Chemical name: [1,1'-Biphenyl]-4,4'-diamine Final regulatory action has been taken for the category: Industrial Final regulatory action: The chemical is Severely Restricted Use or uses prohibited by the final regulatory action: Benzidine has been used primarily as an intermediate in the manufacture of dyes and pigments. It is not produced in Canada, and although it may have been imported in small amounts between 1980 and 1987, there no longer appears to be any commercial activity in Canada involving this substance. Benzidine and its salt are currently used only in very limited specialty laboratory applications, and for research and development purposes. Use or uses that remain allowed: The Regulations prohibit the manufacture, use, sale, offer for sale or import of benzidine and benzidine dihydrochloride, with the exceptions listed below: The Regulations do not apply to benzidine and benzidine dihydrochloride that are: contained in a hazardous waste, hazardous recyclable material or non-hazardous waste; contained in a control product (e.g., pesticide); present as a contaminant in a chemical feedstock used in a process from which there are no releases of the substance and provided that the substance is destroyed or completely converted in that process to a substance that is not a toxic substance listed in the Regulations; or, used in a laboratory for analysis; in scientific research; or, as a laboratory analytical standard. In addition, the Regulations do not apply in respect of the manufacture, use, sale, offering for sale or import of benzidine or benzidine dihydrochloride for the following permitted uses: staining for microscopic examination, such as immunoperoxidase staining, histochemical staining or cytochemical staining reagent for detecting blood in biological fluids niacin test to detect some microorganisms reagent for detecting chloralhydrate in biological fluids. The Regulations also establish a permit system that provides a mechanism for temporarily exempting certain applications of a substance listed in the Regulations. A permit may be granted only if the Minister of the Environment is satisfied that there is no technically or economically feasible alternative or substitute available for the substance. In addition, the Minister must be satisfied that measures have been taken to minimize or eliminate any harmful effects of the substance on the environment and human health. Finally, the applicant must provide an implementation plan that identifies specific timelines for eliminating the substance. Each permit lasts for 12 months, and can be renewed only twice. The final regulatory action was based on a risk or hazard evaluation: Yes Summary of the final regulatory action: The Prohibition of Certain Toxic Substances Regulations, 2005 prohibit the manufacture, use, sale, offer for sale and import of toxic substances listed in Schedules 1 and 2 to the Regulations. Benzidine and benzidine dihydrochloride are found on Schedule 2, which lists substances that are subject to prohibitions related to concentration or use. The reasons for the final regulatory action were relevant to: Human health Summary of known hazards and risks to human health: The Canadian Environmental Protection Act (CEPA) requires the Ministers of the Environment and of Health to prepare and publish a Priority Substances List that identifies substances, including chemicals, groups of chemicals, effluents and wastes that may be harmful to the environment or constitute a danger to human health. Benzidine was placed on this list and was given priority for assessment to determine whether it is "toxic" under CEPA. As benzidine was assessed under the original CEPA (CEPA was reviewed and updated in 1999), it was assessed against the definition for "toxic" as interpreted in section 11 of the 1988 Act, which states: "a substance is toxic if it is entering or may enter the environment in a quantity or concentration or under conditions a)having or that may have an immediate or long-term harmful effect on the environment; b)constituting or that may constitute a danger to the environment on which human life depends; or c)constituting or that may constitute a danger in Canada to human life or health." Data relevant to the assessment of whether benzidine is "toxic" under CEPA 1988 were identified through evaluation of existing review documents, as well as an unpublished review of the environmental behaviour and health effects of this substance prepared under contract, supplemented with information from published reference texts and literature identified through on-line searches (from 1965 to 1992) of various databases. In addition, a number of provincial authorities were requested to provide any available information on the levels of benzidine in the drinking water of their provinces. The Quebec Ministry of the Environment was requested to provide available quantitative data on potential release of this substance from petrochemical facilities. Data relevant to the assessment of the effects of benzidine on the environment and human health obtained after November 1992 and February 1993, respectively, were not considered for inclusion. Review articles were consulted where appropriate. However, all original studies that form the basis for determining whether benzidine is "toxic" under CEPA 1988 have been