United States
kS^laMIjk Environmental Protection
^J^iniiil m11 Agency
EPA/690/R-11/011F
Final
4-04-2011
Provisional Peer-Reviewed Toxicity Values for
1,1-Biphenyl
(CASRN 92-52-4)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Chris Cubbison, PhD (Mentor)
Custodio V. Muianga, PhD, MPH (Student Services Contractor)
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
ICF International
9300 Lee Highway
Fairfax, VA 22031
PRIMARY INTERNAL REVIEWERS
Paul G. Reinhart, PhD, DABT
National Center for Environmental Assessment, Research Triangle Park, NC
Q. Jay Zhao, PhD, MPH, DABT
National Center for Environmental Assessment, Cincinnati, OH
This document was externally peer reviewed under contract to
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this document may be directed to the U.S. EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center (513-569-7300).
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS iii
BACKGROUND 1
HISTORY 1
DISCLAIMERS 1
QUESTIONS REGARDING PPRTVS 2
INTRODUCTION 2
REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER) 4
HUMAN STUDIES 10
Oral Exposures 10
Inhalation Exposures 10
Other Exposures 10
ANIMAL STUDIES 11
Oral Exposures 11
Sub chronic-duration Studies 11
Chronic-duration Studies 13
Developmental and Reproductive Studies 17
Inhalation Exposures 19
Sub chronic-duration Studies 19
Chronic-duration Studies 21
Developmental and Reproductive Studies 21
Other Exposures 22
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 22
DERIVATION 01 PROVISIONAL VALUES 25
DERIVATION OF ORAL REFERENCE DOSES 26
Derivation of Subchronic p-RfD 26
Derivation of Chronic p-RfD 31
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 31
Derivation of Subchronic p-RfC and Chronic p-RfC 32
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR 32
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES 33
Derivation of p-OSF 33
Derivation of p-IUR 33
APPENDIX A. PROVISIONAL SCREENING VALUES 34
APPENDIX B. DATA TABLES 44
APPENDIX C. BMD MODELING OUTPUTS FOR 1,1-BIPHENYL 54
APPENDIX D. REFERENCES 84
li
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COMMONLY USED ABBREVIATIONS
BMC
benchmark concentration
BMD
benchmark dose
BMCL
benchmark concentration lower bound 95% confidence interval
BMDL
benchmark dose lower bound 95% confidence interval
HEC
human equivalent concentration
HED
human equivalent dose
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional reference concentration (inhalation)
p-RfD
provisional reference dose (oral)
POD
point of departure
RfC
reference concentration (inhalation)
RfD
reference dose (oral)
UF
uncertainty factor
UFa
animal-to-human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete-to-complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL-to-NOAEL uncertainty factor
UFS
subchronic-to-chronic uncertainty factor
WOE
weight of evidence
111
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
1,1 -BIPHENYL (CASRN 92-52-4)
BACKGROUND
HISTORY
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1) EPA's Integrated Risk Information System (IRIS)
2) Provisional Peer-Reviewed Toxicity Values (PPRTVs) used in EPA's Superfund
Program
3) Other (peer-reviewed) toxicity values, including
~ Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR);
~ California Environmental Protection Agency (CalEPA) values; and
~ EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's IRIS. PPRTVs are developed according to a Standard
Operating Procedure (SOP) and are derived after a review of the relevant scientific literature
using the same methods, sources of data, and Agency guidance for value derivation generally
used by the EPA IRIS Program. All provisional toxicity values receive internal review by a
panel of six EPA scientists and external peer review by three independently selected scientific
experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the multiprogram
consensus review provided for IRIS values. This is because IRIS values are generally intended
to be used in all EPA programs, while PPRTVs are developed specifically for the Superfund
Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a 5-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV documents conclude that
a PPRTV cannot be derived based on inadequate data.
DISCLAIMERS
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and Resource Conservation and Recovery Act (RCRA) program offices are advised to
carefully review the information provided in this document to ensure that the PPRTVs used are
appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility
in question. PPRTVs are periodically updated; therefore, users should ensure that the values
contained in the PPRTV are current at the time of use.
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It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV document and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
QUESTIONS REGARDING PPRTVS
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
1,1-biphenyl, sometimes called diphenyl or phenyl benzene, is found in varying
concentrations in coal tar, crude oil, and natural gas, and was historically used in the production
of polychlorinated 1,1-biphenyls (PCBs) (Boehncke et al., 1999). The empirical formula for
1,1-biphenyl is C12H10 (see Figure 1). A table of physicochemical properties is provided below
(see Table 1). In this document, unless otherwise noted, "statistically significant" denotes a
p-value of <0.05.
Figure 1. 1,1-Biphenyl Structure
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1,1-Biphenyl
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Table 1. Physicochemical Properties Table (l,l-Biphenyl)a
(CASRN 92-52-4)
Property (unit)
Value
Boiling point (°C)
256
Melting point (°C)
70
Density (g/cm3)
0.992
Vapor pressure (torr or mm Hg at 25°C)
0.998
pH (unitless)
Not available
Solubility in water (g/100 mL at 25°C)
Low soluble (4.4)
Relative vapor density (air =1)
5.3
Molecular weight (g/mol)
154.2
Flash point (°C)
113
Octanol/water partition coefficient (unitless)
3.16/4.09
Conversion factor (ppm to mg/m3)
1 ppm = 6.31 mg/m3
"IPCS and CEC (1994).
IRIS (U.S. EPA, 2010a) lists a chronic oral reference dose (RfD) of 5 x 10 2 mg/kg-day,
but data were inadequate to derive a chronic inhalation reference concentration (RfC). The
carcinogenic potential of 1,1-biphenyl is listed as Group D, Not Classifiable as to Human
Carcinogenicity. No Drinking Water Standards and Health Advisories List values are reported
(U.S. EPA, 2006). A subchronic RfD value of 5 x 10~2 mg/kg-day is included in the HEAST
document (U.S. EPA, 2010b). CARA (U.S. EPA, 1994a) has provided a Health and
Environmental Effects Profile (HEEP) for 1,1-biphenyl (U.S. EPA, 1984) that includes a derived
Acceptable Daily Intake (ADI) for oral exposure of 0.05 mg/kg-day. The American Conference
of Governmental Industrial Hygienists (ACGIH, 2009) has derived a Threshold Limit Value
(TLV) (8-hour time weighted average [TWA]) of 0.2 ppm (1 mg/m3). The National Institute of
Occupational Safety and Health (NIOSH, 2003) has derived a Recommended Exposure Limit
"3
(REL) (10-hour TWA) of 1 mg/m (0.2 ppm) as well as an Immediately Dangerous to Life or
Health Value of 100 mg/m3. A Permissible Exposure Limit (PEL) (8-hour TWA) of 0.2 ppm
"3
(1 mg/m ) has been derived by the Occupational Safety and Health Administration
(Violintzis et al., 2009). The World Health Organization (Boehncke et al., 1999) reported a
provisional Tolerable Daily Intake (TDI) of 38 |ig/kg-day and has published a toxicological
review of 1,1-biphenyl (Boehncke et al., 1999). The International Agency for Research on
Cancer (IARC, 2000) has not reviewed the carcinogenic potential of 1,1-biphenyl, and the
compound is not included in the 11th Report on Carcinogens (NTP, 2005).
Literature searches were conducted on sources published from 1900 through
December 7, 2010, for studies relevant to the derivation of provisional toxicity values for
1,1-biphenyl, CAS No. 92-52-4. Searches were conducted using EPA's Health and
Environmental Research Online (HERO) evergreen database of scientific literature. HERO
searches the following databases: AGRICOLA; American Chemical Society; BioOne; Cochrane
Library; DOE: Energy Information Administration, Information Bridge, and Energy Citations
Database; EBSCO: Academic Search Complete; GeoRef Preview; GPO: Government Printing
Office; Informaworld; IngentaConnect; J-STAGE: Japan Science & Technology; JSTOR:
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1,1-Biphenyl
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Mathematics & Statistics and Life Sciences; NSCEP/NEPIS (EPA publications available through
the National Service Center for Environmental Publications [NSCEP] and National
Environmental Publications Internet Site [NEPIS] database); PubMed: MEDLINE and
CANCERLIT databases; SAGE; Science Direct; Scirus; Scitopia; SpringerLink; TOXNET
(Toxicology Data Network): ANEUPL, CCRIS, ChemlDplus, CIS, CRISP, DART, EMIC,
EPIDEM, ETICBACK, FEDRIP, GENE-TOX, HAPAB, HEEP, HMTC, HSDB, IRIS, ITER,
LactMed, Multi-Database Search, NIOSH, NTIS, PESTAB, PPBIB, RISKLINE, TRI, and
TSCATS; Virtual Health Library; Web of Science (searches Current Content database among
others); World Health Organization; and Worldwide Science. The following databases outside
of HERO were searched for risk assessment values: ACGIH, ATSDR, CalEPA, EPA IRIS, EPA
HEAST, EPA HEEP, EPA OW, EPA TSCATS/TSCATS2, NIOSH, NTP, OSHA, and RTECS.
REVIEW OF POTENTIALLY RELEVANT DATA
(CANCER AND NONCANCER)
Table 2 provides information for all of the potentially relevant toxicity studies. Entries
for the principal studies are bolded and identified by the marking "PS".
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Table 2. Summary of Potentially Relevant Data for 1,1-Biphenyl (CASRN 92-52-4)
Notes3
Category
Number of
Male/Female, Species,
Study Type, Exposure
Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELbc
Reference (Comments)
Human
1. Oral (mg/kg-day)
None
2. Inhalation (mg/m3)
Subchronic
None
Chronic
None
Developmental
None
Reproductive
None
Carcinogenic
None
PR
Occupational
32/1, human,
occupational, duration
varies between 5 and
16 y
0.6-128 mg/m3
Liver damage, central and peripheral
nervous system effects, increased
transaminase levels
None
Not run
None
Hakkinen et al. (1973)
PR
0/1, human,
occupational, 25 y
Not reported
Increased transaminase levels, enlarged
liver
None
Not run
None
Carella and Bettolo
(1994)
Animal
1. Oral (mg/kg-day)
PR
Subchronic
10/0, F344 rat, diet,
7 d/wk, 8 wks
0, 500
Induced microcalculi
None
Not run
5.00 x 102
Shibata et al. (1989)
PR
10/10, Cij:BDFl
mouse, diet, 7 d/wk,
13 wks
Male: 0, 94.6,
378, 1456,
1805, and 2737
Female: 0, 101,
404, 809, 1556,
1929, 2924
Occurrence of peroxisome
proliferation, decrease in body weight,
increased liver weights in female mice
1.929 x
103
Not run
2.924 x 103
Umeda et al. (2004)
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Table 2. Summary of Potentially Relevant Data for 1,1-Biphenyl (CASRN 92-52-4)
Notes3
Category
Number of
Male/Female, Species,
Study Type, Exposure
Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELbc
Reference (Comments)
PR
20/0, B6C3F, mouse,
diet, 7 d/wk, 32 wks
0, 1803.8
Increased incidences of interstitial
nephritis
1.8038 x
103
Not run
None
Tamano et al. (1993)
IRIS
PR
Chronic
15/15, albino rat, diet,
7 d/wk, 700 d
Male: 0, 0.723,
3.62, 7.23,
36.2, 72.3, 362,
723
Female: 0.820,
4.10, 8.20,
41.0, 82.0,410,
820
Increase in kidney damage, reduced
hemoglobin levels, decreased food
intake, decreased longevity (animals
cohoused, no measurement of
individual food intake)
7.23 x 10
Not run
3.62 x 102
Ambrose et al. (I960);
SRI, (1953)
PR
50/50, F344 rat, diet,
7 d/wk, 105 wks
Male: 0, 39.5,
118,355
Female: 0,
45.9, 138,413
Calculi in the kidney, dose-dependent
lesions found in urinary system
None
Not run
3.95x 10
Umeda et al. (2002)
PR
50/50, Wistar rat, diet,
7 d/wk, 75 wks or
104 wks
0, 188, 375
0, 47, 94
75 wks: haematuria, reduction in
weight gain, change in serum activities,
increased incidence of calculi, increase
in relative kidney weights
104 wks: reduction in weight gain,
change in serum activities
None
Not run
4.7 x 10
Takita (1983)
(published in Japanese
with only an abstract,
tables and graphics in
English were unavailable
for review at this time)
PR
50/50, Cij:BDF mouse,
diet, 7 d/wk, 104 wks
Male: 0, 97,
291, 1050
Female: 0, 134,
414, 1420
Mineralization in the inner stripe of the
outer medulla of the kidneys in female
mice, desquamation in the pelvis in
male mice, basophilic cell foci in the
liver in female mice
None
Not run
9.7 x 10
Umeda et al. (2005)
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Table 2. Summary of Potentially Relevant Data for 1,1-Biphenyl (CASRN 92-52-4)
Notes3
Category
Number of
Male/Female, Species,
Study Type, Exposure
Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELbc
Reference (Comments)
PR
PS
Developmental
0/18-20, Wistar rat,
7 d/wk, GDs 6-15
Female: 0,
125,250,500,
1000
Significantly increased number of
fetuses with skeletal anomalies,
increased fetotoxicity, decreased
number of live fetuses, increased
mortality, reduced fetal weight,
increased dead resorbed fetus (not
statistically significant).
250
9.59
500
develop-
mental
effects)
Khera et al. (1979)
PR
Reproductive
5/10, albino rat, diet,
7 d/wk, 60 d (control
and low-dose)
8-9/3-4, rat, diet,
7 d/wk, 60 d
(high-dose)
Male: 0, 72.3,
362
Female: 82.0,
410
No difference in reproductive success
(litters born), number of rats per litter,
or range of litter size
4.10 x
102
Not run
None
Ambrose et al. (1960)
NPR
3/9, long Evans rat,
diet, 7 d/wk, 3-gen
reprod
Male: 9, 89,
887
Female: 10,
101, 1006
No evidence of a cumulative effect over
the three generations. Decreased
fertility, smaller litter size, and reduced
rate of growth in the 1.0% biphenyl-fed
group may have been associated with
unpalatability and resultant decreased
food intake.
8.87 xlO2
Not run
None
Dow Chemical Co.
(1953)
PR
Carcinogenic
50/50, F344 rat, diet,
7 d/wk, 105 wks
Male HED: 0,
10.7, 32.1, 96.4
Female HED:
0, 11.0, 32.9,
98.7
An increased incidence of bladder
tumors, hematuria, and neoplastic
regenerative lesions of the urinary
system
3.21 x 10
Not run
9.64 x 10
Umeda et al. (2002)
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Table 2. Summary of Potentially Relevant Data for 1,1-Biphenyl (CASRN 92-52-4)
Notes3
Category
Number of
Male/Female, Species,
Study Type, Exposure
Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELbc
Reference (Comments)
PS
50/50, Crj:BDF
mouse, diet, 7 d/wk,
104 wks
Male HED: 0,
15.3, 45.8,
154.0
Female HED:
0,19.7, 59.8,
196.2
Increased incidence of hepatocellular
adenoma and carcinoma
1.97 x 10
12.6
5.98 x 10
Umeda et al. (2005)
2. Inhalation (mg/m3)
PS
NPR
Subchronic
50/50, CD1 mouse,
inhalation, 7 hr/d,
5 d/wk, 13 wks
Respiratory
HEC: 0, 72.9,
146.4 for
females; 0,
92.6,189.9 for
male.
Extra-
respiratory
HEC: 32.8,
65.5 for both
sexes.
Congestion and edema in the liver
and kidneys and lungs, inflammation
in trachea, pneumonia in lungs.
None
1.65 for
respiratory
1.2 for
extra-
respiratory
7.29 x 10
for
respiratory
effects and
3.28 x 10
for extra-
respiratory
effects
Cannon Laboratories,
Inc (1977) (46 mice died
after one night of
overheating and
cannibalism)
NPR
10 (sex not reported),
Sprague-Dawley albino
rat, inhalation, 7 hr/d,
5 d/wk, 64 d out of
94 d
HEC: 0, 0.0596
Irritation of the nasal mucosa, death,
weight loss
None
Not run
5.96 x 1(T2
Monsanto Chemical Co.
(1983)
NPR
6 (sex not reported),
Sprague-Dawley albino
rat, inhalation, 7 hr/d,
5 d/wk, 46 d out of
68 d
HEC: 0,
0.00789
Irritation of the nasal mucosa
None
Not run
7.89 x 1(T3
Monsanto Chemical Co.
(1983)
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Table 2. Summary of Potentially Relevant Data for 1,1-Biphenyl (CASRN 92-52-4)
Notes3
Category
Number of
Male/Female, Species,
Study Type, Exposure
Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELbc
Reference (Comments)
NPR
4 (sex not reported),
Sprague-Dawley albino
rat, inhalation, 7 hr/d,
5 d/wk, 62 d out of
92 d
HEC: 0,
0.000934
No reported effects
None
Not run
9.34 x 10~4
Monsanto Chemical Co.
(1983)
NPR
12 (sex and strain not
reported), mouse,
inhalation, 7 hr/d,
5 d/wk, 62 d out of
92 d
HEC: 0,
0.000934
Irritation of the upper respiratory tract
None
Not run
9.34 x 10~4
Monsanto Chemical Co.
(1983)
PR
50/50 CD1 mouse,
aerosol inhalation
study, 7 hr/d, 5 d/wk,
13 wks
0, 32.8, 65.5
Hyperemia and focal hemorrhage in the
lungs
Increase in hyperplasia of the tracheal
epithelium
None
Not run
None
Sun Co. Inc. (1977) as
cited in Boehncke et al.
(1999)
PR
Rabbits
Rats
Mice exposed to 50%
1,1-biphenyl dust on
zeolite, 7 hr/d, 5 d/wk,
13 wks
0, 1.04, 8.33,
62.5
No effects observed in rabbits
Irritation of the mucous membranes and
increased mortality in rats
All mice exhibited irritation of the
upper respiratory tract and
inflammatory bronchopulmonary
changes at 1.04 (the only tested
concentration)
None
1.04 for
rats
None
Not run
None
None
None
Deichmann et al. (1947)
as cited in Boehncke et
al. (1999)
Chronic
None
aNotes: IRIS = Utilized by IRIS, date of last update; PS = Principal study, PR = Peer Reviewed; NPR = Not peer reviewed; HEC = human equivalent concentration.
bDosimetry, NOAEL, BMDL/BMCL, and LOAEL values are converted to human equivalent dose (HED in mg/kg-day), human equivalent concentration (HEC in mg/m3),
or average daily dose (ADD or Doscadj in mg/kg-day) units. Noncancer oral data are only adjusted for continuous exposure.
°Not reported by the study author but determined from data.
BMDL/BMCL = benchmark dose lower bound 95% confidence interval/benchmark concentration lower bound 95% confidence interval, LOAEL = lowest-observed-
adverse-effect level, and NOAEL = no-observed-adverse-effect level.
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HUMAN STUDIES
Oral Exposures
No studies investigating the effects of subchronic- or chronic-duration oral exposure to
1,1-biphenyl in humans have been identified.
Inhalation Exposures
Hakkinen et al. (1973) conducted an occupational study of 33 workers (32 men and
1 woman) exposed to 1,1-biphenyl in a citrus packaging plant. The work employment varied
between 5 and 16 years. Of the 33 workers, 6 were "oil men," or worked in the mixing room, or
"oil room," where 1,1-biphenyl concentrations were found to be higher than in other areas of the
plant. Thirteen men worked on the paper machine, seven men worked at the rolling machine,
four men handled the residue mass, one man was a maintenance worker, and the remaining man
was a stock keeper. The one woman worked as a paper cutter. Air concentrations in the paper
"3
machine hall of the plant ranged from 4.4 to 128 mg/m prior to the installation of a "simple
exhaust hood," and from 0.6 to 64 mg/m3 after the installation of the exhaust hood.
Concentrations in the oil room were not measured prior to the exhaust hood being installed; they
ranged from 3.5 to 123 mg/m3 after the exhaust hood was installed. No control group was used
for this study.
Hakkinen et al. (1973) reported that common complaints of those exposed were
headache, gastrointestinal symptoms, polyneuritic symptoms, and fatigue. Ten of the subjects
showed elevated transaminase levels. Eight men were admitted to the hospital during the course
of the study for further testing based on the results of anamnestic data, clinical findings, or
pathological lab tests performed on all subjects. The exposure duration ranged from 5 to
16 years for the eight men admitted for further testing. Hospital patients and 14 additional men
were given neurophysiological exams. Out of the 22 men examined, 19 had abnormal
pathologies, and 4 had ambiguous pathological findings. Of the remaining 15 men, 3 had
abnormal electroencephalograms (EEGs), 5 had abnormal electromyogram (ENMGs), and 7 had
both an abnormal EEG and ENMG. The study authors concluded that 1,1-biphenyl exerts a
toxic effect on both the brain and peripheral nervous system. A liver biopsy, performed on the
eight hospitalized patients, showed liver damage in five patients and three with hepatic cellular
changes. Based on these findings, the authors concluded that 1,1-biphenyl exerts a toxic effect
on the liver. Confounding factors such as smoking and alcohol use were not accounted for, but
all workers had stable employment for many years and were not known to abuse alcohol.
