Chlorantraniliprole   中文名称: 氯虫苯甲酰胺

氯虫苯甲酰胺是一种强效杀虫剂，可优先触发昆虫兰尼碱受体。氯虫苯甲酰胺通过雷尼定受体刺激细胞内 Ca2+ 储备的释放。与 Drosophila melanogaster 和 H. virescens 昆虫 RyRs (EC50, 40 nM, 50 nM) 相比，Chlorantraniliprole 对大鼠成肌细胞系 C2C12 (EC50, 14 μM) 中的兰尼定受体 (RyRs) 的效力较低约 300 倍。大鼠细胞系 RyR2 表现出低选择性 (EC50 > 100 μM) [1]。

一项为期 90 天的研究发现，氯虫苯甲酰胺在剂量高达 1500 mg/kg/天时表现出几乎最小的毒性，并且对哺乳动物的急性毒性较低，大鼠急性口服 LD50 > 5000 mg/kg [1]。

Absorption, Distribution and Excretion
A lactating goat was orally administered 10 ppm of a BC-labeled and PC-labeled chlorantraniliprole 1:1 mixture once daily for 7 consecutive days. Feces and urine were collected once daily, and milk was collected twice daily. The goat was sacrificed 23 hours after the last administration. The major metabolites are formed through N-demethylation, benzylic hydroxylation, and further oxidation to carboxylic acids and cyclization dehydration to generate various cyclic metabolites. Most of the administered dose was excreted in feces and urine. Undegraded parent compounds were the main terminal residues detected in the kidneys, muscle, and fat, and also in the liver and milk. At least five male and five female Cr1:CD (SD)IGS BR rats were divided into groups and administered chlorantraniliprole (approximately 100% purity) by gavage at doses of 0, 25, 100, and 1000 mg/kg body weight/day for 14 consecutive days. On days 14 and 15, blood samples were collected from three male rats in each group to determine the plasma concentration of chlorantraniliprole. Blood samples were collected before administration (25, 100, and 1000 mg/kg body weight) and at 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours after administration. On day 14, liver tissue was collected from five male and five female rats in each group for liver biochemical assessment (β-oxidation activity, total cytochrome P450, and specific cytochrome P450 content). Blood was separated into plasma and erythrocytes. Fat samples were also collected from male rats in the 25, 100, and 1000 mg/kg body weight/day dose groups to assess the potential bioaccumulation of the test substance. The area under the concentration-time curve (AUC) of chlorantraniliprole was not directly proportional to the dose, indicating decreased absorption at higher doses. The calculated half-lives of chlorantraniliprole in rats at daily doses of 25, 100, and 1000 mg/kg body weight were 3.4, 3.4, and 4.0 hours, respectively. Peak plasma concentrations occurred at 0.25, 0.42, and 2.75 hours, respectively, in the 25, 100, and 1000 mg/kg body weight groups. The maximum plasma concentrations were similar across the dose groups (up to 0.48 μg/ml in the 25 mg/kg body weight group). Twenty-four hours after administration, the concentration of the test substance in adipose tissue was below the limit of quantitation, indicating no significant accumulation of the parent compound. Chlorantraniliprole was readily absorbed in Sprague Dawley Crl:CD(SD)IGS BR rats after oral administration, but absorption was incomplete and dose-dependent; the time to peak concentration (Tmax) was 5–9 hours in the low-dose group and 11–12 hours in the high-dose group. At a dose of 10 mg/kg body weight, the peak plasma concentrations in male and female rats were 3.0 and 5.4 μg equivalents/g, respectively. After 24 hours, the plasma concentrations in male and female rats were approximately 1.4 and 3.6 μg equivalents/g, respectively. At a dose of 200 mg/kg body weight, the peak plasma concentrations in male and female rats reached 5.1 and 7.1 μg equivalents/g, respectively. In experiments with bile duct cannulated rats, the total absorption rate was 73-85% at a dose of 10 mg/kg body weight and 12-13% at a dose of 200 mg/kg body weight. At lower doses, 48 hours after administration, 18-30% and 49-53% of the absorbed radiolabeled material were excreted in urine and bile, respectively, while 2-6% and 10-20% were excreted in tissues and feces, respectively. In the high-dose group, 4% and 5-7% of the absorbed radiolabeled [14C] were excreted in urine and bile 48 hours post-administration, respectively, while 3% and 55-71% remained in tissues and feces, respectively. [14C] residues were widely distributed in tissues. In the low-dose group, 0.8% and 3.3% of the administered dose were recovered from tissues of male and female rats, respectively, 168 hours post-administration. At this time, the tissues of male and female rats in the high-dose group contained 0.2% and 0.5% of the administered dose, respectively. No significant radioactive exhalation as [14C]-labeled volatiles or [14C] CO2 was detected. [14C] residual concentrations in erythrocytes and tissues were lower than in plasma. The mean plasma elimination half-life in male rats (38-43 hours) was shorter than that in female rats (78-82 hours). In a kinetic study conforming to OECD Guideline 417, male and female Sprague-Dawley Crl:CD(SD)IGS BR rats were administered 10 mg/kg body weight of [14C]chlorantraniliprole by gavage daily for up to 14 consecutive days. The experiment used a 1:1 μCi/μCi mixture of (benzamide carbonyl(14C))-chlorantraniliprole (radiochemical purity 97%) and (pyrazolyl carbonyl(14C))-chlorantraniliprole (radiochemical purity 99%), diluted with chlorantraniliprole technical grade (purity 99%). Clinical signs of toxicity in rats were examined daily. Residual [14C] in whole blood, plasma, erythrocytes, fat, kidneys, liver, and muscle were quantitatively measured in three female rats from each group on days 5, 9, 12, 17, and 27. The distribution of ¹⁴C residues in 21 tissues from three male and three female rats in each group was assessed on days 15 and 21. Material balance and the rate and extent of excretion in urine and feces were quantitatively analyzed in male and female rats up to day 21 (7 days after the last administration). Metabolites (as a percentage of the cumulative dose) in urine and feces collected every 24 hours on days 1, 7, and the last day (day 14) were analyzed. …Over 98.4% of the administered dose was recovered. Plasma and tissue concentrations indicated that male rats reached steady-state kinetic behavior after administration. The administration period was 14 days. In female rats, plasma and tissue concentrations of the radiolabeled substance approached steady state at the end of the 14-day administration period. Peak plasma concentrations were reached on day 15 in male and female rats, at 4.6 and 32 μg equivalents/g, respectively, which were approximately 2-fold and 7-fold higher than the concentrations 24 hours after a single 10 mg/kg body weight administration. At 168 hours after the last administration, the concentration of 14C residues in tissues of female rats was higher than that in male rats (2.35% and 0.35% of the administered dose, respectively). Following administration, the concentration of 14C residues in selected tissues of female rats decreased, with half-lives ranging from 3.9 to 7.7 days. The plasma half-life (T_1/2 = 7.2 days) was approximately twice that of plasma collected within 5 days after a single administration (T_1/2 = 3.4 days). A more extensive assessment of tissue residues in 21 different tissues yielded concentration and dose percentage distributions similar to those observed in the single-dose study. The concentration ratio in tissues and plasma was less than 1. The majority of the administered dose was excreted in feces (72.9% in males; 81.6% in females). 16.7% and 12.1% of the administered dose were excreted in urine in males and females, respectively. The overall distribution and excretion pattern of multiple administrations (10 mg/kg body weight/day × 14 days) generally fell between that of a single low-dose (10 mg/kg body weight) and a single high-dose (200 mg/kg body weight) administration.

