Follow-up assessment report on aniline: chapter 2

2. Summary of the Human Health Risk Assessment for Aniline (Published in 1994)

At the time of release of the PSL assessment (Government of Canada, 1994), at least 10 tonnes of aniline and its salts were being manufactured, processed or otherwise used annually in Canada. Aniline and aniline hydrochloride were manufactured and imported for use primarily as intermediates in the production of chemicals for the synthesis of polyurethane and rubber. In the United States, aniline was being used in the rubber, plastics, agricultural, dye, photographic chemical and pharmaceutical industries, including in the manufacture of sulphonamide drugs, acetanilide, hydroquinone, sweetening agents, optical whitening agents, resins, marking inks, perfumes and shoe polishes. Derivatives of aniline were also used in the United States as herbicides, fungicides, insecticides, animal repellents and defoliants.

It was estimated that in 1994, 1.1 tonnes of aniline were being released into the Canadian environment each year from various stages of its commercial life cycle. Aniline was not expected to be persistent in the environment. Data on concentrations of aniline in the principal media of exposure (air, food and water) for the general population of Canada and on concentrations of aniline in breast milk and soil in Canada were not available. Therefore, deterministic estimates of the average daily intake were developed based on limited monitoring data that were identified for ambient air in the United States, indoor air in Canada, food in Germany and mainstream cigarette smoke, and on the detection limit for measurement of aniline in drinking water samples from the province of Quebec. These estimates differed by approximately seven orders of magnitude from ones based on concentrations of aniline in air, water and soil in southern Ontario predicted by Level III fugacity modelling. These modelled values were based, in part, on the amount of aniline imported into Canada in 1989. While such estimates are more relevant to the Canadian situation, they are considerably less reliable than ones based on monitoring data.

Available epidemiological studies were inadequate to serve as a basis for assessment of the carcinogenicity of aniline. In identified chronic studies, aniline induced splenic tumours in male (but not female) rats at high doses; no such tumours were observed in male or female mice. Results from the two most extensive carcinogenesis bioassays were consistent with a greater metabolism of aniline by detoxification pathways in mice than in rats, the saturation of this pathway at higher doses in rats, and sex-related differences in metabolism. The increased incidence of splenic tumours in male rats (at doses that may saturate the detoxification pathway) was associated with cellular damage. Hence, the induction of these tumours was considered potentially a consequence of enhanced cellular proliferation associated with cell damage resulting from the accumulation of damaged erythrocytes within this tissue. Data on the genotoxicity of aniline were mixed but consistent with this hypothesis, since aniline had not been genotoxic in the spleen; however, this observation was based on limited data.

A Tolerable Daily Intake (TDI) (i.e., the level of intake to which it is believed that a person may be exposed daily over a lifetime without deleterious effects) of 1.4 µg/kg-bw per day was derived, therefore, for non-neoplastic effects. This value was derived by dividing the lowest dose of aniline (Lowest-Observed-Adverse-Effect Level [LOAEL] = 7.2 mg/kg-bw per day) at which adverse effects (increased splenic haemosiderin, extramedullary haematopoiesis and congestion in male CD-F rats) were observed in the only available long-term animal study in which an adequate range of endpoints had been examined (CIIT, 1982) by an uncertainty factor of 5000 (×10 for intraspecies variation; ×10 for interspecies variation; ×10 for use of a LOAEL rather than a No-Observed-Adverse-Effect Level [NOAEL]; ×5 for limited evidence of carcinogenicity). This TDI value is similar to that which could be derived (4.2 µg/kg-bw per day) based on the results of a (limited) clinical study on formation of methaemoglobin in volunteers exposed by ingestion (Jenkins et al., 1972) which reported a no effect dose of 15 mg/man (NOEL of 0.21 mg/kg-bw for a 70 kg person) and to which an uncertainty factor of 50 (which takes into account intraspecies variation and limitations of the study) was applied.. However, this clinical study was considered inadequate in itself to serve as a basis for development of a TDI since it was a short-term investigation of a limited range of biochemical effects in a very small number of subjects.

The highly uncertain estimates of exposure to aniline, which were based primarily on data from other countries, and the considerable difference between those estimates and the modelled values precluded meaningful comparison with the TDI in 1994.

Therefore, data were considered insufficient to conclude whether aniline was “toxic” as defined under Paragraph 11(c) of CEPA 1988.