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1,1-Biphenyl
CASRN 92-52-4
Contents
0013
1,1-Biphenyl; CASRN 92-52-4
Health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of chronic toxicity data by U.S. EPA health
scientists from several Program Offices and the Office of Research and
Development. The summaries presented in Sections I and II represent a
consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR 1,1-Biphenyl
File On-Line 01/31/1987
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) on-line 08/01/1989
Inhalation RfC Assessment (I.B.) message 11/01/1990
Carcinogenicity Assessment (II.) on-line 03/01/1991
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- 1,1-Biphenyl
CASRN -- 92-52-4
Last Revised -- 08/01/1989
The oral Reference Dose (RfD) is based on the assumption that thresholds exist
for certain toxic effects such as cellular necrosis. It is expressed in units
of mg/kg-day. In general, the RfD is an estimate (with uncertainty spanning
perhaps an order of magnitude) of a daily exposure to the human population
(including sensitive subgroups) that is likely to be without an appreciable
risk of deleterious effects during a lifetime. Please refer to the Background
Document for an elaboration of these concepts. RfDs can also be derived for
the noncarcinogenic health effects of substances that are also carcinogens.
Therefore, it is essential to refer to other sources of information concerning
the carcinogenicity of this substance. If the U.S. EPA has evaluated this
substance for potential human carcinogenicity, a summary of that evaluation
will be contained in Section II of this file.
___I.A.1. ORAL RfD SUMMARY
Critical Effect Experimental Doses* UF MF RfD
-------------------- ----------------------- ----- --- ---------
Kidney damage NOAEL: 0.1% of diet 100 10 5E-2
(50 mg/kg bw/day) mg/kg/day
Rat Chronic Oral
Study LOAEL: 0.5% of diet
Ambrose et al., 1960
*Conversion Factors: (0.1 g/100 g) x (0.05/day) x (1 E6 mg/kg) = 50
mg/kg/day
___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
Ambrose, A.M., A.N. Booth, F. DeEds and A.J. Cox, Jr. 1960. A toxicological
study of biphenyl, a citrus fungistat. Food Res. 25: 328-336.
Fifteen weanling albino rats of each sex were placed in each of eight
experimental groups: 0.0, 0.001, 0.005, 0.01, 0.05, 0.10, 0.50, and 1.0%
biphenyl in the diet. Dietary levels of 0.5% biphenyl and greater were
associated with kidney damage, reduced hemoglobin levels, decreased food
intake, and decreased longevity. One animal in each of the lower dose groups
and control group had detectable blood in the renal pelvis. A supporting
unpublished work (SRI, 1960) was cited in which a NOAEL of 0.1% biphenyl in
the diet was found in both a subchronic rat feeding study and a three-
generation rat reproduction study.
A NOAEL of 0.1% of diet is chosen because of the uncertainty of the
significance of the effects observed at lower doses as compared to the more
certain AEL of 0.5% of diet. The observation of the same NOAEL in a
supporting study is also a contributing factor.
___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD)
UF -- Factors of 10 each for interspecies conversion and for protection of
sensitive human subpopulations were applied to the NOAEL of 50 mg/kg/day.
MF -- An additional factor of 10 was applied to account for intraspecies
variability demonstrated by uncertainty in the threshold suggested by the data
in the critical study.
___I.A.4. ADDITIONAL COMMENTS (ORAL RfD)
Limited teratogenicity data on 1,1-biphenyl indicate it is not teratogenic.
No fetal or maternal toxicity resulted from pregnant Wistar rat dams receiving
125, 250, or 500 mg/kg 1,1-biphenyl by gavage on days 6-15 of gestation (Khera
et al., 1979). Some evidence (not significant) of fetotoxicity (reduced fetal
weights, decreased number of live fetuses, and increased resorptions) was
observed at 1000 mg/kg, but maternal mortality occurred at this dose level as
well. No significant effects were reported by Ambrose et al. (1960), who gave
0, 0.1, and 0.5% biphenyl in the diet to weanling rats from 60 days before
mating through weaning of their offspring. Biphenyl at 1% in the diet
produced unspecified adverse effects in a three-generation unpublished study
on rats (SRI, 1960).
