Absorption, Distribution and Excretion
Sprague-Dawley Crl:CD/BR rats of both sexes were dosed with either 10 or 1,000 mg/kg of [(14)C] ... /bifenazate/ ... (radiochemical purity: >98%, specific activity: 34.4 mCi/mmol, label on the aromatic ring, /bifenazate/... (unlabeled ... purity: 99.6%) by oral gavage. In the Distribution, Metabolism and Excretion study, 5 animals/sex/group were dosed and urine and feces were collected for 7 days. In the Biliary study, 3 animals/sex/group with cannulated bile ducts were dosed and urine, feces and bile were collected for 72 hrs. The Pilot Pharmacokinetic and Pharmacokinetic studies were performed in which 3 animals/sex/group and 5 animals/sex/group, respectively, were dosed. In the pilot study, urine and feces were collected for 4 days and blood samples were collected via a jugular cannula for 72 hrs. In the main study, urine and blood were collected for 4 days from the animals in the 10 mg/kg treatment group. In the 1,000 mg/kg group, urine, feces and blood were collected for 7 days. In the Tissue Distribution study, 9 animals/sex/group were dosed. In the 10 mg/kg group, 3 animals/sex/time point were serially euthanized at 6, 24 and 48 hrs after dosing. In the 1,000 mg/kg group, 3 animals/sex/time point were euthanized at 18, 42 and 72 hrs post-dose. Urine and feces were collected at designated intervals. Tissue samples from Distribution, Metabolism and Excretion study and the Tissue Distribution study were processed for the presence of radiolabel. Radiolabeled materials were isolated from the urine and feces derived from the Distribution, Metabolism and Excretion and the Biliary studies and structurally analyzed for a metabolic profile. The predominant route of excretion for both doses was via the feces. For the 10 mg/kg group, 66% of the administered dose (AD) was recovered in the feces with 75-82% of that total excreted in the first 24 hrs. Radiolabel recovered in the urine and cage wash constituted 27-29% of the AD after 7 days. For the 1,000 mg/kg treatment group, the % of AD recovered in the feces up to 7 days post-dose was 82% with 46-57% of that total recovered in the first 24 hrs. The % of AD isolated in the urine and cage wash was 10-15%. The Biliary study demonstrated that the bile was a significant pathway for excretion by the 10 mg/kg treatment group with 69-74% of the administered dose recovered in the bile up to 72 hrs after dosing. In contrast, for the high dose group, 21-26% of the dose was isolated in the bile by 72 hrs. Recovery in the feces of the 10 mg/kg group was limited to 7-8% of the AD as compared to 56-64% of the AD for the 1,000 mg/kg group. A significant fraction of the AD for the high dose group was not being absorbed. The following pharmacokinetic parameters were derived: tmax, 5 and 6 hrs and 18- 24 hrs for males and females of the 10 mg/kg and 1,000 mg/kg groups, respectively, Cmax, 6.4 and 5.6 ug equiv./g and 119 and 71 ug equiv./g for the males and females in the 10 mg/kg and 1,000 mg/kg groups, respectively, and t1/2, 11.5 and 13.3 hrs and 12 and 15.6 hrs for males and females in the low and high dose groups, respectively. In the Tissue Distribution study, among the 10 mg/kg animals, maximal residue levels were noted at 6 hrs with none of the radiolabel being sequestered in any of the tissues. In the 1,000 mg/kg group, maximal residue levels were noted in a majority of the tissues at 18 hrs post-dose for the males and 42 hrs post-dose for the females. For some of the organs, appreciable levels of radiolabel were still evident at 7 days (e.g., spleen, red blood cell, liver, and kidney). Analysis of the radiolabeled moieties recovered in the feces revealed a number of modifications of the parent cmpd. Hydrazine oxidation, demethylation, ring hydroxylation, separation into biphenyl and hydrazinecarboxylic acid moieties and conjugation with glucuronic acid or sulfate. For the 10 mg/kg group, identified moieties extracted from the feces constituted 39% of the AD. The predominant compounds were ... /bifenazate/ glucuronide (6.3-8.9% of AD), ... /bifenazate/ (4.8-7.2% of AD) and ... biphenyl, 4-hydroxy (5.5-7.1% of AD). In contrast, for the 1,000 mg/kg group, the parent cmpd which was recovered in the feces constituted 48-61% of the AD. /Bifenazate/... glucuronide constituted 4.7-5.6% of the AD ... Overall, the test material was well absorbed at the low dose, metabolized and conjugated before being excreted in the bile. At the high dose level, a much lower % of the dose was absorbed.