Because Hakkinen et al. (1973) did not report quantitative dose-response data, no NOAEL or
NOAEL has been established and cannot be used as a principal study.
Other Exposures
An additional study analyzing the occupational risks associated with 1,1-biphenyl is
presented as follows. Carella and Bettolo (1994) described the case study of a 46-year-old
female patient with chronic-duration exposure, presumed to be from oral and dermal contact with
1,1-biphenyl in a citrus packaging plant. The patient worked for 25 years with
1,1-biphenyl-impregnated paper and claimed to have to "put her finger in her mouth" to facilitate
the packaging process. She was admitted to the hospital with twice the normal level of serum
glutamic oxaloacetic transaminase/serum glutamic pyruvic transaminase (SGOT/SGPT;
62/90 mU/ml), alkaline phosphatase (ALP; 320 mU/ml), and gamma-glutamyl transferase (GGT;
970 IU/L). Doctors confirmed a moderately enlarged liver by ultrasound. The patient previously
reported episodes of asthenia, marked by transaminase levels at two to three times normal. A
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gradual reduction in asthenia occurred within 3 years of the patient stopping work in the citrus
plant, which was accompanied by the reduction to normal of the transaminase, ALP, and GGT
levels. The patient claimed to have never abused alcohol and was not a smoker.
While both the inhalation exposure and case study provide important data that together
support the possibility of chronic effects of 1,1-biphenyl, they are limited by the small sample
size analyzed, as well as the scope of the outcomes and analysis available. Furthermore, little
information is known regarding the measurement and estimation of dose throughout the exposure
period. These studies do not support the derivation of a provisional toxicity value.
ANIMAL STUDIES
Oral Exposures
The effects of oral exposure of animals to 1,1-biphenyl have been evaluated in
subchronic-duration (Tamano et al., 1993; Shibata et al., 1989; Umeda et al., 2004),
chronic-duration (Ambrose et al., 1960; Takita, 1983; Umeda et al., 2002, 2005), and
reproductive (Ambrose et al., 1960) and developmental (Khera et al., 1979) toxicity studies.
Subchronic-duration Studies
Shibata et al. (1989) conducted a peer-reviewed, subchronic-duration study of 12 bladder
tumor promoters, including 1,1-biphenyl, on F344 male rats of 5 weeks of age at the
commencement of the study. The study authors administered 0.5% 1,1-biphenyl (purity not
specified) in a powdered basal diet to 10 males per dose, 7 days a week, for 8 weeks. The
corresponding adjusted daily dose (DoseADj) is 500 mg/kg-day. Simultaneous controls of
10 male mice were fed an untreated powdered basal diet. Animals were observed daily, and
body weight and food and water consumption were measured weekly. Four weeks into the
study, five rats were sacrificed for histopathologic examination by light microscopy and
estimation of deoxyribonucleic acid (DNA) synthesis levels. At the conclusion of the 8-week
study, morphological investigation was conducted by light microscopy and scanning electron
microscopy in the urinary bladder. No other organs were tested (Shibata et al., 1989).
The study authors reported a significant decrease in body weights compared to the
control group at both 4 and 8 weeks. Microcalculi and increased bromodeoxyuridine (BrdU)1
staining were observed in rats administered 1,1-biphenyl at 4 weeks. At 8 weeks, moderate
incidence of simple hyperplasia, pleomorphic microvilli, and short uniform microvilli, and
severe incidence of ropy microridges were identified. Table B. 1 (see Appendix B) presents the
increased incidence of simple hyperplasia and microcalculi formation in exposed animals. Due
to the microcalculi incidence and BrdU incorporation observed in the exposed animals, a
LOAEL adjusted to continuous exposure duration (LOAELadj) of 5.00 x 102 mg/kg-day was
established, but a no-observed-adverse-effect level (NOAEL) could not be determined. This
study will not be used to support the development of a p-RfD because a NOAEL could not be
identified, and while the lowest-observed-adverse-effect level (LOAEL) from this study is lower
than the LOAEL from the Umeda et al. (2004) study, the protocol used by Shibata et al. (1989),
consisting of fewer animals for a shorter time period and with only one dose-level administered,
increases the uncertainty of the results of the study.
bromodeoxyuridine (BrdU) test is used in the detection of proliferating cells in living tissues.
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Umeda et al. (2004) conducted a 13-week subchronic-duration toxicity study using
10 male and 10 female Cij :BDF1 mice of 6 weeks of age per dose group. The study was
designed to determine if feeding mice a 1,1-biphenyl-containing diet for 90 days induces
peroxisome proliferation in the liver. The mice were treated with 1,1-biphenyl (purity >98%) at
0, 500, 2000, 4000, 8000, 10,000, and 16,000 ppm in the diet, 7 days a week, for 13 weeks.
Dose levels were increased stepwise to prevent taste aversion in groups fed more than 4000-ppm
1,1-biphenyl. Mice fed 8000- and 10,000-ppm- 1,1-biphenyl diets were first fed 4000 ppm for
the first week, and those fed 16,000 ppm were first fed 4000 ppm for the first week and
8000 ppm for the second week. The corresponding DoseADJ are 0, 94.6, 378, 757, 1456, 1805,
and 2737 mg/kg-day and 0, 101, 404, 809, 1556, 1929, and 2924 mg/kg-day for males and
females, respectively. The study authors recorded mortality and clinical observations daily,
while body weight was measured weekly. At the 13-week point, the study authors recorded
weight measurements and microscopic observations of the liver. No other organ or tissue
evaluation results were reported (Umeda et al., 2004).
Umeda et al. (2004) reported one mouse death: a female in the 16,000-ppm dose group.
After 13 weeks of treatment, body weights of mice in the 8000-, 10,000-, and 16,000-ppm
1,1-biphenyl dose groups were significantly lower than their respective controls (for males:
83.3%, 84.9%), and 75.1%>, for females: 93.7%>, 91.6%, and 85.8%, respectively). The study
authors stated (without giving the quantitative data) that female mice in the 8000- and
16,000-ppm dose groups displayed significantly higher liver weights. Histopathological changes
characterized by enlarged centrilobular hepatocytes filled with multiple eosinophilic fine
granules in the centrilobular area, and peroxisomes were observed in female mice treated with
16,000-ppm (2924-mg/kg-day) 1,1-biphenyl. The study authors concluded that oral
administration of 1,1-biphenyl induced enlargement of hepatocytes filled with eosinophilic fine
granules. The study authors also concluded that administration of 2924 mg/kg-day 1,1-biphenyl
caused peroxisome proliferation in female mice. Based on this finding, a LOAELadj of
"3
2.924 x 10 mg/kg-day and aNOAEL adjusted to continuous exposure duration (NOAELadj) of
1.929 x 103 mg/kg-day are established. The absence of test results of other organs (e.g., bladder,
kidneys), statistical data (mean and variance) for body weight and relative liver weight, and
histopathological changes limits the utility of the study for drawing a dose-response relationship
curve between the 1,1-biphenyl oral exposure and liver effects, as well as its comparability with
other available studies in the database.
Tamano et al. (1993) conducted a two-part, peer-reviewed, carcinogenicity study. In the
first experiment, the study authors maintained groups of 20 male B6C3Fi mice on drinking water
with and without an tumor initiator 0.05% A-butyl-A'-(4-hydroxybutyl) nitrosamine (BBN)
supplement for 4 weeks before administering a diet containing 1%>- 1,1-biphenyl (purity not
specified), 7 days a week, for 32 weeks. The corresponding DoseADJ is 1803.8 mg/kg-day. The
study authors recorded clinical observations daily and body weights weekly for the first 5 weeks,
every 4 weeks thereafter, and at study termination. At the 37-week point, the study authors
recorded weight measurements for the urinary bladder. Additionally, at the 37-week point, the
study authors performed histological examinations on the urinary bladder and kidney of every
test animal. In the second part of the study, the study authors fed groups of seven male B6C3Fi
mice a powdered basal diet containing 1%>- 1,1-biphenyl, 7 days a week, for 8 weeks. Urinary pH
and sodium levels were measured from urine samples collected at Weeks 2, 4, 6, and 8. At the
9-week point, mice were injected with BrdU at a dose of 100 mg/kg body weight, and the
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numbers of bladder epithelial cells incorporating BrdU into the DNA per 1000 cells were
recorded.
In the first portion of the study, the final average body weight was significantly lower,
and relative urinary bladder weights were significantly higher in mice administered a diet
containing 1,1-biphenyl following a BBN supplement, but not in those fed 1,1-biphenyl without
BBN pretreatment (see Appendix B, Table B.2). One mouse exposed to 1,1-biphenyl alone
displayed urolithic residues, which was associated with the induction of papillary nodular (PN)
dysplasia of the urinary bladder. No significant differences in the incidences of simple
hyperplasia, papillary or nodular dysplasia, or squamous cell carcinoma were observed in mice
administered 1,1-biphenyl, but incidences of interstitial nephritis in the kidneys were reported to
be 65 and 50% for those with and without BBN pretreatment, respectively, but no further data on
that endpoint were provided. In the second experiment, mice administered 1,1-biphenyl did not
display elevated urinary pH levels. At Week 4, significantly lower sodium concentrations were
observed in mice exposed to 1,1-biphenyl and pretreated with BBN. No significant differences
in BrdU labeling of the DNA in the urinary bladder epithelium were observed. Because no
effects were observed with 1,1-biphenyl alone, a NOAELadj of 1.8038 x 103 mg/kg-day was
established, but no LOAEL could be determined. This study is not used to support a p-RfD
because only one dose level was administered, and no effects were observed.
Chronic-duration Studies
Four studies are summarized in this section. The Ambrose et al. (1960) study is used by
IRIS (U.S. EPA, 2010a) for deriving a chronic RfD. The Umeda et al. (2005) study is used to
support the development of an oral slope factor (OSF), and the other two—Takita (1983) and
Umeda et al. (2002)—are supporting studies.
Ambrose et al. (1960) reported the results of a chronic-duration toxicity study funded by
the Dow Chemical Company (SRI, 1953 as cited by Ambrose et al., 1960) that examined
1,1-biphenyl toxicity in weanling albino rats (strain not specified). The study authors exposed
groups of 15 male and 15 female rats to 0.0, 0.001, 0.005, 0.01, 0.05, 0.10, 0.50, and 1.0%
1,1-biphenyl (purity not specified) in the diet, 7 days a week, for 700 days. The corresponding
DoseADJ are 0, 0.723, 3.62, 7.23, 36.2, 72.3, 362, and 723 mg/kg-day and 0, 0.820, 4.10, 8.20,
41.0, 82.0, 410, and 820 mg/kg-day for males and females, respectively. The study authors
recorded body weights weekly during the period of growth, every 50 days thereafter, and at
termination. Hemoglobin values for rats in the 0.0- and 1.0%- 1,1-biphenyl dose groups were
taken every 100 days, while rats in the 0.5%-dose group were hemoglobin tested at the end of
500, 600, and 700 days, and animals in the 0.1%-dose group were hemoglobin tested at the end
of 500 and 700 days. Paired feeding experiments were conducted for animals in the 1.0-and
0.5%-dose groups. The study authors recorded all instances of abnormal tissue growth. After
700 days, the study authors recorded weight measurements for the liver, kidneys, heart, and
testes. Histopathological examinations were performed on all test animals.
Male and female rats in the 1.0%-dose groups showed lowered hemoglobin values and
body weights after 300 and 400 days, respectively, and the 0.5%-dose group had lowered
hemoglobin values after 500 and 600 days (Ambrose et al., 1960). However, the study authors
concluded that this may be due, in part, to decreased food intake as a result of decreased
palatability. Ambrose et al (1960), reported that abnormal tissue growth, mostly in the form of
mammary tumors and polyps, was observed after 500 days in 2 male and 26 female rats in 1.0-
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and 0.5%-dose groups. Also, Ambrose et al. (1960) reported graphically a positive relationship
between growth rate and body weight in rats fed 1.0 and 0.5% biphenyl, pair-fed controls, and
controls fed ad libitum (see Figures 1 and 2 in the original article not shown in this PPRTV).
After 700 days of treatment, male and female rats in the 1.0- and 0.5%-dose groups displayed
significantly decreased body weights and longevity (see Appendix B, Table B.3). The weights
of liver and kidneys increased in female rats treated with 0.5% (410 mg/kg-day) (see
Appendix B, Table B.3). Growth inhibition of male and female rats in the 0.5- and 1.0%-dose
groups was attributed to decrease food intake. Reduced hemoglobin values may also be due, in
part, to decreased food intake. Prominent irregular scarring, lymphocytic infiltration, tubular
atrophy, and patchy tubular dilation to the point of cyst formation were observed in the kidneys
of all male and female mice in the 0.5%- (362 or 410 mg/kg-day) and 1.0%-dose groups (723 or
820 mg/kg-day), respectively, and were attributed to biphenyl treatment. Ambrose et al. (1960)
reported mean and standard error of hemoglobin, body weight food intake and organ weights of
both male and female rats were, but there is no indication as to what type of statistical test was
performed and because only processed data was reported no additional statistical analysis has
been performed. Based on these findings, a LOAELadj of 3.62 x io2 mg/kg-day and a
NOAELadj of 7.23 x 10 mg/kg-day are identified.
In a peer-reviewed publication, Umeda et al. (2002) reported the results of a 2-year
chronic-duration toxicity and carcinogenicity study. The study authors exposed groups of
50 male and 50 female F344 rats to 0-, 500-, 1500-, or 4500-ppm 1,1-biphenyl (purity >98%) in
the diet, 7 days a week, for 105 weeks. The corresponding DoseADj are 0, 39.5, 118, or
355 mg/kg-day and 0, 45.9, 138, or 413 mg/kg-day for males and females, respectively. The
corresponding human equivalent doses (HEDs) are 0, 10.7, 32.1, or 96.4 mg/kg-day and 0, 11.0,
32.9, or 98.7 mg/kg-day for males and females, respectively. (See Appendix A, "Derivation of
Screening Provisional Oral Slope Factor" for a representative step conversion from animal dose
to FLED). The study authors recorded body weights and clinical observations weekly for the first
14 weeks, every 4 weeks thereafter, and at termination. At the 105-week point, the study authors
recorded urinary parameters, including pH and occult blood, of all surviving rats (105-week
measurement only). Additionally, at the 105-week point, the study authors recorded weight
measurements and macroscopic observations for the bladder, kidney, and ureter. The study
authors performed complete histopathological examinations (including neoplastic and
nonneoplastic lesions and tissue masses) on all test animals.
After 105 weeks of treatment, male and female rats displayed significantly decreased
body weights, and male rats showed decreased survival rates in the 4500-ppm dose group.
Thirty-two males in the 4500-ppm dose group displayed clinical hematuria, with nearly half with
hematuria showing anemia-colored skin and/or eyes. Urinary pH in male rats and occult blood
incidence in male and female rats were significantly increased in the 4500-ppm group. At the
105-week point, male and female rats showed significantly increased relative kidney weights in
the 1500- and 4500-ppm dose groups, and increased absolute kidney weights in males in the
4500-ppm dose group only. Forty-three males and eight females in the 4500-ppm group
displayed bladder calculi.
Neoplastic and nonneoplastic lesions were observed only in the urinary tract, as shown in
Tables B.4 and B.5. Incidences of transitional cell hyperplasia, squamous cell hyperplasia, and
squamous cell metaplasia in the urinary bladder and of simple transitional cell hyperplasia and
dilatation of the lumen in the ureter were significant only in male rats exposed to 96.4 mg/kg-day
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1,1-biphenyl. In the renal pelvis, incidences of simple hyperplasia in the female 1500-ppm were
significant, and incidences of nodular hyperplasia were significant in the 4500-ppm group for
both male and female rats. Mineralization of the cortico-medullary junction and papilla was
significant in males in the 4500-ppm group. Mineralization of papilla, papillary necrosis, infarct,
and hemosiderin deposition was significant in females in the 4500-ppm group, with hemosiderin
deposition also significant in females exposed in the 1500-ppm dose group. The study authors
proposed that the bladder tumors observed were caused by mechanical damage to the tissue by
the bladder calculi, which were observed at high incidence (86%) in males in the 4500-ppm dose
group. More than 93% of the bladder tumors, hyperplasia of the urinary system, and hematurias
of the bladder or kidneys were observed to contain calculi. The study authors further suggested
that the difference in response between the male and female exposed rats may be due to
differences observed in the sizes and shapes of the calculi, which are proposed to be caused by
differences in 1,1-biphenyl metabolism. Based on the histological findings, the study authors
concluded that 1,1-biphenyl was carcinogenic to male rats in the conditions used for this assay.
An increased incidence of bladder tumors, hematuria, and neoplastic regenerative lesions of the
urinary system in males supports a LOAELhed of 9.64 x 10 mg/kg-day and a NOAELhed of
3.21 x 10 mg/kg-day. The bladder tumor response was not observed in the first three dose-group
levels. It was observed only in male rats at the highest level. Because the effect level was
relatively higher, and there was a steep response of about 40% bladder tumors in male rats at the
highest dose (96.4 mg/kg-day) after the absence of bladder tumors in the control group and the
first two dose-group levels (0, 10.7, 32.1 mg/kg-day) of male rats, this study is less preferred for
use as the principal study for deriving a p-OSF.
The original source of Takita (1983), published in Japanese with only an abstract, tables
and graphics in English were unavailable for review at this time. The information from this
study was reviewed by WHO (Boehncke et al., 1999) and will be used for the purposes of this
document. 1,1-Biphenyl (purity not specified) concentrations of 0, 2500, and 5000 mg/kg and 0,
630, and 1250 mg/kg in the diet were administered to Wistar rats (50/sex/dose group), 7 days a
week, for 75 or 104 weeks. The corresponding DoseADJ are 0, 188, and 375 mg/kg-day for the
75-week study and 0, 47, and 94 mg/kg-day for the 104-week study. Method of data collection
and analysis are not discussed in the WHO document (Boehncke et al., 1999). The 75-week
study reported dose-dependent effects on the reduction of weight gain and activities of serum
transaminase, alanine transaminase, and lactate dehydrogenase (LDH). Both males and females
showed a dose-dependent increase in stones of the kidney and ureter (see Appendix B,
Table B.6), which was seen in conjunction with haematuria from 16 weeks of exposure at a dose
of 188 mg/kg-day. At a dose of 375 mg/kg-day, relative kidney weights were found to be
significantly increased in the females, and an increase in stones of the urinary bladder was
observed in both males and females. Histopathology of urinary bladders showed simple or
diffuse hyperplasia and papillomatosis of the epithelium in bladders with stones. Tumor
incidence was not increased over controls. Those kidneys with stones also displayed obstructive
pyelonephritis, tubular atrophy, and fibrosis. Kidney stones were composed of protein, and
urinary stones were composed of magnesium ammonium phosphate. The 104-week study
reported no urolithiasis and no increased tumor incidence. Dose-dependent effects were
reductions in weight gain and activities of serum transaminase, alanine transaminase, and LDH
in both the 47- and 94-mg/kg-day dosed animals (data not reported). The study authors reported
a LOAELadj of 4.7 x 10 mg/kg-day based on body-weight loss seen in both sexes. Because this
is the lowest dose investigated in the study, a NOAEL could not be identified.
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The study by Umeda et al. (2005) is selected as the principal study for deriving the
p-OSF. Umeda et al. (2005) published a peer-reviewed, 2-year, chronic-duration toxicity and
carcinogenicity study in Cij :BDF1 mice. The study authors exposed groups of 50 male mice to
0, 97, 291, or 1050 mg/kg-day and 50 female mice to 0, 134, 414, or 1420 mg/kg-day
1,1-biphenyl (purity >98%) in the diet, 7 days a week, for 104 weeks. The corresponding HEDs
are 0, 15.3, 45.8, or 154.0 mg/kg-day and 0, 19.7, 59.8, or 196.2 mg/kg-day for males and
females, respectively. The study authors recorded body weights and clinical observations
weekly for the first 14 weeks, every 4 weeks thereafter, and at termination. At the 104-week
point, the study authors recorded weight measurements and macroscopic observations of all
organs. Additionally, at the 104-week point, the study authors measured hematological and
blood biochemical parameters of all surviving mice. Additionally, the study authors performed
complete histopathological examinations (including neoplastic and nonneoplastic lesions and
tissue masses) on all test animals.
No differences in survival rate, clinical signs, organ weight (with the exception of relative
liver weights in female mice), or any hematological parameter were observed in any exposure
group, regardless of sex (Umeda et al., 2005). After 104 weeks of treatment, male and female
mice displayed significantly decreased body weights in the middle- and high-dose groups.
Dose-dependent increases of glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic
transaminase (GPT) in the serum were observed in females exposed to 414 and 1420 mg/kg-day.