___I.A.5. CONFIDENCE IN THE ORAL RfD
Study -- High
Data Base -- Low
RfD -- Medium
The principal study was a well-conducted chronic bioassay covering a wide dose
range with an adequate number of both animals and toxicity parameters
assessed. The only supporting data is unpublished, so that the confidence in
the data base is low. Medium confidence in the RfD follows.
___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD
Source Document -- U.S. EPA, 1984
The ADI in the 1984 Health and Environmental Effects Profile document has
received an Agency review with the help of two external scientists.
Other EPA Documentation -- None
Agency Work Group Review -- 10/09/1985
Verification Date -- 10/09/1985
___I.A.7. EPA CONTACTS (ORAL RfD)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- 1,1-Biphenyl
CASRN -- 92-52-4
The health effects data for biphenyl were reviewed by the U.S. EPA RfD/RfC
Work Group and determined to be inadequate for derivation of an inhalation
RfC. The verification status of this chemical is currently not verifiable.
For additional information on health effects of this chemical, interested
parties are referred to the EPA documentation listed below.
U.S. EPA. 1984. Health and Environmental Effects Profile for 1,1-Biphenyl.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste
and Emergency Response, Washington, DC. EPA 600/x-84/147. NTIS PB 88-
137831/AS.
Agency Work Group Review -- 09/20/1990
EPA Contacts:
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- 1,1-Biphenyl
CASRN -- 92-52-4
Last Revised -- 03/01/1991
Section II provides information on three aspects of the carcinogenic
assessment for the substance in question; the weight-of-evidence judgment of
the likelihood that the substance is a human carcinogen, and quantitative
estimates of risk from oral exposure and from inhalation exposure. The
quantitative risk estimates are presented in three ways. The slope factor is
the result of application of a low-dose extrapolation procedure and is
presented as the risk per (mg/kg)/day. The unit risk is the quantitative
estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m
air breathed. The third form in which risk is presented is a drinking water
or air concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or 1
in 1,000,000. The rationale and methods used to develop the carcinogenicity
information in IRIS are described in The Risk Assessment Guidelines of 1986
(EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries
developed since the publication of EPA's more recent Proposed Guidelines for
Carcinogen Risk Assessment also utilize those Guidelines where indicated
(Federal Register 61(79):17960-18011, April 23, 1996). Users are referred to
Section I of this IRIS file for information on long-term toxic effects other
than carcinogenicity.
__II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification -- D; not classifiable as to human carcinogenicity
Basis -- No human data and inadequate studies in mice and rats. Results of
genotoxicity tests are generally negative.
___II.A.2. HUMAN CARCINOGENICITY DATA
None.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Inadequate. The animal carcinogenicity data was found to be inadequate
because the studies were designed to study the toxicology rather than oncology
of 1,1-biphenyl and small group sizes were used. BRL (1968) treated B6AKF1
and B6C3F1 mice (18/sex/strain) with daily gavage doses of 215 mg/kg 1,1-
biphenyl in gelatin from days 7 to 28 of age. The mice were then given a diet
containing 517 ppm 1,1-biphenyl for the subsequent 18 months. Positive,
negative and vehicle controls were included in the study. The animals were
weighed every 6 months and histopathologic examination of the lymphatic and
pulmonary systems, liver, skin, mammary glands and uterus were performed at
the end of the study. No increase in the incidence of tumors was found in any
treated group compared with negative and vehicle controls.
Ambrose et al. (1960) fed 15 weanling albino rats/sex/group diets
containing 0, 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, or 1% (0, 0.5, 2.5, 5.0, 25,
50, 250, or 500 mg/kg/day) 1,1-biphenyl for 700 days. At the end of the
treatment period, histopathologic examination of the mammary gland, pituitary,
adrenals, uterus, lungs, bladder, and other tissues was performed. All rats
in the 250 and 500 mg/kg/day groups showed evidence of kidney damage,
including irregular scarring, lymphocytic infiltration, tubular atrophy and
patchy tubular dilation. Decreased food intake, retarded growth and reduced
hemoglobin levels were also observed in these groups. Survival appeared
reduced in males receiving 250 mg/kg/day and in both sexes at 500 mg/kg/day,
although a statistical analysis of survival was not performed. Based on these
data it appears that an MTD was achieved. Although not designed as an
oncology study, several malignant and benign tumors were found in both the
treated and control rats. These were not considered to be related to 1,1-
biphenyl treatment.
