Tissue-binding and toxicity of compounds structurally related to the herbicide dichlobenil in the mouse olfactory mucosa

Abstract

The herbicides dichlobenil (2,6-dichlorobenzonitrile), chlorthiamid (2,6-dichlorothiobenzamide) and their environmental degradation product 2,6-dichlorobenzamide are irreversibly bound and toxic to the olfactory mucosa following single injections in mice (Brandt et al., Toxicology and Applied Pharmacology 1990, 103, 491–501; Brittebo et al., Fundamental and Applied Toxicology 1991, 17, 92–102). In the present study, autoradiography showed an irreversible binding of radioactivity in the olfactory mucosa (preferentially in the Bowman's glands) in C57B1/6 mice treated with the 14C-labelled analogues [ 14C]2,6-difluorobenzonitrile ([ 14C]DFBN) and [ 14C]2,6-difluorobenzamide ([ 14C]DFBA). Therefore the toxicity of DFBN, DFBA and of some structurally related compounds including benzonitrile (BN) and the herbicides bromoxynil (3,5-dibromo-4-hydroxybenzonitrile) and ioxynil (3,5-diiodo-4-hydroxybenzonitrile) in the mouse olfactory mucosa was examined. No histopathological changes in the olfactory mucosa or in the liver were observed following a single ip dose of any of these compounds [0.145 mmol/kg (all compounds); 0.58 mmol/kg (DFBN, DFBA and BN)]. Also in mice treated with the glutathione-depleting agent phorone, none of these compounds induced any histopathological changes in the olfactory mucosa. The covalent binding of [ 14C]DFBN in the olfactory mucosa was 16 times lower than an equimolar toxic dose of [ 14C]dichlobenil, suggesting a low rate of metabolic activation of DFBN in the olfactory mucosa or a low reactivity of the DFBN metabolites formed. The results of this study thus show that single doses of DFBN, DFBA, BN, IX and BX, compounds structurally related to the potent olfactory toxicant dichlobenil, do not elicit acute toxicity in the olfactory mucosa of mice.