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    Concise International Chemical Assessment Document 6






    BIPHENYL










    This report contains the collective views of an international group of
    experts and does not necessarily represent the decisions or the stated
    policy of the United Nations Environment Programme, the International
    Labour Organisation, or the World Health Organization.

    First draft prepared by Dr A. Boehncke, Dr G. Koennecker, Dr I.
    Mangelsdorf, and Dr A. Wibbertmann, Fraunhofer Institute for
    Toxicology and Aerosol Research, Hanover, Germany


    Published under the joint sponsorship of the United Nations
    Environment Programme, the International Labour Organisation, and the
    World Health Organization, and produced within the framework of the
    Inter-Organization Programme for the Sound Management of Chemicals.




    World Health Organization          Geneva, 1999

         The International Programme on Chemical Safety (IPCS),
    established in 1980, is a joint venture of the United Nations
    Environment Programme (UNEP), the International Labour Organisation
    (ILO), and the World Health Organization (WHO). The overall objectives
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    the risk to human health and the environment from exposure to
    chemicals, through international peer review processes, as a
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    technical assistance in strengthening national capacities for the
    sound management of chemicals.

         The Inter-Organization Programme for the Sound Management of
    Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and
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    sound management of chemicals in relation to human health and the
    environment.

    WHO Library Cataloguing-in-Publication Data

    Biphenyl.

         (Concise international chemical assessment document ; 6)

    1.  Biphenyl compounds - adverse effects
    2.  Biphenyl compounds - toxicity
    3.  Environmental exposure
    I.  International Programme on Chemical Safety
    II. Series

         ISBN 92 4 153006 5                 (NLM classification: WA 240)
         ISSN 1020-6167

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    (c) World Health Organization 1999

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         The Federal Ministry for the Environment, Nature Conservation and
    Nuclear Safety, Germany, provided financial support for the printing
    of this publication.

    TABLE OF CONTENTS

         FOREWORD

    1. EXECUTIVE SUMMARY

    2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES

    3. ANALYTICAL METHODS

    4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         6.1. Environmental levels
         6.2. Human exposure

    7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
         

    8. EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

         8.1. Single exposure
         8.2. Irritation and sensitization
         8.3. Short-term exposure
              8.3.1. Oral exposure
              8.3.2. Inhalation exposure
              8.3.3. Dermal exposure
         8.4. Long-term exposure
              8.4.1. Subchronic exposure
                        8.4.1.1   Oral exposure
                        8.4.1.2   Inhalation exposure
              8.4.2. Chronic exposure and carcinogenicity
                        8.4.2.1   Tumour promotion
         8.5. Genotoxicity and related end-points
         8.6. Reproductive and developmental toxicity
         8.7. Immunological and neurological effects

    9. EFFECTS ON HUMANS

    10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         10.1. Aquatic environment
         10.2. Terrestrial environment

    11. EFFECTS EVALUATION

         11.1. Evaluation of health effects
                   11.1.1. Hazard identification and dose-response assessment
                             
                   11.1.2. Criteria for setting guidance values for biphenyl
                             
                   11.1.3. Sample risk characterization
         11.2. Evaluation of environmental effects

    12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    13. HUMAN HEALTH PROTECTION AND EMERGENCY ACTION

         13.1. Advice to physicians
         13.2. Health surveillance advice
         13.3. Spillage

    14. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS

         INTERNATIONAL CHEMICAL SAFETY CARD

         REFERENCES

         APPENDIX 1 -- SOURCE DOCUMENTS

         APPENDIX 2 -- CICAD PEER REVIEW

         APPENDIX 3 -- CICAD FINAL REVIEW BOARD (Brussels, Belgium)

         APPENDIX 4 -- SPECIALIZED CICAD PEER REVIEW

         APPENDIX 5 -- CICAD FINAL REVIEW BOARD (Washington, DC)

         RÉSUMÉ D'ORIENTATION

         RESUMEN DE ORIENTACION
    

    FOREWORD

         Concise International Chemical Assessment Documents (CICADs) are
    the latest in a family of publications from the International
    Programme on Chemical Safety (IPCS) -- a cooperative programme of the
    World Health Organization (WHO), the International Labour Organisation
    (ILO), and the United Nations Environment Programme (UNEP). CICADs
    join the Environmental Health Criteria documents (EHCs) as
    authoritative documents on the risk assessment of chemicals.

         CICADs are concise documents that provide summaries of the
    relevant scientific information concerning the potential effects of
    chemicals upon human health and/or the environment. They are based on
    selected national or regional evaluation documents or on existing
    EHCs. Before acceptance for publication as CICADs by IPCS, these
    documents undergo extensive peer review by internationally selected
    experts to ensure their completeness, accuracy in the way in which the
    original data are represented, and the validity of the conclusions
    drawn.

         The primary objective of CICADs is characterization of hazard and
    dose-response from exposure to a chemical. CICADs are not a summary of
    all available data on a particular chemical; rather, they include only
    that information considered critical for characterization of the risk
    posed by the chemical. The critical studies are, however, presented in
    sufficient detail to support the conclusions drawn. For additional
    information, the reader should consult the identified source documents
    upon which the CICAD has been based.

         Risks to human health and the environment will vary considerably
    depending upon the type and extent of exposure. Responsible
    authorities are strongly encouraged to characterize risk on the basis
    of locally measured or predicted exposure scenarios. To assist the
    reader, examples of exposure estimation and risk characterization are
    provided in CICADs, whenever possible. These examples cannot be
    considered as representing all possible exposure situations, but are
    provided as guidance only. The reader is referred to EHC 1701 for
    advice on the derivation of health-based guidance values.

         While every effort is made to ensure that CICADs represent the
    current status of knowledge, new information is being developed
    constantly. Unless otherwise stated, CICADs are based on a search of
    the scientific literature to the date shown in the executive summary.
    In the event that a reader becomes aware of new information that would
    change the conclusions drawn in a CICAD, the reader is requested to
    contact IPCS to inform it of the new information.


              
    1 International Programme on Chemical Safety (1994)  Assessing
     human health risks of chemicals: derivation of guidance values 
     for health-based exposure limits. Geneva, World Health Organization
    (Environmental Health Criteria 170).

    Procedures

         The flow chart shows the procedures followed to produce a CICAD.
    These procedures are designed to take advantage of the expertise that
    exists around the world -- expertise that is required to produce the
    high-quality evaluations of toxicological, exposure, and other data
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    environment.

         The first draft is based on an existing national, regional, or
    international review. Authors of the first draft are usually, but not
    necessarily, from the institution that developed the original review.
    A standard outline has been developed to encourage consistency in
    form. The first draft undergoes primary review by IPCS to ensure that
    it meets the specified criteria for CICADs.

         The second stage involves international peer review by scientists
    known for their particular expertise and by scientists selected from
    an international roster compiled by IPCS through recommendations from
    IPCS national Contact Points and from IPCS Participating Institutions.
    Adequate time is allowed for the selected experts to undertake a
    thorough review. Authors are required to take reviewers' comments into
    account and revise their draft, if necessary. The resulting second
    draft is submitted to a Final Review Board together with the
    reviewers' comments.

         The CICAD Final Review Board has several important functions:

    -    to ensure that each CICAD has been subjected to an appropriate
         and thorough peer review;
    -    to verify that the peer reviewers' comments have been addressed
         appropriately;
    -    to provide guidance to those responsible for the preparation of
         CICADs on how to resolve any remaining issues if, in the opinion
         of the Board, the author has not adequately addressed all
         comments of the reviewers; and
    -    to approve CICADs as international assessments.

    Board members serve in their personal capacity, not as representatives
    of any organization, government, or industry. They are selected
    because of their expertise in human and environmental toxicology or
    because of their experience in the regulation of chemicals. Boards are
    chosen according to the range of expertise required for a meeting and
    the need for balanced geographic representation.

         Board members, authors, reviewers, consultants, and advisers who
    participate in the preparation of a CICAD are required to declare any
    real or potential conflict of interest in relation to the subjects
    under discussion at any stage of the process. Representatives of
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    proceedings of the Final Review Board. Observers may participate in
    Board discussions only at the invitation of the Chairperson, and they
    may not participate in the final decision-making process.

    FIGURE 1

    

