Absorption, Distribution and Excretion
Five CRL:CD (SD)IGS BR rats (per sex per level) were administered low or high doses of flunicaamide via gavage in a 0.75% methylcellulose suspension. The expected dose levels in the preliminary excretion and preliminary pharmacokinetic studies were 2 and 50 mg/kg, respectively. Due to error, the actual mean doses administered in the preliminary excretion studies were 0.85 and 21 mg/kg, but this is unlikely to affect the results. In the preliminary excretion studies, CO2 in exhaled breath, as well as in urine, cage cleaning fluid, and feces, was measured every 24 hours or less over 7 days. Measurable CO2 was not detected in exhaled breath. Urine and cage cleaning fluid samples accounted for 89–92% of the administered markers. Approximately 5–6% of the administered markers were detected in feces. Only 2–3% of the markers remained in the cadavers on day 7. …Tmax was estimated to be 0.3 to 0.6 hours.
(14)C flunicaramide (98.5% radiolabeled purity; 99.7% unlabeled purity) was administered to CRL:CD (SD)IGS BR rats via gavage at doses of 0 (0.75% methylcellulose/HPLC grade water; 1 rat per sex per dose, experiments terminated at 6 hours and 168 hours), 2 mg/kg (3 rats per sex per time point, experiments terminated at 0.5, 6, and 24 hours; 5 rats per sex per time point, experiments terminated at 168 hours), and 400 mg/kg (3 rats per sex per time point, experiments terminated at 0.5, 6, and 24 hours; 5 rats per sex per time point, experiments terminated at 168 hours) to determine its elimination and distribution. At doses of 2 and 400 mg/kg, the radioactive material of (14)C flunicaramide was rapidly absorbed and excreted. During the 168-hour collection period, the recovery rate of radioactive material reached quantitative levels. 90% of the administered radioactive material (including cage cleaning fluid) was found in urine, with the majority excreted within 24 hours after administration at a dose of 2 mg/kg and within 48 hours after administration at a dose of 400 mg/kg. Fecal excretion at doses of 2 and 400 mg/kg was 5% of the administered dose. In tissues, radioactivity levels rapidly increased, reaching peak concentrations similar to those in the blood. Although radioactivity was detected in tissues at all early time points, by 168 hours, radioactivity levels (within the detectable range) decreased by 50–100-fold. By 168 hours, the radioactive material content in the carcass was 2%, with the highest radioactivity content (<0.15%) in the liver. At a dose of 2 mg/kg, the highest radioactivity concentrations were observed in the liver (2.54–2.50 ug eq/g), kidney (2.35–2.67 ug eq/g), adrenal gland (5.07–6.52 ug eq/g), thyroid gland (4.02–4.26 ug eq/g), and ovary (female -3.77 ug eq/g) in males at 0.5 hours post-administration. At a dose of 400 mg/kg, the highest radioactivity concentrations were observed in the liver (442 ug eq/g), kidney (311 ug eq/g), adrenal gland (672 ug eq/g), and thyroid gland (652 ug eq/g) in males at 3 hours post-administration. The highest radiolabeled concentrations were observed in the liver (325 μg eq/g), kidney (359 μg eq/g), adrenal gland (689 μg eq/g), and thyroid gland (782 μg eq/g) of female rats one hour after administration. (14)C flunicamycin (98.5% radiolabeled purity; 99.7% unlabeled purity) was administered to CRL:CD (SD)IGS BR rats by gavage at 0 (0.75% methylcellulose/HPLC grade water; 1 rat per sex per dose), 2, and 400 mg/kg (4 rats per sex per dose), followed by a 48-hour observation period. At doses of 2 and 400 mg/kg, the radioactivity of (14)C flunicamycin was rapidly absorbed and excreted. Quantitative recovery was achieved within the 48-hour collection period. The concentration of radioactive material in urine was 85% (including cage flushing fluid) at a dose of 2 mg/kg and 80% at a dose of 400 mg/kg, with the majority being excreted within 24 hours post-administration. Bile excretion was low (4% at 2 mg/kg and 5% at 400 mg/kg), with most radiolabeled material being excreted within 24 hours post-administration. At a dose of 2 mg/kg, low levels of radioactivity were observed in feces (3.5–5.0%) and carcass (2.0–3.2%); at a dose of 400 mg/kg, low levels were observed in feces (3.8%) and carcass (1.5–2.1%). Therefore, bile excretion is not the primary route of radioactive material removal. Increasing the dose level had minimal effect on the distribution of radioactive material, and no accumulation of radioactive material in the residual carcass was observed. No sex differences were observed in any of the measured parameters.

