Chlorantraniliprole is a powerful pesticide that preferentially triggers insect ryanodine receptors. Chlorantraniliprole stimulates the release of intracellular Ca2+ reserves via the ranidine receptor. Chlorantraniliprole has a lower potency against ryanodine receptors (RyRs) in rat myoblast cell line C2C12 (EC50, 14 μM) compared to Drosophila melanogaster and H. virescens insect RyRs (EC50, 40 nM, 50 nM) by approximately 300 times. The rat cell line RyR2 exhibits low selectivity (EC50 > 100 μM) [1].

A 90-day research found that chlorantraniliprole exhibited nearly minimal toxicity at dosages as high as 1500 mg/kg/day and a low acute toxicity to mammals, with an acute oral LD50 > 5000 mg/kg in rats [1].

Absorption, Distribution and Excretion
/A lactating goat/ was given a single daily oral dose of 1:1 mixture of BC-labeled and PC-labeled chlorantraniliprole at 10 ppm for 7 consecutive days. Feces and urine were collected once daily and milk collected twice daily. The goat was sacrificed 23 hours after the last dose. The major metabolites were formed by N-demethylation, hydroxylation at the benzylic position and further oxidation to carboxylic acid and cyclization with loss of water to yield various cyclic metabolites. The majority of the administered dose was eliminated through the feces and urine. Undegraded parent was the major terminal residue identified in kidney, muscle, and fat, and it was also a residue in liver and milk.
Groups of at least five male and five female Crl:CD (SD)IGS BR rats were given chlorantraniliprole (purity, approximately 100%) at a dose of 0, 25, 100 and 1000 mg/kg bw per day by gavage for 14 consecutive days. Blood was collected from three male rats in each of the groups at 25, 100, and 1000 mg/kg bw on test days 14 and 15 immediately before dosing, and then 30 and 60 min, 2, 4, 8, 12, and 24 hr after dosing for determination of plasma concentrations of chlorantraniliprole. On day 14, liver tissue of five male and five female rats per group was processed for hepatic biochemical evaluations (beta-oxidation activity, total and specific cytochrome P450 content). Blood was separated into plasma and erythrocytes. In additional male rats assigned to the groups at 25, 100, and 1000 mg/kg bw per day, fat samples were collected for the purpose of assessing potential bioaccumulation of the test substance. The area under the curve of concentration time (AUC) for chlorantraniliprole was not proportional to dose, indicating that absorption was decreased at higher doses. Calculated half-lives for chlorantraniliprole in rats in the groups at 25, 100, and 1000 mg/kg bw per day were 3.4, 3.4, and 4.0 hr, respectively). Peak plasma concentrations occurred at 0.25, 0.42 and 2.75 h in the groups at 25, 100, and 1000 mg/kg bw per day. The maximum plasma concentrations (up to 0.48 ug/ml at 25 mg/ kg bw) were similar at all doses. The concentrations of the test substance in fat were below the limit of quantitation at 24 hr after dosing, indicating no significant accumulation of the parent compound.
Chlorantraniliprole was readily absorbed after oral administration /in Sprague Dawley Crl:CD(SD)IGS BR rats/, although absorption was incomplete and dose-related, with Tmax values of 5-9 hr after the lower dose and 11-12 hr after the higher dose. At a dose of 10 mg/kg bw, plasma concentrations peaked at 3.0 and 5.4 ug equivalents/g in males and females, respectively. After 24 hr, plasma concentrations in males and females were about 1.4 and 3.6 ug equivalents/g. At 200 mg/kg bw, plasma concentrations peaked at 5.1 and 7.1 ug equivalents/g in males and females, respectively. In the experiment with bile-duct cannulated rats, total absorption was 73-85% after a dose of 10 mg/kg bw and 12-13% after a dose of 200 mg/kg bw. At the lower dose, 48 hr after dosing 18-30% and 49-53% of the absorbed radiolabel was excreted in urine and bile respectively, while 2-6% and 10-20% was found in tissue and feces respectively. At the higher dose, 48 hr after dosing 4% and 5-7% of the absorbed radiolabel was excreted in the urine and bile, respectively, while 3% and 55-71% was found in tissue and feces, respectively. (14)C residues showed extensive distribution in the tissues. In the rats at the lower dose, 0.8% and 3.3% of the administered dose was recovered from the tissues of males and females, respectively, at 168 hr after dosing. At this time-point, tissues of males and females at the higher dose contained 0.2% and 0.5%, respectively, of the administered dose. No significant radioactivity was exhaled as (14)C-labelled volatiles or (14)CO2. Concentrations of (140C residues were lower in erythrocytes and tissues than in plasma. The mean plasma elimination half-lives were shorter in males (38-43 hr) than in females (78-82 hr) rats.
In a kinetic study that complied with OECD guideline 417, male and female Sprague-Dawley Crl:CD(SD)IGS BR rats were given up to 14 daily doses of [14C]chlorantraniliprole at 10 mg/kg bw per day by gavage. The experiments were performed with a 1 : 1 uCi/uCi mixture of (benzamide carbonyl (14)C)-chlorantraniliprole (radiochemical purity, 97%) and (pyrazole-carbonyl (14)C)chlorantraniliprole (radiochemical purity, 99%), diluted with chlorantraniliprole technical (purity, 96.45%). Rats were checked daily for clinical signs of toxicity. In three females per group, (14)C residues were quantified in whole blood, plasma, erythrocytes, fat, kidney, liver and muscle on days 5, 9, 12, 17, and 27. An evaluation of the distribution of (14)C residues in 21 tissues of three males and three females per group was performed on days 15 and 21. Material balance and rate and extent of urine and faecal excretion by male and female rats was quantified until day 21 (seven days after the last dose). Metabolites in urine and feces (% of accumulating dose), collected for intervals of 24 hr after the first, seventh, and last (fourteenth) day of dosing were profiled. ... More than 98.4% of the administered dose was recovered. Plasma and tissue concentrations indicated that steady-state kinetic behaviour was reached in male rats after 14 days of dosing. In female rats, concentrations of radiolabel in the plasma and tissue were near steady-state at the end of the 14-day dosing period. At day 15, plasma concentrations peaked at 4.6 and 32 ug equivalents/g in males and females, respectively, these concentrations being about two- and seven-fold higher than 24 hr after a single dose at 10 mg/kg bw. The concentrations of (14)C residues in tissues were higher in females than in males (2.35% vs 0.35% of the administered dose) at 168 hr after the last dose. After dosing, the concentration of 14C residues in the selected tissues of female rats declined, with half-lives ranging from 3.9 to 7.7 days. The half-life in plasma (T1/2 = 7.2 days) was approximately twofold that determined from plasma collected for up to 5 days after administration of a single dose (T1/2 = 3.4 days). A more extensive evaluation of tissue residues in 21 different tissues produced profiles of concentration and percent of dose that were similar to those observed in the single-dose study. Ratios of concentrations in tissue and plasma were less than 1. Most of the administered dose was excreted in the faeces (males, 72.9%; females, 81.6%). In the urine, 16.7% and 12.1% of the administered dose was excreted by males and females, respectively. The overall pattern of distribution and excretion for multiple dosing (10 mg/kg bw per day X 14 days) generally resided between the pattern observed for administration of a single low dose (10 mg/ kg bw) and a single high dose (200 mg/kg bw).

