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DRAFT: DO NOT CITE OR QUOTE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.
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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.
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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
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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
0176d -6- 04/24/89
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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.
0176d
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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
0176d -8- 06/07/89
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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).
0176d
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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.
0176d -11- 06/07/89
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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).
0176d
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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
0176d -14- 06/07/89
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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.
0176d -15- 04/24/89
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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).
0176d -17- 04/24/89
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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).
0176d -19- 04/24/89
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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
0176d
-20-
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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
0176d
-21-
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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.
0176d -24- 06/07/89
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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
0176d -25- 06/07/89
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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).
0176d -26- 06/07/89
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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
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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
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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
-------
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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09/29/89
-------
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
-------
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
-------
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
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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
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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
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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..
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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).
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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.
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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
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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
0176d
-63-
04/24/89
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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.
0176d -65- 09/29/89
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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.
0176d
-66-
09/29/89
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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
-67-
09/29/89
-------
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0176d
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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
-------
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
-------
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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0176d -86- 09/29/89
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Bromine tissue residue and hepatotoxlc effects of octabromoblphenyl In rats.
Toxlcol. Appl. Pharmacol. 34(1): 115-127.
Loose, L.D., S.P. Mudz1nsk1 and J.B. Sllkworth. 1981. Influence of dietary
polybromlnated blphenyl on antibody and host defense responses In mice.
Toxlcol. Appl. Pharmacol. 59(1): 25-39.
0176d -87- 09/29/89
-------
Luder, G.H., G.J. Davis and J.A. McLachlan. 1978. Transplacental
toxicology of the polychlorlnated and polybromlnated blphenyls. DOE Symp.
Ser. 47: 188-203.
Luster, N.I., R.E. Faith and J.A. Moore. 1978. Effects of polybromlnated
blphenyls on Immune response In rodents. Environ. Health Perspect. 23:
227-232.
Luster, M.I., 6.A. Boorman, M.W. Harris and J.A. Moore. 1980. Laboratory
studies on polybromlnated blphenyl-lnduced Immune alterations following low
level chronic or pre- and postnatal exposure. Int. J. Immunopharmacol.
2{1): 69-80.
Mantel, N. and M.A. Schnelderman. 1975. Estimating "safe" levels, a
hazardous undertaking. Cancer Res. 35: 1379-1386.
Matthews, H.6., S. Kato, N.M. Morales and D.B. Tuey. 1977. Distribution
and excretion of 2,4,5,2',4',5'-hexabromob1phenyl, the major component of
Flremaster 8P-6. J. Toxlcol. Environ. Health. 3(3): 599-605.
McCormack, K.M., L.F. Lepper, D.M. Wilson and J.B. Hook. 1981. Biochemical
and physiological sequelae to perinatal exposure to polybromlnated
blphenyls: Nultlgeneratlon study In rats. Toxlcol. Appl. Pharmacol. 59:
300-313.
McCormack, K.M., J.L. Stlckney, D.U. Bonhaus and J.B. Hook. 1982. Cardiac
and hepatic effects of pre- and postnatal exposure to polybromlnated
blphenyls 1n rats. J. Toxlcol. Environ. Health. 9: 13-26.
0176d -88- 09/29/89
-------
Michigan Chemical Corp. 1971. Flremaster BP-6. A new flame retardant
additive. (Cited 1n Fries, 1985)
M1111S, C.D., R.A. Mills, S.D. Sleight and S.D. Aust. 1985. Toxldty of
3,4,5,3',4',5'-hexabrom1nated blphenyl and 3,4,3',4'-tetrabrom1nated
blphenyl. Toxlcol. Appl. Pharmacol. 78: 88-95.
MUllscher, R., F. Glrault, R. Heywood, G. Clarke, D. Hossack and M. Clalr.
1979. Decabromoblphenyl: Tox1colog1cal study. Toxlcol. Eur. Res. 2(3):
155-161.
Moore, R.W., G.A. Dannan and S.D. Aust. 1978. Induction of drug metaboliz-
ing enzymes In polybromlnated blphenyl-fed lactatlng rats and their pups.
Environ. Health Perspect. 23(4): 159-165.
NorMs, J.M., R.J. Kodba, B.A. Schwetz, et al. 1975. Toxicology of
octabromoblphenyl and decabromodlphenyl oxide. Environ. Health Perspect.
11: 153-161.
NTP (National Toxicology Program). 1983. Carclnogenesls studies of poly-
bromlnated blphenyl mixture 1n F344/N rats and B6C3F1 mice (gavage studies).
Flremaster FF-1. Cas No. 67774-32-7. NTP, Research Triangle Park, NC.
110 p.
Render, J.A., S.D. Aust and S.D. Sleight. 1982. Acute pathologic effects
of 3,3',4,4',5,5'-hexabroiDOb1phenyl In rats: Comparison of Us effects with
Flremaster BP-6 and 2,2',4,4',5,5'-hexabromob1phenyl. Toxlcol. Appl.
Pharmacol. 62(3): 428-444.
0176d
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09/29/89
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Robertson, L.H., B. Chlttlm, S.H. Safe, M.D. MulUn and C.N. Poch1n1. 1983.
Photodecompos1t1on of a commercial polybromlnated blphenyl fire retardant:
High-resolution gas chromatographlc analysis. J. Agrlc. Food Chem. 31:
454-457.
Rozman, K.K., T.A. Rozman, J. Williams and H.A. Grelm. 1982. Effect of
mineral oil and/or cholestryamlne In the diet on biliary and Intestinal
elimination of 2,2',4,4',5,5'-hexabromob1phenyl In the rhesus monkey. J.
Toxlcol. Environ. Health. 9: 611-618.
Ruzo, L.O., G. Sundstrom, 0. Hutzlnger and S. Safe. 1976. 4. Photodegrada-
tlon of polybromoblphenyls (PBB). J. Agrlc. Food Chem. 24(5): 1062-1065.
SablJU, A. 1987. The prediction of fish bloconcentratlon factors of
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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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
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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
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09/29/89
-------
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
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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
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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
0176d
-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
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-109-
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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
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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
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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
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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-
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