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Metabolism/Metabolites
Male and female Sprague-Dawley rats were administered a single dose of (14)C-pyridyl-flunicalamide (2 or 400 mg/kg body weight, respectively) via gavage. Urine samples were collected from rats within 0–48 hours post-administration to determine the metabolic profile of flunicalamide in rats. Flunicalamide was the main component in the urine of both male and female rats, accounting for 52–72% of the administered dose; the main metabolite was 4-trifluoromethylnicotinamide, accounting for 18–25% of the administered dose. The minor metabolites detected included: 4-trifluoromethylnicotinamide N-oxide (3% of the administered dose), flunicacid N-oxide (2% of the administered dose), 4-trifluoromethylnicotinamide (1% of the administered dose), 4-trifluoromethylnicotinamide conjugate (0.52% of the administered dose), hydroxy-4-trifluoromethylnicotinamide (0.44% of the administered dose), TFNA (0.36% of the administered dose), and 4-trifluoromethylnicotinamide N-oxide conjugate (0.30% of the administered dose). TFNG was not detected in the urine. The metabolic analysis results after repeated administration of flunicacid to rats were as follows: After repeated administration of low-dose (14)C-pyridyl-flunicacid, the main components in rat urine were flunicacid (46-54% of the administered dose) and 4-trifluoromethylnicotinamide (21-27% of the administered dose). In liver samples from male rats, the main components of the liver 0.5 and 6 hours after administration were flunicamine (51% and 27% of the total radioactive residue, respectively) and N-(4-trifluoromethylnicotinamide)glycine (24% and 8% of the total radioactive residue, respectively). 4-Trifluoromethylnicotinamide accounted for 10% of the total radioactive residue at 0.5 hours and 45% at 6 hours. In rat bile studies, flunicamine was rapidly absorbed and excreted in the urine within 24 hours. ...The metabolic pathway of flunicamine in rats involves the hydrolysis of the cyano (-CN) and amide (-CONH2) functional groups in the flunicamine molecule. Although in rats, flunicamine is further metabolized through multiple pathways, including N-oxidation and hydroxylation of the pyridine ring, resulting in various metabolites.
(14)C-labeled flunicaramide (radiolabeled purity 98.5%; unlabeled purity 99.7%) was used in three experiments to characterize the metabolism of CRL:CD (SD)IGS BR rats: Study 1 (Bile): Each group of rats (4 males and 4 females) was given a single gavage of 2 or 400 mg/kg of (14)C-labeled flunicaramide and sacrificed 48 hours later. Study #2 (Single Dose Excretion): Each group of rats was given a single gavage of 2 or 400 mg/kg of (14)C flunicaramide by sex/dose/time point, and the experiment was terminated at 0.5, 6, 24 and 168 hours (2 mg/kg) or 3 (males), 1 (female), 14.5 (males), 8 (females), 24 and 168 hours. Study #3 (Multiple Dose Excretion): Two animals in each group were administered (12)C flunicaramide 2 mg/kg via gavage 14 times consecutively at different sexes, doses, and time points, followed by a single dose of (14)C flunicaramide on day 15 after (14)C flunicaramide administration. The experiment was terminated at 0.5, 6, 24, and 168 hours after (14)C flunicaramide administration. Negative controls and solvents were 0.75% methylcellulose/HPLC-grade water. Liver samples were collected and metabolites analyzed in Studies #2 and #3. Flunicaramide and its metabolites are primarily excreted in urine, with a small amount excreted in feces. Its metabolic pathways include nitrile hydrolysis, amide hydrolysis, N-oxidation, and pyridine ring hydroxylation. Combinations of multiple metabolic pathways lead to the formation of multiple metabolites. This study investigated the metabolism of flunicaramide in lactating goats and laying hens. The test substance was [¹⁴C]flunicalamide (pyridine ring 3-position labeled; specific activity 100,000 dpm/ug). In goats, the test substance was administered via gavage at a concentration of 10 ppm (4.2-fold) to the feed for 5 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 added orally to the feed at a dose of 10 ppm (25-fold) for 5 consecutive days. Eggs were collected twice daily throughout the study, and tissues (liver, muscle, skin, and fat) were collected at sacrifice. Available data indicate that flunicalamide is metabolized similarly in goats and hens. Most doses are rapidly excreted. TFNA-AM (4-trifluoromethylnicotinamide) is the major metabolite in goats (tissues and milk) and laying hens (tissues and eggs) (accounting for 29-92% of total recoveries). Trace amounts of flunicamine were detected in both goat and hen tissues, with total recoveries below 6%. Significant amounts of TFNAAM (23-31% of total recoveries) were also detected in the acid hydrolysates of non-extractable residues from goat muscle, liver, and kidney. A metabolite was identified in goat kidney as an unstable conjugate of TFNA, with a recovery of 12%; the metabolite OH-TFNAAM was identified in the acid hydrolysate of liver, with a recovery of 11% (total residue recovery). Metabolism of flunicaramide in livestock showed that its main metabolic pathway involves the hydrolysis of cyano and amide functional groups in the molecule…

