Absorption, Distribution and Excretion
Five CRL:CD (SD)IGS BR rats/sex/level were dosed by gavage in 0.75% methylcellulose suspension with single administrations of either low or high doses of flonicamid. Intended dose levels were 2 and 50 mg/kg for both the pilot excretion study and for the pilot pharmacokinetics study. By error, the actual mean administered doses for the pilot excretion study were 0.85 and 21 mg/kg, which was unlikely to have affected results. The pilot excretion study assessed exhaled CO2 as well as urine, cage washings, and feces at intervals of 24 hr or less for 7 days. No measurable CO2 was detected in exhaled air. Urine plus cage wash samples accounted for 89-92% of administered label. About 5-6% of administered label was found in feces. Only 2-3% of label resided in carcasses at day 7. ... Tmax was estimated to be 0.3 to 0.6 hr.
(14)C Flonicamid (radiolabelled = 98.5% pure; unlabelled = 99.7%) was administered by oral gavage to CRL:CD (SD)IGS BR rats at 0 (0.75% methylcellulose/HPLC Grade H2O; 1/sex/dose at 6 and 168 hr termination), 2 mg/kg (3/sex/time point at 0.5, 6, 24 hours and 5/sex at 168 hour termination) and 400 mg/kg (3/sex/time point at 0.5, 6, 24 hours and 5/sex at 168 hour termination) to determine elimination and distribution. At 2 and 400 mg/kg, (14)C Flonicamid radioactivity was rapidly absorbed and excreted. A quantitative recovery was achieved during the 168 hour collection period. Urine contained 90% (including cage wash) of administered radioactivity, the majority of which was obtained within 24 hours of dosing at 2 mg/kg and by 48 hours at 400 mg/kg. Fecal elimination at 2 and 400 mg/kg was 5% of administered dose. In tissues, radioactivity levels increased rapidly with maximum concentrations mirroring those observed in the blood. While radioactivity was observed at all early time points in tissues, by 168 hours the levels had (where detectable) decreased by 50 - 100 fold. By 168 hours the carcasses contained 2% of radioactivity and liver had the highest tissue content (< 0.15%). At 2 mg/kg the greatest concentrations of radioactivity at 0.5 hours post dose for males and females respectively in liver (2.54-2.50 ug eq/g), kidney (2.35-2.67 ug eq/g), adrenals (5.07-6.52 ug eq/g), thyroid (4.02-4.26 ug eq/g) and ovaries (females - 3.77 ug eq/g). At 400 mg/kg males had the greatest concentration of radiolabel at 3 hours post dose in the liver (442 ug eq/g), kidney (311 ug eq/g), adrenals (672 ug eq/g) and thyroid (652 ug eq/g). Females had the greatest radiolabel concentrations at 1 hour post dose for liver (325 ug eq/g), kidney (359 ug eq/g), adrenals (689 ug eq/g) and thyroid (782 ug eq/g).
(14)C Flonicamid (radiolabelled = 98.5% pure; unlabelled = 99.7%) was administered by oral gavage to CRL:CD (SD)IGS BR rats at 0 (0.75% methylcellulose/HPLC Grade H2O; 1/sex/dose), 2 and 400 mg/kg (4/sex/dose), followed by a 48 hour termination time. At 2 and 400 mg/kg, (14)C Flonicamid radioactivity was rapidly absorbed and excreted. A quantitative recovery was achieved during the 48 hour collection period. Urine contained 85% (including cage wash) of administered radioactivity at 2 mg/kg and 80% at 400 mg/kg, the majority of which was excreted within 24 hours of dosing. Biliary excretion was low (4% at 2 mg/kg and 5% at 400 mg/kg) and the majority of radiolabel was excreted within the first 24 hours. Low levels of radioactivity were in feces (3.5-5.0%) and carcass (2.0-3.2%) at 2 mg/kg and in feces (3.8%) and carcass (1.5-2.1%). Therefore, biliary excretion was not a significant route of elimination of radioactivity. Increasing dose level had little effect on the disposition of radioactivity and there was no accumulation of radioactivity in the residual carcass. No sex-related differences were observed in any of the parameters measured.

