Bee visual learning is hampered, decision-making times are changed, and aberrant behavior is increased by thiamethoxam [2].

Absorption, Distribution and Excretion
Thiamethoxam is rapidly and completely absorbed, rapidly distributed throughout the body, and rapidly excreted. Its toxicokinetics and metabolism are unaffected by route of administration, dose level, pretreatment, labeling site, or animal sex. In rats, thiamethoxam is rapidly and extensively absorbed and distributed, followed by rapid excretion, primarily in the urine. The highest tissue concentrations are found in skeletal muscle (10-15% of the administered dose). After 7 days, tissue residues are extremely low. Within 24 hours, approximately 84-95% of the administered dose is excreted in the urine and 2.5-6% in the feces. The majority is excreted unchanged (70-80% of the administered dose). Enterohepatic circulation is negligible. Fifteen Tiflbm:MAG (SPF) mice per group were supplemented with unlabeled thiamethoxam in their diet for 29 days at concentrations of 0, 100, 500, or 2500 ppm. On day 30, all groups were administered labeled thiamethoxam (10 mg/kg body weight) by gavage, followed by a second gavage 72 hours later (unlabeled feed treatment continued until the end of the experiment). Mice were sacrificed 6 hours after the second radiolabeling treatment. Researchers examined the radiolabeled substance and its metabolites in urine, feces, liver, plasma, and bile. Regardless of dose, within 72 hours, 58–76% of the first dose was present in urine, and 24–36% (94–102% of the dose) was present in feces. Six hours after the second dose, the drug concentration in the liver was approximately 0.9% to 1.5% of the dose, the drug concentration in bile collected from the gallbladder was only 0.01% to 0.22% of the dose, and the drug concentration in plasma was 0.3% to 0.4% of the dose (drug concentrations in liver, bile, or plasma were not affected by pretreatment). Metabolite patterns in excrement and other samples did not show a dose-dependent effect. ...
Non-radiolabeled thiamethoxam (purity >98%) Radiolabeled [thiazol-2-(14)C]thiamethoxam (batch numbers #Ko-73.1A and Ko-73.2A-1, specific activities of 68.9 and 57.3 uCi/mg, purity >97%) and [oxadiazine-4-(14)C]thiamethoxam (batch numbers Ko-75.2A-2 and Ko-75.2A-3, specific activities of 87.0 and 84.6 uCi/mg, purity >96%) were administered to 4 or 5 Tif:RAI f (SPF) rats/sex/dose groups at a dose of 0.5 mg/kg, to 5 rats/sex groups at a dose of 0.5 mg/kg (after administration of unlabeled thiamethoxam for 14 days), and to 5 rats/sex groups at a dose of 0.5 or 100 mg/kg via gavage or intravenous injection. Three groups of four male Tiflbm:MAG (SPF) mice were administered [thiazolyl-2-(14)C]thiamethoxam for 14 days at a dose of 118 mg/kg to determine its excretion and metabolic fate in mice. In rats, the drug dose was rapidly absorbed from the gastrointestinal tract into systemic circulation, with peak plasma concentrations (tCmax (hr)) reached within 1 to 4 hours, regardless of radiolabeling site, dose level, or sex. Cmax ranged from 0.17 to 0.20 ppm (low dose) and 33 to 43 ppm (high dose), and plasma concentrations decreased rapidly (tCmax/2 approximately 8 hours). Bioavailability was 0.6 to 0.8 (male) and 0.7 to 0.9 (female), indicating high oral absorption. The absorbed substance was mainly excreted in urine (approximately 90%), with about 4% excreted in feces within 24 hours. Fecal excretion was primarily due to bile excretion. The half-life in all tissues ranged from 2 to 6 hours. Comparison of metabolite patterns in mice and rats revealed similar major metabolic pathways. In mice, approximately 72% of the administered dose was excreted primarily in urine and 19% in feces. Small but measurable amounts of the drug (approximately 0.2% of the administered dose) were detected in exhaled breath. The parent drug (33–41% of the administered dose) and two major metabolites were detected: 8–12% and 9–18% of the administered dose, respectively. These structures were identical to those most commonly found in rat excrement; however, their proportions in mouse excrement were significantly different. An additional significant metabolite (mouse R6) was isolated from fecal samples. 