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Metabolism/Metabolites
As part of a 3-month rat feeding study, ... the concentrations of chlorantraniliprole were determined in plasma for two major metabolites, IN-GAZ70 and IN-H2H20 (structures shown in Figure 1). Ten male and ten female Cr10:CD(SD) IGS BR rats were randomly divided into four groups and fed diets containing chlorantraniliprole (95.9% purity) at concentrations of 0, 600, 2000, 6000, or 20000 ppm, equivalent to daily body weights of 0, 36.9, 120, 359, or 1188 mg/kg for male rats and 0, 47.0, 157, 460, or 1526 mg/kg for female rats. Plasma samples were collected on day 59, and the concentrations of chlorantraniliprole, IN-GAZ70, and IN-H2H2O were determined using liquid chromatography-mass spectrometry (LC/MS). A quality assurance statement and GLP were provided. The concentrations of chlorantraniliprole, IN-GAZ70, and IN-H2H20 in the plasma of female rats (up to 0.83, 112, and 0.54 μg/mL, respectively) were higher than those in male rats (up to 0.18, 3.7, and 0.08 μg/mL, respectively), with the highest concentration of IN-GAZ70. At the three higher dietary concentrations, the concentrations of these three analytes in the plasma of male and female rats were similar. In two studies, researchers investigated the metabolism of chlorantraniliprole in Sprague-Dawley Crl:CD(SD)IGS BR rats. …The experiments were conducted using a 1:1 (μCi:μCi) mixture of (benzamide carbonyl(14)C)chlorantraniliprole (radiochemical purity 97%) and [pyrazolyl carbonyl]. [14C]chlorantraniliprole (radiochemical purity 99%) was diluted with chlorantraniliprole stock solution (purity 96.45%). Rats were administered 10 or 200 mg/kg body weight via single gavage, or 10 mg/kg body weight daily via gavage for 14 consecutive days. Metabolites were identified and quantified using high-performance liquid chromatography-mass spectrometry (HPLC-MS) or tandem mass spectrometry (MS/MS). The experiments were conducted in accordance with quality assurance (QA) and good laboratory practices (GLP). Chlorantraniliprole undergoes extensive metabolism, characterized by toluyl methylation and N-methyl carbon hydroxylation, followed by N-demethylation, N-carbon cyclization with the loss of a water molecule to form a pyrimidinone ring, alcohol oxidation to carboxylic acid, amide bridge cleavage, amine hydrolysis, and O-glucuronidation. Significant differences were observed at both dosages. Metabolite profiles in the urine and feces of male and female rats showed significant sex differences, indicating that male rats had a higher hydroxylation potential for the toluylmethyl and N-methyl carbon groups than female rats. For example, at a dose of 10 mg/kg body weight, the percentage of the dihydroxylated metabolite IN-K9T00 in the urine of male rats (7.4%) was higher than that in female rats (2.2%) and (4.8%). The concentrations of the methylphenyl monohydroxylated metabolite IN-HXH44 in the urine (4.6%) and feces (7.4%) of male rats were higher than those in female rats (2.4%) and (3.5%). The carboxylic acid metabolite IN-KAA24 of IN-HXH44 was an important metabolite observed in the urine and feces of male rats (total 10.6%), but not in females. The percentage of the N-methylcarbon hydroxylated metabolite IN-H2H20 in females (3.4% in urine; 15.0% in feces) was higher than that in males (0.3% in urine; 1.4% in feces). At high doses, the excretion of the parent compound in urine and feces (78.9–85.5%) was 12–16 times higher than at low doses (4.9–7.3%). The metabolite profiles of rats in the 200 mg/kg body weight dose group were similar to those in the 10 mg/kg body weight dose group. The metabolite profiles in urine and feces of rats in the repeated-dose group were similar to those in the single-dose group. Some subtle differences included a significant increase in the percentage of hydroxylated and polar metabolites (such as IN-H2H20, IN-K7H29, etc.). INKAA24 was detected in the feces of female rats after repeated dosing. IN-GAZ70 was observed in the feces of female rats after 7 and 14 days of repeated dosing, but was not detected after a single dosing.