Significant increases of ALP were shown in males and females fed the high-dose diets, and a
significant increase of LDH was measured in females fed the high dose. Blood urea nitrogen
(BUN) was significantly increased in males in the middle- and high-dose groups and females.
Significantly increased levels of sodium and chloride and decreased levels of potassium were
observed in males fed 1,1-biphenyl, while sodium and calcium levels increased in females fed
1,1-biphenyl. Relative liver weights of female mice fed 134, 414, and 1420 mg/kg-day in the
diet were increased 1.3-, 1.4-, and 1.6-fold, respectively. A dose-related increase of liver
nodules was observed in females.
Neoplastic lesions were observed in the liver with a greater increase in the treated
females and nonneoplastic lesions in the kidneys of male and female mice (Umeda et al., 2005).
A dose-related increase in hepatocellular adenomas and carcinomas was observed in females fed
414- and 1420-mg/kg-day diets, and significantly increased hepatocellular carcinomas were also
observed in females fed a 414-mg/kg-day diet (see Appendix B, Table B.7). Significantly
increased incidence of basophilic cell foci was observed in females exposed to 414 and
1420 mg/kg-day and males exposed to 97 mg/kg-day (see Appendix B, Table B.8), although the
effect in the males was not dose related. Incidence of clear cell foci also was significantly
increased in males treated with 97 mg/kg-day (see Appendix B, Table B.8). In the renal pelvis,
incidences of desquamation of the urothelium were significantly increased in males and females
fed the high-dose diet. In the kidney, incidences of mineralization in the inner stripe of the outer
medulla were significantly increased in females fed 414- and 1420-mg/kg-day diets.
Umeda et al. (2005) concluded that chronic-duration oral exposure to 1,1-biphenyl
induced preneoplastic and neoplastic lesions in the livers of female mice, and nonneoplastic
lesions in the kidneys of male and female mice. The incidence of preneoplastic lesions observed
in the males was not dose related and may be an artifact of the staining method used in this
study. Microscopic examination of the liver tissue, together with a previous study from this
group (Umeda et al., 2004), support the theory suggested by the authors that peroxisome
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proliferation in the liver of the female mice causes the incidence of liver tumors observed in the
female mice. Based on increased incidence of hepatocellular tumors in females, a LOAELhed of
5.98 x 10 mg/kg-day and a NOAELhed of 1.97 x 10 mg/kg-day are identified. Umeda et al.
(2005) is selected as the principal study to support the development of a p-OSF because the study
authors observed a lower LOAEL compared to Umeda et al. (2002), and there was a
dose-response trend at all dose levels except the highest, which showed reduced—but
statistically significant—incidence of combined hepatocellular adenoma and carcinoma in
female mice compared to the control. In addition to liver tumors, Umeda et al. (2005) observed
nonneoplastic lesions in the kidneys of both male and female mice. Alternatively, the
Umeda et al. (2002) study showed a steep response of about 40% bladder tumors in male rats at
the highest dose (96.4 mg/kg-day) following the absence of bladder tumors in the control group
and the first two dose levels (10.7, 32.1 mg/kg-day) of male rats. No bladder tumors were
observed in female rats, and no other organ response was reported.
Developmental and Reproductive Studies
There are limited data on the reproductive toxicity of 1,1-biphenyl: only one oral
developmental study (Khera et al., 1979) and one generation reproductive study (Ambrose et al.,
1960). No other developmental or multigeneration studies were located.
The study by Khera et al., 1979 is selected as the principal study for deriving the
subchronic p-RfD. In a peer-reviewed teratogenic study, Khera et al. (1979) reported the
effects of treating Wistar rats with 1,1-biphenyl (purity not specified) during Gestational Days
(GDs) 6 to 15. Female rats, 18 to 20 per dose group, were administered 0, 125, 250, 500, or
1000 mg/kg-day by gavage. The study authors paired females with proven males and considered
a positive vaginal smear to be GD 1. Body weights were taken on GD 1, GDs 6-15, and again
on GD 22. All females were sacrificed on GD 22 and weighed following removal of uterine
contents and counting of the corpora lutea. Necropsies were performed on the dams, and fetuses
were weighed and examined for external malformations. Parameters evaluated at autopsy
included the number of corpora lutea, fetal weights and viability, and early resorptions.
Two-thirds of the live fetuses/litter were examined for skeletal development and the rest were
examined for the presence of visceral abnormalities. Five of the 20 high-dose dams died prior to
sacrifice. Doses <500 mg/kg-day produced no clinical signs of maternal toxicity or evidence of
treatment-related effects on maternal weight gain. As shown in Table B.9, a significantly
increased number of dams without live fetuses was observed in the high-dose group, compared
with controls. Mean numbers of corpora lutea and live fetuses in the high-dose dams were
similar to those of controls and dams of all other dose levels. However, the percent of dead
fetuses and resorption sites was clearly higher in the high-dose group, and the numbers of
anomalous fetuses and litters bearing anomalous fetuses appeared to increase with increasing
dose. Khera et al. (1979) noted that the slight increases in the number of fetuses with anomalies,
such as missing and unossified sternebrae or delayed calvarial ossification, were not statistically
significant, but, as shown in Table B.9, the incidence of litters with any type of fetal anomalies
("anomalous litters/number examined") was elevated (p < 0.05 by Fisher's exact test) at
500 mg/kg-day, but not at lower doses, compared with control incidences. This study identified
a NOAEL of 500 mg/kg-day and a LOAEL of 1000 mg/kg-day for frank maternal toxicity
(increased mortality and decreased dams with live fetuses) and lethal fetal effects. For less
severe developmentally toxic effects (increased incidence of anomalous litters), 500 mg/kg-day
was a LOAEL and 250 mg/kg-day was a NOAEL.
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Ambrose et al. (1960) reported the results of two peer-reviewed, reproductive toxicity
studies in rats. Animals were exposed to 0, 0.1, or 0.5% 1,1-biphenyl from mating until weaning
of litters (7 days per week during two months for both control and exposed rats). The
corresponding DoseADJ are 0, 72.3, and 362 mg/kg-day and 0, 82.0, and 410 mg/kg-day for males
and females, respectively. Ten female and five male albino rats of weanling age were mated:
two females to one male. In the subsequent experiment, eight to nine females and three to
four male albino rats were exposed and mated in unspecified ratios. Little information is
available on the methods used during this study, but the study authors concluded that
1,1-biphenyl exposure had no effect on the reproductive success in either experiment.
Table B. 10 presents these results (see Appendix B).
Boehncke et al. (1999) summarized results of an unpublished three-generation study.
Dietary 1,1-biphenyl concentrations of 100 or 1000 mg/kg (estimated intakes of approximately
7.5 or 75 mg/kg-day) had no effect on reproduction in rats; following intake of 10,000 mg/kg
(estimated intake of 750 mg/kg-day), decreased fertility, litter size, and growth per day were
noted. The study was performed by SRI (1953); no further information was provided by
Boehncke et al. (1999) and the original report was not available for review. Because this study
did not provide necessary details of design and performance it is considered unsatisfactory as a
multigeneration reproductive study and may not be used in considering the database uncertainty
factor (UFd). Although decreased fertility, litter size, and growth per day were noted at 750 at a
dose of 75 mg/kg-day, all necessary parameters were not reported (Boehnche et al., 1999).
Dow Chemical Co. (1953) reported the results of a multigenerational study in which
groups of 4-month-old male and female Long Evans rats (three males and nine females/group)
were fed diets containing 0, 0.01, 0.1, or 1.0% biphenyl. Based on EPA (1988) subchronic
reference values for body weight and food consumption in male and female Long Evans rats,
doses of biphenyl for the dietary levels of 0.01,0.1, and 1.0% are estimated to be 9, 89, and
887 mg/kg-day, respectively, for the males and 10, 101, and 1006 mg/kg-day, respectively, for
the females. Average cross-gender doses for males and females were 10, 95, and
947 mg/kg-day. For breeding, three females were placed together with one male. Following the
breeding phase, females were separated and number of litters cast, number of days between
mating and delivery, and average number of pups/litter at delivery were recorded. F1 pups were
weighed and culled to seven/litter at 2 days of age and weaned at 3 weeks of age, and weights
were recorded weekly for Postnatal Weeks 3-6. The F1 rats were continued on the same diets as
their parents, and, at 10 weeks of age, nine F1 females and three F1 males were mated to produce
an F2 generation of pups. F2 pups were selected (by the same procedure) for mating and
production of an F3 generation that were sacrificed at 3 weeks of age; twelve F3 pups from each
diet group were subjected to gross pathologic examinations. There were no significant
differences between controls and 0.01 and 0.1% biphenyl-fed groups regarding litters cast;
gestation length; or average number or weight of pups/litter at birth or at 3 or 6 weeks of age.
Decreased fertility in the 1% biphenyl-fed group of females was observed (6/9, 7/9, and
8/9 confirmed pregnancies for the three successive generations of 1.0% biphenyl-fed groups vs.
8/9, 9/9, and 8/9 confirmed pregnancies for controls). Averaged for Fl, F2, and F3 pups
combined, the 1.0% biphenyl-fed group exhibited significantly (p < 0.05) decreased number of
pups/litter at birth (6.2/litter vs. 8.6/litter for controls) and lower average body weight at 3 weeks
of age (36 vs. 48 g for controls) and 6 weeks of age (78 vs. 113 g for controls). Gross pathologic
evaluations of F3 weanlings revealed no signs of biphenyl treatment-related effects. There was
no evidence of a cumulative effect over the three generations. The study authors indicated that
18
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the decreased fertility, smaller litter size, and reduced rate of growth in the 1.0% biphenyl-fed
group may have been associated with unpalatability and resultant decreased food intake.
Inhalation Exposures
The effects of inhalation exposure of animals to 1,1-biphenyl have been evaluated in
several subchronic-duration studies (Cannon Laboratories, Inc., 1977; Monsanto Chemical Co.,
1983; Boehncke et al., 1999), but no chronic-duration, developmental, or reproductive toxicity
studies could be identified. The report by Monsanto Chemical Co. (1983) consists of three
separate subchronic-duration inhalation studies.
Subchronic-duration Studies
The study by Cannon Laboratories, Inc. (1977) is selected as the principal study for
deriving subchronic and chronic p-RfCs. Cannon Laboratories, Inc. (1977) conducted an
unpublished, 90-day, subchronic-duration toxicity study. The study authors exposed groups of
50 male and 50 female CD1 mice to atmospheric concentrations of 0, 25, and 50 ppm
1,1-biphenyl (>99% purity), 7 hours per day, 5 days per week (equivalent to continuous exposure
"3
of 0, 32.8, and 65.5 mg/m ), for 13 weeks. 1,1-Biphenyl was submerged in an oil bath, heated to
melt, volatilized, and introduced in a chamber as a 1,1-biphenyl-air mixture. Sampling
"3
difficulties resulted in unusable data for the first 3 days of the 32.8-mg/m study and the first
5 days of the 65.5-mg/m3 study. Overheating and cannibalization by cage mates forced the
"3
replacement of 46 mice, causing the 32.8-mg/m study to run 117 days to ensure all replacement
mice received exposure according to the protocol. Once the analytical technique was corrected,
significant variation in chamber concentration was noted for the next few days and corrected by
adjusting the amount of inlet air and the temperature of the oil bath. For the 25-ppm study, the
concentration throughout the 117 days was 25 ± 7 ppm (equivalent to a human equivalent
concentration [HEC] of 72.9 ± 20 mg/m3, 92.6 ± 26 mg/m for respiratory effects in females and
"3
males, respectively, and 32.8 ± 9 mg/m for extrarespiratory effects in both sexes). During the
last 72 days (after the proper chamber parameters were obtained), the concentration was
3 3
26.5 ± 1 ppm (HEC of 76 ± 3 mg/m ; 98.4 ± 4 mg/m for respiratory effects in females and
males, respectively, and 34 ± 1 mg/m3 for extrarespiratory effects in both sexes). For the
50-ppm study, the average concentration throughout the 72 days was 50 ± 16 ppm (HEC of
146.4 ± 36 mg/m3, 189.9 ± 61 mg/m3 for respiratory effects in females and males, respectively,
"3
and 65.5 ± 21 mg/m for extrarespiratory effects in both sexes). During the last 55 days, the
average concentration was 51.4 ± 9.6 ppm (HEC of 150.5 ± 28.1 mg/m3, 195.2 ± 36.5 mg/m3 for
"3
respiratory effects in females and males, respectively, and 67.8 ± 13 mg/m for extrarespiratory
effects in both sexes).
The study authors recorded clinical observations daily and body weights of five mice
weekly, from which an average weight per mouse was determined. At the 14-week point, the
study authors microscopically observed urine samples and recorded specific gravity, pH,
ketones, and glucose levels. Additionally, at the 14-week point, blood for each group of animals
was collected and pooled for hematological analysis. Gross and histopathological examinations
were performed on all mice. Ten males and 10 females from each group were held for a 30-day
recovery period before being analyzed.
Table B. 11 (see Appendix B) presents histopathological results for the 13-week study.
"3
All (80/80) control mice, 18/98 mice exposed to 32.8 mg/m , and 1/71 mice exposed to
65.5 mg/m3 of 1,1-biphenyl displayed normal tracheas. Hyperplasia with inflammation was
19
1,1-Biphenyl
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FINAL
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"3
observed in 80/98 mice exposed to 32.8 mg/m , and all but one (70/71) mouse exposed to
65.5 mg/m3 of 1,1-biphenyl. The authors reported that these findings were both significant
(p < 0.05, Fisher's exact test) and dose dependent. Also, the study authors reported that lungs
were within normal limits for all control mice (80/80), while a significant and dose-dependent
"3
incidence of congestion, and edema was observed in the majority of mice exposed to 32.8 mg/m
(95/98) and all mice exposed to 65.5 mg/m3 (71/71). This was accompanied by pneumonia in
"3
15/98 and 20/71 mice exposed to the lower and higher doses, respectively. At 32.8 mg/m ,
1/98 had an abscess, and 2/98 had neoplasia (sarcoma of the lung). All but two (78/80) control
"3
mice and 11/98 mice exposed to 32.8 mg/m displayed a liver within normal limits, and
abscesses were observed in 2/80 control mice. The majority (87/98) of mice exposed to
3 3
32.8-mg/m 1,1-biphenyl and all mice (71/71) exposed to 65.5 mg/m 1,1-biphenyl had
congestion and edema in the liver and kidneys that was significant and dose dependent (p < 0.05,
"3
Chi-square test). The majority of control mice (76/80) and 11/98 mice exposed to 32.8 mg/m
displayed normal kidneys, while 4/80 control mice had abscesses. All control mice (80/80) and
"3
all but one (97/98) of the mice exposed to 32.8-mg/m 1,1-biphenyl had spleens within normal
limits, while a neoplasm (leukemia) was observed in only one (1/98) mouse in this exposure
group. A LOAEL adjusted for dosimetric differences across species to a human (LOAELhec) of
3.28 xio mg/m3 was established for extrarespiratory effects (i.e., congestion and edema in the
livers and kidneys of exposed mice). A NOAEL could not be identified.
All mice were allowed a 30-day recovery period, and all control mice (20/20) displayed
"3
normal lungs, liver, and kidneys. All mice in the 32.8-mg/m exposure group had normal liver
and kidneys; and all mice in the 65.5-mg/m3 exposure group had normal kidneys (see
Appendix B, Table B. 12). A normal trachea was observed in 17/20 control mice, 3/15 mice in
the 32.8-mg/m3 exposure group, and 2/19 mice in the 65.5-mg/m3 exposure group. Chronic
inflammation of the trachea was significant at all doses and was determined to be dose dependent
by independent statistical analysis conducted for this review (see Appendix B, Table B.12). The
3 3
incidences were 10/15 and 12/19 in mice exposed to 32.8 mg/m and 65.5 mg/m , respectively.
A minority of control mice (3/20), mice in the 32.8-mg/m3 exposure group (2/15), and mice in
"3
the 65.5-mg/m exposure group (2/19) displayed hyperplasia with chronic inflammation, and
3/19 mice exposed to the high dose of 1,1-biphenyl had hyperplasia with acute inflammation.
Lungs within normal limits were observed in 4/15 and 5/19 mice exposed to low and high doses
of 1,1-biphenyl, respectively, while congestion in 6/15 and 2/19 and pneumonia in 5/15 and
12/19 were observed in the lungs of mice exposed to the low and high doses, respectively. A
LOAELhec of 7.29 x 10 mg/m can be established based on the following respiratory effects:
inflammation of the trachea, pneumonia, congestion, and edema in the lungs. No NOAEL could
be determined.
Monsanto Chemical Co. (1983) studied the physiological effect of 1,1-biphenyl to
Sprague-Dawley albino rats, an unknown sex and strain of mice, and albino rabbits through oral,
cutaneous, and inhalation exposures in a unpublished study report. The inhalation exposure was
investigated in three separate experiments. The first experiment exposed three rabbits and
10 rats to an average exposure concentration of 0.3 mg/L 1,1-biphenyl (purity not specified), for
7 hours per day, 5 days per week, for a total of 64 out of 94 days. The second experiment
exposed three rabbits and six rats to 0.04 mg/L 1,1-biphenyl, for 7 hours per day, 5 days per
week, for a total of 46 out of 68 days. The final inhalation experiment exposed four rats and
12 mice to 0.005 mg/L 1,1-biphenyl, for 7 hours per day, 5 days per week, for a total of 62 out of
20
1,1-Biphenyl
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92 days. The HECs for experiments 1, 2, and 3 are 5.96 x 10 2, 7.89 x 10 3, and
9.34 x 10~4 mg/m3, respectively.
The study authors reported that the rats in the first experiment experienced irritation of
the nasal mucosa and serosanguineous and that 5 out of 10 rats died from the first experiments;
the surviving rats experienced weight loss averaging 20 grams. The rabbits showed no adverse
effects. A LOAELhec of 5.96 x io~2 mg/m3 was established, but no NOAEL could be
determined based on these results. In the second experiment, the rats also experienced irritation
of the nasal mucosa. One rat died during the experiment, but the surviving rats gained weight at
_3 T
a normal rate. A LOAELhec of 7.89 x 10 mg/m was established, but no NOAEL could be
determined based on the observed nasal irritation. In the third experiment, rats showed no
adverse effects. Mice showed signs of irritation of the upper respiratory tract. A LOAELhec of
9.34 x io~4 mg/m3 is established, but no NOAEL could be determined based on the documented
irritation. Due to poor documentation and a non-Good Laboratory Practice (GLP)-compliant
study design, this study is not be used to support derivation of a p-RfC.
The Concise International Chemical Assessment Document 6: Biphenyl published by the
World Health Organization (WHO) (Boehncke et al., 1999) summarized two
subchronic-duration inhalation exposure studies: Sun Co., Inc. (1977) and Deichmann et al.
(1947). The study authors of Sun Co. Inc. (1977) exposed groups (n = 50) of male and female
"3
CD-I mice to 25- or 50-ppm (160 or 320 mg/m ; analytical concentrations) 1,1-biphenyl
(99+% purity), for 7 hours/day, 5 days/week, for 13 weeks (correspondent HECs: 0, 32.8,
"3
65.5 mg/m ), producing hyperemia and focal haemorrhage in the lung and an increase in
hyperplasia of the tracheal epithelium. Based on Boehncke et al. (1999), these effects were also
observed in some unexposed controls and were attributed to the method of aerosol generation
(i.e., inhalation of hot air). The second study, Deichmann et al. (1947), noted marked species
differences observed in a study in which rabbits, rats, and mice were exposed by inhalation to
1,1-biphenyl in the form of dust (50% 1,1-biphenyl on zeolite) at 5, 40, or 300 mg/m3, for
7 hours/day, 5 days/week, for up to 13 weeks. No adverse effects were observed in rabbits
(correspondent HECs: 1.04, 8.33, 62.5 mg/m3). Rats exposed to 40 or 300 mg/m3 of
1,1-biphenyl exhibited increased mortality and irritation of the mucous membranes; no effects
were observed following exposure to 5 mg/m3 (HEC: 1.04 mg/m3). Mice were the most
"3
sensitive species. Exposure to 5 mg/m (the only concentration tested) resulted in slightly
increased mortality, with all mice exhibiting irritation of the upper respiratory tract (no further
information was available). Necropsy of dead rats and mice revealed mainly inflammatory
bronchopulmonary changes. No information on control animals or particle size was provided.
The original articles were not located, and the summary data provided for both studies
(Sun Co. Inc., 1977, and Deichmann et al., 1947 as cited in Boehncke et al. [1999]) did not
provide sufficient information to support the derivation of a p-RfC.
Chronic-duration Studies
No studies could be located regarding the effects of chronic-duration inhalation exposure
of animals to 1,1-biphenyl.
Developmental and Reproductive Studies
No studies could be located regarding the effects of inhalation exposure of animals to
1,1-biphenyl on reproduction and fetal development.