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Metabolism / Metabolites
Sprague-Dawley Crl:CD/BR rats of both sexes were dosed with either 10 or 1,000 mg/kg of [(14)C] ... /bifenazate/ ( ... radiochemical purity: >98%, specific activity: 34.4 mCi/mmol, label on the aromatic ring, ... /bifenazate/ (unlabeled ... purity: 99.6%) by oral gavage. ... Analysis of the radiolabeled moieties recovered in the feces revealed a number of modifications of the parent cmpd. Hydrazine oxidation, demethylation, ring hydroxylation, separation into biphenyl and hydrazinecarboxylic acid moieties and conjugation with glucuronic acid or sulfate. For the 10 mg/kg group, identified moieties extracted from the feces constituted 39% of the administered dose (AD). The predominant compounds were ... /bifenazate/ glucuronide (6.3-8.9% of AD), ... /bifenazate/ (4.8-7.2% of AD) and ... biphenyl, 4-hydroxy (5.5-7.1% of AD). In contrast, for the 1,000 mg/kg group, the parent cmpd which was recovered in the feces constituted 48-61% of the AD. ... /Bifenazate/ glucuronide constituted 4.7-5.6% of the AD. The primary moieties recovered in the urine were conjugates of ... p, p-biphenol or sulfates of ... /p, p'-biphenol/ and ... /biohenyl, 4-hydroxy/. The total of these cmpds constituted 19-21% of the administered dose for the 10 mg/kg group and 6-7% of the administered dose for the 1,000 mg/kg group. Major metabolites identified in the bile were ... /biphenyl, 4-hydroxy/ (17-20% of AD in the 10 mg/kg group and 2.1-2.5% of the AD in the 1,000 mg/kg group), ... biphenyl, 4-hydroxy, 4-methoxy (17-19% of the AD in the 10 mg/kg and 2.8% of the AD in the 1,000 mg/kg group) and ... /bifenazate/ glucuronide (9-12% of the AD in the 10 mg/kg and 9-13% of the AD in the 1,000 mg/kg group).

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Biological Half-Life
Sprague-Dawley Crl:CD/BR rats of both sexes were dosed with either 10 or 1,000 mg/kg of [(14)C] ... /bifenazate/ ... (radiochemical purity: >98%, specific activity: 34.4 mCi/mmol, label on the aromatic ring, /bifenazate/ ... (unlabeled ... purity: 99.6%) by oral gavage. ... The following pharmacokinetic parameters were derived: tmax, 5 and 6 hrs and 18-24 hrs for males and females of the 10 mg/kg and 1,000 mg/kg groups, respectively, Cmax, 6.4 and 5.6 ug equiv./g and 119 and 71 ug equiv./g for the males and females in the 10 mg/kg and 1,000 mg/kg groups, respectively, and t1/2, 11.5 and 13.3 hrs and 12 and 15.6 hrs for males and females in the low and high dose groups, respectively.