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Biological half-life
(14)C Flunicaramide (radiolabeled purity 98.5%; unlabeled purity 99.7%) was administered to CRL:CD (SD)IGS BR rats by gavage at 0 (0.75% methylcellulose suspension, 1 rat per sex), 2, and 400 mg/kg (5 rats per sex per dose). Blood samples were collected at 0, 10, 20, and 40 minutes after administration and at 1, 2, 3, 4, 8, 24, 48, and 72 hours (72 hours terminated) to determine pharmacokinetics. Flunicaramide was rapidly absorbed after administration, and the peak plasma radioactivity concentration was also rapidly reached. The pharmacokinetics at the 2 mg/kg dose were similar between males and females, but differed at the 400 mg/kg dose. The half-life in females after administration of 400 mg/kg was 6.8 hours, similar to the 4.5-hour half-life after administration of 2 mg/kg. The mean half-life in males at the 2 mg/kg dose was 5.2 hours (similar to females); however, at the 400 mg/kg dose, male plasma concentrations reached a plateau lasting several hours (mean half-life = 11.6 hours), and this was statistically significant compared to both high-dose females and low-dose males.

Interactions
This report describes a case of severe clinical toxicity resulting from acute exposure to a mixture of spinosad and flonicamid. An 80-year-old woman with depression attempted suicide by drinking a mixture of 80 ml of senna water (Dow AgroSciences, Taipei, Taiwan) and 2–3 g of flonicamid powder (Ishihara Sangyo Co., Ltd., Taipei, Taiwan). Spinosad was the predominant ingredient. The clinical presentation was predominantly neurological, including altered consciousness, shock, respiratory failure, pneumonia, and urinary retention. Endoscopic examination revealed grade 2a corrosive esophageal injury. After resuscitation, detoxification, and intensive care, the patient fully recovered without any chronic sequelae. One question raised by this report is: given that both compounds are claimed to be safe in laboratory animals, why were the clinical symptoms so severe? The answer remains unclear. One possible explanation is that the ingested dose of spinosad far exceeded the physiologically safe dose for humans. Other potential factors contributing to the patient's clinical toxicity include solvent components found in the Conserve insecticide formulation. [Su TY et al.; Hum Exp Toxicol March 7, 2011]
Non-human toxicity values

Rat inhalation LC50 >4.9 mg/L/4 hours

Rat dermal LD50 >5000 mg/kg

Female rat oral LD50 1768 mg/kg

Male rat oral LD50 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.

Flunicamide is a pyridine carboxamide, a compound in which nicotinamide is substituted at the 4-position with a trifluoromethyl group and at the carbamoyl nitrogen atom with a cyanomethyl group. It is an exogenous substance, environmental pollutant, and pesticide. It belongs to the pyridine carboxamide, nitrile, and organofluorine compounds classes. Its structure is similar to that of 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.)