1. EXECUTIVE SUMMARY This CICAD on biphenyl was prepared by the Fraunhofer Institute for Toxicology and Aerosol Research, Hanover, Germany, based principally on a review prepared by the German Advisory Committee on Existing Chemicals of Environmental Relevance (BUA, 1990) as well as a supplementary report (BUA, 1994) to assess the potential effects of biphenyl on humans and the environment. The source documents and a description of their review processes are presented in Appendix 1. A comprehensive literature search of several online databases to June 1996 was also conducted to identify any additional data. Additional information identified during review by contact points and consideration by the Final Review Board (Brussels, Belgium) has also been incorporated into this CICAD. Information on the peer review of this CICAD is presented in Appendix 2. This CICAD was given provisional approval as an international assessment at a meeting of the Final Review Board held in Brussels, Belgium, on 18-20 November 1996. Participants at the Brussels Final Review Board meeting are listed in Appendix 3. Following the incorporation of data related to the carcinogenicity of this substance from a recently completed 2-year carcinogenicity bioassay, the revised document was subjected to two rounds of written peer review. In addition, that part of the document dealing specifically with the human health assessment (i.e. section 11.1) was reviewed at a meeting held at the National Center for Environmental Assessment, US Environmental Protection Agency, in Washington, DC (USA), on 7 December 1998. Individuals contributing to the additional specialized reviews of this CICAD are listed in Appendix 4. This CICAD was approved as an international assessment at a meeting of the Final Review Board held in Washington, DC (USA), on 8-11 December 1998. Participants at the Washington Final Review Board meeting are listed in Appendix 5. The International Chemical Safety Card (ICSC 0106) produced by the International Programme on Chemical Safety (IPCS, 1993) has also been reproduced in this document. Biphenyl (CAS No. 92-52-4), an aromatic hydrocarbon, is a colourless solid at room temperature. It is used as an intermediate in the production of a variety of compounds (e.g. emulsifiers, optical brighteners, crop protection products, plastics), as a heat transfer medium in heating fluids, as a dyestuff carrier for textiles and copying paper, as a solvent in pharmaceutical production, and in the preservation of citrus fruits. Biphenyl occurs naturally in coal tar, crude oil, and natural gas. Anthropogenic sources of environmental exposure include production and processing plants, citrus fruit or wood preserving facilities, and municipal waste disposal sites. Biphenyl is formed during the incomplete combustion of mineral oil and coal and is present in the exhaust gases of vehicle traffic and in exhaust air from residential and industrial heating devices. In ambient air, typical concentrations of biphenyl range from 1 to 100 ng/m3. Levels in indoor air are higher (100-1000 ng/m3), likely as a result of cigarette smoke and emissions from heating devices or nearby garages. In measurements conducted in the 1970s, levels of biphenyl in tap-water were usually below 5 ng/litre. More recent data were not identified. In surface waters, concentrations are typically below 500 ng/litre. In sediment, soil, and biota, biphenyl was measured only in the direct vicinity of industrial plants and waste dumps. Biphenyl volatilizes from aqueous solution and has a low water solubility. The main degradation pathway in the troposphere is the reaction with hydroxyl radicals, for which a mean half-life of approximately 2 days has been calculated. The substance is not expected to hydrolyse under environmental conditions. It is biodegradable under aerobic conditions. Based upon available data, biphenyl should be almost immobile in soil; the probability of infiltration into groundwater is low. In the food-chain important to humans, bioaccumulation can take place, specifically in plants; however, based upon the potential bioaccumulation of biphenyl, biomagnification of biphenyl in higher trophic levels of the aquatic or terrestrial food-chain is expected to be of minor importance. Biphenyl is well absorbed through the gastrointestinal tract and presumably also via lung and skin. In those species examined, the metabolites of biphenyl, mainly 4-hydroxybiphenyl, are excreted rapidly and almost exclusively in the urine. The acute oral toxicity of biphenyl is moderate. It is non-irritating to skin and only slightly irritating to the eyes. There is no evidence of dermal sensitization. Toxicity studies with biphenyl after repeated exposure by inhalation are not adequate to establish a no-observed-effect level (NOEL) with confidence. Subchronic exposure by inhalation caused bronchopulmonary changes, whereas long-term toxicity studies following inhalation exposure were not identified in the literature. In toxicological studies in which rodents have been administered diets containing biphenyl for various periods of time, effects on the urinary system have often been reported. A marked increase in the incidence of morphological (i.e. formation of calculi) and histopathological (e.g. hyperplasia, desquamation) effects has been observed within the urinary tract of male rats administered diets containing more than 2500 mg biphenyl/kg. An increase in the occurrence of calculi and squamous metaplasia within the urinary bladder of female rats has also been observed, but at a lower incidence than in males. In male mice, only 1 of 10 animals given a diet containing 10 000 mg biphenyl/kg (1500 mg/kg body weight per day) for 32 weeks developed simple hyperplasia and papillary or nodular dysplasia of the urinary bladder. Effects on blood chemistry and haematological parameters have also been observed in animals administered biphenyl orally; these effects occur in male and female rats and mice at intakes lower than those associated with the development of effects in the urinary bladder of male rats administered biphenyl. For non-neoplastic effects, the lowest-observed-effect level (LOEL) was 38 mg/kg body weight per day, based upon the development of alterations in haematological parameters (i.e. decreased haemoglobin concentration and haematocrit) in rats fed diets containing 0, 500, 1500, or 4500 mg biphenyl/kg (reported intakes of 0, 38, 113, or 338 mg/kg body weight per day) for 2 years. In vitro studies with bacteria have provided no evidence of mutagenic potential for biphenyl; with Saccharomyces cerevisiae D7, gene mutation and mitotic recombination were observed with or without metabolic activation. However, genetic toxicology testing in mammalian cells has produced positive results in the presence of metabolic activation and negative results in the absence of metabolic activation. In one inadequately documented and inadequately performed in vivo study, biphenyl did not induce chromosomal aber rations in the bone marrow of rats after exposure by inhalation. The results of in vitro studies indicate that biphenyl has mutagenic potential; in the absence of reassurance from reliable results from in vivo tests, it is assumed that exposure to biphenyl may be associated with a mutagenic risk. In female mice, there were slight increases in the incidences of benign and malignant liver tumours in animals receiving biphenyl in the diet for 2 years. An increased incidence of bladder tumours was observed in male rats, but not in female rats or male and female mice, administered diets containing high levels of biphenyl. There have been suggestions that the formation of such bladder tumours may be linked to the regenerative hyperplasia of the urinary epithelium, caused by the abrasion and damage to the urothelium that are produced by calculi formed within the urinary tract only at very high levels of exposure; it has also been suggested that, because of anatomical and physiological differences, the sex- and species-specific development of bladder tumours in male rats receiving high doses of biphenyl might not be strictly relevant to humans exposed to lower levels. However, 1) observations of an increased incidence of histopathological effects and the formation of calculi within the urinary bladder, in the absence of bladder tumours, in female rats administered biphenyl for 2 years, 2) a lack of data identifying a direct association between calculi formation, regenerative hyperplasia of the urothelium, and the development of bladder tumours within individual male animals, and 3) the potential genotoxicity of biphenyl could suggest that the development of bladder tumours in the male rats may not have been entirely due to effects associated with the formation of calculi within the urinary bladder. This observation, as well as evidence of hepatocarcinogenicity in female mice, raises some concerns with respect to the potential carcinogenicity of biphenyl. Available data on the reproductive toxicity of biphenyl are limited. Apart from results of a three-generation study in rats, in which adverse effects (decreased fertility, litter size, growth rate) were noted, there was no evidence that biphenyl induced reproductive or developmental effects. Exposure to high levels of biphenyl vapours or dust at the workplace results in irritation of the eyes and inflammation of the respiratory tract. Long-term exposure for several years to high biphenyl concentrations (up to 128 mg/m3) caused damage to the liver and persistent neuronal changes; direct skin contact may have played a part, in addition to uptake through the respiratory tract. The available data on biphenyl levels in the general environment are limited, and the information is insufficient to permit a reasonable estimation of the intake of biphenyl. Inhalation (from polluted air and from the use of biphenyl-containing creosotes in wood preservation) and ingestion (from biphenyl's use as a preservative for citrus fruits) are possible sources of exposure. Biphenyl has weak bactericidal and fungistatic properties. In toxicity studies on aquatic organisms of four trophic levels, the lowest no-observed-effect concentration (NOEC) reported for the most sensitive species ( Daphnia magna) in chronic tests was 0.17 mg/litre. A predicted no-effect concentration (PNEC) of 1.7 µg/litre can be calculated by applying an assessment factor of 10, considering ecotoxicological and environmental fate characteristics of the substance. Valid data on toxic effects on terrestrial organisms and ecosystems, which could be used for risk assessment, are not available. Owing to the lack of data from other parts of the world, a sample risk assessment was performed for Germany. From concentrations measured in German rivers in the 1990s, the ratio of the predicted environmental concentration (PEC) to PNEC is calculated to be <0.29. A PEC/PNEC ratio of <1 indicates that a significant risk for the environment is not to be expected. 2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES Biphenyl (CAS No. 92-52-4; C12H10; 1,1'-biphenyl, diphenyl, phenylbenzene) has the following structural formula: CHEMICAL STRUCTURE 1 The chemical is an aromatic hydrocarbon with a peculiar, strong odour similar to that of geraniums (BUA, 1990). At room temperature, the substance is a colourless solid (melting point 62.2°C). Because of its significant vapour pressure (4 Pa at 20°C) and low water solubility (4.45 mg/litre at 20°C), biphenyl shows considerable volatility from aqueous solutions (BUA, 1990). Its measured n-octanol/water partition coefficient (log Kow) is between 3.88 and 4.04. The commercial product from the only German producer has a biphenyl content of 99.85%; named impurities are terphenyl (0.15%), sulfur (10-20 mg/kg), and benzene (1 mg/kg) (BUA, 1990). Additional physical/chemical properties are presented in the International Chemical Safety Card reproduced in this document. 3. ANALYTICAL METHODS Biphenyl is usually measured in environmental media by capillary gas chromatography in combination with flame ionization or mass spectrometric detection (Malins et al., 1985; BUA, 1990; Hawthorne et al., 1992; Anklam & Mueller, 1994; Karanassios et al., 1994; Otson et al., 1994; Kostiainen, 1995). For aquatic samples, methods involving high-performance liquid chromatography with ultraviolet detection at 254 nm have also been described. The following enrichment techniques are used: solid-phase adsorption (Tenax material or XAD resins) with thermal desorption or liquid extraction for air samples, solid-phase adsorption (XAD resins) or liquid/liquid extraction (diethylether) for water samples, and liquid extraction (dichloromethane/methanol, ethanol) for soil and biotic samples. The detection limits range from 0.1 to 5 ng/m3 for air and from 0.01 to 8000 ng/litre for water. For sediment, a detection limit of 2 µg/kg dry weight has been reported. Detection limits between 12 and 87 µg/kg have been reported for levels of biphenyl in fish (Malins et al., 1985). 4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE Biphenyl occurs in varying concentrations in coal tar, crude oil (up to 0.4 mg/g oil), and natural gas (3-42 µg/m3) (BUA, 1990). Because of its natural occurrence in coal tar and crude oil, biphenyl has also been detected in products derived from these substances. The biphenyl content in coal tar-derived creosotes ranges between 0.2 and 1.6% (IARC, 1985; ATSDR, 1990; Collin & Hoeke, 1995). In the aromatic fraction of an unused lubricating oil sample, biphenyl was measured at a concentration of 1.5 mg/kg (Paschke et al., 1992). Biphenyl is also produced from anthropogenic sources. In 1984, the estimated production capacities of biphenyl in the Federal Republic of Germany, in Western Europe, and throughout the world were approximately >6000, 30 000, and 80 000 t, respectively. In 1989, 2000-2500 t of biphenyl were produced in Germany, of which about 900 t were exported and 200-300 t sold domestically (BUA, 1990). Approximately 5000 t of biphenyl were manufactured in each of 1992 and 1993 in Japan (Anon., 1994-95). Until the early 1970s, biphenyl was used principally as an intermediate in the production of polychlorinated biphenyls (PCBs). As the production, processing, distribution, and use of PCB compounds are now prohibited or restricted in many countries (e.g. USA, Germany, United Kingdom) (IRPTC, 1994), it is likely that previous production levels were much higher than those today. In 1984, the estimated use patterns of biphenyl worldwide were, as a final product: 35% in heat transfer medium in heating fluids, 20% as a dyestuff carrier for textiles, 5% as a solvent in pharmaceutical production, 5% as a dyestuff carrier for copying paper, and 5% as a preservative for citrus fruits; patterns of biphenyl use as an intermediate were: 10% each in emulsifiers and optical brighteners, 5% for crop protection products, and 5% for precursors and auxiliaries for plastics (BUA, 1990). At present in Germany, the use of biphenyl as a dyestuff carrier in textiles is minor.1 Although emissions from exhaust gases during production and processing of biphenyl and during the use of biphenyl-containing creosotes for wood preservation may be significant, available data were not identified. Biphenyl is also released into the atmosphere during the incomplete combustion of fossil fuels in motor vehicles (post-catalyst emission factor of 3.5 µg/km; Siegl & Chladek, 1992), residential heating (1.24 mg biphenyl/kg burnt coal; Engewald et al., 1993), and coal-burning power plants (with concentrations in flue gas up to 30 µg/m3; Yao & Xu, 1991; Wienecke et al., 1992) or foundries (qualitatively detected; Deusen & Kleinermanns, 1993). 1 Personal communication from Verband d. Textilhilfsmittel-, Lederhilfsmittel-, Gerbstoff- und Waschrohstoff-Industrie e.V., Frankfurt/M., Germany, to Bayer AG, 1996. In 1990, biphenyl was not detected in the effluent of the sewage plant of the German producer (detection limit 5 µg/litre; weekly sampling). Based on a biphenyl concentration of <5 µg/litre, a maximum annual release of 274 kg biphenyl can be calculated for this plant. No data are available from other producing or processing facilities. Biphenyl may also be released to surface water through the processing of coal tar (e.g. coking plants) and mineral oils (e.g. processing residual oils from pyrolysis in refineries) (BUA, 1990).1 Based upon levels of biphenyl measured in sediment samples during the 1970s, this chemical has been released from various industrial wastewater outlets associated with a melting plant for iron alloys, a chemical factory, and an oil storage depot. Data were not available on releases of biphenyl from textile industries where the chemical is used as a dyestuff carrier, from wood preservation plants that use creosotes containing biphenyl, or from treated citrus fruits and their packaging materials contained in domestic waste sites. Concentrations of biphenyl between 0.016 µg/kg and 1730 mg/kg have been measured in sewage sludge, which may be applied to arable land (BUA, 1990). 