The comparative metabolism of 2,6-dichlorothiobenzamide (Prefix) and 2,6-dichlorobenzonitrile in the dog and rat

Abstract

1. A single oral dose of either [(14)C]Prefix or 2,6-dichlorobenzo[(14)C]nitrile to rats is almost entirely eliminated in 4 days: 84.8-100.5% of (14)C from [(14)C]Prefix is excreted, 67.3-79.7% in the urine, and 85.8-97.2% of (14)C from 2,6-dichlorobenzo-[(14)C]nitrile is excreted, 72.3-80.7% in the urine. Only 0.37+/-0.03% of the dose of [(14)C]Prefix and 0.25+/-0.03% of the dose of 2,6-dichlorobenzo[(14)C]nitrile are present in the carcass plus viscera after removal of the gut. Rats do not show sex differences in the pattern of elimination of the respective metabolites of the two herbicides. The rates of elimination of (14)C from the two compounds in the 24hr. and 48hr. urines are not significantly different (P >0.05) from one another. 2. After oral administration to dogs, 85.9-106.1% of (14)C from [(14)C]Prefix is excreted, 66.6-80.9% in the urine, and 86.8-92.5% of (14)C from 2,6-dichlorobenzo[(14)C]nitrile is excreted, 60.0-70.1% in the urine. Dogs do not show sex differences in the pattern of eliminating the metabolites of either Prefix or 2,6-dichlorobenzonitrile. 3. Dogs and rats do not show species differences in the patterns of elimination of the two herbicides. 4. Prefix and 2,6-dichlorobenzonitrile are completely metabolized; unchanged Prefix and 2,6-dichlorobenzonitrile are absent from the urine and faeces, and from the carcasses when elimination is complete. In the hydrolysed urine of rats dosed with either [(14)C]Prefix or 2,6-dichlorobenzo[(14)C]nitrile, 2,6-dichloro-3-hydroxybenzonitrile accounts for approx. 42% of the (14)C, a further 10-11% is accounted for by 2,6-dichlorobenzamide, 2,6-dichlorobenzoic acid, 2,6-dichloro-3- and -4-hydroxybenzoic acid and 2,6-dichloro-4-hydroxybenzonitrile collectively, and 25-30% by six polar constituents, of which two are sulphur-containing amino acids. 5. In the unhydrolysed urines of rats dosed with either [(14)C]Prefix or 2,6-dichlorobenzo[(14)C]nitrile, there are present free 2,6-dichloro-3- and -4-hydroxybenzonitrile, their glucuronide conjugates, ester glucuronides of the principal aromatic acids that are present in the hydrolysed urines, and two sulphur-containing metabolites analogous to mercapturic acids or premercapturic acids. 6. Prefix is thus extensively transformed into 2,6-dichlorobenzonitrile: R.CS.NH(2)-->R.CN+H(2)S, where R=C(6)H(3)Cl(2). However, the competitive reaction: R.CS.NH(2)+H(2)O-->R.CO.NH(2)+H(2)S takes place to a very limited extent.

Metabolism of the herbicide 2,6-dichlorobenzonitrile in rabbits and rats

“…In general, our results agree qualitatively with those published by Griffiths, Moss, Rose & Hathway (1966). In their study the presence of two additional metabolites of 2,6-dichlorobenzonitrile, containing sulphur amino acid residues, was demonstrated.…”

Toxicology of the herbicide dichlobenil (2,6-dichlorobenzonitrile) and its main metabolites

“…In the urine of both rats and rabbits, conjugates of 3-and 4-hydroxy-2,6-dichlorobenzonitriles could be identified as the major metabolites. Griffiths et al (.1966) found that after administration of a small dose to rats, 41 "7 ~o and 4.0% of the radioactivity excreted in the urine was in the form of the 3-hydroxy and 4-hydroxy derivatives respectively (of a total recovery of 81%). Wit & van Genderen (1966a), using higher doses, obtained a recovery in rats of 22°,o of the dose in the form of the 3-hydroxy and 9 , %0 as the 4-hydroxy derivative.…”

“…The metabolism of dichlobenil was studied in dogs, rats and rabbits with ~4C-labelled preparations (Griffiths, Moss, Rose & Hathway, 1966;Wit & van Genderen, 1966a). The radioactivity was almost entirely eliminated within 4 days, mainly as more polar metabolites in the urine.…”

Metabolism of 2,6-dichlorobenzamide in rats and mice

“…as methyl derivatives (mass spectra not shown). These are assumed to be 3and 4-hydroxy-DCB formed by rearrangement of the 3,4-epoxide Structures assigned to the metabolites isolated from urine and bile from rats dosed with as proposed by Griffiths et al (1966) in the metabolism of 2,6-dichlorobenzonitrile.…”