Concise international chemical assessment document 6

Abstract

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 volatizes 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 with in 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 effect 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 alteration s 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 induced chromosomal aberrations 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 tumors 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.