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Metabolism / Metabolites
As part of a 3-month feeding study in rats, ... concentrations of chlorantraniliprole and the two major metabolites, IN-GAZ70 and IN-H2H20 (for structures, see Figure 1) were measured in the plasma. Groups of 10 male and 10 female Crl:CD(SD) IGS BR rats were given diets containing chlorantraniliprole (purity, 95.9%) at a concentration of 0, 600, 2000, 6000, or 20 000 ppm, equal to 0, 36.9, 120, 359, or 1188 mg/kg bw per day for males and 0, 47.0, 157, 460, or 1526 mg/kg bw per day for females. Concentrations of chlorantraniliprole, INGAZ70 and IN-H2H20 were determined by liquid chromatography (LC)/MS in plasma obtained on day 59. Statements of adherence to QA and GLP were provided. Chlorantraniliprole, IN-GAZ70 and IN-H2H20 were present in the plasma at greater concentrations in female rats (up to 0.83, 112 and 0.54 ug/mL, respectively) than in male rats (up to 0.18, 3.7 and 0.08 ug/mL, respectively) with concentrations of IN-GAZ70 being highest. The plasma concentrations of all three analytes were similar at the three higher dietary concentrations in both sexes
The metabolism of chlorantraniliprole was investigated in two studies in Sprague-Dawley Crl:CD(SD)IGS BR rats. ... The experiments were performed with a 1 : 1 (uCi : uCi) mixture of (benzamide carbonyl (14)C)chlorantraniliprole (radiochemical purity, 97%) and [pyrazole-carbonyl 14C]chlorantraniliprole (radiochemical purity, 99%), diluted with chlorantraniliprole technical (purity, 96.45%). The rats were given a single dose at 10 or 200 mg/kg bw or daily doses of 10 mg/kg bw by gavage for 14 days. Metabolites were identified and quantified by high-performance liquid chromatography (HPLC) and mass spectrometry (MS) or tandem mass spectrometry (MS/MS). Statements of adherence to QA and GLP were provided. The metabolism of chlorantraniliprole was extensive and characterized by tolyl methyl and N-methyl carbon hydroxylation, followed by N-demethylation, nitrogen-to-carbon cyclization with loss of a water molecule resulting in the formation of the pyrimidone ring, oxidation of alcohols to carboxylic acids, amide-bridge cleavage, amine hydrolysis, and O-glucuronidation. At both doses, a significant difference between the sexes was apparent in the profile of metabolites in the urine and faeces, which indicated greater potential for hydroxylation of the tolyl methyl and N-methyl carbon groups in male rats than in female rats. For example, in rats at 10 mg/kg bw, the percentage of the administered dose represented by the di-hydroxylated metabolite IN-K9T00 was greater in males (urine, 7.4%; feces, 10.4%) than in females (urine, 2.2%; feces, 4.8%). Concentrations of the methylphenyl mono-hydroxylated metabolite IN-HXH44 were higher in the urine (4.6%) and feces (7.4%) of males than urine (2.4%) and feces (3.5%) of females. IN-KAA24, a carboxylic-acid metabolite of IN-HXH44, was a significant metabolite observed in the urine and faeces of males (10.6% combined), but not in females. Percentages of the N-methyl carbon hydroxylated metabolite IN-H2H20 were higher in females (urine, 3.4%; feces, 15.0%) than in males (urine, 0.3%; feces, 1.4%). At the higher dose, excretion of the parent compound in the urine and feces (78.9-85.5%) was 12-16-fold that at the lower dose (4.9-7.3%). The profile of metabolites in rats at 200 mg/kg bw was similar to that in rats at 10 mg/kg bw. The profile of metabolites in the urine and faeces of rats given repeated doses was similar to that observed for rats given single doses. Some minor differences included an apparent increase in the percentages of hydroxylated and polar metabolites such as IN-H2H20, IN-K7H29, and INKAA24 after repeated doses. IN-GAZ70 was observed in the faeces of female rats after 7 and 14 days of repeated doses, but not after a single dose.