1 Personal communication from Bayer AG to the GDCh- Advisory Committee on Existing Chemicals of Environmental Relevance, 1997. 5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION Based upon a Level II fugacity model (Mackay et al., 1992), the atmosphere appears to be the main target compartment (>90%) for biphenyl. Biphenyl's Henry's law constant indicates that it volatilizes from aqueous solutions. The calculated half-life for the photooxidative degradation of biphenyl by hydroxyl radicals in air is about 2 days (Atkinson & Aschmann, 1985; BUA, 1990; Atkinson & Arey, 1994). Reactions with tropospheric ozone and nitrate are expected to be of minor importance, with calculated half-lives of >80 days and >105 days, respectively. Data on the photodegradation of biphenyl in water are not available. Biphenyl is not expected to hydrolyse under environmental conditions. In one reported standard test with activated sludge, according to Guideline 301C of the Organisation for Economic Co-operation and Development (OECD), a biochemical oxygen demand of 66% after 14 days' incubation was reported when non-adapted inoculum was used (CITI, 1992). Microbial populations from natural waters mineralize biphenyl; 100% degradation was observed after 4 days' incubation of biphenyl in river water (BUA, 1990). Numerous microorganisms isolated from soil, sediment, surface water, and groundwater samples have been shown to metabolize biphenyl (BUA, 1990; Bevinakatti & Ninnekar, 1992; Kiyohara et al., 1992; Nielsen & Christensen, 1994). Investigations on the anaerobic biodegradation of biphenyl were not identified. Soil sorption coefficients ( Koc) based upon laboratory experiments and calculated values range from 1100 to 18 000 (BUA, 1990; Kishi & Hasimoto, 1991); from numerous literature data, Jeng et al. (1992) calculated a mean value of 4230. On the basis of these data, it is expected that biphenyl will be almost immobile in soil, with a low probability of groundwater infiltration. Volatilization from soil surfaces is significantly lower than that from aqueous media; however, no significant geoaccumulation of biphenyl is expected under aerobic conditions owing to its degradation by microbial organisms. In static tests on the bioaccumulation of biphenyl in activated sludge conducted with several aquatic species (yeast, algae, molluscs, daphnia, and freshwater fish), bioconcentration factors (BCFs) ranging between 57 for the marine mussel Mytilus edulis (calculated on wet weight) (Donkin et al., 1991) and 540 for the green alga Chlorella vulgaris (based on dry weight) (Kotzias et al., 1980; Freitag et al., 1982) have been reported. With the exception of two tests, there was no information on whether equilibrium was reached before the determination of the BCF. The depuration of accumulated biphenyl was determined in one study. After a 24-h incubation in a static test system, the BCF at equilibrium (based on wet weight) for Daphnia magna was 473; depuration was dependent upon the temperature of the water. Twenty-four hours after being transferred to pure water, 53% of the accumulated biphenyl was depurated at 2-3°C, whereas 88% was depurated at 22°C (Zhang et al., 1983). Although the available data indicate a potential for bioaccumulation, evaporation, adsorption to soil/sediment, and degradation are expected to reduce the bioavailability of biphenyl. Therefore, bioaccumulation of the chemical should be of minor importance for aquatic organisms. 6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE 6.1 Environmental levels In 1985, concentrations of biphenyl in the air of an industrialized city in Finland ranged from 1.7 to 26.2 ng/m3 (BUA, 1990). Similar concentrations were measured during the winter of 1988-89 in two US cities (12-119 ng/m3; 30 ng/m3 mean value; Hawthorne et al., 1992) and in 1992 in two Greek cities (all data below the detection limit of 5 ng/m3; Karanassios et al., 1994). The concentrations of biphenyl in the German parts of the Rhine River declined from a maximum of 1000 ng/litre in the 1970s (BUA, 1990) to levels below 500 ng/litre (the detection limit) in 1993-1995 (LWA, 1993-94).1 Although levels in most of the German tributaries have remained below the detection limit (500 ng/litre), peak concentrations of 560 and 1600 ng/litre were reported in 1993 and 1994, respectively, for the highly polluted Emscher tributary (LWA, 1993-94); these elevated levels were attributed to the coking plants in this area.2 In the USA, similar data for one river have been reported (Hites, 1973). In some German estuaries, biphenyl concentrations were significantly lower (1-5 ng/litre) (BUA, 1990). During 1986-1989, biphenyl was detected at concentrations between 10 and 100 ng/litre in samples of groundwater obtained near Zagreb, in the former Yugoslavia, in the vicinity of a municipal landfill site. In a test well sunk 720 m from a heavily polluted river, the levels were about 10-fold lower (Ahel, 1991). Concentrations of biphenyl between 2 and 17 ng/litre have been measured in samples of snow and rain collected in Switzerland (BUA, 1990). In river and estuarine sediments, biphenyl was detected at very high concentrations in the direct vicinity of industrial plants or waste dumps; concentrations ranged between 0.1 and 8 mg/kg, depending on the source. The highest concentrations were found near waste dump sites in the USA (Malins et al., 1985; BUA, 1990). Information on the occurrence of biphenyl in soils with no direct pollution was not identified. A maximum biphenyl concentration of 13 µg/kg was found in soil samples collected near a pit for wastewater from oil production in New Mexico, USA (BUA, 1990). Biphenyl has been found in fish collected from water contaminated with mineral oil; concentrations in liver samples were <25 µg/kg dry weight (i.e. below the detection limit) and 13 620 µg/kg fresh weight (Paasivirta et al., 1982; Malins et al., 1985). 1 Personal communication from the Northrhine-Westfalian Environmental Protection Agency to Bayer AG, 1996. 2 Personal communication from Bayer AG to the GDCh- Advisory Committee on Existing Chemicals of Environmental Relevance, 1997. 6.2 Human exposure The levels of biphenyl in indoor air may depend mainly on smoking habits (BUA, 1990). Concentrations of biphenyl are also elevated in homes having a source of oil and exhaust fumes nearby (e.g. gasoline station, parking garage) (Otson et al., 1994; Kostiainen, 1995). Monitoring data from Finnish ( n = 50) (Kostiainen, 1995) and Canadian ( n = 757) homes (Otson et al., 1994) have revealed average biphenyl concentrations in the range of 160-1000 ng/m3, with a maximum concentration of 4700 ng/m3 (Kostiainen, 1995). Biphenyl has been detected in floor dust collected from five of nine investigated Danish city halls (Wilkins et al., 1993). Assuming that 20 h are spent indoors (exposure to 160-1000 ng/m3) and 4 h are spent outdoors (exposure to 30 ng/m3) each day and that the inhalation volume and weight of the average adult are 22 m3/day and 64 kg, respectively, the intake of biphenyl from air can be calculated from these data to range from 45 to 300 ng/kg body weight per day. There is only limited intake of biphenyl from drinking-water. Although more recent data were not identified, concentrations of biphenyl in tap-water in various countries, such as Finland, Norway, Sweden, the USA, and Canada, were low (i.e. 0.1-5 ng/litre) in the 1970s (BUA, 1990). Based upon these data and assuming that the average adult (weighing 64 kg) consumes 2 litres of drinking-water per day, the estimated intake of biphenyl from drinking-water may range from 0.003 to 0.16 ng/kg body weight per day. Food may contain biphenyl as a result of its use as a fungistatic agent for citrus fruits. In older studies with citrus fruits to which a biphenyl-containing wax had been applied, peels of treated fruits were found to contain up to 220 mg biphenyl/kg (whole fruit) and the pulp up to 3.9 mg/kg (whole fruit) (BUA, 1990); however, these levels were determined with a rather unspecific spectrophotometric method, which may have overestimated the biphenyl content. In a more reliable study with 6 grapefruits, 8 oranges, and 10 lemons obtained from Japanese markets, levels of biphenyl ranged from 17 to 123 mg/kg in the peel and from <0.01 (the detection limit) to 0.18 mg/kg (average 0.06 mg/kg pulp) in the edible parts of the fruit. In samples of lemon tea, levels of biphenyl were similar to those in the edible parts of the fruit (Isshiki et al., 1982). In a survey of foodstuffs conducted in Italy between 1988 and 1995, which included more than 70 types of food, biphenyl was detected in only one peach sample (detection limit not given) (Di Muccio et al., 1995). Based upon the average content of biphenyl in the pulp of citrus fruits of about 0.06 mg/kg (calculated from the concentrations measured by Isshiki et al., 1982), the intake from the consumption of the pulp of one biphenyl-preserved citrus fruit weighing about 120-400 g is calculated to be about 113-375 ng/kg body weight. An average intake of 64 ng biphenyl/kg body weight per day from food was calculated based upon the consumption of foodstuffs in Finland (Penttilae & Siivinen, 1996). The general population may also be exposed to biphenyl through contact with consumer products, such as creosote-preserved wood, textiles, copying papers, or pharmaceuticals, although quantitative data were not identified. The intake of biphenyl from the occupational environment may occur via inhalation and dermal contact. Concentrations of biphenyl in the air of one facility producing biphenyl-impregnated paper were reported to range from 4.4 to 128 mg/m3 in 1959 and from 0.6 to 123 mg/m3 in 1970 (Haekkinen et al., 1973). In a nylon production facility in which workers were exposed to a eutectic mixture of 26.5% (w/w) biphenyl and 73.5% (w/w) biphenyl ether, time-weighted average concentrations of biphenyl were reported to range from 0.24 to 1.28 mg/m3 (Dorgelo et al., 1985). Coke oven emissions to indoor air at a coking plant in Australia contained 0.2-0.5% biphenyl (Kirton et al., 1991). In a Polish bituminous pulp production facility, reported time-weighted average concentrations (1988-89) of biphenyl ranged from 0.5 to 0.6 µg/m3 (Baranski, 1991). In a study of two Canadian pilot-scale coal liquefaction facilities, the levels of biphenyl were below the detection limit of 60 µg/m3 (Leach et al., 1987). 7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS Studies providing quantitative information on the absorption or distribution of biphenyl in humans were not identified. In various species of experimental animals, the absorption of biphenyl following oral exposure has been inferred by the detection of metabolites in the urine and faeces. Biphenyl is oxidized by multifunctional oxygenases, irrespective of the route of exposure. Mono-, di-, and trihydroxy metabolites of biphenyl have been identified in the urine of exposed species. 4-Hydroxybiphenyl has been observed as the major metabolite in rats, rabbits, guinea-pigs, and pigs; minor metabolites include mono-, di-, and trihydroxymethoxy biphenyls, dihydrodiols, and hydroxydihydrodiols. The phenolic compounds are conjugated with sulfate or glucuronic acid. The formation of mercapturic acid as well as evidence of a metabolic pathway involving opening of the benzene ring have also been described (BUA, 1990). There is no evidence for enterohepatic circulation in different species (Meyer & Scheline, 1976; Meyer et al., 1976a; Meyer, 1977). On the basis of in vitro studies, the metabolism of biphenyl is not restricted to the liver (Bend et al., 1972; Hook et al., 1972; Matsubara et al., 1974; Prough & Burke, 1975; Hook & Bend, 1976; Powis et al., 1987). Based upon total cytochrome P-450 content, biphenyl-4-hydroxylase activity was higher in pulmonary microsomes than in liver microsomes (Hook et al., 1972; Hook & Bend, 1976). A time-dependent covalent binding of [14C]bi phenyl to mouse hepatic microsomal proteins has been observed after metabolic activation (Tanaka et al., 1993). In rats, rabbits, and pigs, most biphenyl metabolites are excreted in the urine (BUA, 1990). Following an oral dose of 100 mg [14C]biphenyl/kg body weight, rats excreted 82% of the administered radioactivity (76% in urine) within 24 h. The recovery rate after 4 days was 92%, with 7% of the administered radioactivity detected in the faeces and traces in the exhaled air. Eight days after administration, radioactivity in the tissues was 0.6% of the applied dose (Meyer et al., 1976b). In none of the species examined was unmetabolized biphenyl found in the urine (BUA, 1990). 8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS 8.1 Single exposure The acute oral toxicity of biphenyl is moderate. The LD50 for rats and mice is >1900 mg/kg body weight (BUA, 1990). Acute effects include polyuria, accelerated breathing, lacrimation, anorexia, weight loss, muscular weakness and coma, fatty liver cell degeneration, severe nephrotic lesions (often manifested as acute and subacute glomerulotubular nephritis), degenerative myocardial lesions, pulmonary hyperaemia, and, occasionally, alveolar oedema. Interstitial and lobular pneumonitis have been observed in animals that survived for a few days. The LC50 (4-h) for the mouse is >43 ppm (275 mg/m3). During exposure, hyperactivity and mild respiratory discomfort have been observed; however, these effects were not evident at the end of a 14-day recovery period. Gross pathological examination performed on surviving animals revealed slight lung congestion (Sun Co. Inc., 1977a). In an inhalation study conducted with Sprague-Dawley rats, no effects were observed after a 6-h exposure to 0.8 or 3 ppm (5.1 or 19.2 mg/m3) biphenyl at temperatures of approximately 26°C or 32°C, respectively (Monsanto Co., 1959). No treatment-related alterations in appearance, demeanour, food consumption, or survival were observed following a 7-h inhalation exposure of rats to 3 g biphenyl/m3 (nominal concentration); no detailed information on the methods or particle size of the substance were presented (Dow Chemical Co., 1974). Information on the acute toxicity of biphenyl associated with dermal exposure was not identified. 8.2 Irritation and sensitization Biphenyl is non-irritating to both intact and scarified rabbit skin. The substance was slightly irritating when applied to rabbits' eyes in an eye irritation test (BUA, 1990). In a guinea-pig maximization test conducted according to OECD Guideline 406, there was reportedly no evidence of a skin sensitizing potential for biphenyl (Dreist & Kolb, 1993). 8.3 Short-term exposure 8.3.1 Oral exposure In the studies cited below, the histopathological examination was focused on the urinary system. In a study in which male and female Wistar rats were fed 0, 50, 150, 300, or 450 mg biphenyl/kg body weight per day via the diet for 21 days, increased relative kidney weights and polycystic renal changes (with increased urine volume and specific gravity) were observed at doses of 50 and 150 mg/kg body weight per day, respectively. An increase in urine volume, specific gravity, and absolute kidney weight as well as polycystic renal changes were also observed in rats administered 500 or 1000 mg biphenyl/kg body weight per day in the diet for 14 days (Sœndergaard & Blom, 1979). When male albino rats were administered diets containing 0, 1000, 2500, 5000, or 10 000 mg biphenyl/kg (estimated intakes of 0, 75, 188, 375, or 750 mg/kg body weight per day) for 26 days, there was a dose-dependent (at doses of >188 mg/kg body weight per day) intensification of cloudiness in the urine, associated with an increase in precipitate formation in samples, which had been cooled or treated with sulfosalicylic acid. The precipitate consisted of free 4-hydroxybiphenyl and its glucuronide. These effects were largely reversible during a 28-day recovery period (Booth et al., 1956, 1961). 8.3.2 Inhalation exposure No evidence of histopathological changes in the lung, trachea, liver, kidney, or spleen were observed in male and female mice exposed by inhalation to 25 or 55 ppm (about 160 or 350 mg/m3) biphenyl for 7 h/day, 5 days/week, for 2 weeks (Sun Co. Inc., 1977b). 8.3.3 Dermal exposure In rabbits, the repeated dermal application (20 in total) of purified biphenyl (0.5 g/kg body weight) for 2 h/day, 5 days/week, produced decreased body weight; one animal died after 8 applications. A decrease in body weight was also observed after repeated dermal application of technical biphenyl. In both studies, no effect upon the skin was observed. Histopathological examination revealed minimal changes in the heart, liver, kidneys, and, in some cases, spleen (no further details provided) (Deichmann et al., 1947). No adverse effects were observed when biphenyl was applied (8 h/day, 5 days/week, for a total of 30 applications) to the intact and abraded skin of rabbits at doses of 600 or 2000 mg/kg body weight per day (no further information provided) (Newell, 1953). 