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1351. Metabolism of trifluralin
AGRICULTURAL CHEMICALS
579
Single oral doses of I labelled with carbon-14 (t4C) were given to rats. At the lowest dose levels (1-10 mg/rat), ~4C was eliminated almost quantitatively in the urine and faeces within 2 days, but at the highest dose level (100 mg/rat) absorption and excretion was slower and even after 6 days less than 80 % of the 14C had been excreted. At n9 dose level was any t4C detected in the expired air. Absorption of I was rapid since 14C was found in all the tissues and organs examined, reaching a maximum after about 6-8 hr and then declining rapidly after small doses but persisting for a longer period after large doses. Most of the ~4C in both urine and tissues was present as unchanged I, but minute amounts (0.25 % of the dose) of an unidentified metabolite were found in the urine and tissues, particularly in the liver. The intracellular distribution of the ~4C was also determined and in six organs examined the majority was found.in the cell sap, substantial amounts in the nuclei and small amounts in the mitochondria and microsomes. The pattern of intraceUular distribution was unaffected by the dose level used, indicating that the slower rate of elimination of large doses is not due to greater incorporation of I into cellular components, but rather to slower absorption. 1351. Metabolism of trifluralin Emmerson, J. L. & Anderson, R. C. (1966). Metabolism of trifluralin in the rat and dog. Toxic. appl. Pharmac. 9, 84. Trifluralin (2,6-diuitro-N,N-di-n-propyl-~,~,cc-trifluoro-p-toluidine; I) is a selective herbicide. In order to assess the possible environmental hazard of I and to supplement animal toxicity studies now in progress, its metabolic fate has been investigated in the rat and dog. An oral dose of I, labelled with carbon-14 (14C) in the CF 3 group, was rapidly excreted in the rat, 80 % o f the 14C appearing in the faeces and the remainder in the urine. The high faecal excretion was due mainly to poor absorption although some was shown to be derived from biliary excretion following absorption. Although the faeces contained some unchanged I most of the excreted product was identified as an amino derivative of I formed by the reduction of one nitro group. This was probably produced by microbial reduction of I in the gut. Other experiments carried out with I labelled with ~4C in one of the N-propyl groups showed that I was extensively dealkylated following absorption. Thus nearly 20 ~o of the 14C from an oral dose was recovered in the respiratory carbon dioxide and three urinary metabolites identified had one or both propyl groups missing. In two of these one nitro group was reduced. At least seven other urinary metabolites were detected but so far they have not been identified. The metabolic fate of I was found to be similar in the dog, two of the main pathways of metabolism being N-dealkylation and nitro reduction. Since I is rather poorly absorbed from the gut and is rapidly excreted, only trace amounts are likely to be retained in body tissues. 1352. 2,6-Dichlorobenzonitrile: Metabolism and metabolic effects Wit, J. G. & van Genderen, H. (1966). Metabolism of the herbicide 2,6-dichlorobenzonitrile in rabbits and rats. Biochem. J. 101, 698. Wit, J. G. & van Genderen, H. (1966). The monophenolic metabolites of the herbicide 2,6dichlorobenzonitrile in animals as uncouplers of oxidative phosphorylation. Biochem. J. 101, 707. 2,6-Dichlorobenzonitrile (I) has relatively low toxicity and is a powerful herbicide and a potential anti-sprouting agent for potatoes. But somewhat surprisingly, rabbits are much more sensitive than rats to its acute effects and large oral doses can cause liver injury resulting in death. To determine whether this species difference in toxicity is due to differences in metabolism, the metabolic fate o f I has been studied in rabbits and rats (first paper, cited above). The
579
Single oral doses of I labelled with carbon-14 (t4C) were given to rats. At the lowest dose levels (1-10 mg/rat), ~4C was eliminated almost quantitatively in the urine and faeces within 2 days, but at the highest dose level (100 mg/rat) absorption and excretion was slower and even after 6 days less than 80 % of the 14C had been excreted. At n9 dose level was any t4C detected in the expired air. Absorption of I was rapid since 14C was found in all the tissues and organs examined, reaching a maximum after about 6-8 hr and then declining rapidly after small doses but persisting for a longer period after large doses. Most of the ~4C in both urine and tissues was present as unchanged I, but minute amounts (0.25 % of the dose) of an unidentified metabolite were found in the urine and tissues, particularly in the liver. The intracellular distribution of the ~4C was also determined and in six organs examined the majority was found.in the cell sap, substantial amounts in the nuclei and small amounts in the mitochondria and microsomes. The pattern of intraceUular distribution was unaffected by the dose level used, indicating that the slower rate of elimination of large doses is not due to greater incorporation of I into cellular components, but rather to slower absorption. 1351. Metabolism of trifluralin Emmerson, J. L. & Anderson, R. C. (1966). Metabolism of trifluralin in the rat and dog. Toxic. appl. Pharmac. 9, 84. Trifluralin (2,6-diuitro-N,N-di-n-propyl-~,~,cc-trifluoro-p-toluidine; I) is a selective herbicide. In order to assess the possible environmental hazard of I and to supplement animal toxicity studies now in progress, its metabolic fate has been investigated in the rat and dog. An oral dose of I, labelled with carbon-14 (14C) in the CF 3 group, was rapidly excreted in the rat, 80 % o f the 14C appearing in the faeces and the remainder in the urine. The high faecal excretion was due mainly to poor absorption although some was shown to be derived from biliary excretion following absorption. Although the faeces contained some unchanged I most of the excreted product was identified as an amino derivative of I formed by the reduction of one nitro group. This was probably produced by microbial reduction of I in the gut. Other experiments carried out with I labelled with ~4C in one of the N-propyl groups showed that I was extensively dealkylated following absorption. Thus nearly 20 ~o of the 14C from an oral dose was recovered in the respiratory carbon dioxide and three urinary metabolites identified had one or both propyl groups missing. In two of these one nitro group was reduced. At least seven other urinary metabolites were detected but so far they have not been identified. The metabolic fate of I was found to be similar in the dog, two of the main pathways of metabolism being N-dealkylation and nitro reduction. Since I is rather poorly absorbed from the gut and is rapidly excreted, only trace amounts are likely to be retained in body tissues. 1352. 2,6-Dichlorobenzonitrile: Metabolism and metabolic effects Wit, J. G. & van Genderen, H. (1966). Metabolism of the herbicide 2,6-dichlorobenzonitrile in rabbits and rats. Biochem. J. 101, 698. Wit, J. G. & van Genderen, H. (1966). The monophenolic metabolites of the herbicide 2,6dichlorobenzonitrile in animals as uncouplers of oxidative phosphorylation. Biochem. J. 101, 707. 2,6-Dichlorobenzonitrile (I) has relatively low toxicity and is a powerful herbicide and a potential anti-sprouting agent for potatoes. But somewhat surprisingly, rabbits are much more sensitive than rats to its acute effects and large oral doses can cause liver injury resulting in death. To determine whether this species difference in toxicity is due to differences in metabolism, the metabolic fate o f I has been studied in rabbits and rats (first paper, cited above). The