The major (and only identified) metabolite of brodifacoum in bile was the glucuronide (attachment to the 4-hydroxy moiety of brodifacoum), which accounted for 39.43 to 77.28% of the total radioactivity in individual bile samples, while brodifacoum represented 0.00 to 24.95% of the total activity. Further characterization appeared to split the glucuronide peak into 2 components, and while the cis:trans ratio of parent material was 70:30, the ratio in the glucuronide was reversed (30:70). One unidentified metabolite (region 10) ranged from 1.59 to 21.7% total radiolabel.
Warfarin-sensitive rats were admin doses of brodifacoum ranging from 0.1 to 0.33 mg/kg. Phenobarbital pretreatment decreased the anticoagulant effect, whereas SKF525A increased it, suggesting that a substantial portion of brodifacoum-induced hypoprothrombinemia is mediated by brodifacoum itself rather than by metabolites.
The relationship between pharmacological response and disposition of a dose of vitamin K1 (10 mg/kg iv) in normal rabbits and in rabbits treated with the coumarin anticoagulant brodifacoum has been studied. After iv admin of vitamin K1, plasma concentrations of the vitamin declined in a tri-exponential fashion. There were no differences between the two groups over the first 24 hr of the experiment. However between 24 hr and the end of the study plasma concentrations of vitamin K1 in the presence of brodifacoum were significantly below those of vehicle treated rabbits. ... Three hours after admin of vitamin K1 the concentrations of the vitamin in whole liver were 46.6 +/- 4.3 ug/g in the presence of brodifacoum, and 32.8 +/- 6.4 ug/g in the absence of brodifacoum; and were significantly greater than normal (1127.7 +/- 44.3 ng/g). Likewise microsomal concentrations of vitamin K1 (4.00 +/- 2.38 ug/mg protein and 2.65 +/- 1.01 ug/ng protein in the presence and absence of brodifacoum, respectively) were significantly ... greater than normal (16.0 +/- 3.5 ng/mg) protein).
IDENTIFICATION: Brodifacoum is a coumarin derived rodenticide. It was first introduced in 1975 to deal with the public health problem of warfarin resistant rodents. Brodifacoum exists as cis and trans isomers that may be separated by chromatography and identified by nuclear magnetic resonance spectroscopy. The commercially available preparation contains variable proportions of cis/trans isomers as 50:50 and 70:30. There is no significant difference in activity between the two isomers. Brodifacoum is an off white powder. It is a weak acid which does not readily form water soluble salts. It does not lose activity after 30 days in direct sunlight. This rodenticide is effective against warfarin resistant rats. It is usually sold as a ready to use bait in pellets, mini-pellets and water proof bait containing 0.005% brodifacoum (loose or in bait packs). Indicated for the control of Norwegian rats, roof rats and house mice in public, industrial and commercial buildings, in residences and outdoor urban areas. The application may be carried out by professional pest control personnel or by the general public. HUMAN EXPOSURE: The target system is the hematological system, with impairment of clotting. The main risks are associated with potentially fatal gastrointestinal and intracerebral hemorrhage. If toxic amounts have been ingested, coagulation will be impaired, with gum bleeding, epistaxis, ecchymosis, hematomata, hematesis, melena and hematuria. Oral exposure is the commonest route of entry. Brodifacoum is readily absorbed in the gastrointestinal tract. The ingestion of a large amount of brodifacoum over a two day period by a 31yr old psychotic woman produced generalized ecchymosis and abortion. A 17 yr old male ingested brodifacoum had flank pain and hematuria followed by epistaxis and gum bleeding. In an adult ingestion of brodifacoum produced bleeding for more than two months.In a longitudinal analysis of alterations in specific coagulation factors in a poisoning case demonstrated a profound decrease in factors II, VII, IX and X. The prognosis is poor in cases with internal bleeding or intracerebral hemorrhage and in patients with previous hematological illnesses or renal insufficiency. Muscular hematoma may result, especially on the elbows, knees and buttocks. Although the liver is the site of metabolism of brodifacoum, no observable clinical effects are apparent except coagulopathy. ANIMAL STUDIES: Brodifacoum and related compounds bind more strongly to a lipophilic site in the liver than does warfarin. In the poisoned rat, hepatic concentrations of the substance are 20 times higher than the serum concentrations. Brodifacoum has a very long plasma half life. Metabolic studies in animals have shown a half life of approximately 24 days, 120 days in the dog and 156 hours in the rat. Brodifacoum is hydroxylated to inactive compounds by mixed function oxidase enzymes in hepatic microsomes. Phenobarbital is known to increase the activity of hepatocellular microsomal enzymes and would increase the anticoagulant's metabolism as it does with warfarin. In the animal, it has been demonstrated that pretreatment with phenobarbital decreases the effect of brodifacoum. This compound acts by inhibiting the vitamin K epoxide reductase in the vitamin K1-epoxide cycle. Impeding the cyclic regeneration of vitamin K1, resulting in hypoprothrombinemia. The superwarfarins produce a diminution of the vitamin K dependent carboxylation of glutamic acid residues in prothrombin factor precursors. The effect is 100 times greater on a molar basis than that of warfarin. With its very long plasma half life, results in a potent anticoagulant effect. Brodifacoum is slightly irritating when applied to the skin or rabbits and to the eye. No effect has been demonstrated with technical brodifacoum in long term carcinogenicity tests. Studies in rats and rabbits have demonstrated no fetotoxic, embryotoxic or teratogenic effects.[
Brodifacoum is absorbed through the gastrointestinal tract. When orally administered to male Sprague-Dawley rats at doses ranging from 0.1 to 0.33 mg/kg , brodifacoum exhibited a remarkably steep dose response curve; 0.1 mg/kg failed to show an effect on the plasma prothrombin level within 24 hr, whereas 0.2 mg/kg reduced the prothrombin complex activity to 7% of normal values and 0.33 mg/kg reduced it to 4% of normal. Concentrations in the liver were rapidly established and remained relatively constant for at least 96 hr.