8.4 Long-term exposure 8.4.1 Subchronic exposure 8.4.1.1 Oral exposure In all of the studies cited below, the histopathological examination was focused on the urinary system. A summary of the effects related to this specific end-point (changes in kidneys, ureter, and urinary bladder) for both subchronic and chronic exposures is provided in Table 1. Table 1: Summary of the effects of repeated biphenyl administration via diet on urine status, urinary bladder, and kidneys. Species/strain/ Application/duration NO(A)EL sex (mg/kg) Urine status Urinary bladder Kidneys Reference rat/F344/male 0 or 5000 mg/kg <5000 crystals with simple hyperplasia not examined Shibata et al. 8 weeks microcalculi in and increased (1989a) urinary sediment DNA synthesis in the urothelium rat/F344/male 0 or 5000 mg/kg <5000 microcalculi simple hyperplasia, increase in absolute/relative Shibata et al. up to 24 weeks papillary or kidney weights; no (1989b) nodular hyperplasia morphological changes of of the urothelium the renal papillae or after >16 weeks pelvis; no changes in DNA synthesis in the renal papillae and pelvis; focal calcification of the renal medulla rat/albino/male 0, 1000, 2500, or 1000 >2500 mg/kg: not examined 2500 mg/kg: morphological Booth et al. and female 5000 mg/kg increase in changes (tubular dilation) (1961) up to 24 weeksa volume, turbidity, after >60 days and precipitate 5000 mg/kg: morphological after >30 days; changes (tubular dilation) urinary sediment: after >30 days; effects 4-hydroxybiphenyl not completely reversible and its glucuronide; effects reversible rat/F344/male 0 or 5000 mg/kg <5000 increase in pH increased incidence not given Kurata et al. 32 weeks value and Na+ of calculi; (1986) concentration; histopathology: urinary sediment: no effects 4-hydroxybiphenyl Table 1 (Cont'd.) Species/strain/ Application/duration NO(A)EL sex (mg/kg) Urine status Urinary bladder Kidneys Reference rat/Wistar/male 0, 1250, or 1250 not given 5000 mg/kg: 5000 mg/kg: increased Shiraiwa et al. 5000 mg/kg increased incidence incidence of calculi (1989) 36 weeks of calculi in ureter and increase in and bladder relative kidney weights rat/Wistar/male 0, 2500, or <2500 haematuria at >2500 mg/kg: >2500 mg/kg: increased Takita (1983); and female 5000 mg/kg >2500 mg/kg increased incidence incidence of calculi Shiraiwa et al. 75 weeks after >16 weeks of calculi (composed (composed of protein) (1989) of magnesium after >16 weeks; ammonium phosphate) kidneys with stones: after >16 weeks in obstructive ureter (females) pyelonephritis, 5000 mg/kg:increased tubular atrophy, incidence of calculi fibrosis in ureter and 5000 mg/kg: increase bladder after >16 in relative kidney weeks; bladder with weights in females calculi: simple or diffuse hyperplasia and papillomatosis of the urothelium rat/Wistar/male 0, 630, or 1250 mg/kg 1250 not given no urolithiasis not given Takita (1983) and female 104 weeks (no further information given) rat/F344/DuCrj/ 0, 500, 1500, or <500b >500 mg/kg: 4500 mg/kg: increase >1500 mg/kg: increase Japan Bioassay male and female 4500 mg/kg decrease in in pH (males and in hyperplasia of Research Center 104 weeks protein (males) females) 4500 mg/kg: the renal pelvis in (1996) >1500 mg/kg: increase in calculi females decrease in and hyperplasia 4500 mg/kg: increase protein (females) of the urothelium in calculi (males > Table 1 (Cont'd.) Species/strain/ Application/duration NO(A)EL sex (mg/kg) Urine status Urinary bladder Kidneys Reference (males >> females); females) and increased tumour hyperplasia of the incidence in males renal pelvis (males) mouse/B6C3F1/ 0 or 10 000 mg/kg 10 000 decreased Na+ no changes in DNA not given Tamano et al. male 8 weeks concentration synthesis of the (1993) at week 4 urothelium mouse/B6C3F1/ 0 or 10 000 mg/kg <10 000 small amounts of simple hyperplasia interstitial nephritis Tamano et al. male 32 weeks greyish white and papillary or in 5/10 (1993) and finely nodular dysplasia granular material in 1/10 mice mouse/Crj:BDF1/ 0, 667, 2000, or 667 6000 mg/kg: no changes >2000 mg/kg: mineralization Japan Bioassay male and female 6000 mg/kg decrease in of the medulla in females Research Center 104 weeks protein and 6000 mg/kg: desquamation (1996) ketone body and mineralization of the pelvis in males a Plus a post-treatment observation period of 9 weeks. b Effects were observed at the lowest dose tested. Effects on the urinary tract (i.e. an increased number of microcalculi in urinary sediment, simple hyperplasia of the bladder epithelium) were observed in male F344 rats administered 5000 mg biphenyl/kg (estimated intake 252 mg/kg body weight per day) in the diet for 8 weeks. Morphological changes and the increased synthesis of DNA detected in the bladder epithelium after 4 weeks were attributed to constant irritation by the microcalculi (Shibata et al., 1989a). In male B6C3F1 mice, no changes in the urinary pH or in levels of DNA synthesis in the urinary bladder were noted after administration of 0 or 10 000 mg biphenyl/kg in the diet (0 or 1500 mg/kg body weight per day) over a period of 8 weeks. The urinary Na+ concentration was significantly lower in mice administered 1500 mg/kg body weight per day compared with controls only at week 4 (Tamano et al., 1993). In a range-finding study in which male and female Wistar rats were administered diets containing biphenyl at 0, 1250, 2500, 5000, 10 000, or 20 000 mg/kg (estimated intakes of 0, 94, 188, 375, 750, or 1500 mg/kg body weight per day) for 10 weeks, dose-dependent effects (i.e. reduction in weight gain; increased serum activities of aspartate transaminase, alanine transaminase, and lactate dehydrogenase; and an increase in blood urea nitrogen) were observed at all doses (Takita, 1983). In male F344 rats (20 per group) administered 0 or 5000 mg biphenyl/kg in the diet (0 or 375 mg/kg body weight per day) for 24 weeks (5 rats per group were sacrificed after 4, 8, 16, or 24 weeks), reduced body weight gain and an increase in absolute/relative kidney weights without differences in feed intake were observed in the biphenyl-exposed rats. The analysis of the urine showed that administration of biphenyl was associated with the formation of microcalculi. The histopathological examination of the renal papillae or pelvis performed after 4, 8, 16, and 24 weeks revealed no morphological changes; the rate of DNA synthesis in the renal papillae and pelvis determined after 4 weeks of treatment was unchanged. In most of the treated animals, a focal calcification of the renal medulla (no further information given) was noted. The examination of the epithelium of the urinary bladder revealed a simple hyperplasia in 5/5 rats after 16 and 24 weeks and papillary or nodular hyperplasia in 3/5 rats at week 16 and in 5/5 rats at week 24; no data on controls were presented (Shibata et al., 1989b). In albino rats (42 animals of each sex per group) given 0, 1000, 2500, or 5000 mg biphenyl/kg in the diet (0, 75, 188, or 375 mg/kg body weight per day) for up to 24 weeks, the urine analysis and histopathological investigations of the kidneys during the study (days 30, 60, and 120) showed no apparent effects at a dose level of 75 mg/kg body weight (Booth et al., 1961). In some animals, early indications of a kidney-damaging effect were observed at doses of 188 and 375 mg/kg body weight at 30 days -- polyuria, increasing cloudiness of the urine, and initial morphological changes (tubular dilation) in the kidney. These effects increased in frequency and degree as the administrations progressed. The urinary sediment consisted of 4-hydroxybiphenyl and its glucuronide. During a subsequent 60-day observation period, the urinary status normalized; however, changes in kidneys were not completely reversible (a few dilated tubules and scars remained) (Booth et al., 1961). In male F344 rats (25 per group) administered 0 or 5000 mg biphenyl/kg in the diet (0 or 375 mg/kg body weight per day) for 32 weeks, a reduction in body weight gain but no clinical signs of poisoning were observed in dosed animals. In urine, an increase in pH value and Na+ concentration was noted. At terminal necropsy, calculi were found in the urinary bladder. The urinary sediment consisted mainly of 4-hydroxybiphenyl. No associated histopathology was detected upon microscopic examination of the urinary bladder (Kurata et al., 1986). When groups ( n = 25) of male Wistar rats were provided diets containing 0, 1250, or 5000 mg biphenyl/kg (0, 94, or 375 mg/kg body weight per day) for 36 weeks, a reduction in body weight, increased relative kidney weights, and an increase in the number of animals with stones in the kidneys (0/25, 0/25, and 4/25, respectively), ureter (0/25, 0/25, and 1/25, respectively), and urinary bladder (0/25, 0/25, and 3/25, respectively) were noted in the high-dose group (Shiraiwa et al., 1989). 8.4.1.2 Inhalation exposure Exposure of groups ( n = 50) of male and female CD-1 mice to 25 or 50 ppm (160 or 320 mg/m3; analytical concentrations) biphenyl for 7 h/day, 5 days/week, for 13 weeks produced hyperaemia and focal haemorrhage in the lung and an increase in hyperplasia of the tracheal epithelium. As these effects were also observed in some unexposed controls, they were attributed to the method of aerosol generation (i.e. inhalation of hot air) (Sun Co. Inc., 1977c). Marked species differences were observed in a study in which rabbits, rats, and mice were exposed by inhalation to biphenyl in the form of dust (50% biphenyl on zeolite) at 5, 40, or 300 mg/m3, 7 h/day, 5 days/week, for up to 13 weeks. No adverse effects were observed in rabbits. Rats exposed to 40 or 300 mg biphenyl/m3 exhibited increased mortality and irritation of the mucous membranes; no effects were observed following exposure to 5 mg/m3. Mice were the most sensitive species. Exposure to 5 mg biphenyl/m3 (the only concentration tested) resulted in slightly increased mortality, with all mice exhibiting irritation of the upper respiratory tract (no further information available). Necropsy of dead rats and mice revealed mainly inflammatory bronchopulmonary changes. No information on control animals or particle size was provided (Deichmann et al., 1947). 8.4.2 Chronic exposure and carcinogenicity In older studies, which were not further taken into consideration because of the small number of animals used, limited documentation, and/or limited exposures, no increase in tumour incidence was observed in rats and mice when biphenyl was administered orally (at doses up to 750 mg/kg body weight per day for 2 years) (Ambrose et al., 1960; Innes et al., 1969) or following a single subcutaneous injection of 46.4 mg biphenyl/kg body weight, in which the animals were examined macroscopically and microscopically after an 18-month observation period (NTIS, 1968). In Wistar rats (50 animals of each sex per group) given 0, 2500, or 5000 mg biphenyl/kg in the diet (0, 188, or 375 mg/kg body weight per day) for 75 weeks, dose-dependent effects (i.e. reduction in weight gain; alterations in serum activities of aspartate transaminase [increased and decreased], alanine transaminase [increased], and lactate dehydrogenase [increased]; and an increase in blood urea nitrogen) and a dose-dependent increase in stones of the kidney (females: 0/43, 1/43, 18/39; males: 0/44, 6/46, 15/47) and ureter (females: 0/43, 1/43, 2/39; males: 0/44, 0/46, 2/47), accompanied by haematuria as early as 16 weeks after initiation of exposure, were seen at >188 mg/kg body weight. At 375 mg/kg body weight, the relative kidney weights were significantly increased in females, and an increase in stones of the urinary bladder was seen in males and females (females: 0/43, 0/43, 6/39; males: 0/44, 0/46, 13/47). The histopathological examination of the urinary bladder with stones revealed simple or diffuse hyperplasia and papillomatosis of the epithelium, but no cancerous changes. The overall tumour incidence was not increased compared with controls. Kidneys with stones exhibited obstructive pyelonephritis, tubular atrophy, and fibrosis. Kidney stones were composed of protein, whereas urinary stones were composed of magnesium ammonium phosphate (Takita, 1983; Shiraiwa et al., 1989). No urolithiasis and no increased overall tumour incidence compared with controls were observed in Wistar rats (50 animals of each sex per group) provided with diets containing 0, 630, or 1250 mg biphenyl/kg (0, 47, or 94 mg/kg body weight per day) for 104 weeks. Dose-dependent effects (i.e. reduction in weight gain; alterations in serum activities of aspartate transaminase [decreased], alanine transaminase [increased and decreased], and lactate dehydrogenase [increased and decreased]) were noted at both doses; 47 mg/kg body weight is considered the lowest-observed-(adverse-)effect level, or LO(A)EL (Takita, 1983). In a study with F344/DuCrj rats performed according to standard protocols and described in sufficient detail, a significant increase in neoplastic and non-neoplastic lesions of the urinary bladder and a significant increase in calculi within the urinary bladder were observed in high-dose males, after the animals had been given diets containing 0, 500, 1500, or 4500 mg biphenyl/kg (0, 38, 113, or 338 mg/kg body weight per day) for 104 weeks. In males and females, a dose-dependent increase in hyperplasia of the epithelium of the renal pelvis was seen. The results of the histopathological findings in the urinary bladder and kidneys are summarized in Table 2. Other findings included increased serum enzyme levels (alkaline phosphatase, aspartate transaminase, and alanine transaminase) and an increased urea nitrogen level in low-dose males and mid-dose females, which became more pronounced with increasing doses. In mid- and high-dose females and high-dose males, haematological effects (i.e. reduced haemoglobin concentration and haematocrit) were noted (Japan Bioassay Research Center, 1996). From this study, a LOEL of 38 mg/kg body weight was derived. In a study in which groups of male and female Crj:BDF1 mice were given diets containing 0, 667, 2000, or 6000 mg biphenyl/kg (0, 100, 300, or 900 mg/kg body weight per day) for 104 weeks, a slight increase in liver tumours (hepatocellular adenomas and carcinomas) and basophilic cell foci of the liver was observed in the females at doses of 300 and 900 mg/kg body weight per day; however, the effects were not concentration dependent (Japan Bioassay Research Center, 1996) (see Table 3). In the male and female mice, degenerative changes of the respiratory epithelium of the nasal cavity and nasopharynx were observed at doses of >100 mg/kg body weight per day or >300 mg/kg body weight per day, respectively. Other findings included variations in serum enzyme levels (increase in alkaline phosphatase, aspartate transaminase, and alanine transaminase) and an increased urea nitrogen level in the low-dose males and females, which became more pronounced with increasing doses. In female mice receiving >300 mg biphenyl/ kg body weight per day and in the high-dose males, degenerative changes in the kidney (increased mineralization of the inner stripe of the outer medulla, increase in desquamation of the epithelium of the renal pelvis) were also observed. Body weight gain and food consumption were reduced in the high-dose animals (Japan Bioassay Research Center, 1996). Information on the toxicological effects of biphenyl following chronic inhalation or dermal exposure were not identified. 