Comparative metabolism of 2,4-dichlorophenoxyacetic acid (2,4-D) in rat and dog.

1. There is a significant species difference in the toxicity of 2,4-dichlorophenoxyacetic acid (2,4-D). The oral no overall adverse effect level (NOAEL) for chronic toxicity of 2,4-D in rat is 5 mg kg(-1) day(-1) and in dog is 1 mg kg(-1) day(-1). The maximum tolerated dose (MTD) in rat is 150 and 75 kg(-1) day(-1) for male and females, respectively. The MTD in dog is 7.5 mg kg(-1) day(-1) for males and females. 2. In an attempt to explain the increased sensitivity to 2,4-D in dog, male and female rats and dogs were orally dosed with either 5 or 50 mg kg(-1) 14C-2,4-D. The rates and routes of excretion were investigated along with plasma toxicokinetics and biotransformation of the compound. 3. Elimination of the radioactive dose of 2,4-D from rat plasma was significantly faster than in dog. The approximate t(1/2) were 1.3-3.4 h for rat and 99-134 h for dog following a 5 or 50 mg kg(-1) dose, respectively. This led to large differences in the calculated AUC(0-infinity) 21-57 microg eq. h g(-1) for rat and 4889-5298 microg eq. h g(-1) for dog at 5 mg kg(-1), and 122-2358 microg eq. h g(-1) for rat and 34,110-44,296 microg eq. h g(-1) for dog at 50 mg kg(-1)). 4. In rat, the major route of excretion was in the urine. Excretion was essentially complete after 24 h for the low dose and after 48 h for the high dose. For dog, elimination was incomplete over the sampling period with only about 50% of the dose recovered. Urine was the principal route of excretion at the low dose, but about equal amounts were excreted in urine and faeces at the high dose over 120 h. 5. In rat, 2,4-D was unmetabolized and excreted in urine as the parent compound. In dog, the dose was excreted mainly following metabolism. 2,4-D in dog was conjugated forming the taurine, serine, glycine, glutamic acid, cysteine, sulphate and glucuronide conjugates, plus an unidentified metabolite, which were excreted in urine. Plasma, however, only contained unmetabolized 2,4-D. 6. The results show that the body burden of 2,4-D in dog is significantly higher than in rat for an equivalent dose, which is consistent with the increased sensitivity of dog to 2,4-D toxicity.

Metabolism of methyl-(E)-2-[2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate (azoxystrobin) in rat.

1. The metabolic fate of [(14)C]-methyl-(E)-2-[2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate (azoxystrobin) was determined in the male and female rat following a single oral dose of 1 and 100 mg x kg(-1) and in surgically prepared, bile duct-cannulated rats following a single oral dose of 100 mg x kg(-1). 2. Azoxystrobin was extensively metabolized with at least 15 metabolites. There was a sex difference, with females producing more metabolites than males. 3. The two principal metabolic pathways were hydrolysis of the methoxyacid followed by glucuronic acid conjugation and glutathione conjugation of the cyanophenyl ring followed by further metabolism leading to the mercapturic acid. There were also several other minor pathways.

Absorption, metabolism and excretion of 4-chloro-2-methylphenoxyacetic acid (MCPA) in rat and dog.

1. The oral no overall adverse effect level (NOAEL) for chronic toxicity of 4-chloro-2-methylphenoxyacetic acid (MCPA) in rat is approximately 1.3 mg kg(-1) and in dog is 0.2 mg kg(-1). In an attempt to explain the difference in toxicology between these species, rats and dogs were orally dosed with (14C)-MCPA at 5 or 100 mgkg(-1) and plasma toxicokinetics, rates and routes of excretion and biotransformation were investigated. 2. Elimination of radioactivity in rat plasma was biphasic and in dog was monophasic. Rat eliminated radioactivity from plasma significantly faster than dog (approximate values biased on total radioactivity: 5 mg kg(-1) rat: t 1/2 dist 3.5 h, t 1/2 elim 17.2-36.2 h, AUC(0-infinity) 230 microg equiv hg(-1); 5 mg kg(-1) dog: t 1/2 47h, AUC(0-infinity) 2,500 microg equiv h g(-1); 100 mg kg(-1) rat: t 1/2 dist 10h, t 1/2 elim 10.27-25.4h, AUC(0-infinity) 5,400 microg equiv hg(-1); l00 mg kg(-1) dog: t 1/2 h, AUC(0-infinity) 20,500 microg eqiv h g(-1). 3. For both species, the principal route of excretion was in urine but renal elimination was notably more rapid and more extensive in rat. 4. In both rat and dog, excretion of radioactivity was mainly as MCPA and its hydroxylated metabolite hydroxymethylphenoxyacetic acid (HMCPA). In rat, both were mainly excreted as the free acids although a small proportion was conjugated. In dog, the proportion of HMCPA was increased and the majority of both species was excreted as glycine or taurine conjugates. 5. These data, along with previously published accounts, indicate that renal elimination of MCPA in dog is substantially slower than in rat resulting in disproportionate elevation of AUC (based on total radioactivity) in dog compared with rat.

Metabolism of 2,3,5,6-tetrachloronitrobenzene (tecnazene) in rat.

1. The metabolic fate of [U-14C]-2,3,5,6-tetrachloronitrobenzene (tecnazene) has been determined in the male and female rat following a single dose of 1 mg/kg and in surgically prepared, bile-duct-cannulated rats following a single oral dose of 135 mg/kg. 2. Radioactivity in the female rat was excreted mainly in urine (82%). The male rat, however, excreted approximately equal amounts of radioactivity in urine and faeces (the latter via bile). 3. The principal metabolic pathway was conjugation with glutathione (GSH) and concomitant nitro-displacement. The GSH-conjugate and related metabolites were excreted in the bile and ultimately in the urine as the mercapturic acid conjugate. The cysteine conjugate underwent beta-lyase-mediated metabolism to yield a thiol that underwent subsequent methylation to the thioanisole followed by S-oxidation. 4. A novel tetrachloromethyldisulphide metabolite was also formed.