21
1,1-Biphenyl
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Other Exposures
No pertinent studies could be located regarding the effects of inhalation exposure of
animals to 1,1-biphenyl on immunological or neurological toxicity.
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
A few studies on the toxicokinetics of 1,1-biphenyl are available (BUA, 1990;
Ohnishi et al., 2000; Umeda et al., 2004; Meyer et al., 1976). Results of available studies
indicate that 1,1-biphenyl is hydroxylated in the liver upon entering the body in the first phase,
irrespective of the route of exposure. The second phase of metabolism is conjugation with
sulfate or glucuronide, followed by excretion (Umeda et al., 2005). 1,1-Biphenyl metabolites
have been shown to primarily be excreted in the urine of exposed animals, with most of the
excretion taking place in the first 24 hours following exposure (Meyer et al., 1976; BUA, 1990).
Eight days after administration, only 0.6% of the original dose remained in the tissues of rats
(Meyer et al., 1976). No unmetabolized 1,1-biphenyl has been found in excretions (BUA, 1990).
The specific metabolism of 1,1-biphenyl seems to be species and sex dependent. 1,1-Biphenyl
has been shown to cause calculi in rats, effecting males more than females. An analysis of the
composition of these calculi showed that the male stones were composed of potassium
4-hydroxybiphenyl-o-sulfate (4-HBPOSK), while the stones in female rats were composed of
mostly 4-hydroxybiphenyl (4-HBP) and KHSO4 which were formed by the hydrolysis of
4-HBPOSK (Ohnishi et al., 2000). Mice preferentially metabolize 1,1-biphenyl to
2-hydroxybiphenyl (2-HBP), which is further metabolized to 2,5-dihydroxybiphenyl (2,5-DHBP)
and 2-phenyl-l,4-benzoquinone (2-PBQ), a possible peroxisome proliferator and a known
genotoxicant, respectively. This pathway difference may be responsible for the hepatotoxicity
seen in mice but not rats, as a result of the possible genotoxic mechanism of action of the
metabolites (Umeda et al., 2005). Rats, however, particularly males, develop bladder cancers
presumed to be a result of calculi formation due to chronic mechanical damage to the bladder
epithelium (Umeda et al., 2002). Bentley et al. (1993) studied hepatic peroxisome proliferation
in rodents and its significance for humans and reported that marked species differences are
apparent in response to peroxisome proliferations. Rats and mice are extremely sensitive, and
hamsters show an intermediated response, while guinea pigs, monkeys, and humans appear to be
relatively insensitive or nonresponsive at dose levels that produce a marked response in rodents.
These findings were consistent with an in vitro study by Clemencet et al. (2005), which
evaluated species differences in cell proliferative response to peroxisome proliferators by using
rat and human tumor liver cell lines and found that rat 7777 hepatoma cells are more responsive
than human hepatocellular liver carcinoma (HepG2) cells.
The genotoxicity of 1,1-biphenyl has been tested in several studies using in vitro test
systems (Sasaki et al., 1997; Hirayama et al., 1982; Anderson and Styles, 1978; Wangenheim
and Bolcsfoldi, 1988; Williams, 1978; Brouns et al., 1979; Pagano et al., 1983). These test
results generally indicate that 1,1-biphenyl does not have mutagenic activity when tested in
bacteria, while the majority of mammalian tests indicate some ability to induce gene mutations.
Although only one study investigated the genotoxic potential of 1,1-biphenyl in vivo, the results
demonstrate that oral exposure can cause DNA damage in the organs of mice, with the kinetics
indicating that this activity may be the result of the formation of metabolites (Sasaki et al., 1997).
The literature on the mutagenic action of 1,1-biphenyl is equivocal, and further investigations are
needed before a conclusive mechanism of action can be established.
Table 3 summarizes the metabolism and genotoxicity studies.
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Table 3. Other Studies (CASRN 92-52-4)
Tests
Materials and Methods
Results
Conclusions
References
Metabolism
50 male and 50 female F344/DuCij rats were
treated with 0.45%-1,1-biphenyl in the diet for
104 weeks. Calculi were collected from the
urinary bladder upon necropsy. Calculi content
was analyzed by high performance liquid
chromatography (HPLC). The calculi were
analyzed for structure.
86% of treated male rats had calculi in the urinary
bladder, and only 16% of female rats had calculi
present. Male calculi were primarily composed of
potassium salt of 4-hydroxy-biphenyl-O-suldfate
(4-HBPOSK), while female calculi were
composed of 4-hydroxylbiphenyl (4-HBP) and
KHS04. The male calculi were found to have
sharp edges composed of multiple layers of
Ca3(P04)2, while the female calculi were
smoother and more rounded.
Differences in the metabolism
of 1,1-biphenyl account for the
sex difference seen in calculi
incidence in the urinary
bladder in rats. Male calculi
formation is the result of
stable and irreversible
metabolism.
Ohnishi et al. (2000)
Metabolism
Single exposure of 1900 mg/kg in an
unreported number, strain, and gender of rats
and mice.
In rats, rabbits, and pigs, most 1,1-biphenyl
metabolites are excreted in the urine. In none of
the species examined was unmetabolized
1,1-biphenyl found in the urine.
1,1-biphenyl is conjugated
with sulfuric acid or
glucuronic acid, followed by
excretion in the urine.
The original source of
BUA (1990) was
unavailable for review
at this time.
Information presented
here is from the WHO
report cited as
(Boehncke et al., 1999).
Metabolism
Male albino rats were given an oral dose of
14C-biphenyl (100 mg/kg), and excretion was
measured every 24 hours for 4 days following
dosing.
Urinary excretion was 84.8%, and fecal excretion
was 7.3% of the dose. 75.8% and 5.8 % were
excreted with urine and feces, respectively, in the
first 24 hours. 0.6% of the dose was excreted
96 hours after administration. Nearly 30% of the
dose consisted of conjugated phenolic metabolites
in the 24-hour samples. Acidic metabolites made
up 25% of the administered dose.
1,1-biphenyl was largely
excreted by male rats through
urine in the first 24 hours.
Meyer etal. (1976)
Genotoxicity
A modified Comet assay was used to test the in
vivo genotoxicity of 1,1-biphenyl on stomach,
liver, kidneys, bladder, lungs, brain, and bone
marrow. Four male CD-I mice were sacrificed
3, 8, and 24 hours after oral treatment.
2000-mg/kg dose of 1,1-biphenyl induced DNA
damage in all the organs studied, with activity
peaking 24 hours following exposure, possibly
due to the metabolic pathway of 1,1-biphenyl.
Treatment with 1,1-biphenyl
caused genotoxicity in all
organs examined.
Sasaki et al. (1997)
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Table 3. Other Studies (CASRN 92-52-4)
Tests
Materials and Methods
Results
Conclusions
References
Genotoxicity
The mutagenic potential of 1,1-biphenyl and the
reactivity of 1,1-biphenyl and NOx, were
assessed using the Escherichia coli DNA repair
tests in strains WP2, EP2 uvrA, CM571, and
WP100 and the Ames test in Escherichia coli
strains TA98 and TA100, in the absence and
presence of metabolic activation (S-9).
1,1-Biphenyl photochemically reacted with NOx
did not have an inhibitory effect on the growth of
bacterial cultures. The mixture of 1,1-biphenyl
with NOx showed mutagenicity in TA98 and
TA100, with more potency observed in the
presence of metabolic activation. 1,1-Biphenyl,
alone, was not positive for mutagenicity in TA98
or TA100, with or without metabolic activation.
1,1-Biphenyl tested negative
in the Ames test for
mutagenicity in bacteria.
1,1-biphenyl, reacted with
NOx and was positive for
mutagenicity.
Hirayama et al. (1982)
Genotoxicity
Bacterial mutation tests were carried out with
four strains of Salmonella typhimurium (Ames
test), with and without metabolic (S-9)
activation.
Results were negative for the induction of
revertants for 1,1-biphenyl in all strains of
Salmonella, with and without metabolic activation
at the following concentrations: 4, 20, 100, 500,
and 2500 (ig/plate.
1,1-Biphenyl tested negative
in the Ames test for
mutagenicity in bacteria.
Anderson and Styles
(1978)
Genotoxicity
The mouse lymphoma TK+/- — TK-/-
forward-mutation assay was used to test
mutagenicity, with and without metabolic
activation (S-9).
Mutation frequency increased between 3- and
4-fold, with metabolic activation at 1,1-biphenyl
concentrations greater than 2.96 x 10 4 mol/L.
1,1-Biphenyl tested positive in
the mouse lymphoma assay for
gene mutations in the presence
of metabolic activation.
Wangenheim and
Bolcsfoldi (1988)
Genotoxicity
Induced DNA repair in rat hepatocyte primary
cultures was assessed following treatment with
1,1-biphenyl and [3H] thymidine for 18 hours
after cell attachment. DNA synthesis induced
by carcinogens was measured by
liquid-scintillation counting.
1,1-Biphenyl (10 2 and 10 3 M) was not
carcinogenic, but some of its derivatives were.
Carcinogenicity was determined by the amount of
unexpected DNA synthesis observed.
1,1-Biphenyl tested negative
in unscheduled DNA synthesis
in rat hepatocytes.
Williams (1978);
Brouns et al. (1979)
Genotoxicity
The diploid D7 strain of Saccharomyces
cerevisiae was tested for gene conversion (trp
locus) and mitotic recombination (ade locus),
with metabolic activation (S-9) following
4-hour exposure to 1,1-biphenyl. Salmonella
typhimurium strains TA100, TA98, TA1535,
TA1537, TA1538, TA1532, and TA2636 were
exposed to 1,1-biphenyl in a microsome assay
(Ames test) by standard plate incorporation and
by liquid incubation, with and without
metabolic activation.
1,1-Biphenyl was positive for mitotic
recombination in S. cerevisiae, with and without
metabolic activation (154 g/mL). Toxicity was
only observed when 1,1-Biphenyl was suspended
in dimethyl sulfoxide (DMSO), as opposed to in
the media directly. 1,1-Biphenyl tested negative
under all conditions in the Ames test (0.1 (ig/plate
to 500 (ig/plate).
1,1-Biphenyl was positive for
mitotic recombination in yeast
but negative for mutagenicity
in bacteria.
Pagano et al. (1983)
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4-4-2011
DERIVATION OF PROVISIONAL VALUES
Table 4 summarizes the noncancer reference values. Table 5 summarizes the cancer
values. IRIS data are indicated in the table if available.
Table 4. Summary of Reference Values for 1,1-Biphenyl (CASRN 92-52-4)
Toxicity Type
(units)
Species/Sex
Critical Effect
p-Reference
Value
POD
Method
POD
UFC
Principal Study
Subchronic p-RfD
(mg/kg-day)
Rat/F
Increased incidence
of fetal skeletal
anomalies
1 x KT1
bmdl5
9.59
100
Khera et al. (1979)
Chronic RfDa
(mg/kg-day) IRIS,
1989
Rat/M, F
Kidney damage
5 x 10~2
NOAEL
50
100
Ambrose et al.
(1960)
Screening
Subchronic p-RfC
(mg/m3)b
Mouse/M,
F
Congestion and
edema of the liver
and kidneys
4 x 10~3
BMCLjqhec
1.23
300
Cannon
Laboratories, Inc.
(1977)
Screening Chronic
p-RfC (mg/m3)b
Mouse/M,
F
Congestion and
edema of the liver
and kidneys
4 x 10~4
BMCLjqhec
1.23
3000
Cannon
Laboratories, Inc.
(1977)
aAll the reference values obtained from IRIS are indicated with the latest review date. The IRIS RfD was last
revised in 1989.
bA screening value is provided in Appendix A of this document.
Table 5. Summary of Cancer Values for 1,1-Biphenyl (CASRN 92-52-4)
Toxicity Type
Species/Sex
Tumor Type
Cancer
Value
Principal Study
Screening p-OSF
(mg/kg-day)
Mouse/F
Combined hepatocellular adenomas and
carcinomas
8 x 10~3
Umeda et al.
(2005)
p-IUR (mg/m3)
None
None
None
None
aA screening value is provided in Appendix A of this document.
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DERIVATION OF ORAL REFERENCE DOSES
Table 6 summarizes relevant subchronic- and chronic-duration oral toxicity studies.
Table 6. Summary of Relevant Oral Systemic Toxicity
Studies for 1,1-Biphenyl (CASRN 92-52-4)
References
# M/F,
Species
Exposure
(mg/kg-day)d
Frequency/
Duration
NOAEW
(mg/kg-day)
LOAELadj"
(mg/kg-day)
Critical Endpoint
Umeda et al.
(2004)
0/10,
mouse
0, 101, 404, 809,
1556, 1929, 2924
7 d/wk, for
13 wks, in diet
1.93 x 103
2.92 x 103
Peroxisome
proliferation
Shibata et al.
(1989)
5/0, rat
500
7 d/wk, for
8 wks, in diet
C
5.00 x 102
Induced microcalculi
Tamano et al.
(1993)
20/0,
mouse
1803.8
7 d/wk, for
32 wks, in diet
1.80 x 103
None
Increased incidences
of interstitial
nephritis
Ambrose et al.
(1960); SRI
(1953)
15/15,
rat
Male:
0.723, 3.62, 7.23,
36.2, 72.3, 362,
723
Female:
0.820,4.10, 8.20,
41.0, 82.0,410,
820
7 d/wk, for
700 d, in diet
7.23 x 10
3.62 x 102
Kidney damage
Umeda et al.
(2002)
50/50,
rat
Male: 0, 39.5,
118, 335
Female: 0, 45.9,
138,413
7 d/wk for
105 wks in
diet
C
3.95 x 10
Calculi in the kidney
and urinary lesions
Khera et al.
(1979)
0/18-20,
rat
0,125, 250, 500,
1000
7 d/wk,
GDs 6-15
2.5 x 102
5 x 102
Increased incidence
of fetuses with
skeletal anomalies
"NOAELA|,[ = NOAEL x (feeding schedule).
YOAELadj = LOAEL x (feeding schedule).
°No NOAEL was identified. NOAEL is considered equal to a LOAEL/10 for screening purposes.
dExposure is given in average daily dose (ADD) in mg/kg-day adjusted for duration (DoseADj)-
Derivation of Subchronic p-RfD
An oral developmental toxicity study by Khera et al. (1979) is selected as the principal
study for derivation of subchronic p-RfD. The critical effect is increased numbers of fetuses
with skeletal anomalies. This study is a peer reviewed published study with adequate number of
dose groups and dose spacing, sufficient group sizes, comprehensive endpoint assessment and
quantitation of results to describe dose-response relationships for the critical effects in rats and
mice associated with gestational oral exposure to biphenyl. Among the available acceptable
studies, Khera et al. (1979) study represents the lowest credible point of departure for developing
a subchronic p-RfD.
Of the two sub chronic-duration studies available in the database (see Table 2), none
presents a dose-response relationship and quantitative data to be utilized as the principal study.
Shibata et al. (1989) observed microcalculi in the bladder after administration of 500-mg/kg-day
26
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1,1-biphenyl in a powdered basal diet for 8 weeks. No other organs were examined.
Umeda et al. (2004) examined the livers and observed peroxisome proliferation in female mice
after administration of 2924 mg/kg-day of 1,1-biphenyl. No other organs were examined.
Additional studies are needed to clarify subchronic-duration toxicity associated with
1,1-biphenyl oral exposure. A carcinogenic study by Tamano et al. (1993) observed incidence of
interstitial nephritis in the kidneys of mice after administration of 1803.8-mg/kg-day
1,1-biphenyl in the diet for 32 weeks. This study did not investigate other organs such as liver
effects. While, there is no consistency on results from subchronic-duration studies, four
chronic-duration studies reported in the database consistently observed kidney and urinary
bladder effects as the most sensitive endpoint and interim subchronic effects were reported in
these chronic studies (Ambrose et al., 1960; Umeda et al., 2002, 2005; Takita, 1983) (see
Table 2). The database includes a single developmental toxicity study in pregnant Wistar rats
exposed by gavage on GDs 6-15 (Khera et al., 1979), and one- and three-generation
reproductive toxicity studies of rats (Ambrose et al., 1960) (see Table 2). No exposure-related
effect on the number of dams with litters was found following dietary exposure of male and
female albino rats to dietary doses as high as 410 mg/kg-day for 11 or 60 days prior to mating
(Ambrose et al., 1960). The oral developmental toxicity study (Khera et al., 1979), reported
frank maternal toxicity (increased mortality [5/20 vs. 0/18 in controls] and decreased number of
dams with live fetuses [9/20 vs. 16/18 in controls]) at the highest dose (1000 mg/kg-day).
Significantly increased incidences of fetuses with skeletal anomalies were noted at doses
>500 mg/kg-day.
While the selected kidney effects (i.e., transitional cell simple hyperplasia and
mineralization in the renal pelvis, hemosiderin deposition in females, and papillary
mineralization in males) in chronically-exposed F344 rats (Umeda et al., 2002) are good
candidate critical effects for deriving chronic RfD, in the absence of a suitable subchronic study,
the fetal skeletal anomalies (on a per litter basis) in litters from biphenyl-treated pregnant Wistar
rats by Khera et al. (1979) represent the best option as principal study for deriving a subchronic
p-RfD. In the oral developmental toxicity study, pregnant Wistar rats were exposed by gavage to
0, 125, 250, 500, or 1000 mg biphenyl/kg-day on GDs 6-15 (Khera et al., 1979). Significantly
increased numbers of fetuses with skeletal anomalies (wavy ribs, extra ribs, small 13th rib,
missing or unossified sternebrae, delayed ossification of the calvarium) were noted at doses
>500 mg/kg-day, and the number of litters exhibiting any of these anomalies was significantly
higher at the 500 mg/kg-day dose level relative to controls. Frank maternal toxicity (increased
mortality [5/20 vs. 0/18 in controls] and decreased number of dams with live fetuses [9/20 vs.
16/18 in controls]) occurred at the highest dose (1000 mg/kg-day). Khera et al. (1979) is a
developmental toxicity resulting from a narrow period of exposure and the developmental period
is recognized as a susceptible life stage when exposure during a time window of development is
more relevant to the induction of developmental effects than lifetime exposure (U.S. EPA, 1991).
Khera et al. (1979) with a NOAEL and LOAEL of 250 and 500 mg/kg-day for delayed skeletal
development is selected as the principal study for deriving subchronic p-RfD.
A BMDL5 of 9.59 mg/kg-day due to fetal skeletal anomalies (on a per litter basis) in
litters from biphenyl-treated pregnant Wistar rats was the POD for deriving an oral subchronic
p-RfD for 1,1-biphenyl.
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Female rats, 18 to 20 per dose group, were administered by gavage a daily dose of 0, 125,
250, 500, or 1000 mg/kg. No additional dose adjustments or units conversion is needed for
deriving subchronic p-RfD.
All available core dichotomous models in the EPA BMDS (version 2.1.2) were fit to the
incidence data of anomalous litters (see Table 7). The multistage model was run for all
polynomial degrees up to n - 1 (where n is the number of dose groups including control).
Adequate model fit was judged by three criteria: goodness-of-fit p-value (p > 0.1), visual
inspection of the dose-response curve, and a value of <2 for the largest scaled residual for any
data point in the dataset (including the control). Among all of the models providing adequate fit
to the data, the lowest BMDL was selected as the potential POD when the difference between the
BMDLs estimated from these models was more than threefold; otherwise, the BMDL from the
model with the lowest AIC was chosen as the candidate POD. In accordance with EPA (2000b)
guidance, BMDs and BMDLs associated with an extra risk of 5% were calculated for all models,
considering that the critical effect and the principal studies are from a developmental study.
When core models failed to provide adequate fit to the data, manipulations of the models (model
restriction adjustments, specification of initial parameters, and use of alternative models) were
attempted in an effort to achieve adequate fit. If these manipulations failed to achieve better fit,
the highest dose was dropped and the entire modeling procedure was repeated. If an adequate fit
could not be achieved after dropping the highest dose, then the dataset was determined to be
unsuitable for BMD modeling. The log-logistic model with BMD5 of 27.03 mg/kg-day and
BMDL5 of 9.59 mg/kg-day is the best model fit and presents the lowest BMD/BMDL.
Table 7. BMD Modeling Dataset for Incidence of Litters with Fetal Skeletal
Anomalies from Wistar Rat Dams Administered Biphenyl by Gavage on GDs 6-15a
(DOSExhera et al.[1979])n
(mg/kg-day)
(DOSEA|,.i)n
(mg/kg-day)
Number of Subjects
Litters with Fetal
Skeletal Anomaliesb
0
0
16
8
125
125
20
11
250
250
18
13
500
500
18
15
1000
1000
9
6
aKhera et al. (1979).
bThe study authors reported one runted fetus in the control group and one fetus with kinky tail in the
250-mg/kg-day dose group, which may have influenced the reported incidence data for anomalous
litters/litters examined.
Significantly different from controls (p < 0.05) according to Fisher's exact test conducted for this review.