Six horses gavaged with a commercial brodifacoum at a dosage of 0.125 mg of BDF/kg of body weight. ... Peak plasma concentrations of brodifacoum occurred 2 to 3 hr after oral administration; two horses had detectable levels of brodifacoum at nine days. Pharmacokinetic evaluation indicated that brodifacoum has a half-life of 1.22 +/- 0.22 days, a body clearance of 1073.1 +/- 53.21 L/kg/day, a volume of distribution of 1853.7 +/- 26.41 ng/day/mL and closely approximates a one compartment model in the elimination phase. Maximum plasma brodifacoum concentrations and the highest area under the plasma drug concentration time curve were found in horses with the most severe clinical signs. ...
After single oral administration of brodifacoum (0.2 and 2 mg/kg body weight) to sheep, about 20% and 30%, respectively, was excreted in the feces within 8 days. ... Brodifacoum could not be detected in the omental fat... .
In the first part of a metabolism study brodifacoum, 3-[3-(4'-bromo- [1,1'-biphenyl]-4-yl)-1,2,3,4-tetrahydro-1-naphthalenyl]-4-hydroxy-2H-1-benzopyr an-2-one, radiochemical purity >98%, radiolabeled ((14)C) in the benzene ring of the benzopyran, was administered to 3 previously bile-duct cannulated Crl:CD(SD)BR strain male rats as a single oral administration at a nominal dose level of 10 mg/kg bw, well above the LD50 value of 0.3 mg/kg. The rats had been pre-dosed with vitamin K1 in their drinking water, but showed symptoms of anticoagulant toxicity before sacrifice at 48 hours. Bile, urine and feces were collected at pre-dose, 6, 12, 24, and 48 hr post-dose, and radioactivity was determined in these samples, as well as in the livers and residual carcasses. The metabolite profiles of (14)C-brodifacoum in bile and bile extracts were examined by chromatographic and spectroscopic techniques. Total mean recovery of radioactivity was 102.9 (8.1%). Recovery from feces ... was 36.11 (8.83%); from liver was 14.79 (0.41%); from the residual carcass: 42.85 (5.06%). The mean from bile (all 3 animals) was 6.40 (5.45%), but one rat had poor bile flow, possibly from blockage in the cannula. The two remaining animals had a mean 9.53% of the label in bile.
Compounds of formula I
wherein the substituents are as defined in claim 1, and the agrochemically acceptable salts and all stereoisomers and tautomeric forms of the compounds of formula I can be used as insecticides and can be prepared in a manner known per se.
Molecules having pesticidal utility, and intermediates, compositions, and processes, related thereto
申请人：Dow AgroSciences LLC
公开号：US20180279612A1
公开（公告）日：2018-10-04
This disclosure relates to the field of molecules having pesticidal utility against pests in Phyla Arthropoda, Mollusca, and Nematoda, processes to produce such molecules, intermediates used in such processes, pesticidal compositions containing such molecules, and processes of using such pesticidal compositions against such pests. These pesticidal compositions may be used, for example, as acaricides, insecticides, miticides, molluscicides, and nematicides. This document discloses molecules having the following formula (“Formula One”).
[EN] MOLECULES HAVING PESTICIDAL UTILITY, AND INTERMEDIATES, COMPOSITIONS, AND PROCESSES, RELATED THERETO<br/>[FR] MOLÉCULES PRÉSENTANT UNE UTILITÉ EN TANT QUE PESTICIDE, ET LEURS INTERMÉDIAIRES, COMPOSITIONS ET PROCÉDÉS
申请人：DOW AGROSCIENCES LLC
公开号：WO2017040194A1
公开（公告）日：2017-03-09
This disclosure relates to the field of molecules having pesticidal utility against pests in Phyla Arthropoda, Mollusca, and Nematoda, processes to produce such molecules, intermediates used in such processes, pesticidal compositions containing such molecules, and processes of using such pesticidal compositions aga inst such pests. These pesticidal compositions may be used, for example, as acaricides, insecticides, miticides, molluscicides, and nematicides. This document discloses molecules having the following formula ("Formula One").