Stanford Research Institute (SRI, 1953) fed diets containing corn oil and
0, 0.01, 0.1, or 1.0% 1,1-biphenyl to groups of 12 male and 12 female Sprague-
Dawley rats for 2 years. Malignancies were reported in two rats; one (sex not
specified) on the 0.1% diet had an adenocarcinoma of the colon and one female
on the 1.0% diet had a peritoneal tumor. Many of the treated and control male
rats had tubular dilation of the kidneys to varying degrees of severity;
however, the incidence and severity of the renal lesions were greater in the
group fed 1.0% 1,1-biphenyl than in the controls. This study is limited by
small group sizes, excess mortality due to a refractory fulminating
respiratory infection, and concurrent antibiotic therapy.
BRL (1968) treated B6AKF1 and B6C3F1 28-day-old mice (18/sex/strain) with
a single subcutaneous 46.4 mg/kg dose of 1,1-biphenyl in DMSO. The mice were
observed for 18 months before sacrifice. Gross and microscopic observations
were performed on internal body organs of the chest and abdomen. No increase
in the incidence of tumors was found in any treated group compared with
controls.
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Kurata et al. (1986) provided groups of 25 male F344 rats with 0.05% N-
butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in the drinking water for 4 weeks
followed by either a basal diet or diet containing 0.5% 1,1-biphenyl for 32
weeks. A group of five rats received the 1,1-biphenyl-containing diet without
pretreatment with BBN. Rats receiving the 1,1-biphenyl diet, both with and
without BBN pretreatment, gained less weight than control rats that received
only BBN. In the 18 surviving rats treated with BBN followed by 1,1-biphenyl,
the incidences of hyperplasia, papillomas and carcinomas in the urinary
bladder was 94, 83 and 61%, respectively. These increases were statistically
significant. The incidences of hyperplasia, papillomas and carcinomas in rats
treated with BBN alone were 25, 12 and 0%, respectively. Hyperplasia,
papillomas and carcinomas were not observed in the 5 rats fed the 1,1-
biphenyl-containing diet without pretreatment with BBN. Urinary bladder
stones occurred in 25% of rats receiving BBN and 1,1-biphenyl but in only 12%
of the BBN control. 1,1-Biphenyl appeared to be a tumor promoter in this
experiment.
1,1-Biphenyl was not mutagenic in reverse mutation tests in Salmonella and
Eshcerichia coli and in a DNA repair test in E. coli (Anderson and Styles,
1978; Cline and McMahon, 1977; Hirayama et al., 1981). 1,1-Biphenyl did not
induce chromosomal aberrations in Chinese hamster cells or unscheduled DNA
synthesis in rat hepatocytes (Abe and Sasaki, 1977; Ishidate and Odashima,
1977; Brouns et al., 1979; Williams, 1978). 1,1-Biphenyl did induce forward
mutation in mouse lymphoma cells and sister chromatid exchanges in Chinese
hamster cells, although a dose-response relationship was not observed in the
latter test (Wangenheim and Bolcsfoldi, 1988; Abe and Sasaki, 1977).
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
None.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
None.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1990
The Health and Environmental Effects Document for 1,1-Biphenyl will be
subjected to external peer review and Agency review.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 12/06/1990
Verification Date -- 12/06/1990
___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_VI. BIBLIOGRAPHY
Substance Name -- 1,1-Biphenyl
CASRN -- 92-52-4
Last Revised -- 03/01/1991
__VI.A. ORAL RfD REFERENCES
Ambrose, A.M., A.N. Booth, F. DeEds and A.J. Cox, Jr. 1960. A toxicological
study of biphenyl, a citrus fungistat. Food Res. 25: 328-336.
Khera, K.S., C. Whalen, G. Angers and G. Trivett. 1979. Assessment of
teratogenic potential of piperonyl butoxide, biphenyl and phosalone in the
rat. Toxicol. Appl. Pharmacol. 47(2): 353-358.
SRI (Stanford Research Institute). 1960. Final Report A toxicological study
of diphenyl in citrus wraps. EPA/OTS; Doc. No. 878213721. (Cited in Ambrose
et al., 1960).
