LOAEL
Gavage
Dose:
Duration
Duration


Exposure:
Observation:

1000.000
1.0 days
60.0 days

Comment:
Citation:
Number Exposed:     160
Number Responses:   NR
Type of Effect:     DEGEN
Site of Effect:     LIVER
Severity Effect:    6

Single dose, sacrifice after 2, 6, 10 or 14 months;  severity
of lesions Increased with Increasing postexposure time;
Flremaster FF-1.

Klmbrough et al., 1978
0176d
                     -116-
                                           09/29/89

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RECORD #32:
Comment:


Citation:
Species:
Sex:
Effect:
Route:
Mice
Hale
LOAEL
Food
Dose:                  130.000
Duration Exposure:     4.0 days
Duration Observation:   14.0 days
Number Exposed:     3
Number Responses:   NR
Type of Effect:     WGTIN
Site of Effect:     LIVER
Severity Effect:    4

1000 ppm (food factor 0.13) fed for 4-14 days; biochemical and
hlstopathologlcal lesions reported at 8 days; Flremaster BP-6.

Corbett et al., 1978
RECORD #33:



Species:
Sex:
Effect:
Route:
Rats
Male
LOAEL
Food
Dose:
Duration
Duration


Exposure:
Observation:

0.300
9.0 days
9.0 days

               Number Exposed:     6
               Number Responses:   NR
               Type of Effect:     HYPRP
               SHe of Effect:     LIVER
               Severity Effect:    4

Comment:       1 ppm (range 0.1, 1. 10, 100 ppm), dose estimated from food
               Intake and body weight data; biochemical and hepatocellular
               changes; 3,4,5,3',4',5'-HBB.  Effects more severe than with
               2,4,5,2',4',5I-HBB, Flremaster BP6.

Citation:      Render et al.t 1982
RECORD #34:



Species:
Sex:
Effect:
Route:
Rats
Female
LOAEL
Food
Dose:
Duration
Duration


Exposure:
Observation:

2.500
14.0 days
14.0 days

Comment:
Citation:
Number Exposed:     6
Number Responses:   NR
Type of Effect:     WGTDC
Site of Effect:     FETUS
Severity Effect:    7

SO ppm (range 50, 100, 1000 ppm),  food factor  0.05 dose-
related decrease In fetal body weight, no visceral or  skeletal
effects; Flremaster BP-6 given during gestation.

Corbett et al., 1975
0176d
                     -117-
                                          09/29/89

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RECORD #35:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Mice
Female
LOAEL
Food
Dose:                  6.500
Duration Exposure:     12.0 days
Duration Observation:  14.0 days
Number Exposed:     9
Number Responses:   NR
Type of Effect:     WGTDC
Site of Effect:     FETUS
Severity Effect:    7

50 ppm (range 50, 100, 1000 ppm), food factor 0.13 dose-
related effect on fetal body weight, some maternal mortality
In unspecified groups; F1remaster BP-6 given during gestation.

Corbett et al.. 1975
RECORD #36:



Species:
Sex:
Effect:
Route:
Rats
Female
LOAEL
Food
Dose:
Duration
Duration


Exposure:
Observation:

2.500
12.0 days
27.0 days

Comment:


Citation:
Number Exposed:     NR
Number Responses:   NR
Type of Effect:     WGTIN
Site of Effect:     LIVER
Severity Effect:    4

50 ppm, food factor 0.05, Increased liver weight, HFQ
activities of offspring; Flremaster BP-6.

Dent et al., 1978
RECORD #37:



Species:
Sex:
Effect:
Route:
Rats
Female
LOAEL
Food
Dose:
Duration
Duration


Exposure:
Observation:

0.500
19.0 days
19.0 days

Comment:
Citation:
Number Exposed:     NR
Number Responses:   NR
Type of Effect:     WGTIN
SHe of Effect:     LIVER
Severity Effect:    4

10 ppm (range 0.1, 1.0, 10),  food factor  0.05;  Increased  liver
weight, mlcrosomal protein,  MFO activity  of offspring exposed
for first 19 days of nursing;  Flremaster  FF-1.

Moore et al., 1978
0176d
                     -118-
                                          09/29/89

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RECORD #38:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Nice
Female
LOAEL
Food
               Number Exposed:     6
               Number Responses:   NR
               Type of Effect:     REPRO
               SHe of Effect:     UTERS
               Severity Effect:    9
Dose:
Duration Exposure:
Duration Observation:
                             NR
                             NR
                             TERAO
                             FETUS
                             10
63.000
10.0 days
12.0 days
300 ppm (range 100, 300, 500,  750 ppm), dose estimated by
authors, reduced pregnancy success rate, reduced fetal body
weight, Increased malformations.   2,4,5,2',4',5'-HBB given
during gestation.

Melsch and Morgan, 1985
RECORD #39:



Species:
Sex:
Effect:
Route:
Rats
Female
LOAEL
Food
Dose:
Duration
Duration


Exposure:
Observation:

5.000
40.0 days
40.0 days

Comment:
Citation:
Number Exposed:     NR
Number Responses:   NR
Type of Effect:     REPRO
Site of Effect:     BODY
Severity Effect:    9

100 ppm (range 10, 100 ppm), food factor 0.05;  reduced
survival, delayed growth and development of offspring In
Fl pups; dams fed Flremaster BP-6 1n perinatal  period.

McCormack et al., 1981
NR = Not reported
0176d
                     -119-
                                           09/29/89

-------