Environmental Project, 943 – Evaluation of health hazards by exposure to BAM (2,6-Dichlorobenzamide) and risk characterisation of drinking water exposure

Evaluation of health hazards by exposure to BAM (2,6-Dichlorobenzamide) and risk characterisation of drinking water exposure

7 Evaluation

The toxicity of BAM has not been fully investigated. Test results from studies performed over 30 years ago have been available. The tests do not comply with current internationally accepted guidelines, and they have not been performed in accordance with current requirements to good laboratory practice. Despite the lacks in study design and performance, the studies, in general, appear to be well performed, and for lack of any better studies they can be used for the toxicological assessment of BAM.

The skin and eye irritation potential and the skin sensitising properties of BAM have not been studied.

In more recent studies with mice and rats, the nasal cavity with the olfactory epithelia and especially the Bowman's glands has been demonstrated as a target organ for BAM toxicity. This has been supported by autoradiographic studies where retention of radioactivity was located to the Bowman's glands. Mild reversible effects, i.e. reduced PAS-staining of Bowman's glands, were observed after a single intraperitoneal dose of 25 or 50 mg/kg bw to mice. This effect was especially evident in the dorsal meatus, whereas PAS-positive Bowman's glands were present in the lateral aspects of the nasal cavity. Twenty days after the administration, the PAS-staining intensity appeared normalised. PAS (periodic acid-Schiff) is a sensitive staining method that stains glycogen (and other periodate reactive carbohydrates), mucin, mucoprotein, and glycoprotein. The reduced staining in the Bowman's glands indicates a reduced presence of stainable material (e.g. glycoproteins) in these cells. This again indicates a disturbance of the cellular function.

When the dose was raised to 100 mg/kg bw a clear pathological effect was observed in the olfactory epithelia (undulating and necrotic) and the Bowman's glands (necrotic).

It is not known how repeated exposure to BAM will affect the nasal mucosa, as this has not been investigated in the repeated dose studies. One may suspect a potential for increased retention of BAM (metabolites) at low dose levels with resultant destruction of the Bowman's glands and subsequent the olfactory epithelia. This may reduce the function of the nasal mucosa (e.g. reduced ability to smell and reduced mucosal immune defence). Another unsolved question is whether the findings in rodents are predictive for humans. The pathogenesis apparently involves a local cytochrome P450-dependent activation of BAM that may not be expressed that clearly in humans. Provided that the decreased PAS-staining of rodent Bowman's glands does not affect the function of the nasal cavity, an acute NOAEL of 50 mg/kg may be assigned.

The carcinogenic potential of BAM has not been fully investigated. As BAM was not shown to be mutagenic, a possible carcinogenic effect may be considered mediated through a non-genotoxic mechanism secondary to organ toxicity. A threshold for such an effect can be anticipated.

The toxicological profile of BAM does show some resemblance to dichlobenil. Despite the generally poor quality of the studies performed with BAM and dichlobenil the results indicate some common toxicological features. The liver appears to be the target organ for both substances. The substances may promote the development of liver tumours by a non-genotoxic mechanism secondary to the organ toxicity. They both have an affinity to the nasal mucosa. However, dichlobenil is clearly more acute toxic to the olfactory epithelium and Bowman's gland than BAM. They do not have common metabolites in vivo but probably share metabolising enzymes. The NOAEL was 1.25 mg/kg/day in a two-year dog feeding study with dichlobenil. The LOAEL was 8.75 mg/kg/day based on liver toxicity. These values are comparable to those in another 2-year dog feeding with BAM. In the BAM study a NOAEL of 4.5 mg/kg/day was determined, and the LOAEL of 12.5 mg/kg/day was based on decreased body weight gain in both males and females and increased relative liver weight in males.

The NOAEL (4.5 mg/kg bw/day) from the 2-year dog feeding with BAM may be preferred as the end point of concern identified for chronic exposure instead of the NOAEL of 2.5 mg/kg bw/day from the 13 week dog study, because the NOAEL of the 2 year study was lower than the LOAEL (7.5 mg/kg bw/day) in the 13 week dog study. However, the NOAELs lie within a close range (Table 5). The critical effect of BAM is not very clearly expressed as systemic toxicity, and the LOAELs are often based on reduced weight gain.

From the toxicological database an overall NOAEL range of 2.5 – 6 mg/kg bw/day is selected for further risk characterisation.