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Metabolism / Metabolites
The metabolic profile of flonicamid in rats was determined from the 0-48 hour interval rat urine after single dose administration of (14)C- pyridyl-flonicamid by oral gavage in male and female Sprague-Dawley rats at levels of 2 or 400 mg/kg body weight. Flonicamid was the major component in male and female rats with 52-72% of administered dose and the major metabolite is 4-trifluoromethylnicotinamide, with 18-25% of administered dose. Minor metabolites identified were: 4-trifluoromethylnicotinamide N-oxide (3% of administered dose), Flonicamid N-oxide (2% of administered dose), 4-trifluoromethylnicotinamide (1% of administered dose), 4-trifluoromethylnicotinamide conjugate (0.52% of administered dose), OH-4-trifluoromethylnicotinamide (0.44% of administered dose), TFNA (0.36% of administered dose), and 4-trifluoromethylnicotinamide N-Oxide conjugates (0.30% of administered dose). TFNG was not detected in the urine. Analysis of flonicamid rat metabolism for repeated dosing gave the following results: Flonicamid (46-54% of administered dose) and 4-trifluoromethylnicotinamide (21-27% administered dose) were the major components found in rat urine following multiple low doses of (14)C- pyridyl-flonicamid.
In liver samples, the major components in male rat liver following 0.5 and 6 hours were flonicamid (51% and 27% total radioactive residues, respectively) and N-(4-trifluoromethylnicotinoyl)glycine (24% and 8% of total radioactive residues, respectively). 4-Trifluoromethylnicotinamide was 10% of total radioactive residues after 0.5 hours and 45% after 6 hours. In the rat biliary study, flonicamid was rapidly absorbed and excreted in the urine within 24 hours. ... The metabolic pathway of flonicamid in rats involves hydrolysis of the cyano (-CN) and amide (-CONH2) functional groups in the flonicamid molecule, although in rats, flonicamid was further metabolized by several routes, including N-oxidation and hydroxylation of the pyridine ring, leading to multiple metabolites.
(14)C Flonicamid (radiolabelled = 98.5% pure; unlabelled = 99.7%) was used in 3 experiments in order to characterize metabolism in CRL:CD (SD)IGS BR rats: Study #1(Biliary): 4 rats/sex/dose were administered a single oral gavage dose of (14)C Flonicamid at 2 or 400 mg/kg, then terminated at 48 hours. Study #2 (Single-Dose Excretion): 3 or 5/sex/dose/time point were treated with a single oral gavage dose of (14)C Flonicamid at 2 or 400 mg/kg and terminated at 0.5, 6, 24 and 168 hours (2 mg/kg) or 3 (M), 1 (F), 14.5 (M), 8 (F), 24 and 168 hours. Study #3 (Multi-Dose Excretion): 2/sex/dose/time point were treated with 14 consecutive oral gavage doses of (12)C Flonicamid at 2 mg/kg, then one dose of (14)C Flonicamid on the 15th day before termination at 0.5, 6, 24 and 168 hours following (14)C Flonicamid administration. The negative control and vehicle was 0.75% methylcellulose/HPLC Grade H2O. Livers were collected and analyzed for metabolites in study #2 and #3. Excretion of Flonicamid and metabolites occurred primarily in the urine and to a lesser extent in the feces. It was metabolized by several routes, including nitrile hydrolysis, amide hydrolysis, N-oxidation and hydroxylation of the pyridine ring. Combinations of pathways occurred, leading to the formation of multiple metabolites.
The metabolism of flonicamid was investigated in livestock using lactating goats and laying hens. The test substance was [14C] flonicamid (labeled at the 3 position of the pyridine ring; specific activity 100,000 dpm/ug). In goats, the test substance was administered orally at 10 ppm (4.2x) in the diet for five consecutive days. Milk was collected twice daily throughout the study, and tissues (liver, kidney, muscle, and fat) were collected at sacrifice. In hens, the test substance was also administered orally at 10 ppm (25x) in the diet for five consecutive days. Eggs were collected twice daily throughout the study, and tissues (liver, muscle, skin, and fat) were collected at sacrifice. The available data indicate that the metabolism of flonicamid is similar in goats and hens. The majority of the dose was rapidly excreted. TFNA-AM (4-trifluoromethylnicotinamide) was the major metabolite (29-92% TRR) in goats (tissues and milk) and in laying hens (tissues and eggs). Flonicamid was found in minor quantities in goat and hen matrices, at <6% TRR. TFNAAM was also identified in goat muscle, liver, and kidney in significant quantities (23-31% TRR) in the acid hydrolysates of nonextractable residues. A metabolite determined to be an unstable conjugate of TFNA was identified in goat kidney at 12% TRR and the metabolite OH-TFNAAM was identified in liver acid hydrolysate at 11% /total residues recovered/ (TRR). The metabolism of flonicamid in livestock shows the main pathway of metabolism involves hydrolysis of the cyano and amide functional groups in the molecule ...