Goodness of fit statistics and benchmark results for the gestationally-exposed rats
(Khera et al., 1979) dataset are summarized in Table 8. Appendix C presents graphical and
textual output of BMDS.
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Table 8. Summary of BMD Modeling Results for Incidence of Litters
with Fetal Skeletal Anomalies from Wistar Rat Dams Administered
Biphenyl by Gavage on GDs 6-15a
Model
Goodness-of-Fit
Benchmark Result (mg/kg-d)
%2 /?-Valueb
Largest
Residual
AIC
BMDS
BMDL5
Gammab, WeibulF, Multistage
(l-degree)d
0.31
-1.25
106.11
54.45
24.15
Logistic
0.28
1.17
106.42
73.97
36.73
Log-Logistice'e
0.41
-1.32
105.33
27.03
9.59
Log-Probitc
0.23
-1.59
106.55
125.14
55.10
Probit
0.28
1.20
106.50
79.59
41.02
aKhera et al. (1979).
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
°Power restricted to >1.
dBetas restricted to >0.
"Selected model; the model with the lowest BMDL was selected because BMDL values for models providing
adequate fit differed by more than threefold; this model also had the lowest AIC.
BMD = maximum likelihood estimate of the dose associated with the selected benchmark response; BMDL = 95%
lower confidence limit on the BMD (subscripts denote benchmark response: i.e., 5 = dose associated with 5% extra
risk)
A subchronic p-RfD of 1 x 1CT1 mg/kg-day using a BMDL5 of 9.59 mg/kg-day as the
POD due to incidence of litters with fetal skeletal anomalies from Wistar rat dams administered
biphenyl by gavage on GDs 6-15 (Khera et al., 1979) is derived as follows:
Subchronic p-RfD = BMDL5 -h UFc
= 9.59 mg/kg-day -MOO
= 1 x 10-1 mg/kg-day
Tables 9 and 10, respectively, summarize the UFs and the confidence descriptor for the
subchronic p-RfD for 1,1-biphenyl.
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Table 9. UFs for Subchronic p-RfD of 1,1-Biphenyl (CASRN 92-52-4)
UF
Value
Justification
ufa
10
A UFa of 10 is applied for interspecies extrapolation to account for potential
toxicokinetic and toxicodynamic differences between rats and humans. There are
no data to determine whether humans are more or less sensitive than rats to
subchronic-duration oral exposure to 1,1-biphenyl.
ufd
1
A UFd of 1 is applied because the database includes one acceptable
multigeneration reproductive study (Dow Chemical Co, 1953), one acceptable
developmental study in rats (Khera et al., 1979).
UFh
10
A UFh of 10 is applied for intraspecies differences to account for potentially
susceptible individuals in the absence of information on the variability of response
in humans.
ufl
1
A UFl of 1 is applied because the POD has been developed using a BMDL5.
UFS
1
A UFS of 1 is applied because a developmental toxicity study (Khera et al., 1979)
is utilized as the principal study.
UFC
100
Table 10. Confidence Descriptor for Subchronic p-RfD
for 1,1-Biphenyl (CASRN 92-52-4)
Confidence Categories
Designation3
Discussion
Confidence in the study
H
Confidence in the principal study (Khera et al.,
1979) is high. The design, conduct and reporting of
this developmental toxicity study of Wistar rats
were adequate.
Confidence in the database
H
Confidence in the database is high due to the
availability of chronic-duration oral exposure
studies in several rat and mouse strains, an
adequate developmental toxicity study in Wistar
rats, and the availability of one- and
three-generation reproductive toxicity studies in
rats.
Confidence in the subchronic
p-RfDb
H
Overall confidence in the subchronic p-RfD is high.
aL = Low, M = Medium, H = High.
bThe overall confidence cannot be greater than the lowest entry in the table.
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Derivation of Chronic p-RfD
IRIS (U.S. EPA, 2010a) has derived a chronic RfD of 5 x 10~2 mg/kg-day based on a
chronic-duration toxicity study of albino rats by Ambrose et al. (1960) with kidney damage as
the critical effect. The IRIS database (U.S. EPA, 2010a) should be checked to determine if any
changes have been made.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
Table 11 summarizes relevant inhalation toxicity studies for 1,1-biphenyl.
Table 11. Summary of Relevant Inhalation Toxicity Studies
for 1,1-Biphenyl (CASRN 92-52-4)
References
# M/F,
Species
Exposure
(mg/m3)
Frequency/
Duration
NOAELhec"
(mg/m3)
LOAEL|||(
(mg/m3)
Critical Endpoint
Monsanto Chemical Co.
(1983)
4 (sex not
reported),
rat
0, 9.34 x 10~4
7 h/d, 5
d/wk, 62 d
of 92 d
None
9.34 x 10~4
No effects
Monsanto Chemical Co.
(1983)
10 (sex
not
reported),
rat
0, 5.96 x 10~2
7 h/d, 5
d/wk, 64 d
of 94 d
None
5.96 x 10~2
Irritation of the nasal
mucosa
Monsanto Chemical Co.
(1983)
6 (sex not
reported),
rat
0, 7.89 x 10~3
7 h/d, 5
d/wk, 46 d
of 68 d
None
7.89 x 10~3
Irritation of the nasal
mucosa
Cannon Laboratories,
Inc. (1977)
50/50,
mouse
Respiratory
effects:
M: 0,94.6,
189.9; F: 0,
72.9,146.4
Extra-
respiratory
effects:
0,32.8,65.5
for both
sexes
7 h/d, 5
d/wk, 13
wks
c
c
Respiratory
effects: 72.9
Extra-
respiratory:
32.8
Congestion and
edema in the liver
the kidneys and the
lungs, inflammation
in the trachea, and
pneumonia in the
lungs
Monsanto Chemical Co.
(1983)
12 (sex
not
reported),
mouse
9.34 x 10~4
7 h/d,
5 d/wk, 62
of 92 d
None
9.34 x 10~4
Irritation of the
upper respiratory
tract
aNOAELADj = NOAEL x (MW ^ 24.45) x (hours exposed ^ 24) x (days exposed ^ total days).
YOAELadj = LOAEL x (MW ^ 24.45) x (hours exposed ^ 24) x (days exposed ^ total days).
°No NOAEL was identified. NOAEL is considered equal to a LOAEL 10 for screening purposes.
NOAELhec = NOAELA|,[ x DAF; DAF = dosimetric adjustment factor for specific site of effects (e.g., respiratory
tract region or extrarespiratory).
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Derivation of Subchronic p-RfC and Chronic p-RfC
There are no peer-reviewed published studies of subchronic- or chronic-duration human
or animal studies suitable for deriving subchronic and chronic p-RfCs. The 13-week inhalation
mouse study of Cannon Laboratories, Inc. (1977) is the only available study that employed at
least subchronic-duration exposure and included multiple biphenyl exposure levels. This study
is considered inadequate for subchronic and chronic p-RfC derivation because: (1) is a
nonpeer-reviewed and unpublished report; (2) exposure levels were highly variable during the
first half of the 13-week exposure period; (3) one of the exposure groups experienced high losses
(46/100) due to an overheating event and cannibalization after 46 exposures, although
replacement mice were subsequently added and received a total of 65 exposures; and (4) the
steep dose-response at the lowest concentration tested, which resulted in a BMCio/BMCLio well
outside the range of experimental data (no tests were performed in the lower exposure ranges).
However, the study is suitable to derive screening toxicity values. Cannon Laboratories, Inc.
(1977) is a nonpeer-reviewed and unpublished study submitted to the EPA under the Toxic
Substances Control Act (TSCA), Section 8d. Exposure concentrations were continuously
monitored and reported along with the observed health effects, and the overheating and
cannibalization by cage mates which resulted in 46/100 mortality was corrected, animals were
replaced with extended exposure time to ensure exposure uniformity under the experimental
protocol (Cannon Laboratories, Inc. 1977). Appendix A provides the derivation of screening
subchronic and chronic p-RfCs.
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR
Table 12 identifies the cancer weight-of-evidence (WOE) descriptor for 1,1-biphenyl.
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Table 12. Cancer WOE Descriptor for 1,1-Biphenyl
Possible WOE
Descriptor
Designation3
Route of Entry
(Oral,
Inhalation, or
Both)
Comments
"Carcinogenic to
Humans "
N/A
N/A
No human cancer studies are available.
"Likely to Be
Carcinogenic to
Humans "
N/A
N/A
There is no adequate evidence of plausible
association between human exposure and cancer.
"Suggestive of
Evidence of
Carcinogenic
Potential"
X
Oral
administration in
the diet only
Under the Guidelines for Carcinogen Risk
Assessment (U.S. EPA, 2005), the available
evidence for oral exposure to 1,1-biphenyl is
suggestive of carcinogenicity based on evidence
of carcinogenicity in rats in the study by
Umeda et al. (2002) and in mice as reported by
Umeda et al. (2005), but there are no assessments
between exposure to 1,1-biphenyl and increased
risk of cancer in humans. Results of both studies
show significant increases over the ranges for
historical controls and significant positive trends
for tumors observed mainly in the rat urinary
bladder and mouse liver, which are supported by
metabolism studies. Studies evaluating the
carcinogenic potential of inhaled 1,1-biphenyl in
animals were not located.
"Inadequate
Information to
Assess
Carcinogenic
Potential"
N/A
N/A
Adequate information is available to assess
carcinogenic potential.
"Not likely to be
Carcinogenic to
Humans "
N/A
N/A
No strong evidence of noncarcinogenicity in
humans is available.
aThe designation N/A means not available, and X indicates the assigned cancer WOE descriptor.
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
Derivation of p-OSF
No p-OSF can be derived because the cancer WOE descriptor for 1,1-biphenyl is
"Suggestive of Evidence of Carcinogenic PotentialHowever, Appendix A presents a screening
p-OSF.
Derivation of p-IUR
No human or animal studies examining the carcinogenicity of 1,1-biphenyl following
inhalation exposure have been located, thereby precluding derivation of a provisional inhalation
unit risk (IUR).
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APPENDIX A. PROVISIONAL SCREENING VALUES
DERIVATION OF SCREENING PROVISIONAL INHALATION REFERENCE
CONCENTRATIONS
For the reasons noted in the main document, it is inappropriate to derive subchronic and
chronic p-RfCs for 1,1-biphenyl. However, information is available for this chemical which,
although insufficient to support derivation of a provisional toxicity value, under current
guidelines, may be of limited use to risk assessors. In such cases, the Superfund Health Risk
Technical Support Center summarizes available information in an Appendix and develops a
"screening value." Appendices receive the same level of internal and external scientific peer
review as the PPRTV documents to ensure their appropriateness within the limitations detailed in
the document. Users of screening toxicity values in an appendix to a PPRTV assessment should
understand that there is considerably more uncertainty associated with the derivation of an
appendix screening toxicity value than for a value presented in the body of the assessment.
Questions or concerns about the appropriate use of screening values should be directed to the
Superfund Health Risk Technical Support Center.
Derivation of Screening Subchronic p-RfC
The study by Cannon Laboratories, Inc. (1977) is selected as the principal study for the
derivation of a screening subchronic p-RfC. Congestion and edema of the lungs were identified
as critical respiratory effects, and congestion and edema in the liver and kidneys were identified
as critical effects at the remote site of studied CD1 mice. The study authors did not report results
separately for male and female mice. Congestion and edema of the lungs, liver, and kidneys can
indicate adverse health events in humans and rodents. The study is unpublished but was
submitted to EPA under TSCA, Section 8d. The study predates current GLP principles and was
not conducted according to the current guidelines. Although the authors reported sampling
difficulties during the first 5 days of the experiment, overheating of the chamber, which forced
the replacement of 46 mice, and caused the study to run an additional 117 days to ensure all
animals were dosed as planned in the protocol. Cannon Laboratories, Inc. (1977) study
represents the only available, acceptable study for developing a screening p-RfC. Monsanto
Chemical Co. (1983) and WHO (Boehncke et al., 1999) reported similar respiratory effects in
mice and rats. No information was reported on extrarespiratory effects in both reports.
The physicochemical characteristics of 1,1-biphenyl; vapor pressure of 0.03 torr
(mm Hg), low solubility in water (4.4 mg/L), and a //-octanol/water partition coefficient of about
4.0 at 20°C, and the potential to cause both respiratory and remote effects requires that the
dosimetric adjustment be based on the regional gas dose ratio (RGDRPU) for the affected portion
of the respiratory tract (edema of the lungs) and the RGDR for extrarespiratory effects
(RGDRer), which are congestion and edema of the liver and kidneys. The most sensitive
endpoint is considered as the critical effect (U.S. EPA, 1994b).
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Exposure concentration adjustment for continuous exposure
ConcADJ
ConCcannon
Laboratories, Inc., 1977
(MW - 24.45)
(hours exposed - 24) x (days exposed - 7 days per week)
25 ppm x (154.2 - 24.45) x (7 hours - 24 hours) x
(5 days - 7 days)
25 x 1.31
= 32.8 mg/m
HEC conversion for respiratory effects
ConcHEC
RGDRpu
V Emice
V Ehuman
SAmice
SAh
uman
Female mice RGDRpu
Male mice RGDRpu
u
— ConcADJ x RGDRpi
— (Ve ~ SApu^pdent
(Ve ~ SApu)human
= mice minute volume (mice = 0.0284 L/min and
0.036 L/min, based on a default body weight of 0.0246 kg
forB6C3Fi female mice and 0.0316 kg for B6C3Fi male
mice, respectively) (see U.S. EPA, 1994b)
= 13.8 L/min
= Mice default surface area of the pulmonary region
(0.05 m2)
= Human default surface area of the pulmonary region
(54 m2)
= (0.0284-0.05)-(13.8-54) = 2.22
= (0.036 - 0.05) - (13.8 - 54)
= 2.82
ConcnEc, resp _ ConcADJ x RGDRpu
= 32.848 mg/m3 x 2.22
3 3
= 72.9 mg/m for females or 92.6 mg/m for males
Table A. 1 below presents HECs for respiratory effects for female mice treated with
1,1-biphenyl for 13 weeks. Use of female data allows for protection of both sexes because no
sex-specific data were reported, and the HEC converted from female mice is lower than the HEC
obtained from male mice.
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Table A.l. Concentration-Response Data for 1,1-Biphenyl-Induced Congestion
and Edema of the Lungs (HEC for Respiratory Effects) in Female Mice Exposed
by Inhalation for 13 Weeks"
Cone (ppm)
Conc^ (mg/m3)b
Concise (mg/m3)c
Incidence
0
0
0
0/80
25
32.8
72.9
95/98d
50
65.95
146.4
71/7 ld
aCannon Laboratories, Inc. (1977).
bConcADj = Cone x 6 24 hrs x 5 7 d.
CPhec, resp = (ppm conversion) x (average daily concentration) x RGDR. The critical effect: respiratory effects
(congestion and edema of the lungs), Category 2 gas, pulmonary (PU) and the RGDRPU = (VE ^ SAPU)mice-^ (VE^
SAPU)human = 2.22 for females.
dNot listed as statistically significant in the study but significantly different from control (p < 0.0001) by Fisher's
exact test (two-tailed) performed for this review.
An HEC conversion was performed for remote site effects (congestion and edema in the
liver and kidneys).
ConcnEC, er = ConcADJ x [(Hb/ g)mice ' (Hb/g)human]
The value of 1.0 is used for the ratio of (Hb/g)A > (Hb/g)H- A value of 1.0 is used as the
default when one or both of the partition coefficients are not available.
ConcHEC, er = 32.848 x 1.0 = 32.8 mg/m3
Table A.2 below presents HECs for extrarespiratory effects for both female and male
mice treated with 1,1-biphenyl for 13 weeks. Use of female data allows for protection of both
sexes because no sex-specific data were reported.
Table A.2. Concentration-Response Data for 1,1-Biphenyl-Induced Congestion
and Edema of the Liver and Kidneys (HEC for Extrarespiratory Effects) in Male
and Female Mice Exposed by Inhalation for 13 Weeks"
Conc (ppm)
ConcADJ (mg/m3)b
ConcnEc (mg/m3)c
Incidence
0
0
0
0/80
25
32.9
32.9
87/98d
50
65.5
65.5
71/7 ld
aCannon Laboratories, Inc. (1977).
bConcADi = Cone x 6 24 hrs x 5 7 d.
°ConCHEC ER = ConCADJ X [(Hb/g)mice (Hb/g)human] •
dNot listed as statistically significant in the report but significantly different from control (p < 0.0001) by Fisher's
exact test (two-tailed) performed for this review.
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The data for respiratory (see Table A. 1) and extrarespiratory (see Table A.2) were
modeled and compared in order to determine and identify the most sensitive effects and,
ultimately, the critical effect. Tables A.3 and A.4 below are the summary results of the BMDS
output for concentration-respiratory effects and concentration-extrarespiratory effects response
curve results, respectively.
Table A.3. Model Predictions for Concentration-Respiratory Effects of
Congestion and Edema of the Lungs"
Model
Goodness-of-Fit
/?-Valueb
AICb for
Fitted
Model
BMCiohec
(mg/kg-day)
BMCLiohec
(mg/kg-day)
Conclusions
Log-Logistic
1.00
28.8171
53.2522
0.104152
BMC/BMCL ratio >3
Quantal
Linear
0.9682
28.9412
2.17812
1.65871
Selected as the lowest BMCL
for the POD with a range of
0.054 to 10.007, among models
with a BMC/BMCL ratio <3.
Selected as the lowest AIC for
the POD with a range of 0.054
to 10.007, among models with a
BMC/BMCL ratio <3.
Multistage
0.4863
23.4848
11.9458
1.44597
BMC/BMCL ratio >3
Gamma
0.9991
30.8171
33.2408
1.66971
BMC/BMCL ratio >3
Weibull
0.9988
30.8171
16.013
1.66971
BMC/BMCL ratio >3
Log-Probit
0.9997
30.817
42.3942
8.55 x 10~9
BMC/BMCL ratio >3
Probit
0.9997
30.817
43.1953
16.013
Logistic
0.9997
30.817
55.4769
19.4002
aCannon Laboratories, Inc. (1977).
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
AIC = Akaike's Information Criteria; BMD = benchmark dose; BMDL = lower confidence limit (95%) on the
benchmark dose.
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Table A.4. Model Predictions for Concentration-Respiratory Effects
of Congestion and Edema of the Liver and Kidneys"
Model
Goodness-of-Fit
/?-Valueb
AICb for
Fitted
Model
BMCiohec
(mg/kg-day)
BMCLjohec
(mg/kg-day)
Conclusions
Log-Logistic
1.00
28.8171
25.8765
6.00398
BMC/BMCL ratio >3
Quantal
Linear
0.6435
28.9412
1.49511
1.22974
Selected as the lowest BMCL
for the POD with a range of
0.054 to 10.007, among models
with a BMC/BMCL ratio <3.
Selected as the lowest AIC for
the POD with a range of 0.054
to 10.007, among models with a
BMC/BMCL ratio <3
Multistage
0.9946
23.4848
7.1934
1.31769
BMC/BMCL ratio >3
Gamma
1.000
70.7329
18.0692
1.3176
BMC/BMCL ratio >3
Weibull
0.9995
30.8171
16.7222
1.31769
BMC/BMCL ratio >3
Log-Probit
0.9996
30.817
22.4429
3.59818
BMC/BMCL ratio >3
Probit
0.9996
30.817
21.1293
9.0211
Logistic
0.9996
72.7326
26.2308
10.8064
aCannon Laboratories, Inc. (1977).
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
AIC = Akaike's Information Criteria; BMD = benchmark dose; BMDL = lower confidence limit (95%) on the
benchmark dose.
Following the above procedure, dichotomous-variable models in the EPA BMDS
(version 2.1.1) with a benchmark response (BMR) of 10% extra risk with restricted parameters
(U.S. EPA, 2008) were fit to the data shown in Table A. 1 for congestion and edema in lungs in
female mice, and Table A.2 for congestion and edema in the liver and kidneys in female and
male mice (Cannon Laboratories, Inc., 1977). Tables A.3 and A.4 provide summary statistics
and outputs for benchmark concentration (BMC) modeling of the 13-week inhalation data for
respiratory effects and extrarespiratory effects, respectively. Adequate fit (/>value > 0.1) is
achieved for the all the dichotomous-variable models in the EPA BMDS (version 2.1.1) for both
respiratory and extrarespiratory effects data. The scaled residuals are all less than 2. The range
of BMC lower bound 95% confidence interval (BMCLs) is greater than 3-fold, which requires
selecting the lowest BMCL value, independently of the AIC values. The quantal linear model
for respiratory and extrarespiratory effects data presented the lowest BMCio and BMCLio values:
a BMCiohec of 2.17 mg/m3 and aBMCLioHEC of 1.65 mg/m3, and aBMCioHEC of 1.5 mg/m3 and
a BMCLiohec of 1.23 mg/m3, respectively. The lower BMCLiohec of 1.23 mg/m3 from
extrarespiratory effects in male and female mice is selected as the POD for deriving a screening
subchronic p-RfC for 1,1-biphenyl. The POD based on a BMCLiohec of 1.23 mg/m3 due to
extrarespiratory effects (congestion and edema of the liver and kidneys) in both sexes is also
protective respiratory effects with a predicted BMCLiohec of 1.65 mg/m3. Appendix C presents
details of the BMC analysis and the curve-output statistics.