Toxicity Summary
IDENTIFICATION AND USE: Bifenazate is a solid. It is used as acaricide/miticide (insecticide). HUMAN EXPOSURE AND TOXICITY: There are no data available. ANIMAL STUDIES: Bifenazate causes slight eye and skin irritant to rabbits. In dogs it caused myeloid hyperplasia and a dose-related decrease in numbers of erythrocytes and increased numbers of platelets and level of serum bilirubin at concentrations of 400 and 1000 ppm. The only developmental effects noted in rats were a slightly delayed balanopreputial separation for the males treated with concentrations of 80 and 200 ppm, and vaginal perforation for the females treated with 200 ppm. It was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, and TA1537 and E. coli strain WP2 uvrA. There was no treatment-related increase in the percentage of cells with chromosomal aberrations in Chinese Hamster Ovary cells. Treatment with bifenazate did not result in an increase in the number of micronuclei in mice. ECOTOXICITY STUDIES: Bifenazate is categorized as slightly toxic to avian species on an acute oral basis (LD50=1032 mg/kg) and as moderately toxic to avian species on a subacute dietary basis (LC50=656-1862 ppm). Bifenazate is categorized as practically nontoxic to small mammals on an acute oral basis (LD50>5000 mg/kg). The available data indicate that bifenazate is categorized as highly toxic to freshwater fish (LC50=0.58-76 ppm) and aquatic invertebrates (LC50/EC50=0.50 ppm) on an acute basis.

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Interactions
... The ability of well-known organophosphates and carbamates to inhibit the activation of bifenazate and thus compromise its acaricidal potential was tested. Esterase activity determined in vivo after pre-exposure of mites with organophosphates and carbamates revealed-depending on the compound-varying esterase inhibition nicely correlated with the ability of the individual compound to antagonise bifenazate action on mites. The findings illustrate that organophosphates and carbamates interfere with bifenazate efficacy, most probably by inhibiting carboxylesterases responsible for the activation of the pro-drug. As a result of the strong antagonism, mixtures of bifenazate with carbamates or organophosphates should not be used under field conditions. Moreover, there exists a real threat in repeatedly applying organophosphates and bifenazate. The present study again illustrates how important mode of action information is for the proper planning of resistance management strategies.

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Non-Human Toxicity Values
LD50 Rat oral >5000 mg/kg
LD50 Rat dermal >5000 mg/kg

[1]. Dekeyser, M.A., McDonald, P.T., and Angle, G.W., Jr. The discovery of bifenazate, a novel carbazate acaricide Chimia 57(11), 702-704 (2003).

[2]. A novel action of highly specific acaricide; bifenazate as a synergist for a GABA-gated chloride channel of Tetranychus urticae [Acari: Tetranychidae]. Neurotoxicology. 2012 Jun;33(3):307-13.

Bifenazate is a carboxylic ester obtained by formal condensation of 2-(4-methoxy[1,1'-biphenyl]-3-yl)hydrazinecarboxylic acid with 2-propanol. It has a role as an acaricide. It is functionally related to a carbazic acid. It derives from a hydride of a biphenyl.
Bifenazate has been reported in Ganoderma lucidum with data available.
Bifenazate is a pesticide use for control of mite pests on greenhouse, shadehouse, nursery, field, landscape and interiorscape grown ornamental plants. Bifenazate possesses low acute toxicity by all routes of exposure (Category IV) with no evidence of dermal sensitization potential. It is non-irritating to skin and minimally irritating to eyes. Bifenazate is negative for mutagenic potential in a battery of required mutagenicity studies.

C17H20N2O3

300.3523

300.147

149877-41-8

176879

Light yellow to yellow solid powder

1.2±0.1 g/cm3

122℃

1.578

3.12

2

4

6

22

343

0

VHLKTXFWDRXILV-UHFFFAOYSA-N

InChI=1S/C17H20N2O3/c1-12(2)22-17(20)19-18-15-11-14(9-10-16(15)21-3)13-7-5-4-6-8-13/h4-12,18H,1-3H3,(H,19,20)

propan-2-yl N-(2-methoxy-5-phenylanilino)carbamate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 250 mg/mL (~832.36 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (6.93 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (6.93 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)