3,3'-Dichlorobenzidine - PSL1

3.0 Assessment of "Toxic" under CEPA

3.1 CEPA 11(a): Environment

The most sensitive aquatic species of those examined or those for which estimates have been made was bacteria in the Microtox assay, with an IC₅₀ value of 0.06 mg/L. There are no data on the occurrence of 3,3'-dichlorobenzidine in Canada with which to compare this value; however, this value is about 1.7x10¹¹ times greater than the concentration predicted in water using worst-case assumptions regarding release in southern Ontario (3.44x10^-7 ng/L).

Therefore, on the basis of the limited available data, 3,3'-dichlorobenzidine is not considered to be "toxic" as defined under paragraph 11(a) of CEPA.

3.2 CEPA 11(b): Environment on Which Human Life Depends

Due to its relatively low volatility, very short residence time and low concentrations in the atmosphere, 3,3'-dichlorobenzidine is not expected to contribute to the greenhouse effect, the depletion of the ozone layer or the formation of ground-level ozone.

Therefore, on the basis of available data, 3,3'-dichlorobenzidine is not considered to be "toxic" as defined under paragraph 11(b) of CEPA.

3.3 CEPA 11(c): Human Life or Health

Population Exposure

Based on the predicted levels of 3,3'-dichlorobenzidine in air, water and soil, as well as the estimated intakes by the population of Canada (EHD, 1992), the estimated daily intake of 3,3'-dichlorobenzidine by various age groups of the population can be calculated. For example, the total intake of 3,3'-dichlorobenzidine by adults¹ (≥ 20 years of age) was predicted to be approximately 7.4 x 10^-9 ng/kg b.w./day. For infants up to 6 months of age², the group with the greatest predicted exposure on a body-weight basis, the total intake of 3,3'-dichlorobenzidine estimated on the basis of predicted concentrations in environmental media was approximately 3.6 x 10^-8 ng/kg b.w./day.

Effects

Epidemiological investigations concerning the carcinogenicity of 3,3'-dichlorobenzidine are restricted to three limited studies, in which the health of occupationally exposed individuals was examined (MacIntyre, 1975; Gadian, 1975; Gerarde and Gerarde, 1974). Although no evidence of a relationship between occupational exposure to 3,3'-dichlorobenzidine and an increased incidence of tumours or death due to cancer was reported in these investigations, owing to the limited power of these studies to detect an effect due to the small sizes of the populations examined following short periods of exposure (i.e., less than 16 years) and methodological limitations such as lack of appropriate control groups, the available information is considered inadequate to assess the carcinogenicity of 3,3'-dichlorobenzidine in humans.

3,3'-Dichlorobenzidine has been shown to be carcinogenic in rats, mice, dogs and possibly hamsters (Stula et al., 1975; Osanai, 1976; Stula et al., 1978; Pliss, 1959; 1963; Sellakumar et al., 1969). It should be noted, however, that all of these studies were limited, due to small group sizes, single dose levels, relatively short periods of exposure and/or, in some cases, inadequate histopathological analysis and reporting of data.

In view of the sufficient evidence for the carcinogenicity of 3,3'-dichlorobenzidine in a number of animal species, this substance has been classified in Group II ("Probably Carcinogenic to Humans") of the classification scheme developed for the determination of "toxic" under paragraph 11(c) of CEPA (EHD, 1992). Confidence in the classification of 3,3'-dichlorobenzidine as a probable human carcinogen is strengthened by substantial evidence for the genotoxicity of 3,3'-dichlorobenzidine in bacterial and mammalian cells, both in vitro and in vivo. The genotoxic effects of 3,3'-dichlorobenzidine are believed to be dependent upon the formation of highly reactive N-oxygenated intermediates that arise following the (hepatic) cytochrome P450-mediated oxidation of 3,3'-dichlorobenzidine (Iba, 1990; lba and Thomas, 1988).

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) under the Act. The carcinogenic potency (TD_0.05) of 3,3'-dichlorobenzidine was derived based on the increased incidence of mammary tumours ("fibroadenomas" and adenocarcinomas (combined) in males and females), granulocytic leukemias (males) and zymbal gland carcinomas (males) in ChR-CD rats administered 3,3'-dichlorobenzidine in the diet in the study conducted by Stula et al. (1975). This study was considered most appropriate for quantitative assessment, owing to the size (n = 50) of the study groups, which were relatively large compared to that in other available investigations, and to the relative adequacy of documentation of the protocol and results. It should be noted, however, that only one dose level was administered in this study, and that the period of administration was less than 2 years (up to 488 days).

Based on the study conducted in rats by Stula et al. (1975), TD_0.05s calculated based on linear interpolation, incorporating a body weight:surface area correction (owing to the lack of identification of the active metabolite(s), and correcting for less than 2 years exposure, range from 0.74 to 1.4 mg/kg b.w./day. Calculated exposure/carcinogenic potency indices for the age group with greatest exposure on a body-weight basis estimated based on predicted concentrations in environmental media range from 2.6 x 10^-14 to 4.9 x 10^-14 (3.6 x 10^-8 ng/kg b.w./day divided by 0.74 to 1.4 mg/kg b.w./day). The priority for further action (i.e. analysis of options to reduce exposure) is, therefore, considered to be very low.

3,3'-Dichlorobenzidine has been classified as being "Probably Carcinogenic to Humans" and is therefore considered to be "toxic" under paragraph 11(c) of CEPA.

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.

3.4 Conclusion

Based on the available data, 3,3'-dichlorobenzidine is not considered to be "toxic" as defined under paragraphs 11(a) or 11(b) of CEPA. 3,3'-Dichlorobenzidine is considered to be "toxic" as defined under paragraph 11(c) of CEPA.

1  Assumed to weigh 70 kg, breathe 23 m3 air, drink 1.5 L of water and consume 20 mg soil per day.

2  Assumed to weigh 7 kg, breathe 2 m3 air, drink 750 mL of infant formula (water) and consume 35 mg soil per day.