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"3
The screening subchronic p-RfC for 1,1-biphenyl, based on a BMCLiohec of 1.2 mg/m
in mice (Cannon Laboratories, Inc., 1977), is derived as follows:
Screening Subchronic p-RfC = BMCLiohec ^ UFc
= 1.23-300
= 4 x 10 3 mg/m3
Table A.5 summarizes the UFs for the screening subchronic p-RfC for 1,1-biphenyl.
Table A.5. UFs for Screening Subchronic p-RfC for 1,1-Biphenyl
UF
Value
Justification
ufa
3
A UFa of 3 is applied for animal-to-human extrapolation to account for the toxicodynamic
portion of a UFA because the toxicokinetic portion (100 5) has been addressed in dosimetric
conversions.
ufd
10
A UFd of 10 is selected because there are no acceptable two-generation reproduction studies
or developmental studies, and there are no indications of any other studies that may be
relevant for the database UF.
UFh
10
A UFh of 10 is applied for intraspecies differences to account for potentially susceptible
individuals in the absence of information on the variability of response in humans.
ufl
1
A UFl of 1 is applied because the POD has been developed using a BMCL.
UFS
1
A UFS of 1 is applied because a subchronic-duration study was utilized as the critical study.
UFC
300
Derivation of Screening Chronic p-RfC
Chronic-duration toxicity studies for inhalation of 1,1-biphenyl are not available.
Therefore, the same POD used for the screening subchronic p-RfC (BMCLiohec of 1.2 mg/m3)
from 13-weeks inhalation exposure to 1,1-biphenyl in mice (Cannon Laboratories, Inc., 1977) is
used for deriving a screening chronic p-RfC.
Screening Chronic p-RfC = BMCLiohec ^ UFc
= 1.2-3000
= 4 x 10 4 mg/m3
Table A.6 summarizes the UFs for the screening chronic p-RfC for 1,1-biphenyl.
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Table A.6. UFs for Screening Chronic p-RfC for 1,1-Biphenyl
UF
Value
Justification
ufa
3
A UFa of 3 is applied for animal-to-human extrapolation to account for the toxicodynamic
portion of a UFA because the toxicokinetic portion (100 5) has been addressed in dosimetric
conversions.
ufd
10
A UFd of 10 is selected because there are no acceptable two-generation reproduction studies
or developmental studies, and there are no indications of any other studies that may be
relevant for the database UF.
UFh
10
A UFh of 10 is applied for intraspecies differences to account for potentially susceptible
individuals in the absence of information on the variability of response to humans.
ufl
1
A UFl of 1 is applied because the POD was developed using a BMCL.
UFS
10
A UFS of 10 is applied for using data from a subchronic-duration study to assess potential
effects from chronic-duration exposure because data for evaluating response from
chronic-duration exposure are unavailable.
UFC
3000
Derivation of Screening Provisional Oral Slope Factor (Screening p-OSF)
For the reasons noted in the main document, it is inappropriate to derive a p-OSF for
1,1-biphenyl. However, information is available for this chemical which, although insufficient to
support derivation of a provisional toxicity value, under current guidelines, may be of limited use
to risk assessors. In such cases, the Superfund Health Risk Technical Support Center
summarizes available information in an Appendix and develops a "screening value."
Appendices receive the same level of internal and external scientific peer review as the PPRTV
documents to ensure their appropriateness within the limitations detailed in the document. Users
of screening toxicity values in an appendix to a PPRTV assessment should understand that there
is considerably more uncertainty associated with the derivation of an appendix screening toxicity
value than for a value presented in the body of the assessment. Questions or concerns about the
appropriate use of screening values should be directed to the Superfund Health Risk Technical
Support Center.
The study by Umeda et al. (2005) is selected as the principal study. The Umeda et al.
(2005) study, a 2-year oral administration of a 1,1-biphenyl-containing diet, produced
dose-related increases in benign and malignant hepatocellular tumors and preneoplastic liver
lesions in female mice, together with nonneoplastic kidney lesions in both male and female mice
at an effect level of 52.5 mg/kg-day. Comparatively, the Umeda et al. (2002) report, a 105-week,
carcinogenicity study yielded evidence in male rats of 1,1-biphenyl-induced papillomas and
carcinomas in the urinary bladder at 96.4 mg/kg-day. The data set from the female rats did not
have statistically significant cancer endpoints; only male rats showed bladder tumor responses
(about 40%) at the highest dose. The control group and the first two dose levels showed no
bladder response in male rats. No bladder tumors were observed in female rats, and no other
organ response was reported. Also, the bladder tumors were observed at a relatively higher dose
(96.4 mg/kg-day) compared to the liver tumor observed in mice at 52.5 mg/kg-day (Umeda et al.,
2005). Both studies (Umeda et al., 2005, 2002) are peer-reviewed publications, well conducted,
and performed according to GLP principles, and otherwise meet the standards of study design
and performance in terms of number of animals, examination of endpoints, and presentation of
40
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information. However, the Umeda et al. (2005) study presents a better dose-response trend and
is more suitable for a quantitative cancer dose-response assessment.
The dosimetric adjustments shown below were made for dietary treatment in adjusting
doses for oral cancer analysis. Umeda et al. (2005) reported mice body weight, average food
consumption, and daily 1,1-biphenyl intake (see Table A.7) , which are used for calculations of
the adjusted average daily dose and the HED (U.S. EPA, 1988).
(DOSEaDJ, HED)umeda et al.
2005
Body-weight adjustment
BWh
BWa and daily food consumption
Body-weight adjustment
(DOSEaDJ, HED)umeda
et al, 2005
(DOSEADj)umeda et al, 2005
(DOSEaDJ, HED)umeda et al, 2005
(DOSEaDJ, HED)umeda et al, 2005
(DOSEaDJ, HED)umeda et al, 2005
(DOSEaDJ, HED)umeda et al, 2005
(DOSEaDJ, HED)umeda et al, 2005
(Dose)umeda et ai, 2005 x (days dosed
week) x body-weight adjustment
7 days per
v 1/4
= (BWa^BWh)
= 70 kg (human reference body [U.S. EPA, 1997])
= (see Table A.7)
= (0.0431 70)1 4 = 0.1575 for male mice in the
667-ppm (97-mg/kg-day) dose group.
= (0.0325 -h 70)1/4
= 0.1468 for female mice in the 667-ppm
(134-mg/kg-day) dose group.
= (Dose)umeda et ai, 2005 x (days dosed h- total days)
x body-weight adjustment
= (Dose)„ x (7 days ^ 7 days per week)
= 97 mg/kg-day x 1.0
= 97 mg/kg-day x 1.0 x body-weight adjustment
= 97 mg/kg-day x 0.1575
= 15.2775 mg/kg-day for male mice
= 134 mg/kg-day x 1.0 x body-weight adjustment
= 134 mg/kg-day x 0.1468 = 19.6712 mg/kg-day
for female mice
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Table A.7. Body Weight, Food Consumption, and Daily Intake of the Mice Fed Diets
Containing 1,1-Biphenyl for 2 Years, and Calculated HEDa
Concentration in
Diet (ppm)
Body
Weightb
(g)
Average F ood
Consumption
(g/day)c
Daily 1,1-Biphenyl
Intake (mg/kg-day)c
Doscad/
(mg/kg-day)
HEDg
(mg/kg-day)
Male
0
46.9 ±4.9
5.6
0
0
0
667
43.1 ±7.9
5.5
97
97
15.3
2000
42.9 ± 6.0d
5.5
291
291
45.8
6000
32.4 ± 3.6e
5.4
1050
1050
154.0
Female
0
34.0 ±4.0
5.9
0
0
0
667
32.5 ±3.3
5.8
134
134
19.7
2000
30.5 ± 3.1s
5.9
414
414
59.8
6000
25.5 ± 3.0e
5.9
1420
1420
196.2
aUmeda et al. (2005).
bValues of body weight were expressed as mean ± standard deviation at the end of the 2-year administration period.
°Food consumption and 1,1-biphenyl intake were averaged over the 2-year administration period (reported by
Umeda et al., 2005).
Statistically significantly different atp< 0.05, by Dunnett's test.
"Statistically significantly different atp< 0.01, by Dunnett's test.
f
Adjusted daily average dose (DoseADj) = Dose x (days dosed/7 days per week).
8Human equivalent dose (HED) = Doscadj x BWadj; Body-weight adjustment (BWadj) for HED conversion for
OSF derivation = [animal body weight (BWA) ^ human body weight (BWH)]14.
Table A. 8 presents the benchmark dose (BMD) input data for combined hepatocellular
adenomas and carcinoma incidence in female mice exposed to 1,1-biphenyl for 2 years.
Table A.8. Dose-Response Data for 1,1-Biphenyl Incidence of Hepatocellular Adenomas
and the Combined Incidences of Hepatocellular Adenomas and Carcinomas in Female
BDF1 Mice Fed Diet for 2 Years"
Dose
(ppm)b
Dosched
(mg/kg-day)c
Incidence of Tumor Response
Hepatocellular
Adenoma
Hepatocellular
Carcinoma
Combined Adenoma +
Carcinoma
0
0
2/50
1/50
3/50
667
19.7
3/50
5/50
8/50
2000
59.8
12/50
7/50
16/50
6000
196.2
10/50
5/50
14/50
aUmeda et al. (2005).
bDoseADi = (Dose)umeda et ai, 2005 x food consumption per day x (l -f- body weight) x (days dosed total days).
°DoseHED = (Dose)ADj x body-weight adjustment.
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Table A.9 provides BMD multistage model predictions for the cancer OSF (Umeda et al.,
2005).
Table A.9. Multistage Cancer Model Predictions for OSFa
Model
Goodness-of-Fit
/?-Valueb
AICb for
Fitted
Model
BMD10
(mg/kg-day)
BMDL10
(mg/kg-day)
Conclusions
Combined hepatocellular
adenoma0 + carcinoma
0.9366
133.357
19.3121
12.5765
Lowest BMDL
(31 =0
The BMDL lower
than the NOAEL
8.0 x 10~3
(mg/kg-day) 1
aUmeda et al. (2005).
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
°The hepatocellular adenoma data did not fit the BMD model even after dropping the highest dose.
AIC = Akaike's Information Criteria; BMD = benchmark dose; BMDL lower confidence limit (95%) on the
benchmark dose.
The BMDLiohed , the BMD lower bound 95% confidence interval at 10% extra risk, is
12.58 mg/kg-day, and the cancer p-OSF, the slope of the linear extrapolation from the
_3 _ i
BMDLiohed to 0, or the screening p-OSFumedaetai, 2005, is 8 x 10 (mg/kg-day) based on BMD
modeling (U.S. EPA, 2008a).
Screening p-OSFumeda et ai., 2005 = 0.1 BMDLiohed
= 0.1 ^ 12.5765 (mg/kg-day)"1
= 8 x 10~3 (mg/kg-day)-1
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APPENDIX B. DATA TABLES
Table B.l. Organ Weights and Selected Urinary Bladder Lesions Incidence in Male F344
Rats Exposed to 1,1-Biphenyl in the Diet for 8 Weeks"
Parameter
Exposure Group (HED, mg/kg-day)
Control (0)
0.5% (113)
Sample size
5
5
Average final body weight (g)
327
300c
Urinary pHb
6.6 ±0.3
6.6 ±0.6
Osmolality (mOsm/kgH20)b
2011±181
2023 ± 243
Crystals (urine)
Slight
d,e
severe
BrdU labeling index (%)b
0.13 ±0.09
0.58 ±3C
Simple hyperplasiaf
0(0)
5 (100), moderate6
Pleomorphic microvilli
0(0)
5/5 (100), moderate6
Short uniform microvilli
0(0)
5/5 (100), moderate6
Ropy or leafy microridgesf
0(0)
5/5 (100), severe6
aShibata et al. (1989).
''Mean ± standard deviation (SD).
Statistically significantly different from BBN only (p < 0.05) by the Student's /-test performed by study authors.
dNumerous microcalculi seen among crystals.
"Grading (mean of group): trace, slight, moderate, severe.
fNumber of animals with morphologies, () = percent of total, average grading.
Table B.2. Organ Weights and Selected Lesion Incidence in Male B6C3Fi Mice
Exposed to 1,1-Biphenyl in the Diet for 32 Weeks"
Parameter
Exposure Group (HED, mg/kg-day)
BBN Only (0)
BBN with 1%
1,1-Biphenyl (263)
1% 1,1-Biphenyl
Only (263)
Sample size
20
20
10
Final body weight (g)b
38.4 ±2.6
32.2 ± 1.8°
30.6 ± 1.9
Urinary bladder (relative weight)b
0.11 ±0.02
0.13 ± 0.02d
0.16 ±0.09
Kidney (relative weight)b
1.56 ± 0.11
1.52 ± 0.10
1.62 ±0.09
Simple hyperplasia6
12 (60)
14 (70)
1(10)
Papillary or nodular dysplasia6
2(10)
1(5)
1(10)
Squamous cell carcinoma6
0(0)
0(0)
0(0)
aTamano et al. (1993).
bMean ± standard deviation (SD).
"Statistically significantly different from BBN only (p < 0.01) by the Student's /-test performed by study authors.
Statistically significantly different from BBN only (p < 0.05) by the Student's /-test performed by study authors.
"Number of animals with lesions, () = percent of total.
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Table B.3. Organ Weights and Survival in Albino Rats Exposed to 1,1-Biphenyl in the Diet for 2 Years"
Exposure Group (DoscAd.i, mg/kg-day)
Male rats
0.0%
0.001%
0.005%
0.01%
0.05%
0.1%
0.5%
1.0%d
Parameter
(0)
(0.723)
(3.62)
(7.23)
(36.2)
(72.3)
(362)c
(723)
Survival at 750 days
9
8
10
11
13
10
2
2
Average final body weight (g)b
396 ±24.6
424 ±5.1
383 ± 19.8
394 ± 14.2
371 ± 15.8
366 ±23.7
345
--
Relative liver weight (g/lOOg bw)b
2.89 ±0.16
2.66 ±0.06
2.84 ±0.15
2.47 ± 0.07
3.03 ±0.12
2.98 ±0.19
3.12
--
Relative kidney weight (g/lOOg bw)b
0.75 ± 0.02
0.70 ±0.03
0.73 ± 0.02
0.72 ±0.01
0.74 ±0.02
0.83 ±0.05
1.17
--
Relative heart weight (g/lOOg bw)b
0.32 ±0.015
0.28 ±0.008
0.30 ±0.01
0.31 ±0.008
0.31 ±0.007
0.34 ±0.012
0.36
--
Relative testes weight (g/lOOg bw)b
0.72 ±0.03
0.62 ± 0.07
0.56 ±0.06
0.67 ± 0.07
0.65 ±0.06
0.60 ±0.08
0.38
--
Female rats
0.0%
0.001%
0.005%
0.01%
0.05%
0.1%
0.5%
1.0%
Parameter
(0)
(0.820)
(4.10)
(8.20)
(41.0)
(82.0)
(410)
(820)
Survival at 750 days
9
6
5
11
5
5
5
2
Average final body weight (g)b
333 ±9.4
414 ± 13.4
335 ± 16.6
341 ±9.1
306 ± 12.5
327 ±6.8
226 ±25.8
-
Relative liver weight (g/lOOg bw)b
3.11 ± 0.15
3.21 ±0.17
2.81 ±0.28
3.46 ±0.74
3.51 ± 0.12
3.18 ± 0.10
4.52 ±0.20
-
Relative kidney weight (g/lOOg bw)b
0.65 ±0.01
0.62 ±0.02
0.64 ± 0.02
0.62 ± 0.02
0.68 ±0.02
0.65 ±0.01
1.39 ±0.14
-
Relative heart weight (g/lOOg bw)b
0.33 ±0.01
0.28 ±0.07
0.31 ±0.03
0.30 ±0.01
0.31 ±0.01
0.32 ±0.01
0.46 ± 0.04
-
aAmbrose et al. (1960).
bMean ± standard error (SE).
°SE values for 0.5%-exposure group in male rats was not reported.
dAmbrose et al. (1960) did not report results for 1% dose level.
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Table B.4. Selected Incidence of Kidney Lesions in Male F344 Rats Exposed
to 1,1-Biphenyl in the Diet for 105 Weeks"
Parameter
Exposure Group (HED, mg/kg-day)
0 ppm (0)
500 ppm (10.7)
1500 ppm (32.1)
4500 ppm (96.4)
Urinary bladder lesions
Simple hyperplasiab
0/50 (0)
0/50 (0)
0/50 (0)
12/50 (24)c
Nodular hyperplasiab
0/50 (0)
0/50 (0)
0/50 (0)
40/50 (80)c
Papillary hyperplasiab
0/50 (0)
0/50 (0)
0/50 (0)
17/50 (34)c
Total cell hyperplasiab
0/50 (0)
0/50 (0)
0/50 (0)
45/50 (90)
Transitional cell papillomab
0/50 (0)
0/50 (0)
0/50 (0)
10/50 (20)d
Transitional cell carcinomab
0/50 (0)
0/50 (0)
0/50 (0)
24/50 (48)d
Total bladder tumorsb
0/50 (0)
0/50 (0)
0/50 (0)
31/50 (62)
Squamous metaplasiab
0/50 (0)
0/50 (0)
0/50 (0)
19/50 (38)c
Squamous cell hyperplasiab
0/50 (0)
0/50 (0)
0/50 (0)
13/50 (26)c
Squamous cell papilloma and carcinomab
0/50 (0)
0/50 (0)
0/50 (0)
1/50 (2)
Inflammatory polypb
0/50 (0)
0/50 (0)
0/50 (0)
10/50 (20)c
Calculusb
0/50 (0)
0/50 (0)
0/50 (0)
43/50 (86)
Ureter lesions
Simple hyperplasiab
1/50 (2)
0/50 (0)
0/50 (0)
8/50 (16)c
Nodular hyperplasiab
0/50 (0)
0/50 (0)
0/50 (0)
1/50 (2)
Dilationb
0/50 (0)
0/50 (0)
0/50 (0)
14/50 (28)c
Kidney lesions
Simple hyperplasiab
6/50 (12)
8/50 (16)
5/50 (10)
19/50 (38)e
Nodular hyperplasiab
0/50 (0)
1/50 (2)
1/50 (2)
21/50 (42)c
Squamous metaplasiab
0/50 (0)
0/50 (0)
0/50 (0)
2/50 (4)
Mineralization of pelvisb
9/50 (18)
6/50 (12)
10/50 (20)
18/50 (36)
Desquamation: pelvisb
1/50 (2)
0/50 (0)
0/50 (0)
11/50 (22)c
Calculusb
0/50 (0)
0/50 (0)
0/50 (0)
13/50 (26)c
Other lesions
Mineralization of cortico-medullary junctionb
0/50 (0)
0/50 (0)
0/50 (0)
10/50 (20)c
Mineralization of papillab
9/50 (18)
9/50 (18)
14/50 (28)
23/50 (46)e
Papillary necrosisb
0/50 (0)
0/50 (0)
0/50 (0)
7/50 (14)
Infarctb
0/50 (0)
0/50 (0)
0/50 (0)
0/50 (0)
Deposit of hemosiderin15
0/50 (0)
0/50 (0)
0/50 (0)
0/50 (0)
Chronic nephrophathyb
45/50 (90)
45/50 (90)
43/50 (86)
34/50 (68)
"Umcda et al. (2002).
dumber of animals with endpoint/number of animals examined, () = percent of total.
Statistically significantly different from control (p < 0.01) by Chi-square test performed by study authors.
Statistically significantly different from control (p < 0.01) by Fisher's exact test performed by study authors.
"Statistically significantly different from control (p < 0.05) by Chi-square test performed by study authors.