critically evaluated by staff of Health Canada (human exposure and effects on human health) and Environment Canada (entry and environmental exposure and effects). The environmental sections of the assessment report were reviewed by Drs. C.M. Auer and W.H. Farland of the U.S. Environmental Protection Agency. Sections related to the assessment of effects on human health were approved by the Standards and Guidelines Ruling Committee of the Bureau of Chemical Hazards of Health Canada. Entry into the Environment No conclusive data on the environmental release of benzidine in Canada were identified. It can enter the environment from any stage in the production, storage, transport, use and disposal of benzidine itself or benzidine-containing materials (such as dyes and pigments), or possibly by atmospheric and water-borne transport from other countries. In water, benzidine can be produced by the photodegradation of 3,3'-dichlorobenzidine. No information on the extent to which benzidine may be formed and released into the environment by this mechanism was identified. Exposure-related Information Fate Oxidation, photochemical transformation, partitioning to sediment or soil, and microbial degradation are expected to be the main pathways of distribution and transformation of benzidine in the environment. Benzidine is not expected to persist in the environment, with overall half-lives in water, soil and air of less than a few weeks. The products formed by the degradation of this substance have not been well characterized. Benzidine is expected to be slightly volatile (from water), based on its low Henry's law constant of 2.2 10-2 Pa m3/mol. In water, although oxidation (by hydroperoxyl radical or molecular oxygen), biodegradation and photolysis may be significant processes, the most important process controlling the fate of benzidine appears to be oxidation by naturally occurring metal cations; the half-life is approximately a few hours. Benzidine is quickly absorbed into clays and subsequently oxidized. Although the environmental fate of such complexes is not known with certainty, it is assumed that further oxidation would be facile. Estimated half-lives for the biodegradation of benzidine in surface water and groundwater are 31 to 192 h and 96 to 384 h, respectively. Benzidine is quickly bound in soils and sediments; however, information on the bioavailability of such bound residues was not identified. It was noted that benzidine adsorption to soil or sediment was favoured by low pH, and highly correlated with the surface area of the soil or sediment. In soil, benzidine is degraded microbially. The half-life of benzidine was estimated to be 48 to 192 h for aerobic degradation. In air, benzidine is expected to photooxidize moderately rapidly, with an estimated half-life ranging from 0.3 to 3.2 h. Concentrations Benzidine was not detected (detection limit = 2 mg/L) in 34 samples of raw and 1 015 samples of treated drinking water obtained in the province of Alberta between 1987 and 1991. No other data on the concentrations of benzidine within Canada in drinking water, surface water, groundwater, air, biota, soil or sediment, foodstuffs or products containing dyes derived from this substance were identified. In the United States, benzidine was not detected in a survey of biota and sediment; however, it was detected (but not quantitated) in 1.1% of 1 235 samples of industrial effluent and 0.1% of 879 samples of natural water collected between 1980 and 1982. Benzidine accumulates only moderately in aquatic biota. Bioconcentration factors (after 3 days) were 55 for mosquito fish (Gambusia affinis), 293 for Daphnia magna, 456 for mosquito larva (Culex pipiens quinquefasciatus), 645 for snail (Physa sp.) and 2 617 for a filamentous green alga (Oedogonium cardiacum). A 5-day bioaccumulation factor in activated sludge of 1 200, a 1-day bioaccumulation factor in algae (Chlorella fusca) of 850, and a 3-day bioaccumulation factor in fish (golden orfe, Leuciscus idus melanotus) of 83 were reported. While some of the results may suggest some potential for the bioaccumulation of benzidine by predator organisms, none has been observed, nor would it be expected for a chemical with a log octanol-water partition coefficient of 1.34. Assessment of Benzidine under the Canadian Environmental Protection Act (CEPA) Environment The most sensitive species of fish identified was the red shiner (Notropis lutrensis) with a 72- and 96-hour LC50 of 2.5 mg/L. This concentration was divided by a factor of 20 to convert it to a chronic no-observed-effect-level, to account for interspecies differences and to extrapolate laboratory results to the field. This yielded an estimated effect threshold of 0.13 mg/L. Since benzidine was not produced in or imported into Canada at the time the Assessment Report was published, and since its half-life in environmental media is less than a few weeks, concentrations of benzidine in surface water in the range of the estimated effect threshold were considered very unlikely. Therefore, on the basis of the limited available data, benzidine was not considered to be "toxic" to the environment. Environment on Which Life Depends Benzidine is expected to be slightly volatile and to photooxidize rapidly in air. Therefore, this substance is not expected to contribute to ozone