U.S. EPA. 1984. Health and Environmental Effects Profile for 1,1-Biphenyl.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste,
Washington, DC.
__VI.B. INHALATION RfC REFERENCES
U.S. EPA. 1984. Health and Environmental Effects Profile for 1,1-Biphenyl.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste
and Emergency Response, Washington, DC. EPA 600/X-84/147. NTIS PB 88-
137831/AS.
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Abe, S. and M. Sasaki. 1977. Chromosome aberrations and sister chromatid
exchanges in chinese hamster cells exposed to various chemicals. J. Natl.
Cancer Inst. 58(6): 1635-1641.
Ambrose, A.M., A.N. Booth, F. DeEds and A.J. Cox. 1960. A toxicological
study of biphenyl, a citrus fungistat. Food Res. 25: 328-336.
Anderson, D. and J.A. Styles. 1978. An evaluation of 6 short-term tests for
detecting organic chemical carcinogens. Appendix 2. The bacterial mutation
test. Br. J. Cancer. 37: 924-930.
BRL (Bionetics Research Labs, Inc.) 1968. Evaluation of Carcinogenic,
Teratogenic and Mutagenic Activities of Selected Pesticides and Industrial
Chemicals. Volume I. Carcinogenic Study. NTIS PB-223159.
Brouns, R.E., M. Poot, R. DeVrind, T. Von Hoek-kon, P.T. Henderson and C.M.A.
Kuyper. 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. Mutat. Res. 64: 425-432.
Cline, J.C. and R.E. McMahon. 1977. Detection of chemical mutagens: Use of
concentration gradient plates in a high capacity screen. Res. Commun. Chem.
Pathol. Pharmacol. 16(3): 523-533.
Hirayama, T., M. Nohara, H. Shindo and S. Fukui. 1981. Mutagenicity assays
of photochemical reaction products of biphenyl (BP) and o-phenylphenol (OPP)
with NOx. Chemosphere. 10(2): 223-228.
Ishidate, M., Jr. and S. Odashima. 1977. Chromosome tests with 134 compounds
on Chinese hamster cells in vitro - A screening for chemical carcinogens.
Mutat. Res. 48(3-4): 337-354.
Kurata, Y., M. Asamoto, A. Hagiwara, T. Masui and S. Fukushima. 1986.
Promoting effects of various agents in rat urinary bladder carcinogenesis
initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine. Cancer Lett. 32(2):
125-136.
SRI (Stanford Research Institute). 1953. Toxicological study of diphenyl in
citrus wraps. Unpublished data. Dow Chemical Company, Midland, MI. OTS No.
84003A.
U.S. EPA. 1990. Health and Environmental Effects Document for 1,1-Biphenyl.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office Cincinnati, OH for the Office of Solid Waste
and Emergency Response, Washington, DC.
Wangenheim, J. and G. Bolcsfoldi. 1988. Mouse lymphoma L5178Y thymidine
kinase locus assay of 50 compounds. Mutagenesis. 3(3): 193-205.
Williams, G.M. 1978. Further improvements in the hepatocyte primary culture
DNA repair test for carcinogens: Detection of carcinogenic biphenyl
derivatives. Cancer Lett. 4: 69-75.
_VII. REVISION HISTORY
Substance Name -- 1,1-Biphenyl
CASRN -- 92-52-4
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
08/01/1989 I.A. SRI citation clarified
08/01/1989 VI. Bibliography on-line
10/01/1990 I.B. Not verified; data inadequate
11/01/1990 I.B. Inhalation RfC message added
11/01/1990 VI.B. Inhalation RfC references added
01/01/1991 II. Carcinogen assessment now under review
03/01/1991 II. Carcinogenicity assessment on-line
03/01/1991 VI.C. Carcinogenicity references added
01/01/1992 I.A.7. Secondary contact changed
01/01/1992 IV. Regulatory Action section on-line
VIII. SYNONYMS
Substance Name -- 1,1-Biphenyl
CASRN -- 92-52-4
Last Revised -- 01/31/1987
92-52-4
Bibenzene
Biphenyl
Biphenyl, 1,1-
Diphenyl
Lemonene
Phenador-X
Phenylbenzene
PHPH
Xenene
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0013.HTM
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