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Table B.5. Selected Incidence of Kidney Lesions in Female F344 Rats Exposed
to 1,1-Biphenyl in the Diet for 105 Weeks"
Parameter
Exposure Group (HED, mg/kg-day)
0 ppm (0)
500 ppm (11.0)
1500 ppm (32.9)
4500 ppm (98.7)
Urinary bladder lesions
Simple hyperplasiab
0/50 (0)
0/50 (0)
1/50 (20)
1/50 (20)
Nodular hyperplasiab
1/50 (20)
0/50 (0)
0/50 (0)
5/50 (10)
Papillary hyperplasiab
0/50 (0)
0/50 (0)
0/50 (0)
4/50 (8)
Total cell hyperplasiab
1/50 (20)
0/50 (0)
1/50 (20)
10/50 (20)
Transitional cell papillomab
0/50 (0)
0/50 (0)
0/50 (0)
0/50 (0)
Transitional cell carcinomab
0/50 (0)
0/50 (0)
0/50 (0)
0/50 (0)
Total bladder tumorsb
0/50 (0)
0/50 (0)
0/50 (0)
0/50 (0)
Squamous metaplasiab
0/50 (0)
0/50 (0)
0/50 (0)
4/50 (8)
Squamous cell hyperplasiab
0/50 (0)
0/50 (0)
0/50 (0)
1/50 (2)
Squamous cell papilloma and carcinomab
0/50 (0)
0/50 (0)
0/50 (0)
0/50 (0)
Inflammatory polypb
0/50 (0)
0/50 (0)
0/50 (0)
0/50 (0)
Calculusb
0/50 (0)
0/50 (0)
0/50 (0)
8/50 (16)
Ureter lesions
Simple hyperplasiab
0/50 (0)
0/50 (0)
0/50 (0)
2/50 (4)
Nodular hyperplasiab
0/50 (0)
0/50 (0)
0/50 (0)
0/50 (0)
Dilationb
0/50 (0)
0/50 (0)
0/50 (0)
6/50 (12)
Kidney lesions
Simple hyperplasiab
3/50 (6)
5/50 (10)
12/50 (24)c
25/50 (50)d
Nodular hyperplasiab
0/50 (0)
0/50 (0)
1/50 (2)
12/50 (24)d
Squamous metaplasiab
0/50 (0)
0/50 (0)
0/50 (0)
0/50 (0)
Mineralization of pelvisb
12/50 (24)
12/50 (24)
18/50 (36)
27/50 (54)d
Desquamation: pelvisb
0/50 (0)
0/50 (0)
0/50 (0)
2/50 (4)
Calculusb
0/50 (0)
0/50 (0)
0/50 (0)
3/50 (6)
Other lesions
Mineralization of cortico-medullary junctionb
21/50 (42)
2/50 (4)
26/50 (52)
18/50 (36)
Mineralization of papillab
2/50 (4)
6/50 (12)
3/50 (6)
12/50 (24)d
Papillary necrosisb
0/50 (0)
0/50 (0)
0/50 (0)
23/50 (46)d
Infarctb
1/50 (2)
0/50 (0)
0/50 (0)
8/50 (16)e
Deposit of hemosiderinb
4/50 (8)
8/50 (16)
22/50 (44)d
25/50 (50)d
Chronic nephrophathyb
33/50 (66)
35/50 (70)
33/50 (60)
26/50 (52)
aUmeda et al. (2002).
dumber of animals with endpoint/number of animals examined, () = percent of total.
Statistically significantly different from control (p < 0.01) by Fisher's exact test performed by study authors.
Statistically significantly different from control (p < 0.01) by Chi-square test performed by study authors.
"Statistically significantly different from control (p < 0.05) by Chi-square test performed by study authors.
47
1,1-Biphenyl
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4-4-2011
Table B.6. Stones of the Urinary System in Wistar Rats Exposed
to 1,1-Biphenyl in the Diet for 75 Weeks"
Exposure Group (DoscAim, mg/kg-day)
Parameter
0 mg/kg (0)
2500 mg/kg (188)
5000 mg/kg (375)
Male rats
Kidney stonesb
0/44 (0)
6/46 (13)
15/47 (32)
Ureter stonesb
0/44 (0)
0/46 (0)
2/47 (4)
Urinary bladder stonesb
0/44 (0)
0/46 (0)
13/47 (28)
Female rats
Kidney stonesb
0/43 (0)
1/43 (2)
18/39 (46)
Ureter stonesb
0/43 (0)
1/43 (2)
2/39(51)
Urinary bladder stonesb
0/43 (0)
0/43 (0)
6/39 (15)
aBoehncke et al. (1999).
bNumber of animals with litters/number of animals exposed, () = percent of total.
Table B.7. Selected Incidence of Liver Lesions in Female BDF1 Mice Exposed
to 1,1-Biphenyl in the Diet for 104 Weeks"
Parameter
Exposure Group (HED, mg/kg-day)
0 mg/kg-day
(0)
123 mg/kg-day
(17.5)
414 mg/kg-day
(52.5)
1420 mg/kg-day
(157.5)
Liver
Noduleb
7/50 (14)
13/50 (16)
24/50 (48)
26/50 (52)
Hepatocellular adenomab
2/50 (4)
3/50 (6)
12/50 (24)°
10/50 (20)°'d
Hepatocellular carcinomab
1/50 (2)
5/50 (10)
7/50 (14)°
5/50 (10)
Hepatocellular adenoma or carcinomab
3/50 (6)
8/50 (16)
16/50 (32)e
14/50 (28)°'d
Basophilic cell focib
1/50 (2)
1/50 (2)
12/50 (24)e
6/50 (12)°
Clear cell focib
2/50 (4)
1/50 (2)
3/50 (6)
2/50 (4)
Eosinophilic cell focib
0/50 (0)
1/50 (2)
0/50 (0)
0/50 (0)
Kidney
Desquamation: pelvisb
4/50 (8)
0/50 (0)
0/50 (0)
15/50 (30)e
Mineralization in the inner stripe-outer
medullab
3/50 (6)
5/50 (10)
12/50 (24)°
26/50 (52)e
aUmeda et al. (2005).
dumber of animals with endpoint/number of animals examined, () = percent of total.
Statistically significantly different from control (p < 0.05) by Fisher's exact test performed by study authors.
Statistically significantly different from control (p < 0.05) by Peto's test performed by researchers.
"Statistically significantly different from control (p < 0.01) by Fisher's exact test performed by study authors.
48
1,1-Biphenyl
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Table B.8. Selected Incidence of Liver Lesions in the Male BDF1 Mice Exposed
to 1,1-Biphenyl in the Diet for 104 Weeks"
Parameter
Exposure Group (HED, mg/kg-day)
0 mg/kg-day
(0)
97 mg/kg-day
(17.5)
360 mg/kg-day
(52.5)
1079 mg/kg-day
(157.5)
Liver
Noduleb
20/50 (40)
16/50 (32)
14/50 (28)
11/50 (22)
Hepatocellular adenomab
8/50 (16)
6/50 (12)
7/50 (14)
3/50 (6)
Hepatocellular carcinomab
8/50 (16)
8/50 (16)
5/50 (10)
4/50 (8)
Hepatocellular adenoma or
carcinomab
16/50 (32)
12/50 (24)
9/50 (18)
7/50 (14)
Basophilic cell focib
0/50 (0)
6/50 (12)°
1/50 (2)
2/50 (4)
Clear cell focib
0/50 (0)
6/50 (12)°
2/50 (4)
0/50 (0)
Eosinophilic cell focib
0/50 (0)
0/50 (0)
0/50 (0)
0/50 (0)
Kidney
Desquamation: pelvisb
0/50 (0)
0/50 (0)
0/50 (0)
10/50 (20)°
Mineralization in the inner stripe-outer
medullab
9/50 (18)
8/50 (16)
14/50 (28)
14/50 (28)
aUmeda et al. (2005).
bNumber of animals with endpoint/number of animals examined, () = percent of total.
Statistically significantly different from control (p < 0.01) by Fisher's exact test performed by study authors.
49
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Table B.9. Prenatal Effects Following Oral Administration of Biphenyl to
Pregnant Wistar Rats on GDs 6-15a
Effect
Dose (mg/kg-d)
0
125
250
500
1000
Rats without live fetuses at term/number
mated
2/18
0/20
1/19
2/20
1 l/20b
Corpora lutea/pregnancy (mean ± SE)
12.6 ±0.4
12.9 ±0.4
13.7 ±0.5
13.3 ±0.4
12.5 ±0.7
Live fetuses/pregnancy (mean ± SE)
11.3 ±0.7
11.8 ±0.6
11.9 ±0.6
11.2 ± 0.5
10.7 ± 1.3
Dead or resorbed fetuses (%)
4.8
3.3
6.1
7.8
13.7°
Fetal weight (g mean ± SE)
5.1 ± 0.1
5.3 ±0.1
5.2 ±0.1
5.2 ±0.1
4.5 ±0.3
Anomalous fetuses/number examined
17/176
22/236
22/213
35/199d
25/107d
Anomalous litters/number examined
8/16
11/20
13/18
15/18d
6/9
Anomalies (number of fetuses affected)
Wavy ribs, uni- and bilateral
3
7
9
8
5
Extra ribs, uni- and bilateral
9
12
9
15
6
13th rib, small sized
1
1
2
1
0
Sternebrae, missing or unossified
4
3
4
16
17
Calvarium, delayed ossification
0
2
0
0
8
Miscellaneous
1
1
1
0
0
aKhera et al. (1979).
bSignificantly (p < 0.05) different from control incidence according to Fisher's exact test. Five dams died prior to
scheduled sacrifice, five other dams were not pregnant at term, and one dam had seven resorption sites and no live
fetuses.
°Derived from nine pregnant dams with live fetuses and one dam with seven resorptions and no live fetuses. The
study author stated that the percentage of dead or resorbed fetuses in the 1000-mg/kg dose group was not
statistically significantly different from controls.
Significantly (p < 0.05) different from controls according to Fisher's exact test.
50
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Table B.10. Reproductive Summary in Albino Rats Exposed
to 1,1-Biphenyl in the Diet"
Exposure Group (HED, mg/kg-day)b
Parameter
Control
0.1% (82.0)
0.5% (410)
Experiment one
Number casting litters0
9/10 (90)
10/10 (100)
8/10 (80)
Total born
59
67
53
Range of litter size
3 to 9
2 to 10
3 to 9
Experiment two
Number casting litters0
8/8 (100)
6/8 (75)
8/9 (89)
Total born
64
63
48
Range of litter size
5 to 13
3 to 10
3 to 9
aAmbrose et al. (1960).
bAverage daily doses are for female mice only because all endpoints are female.
°Number of animals with litters/number of animals exposed, () = percent of total.
51
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Table B.ll. Histopathology of CD1 Mice Exposed to 1,1-Biphenyl
by Inhalation for 13 Weeks"
Parameter
Exposure Group (HEC, mg/m3)
0 ppm (control)
25 ppm (32.8)
50 ppm (65.5)
Trachea
Within normal limits'3
80/80 (100)
18/98 (18)
1/71 (1)
Hyperplasia with inflammation13
0/80 (0)
80/98 (82)°'d
70/71 (99)°'d
Lungs
Within normal limits'3
80/80 (0)
DNR
0/71 (0)
Abscessb
0/80 (0)
1/98 (1)
0/71 (0)
Congestion and edemab
0/80 (0)
95/98 (97)°'d
71/71 (100)od
Pneumonia b
0/80 (0)
15/98 (15)
20/71 (28)
Neoplasia13
0/80 (0)
2/98 (2)
0/71 (0)
Liver
Within normal limits'3
78/80 (98)
11/98(11)
0/71 (0)
Abscesses'3
2/80 (3)
0/98 (0)
0/71 (0)
Congestion and edemab
Not reported
87/98 (89)°'d
71/71 (100)od
Kidneys6
Within normal limits'3
76/80 (95)
11/98(11)
0/71 (0)
Abscesses b
4/80 (5)
0/98 (0)
0/71 (0)
Congestion and edemab
0/80 (0)
87/98 (89)°'d
71/71 (100)° d
Spleen®
Within normal limits'3
80/80 (100)
97/98 (99)
DNR
Neoplasia13
0/80 (0)
1/98 (1)
DNR
aCannon Laboratories, Inc. (1977).
bNumber of animals with endpoint/number of animals exposed, () = percent of total.
Significantly different from control (p < 0.05) by Fisher's exact test (two-tailed) performed for this review.
Significant association between dose and endpoint (p < 0.05) by the Chi-square test for independence performed
for this review.
eHEC is for extrarespiratory effects (25-ppm dose = 32.8 mg/m3; 50-ppm dose = 65.5 mg/m3).
DNR = data not reported.
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1,1-Biphenyl
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Table B.12. Histopathology of CD1 Mice Exposed to 1,1-Biphenyl by
Inhalation for 13 Weeks Followed by 30-Day Recovery Period"
Parameter
Exposure Group (HEC, mg/m3)
0 ppm (control)
25 ppm (32.8 mg/m3)
65.5 ppm (56.6 mg/m3)
Trachea
Within normal limits'3
17/20 (85)
3/15 (20)
2/19(11)
Chronic inflammation13
DNR
10/15 (67)°'d
12/19 (63)cd
Hyperplasia with acute
inflammation3
0/20 (0)
0/15 (0)
3/19 (16)
Hyperplasia with chronic
inflammation3
3/20 (15)
2/15 (13)
2/19(11)
Lungs
Within normal limits'3
20/20 (100)
4/15 (27)
5/19 (26)
Congestion and edemab
0/20 (0)
6/15 (40)°'d
2/19 (ll)c
Pneumonia13
-
5/15 (33)°'d
12/19 (63)cd
Neoplasia13
0/20 (0)
0/15 (0)
0/19 (0)
Liver6
Within normal limits'3
20/20 (100)
15/15 (100)
19/19 (100)
Neoplasia13
0/20 (0)
0/15 (0)
0/19 (0)
Kidneys6
Within normal limits'3
20/20 (100)
15/15 (100)
19/19 (100)
Neoplasia13
0/20 (0)
0/15 (0)
0/19 (0)
Within normal limits'3
DNR
DNR
DNR
aCannon Laboratories, Inc. (1977).
bNumber of animals with endpoint/number of animals exposed, () = percent of total.
Significant association between dose and endpoint (p < 0.05) by independent Chi-square test for independence
performed for this review.
Significantly different from control (p < 0.05) by Fisher's exact test (two-tailed) performed for this review.
eHEC is for extrarespiratory effects (25-ppm dose = 24.7 mg/m3, 50-ppm dose = 49.4 mg/m3).
DNR = data not reported.
53
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APPENDIX C. BMD MODELING OUTPUTS FOR 1,1-BIPHENYL
DERIVATION OF AN OSF FOR 1,1-BIPHENYL
T3
0)
+->
O
it
<
c
o
¦-4-'
o
ro
0.5
0.4
0.3
0.2
0.1
Multistage Cancer Model with 0.95 Confidence Level
Multistage Cancer
Linear extrapolation
16:00 09/08 2010
Figure C.l. Multistage Cancer BMDS Model for Combined Hepatocellular
Adenoma and Carcinoma in Female BDF1 Mice for 2-Years 1,1-Biphenyl Exposure
(Umeda et al. [2005])
54
1,1-Biphenyl
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FINAL
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Text Output for Multistage Cancer BMDS Model for Combined Hepatocellular Adenoma
and Carcinoma in Female BDF1 Mice for 2-Years 1,1-Biphenyl Exposure
(Umeda et al. [2005])
Multistage Cancer Model. (Version: 1.7; Date: 05/16/2008)
Input Data File:
C:\USEPA\BMDS21\Data\biphenyl\msc_bip08 0910_osfbiphenylrecalc.(d)
Gnuplot Plotting File:
C:\USEPA\BMDS21\Data\biphenyl\msc_bip08 0910_osfbiphenylrecalc.pit
Wed Sep 08 16:00:12 2010
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*dose/s2) ]
The parameter betas are restricted to be positive
Dependent variable = Percent
Independent variable = Cone
Total number of observations = 3
Total number of records with missing values = 0
Total number of parameters in model = 3
Total number of specified parameters = 0
Degree of polynomial = 2
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0.0623483
Beta(1) = 0.00539322
Beta(2) = 0
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Beta(2)
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
Background Beta(l)
Background 1 -0.7
Beta (1) -0.7 1
Parameter Estimates
55
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95.0% Wald Confidence
Interval
Variable Estimate Std. Err. Lower Conf. Limit Upper Conf.
Limit
Background 0.0608898 * * *
Beta(1) 0.00545566 * * *
Beta(2) 0 * * *
* - Indicates that this value is not calculated.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-64.6753
-64.6785
-70.709
# Param's
3
2
1
Deviance Test d.f.
0. 00630587
12.0674
P-value
0.9367
0.002397
AIC:
133.357
Goodness of Fit
Scaled
Dose Est._Prob. Expected Observed Size Residual
0.0000
0.0609
3.044
3.000
50
-0.026
19.7000
0.1566
7.829
8.000
50
0.066
59.8000
0.3223
16.116
16.000
50
-0.035
Chi^2 = 0.01 d.f. = 1 P-value = 0.9366
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 19.3121
BMDL = 12.57 65
BMDU = 4 4.5875
Taken together, (12.5765, 44.5875) is a 90 % two-sided confidence
interval for the BMD
Multistage Cancer Slope Factor = 0.00795133
56 1,1-Biphenyl
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DERIVATION OF SUBCHRONIC AND CHRONIC P-RFCS FOR 1,1-BIPHENYL
Quantal Linear Model with 0.95 Confidence Level
Quantal Linear
0.8
0.6
0.4
0.2
ESMDLBMD
12:58 06/22 2010
10
20
30
40
50
60
dose
Figure C.2. Quantal Linear BMD Model for CD1 Mouse Liver andKidney Congestion
and Edema (Cannon Laboratories, Inc. [1977])
57
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Text Output for Quantal Linear BMD Model of CD1 Mouse Liver and Kidney Congestion
and Edema (Cannon Laboratories, Inc. [1977])
Quantal Linear Model using Weibull Model (Version: 2.12; Date: 05/16/2008)
Input Data File: C:\USEPA\BMDS2l\Data\biphenyl\qln_biphRfC-ER_biphRfC-ER8.(d)
Gnuplot Plotting File: C:\USEPA\BMDS21\Data\biphenyl\qln_biphRfC-ER_biphRfC-
ER8.pit
Tue Jun 22 12:58:42 2010
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(-slope*dose)]
Dependent variable = Percent
Independent variable = Cone
Total number of observations = 3
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial (and Specified) Parameter Values
Background = 0.00617284
Slope = 0.0755498
Power = 1 Specified
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Background -Power
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
Slope
Slope 1
Parameter Estimates
95.0% Wald Confidence
Interval
Variable Estimate Std. Err. Lower Conf. Limit Upper Conf.
Limit
Background 0 NA
Slope 0.0704702 0.00830928 0.0541843
0.0867561
NA - Indicates that this parameter has hit a bound
implied by some inequality constraint and thus
has no standard error.
58
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Model
Full model
Fitted model
Reduced model
Analysis of Deviance Table
#
Log(likelihood)
-34.3663
-35.1501
-163.454
Param's
3
1
1
Deviance Test d.f.
1.5676
258.176
P-value
0.4567
<.0001
AIC:
72.3002
Goodness of Fit
Scaled
Dose Est._Prob. Expected Observed Size Residual
0.0000
0.0000
0.000
0.000
80
0. 000
32.8000
0.9009
88.286
87.024
98
-0.427
65.7000
0.9902
70.307
71.000
71
0. 836
Chi^2 = 0.88 d.f. = 2 P-value = 0.6435
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 1.4 9511
BMDL = 1.22974
59
1,1-Biphenyl
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Gamma Multi-Hit Model with 0.95 Confidence Level
dose
12:58 06/22 2010
Figure C.3. Gamma BMD Model for CD1 Mouse Liver and Kidney Congestion
and Edema (Cannon Laboratories, Inc. [1977])
60
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FINAL
4-4-2011
Text Output for Gamma BMD Model of CD1 Mouse Liver and Kidney Congestion
and Edema (Cannon Laboratories, Inc. [1977])
Gamma Model. (Version: 2.13; Date: 05/16/2008)
Input Data File: C:\USEPA\BMDS2l\Data\biphenyl\gam_biphRfC-ER_bipRfC-ER1.(d)
Gnuplot Plotting File: C:\USEPA\BMDS21\Data\biphenyl\gam_biphRfC-ER_bipRfC-
ER1.pit
Tue Jun 22 12:58:38 2010
BMDS Model Run
The form of the probability function is:
P[response]= background+(1-background)*CumGamma[siope*dose,power],
where CumGamma(.) is the cumulative Gamma distribution function
Dependent variable = Percent
Independent variable = Cone
Power parameter is restricted as power >=1
Total number of observations = 3
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial (and Specified) Parameter Values
Background = 0.00617284
Slope = 0.0530607
Power = 1.3
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Background -Power
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
Slope
Slope 1
Parameter Estimates
95.0% Wald Confidence
Interval
Variable Estimate Std. Err. Lower Conf. Limit Upper Conf.
Limit
Background 0 NA
Slope 0.709585 0.0256681 0.659277
0.759894
Power 18 NA
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NA - Indicates that this parameter has hit a bound
implied by some inequality constraint and thus
has no standard error.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-34.3663
-34.3663
-163.454
# Param's
3
1
1
Deviance Test d.f.