8.4.2.1 Tumour promotion A number of studies have investigated the tumour-promoting potential of biphenyl. Kurata et al. (1986) considered biphenyl a tumour promoter, based upon the results of a study in which groups of male F344 rats were administered drinking-water containing 0.05% N-butyl- N-(4-hydroxybutyl)nitrosamine (BBN) (as an initiator) for 4 weeks, followed by 0.5% biphenyl in the diet (estimated intake of approximately 375 mg/kg body weight per day) for a further 32 weeks, after which time the animals were examined histopathologically. The results are provided in Table 4. The effects of biphenyl were attributed to the increased Na+ content in the urine of exposed rats, as well as to crystals containing mainly 4-hydroxybiphenyl detected in the urine. In a study in which male Wistar rats were administered 0.1% N-ethyl- N-hydroxyethylnitrosamine in the diet for 2 weeks, followed by 0, 0.125, or 0.5% biphenyl in the diet for 34 weeks, exposure to biphenyl had no effect upon the incidence of dysplastic foci and renal cell tumours induced by N-ethyl- N-hydroxyethylnitro samine; however, an increase in stones of the kidneys, ureter, and bladder was observed in rats administered 0.5% biphenyl with or without N-ethyl- N-hydroxyethyl nitrosamine (Shiraiwa et al., 1989). Tamano et al. (1993) maintained male B6C3F1 mice on drinking-water containing 0.05% BBN supplement for 4 weeks. After the BBN pre-treatment, the animals received diets with 10 000 mg biphenyl/kg (1500 mg/kg body weight per day) for 32 weeks. At the end of the study, the urinary bladder and kidneys were examined histopathologically. The results are provided in Table 5. In mice exposed to BBN and biphenyl, the average food consumption and the final body weight were reduced, whereas the relative weight of the urinary bladder was increased. The induction of simple hyperplasia and papillary or nodular dysplasia of the urinary bladder in 1/10 mice treated with biphenyl only was associated with urolithic residues (small amounts of greyish white and finely granular material). In mice treated with biphenyl with or without BBN pre-treatment, the incidence of interstitial nephritis in the kidneys was 65 and 50%, respectively. In an early study in which albino mice "initiated" with a single dermal application of 9,10-dimethyl-1,2-benzanthracene (0.3% in benzene) received dermal applications of biphenyl (20% in benzene) twice weekly for 15 weeks, no skin papillomas or carcinomas were observed in either the vehicle controls or exposed mice 16 weeks after application of the initiator (Boutwell & Bosch, 1959). Table 2: Data from Japanese cancer bioassay with male and female rats fed biphenyl in the diet for 2 years.a Male rats Female rats 0 500 1500 4500 0 500 1500 4500 End-point mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg survival rate 37/50 41/50 38/50 31/50 44/50 38/50 44/50 37/50 urinary bladder: neoplastic lesions transitional cell papilloma 0 0 0 10/50 0 0 0 0 transitional cell carcinoma 0 0 0 24/50 0 0 0 0 (p=0.0001)b squamous cell papilloma 0 0 0 1/50 0 0 0 0 squamous cell carcinoma 0 0 0 1/50 0 0 0 0 urinary bladder: non-neoplastic lesions (transitional epithelium) simple hyperplasia 0 0 0 12/50 0 0 1/50 1/50 nodular hyperplasia 0 0 0 40/50 1/50 0 0 5/50 papillary hyperplasia 0 0 0 17/50 0 0 0 4/50 basal cell hyperplasia 0 0 0 27/50 0 0 0 4/50 squamous cell hyperplasia 0 0 0 13/50 0 0 0 1/50 squamous cell metaplasia 0 0 0 19/50 0 0 0 4/50 inflammatory polyps 0 0 0 10/50 0 0 0 0 calculi 0 0 0 43/50 0 0 0 8/50 kidney mineralization -- papilla 9/50 9/50 14/50 23/50 2/50 6/50 3/50 13/50 mineralization -- pelvis 9/50 6/50 10/50 18/50 12/50 12/50 18/50 27/50 calculi 0/50 0/50 0/50 13/50 0/50 0/50 0/50 3/50 desquamation -- pelvis 1/50 0/50 0/50 11/50 0/50 0/50 0/50 2/50 simple hyperplasia of the 6/50 8/50 5/50 19/50 3/50 5/50 12/50 25/50 transitional epithelium nodular hyperplasia of the 0/50 1/50 1/50 21/50 0/50 0/50 1/50 12/50 transitional epithelium ureter dilatation 0/50 0/50 1/50 14/50 0/50 0/50 0/50 6/50 a From Japan Bioassay Research Center (1996). b Fisher Exact Test. Table 3: Data from Japanese cancer bioassay with male and female mice fed biphenyl in the diet for 2 years.a Male mice Female mice 0 667 2000 6000 0 667 2000 6000 End-point mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg survival rate 35/50 41/50 41/50 39/50 31/50 22/50 25/50 32/49 liver: neoplastic lesions hepatocellular carcinoma 8/50 8/49 5/50 4/50 1/50 5/50 7/50 5/49 (p=0.121)b (p=0.043)b (p=0.1163)b hepatocellular adenoma 8/50 6/49 7/50 3/50 2/50 3/50 12/50 10/49 (p=0.4909)b (p=0.016)b (p=0.0251)b historical control data: historical control data: carcinoma: 171/700 with a range of 1/50 - 19/50 carcinoma: 15/699 with a range of 0/50 - 2/50 adenoma: 119/700 with a range of 2/50 - 15/50 adenoma: 33/699 with a range of 1/50 - 5/50 basophilic cell foci 0/50 6/49 1/50 2/50 1/50 1/50 12/50 6/49 a From Japan Bioassay Research Center (1996). b Fisher Exact Test. Table 4: Results of the tumour-promoting potential (urinary bladder) of biphenyl in male rats.a Hyperplasia Papilloma Carcinoma n (%) n (%) n (%) biphenyl only (21 rats) 0 0 0 0 0 0 BBNb only (24 rats) 6 -25 3 -12 0 0 BBN and biphenyl (18 rats) 17 -94 15 -83 11 -61 a Taken from Kurata et al. (1986). b BBN = N-butyl-N-(4-hydroxybutyl)nitrosamine. Table 5: Results of the tumour-promoting potential (urinary bladder) of biphenyl in male mice.a Papillary or Hyperplasia nodular dysplasia Carcinoma n (%) n (%) n (%) biphenyl only (10 mice) 1 -10 1 -10 0 0 BBNb only (20 mice) 12 -60 2 -10 0 0 BBN and biphenyl (20 mice) 14 -70 1 -5 0 0 a Taken from Tamano et al. (1993). b BBN = N-butyl-N-(4-hydroxybutyl)nitrosamine. 8.5 Genotoxicity and related end-points The results of the in vitro tests with biphenyl are summarized in Table 6. In vitro studies with bacteria have yielded no evidence of mutagenic potential for biphenyl, whereas gene mutation and mitotic recombination were observed with Saccharomyces cerevisiae D7 in the presence or absence of metabolic activation. However, no gene conversion was observed with S. cerevisiae D3. Testing in mammalian cells has produced positive results for gene mutations and clastogenicity in the presence of metabolic activation and negative results in the absence of metabolic activation. In an in vivo rat cytogenetic assay of bone marrow cells, the incidence of chromosomal aberrations was not increased (no further information available) (Kawachi et al., 1980). The exposure by inhalation of male Sprague-Dawley rats to 64 or 320 mg biphenyl/m3 (as dust aerosol) for 7 h/day, 5 days/week, for 30 days (20 exposures in total) reportedly did not increase the frequency of chromosomal aberrations in the bone marrow (Dow Chemical Co., 1976). However, owing to insufficient documentation (i.e. no data available concerning dust particle size distribution or cell harvesting times) and the low number of metaphase cells examined (i.e. 50 cells per animal), the validity of this study cannot be ascertained. The results of in vitro studies indicate that biphenyl has mutagenic potential; in the absence of reassurance from reliable results from in vivo tests, it is assumed that exposure to biphenyl may be associated with a mutagenic risk. 8.6 Reproductive and developmental toxicity Available data on the reproductive or developmental toxicity of biphenyl are limited. In Wistar rats administered (by gavage) 0, 125, 250, 500, or 1000 mg biphenyl/kg body weight (in corn oil) on days 6-15 of gestation, no maternal toxicity occurred at doses of <500 mg/kg body weight. In the highest dose group, 5 of 20 rats died. Also at 1000 mg/kg body weight, reduced fetal weight and an increased number of dead and resorbed fetuses were noted; however, these values were statistically not significantly different from those of control animals. At doses of >500 mg/kg body weight, there were non-significant increases in the incidence of fetuses with missing or non-ossified sternebrae (Khera et al., 1979). Table 6: Results of in vitro genotoxicity studies on biphenyl. Resultsa Species Concentration Without With (test system) End-point range MA MA References Salmonella typhimurium Reverse 0-5000 µg/plate - - Cline & McMahon (1977); Purchase et al. TA92, TA94, TA97, TA97a, mutations (1978); Kawachi et al. (1980); NTP (1980); TA98, TA100, TA102, Bronzetti et al. (1981); Probst et al. (1981); TA1532, TA1535, TA1537, Waters et al. (1982); Haworth et al. (1983); TA1538, TA2636 Pagano et al. (1983, 1988); Ishidate et al. (1984); Fujita et al. (1985); Brams et al. (1987); Bos et al. (1988); Glatt et al. (1992) Escherichia coli WP2, WP2 Gene mutations 0.1-1000 µg/ml - - Cline & McMahon (1977); Probst et al. (1981); uvrA- Waters et al. (1982) E. coli PQ37 DNA damage 2.4-154 µg/ml - - Brams et al. (1987) Bacillus subtilis rec assay DNA damage no data - 0 Kawachi et al. (1980) Saccharomyces cerevisiae Gene mutation/ <154 µg/ml + + Pagano et al. (1983) D7 gene conversion S. cerevisiae D3 Gene conversion no data - - Waters et al. (1982); Zimmermann et al. (1984) Chinese hamster cells Gene mutation 0-100 µg/ml - + Glatt et al. (1992) (V79) L5178Y TK+/- cells Gene mutation 0-61 µg/ml - (+) Wangenheim & Bolcsfoldi (1988) (mouse lymphoma assay) Chinese hamster cells Chromosomal 0-125 µg/ml - 0 Ishidate & Odashima (1977); Kawachi et al. (CHL) aberration (1980); Sofuni et al. (1985) Table 6 (Cont'd.) Resultsa Species Concentration Without With (test system) End-point range MA MA References Chinese hamster cells Chromosomal 0-20 µg/ml - + Sofuni et al. (1985) (CHL) aberration Chinese hamster cells Chromosomal 15.4-154 µg/ml - 0 Abe & Sasaki (1977) (DON) aberration Rat hepatocytes Unscheduled 0.002-154 µg/ml 0 - Williams (1978); Brouns et al. (1979); DNA synthesis Probst et al. (1981) Chinese hamster cells Sister chromatid no data - 0 Kawachi et al. (1980) (CHL) exchange Chinese hamster cells Sister chromatid 15.4-154 µg/ml - 0 Abe & Sasaki (1977) (DON) exchange L5178Y cells (alkaline DNA damage 0-231 µg/ml - + Garberg et al. (1988) unwinding assay) human lung fibroblasts Unscheduled no data - - Waters et al. (1982) (WI-38 cells) DNA synthesis human fibroblasts ("nick DNA damage 15.4 µg/ml - 0 Snyder & Matheson (1985) translation assay") a -, negative; +, positive; (+) weakly positive; 0, not tested; MA, metabolic activation. Compared with unexposed controls, litter size (the only parameter examined) was not affected in a study in which small numbers of male and female rats were administered diets containing 0.1 or 0.5% biphenyl (estimated intakes of 75 and 375 mg/kg body weight per day) before mating and throughout gestation (Ambrose et al., 1960). In an unpublished three-generation study, dietary biphenyl concentrations of 100 or 1000 mg/kg (estimated intakes of approximately 7.5 or 75 mg biphenyl/kg body weight per day) had no effect on reproduction in rats; after intake of 10 000 mg/kg (estimated intake of 750 mg/kg body weight per day), decreased fertility, litter size, and growth rate were noted (no further information available) (Stanford Research Institute, undated). Histopathological changes within the male and female reproductive systems were not observed in rats or mice administered biphenyl at 500-4500 mg/kg in the diet for 2 years (Japan Bioassay Research Center, 1996). 8.7 Immunological and neurological effects Data on immunological and neurological effects of biphenyl in laboratory animals were not identified. 9. EFFECTS ON HUMANS Information on effects on human health resulting from exposure to biphenyl are limited to case reports; epidemiological studies were not identified. In one report, a single application of 0.5 ml of a 4% biphenyl solution (no further details provided) to the skin of the lower arm of two test subjects caused no apparent irritation (Macintosh, 1945). Biphenyl did not cause skin irritation in a study in which a solution of 23% biphenyl in oil was applied to the forearm three times per week for 8 weeks (Selle, 1952). In one human volunteer orally given 35 mg biphenyl per week for 13 weeks, no adverse effects were reported (Farkas, 1939). Cases of headache, nausea, and inflammation of the respiratory tract have been reported in workers exposed to biphenyl vapours (and other substances) during paper production (Weil et al., 1965). Liver damage and effects upon the central and peripheral nervous systems were attributed to long-term exposure to high concentrations of biphenyl (see section 6.2) in a case-study of workers engaged in the production of biphenyl-impregnated paper (Haekkinen et al., 1973). Chronic persistent hepatitis in a woman who had worked for 25 years in a citrus packing plant in which biphenyl-impregnated paper was used was attributed to the absorption of biphenyl through the skin and digestive tract (Carella & Bettolo, 1994). 10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD 10.1 Aquatic environment The acute toxicity of biphenyl in aquatic organisms has been investigated in microorganisms, plants, invertebrates, and vertebrates; however, in several studies cited in the main source document (BUA, 1990), information on whether results were based on nominal or effective concentrations was either lacking or not clearly stated. For biphenyl, nominal concentrations may not correspond to the effective concentrations, as the water solubility of biphenyl is low (4.45 mg/litre at 20°C) (test results with higher nominal effect concentrations have not been reported here) and its volatility significant. In tests with open systems and longer test durations, results based on nominal concentrations may lead to an underestimation of toxic effects because of evaporation of the chemical; therefore, emphasis has been placed on studies with lowest reported effect levels in which loss of the test substance was minimized. Several studies were conducted on the toxic effects of biphenyl on mixed microbial cultures as well as on single bacterial species. The most sensitive species was Photobacterium phosphoreum, with a 30-min EC50 of 1.9 mg/litre in a bioluminescence inhibition test (BUA, 1990). For Colpidium campylum, one of three different species of ciliata tested, the minimal active concentration of biphenyl for the inhibition of cell proliferation after a 43-h exposure was 5.6 mg/litre (nominal concentration; test substance predissolved in acetone) (Dive et al., 1980). In studies on the reduction of photosynthesis, 3-h EC50 values of 3.86 and 1.28 mg/litre were deter mined with the unicellular green algae Chlorella vulgaris and Chlamydomonas angulosa, respectively (BUA, 1990). Forty-eight-hour LC50 values from acute toxicity tests with Daphnia magna were in the range of 1.1-4.7 mg/litre when experiments were conducted in more or less tightly closed test vessels. From a test in a closed system with continuous flow, a 48-h LC50 of 0.36 mg/litre and a NOEC of 0.04 mg/litre were reported. In a reproduction test with Daphnia magna in the same closed continuous-flow system, the NOEC after 21 days' incubation was 0.17 mg/litre (LC50 = 0.23 mg/litre) (Gersich et al., 1989). In studies on the inhibition of food intake by the marine mussel Mytilus edulis in a static system with loosely covered (not airtight) test vessels, a 40-min EC50 of 0.3 mg biphenyl/litre was reported (Donkin et al., 1991). From static tests on the toxicity of biphenyl on freshwater fish, 96-h LC50 values in the range of 1.5-4.7 mg/litre have been reported, with rainbow trout (Oncorhynchus mykiss) and fathead minnow (Pimephales promelas) the most sensitive species (BUA, 1990). 10.2 Terrestrial environment Biphenyl has weak bactericidal and fungistatic properties. In studies with numerous mould fungus species, biphenyl (applied as vapour or imbedded in solid media) caused a reversible inhibition (50-100%) of cellular proliferation. Suppression of sporogenesis and, in Penicillium digitatum and Diplodia natalensis, the occurrence of biphenyl-resistant mutants were observed. Yeast species showed little or no inhibition of cell proliferation following exposure to biphenyl (BUA, 1990). In a plant growth inhibition test conducted according to OECD Guideline 208, a nominal NOEC of 100 mg/kg dry soil was reported for sorghum (Sorghum bicolor) and soya bean (Glycine max); a NOEC of >1000 mg biphenyl/kg was reported for the sunflower (Helianthus annuus) (Windeatt et al., 1991). Biphenyl mixed into soil inhibited growth of lettuce (Lactuca sativa) seedlings with a 7-day EC50 of 54 mg/kg (nominal concentration). At the end of incubation, the concentration of test substance in the soil had decreased to <10% of the initial level (Hulzebos et al., 1993). Data on toxic effects of biphenyl on terrestrial animals and ecosystems were not identified. 