depletion, global warming or the formation of ground-level ozone. Therefore, on the basis of available data, benzidine was not considered to be "toxic" to the environment on which life depends. Human Life or Health Population Exposure Quantitative data on the concentrations of benzidine in air, drinking water, soil or foodstuffs within Canada (or elsewhere) were not identified. Consequently, the available data were inadequate to estimate the exposure of the general population of Canada to benzidine. Effects The results of a number of analytical epidemiological studies as well as supporting data from case reports and series of workers occupationally exposed to benzidine have provided clear evidence for the carcinogenicity of this substance in humans. Indeed, the observed association between the occurrence of bladder carcinoma and occupational exposure to benzidine fulfils the traditional criteria (consistency, strength, specificity, temporal relationship, exposure-response relationship and plausibility) for assessment of causality in epidemiological studies. The observed associations have been very specific, in that occupational exposure to benzidine has been associated with an increased incidence of, or death due to, cancer of the bladder-almost exclusively, transitional cell carcinoma. The results have been remarkably consistent, with an association between occupational exposure to benzidine and an increased incidence of, or mortality due to, bladder cancer observed in all the analytical epidemiological studies in which these relationships were examined. The association between the increased incidence of, or mortality due to, bladder carcinoma is strong. Reported standardized incidence ratios (SIRs) for bladder cancer in occupationally exposed workers are 3.4 and 19.2. Reported standardized mortality ratios (SMRs) for death due to bladder cancer in occupationally exposed workers range from 12 to 83.3. Although quantitative information on exposure to benzidine was not assessed in any of the available analytical epidemiological studies, a relationship between qualitative measures of exposure and an increased incidence of bladder cancer was reported in two studies. Although the data are limited, there is evidence indicating that a reduction in the (occupational) exposure to benzidine was associated with a decrease in the incidence of bladder carcinoma. The carcinogenicity of benzidine in humans is plausible, based on the overwhelming evidence of the genotoxicity of this substance. Moreover, the carcinogenicity of benzidine in experimental animals (i.e., rats, mice, hamsters) has been well documented. Since the observed association of bladder cancer (predominantly transitional cell carcinoma) with occupational exposure to benzidine fulfils the traditional criteria for assessment of causality in epidemiological studies, on the basis of the available data, benzidine was classified in Group I (Carcinogenic to Humans) of the classification scheme developed for the determination of "toxic" to human life or health under CEPA. For such substances, where possible, estimated total daily intake by the general population in Canada is compared to quantitative estimates of carcinogenic potency to characterize risk and provide guidance for further action (i.e., analysis of options to reduce exposure). Owing to the lack of available information on concentrations of benzidine in environmental media to which humans are exposed, it was not possible to quantitatively estimate the total daily intake of this substance by the general population of Canada. Consequently, estimates of total daily intake were not compared to quantitative estimates of cancer potency, although such values would be expected to be low owing to the lack of reported use of this substance in Canada. Benzidine has been classified as being "Carcinogenic to Humans", and is therefore considered to be "toxic" to human life or health. This approach is consistent with the objective that exposure to non-threshold toxicants should be reduced wherever possible, and obviates the need to establish an arbitrary de minimis level of risk for determination of "toxic" under CEPA. Overall Conclusion Based on the available data, benzidine was not considered to be "toxic" to the environment or the environment on which life depends. Benzidine was considered to be "toxic" to human life or health. Benzidine has been shown to cause cancer in occupationally exposed workers and experimental animals and is considered to be a "non-threshold toxicant" (i.e., a substance for which there is believed to be some chance of adverse effect at any level of exposure). Note: Benzidine dihydrochloride is also being addressed in the Regulations because it dissociates in water into benzidine. Expected effect of the final regulatory action in relation to human health: Levels of use of benzidine and benzidine dihydrochloride in Canada at the time the Regulations were published did not pose a threat to human health and the environment. The Regulations were put in place as a precautionary measure to protect the health of Canadians and ecosystems by ensuring that future production, importation and use of benzidine and benzidine dihydrochloride is prohibited with very limited exemptions. Date of entry into force of the final regulatory action: 15/05/2005 |