8.121e-005
258.176
P-value
<.0001
AIC:
70.7327
Goodness of Fit
Scaled
Dose Est._Prob. Expected Observed Size Residual
0.0000
0.0000
0.000
0.000
80
0. 000
32.8000
0.8880
87.024
87.024
98
-0.000
65.7000
1.0000
71.000
71.000
71
0. 006
Chi^2 = 0.00 d.f. = 2 P-value = 1.0000
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 18.0692
BMDL = 1.317 6
62
1,1-Biphenyl
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FINAL
4-4-2011
Logistic Model with 0.95 Confidence Level
dose
12:58 06/22 2010
Figure C.4. Logistic BMD Model for CD1 Mouse Liver and Kidney Congestion
and Edema (Cannon Laboratories, Inc. [1977])
63
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Text Output for Logistic BMD Model of CD1 Mouse Liver and Kidney Congestion
and Edema (Cannon Laboratories, Inc. [1977])
Logistic Model. (Version: 2.12; Date: 05/16/2008)
Input Data File: C:\USEPA\BMDS2l\Data\biphenyl\log_biphRfC-ER_biphRfC-ER2.(d)
Gnuplot Plotting File: C:\USEPA\BMDS21\Data\biphenyl\log_biphRfC-ER_biphRfC-
ER2.pit
Tue Jun 22 12:58:39 2010
BMDS Model Run
The form of the probability function is:
P[response] = 1/[1+EXP (-intercept-slope*dose)]
Dependent variable = Percent
Independent variable = Cone
Slope parameter is not restricted
Total number of observations = 3
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
background = 0 Specified
intercept = -4.38081
slope = 0.152848
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -background
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
intercept slope
intercept 1 -1
slope -1 1
Parameter Estimates
95.0% Wald Confidence
Interval
Variable Estimate Std. Err. Lower Conf. Limit Upper Conf.
Limit
intercept -19.2382 1469.75 -2899.89
2861.42
slope 0.649654 44.8094 -87.1751
88.4744
64
1,1-Biphenyl
-------
FINAL
4-4-2011
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-34.3663
-34.3663
-163.454
Param's
3
2 7
1
Deviance Test d.f.
1581e-007
258.176
P-value
0.9993
<.0001
AIC:
72.7326
Goodness of Fit
Scaled
Dose Est._Prob. Expected Observed Size Residual
0.0000
0.0000
0.000
0.000
80
-0.001
32.8000
0.8880
87.024
87.024
98
-0.000
65.7000
1.0000
71.000
71.000
71
0. 000
Chi^2 =0.00 d.f. = 1 P-value = 0.9995
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 2 6.2308
BMDL = 10.8064
65
1,1-Biphenyl
-------
FINAL
4-4-2011
Log-Logistic Model with 0.95 Confidence Level
dose
12:58 06/22 2010
Figure C.5. Log-Logistic BMD Model for CD1 Mouse Liver and Kidney Congestion
and Edema (Cannon Laboratories, Inc. [1977])
66
1,1-Biphenyl
-------
FINAL
4-4-2011
Text Output for Logistic BMD Model of CD1 Mouse Liver and Kidney Congestion
and Edema (Cannon Laboratories, Inc. [1977])
Logistic Model. (Version: 2.12; Date: 05/16/2008)
Input Data File: C:\USEPA\BMDS2l\Data\biphenyl\lnl_biphRfC-ER_biphRfC-ER3.(d)
Gnuplot Plotting File: C:\USEPA\BMDS21\Data\biphenyl\lnl_biphRfC-ER_biphRfC-
ER3.pit
Tue Jun 22 12:58:40 2010
BMDS Model Run
The form of the probability function is:
P[response] = background+(1-background)/[1+EXP(-intercept-siope*Log(dose))]
Dependent variable = Percent
Independent variable = Cone
Slope parameter is restricted as slope >= 1
Total number of observations = 3
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
User has chosen the log transformed model
Default Initial Parameter Values
background = 0
intercept = -12.4625
slope = 4.16366
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -background -slope
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
intercept
intercept 1
Parameter Estimates
95.0% Wald Confidence
Interval
Variable Estimate Std. Err. Lower Conf. Limit Upper Conf.
Limit
background 0 * * *
intercept -60.7572 * * *
slope 18 * * *
67
1,1-Biphenyl
-------
FINAL
4-4-2011
* - Indicates that this value is not calculated.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-34.3663
-34.3663
-163.454
# Param's Deviance Test d.f. P-value
3
1 6.6473e-005 2 ]
1 258.176 2 <.0001
AIC:
70.7327
Goodness of Fit
Scaled
Dose Est._Prob. Expected Observed Size Residual
0.0000
0.0000
0.000
0.000
80
0. 000
32.8000
0.8880
87.024
87.024
98
-0.000
65.7000
1.0000
71.000
71.000
71
0. 006
Chi^2 = 0.00 d.f. = 2 P-value = 1.0000
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 25.8765
BMDL = 6.00398
68
1,1-Biphenyl
-------
FINAL
4-4-2011
LogProbit Model with 0.95 Confidence Level
dose
12:58 06/22 2010
Figure C.6. Log-Probit BMD Model for CD1 Mouse Liver and Kidney Congestion
and Edema (Cannon Laboratories, Inc. [1977])
69
1,1-Biphenyl
-------
FINAL
4-4-2011
Text Output for Log-Probit BMD Model of CD1 Mouse Liver and Kidney Congestion
and Edema (Cannon Laboratories, Inc. [1977])
Probit Model. (Version: 3.1; Date: 05/16/2008)
Input Data File: C:\USEPA\BMDS2l\Data\biphenyl\lnp_biphRfC-ER_biphRfC-ER4.(d)
Gnuplot Plotting File: C:\USEPA\BMDS21\Data\biphenyl\lnp_biphRfC-ER_biphRfC-
ER4.pit
Tue Jun 22 12:58:40 2010
BMDS Model Run
The form of the probability function is:
P[response] = Background
+ (1-Background) * CumNorm(Intercept+Slope*Log(Dose)) ,
where CumNormf .) is the cumulative normal distribution function
Dependent variable = Percent
Independent variable = Cone
Slope parameter is not restricted
Total number of observations = 3
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
User has chosen the log transformed model
Default Initial (and Specified) Parameter Values
background = 0
intercept = -5.03544
slope = 1.79101
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -background
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
intercept slope
intercept 1 -1
slope -1 1
Parameter Estimates
95.0% Wald Confidence
Interval
70
1,1-Biphenyl
-------
FINAL
4-4-2011
Variable
Limit
background
intercept
2334.01
slope
681.503
Estimate
0
-21.7575
6.58184
Std. Err.
NA
971.94
344.354
NA - Indicates that this parameter has hit a bound
implied by some inequality constraint and thus
has no standard error.
Lower Conf. Limit Upper Conf.
-2377.52
-668.34
Model
Full model
Fitted model
Reduced model
Analysis of Deviance Table
Log(likelihood)
-34.3663
-34.3663
-163.454
# Param's Deviance Test d.f. P-value
3
2 5.0521e-007 1 0.9994
1 258.176 2 <.0001
AIC:
72.7326
Goodness of Fit
Scaled
Dose Est._Prob. Expected Observed Size Residual
0.0000
0.0000
0.000
0.000
80
0. 000
32.8000
0.8880
87.024
87.024
98
-0.000
65.7000
1.0000
71.000
71.000
71
0. 001
Chi^2 = 0.00 d.f. = 1 P-value = 0.9996
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 22.4429
BMDL = 3.5 9818
71
1,1-Biphenyl
-------
FINAL
4-4-2011
Multistage Model with 0.95 Confidence Level
dose
12:58 06/22 2010
Figure C.7. Multistage BMD Model for CD1 Mouse Liver and Kidney Congestion
and Edema (Cannon Laboratories, Inc. [1977])
72
1,1-Biphenyl
-------
FINAL
4-4-2011
Text Output for Multistage BMD Model of CD1 Mouse Liver and Kidney Congestion
and Edema (Cannon Laboratories, Inc. [1977])
Multistage Model. (Version: 3.0; Date: 05/16/2008)
Input Data File: C:\USEPA\BMDS2l\Data\biphenyl\mst_biphRfC-ER_biphRfC-ER5.(d)
Gnuplot Plotting File: C:\USEPA\BMDS21\Data\biphenyl\mst_biphRfC-ER_biphRfC-
ER5.pit
Tue Jun 22 12:58:41 2010
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*dose/s2) ]
The parameter betas are restricted to be positive
Dependent variable = Percent
Independent variable = Cone
Total number of observations = 3
Total number of records with missing values = 0
Total number of parameters in model = 3
Total number of specified parameters = 0
Degree of polynomial = 2
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0
Beta(l) = 0
Beta(2) = 2.49482e+016
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Background -Beta(l)
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
Beta(2)
Beta (2) 1
Parameter Estimates
95.0% Wald Confidence
Interval
73
1,1-Biphenyl
-------
FINAL
4-4-2011
Variable Estimate Std. Err. Lower Conf. Limit Upper Conf.
Limit
Background 0 * * *
Beta(1) 0 * * *
Beta(2) 0.00203615 * * *
* - Indicates that this value is not calculated.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-34.3663
-34.4269
-163.454
# Param's
3
1
1
Deviance Test d.f.
0.121117
258.176
P-value
0.9412
<.0001
AIC:
70.8537
Goodness of Fit
Scaled
Dose Est._Prob. Expected Observed Size Residual
0.0000
0.0000
0.000
0.000
80
-0.000
32.8000
0.8881
87.038
87.024
98
-0.005
65.7000
0.9998
70.989
71.000
71
0.104
Chi^2 = 0.01 d.f. = 2 P-value = 0.9946
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 7.1934
BMDL = 1.317 69
BMDU = 8 .00427
Taken together, (1.31769, 8.00427) is a 90 % two-sided confidence
interval for the BMD
74
1,1-Biphenyl
-------
FINAL
4-4-2011
Probit Model with 0.95 Confidence Level
dose
12:58 06/22 2010
Figure C.8. Probit BMD Model for CD1 Mouse Liver and Kidney Congestion
and Edema (Cannon Laboratories, Inc. [1977])
75
1,1-Biphenyl
-------
FINAL
4-4-2011
Text Output for Probit BMD Model of CD1 Mouse Liver and Kidney Congestion and
Edema (Cannon Laboratories, Inc. [1977])
Probit Model. (Version: 3.1; Date: 05/16/2008)
Input Data File: C:\USEPA\BMDS2l\Data\biphenyl\pro_biphRfC-ER_biphRfC-ER6.(d)
Gnuplot Plotting File: C:\USEPA\BMDS21\Data\biphenyl\pro_biphRfC-ER_biphRfC-
ER6.pit
Tue Jun 22 12:58:41 2010
BMDS Model Run
The form of the probability function is:
P[response] = CumNorm(Intercept+Slope*Dose) ,
where CumNormf .) is the cumulative normal distribution function
Dependent variable = Percent
Independent variable = Cone
Slope parameter is not restricted
Total number of observations = 3
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial (and Specified) Parameter Values
background = 0 Specified
intercept = -2.41713
slope = 0.086286
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -background
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
intercept slope
intercept 1 -1
slope -1 1
Parameter Estimates
95.0% Wald Confidence
Interval
Variable Estimate Std. Err. Lower Conf. Limit Upper Conf.
Limit
intercept -5.8032 366.377 -723.888
712 .282
76
1,1-Biphenyl
-------
slope
22.10(
FINAL
4-4-2011
0.213999
11.17
-21.6788
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
AIC:
Log(likelihood)
-34.3663
-34.3663
-163.454
72.7326
# Param's Deviance Test d.f. P-value
3
2 5.20497e-007 1 0.9994
1 258.176 2 <.0001
Dose
Goodness of Fit
Est._Prob. Expected Observed Size
Scaled
Residual
0.0000
32.8000
65.7000
Chi^2 = 0.00
0.0000
0.8880
1.0000
d.f. = 1
0.000 0.000 80
87.024 87.024 98
71.000 71.000 71
P-value = 0.9996
-0. 001
0. 000
0. 000
Benchmark Dose Computation
Specified effect
Risk Type
Confidence level
BMD
BMDL
0.1
Extra risk
0. 95
21.1293
9. 0211
77
1,1-Biphenyl
-------
FINAL
4-4-2011
Weibull Model with 0.95 Confidence Level
dose
12:58 06/22 2010
Figure C.9. Weibull BMD Model for CD1 Mouse Liver and Kidney Congestion
and Edema (Cannon Laboratories, Inc. [1977])
78
1,1-Biphenyl
-------
FINAL
4-4-2011
Text Output for Weibull BMD Model of CD1 Mouse Liver and Kidney Congestion
and Edema (Cannon Laboratories, Inc. [1977])
Weibull Model using Weibull Model (Version: 2.12; Date: 05/16/2008)
Input Data File: C:\USEPA\BMDS2l\Data\biphenyl\wei_biphRfC-ER_biphRfC-ER7.(d)
Gnuplot Plotting File: C:\USEPA\BMDS21\Data\biphenyl\wei_biphRfC-ER_biphRfC-
ER7.pit
Tue Jun 22 12:58:41 2010
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(-slope*dose/spower)]
Dependent variable = Percent
Independent variable = Cone
Power parameter is restricted as power >=1
Total number of observations = 3
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial (and Specified) Parameter Values
Background = 0.00617284
Slope = 0.00728578
Power = 1.55886
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Background
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
Slope Power
Slope 1 -1
Power -1 1
Parameter Estimates
95.0% Wald Confidence
Interval
Variable Estimate Std. Err. Lower Conf. Limit Upper Conf.
Limit
Background 0 NA
Slope 7.42391e-005 0.00180342 -0.0034604
0.00360888
79
1,1-Biphenyl
-------
FINAL
4-4-2011
Power 2.94856 6.9597 -10.6922
16.5893
NA - Indicates that this parameter has hit a bound
implied by some inequality constraint and thus
has no standard error.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-34.3663
-34.3663
-163.454
# Param's
3
2 6.
1
Deviance Test d.f.
06381e-006
258.176
P-value
0. 998
<.0001
AIC:
72.7326
Goodness of Fit
Scaled
Dose Est._Prob. Expected Observed Size Residual
0.0000
0.0000
0.000
0.000
80
0. 000
32.8000
0.8880
87.023
87.024
98
0. 000
65.7000
1.0000
71.000
71.000
71
0. 002
Chi^2 = 0.00 d.f. = 1 P-value = 0.9986
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 11.7222
BMDL = 1.3176
80
1,1-Biphenyl
-------
FINAL
4-4-2011
DERIVATION OF A SUBCHRONIC AND CHRONIC P-RFD FOR 1,1-BIPHENYL
Log-Logistic Model with 0.95 Confidence Level
dose
17:16 12/11 2009
Figure C.10. Log-Logistic BMDS Model for Incidence of Litters with Fetal Skeletal
Anomalies from Wistar Rat Dams Administered Biphenyl by Gavage on GDs 6-15
(Khera et al., 1979)
81
1,1-Biphenyl
-------
FINAL
4-4-2011
Text Output for Log-Logistic BMDS Model for Incidence of Litters with Fetal Skeletal
Anomalies from Wistar Rat Dams Administered Biphenyl by Gavage on GDs 6-15
(Khera et al., 1979)
Logistic Model. (Version: 2.12; Date: 05/16/2008)
Input Data File:
C:\USEPA\IRIS\biphenyl\rat\develop\anomlitt\lnl_anomlitt_loglogistic.(d)
Gnuplot Plotting File:
C:\USEPA\IRIS\biphenyl\rat\develop\anomlitt\lnl_anomlitt_loglogistic.pit
Fri Dec 11 17:16:25 2009
BMDS Model Run
The form of the probability function is:
P[response] = background+(1-background)/[1+EXP(-intercept-siope*Log(dose))]
Dependent variable = incidence
Independent variable = dose
Slope parameter is restricted as slope >= 1
Total number of observations = 5
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
User has chosen the log transformed model
Default Initial Parameter Values
background =
intercept =
slope =
0.5
-6.54827
1
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -slope
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
background intercept
background
1
-0.77
intercept
-0.77
1
Parameter Estimates
95.0% Wald Confidence
Interval
82
1,1-Biphenyl
-------
FINAL
4-4-2011
Variable Estimate Std. Err. Lower Conf. Limit Upper Conf.
Limit
background 0.503241 * * *
intercept -6.24131 * * *
slope 1 * * *
* - Indicates that this value is not calculated.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-49.327
-50.6629
-52.2232
# Param's
5
2
1
Deviance Test d.f.
2.67182
5.79233
P-value
0.445
0.2152
AIC:
105.326
Goodness of Fit
Scaled
Dose Est._Prob. Expected Observed Size Residual
0.0000
0.5032
8.052
8.000
16
-0.026
125.0000
0.6005
12.010
11.000
20
-0.461
250.0000
0.6659
11.986
13.000
18
0.507
500.0000
0.7483
13.469
15.000
18
0. 831
1000.0000
0.8315
7.483
6.000
9
-1.321
Chi^2 =2.90
d.f.
= 3 P-
-value = 0.40 65
Benchmark Dose Computation
Specified effect = 0.05
Risk Type = Extra risk
Confidence level = 0.95
BMD = 27.028
BMDL = 9.5 8732
83
1,1-Biphenyl
-------
FINAL
4-4-2011
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594532
Bentley, P; Clader, I; Elcombes, C; et al. (1993) Hepatic peroxisome proliferation in rodents
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594577
Brouns, RE; Poot, M; de Vrind, R; et al. (1979) Measurement of DNA-excision repair in
suspensions of freshly isolated rat hepatocytes after exposure to some carcinogenic compounds:
Its possible use in carcinogenicity screening. MutatRes 64(6):425-432. 594542
BUA (Beratergremium fiir umweltrelevante Altstoffe). (1990) Biphenyl (l,l'-Biphenyl).
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Cannon Laboratories, Inc. (1977) 90-day inhalation toxicity study of biphenyl (99 + % purity)
in CD1 mice. Cannon Laboratories, Inc., Reading, PA. 061475
Carella, G; Bettolo, PM. (1994) Reversible hepatotoxic effects of diphenyl: report of a case and
a review of the literature. J Occup Med 36(5):575-576. 594548
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and human hepatic derived cell lines exposure to ciprofibrate. Cancer Letters 222:217-226.
Deichmann, WB, Kitzmiller, KV, Dierker, M; et al. (1947) Observations on the effects of
diphenyl, o- and paminodiphenyl, o- and/>nitrodiphenyl and dihydroxyoctachlorodiphenyl upon
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Dow Chemical Co. (1953) Toxicological study of diphenyl in citrus wraps with cover letter.
Prepared by Stanford Research Institute. Submitted under TSCA Section 8D. EPA Document
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Hakkinen, I; Siltanen, E; Hernberg, S; et al. (1973) Diphenyl poisoning in fruit paper
production: a new health hazard. Arch Environ Health 26(2):70-74. 061481
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1,1-Biphenyl
-------
FINAL
4-4-2011
Hirayama, T; Nohara, M; Shindo, H; et al. (1982) Mutagenicity assays of photochemical
reaction products of biphenyl (BP) and o-phenyl phenol (OPP) with NOx. Chemosphere
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IARC (International Agency for Research on Cancer). (2000) Some industrial chemicals.
Summary of data reported and evaluation. IARC monographs on the evaluation of carcinogenic
risks to humans, volume 77. Geneva, Switzerland: WHO. Available online at
http://monoeraphs.iarc.fr/ENG/Monoeraphs/vol77/volume77.pdf. Accessed on 12/07/2010.
IPCS/CEC (International Programme on Chemical Safety and the Commission of the European
Communities). (1994) International chemical safety cards: Biphenyl. Available at
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Khera, KS; Whalen, C; Angers, G; et al. (1979) Assessment of the teratogenic potential of
piperonyl butoxide, biphenyl, and phosalone in the rat. Toxicol ApplPharmacol 47(2):353-358.
061485
Meyer, T; Aarbakke, J; Scheline, RR. (1976) The metabolism of biphenyl. I. Metabolic
disposition of 14C-biphenyl in the rat. Actapharmacol toxicol 39(4):412-418. 061490
Monsanto Chemical Co. (1983) Physiological response of experimental animals to the
absorption of diphenyl, and several resins, elastomers and plastics with cover letter. Final report.
U.S. Environmental Protection Agency, Washington, DC. Available online at
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NIOSH (National Institute for Occupational Safety and Health). (2003) NIOSH pocket guide to
chemical hazards. Index of Chemical Abstracts Service Registry Numbers (CAS No.). Atlanta,
Ga: Center for Disease Control and Prevention, U.S. Department of Health, Education and
Welfare. Available online at http://www.cdc.eov/niosh/npe/npedcas.html. 081445
NTP (National Toxicology Program). (2005) 11th Report on Carcinogens. U.S. Department of
Health and Human Services, Public Health Service, National Institutes of Health, Research
Triangle Park, NC. Available online at http://ntp-server.niehs.nih.eov/index.cfm?obiectid=
32BA9724-F1F6-975E-7FCE50709CB4C932. Accessed on 12/07/2010. 091126
Ohnishi, M; Yajima, H; Yamamoto, S; et al. (2000) Sex dependence of the components and
structure of urinary calculi induced by biphenyl administration in rats. Chem Res Toxicol
13(8):727-735. 595053
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