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Biological Half-Life
Groups of at least five male and five female Crl:CD (SD)IGS BR rats were given chlorantraniliprole (purity, approximately 100%) at a dose of 0, 25, 100 and 1000 mg/kg bw per day by gavage for 14 consecutive days. Blood was collected from three male rats in each of the groups at 25, 100, and 1000 mg/kg bw on test days 14 and 15 immediately before dosing, and then 30 and 60 min, 2, 4, 8, 12, and 24 hr after dosing for determination of plasma concentrations of chlorantraniliprole. ... Calculated half-lives for chlorantraniliprole in rats in the groups at 25, 100, and 1000 mg/kg bw per day were 3.4, 3.4, and 4.0 hr, respectively).

[1]. Rynaxypyr: A new insecticidal anthranilic diamide that acts as a potent and selective ryanodine receptor activator. Bioorganic & Medicinal Chemistry Letters. 2007 Nov 15;17(22):6274-6279.

Chlorantraniliprole is a carboxamide resulting from the formal condensation of the carboxylic acid group of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid with the primary amino group of 2-amino-5-chloro-N,3-dimethylbenzamide. The first of the anthranilic diamide insecticides, it is a ryanodine receptor activator and is used to protect a wide variety of crops, including corn, cotton, grapes, rice and potatoes. It has a role as a ryanodine receptor agonist. It is an organobromine compound, a member of pyridines, a member of pyrazoles, a pyrazole insecticide, a member of monochlorobenzenes and a secondary carboxamide.

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Mechanism of Action
Chlorantraniliprole is a novel anthranilic diamide insecticide that functions via activation of the insect ryanodine receptors within the sarcoplasmic reticulum causing impaired regulation of muscle contraction. Ryanodine receptor channels regulate the release of internal calcium stores and are important in muscle contraction. Sustained release of calcium levels within the cytosol leads to muscle contraction, paralysis and eventual death of the organism. While insects possess a single form of the ryanodine receptor distributed in muscle and neuronal tissue, mammals possess three forms which are widely distributed in muscle and nonmuscle tissues. Chlorantraniliprole, along with other anthranilic diamide compounds tested, exhibits >500-fold in vitro differential selectivity for insect ryanodine receptors over those of the mammals.

C18H14BRCL2N5O2

483.14

480.97

C, 44.75; H, 2.92; Br, 16.54; Cl, 14.67; N, 14.50; O, 6.62

500008-45-7

11271640

White to off-white solid powder

1.7±0.1 g/cm3

526.6±50.0 °C at 760 mmHg

208 - 210 °C

272.3±30.1 °C

0.0±1.4 mmHg at 25°C

1.699

5.55

2

4

4

28

586

0

O=C(C1=CC(Br)=NN1C2=NC=CC=C2Cl)NC3=C(C(NC)=O)C=C(Cl)C=C3C

PSOVNZZNOMJUBI-UHFFFAOYSA-N

InChI=1S/C18H14BrCl2N5O2/c1-9-6-10(20)7-11(17(27)22-2)15(9)24-18(28)13-8-14(19)25-26(13)16-12(21)4-3-5-23-16/h3-8H,1-2H3,(H,22,27)(H,24,28)

5-bromo-N-[4-chloro-2-methyl-6-(methylcarbamoyl)phenyl]-2-(3-chloropyridin-2-yl)pyrazole-3-carboxamide

Rynaxpyr; Chlorantraniliprole

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 : ≥ 62.5 mg/mL (~129.36 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.31 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 (4.31 mM) 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.)