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Biological Half-Life
(14)C Flonicamid (radiolabelled = 98.5% pure; unlabelled = 99.7%) was administered by gavage to CRL:CD (SD)IGS BR rats at 0 (0.75% methylcellulose suspension, 1/sex), 2 and 400 mg/kg (5/sex/dose). Blood samples were taken at 0, 10, 20 and 40 minutes and at 1, 2, 3, 4, 8, 24, 48 and 72 hours (terminated at 72 hours) to determine pharmacokinetics. After treatment, Flonicamid was rapidly absorbed and peak plasma radioconcentrations were rapidly achieved. Pharmacokinetics at 2 mg/kg were similar between the sexes but were different at 400 mg/kg. Females had a half-life of 6.8 hours after 400 mg/kg treatment. This was similar to the 4.5 hour half-life after treatment with 2 mg/kg. The average half-life in males at 2 mg/kg was 5.2 hours (similar to females), however at 400 mg/kg the plasma concentrations reached a plateau that lasted several hours (average half-life = 11.6 hours) in males and was statistically significantly different than high dose females and low dose males.

Interactions
This report describes /a case/ of acute exposure to a mixture of spinosad and flonicamid that resulted in a substantial clinical toxicities. An 80-year-old depressed female attempted suicide by drinking a mixture of 80-mL Conserve (Dow AgroSciences, Taipei, Taiwan) and 2-3 gram powder of flonicamid (Ishihara Sangyo Kaisha, Taipei, Taiwan). Spinosad was the main compound ingested. The clinical manifestations were mostly neurological, i.e. consciousness disturbance, shock, respiratory failure, pneumonitis and urinary retention. Endoscopic examination found grade 2a corrosive esophageal injury. After resuscitation, detoxification procedures and intensive care, the patient recovered fully without leaving any chronic sequels. An emerging question arising from this report is, why are the clinical symptoms so severe, given that both compounds were claimed safe in laboratory animals? The answer is unclear. One possible explanation is, the amount of spinosad ingested was far beyond the physiological safety dose that can be handled by human body. Other potential contributors to the clinical toxicities in this patient are the solvent compositions that were found in the Conserve insecticide formulation.[Su TY et al; Hum Exp Toxicol Mar 7 2011

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Non-Human Toxicity Values
LC50 Rat inhalation >4.9 mg/L/4 hr
LD50 Rat dermal >5000 mg/kg
LD50 Rat oral (female) 1768 mg/kg
LD50 Rat oral (male) 884 mg/kg

[1]. Flonicamid, a novel insecticide with a rapid inhibitory effect on aphid feeding. Pest Manag Sci. 2007 Oct;63(10):969-73.

[2]. Flonicamid, a novel insecticide with a rapid inhibitory effect on aphid feeding. Pest Manag Sci. 2007 Oct;63(10):969-73.

Flonicamid is a pyridinecarboxamide that is nicotinamide substituted by a trifluoromethyl group at position 4 and a cyanomethyl group at the carbamoyl nitrogen atom. It has a role as a xenobiotic, an environmental contaminant and an insecticide. It is a pyridinecarboxamide, a nitrile and an organofluorine compound. It is functionally related to a nicotinamide.

C9H6F3N3O

229.1622

229.046

158062-67-0

9834513

Light brown to brown solid powder

1.4±0.1 g/cm3

381.4±52.0 °C at 760 mmHg

157.5°

184.4±30.7 °C

0.0±0.9 mmHg at 25°C

1.518

1.04

1

6

2

16

307

0

RLQJEEJISHYWON-UHFFFAOYSA-N

InChI=1S/C9H6F3N3O/c10-9(11,12)7-1-3-14-5-6(7)8(16)15-4-2-13/h1,3,5H,4H2,(H,15,16)

N-(cyanomethyl)-4-(trifluoromethyl)pyridine-3-carboxamide

PESTANAL (Sigma-Aldrich); Flonicamid

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 : ~100 mg/mL (~436.38 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (10.91 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 25.0 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: ≥ 2.5 mg/mL (10.91 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (10.91 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 25.0 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.)