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1,1-Biphenyl (CASRN 92-52-4)
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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 First 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 Rat Chronic Oral Study Ambrose et al., 1960 |
NOAEL: 0.1% of diet (50 mg/kg bw/day) LOAEL: 0.5% of diet |
100
|
10
|
5E-2
mg/kg/day |
*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 Studies/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
Database — 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 database 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
Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for 1,1-Biphenyl conducted in September 2002 did not identify any critical new studies. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676.
__I.A.7. EPA Contacts (Oral RfD)
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@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
Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfC for 1,1-Biphenyl conducted in September 2002 did not identify any critical new studies. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676.
EPA Contacts:
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@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 Human Carcinogenicity
__II.A.1. Weight-of-Evidence Characterization
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. EPA Review (Carcinogenicity Assessment)
Agency Work Group Review — 12/06/1990
Verification Date — 12/06/1990
Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for 1,1-Biphenyl conducted in September 2002 did not identify any critical new studies. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676.
__II.D.3. EPA Contacts (Carcinogenicity Assessment)
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@epa.gov (internet address).
_III.
[reserved]
_IV. [reserved]
_V. [reserved]
_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 |
| 04/01/1997 | III., IV., V. | Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. |
| 12/03/2002 | I.A.6., I.B., II.D.2. | Screening-Level Literature Review Findings message has been added. |
_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