11. EFFECTS EVALUATION 11.1 Evaluation of health effects 11.1.1 Hazard identification and dose-response assessment There are limited data on the effects of biphenyl exposure on humans. The assessment of potential health hazards has relied primarily on studies conducted in laboratory animals. The acute oral toxicity of biphenyl is moderate. The chemical is not irritating to the skin and is slightly irritating to the eyes, and there is no evidence of skin sensitizing potential. Aside from differences in mortality among laboratory species exposed subchronically to biphenyl-containing dusts, the available data on effects associated with the inhalation of biphenyl are insufficient to form the basis of an assessment of potential health hazards associated with long-term airborne exposure to this chemical. In toxicological studies in which rodents have been administered diets containing biphenyl for various periods of time, effects on the urinary system have often been reported. A marked increase in the incidence of morphological (i.e. formation of calculi) and/or histopathological (e.g. hyperplasia, desquamation) effects has been observed within the urinary tract of male rats administered diets containing more than 2500 mg biphenyl/kg for periods ranging from 32 to 104 weeks (Takita, 1983; Kurata et al., 1986; Shiraiwa et al., 1989; Japan Bioassay Research Center, 1996). An increase in the occurrence of calculi within the urinary bladder has also been observed in female rats, but at a lower incidence than in males (Takita, 1983; Shiraiwa et al., 1989; Japan Bioassay Research Center, 1996). Similarly, in a long-term dietary study (Japan Bioassay Research Center, 1996), increased squamous metaplasia within the urinary transitional epithelium was also observed in female rats; again, however, the incidence was lower than that observed in males. In male mice, only 1 of 10 animals given a diet containing 10 000 mg biphenyl/kg (1500 mg/kg body weight per day) for 32 weeks developed simple hyperplasia and papillary or nodular dysplasia of the urinary bladder (Tamano et al., 1993). Effects on blood chemistry and haematological parameters have also been observed in animals administered biphenyl orally; these effects occurred in male and female rats and mice at intakes lower than those associated with the development of effects in the urinary bladder of male rats administered biphenyl (Takita, 1983; Shiraiwa et al., 1989; Japan Bioassay Research Center, 1996). For non-neoplastic effects, the LOEL was 38 mg/kg body weight per day based upon the development of alterations in haematological parameters (i.e. decreased haemoglobin concentration and haematocrit) in rats fed diets containing 0, 500, 1500, or 4500 mg biphenyl/kg (reported intakes of 0, 38, 113, or 338 mg/kg body weight per day) for 2 years (Japan Bioassay Research Center, 1996). Although limited, the available information indicates that biphenyl has no reproductive or developmental effects at doses lower than those associated with the development of adverse effects in the parental generation. In one study, an increased incidence of benign and malignant tumours within the urinary bladder was observed in male F344/DuCrj rats administered diets containing high levels (i.e. not less than 4500 mg/kg) of biphenyl for 2 years. Tumour incidence was not increased in female rats or in male or female Crj:BDF1 mice (Japan Bioassay Research Center, 1996). In female mice, there were slight increases in the incidences of benign and malignant liver tumours in animals receiving biphenyl in the diet; however, the results were not dose dependent over the entire range of concentrations tested. In other studies, biphenyl exhibited tumour-promoting activity with respect to the development of bladder neoplasms in male rats (Kurata et al., 1986) but not in male mice (Tamano et al., 1993). The mechanism by which high doses of biphenyl induce bladder tumours specifically in male rats has not been fully elucidated. There have been suggestions that for some non-genotoxic chemicals, the formation of such tumours is linked to the regenerative hyperplasia of the urinary epithelium, caused by the abrasion and damage to the urothelium that are produced by calculi formed within the urinary tract only at very high levels of exposure (Cohen, 1995). Owing to anatomical and physiological differences, male rats are considered to be more susceptible than female rats, mice, and humans to the development of bladder tumours via such a mechanism; it has therefore been suggested that the sex- and species-specific development of bladder tumours in male rats receiving high doses of biphenyl might not be strictly relevant to humans exposed to lower levels. However, the incidence of histopathological effects and calculi formation within the urinary bladder also increased in female rats administered biphenyl for 2 years, in the absence of bladder tumours (Japan Bioassay Research Center, 1996). Moreover, data identifying a direct association between calculi formation, regenerative hyperplasia of the urothelium, and the development of bladder tumours within individual male animals are not available. Biphenyl has been reported to be mutagenic and clastogenic in some, but not all, in vitro assays and to bind covalently to macromolecules (i.e. proteins) following metabolic activation; the available data have been considered inadequate to assess its genotoxicity in vivo. These considerations, coupled with the structural relationship of 4-hydroxybiphenyl, a major metabolite of biphenyl, to the potent human bladder carcinogen 4-aminobiphenyl and the lack of critical information related to the mechanism by which these bladder tumours arise in male rats, could suggest that the development of bladder tumours in the male rats may not have been entirely due to effects associated with the formation of calculi within the urinary bladder. This observation, as well as the slightly increased incidence of liver tumours in female mice, raises some concerns with respect to the potential carcinogenicity of biphenyl to humans. 11.1.2 Criteria for setting guidance values for biphenyl A provisional tolerable daily intake (TDI), based upon the development of effects in the blood of rats administered diets containing biphenyl for 2 years (Japan Bioassay Research Center, 1996), can be derived as follows: TDI = 38 mg/kg body weight per day 1000 = 38 µg/kg body weight per day where: * 38 mg/kg body weight per day is the lowest LOEL for the development of alterations in blood chemistry in rats provided diets containing biphenyl for 2 years. This intake is lower than intakes associated with the development of haematological effects, calculi, and histopathological changes in the bladder and/or kidneys in rats and the development of haematological and histopathological effects in mice administered biphenyl in the diet for 2 years. * 1000 is the uncertainty factor (×10 for interspecies variation; ×10 for intraspecies variation; ×10 for extrapolation from a LOEL to a NOEL). However, based upon the currently available data, there is some uncertainty surrounding the health-protective nature of the value, owing to lack of critical information concerning the mechanism by which biphenyl induces bladder tumours in male rats, the slight increase in hepatocellular tumours in female mice, and the potential genotoxicity of this substance. Because of this uncertainty, the TDI is designated provisional. Available data were inadequate to serve as a basis for the derivation of guidance values for biphenyl in air. 11.1.3 Sample risk characterization For the general population, there is insufficient information available concerning the intake of biphenyl from the general environment; therefore, comparisons with the provisional TDI are provided merely as an example. From limited information on the content of biphenyl in citrus fruits, the estimated daily intake is <375 ng biphenyl/kg body weight from each individual fruit consumed, while the estimated daily intake from tap-water is <0.16 ng/kg body weight. Assuming that a person consumes one citrus fruit per day, the estimated intake of biphenyl from drinking-water and citrus fruit consumption is approximately two orders of magnitude lower than the provisional TDI based upon the development of effects in the blood. From a study on workers exposed in a plant producing biphenyl-impregnated paper, it can be derived that exposure to high biphenyl concentrations up to 128 mg/m3 pose a hazard. Neurotoxic effects and liver damage have been observed. Additional information is required to better define any potential carcinogenic risks that might be associated with exposure to biphenyl. 11.2 Evaluation of environmental effects The atmosphere is likely the main target compartment for biphenyl; however, the chemical has been detected in all environmental compartments as a result of its release from vehicle emissions, heating, smoking, and industrial activities. Water, soil, and biota appear to be affected mainly in the direct vicinity of industrial activities. The decline in the levels of biphenyl in surface waters may be due to restrictions on the production and use of PCBs. There are no data available on the release of biphenyl into environmental compartments from industrial use, from the application of biphenyl-contaminated sewage sludge to arable land, from volatilization during the storage of treated fruits, and from leaching from preserved citrus fruits and their packaging materials in domestic waste dumps. Only estimated values are available for the photooxidation of biphenyl in the atmosphere, which is probably the most important degradation process in this compartment. Biomagnification of biphenyl in higher trophic levels of the aquatic or terrestrial food-chain, based upon the potential of biphenyl to bioaccumulate, is expected to be of minor importance. For the aquatic compartment, a significant elimination of biphenyl can be expected as a result of evaporation and degradation. Furthermore, rapid metabolism of biphenyl in laboratory animals and low acute toxicity after ingestion have been reported. Data on effect concentrations for terrestrial organisms and exposure levels in air and soil are insufficient for risk characterization for terrestrial organisms. A sample risk characterization with respect to the aquatic environment can be performed (based upon data derived from Germany) by calculating the ratio between a (local or regional) PEC (based on measured or model concentrations) and a PNEC (EC, 1996). The annual average concentration of biphenyl (<0.5 µg/litre) measured in the 1990s in the Rhine River and its tributaries was used as a PECmeasured. A PEClocal (water), based upon data derived from the effluent of the wastewater treatment plant of a German producer, may be calculated as follows: PEClocal (water) = Ceffluent (1 + Kp (susp) × Csusp × 10-6) × D = <0.0064 µg/litre where: * Ceffluent is <5 µg/litre, the concentration of biphenyl in wastewater in 1990 (BUA, 1990); * Kp (susp) = 423, the suspended matter/water adsorption coefficient, estimated from the mean soil sorption coefficient ( Koc) of 4230 ( Kp (susp) = Koc × 0.1, where 0.1 is the fraction of organic carbon in suspended matter, foc(susp)); * Csusp = 15 mg/litre (default value; EC, 1996), the concentration of suspended matter in the river; and * D = 781, the dilution factor for river flow, calculated from sewage treatment plant and river flow data (EC, 1996).1 A PNEC for surface waters may be calculated by dividing the lowest valid LC50 or NOEC by an appropriate assessment factor (equal to a safety factor): PNEC = 170 µg/litre 10 = 1.7 µg/litre where: * 170 µg/litre is the lowest NOEC from a chronic study with Daphnia magna; and 1 Personal communication from Verband d. Textilhilfsmittel-, Lederhilfsmittel-, Gerbstoff- und Waschrohstoff-Industrie e.V., Frankfurt/M., Germany, to Bayer AG, 1996. * 10 is the assessment factor. For biphenyl, based upon data for four trophic levels, including one long-term NOEC, the recommended assessment factor would be 100 (EC, 1996). However, because of its significant volatility and degradation, and as effect concentrations from a wide selection of species covering different taxonomic groups are reported, an assessment factor of 10 is used. Therefore, based upon the annual average concentrations of biphenyl measured in the Rhine River and in industrial wastewater effluent in Germany, the PECmeasured/PNEC and PEClocal (water)/PNEC ratios are <0.29 and <0.04, respectively. In some jurisdictions (EC, 1996), chemicals with a PEC/PNEC ratio of <1 may not require implementation of risk reduction measures beyond those already in place. 12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES The Joint FAO/WHO Meeting on Pesticide Residues has allocated an acceptable daily intake of biphenyl of 0-0.125 mg/kg body weight (JMPR, 1967). Information on international hazard classification and labelling is included in the International Chemical Safety Card reproduced in this document. 13. HUMAN HEALTH PROTECTION AND EMERGENCY ACTION Human health hazards, together with preventative and protective measures and first aid recommendations, are presented in the International Chemical Safety Card (ICSC 0106) reproduced in this document. 13.1 Advice to physicians Treatment is symptomatic and supportive following intoxication. The clinical picture is characterized by central and peripheral nerve damage and liver injury in human poisoning. There is some evidence to indicate that electroencephalographic abnormalities could persist up to 1 or 2 years after exposure. 13.2 Health surveillance advice Objective change in electroencephalogram and electroneuromyogram could be an indication of biphenyl poisoning in exposed individuals. Monitoring of liver function could also be integrated into a medical surveillance programme. 13.3 Spillage In the event of spillage, measures should be under taken to prevent biphenyl from reaching drains and watercourses, because of its toxicity to aquatic organisms. 14. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS Information on national regulations, guidelines, and standards can be found in the International Register of Potentially Toxic Chemicals (IRPTC), available from UNEP Chemicals (IRPTC), Geneva. The reader should be aware that regulatory decisions about chemicals taken in a certain country can be fully understood only in the framework of the legislation of that country. The regulations and guidelines of all countries are subject to change and should always be verified with appropriate regulatory authorities before application. INTERNATIONAL CHEMICAL SAFETY CARD BIPHENYL ICSC: 0106 April 1994 CAS # 92-52-4 Diphenyl RTECS # DU8050000 Phenylbenzene EC # 601-042-00-8 Dibenzene C12H10/C6H5C6H5 Molecular mass: 154.2 TYPES OF HAZARD/ ACUTE HAZARDS/ PREVENTION FIRST AID/FIRE FIGHTING EXPOSURE SYMPTOMS FIRE Combustible NO open flames Water spray, powder, AFFF, foam, carbon dioxide EXPLOSION Finely dispersed particles Prevent deposition of dust, closed form explosive mixtures in air. system, dust explosion-proof electrical equipment and lighting. Prevent build-up of electrostatic charges (e.g., by grounding) EXPOSURE PREVENT DISPERSION OF DUST! Inhalation Cough, Nausea, Vomiting Avoid inhalation of fine dust Fresh air, rest. Refer for medical and mist. attention. Skin Protective gloves. Remove contaminated clothes. Rinse and then wash skin with water and soap. Eyes Redness. Pain Safety goggles, or eye protection First rinse with plenty of water for in combination with breathing several minutes (remove contact lenses protection if powder. if easily possible), then take to a doctor. TYPES OF HAZARD/ ACUTE HAZARDS/ PREVENTION FIRST AID/FIRE FIGHTING EXPOSURE SYMPTOMS Ingestion (further see Inhalation) Do not eat, drink, or smoke Rinse mouth. Refer for medical during work. Wash hands before attention. eating. SPILLAGE DISPOSAL PACKAGING & LABELLING Sweep spilled substance into sealable containers; if appropriate, moisten Do not transport with food and feedstuffs. first to prevent dusting. Carefully collect remainder, then remove to safe EU Classification place. (Extra personal protection: A/P2 filter respirator for organic vapour Symbol: Xi and harmful dust). R: 36/37/38 S: (2-)23 UN Classification EMERGENCY RESPONSE STORAGE NFPA Code: H 2; F1; R O; Separated from food and feedstuffs and oxidants. IMPORTANT DATA PHYSICAL STATE; APPEARANCE: ROUTES OF EXPOSURE: WHITE CRYSTALS OR FLAKES, WITH CHARACTERISTIC ODOUR The substance can be absorbed into the body by inhalation and by ingestion. PHYSICAL DANGERS: INHALATION RISK: Dust explosion possible if in powder or granular form, A harmful contamination of the air can be reached rather quickly on mixed with air. evaporation of this substance at 20°C. CHEMICAL DANGERS: EFFECTS OF SHORT-TERM EXPOSURE: Reacts with oxidants. The substance irritates the eyes and the respiratory tract. OCCUPATIONAL EXPOSURE LIMITS: EFFECTS OF LONG-TERM OR REPEATED EXPOSURE: TLV: 0.2 ppm; 1.3 mg/m3 (ACGIH 1993-1994) The substance may have effects on the liver and nervous system, resulting impaired functions. PHYSICAL PROPERTIES Boiling point 256°C Flash point: 113°C c.c. Melting point 70°C Auto-ignition temperature: 540°C Relative density (water = 1): 1.04 Explosive limits, vol% in air: 0.6 (at 111°C) - 5.8 (at 166°C) Solubility in water: none Octanol/water partition coefficient as log Pow: 3.16/4.09 Vapour pressure, Pa at 71°C: 133 Relative vapour density (air = 1): 5.3 Relative density of the vapour/air-mixture at 20°C (air = 1): 1.0 ENVIRONMENTAL DATA The substance may be hazardous to the environment, special attention should be given to water. In the food chain important to humans, bioaccumulation takes place, specifically in plants. It is strongly advised not to let the chemical enter into the environment because it persists in the environment. NOTES Do NOT take working clothes home. Dowtherm A is a trade name. ADDITIONAL INFORMATION LEGAL NOTICE: Neither the CEC or the IPCS nor any person acting on behalf of the CEC or the IPCS is responsible for the use which might be made of this information. 