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Biological Half-Life
At least five male and five female Cr1:CD (SD)IGS BR rats were divided into groups and administered chlorantraniliprole (approximately 100% purity) by gavage for 14 consecutive days at doses of 0, 25, 100, and 1000 mg/kg body weight/day. On days 14 and 15, blood samples were collected from three male rats in each group before administration and at 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours after administration to determine the plasma concentration of chlorantraniliprole. The calculated half-lives of chlorantraniliprole administered to rats daily at doses of 25, 100, and 1000 mg/kg body weight were 3.4, 3.4, and 4.0 hours, 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 insecticide formed by the 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. It is the first anthranilamide insecticide and a Reynoldsin receptor activator used to protect various crops, including corn, cotton, grapes, rice, and potatoes. It functions as a Reynoldsin receptor agonist. It is an organobromine compound belonging to the pyridine, pyrazole, monochlorobenzene, and secondary amide classes of insecticides.

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Mechanism of Action
Chlorantraniliprole is a novel anthranilamide insecticide whose mechanism of action is through activation of renystatin receptors in the insect sarcoplasmic reticulum, leading to impaired muscle contraction regulation. Renystatin receptor channels regulate the release of intracellular calcium ions, playing a crucial role in muscle contraction. Sustained release of intracellular calcium ions leads to muscle contraction, paralysis, and ultimately, organism death. Insects possess one type of rennet receptor in their muscle and nerve tissues, while mammals possess three types of rennet receptors, widely distributed in both muscle and non-muscle tissues. Chlorantraniliprole and other tested anthranilamide compounds exhibit more than 500 times greater selectivity for insect rennet receptors than for mammalian rennet receptors in vitro.

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

88.91

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)

配方 1 中的溶解度: ≥ 2.08 mg/mL (4.31 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: 2.08 mg/mL (4.31 mM) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。