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Philadelphia, PA, American Society for Testing and Materials, pp. 29-40 (ASTM Special Technical Publication 1115). Yao W, Xu X (1991) Determination of pollutants emitted from burning coal and of their mutagenicities. Analytical science, 7:1381-1384. Zhang Y, Rott B, Freitag D (1983) Accumulation and elimination of 14-C-PCB's by Daphnia magna Straus 1820. Chemosphere, 12:1645-1651. Zimmermann FK, von Borstel RC, von Halle ES, Parry JM, Siebert D, Zetterberg G, Barale R, Loprieno N (1984) Testing of chemicals for genetic activity with Saccharomyces cerevisiae: a report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation research, 133:199-244. APPENDIX 1 -- SOURCE DOCUMENTS BUA-Stoffbericht Biphenyl (1,1'-Biphenyl). Beratergremium fuer Umweltrelevante Altstoffe (Report No. 50; July 1990). VCH VerlagsGmbH, Weinheim BUA-Stoffbericht 133 (Ergaenzungsberichte II). Beratergremium fuer Umweltrelevante Altstoffe (1994). VCH VerlagsGmbH, Weinheim For the BUA review process, the company that is in charge of writing the report (usually the largest producer in Germany) prepares a draft report using literature from an extensive literature search as well as internal company studies. This draft is subject to a peer review during several readings of a working group consisting of representatives from government agencies, the scientific community, and industry. The English translation of BUA Report No. 50 (BUA Report Biphenyl (1,1'-Biphenyl). GDCh-Advisory Committee on Existing Chemicals of Environmental Relevance (July 1990). VCH VerlagsGmbH, Weinheim) was released in 1992. The English translation of its Supplementary Report No. 133 is in preparation. APPENDIX 2 -- CICAD PEER REVIEW The draft CICAD on biphenyl was sent for review to institutions and organizations identified by IPCS after contact with IPCS national Contact Points and Participating Institutions, as well as to identified experts. Comments were received from: Bayer AG, Leverkusen, Germany Department of Health, London, United Kingdom Department of Public Health, Albert Szent-Gyorgyi University Medical School, Szeged, Hungary Environmental Health Directorate, Health Canada, Ottawa, Canada International Agency for Research on Cancer, Lyon, France Ministry of Health and Welfare, International Affairs Division, Government of Japan, Tokyo, Japan Monsanto Europe SA, Louvain-La-Neuve, Belgium National Institute for Working Life, Solna, Sweden National Institute of Occupational Health, Budapest, Hungary United States Department of Health and Human Services (National Institute of Environmental Health Sciences) United States Environmental Protection Agency (Office of Pollution Prevention and Toxics; Office of Drinking Water) APPENDIX 3 -- CICAD FINAL REVIEW BOARD (Brussels, Belgium) Brussels, Belgium, 18-20 November 1996 Members Dr A. Aitio, Institute of Occupational Health, Helsinki, Finland Dr K. Bentley, Director, Environment Policy Section, Commonwealth Department of Human Services and Health, Canberra, Australia Mr R. Cary, Toxicology and Existing Substances Regulation Unit, Health and Safety Executive, Merseyside, United Kingdom Dr J. de Fouw, National Institute of Public Health and Environmental Protection, Bilthoven, The Netherlands Dr C. DeRosa, Director, Division of Toxicology, Agency for Toxic Substances and Disease Registry, Atlanta, GA, USA Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood, Abbots Ripton, Huntingdon, Cambridgeshire, United Kingdom Dr W. Farland, Director, National Center for Environmental Assessment, Office of Research and Development, US Environmental Protection Agency, Washington, DC, USA (Chairperson) Dr T.I. Fortoul, Depto. Biologia Celular y Tisular, National University of Mexico and Environmental Health Directorate of the Health Ministry, Mexico D.F., Mexico Dr H. Gibb, National Center for Environmental Assessment, US Environmental Protection Agency, Washington, DC, USA Dr R.F. Hertel, Federal Institute for Health Protection of Consumers & Veterinary Medicine, Berlin, Germany Mr J.R. Hickman, Environmental Health Directorate, Health Canada, Ottawa, Ontario, Canada Dr T. Lakhanisky, Head, Division of Toxicology, Institute of Hygiene and Epidemiology, Brussels, Belgium (Vice-Chairperson) Dr I. Mangelsdorf, Documentation and Assessment of Chemicals, Fraunhofer Institute for Toxicology and Aerosol Research, Hanover, Germany Ms M.E. Meek, Head, Priority Substances Section, Environmental Health Directorate, Health Canada, Ottawa, Ontario, Canada Dr K. Paksy, National Institute of Occupational Health, Budapest, Hungary Mr D. Renshaw, Department of Health, London, United Kingdom Dr J. Sekizawa, Division of Chem-Bio Informatics, National Institute of Health Sciences, Tokyo, Japan Dr H. Sterzl-Eckert, GSF-Forschungszentrum für Umwelt und Gesundheit GmbH, Institut für Toxikologie, Oberschleissheim, Germany Professor S. Tarkowski, Department of Environmental Health Hazards, The Nofer Institute of Occupational Medicine, Lodz, Poland Dr M. Wallen, National Chemicals Inspectorate (KEMI), Solna, Sweden Observers Professor F.M.C. Carpanini,1 Director, Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), Brussels, Belgium Mr R. Haigh,1 Head of Unit, Health and Safety Directorate, European Commission, Luxembourg Mr B.U. Hildebrandt, Federal Ministry for the Environment, Nature Conservation and Nuclear Safety, Bonn, Germany Mr P. Hurst,1 Chemical and Consumer Policy Officer, Conservation Policy Division, World Wide Fund for Nature, Gland, Switzerland Dr A. Lombard (CEFIC representative), ELF-ATOCHEM, Paris, France Dr P. McCutcheon,1 Environment, Consumer Protection and Nuclear Safety, European Commission, Brussels, Belgium Dr R. Montaigne, Counsellor, Technical Affairs Department, European Chemical Industry Council (CEFIC), Brussels, Belgium Dr M. Pemberton, ICI Acrylics, Lancashire, United Kingdom Dr A. Smith, Environment Division, Organisation for Economic Co-operation and Development, Paris, France Secretariat Dr M. Baril, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland Dr L. Harrison, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland Dr M. Mercier, Director, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland Dr P. Toft, Associate Director, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland 1 Invited but unable to attend. APPENDIX 4 -- SPECIALIZED CICAD PEER REVIEW Individuals contributing written comments to the specialized review of this CICAD were: Dr S. Cohen, University of Nebraska Medical Center, Omaha, USA Ms M.E. Meek, Environmental Health Directorate, Health Canada, Ottawa, Canada Mr D. Renshaw, Department of Health, London, United Kingdom Dr J. Rice, Unit of Carcinogen Identification and Evaluation, International Agency for Research on Cancer, Lyon, France Dr J. Sekizawa, Division of Chem-Bio Informatics, National Institute of Health Sciences, Tokyo, Japan Dr D. Singh, National Center for Environmental Assessment, US Environmental Protection Agency, Washington, DC, USA Individuals participating in the review of the human health assessment (section 11.1) were: Dr A. Chiu, National Center for Environmental Assessment, US Environmental Protection Agency, Washington, DC, USA Dr C. Hiremath, National Center for Environmental Assessment, US Environmental Protection Agency, Washington, DC, USA Dr R.G. Liteplo, Environmental Health Directorate, Health Canada, Ottawa, Canada Dr D. Singh, National Center for Environmental Assessment, US Environmental Protection Agency, Washington, DC, USA APPENDIX 5 -- CICAD FINAL REVIEW BOARD (Washington, DC) Washington, DC (USA), 8-11 December 1998 Members Dr T. Berzins, National Chemicals Inspectorate (KEMI), Solna, Sweden Mr R. Cary, Toxicology Unit, Health Directorate, Health and Safety Executive, Bootle, Merseyside, United Kingdom Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood, Abbots Ripton, Huntingdon, Cambridgeshire, United Kingdom Dr O. Faroon, Agency for Toxic Substances and Disease Registry, Centers for Disease Control and Prevention, Atlanta, GA, USA Dr G. Foureman, National Center for Environmental Assessment, US Environmental Protection Agency, Research Triangle Park, NC, USA Dr H. Gibb, National Center for Environmental Assessment, US Environmental Protection Agency, Washington, DC, USA Dr R.F. Hertel, Federal Institute for Health Protection of Consumers & Veterinary Medicine, Berlin, Germany Dr I. Mangelsdorf, Documentation and Assessment of Chemicals, Fraunhofer Institute for Toxicology and Aerosol Research, Hanover, Germany Dr A. Nishikawa, Division of Pathology, National Institute of Health Sciences, Tokyo, Japan Dr E.V. Ohanian, Office of Water/Office of Science and Technology, US Environmental Protection Agency, Washington, DC, USA Dr J. Sekizawa, Division of Chem-Bio Informatics, National Institute of Health Sciences, Tokyo, Japan Professor P. Yao, Institute of Occupational Medicine, Chinese Academy of Preventive Medicine, Beijing, People's Republic of China Observers Dr K. Austin, National Center for Environmental Assessment, US Environmental Protection Agency, Washington, DC, USA Dr I. Daly (ICCA representative), Regulatory and Technical Associates, Lebanon, PA, USA Ms K.L. Lang (CEFIC representative), Shell International, London, United Kingdom Ms K. Roberts (ICCA representative), Chemical Self-funded Technical Advocacy and Research (CHEMSTAR), Chemical Manufacturers Association, Arlington, VA, USA Dr W. Snellings (ICCA representative), Union Carbide Corporation, Danbury, CN, USA Dr M. Sweeney, Document Development Branch, National Institute for Occupational Safety and Health, Cincinnati, OH, USA Dr K. Ziegler-Skylakakis, GSF-Forschungszentrum für Umwelt und Gesundheit GmbH, Institut für Toxikologie, Oberschleissheim, Germany Secretariat Dr A. Aitio,1 International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland 1 Invited but unable to attend. Dr M. Baril, Institut de recherche en santé et en sécurité du travail du Québec, Montreal, Quebec, Canada Dr H. Galal-Gorchev, Chevy Chase, MD, USA Ms M. Godden, Health and Safety Executive, Bootle, Merseyside, United Kingdom Dr R.G. Liteplo, Environmental Health Directorate, Health Canada, Ottawa, Ontario, Canada Ms L. Regis, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland Mr A. Strawson, Health and Safety Executive, London, United Kingdom Dr P. Toft, Associate Director, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland RÉSUMÉ D'ORIENTATION Ce CICAD relatif au biphényle a été préparé par l'Institut Fraunhofer de Toxicologie et de Recherche sur les Aérosols de Hanovre (Allemagne), principalement sur la base d'une étude préparée par le Comité consultatif allemand sur les substances chimiques importantes pour l'environnement (BUA, 1990) et d'un rapport complémentaire (BUA, 1994) afin d'évaluer les effets potentiels du biphényle sur l'Homme et l'environnement. On trouvera à l'appendice 1 des indications sur les sources documentaires utilisées ainsi que sur leur mode de dépouillement. Une étude bibliographique approfondie a été menée sur plusieurs bases de données jusqu'en juin 1996 à la recherche de données supplémentaires. Ce CICAD contient également les renseignements complémentaires recueillis par les points de contact et le Comité d'évaluation finale (Bruxelles, Belgique) lors du dépouillement des documents. Les renseignements concernant l'examen du CICAD par les pairs font l'objet de l'appendice 2. Ce CICAD a été approuvé en tant qu'évaluation internationale lors d'une réunion du Comité d'évaluation finale qui s'est tenue à Bruxelles (Belgique) du 18 au 20 novembre 1996. La liste des participants à cette réunion figure à l'appendice 3. Après avoir été révisé pour y incorporer les résultats d'une étude de cancérogénicité de 2 ans récemment achevée, le document a été soumis à des pairs pour deux séries d'évaluations écrites. En outre, la partie du document spécialement consacrée à l'évaluation des effets sur la santé humaine (à savoir la section 11.1), a été examinée lors d'une réunion qui s'est tenue le 7 décembre 1998 à Washington (Etats-Unis), dans les locaux du National Center for Environmental Assessment, US Environmental Protection Agency. La liste des personnes qui ont participé aux évaluations spécialisées du présent CICAD figure à l'appendice 4. Ce CICAD a été approuvé en tant qu'évaluation internationale lors de la réunion du Comité d'évaluation finale qui a eu lieu à Washington du 8 au 11 décembre 1998. La liste des participants à cette réunion figure à l'appendice 5. La fiche d'information internationale sur la sécurité chimique (ICSC 0106) établie par le Programme international sur la sécurité chimique (IPCS, 1993) est également reproduite dans ce document. Le biphényle (CAS N° 92-52-4) est un hydro carbure aromatique qui se présente à la température ambiante sous la forme d'un solide cristallin incolore. Il est utilisé comme intermédiaire dans la production de divers composés (par exemple, émulsifiants, azurants optiques, produits pour la protection des cultures, matières plastiques), comme fluide caloporteur, comme support de colorants pour textiles et papier à photocopie, comme solvant dans l'industrie pharmaceutique ou encore pour la conservation des agrumes. Le biphényle existe à l'état naturel dans le goudron de houille, le pétrole brut et le gaz naturel. Parmi les sources artificielles de pollution par le biphényle figurent les unités qui produisent ou utilisent ce composé, les installations où l'on traite des agrumes ou des bois ou encore les décharges municipales. Il se forme lors de la combustion incomplète des huiles minérales et de la houille et on en trouve dans les gaz d'échappement des véhicules à moteur et dans l'air libéré dans l'atmosphère par les appareils de chauffage des installations industrielles ou des immeubles résidentiels. Des valeurs de 1 à 100 ng/m3 sont caractéristiques de la concentration dans l'air ambiant. A l'intérieur des bâtiments, elles sont plus élevées (100-1000 ng/m3), probablement par suite de la présence de fumée de cigarette, d'émissions provenant des appareils de chauffage et de garages situés dans le voisinage. Des mesures effectuées dans les années 70 ont donné des valeurs généralement inférieures à 5 ng/litre pour l'eau du robinet. On n'a pas connaissance de valeurs plus récentes. Dans les eaux superficielles, la concentration usuelle est inférieure à 500 ng/litre. Dans les sédiments, le sol et les êtres vivants, on n'a procédé à des dosages de biphényle qu'à proximité immédiate d'installations industrielles et de décharges. Peu soluble dans l'eau, le biphényle s'évapore de ses solutions aqueuses. Sa principale voie de décomposition troposphérique est due à l'action des radicaux hydroxyles et la demi-vie calculée dans ces conditions est de l'ordre de 2 jours en moyenne. Le biphényle ne devrait pas s'hydrolyser dans les conditions qui règnent dans l'environnement. Il est biodégradable en aérobiose. D'après les données disponibles, il devrait être quasiment immobile dans le sol; sa probabilité d'infiltration dans les eaux souterraines est faible. Dans la chaîne alimentaire qui joue un rôle important pour l'alimentation humaine, il peut y avoir accumulation du biphényle, notamment dans les plantes. Toutefois, compte tenu de son potentiel de bioaccumulation, il ne semble pas qu'il puisse subir une bioamplification importante aux niveaux trophiques supérieurs de la chaîne alimentaire aquatique ou terrestre. Le biphényle est bien absorbé dans les voies digestives et probablement aussi par la voie pulmonaire et percutanée. Chez les espèces étudiées, les métabolites du biphényle, principalement le 4-hydroxybiphényle, sont rapidement excrétés et presque exclusivement par la voie urinaire. Le biphényle est modérément toxique par voie buccale. Il n'est pas irritant pour la peau et n'irrite que très légèrement la muqueuse oculaire. Rien n'indique qu'il puisse provoquer une sensibilisation cutanée. Les études toxicologiques au cours desquels on a soumis les animaux de laboratoire à des expositions répétées au biphényle, ne permettent pas d'établir la valeur de la dose sans effet observable (NOEL) avec un bon niveau de confiance. Une exposition subchronique par la voie respiratoire a provoqué l'apparition d'anomalies bronchopulmonaires, mais la littérature ne mentionne pas d'études toxicologiques de longue durée comportant une exposition par cette voie. Les études toxicologiques comportant l'administration, pendant diverses périodes, de nourriture additionnée de biphényle à des rongeurs, font souvent mention d'effets aux niveau des voies urinaires. Chez des rats mâles ayant reçu une alimentation contenant plus de 2500 mg de biphényle par kg, on a observé une augmentation sensible dans l'incidence des effets morphologiques (par ex. formation de calculs) et histopathologiques (par ex. hyperplasie, desquamation) au niveau des voies urinaires. On a également observé une augmentation des calculs et des cas de métaplasie spino-cellulaire vésicale chez des rattes, mais dans une proportion moindre que chez les mâles. Chez des souris mâles soumises pendant 32 semaines à un régime alimentaire comportant 10 000 mg de biphényle par kg (1500 mg par kg de poids corporel), on a observé une simple hyperplasie et une dysplasie papillomateuse ou nodulaire de la vessie, mais chez seulement un animal sur dix. Sur des animaux à qui on avait fait ingérer du biphényle, on a également observé des effets hématologiques (biochimiques et autres); ces effets peuvent être constatés chez des rats ou des souris mâles et femelles à des doses inférieures à celles qui produisent des effets sur la vessie des rats mâles. En ce qui concerne les effets non néoplasiques, la dose la plus faible produisant un effet observable (LOEL) se situait à 38 mg/kg p.c. par jour, le critère retenu étant l'apparition d'anomalies hématologiques (diminution du taux d'hémoglobine et de l'hématocrite) chez des rats ayant reçu pendant 2 ans une nourriture contenant respectivement 0, 500, 1500 ou 4500 mg/kg de biphényle (les doses indiquées étant égales à 0, 38, 113 ou 338 mg/kg p.c.). Les études in vitro sur des bactéries n'ont pas mis en évidence d'activité mutagène. On a observé des mutations et des recombinaisons mitotiques chez Saccharomyces cerevisiae D7 avec ou sans activation métabolique. Les tests de génotoxicité sur cellules mammaliennes ont toutefois donné des résultats positifs en présence d'activation métabolique et des résultats négatifs en l'absence d'une telle activation. Une étude in vivo insuffisamment documentée et dont l'exécution laisse à désirer, n'a pas permis de constater la présence d'aberrations chromosomiques dans la moelle osseuse de rats exposés à du biphényle par la voie respiratoire. Les résultats d'autres études in vitro indiquent que le biphényle possède un pouvoir mutagène; dans ces conditions et devant le manque de fiabilité des résultats fournis par les études in vivo, on estime que le biphényle comporte un risque mutagène. Chez des souris femelles, on a constaté une légère augmentation de l'incidence des tumeurs bénignes ou malignes du foie lorsque les animaux avaient reçu pendant 2 ans du biphényle mêlé à leur nourriture. Une augmentation de l'incidence des tumeurs vésicales a été observée chez des rats mâles, mais ni chez les femelles ni chez des souris des deux sexes, après administration d'une nourriture contenant une grande quantité de biphényle. On a avancé que ces tumeurs pouvaient être dues à l'hyperplasie régénérative de l'épithélium vésical provoquée par l'abrasion et les lésions que produisent les calculs, lesquels ne se forment que si l'exposition au biphényle est suffisamment intense. On pense également qu'en raison de différences anatomiques et physiologiques, ces tumeurs vésicales observées à forte doses chez des rats mâles et qui présentent une spécificité de sexe et d'espèce, n'ont guère de signification pour des sujets humains exposés à des doses plus faibles. Quoi qu'il en soit, 1) l'observation d'un accroissement de l'incidence des effets histopathologiques et la formation de calculs au niveau de la vessie, en l'absence de tumeurs vésicales , chez des rattes ayant reçu du biphényle pendant 2 ans, 2) l'absence de données permettant de mettre en évidence une association directe entre cette lithiase vésicale, l'hyperplasie régénérative de l'urothélium et l'apparition de tumeurs vésicales chez les rats mâles et 3) la génotoxicité potentielle du biphényle, incitent à penser que la formation de tumeurs vésicales chez les rats mâles n'est peut-être pas entièrement due à l'action des calculs. Cette observation, de même que les signes d'hépatotoxicité relevés chez les souris femelles, font craindre que le biphényle ne comporte un risque de cancérogénicité. Les données relatives à la toxicité génésique du biphényle sont limitées. A part une étude portant sur trois générations de rats, qui a mis en évidence des effets indésirables (réduction de la fécondité, de la taille des portées et du taux de croissance), rien ne prouve que le biphényle puisse avoir des effets sur la reproduction ou le développement. L'exposition, sur les lieux de travail, à des vapeurs ou à des poussières à forte teneur en biphényle entraîne une irritation des yeux et une inflammation des voies respiratoires. Une exposition pendant plusieurs années à de fortes concentrations de biphényle (jusqu'à 128 mg/m3) a provoqué des lésions hépatiques et les anomalies neuronales permanentes; il est possible que dans ce cas, l'effet du contact cutané avec le composé se soit ajouté à celui de son absorption par la voie respiratoire. On ne possède qu'un nombre limité de données sur la concentration du biphényle dans l'environnement et les renseignements qu'on peut en tirer sont insuffisants pour permettre une estimation raisonnable de la dose de composé absorbée. Il peut y avoir exposition par inhalation (inhalation d'air pollué et utilisation de créosote contenant du biphényle pour la préservation du bois) ou par ingestion (lorsque le biphényle est utilisé comme conservateur d'agrumes). Le biphényle est faiblement bactéricide et fongistatique. Lors d'études toxicologiques sur des organismes aquatiques représentant quatre niveaux trophiques, la concentration la plus faible sans effet observable (NOEC) pour l'espèce la plus sensible (Daphnia magna) a été trouvée égale 0,17 mg/litre lors de tests de longue durée. Le calcul donne une concentration sans effet prévisible (PNEC) de 1,7 µg/litre en utilisant un facteur d'évaluation de 10, compte tenu des caractéristiques écotoxicologiques et du devenir environnemental du composé. On ne dispose pas, au sujet des effets toxiques du biphényle sur les organismes terrestres et les écosystèmes, de données valables permettant une évaluation du risque. En raison de l'absence de données émanant d'autres régions du monde, l'évaluation du risque qui a été effectuée concerne spécifiquement l'Allemagne. A partir des concentrations mesurées dans les cours d'eau allemands au cours des années 90, on a obtenu un rapport de la concentration environnementale prévue (PEC) à la concentration sans effet prévisible (PNEC) qui est égal à <0,29. Un rapport PEC/PNEC <1 signifie qu'il n'y a vraisemblablement pas de risque important pour l'environnement. RESUMEN DE ORIENTACION El presente CICAD, preparado por el Instituto Fraunhofer de Toxicología y de Investigación sobre los Aerosoles de Hannover, Alemania, se basa fundamentalmente en un examen preparado por el Comité Consultivo Alemán sobre las Sustancias Químicas Importantes para el Medio Ambiente (BUA, 1990), así como en un informe complementario (BUA, 1994) para evaluar los efectos potenciales del bifenilo en el ser humano y en el medio ambiente. En el apéndice 1 figuran los documentos originales y una descripción de sus procesos de examen. Se realizó asimismo una búsqueda bibliografía amplia en varias bases de datos en línea en junio de 1996 para identificar datos adicionales. También se ha incorporado a este CICAD nueva información adicional obtenida durante el examen efectuado por los servicios de información y por la Junta de Evaluación Final (Bruselas, Bélgica). En el apéndice 2 se presenta información relativa al examen colegiado de este CICAD. La Junta de Evaluación Final lo aprobó provisionalmente como evaluación internacional en una reunión celebrada en Bruselas (Bélgica) los días 18-20 de noviembre de 1996. En el apéndice 3 figura la lista de participantes en dicha reunión. Tras la incorporación de los datos relativos a la carcinogenicidad de esta sustancia obtenidos de una biovaloración de la carcinogenicidad de dos años de duración completada recientemente, el documento revisado se sometió a dos rondas de examen colegiado por escrito. Además, la parte del documento en la que se aborda específicamente la evaluación de la salud humana (es decir, la sección 11.1) se examinó en una reunión celebrada en el Centro Nacional para la Evaluación del Medio Ambiente, Organismo para la Protección del Medio Ambiente de los Estados Unidos, en Washington, DC (Estados Unidos) el 7 de diciembre de 1998. El apéndice 4 contiene la lista de quienes contribuyeron a los exámenes especializados adicionales del presente CICAD. Este CICAD se aprobó como evaluación internacional en una reunión de la Junta de Evaluación Final celebrada en Washington, DC (Estados Unidos), los días 8-11 de diciembre de 1998. En el apéndice 5 figura la lista de participantes en esta reunión. La Ficha internacional de seguridad química (ICSC 0106), preparada por el Programa Internacional de Seguridad de las Sustancias Químicas (IPCS, 1993), también se reproduce en el presente documento. El bifenilo (CAS N° 92-52-4), un hidrocarburo aromático, es una sustancia sólida incolora a temperatura ambiente. Se utiliza como intermediario en la producción de diversos compuestos (por ejemplo, emulsionantes, abrillantadores ópticos, productos para la protección de los cultivos, plásticos), como medio de transferencia de calor en fluidos térmicos, como colorante de textiles y papel para copias, como disolvente en la producción farmacéutica y en la conservación de cítricos. El bifenilo se encuentra en la naturaleza en el alquitrán mineral, el petróleo bruto y el gas natural. Las fuentes antropogénicas de exposición en el medio ambiente incluyen las plantas de producción y elaboración, las instalaciones de conservación de cítricos o de madera y los vertederos municipales. Se forma bifenilo durante la combustión incompleta del aceite mineral y el carbón y está presente en los gases de escape de los vehículos y de las calderas de calefacción de las viviendas y las industrias. En la atmósfera, las concentraciones habituales de bifenilo oscilan entre 1 y 100 ng/m3; en el aire de espacios cerrados los niveles son superiores (100-1000 ng/m3), probablemente debido al humo de los cigarrillos y a las emisiones de las calderas de calefacción o de garajes cercanos. En las mediciones realizadas en los años setenta, las concentraciones de bifenilo en el agua de grifo eran normalmente inferiores a 5 ng/litro. No se conocen datos más recientes. En el agua superficial, las concentraciones suelen ser inferiores a 500 ng/litro. En los sedimentos, el suelo y la biota, sólo se midió el bifenilo en las cercanías de instalaciones industriales y vertederos. El bifenilo se volatiliza de la solución acuosa y tiene una solubilidad baja en agua. La principal vía de degradación en la troposfera es la reacción con radicales hidroxilo, para la que se ha calculado una semivida de unos dos días. No cabe prever que la sustancia se hidrolice en las condiciones del medio ambiente. Es biodegradable en condiciones aerobias. Según los datos disponibles, el bifenilo debería mantenerse casi inmóvil en el suelo; la probabilidad de infiltración hacia el agua freática es baja. En la cadena alimentaria importante para el ser humano se puede producir bioacumulación, especialmente en las plantas; sin embargo, teniendo en cuenta la posible bioacumulación del bifenilo, cabe prever que su bioamplificación en los niveles tróficos superiores de la cadena alimentaria acuática o terrestre será de escasa importancia. El bifenilo se absorbe bien a través del tracto gastrointestinal y posiblemente también por vía pulmonar y cutánea. En las especies examinadas, los metabolitos del bifenilo, sobre todo el 4-hidroxibifenilo, se excretan con rapidez y casi exclusivamente en la orina. La toxicidad aguda del bifenilo por vía oral es moderada. No es irritante de la piel y sólo ligeramente de los ojos. No hay pruebas de sensibilización cutánea. Los estudios de toxicidad con bifenilo tras la exposición repetida por inhalación no son adecuados para establecer con confianza una concentración sin efectos observados (NOEL). La exposición subcrónica por inhalación produjo cambios broncopulmonares, pero no se han encontrado en la bibliografía estudios de toxicidad prolongados tras la exposición por inhalación. En estudios toxicológicos realizados con roedores que recibieron alimentos con bifenilo durante diversos períodos de tiempo, se han notificado con frecuencia efectos en el sistema urinario. Se ha observado un aumento acentuado en la incidencia de efectos morfológicos (es decir, formación de cálculos) e histopatológicos (por ejemplo, hiperplasia, descamación) en el tracto urinario de ratas macho a las que se suministraron alimentos con concentraciones de bifenilo superiores a 2500 mg/kg. Se observó asimismo un aumento en la aparición de cálculos y metaplasia escamosa en la vejiga urinaria de ratas hembras, pero con una incidencia inferior a la registrada en los machos. En ratones macho, sólo uno de 10 animales que recibieron alimentos con 10 000 mg de bifenilo/kg (1500 mg/kg de peso corporal al día) durante 32 semanas presentó hiperplasia simple y displasia papilar o nodular en la vejiga urinaria. En animales que recibieron bifenilo por vía oral se detectaron asimismo efectos en la química sanguínea y los parámetros hematológicos; estos efectos se producen en ratas y ratones machos y hembras con ingestas inferiores a las asociadas con la aparición de efectos en la vejiga urinaria de las ratas machos tratadas con bifenilo. Para los efectos no neoplásicos, la concentración más baja de efectos observados (LOEL) fue de 38 mg/kg de peso corporal al día, basada en la aparición de alteraciones en los parámetros hematológicos (es decir, disminución de la concentración de hemoglobina y del valor hematócrito) en ratas a las que se suministraron alimentos que contenían 0, 500, 1500 ó 4500 mg de bifenilo/kg (ingestas notificadas de 0, 38, 113 ó 338 mg/kg de peso corporal al día) durante dos años. En estudios in vitro con bacterias no se han obtenido pruebas de potencial mutagénico del bifenilo; con Saccharomyces cerevisiae D7, se observaron mutaciones genéticas y recombinación mitótica con activación metabólica y sin ella. Sin embargo, en pruebas de toxicología genética en células de mamíferos se obtuvieron resultados positivos con activación metabólica y negativos en su ausencia. En un estudio in vivo insuficientemente documentado y realizado de manera inadecuada, el bifenilo no indujo aberraciones cromosómicas en la médula ósea de ratas tras la exposición por inhalación. Los resultados de los estudios in vitro ponen de manifiesto que el bifenilo tiene potencial mutagénico; sin la garantía de resultados fidedignos de pruebas in vivo, se supone que la exposición al bifenillo se puede asociar con un riesgo mutagénico. En ratones hembra, se produjo un ligero aumento de la incidencia de tumores hepáticos benignos y malignos en animales que recibieron bifenilo con los alimentos durante dos años. Se observó un aumento de la incidencia de tumores de vejiga en ratas machos, pero no en las ratas hembras o los ratones machos y hembras, que recibieron alimentos con concentraciones elevadas de bifenilo. Se ha indicado que la formación de dichos tumores de vejiga podría estar vinculada a la hiperplasia regenerativa del epitelio urinario, debida a la abrasión y las lesiones del urotelio producidas por los cálculos formados en el tracto urinario sólo con niveles muy altos de exposición; se ha señalado asimismo que, debido a las diferencias anatómicas y fisiológicas, la aparición de tumores de vejiga específicos del sexo y la especie en ratas macho que recibieron dosis elevadas de bifenilo tal vez no sea pertinente para las personas expuestas a niveles más bajos. Sin embargo, 1) las observaciones de una mayor incidencia de efectos histopatológicos y la formación de cálculos en la vejiga urinaria, en ausencia de tumores de vejiga, en ratas hembras tratadas con bifenilo durante dos años, 2) la falta de datos que establezcan una asociación directa entre la formación de cálculos, la hiperplasia regenerativa del urotelio y la aparición de tumores de vejiga en determinados animales machos, y 3) la genotoxicidad del bifenilo, podrían indicar que la aparición de tumores de vejiga en ratas macho tal vez no se deba completamente a los efectos asociados a la formación de cálculos en la vejiga urinaria. Esta observación, así como la prueba de hepatocarcinogenicidad en ratones hembras, despierta alguna preocupación con respecto a la carcinogenicidad potencial del bifenilo. Los datos disponibles sobre la toxicidad reproductiva del bifenilo son limitados. Si se exceptúan los resultados obtenidos en un estudio de tres generaciones en ratas, en el que se observaron efectos adversos (disminución de la fecundidad, del tamaño de la camada y de la tasa de crecimiento), no se encontraron pruebas de que el bifenilo indujera efectos reproductivos o en el desarrollo. La exposición a concentraciones elevadas de vapores o polvo de bifenilo en el lugar de trabajo produce irritación de los ojos e inflamación del tracto respiratorio. La exposición prolongada durante varios años a concentraciones elevadas de bifenilo (hasta 128 mg/m3) provo có lesiones hepáticas y cambios neuronales persistentes; el contacto directo con la piel puede haber influido, además de la absorción a través del tracto respiratorio. Los datos disponibles sobre las concentraciones de bifenilo en el medio ambiente general son limitados y la información es insuficiente para permitir una estimación razonable de su ingesta. La inhalación (del aire contaminado y por el uso de creosotas con bifenilos en la conservación de la madera) y la ingestión (debido a su uso como conservante de cítricos) pueden ser fuentes de exposición. El bifenilo tiene propiedades bactericidas y fungicidas débiles. En estudios de toxicidad sobre organismos acuáticos de cuatro niveles tróficos, la concentración más baja sin efectos observados (NOEC) notificada para la especie más sensible (Daphnia magna) en pruebas crónicas fue de 0,17 mg/litro. Se puede calcular una concentración sin efectos prevista (PNEC) de 1,7 µg/litro mediante la aplicación de un factor de evaluación de 10, teniendo en cuenta las características de ecotoxicidad y destino en el medio ambiente de la sustancia. No se dispone de datos válidos sobre efectos tóxicos en organismos y ecosistemas terrestres, que se podrían utilizar para la evaluación del riesgo. Debido a la falta de datos de otras partes del mundo, se realizó en Alemania una evaluación del riesgo de muestra. A partir de las concentraciones medias en los ríos alemanes en los años noventa, la relación entre la concentración prevista en el medio ambiente (PEC) y la PNEC se calcula que es <0,29. Una razón PEC/PNEC <1 indica que no cabe prever un riesgo importante para el medio ambiente.



    See Also:
       Toxicological Abbreviations
       Biphenyl (ICSC)
       BIPHENYL (JECFA Evaluation)