30–60% of the administered dose was excreted as metabolites. The major biotransformation reaction was the cleavage of the diazine ring to form the corresponding nitroguanidine compound (i.e., chlorothiazide, a regulated metabolite in plants and livestock). In in vivo studies, plasma from rats and mice was compared. Metabolite levels were measured in rats after administration of 3000 ppm thiamethoxam for 1 and 10 weeks, and in mice after administration of 2500 ppm thiamethoxam for 1 and 10 weeks (N = 5). Plasma thiamethoxam concentrations in mice were 12 and 4 μg/mL at 1 week and 10 weeks, respectively, and in rats, 7 and 19 μg/mL, respectively. In mice, metabolic induction appeared to be continuous during this period, as the concentration of CGA 265307 (a downstream metabolite of CGA 322704 and CGA 330050) increased from 2 μg/mL to 5 μg/mL. The concentration of CGA 322704 in mice remained essentially constant, while the concentration of CGA 330050 decreased slightly during this period. In rats, the concentration of CGA 322704 ranged from 1.0 to 0.6 μg/mL. Other metabolites were present in extremely low concentrations in rats: CGA thiamethoxam 265307 ranged from 0.05 to 0.09 μg/mL, and CGA 330050 ranged from 0.10 to 0.14 μg/mL. Liver microsomal fractions were prepared from mouse, rat, and human liver microsomes for in vitro studies of thiamethoxam metabolism. In all cases, mice exhibited the fastest metabolic rates (i.e., thiamethoxam metabolized to CGA 322704, thiamethoxam to CGA 330050, CGA 322704 to CGA 265307, and CGA 330050 to CGA 265307). The metabolic rates in rats were slightly higher than in humans.
Two male Tiflbm:RAI (SPF) rats per group were administered a single injection of 100 mg/kg [oxadiazine-4-(14)C] CGA 293343 via gavage. Animals were sacrificed at 0.5, 1, 2, 4, 6, 8, or 24 hours post-administration. Blood samples were collected to assess total residues and identify major metabolites. Thin-layer radiochromatograms of whole blood extracts collected 4 hours post-administration showed one strong peak, one weak peak, and very few markers. Corresponding high-performance liquid chromatography radiochromatograms showed two identifiable peaks: thiamethoxam and CGA 322704. At the peak concentration of thiamethoxam (6 hours post-administration), 99.8% of the radiolabeled material was extractable. Other extractable residues, excluding thiamethoxam and its two metabolites, accounted for 1.74% of the markers. The maximum concentrations of thiamethoxam and its metabolites occurred at 6 hours post-administration. The estimated half-life of thiamethoxam is 2 hours, and that of CGA 322704 is 4 hours. The peak time for both CGA 322704 and CGA 265307 is 8 hours. Within 0.5 to 8 hours post-administration, "other" residues comprised 0.3% to 2.2% of the extractable markers. At 24 hours, total residues in the blood were only 2% of the peak (6 hours). The metabolites (percentage of total radioactive residues at a given sampling time) for thiamethoxam, CGA 322704, and CGA 265307 were: 94.6%, 5.0%, and (below quantitative level) at 1 hour; 81.9%, 15.0%, and 1.2% at 6 hours; and 15.5%, 30.6%, and 17.6% at 24 hours. CGA 330050 is an important metabolite in mice. Not detected. Six male Tiflbm:MAG (SPF) mice in each group were administered 100 mg/kg of [oxadiazine-4-(14)C]thiamethoxam by gavage. Mice were sacrificed at 0.5, 1, 2, 4, 6, 8 or 24 hours after administration. Blood samples were collected to assess total residues and identify major metabolites. Thin-layer chromatography radiochromatograms of whole blood extracts collected 1 hour after administration showed three strong peaks with almost no markers outside the peaks. One of the peaks represented two components, so high-performance liquid chromatography radiochromatograms showed four identifiable peaks. These peaks were thiamethoxam (main peak) and three metabolites: CGA 322704, CGA 265307 and CGA 330050. Within the first hour, approximately 1.5% to 2.9% of the markers were unextractable, and all other residues except thiamethoxam and its metabolites were below the limit of detection. The TCmax (hours) of thiamethoxam was 0.5, and the TCmax of the three metabolites was 2. The estimated t1/2 (hours) was 3 hours for all three metabolites (thiamethoxam and all its metabolites). Within 4–8 hours post-administration, “other” residues comprised approximately 5% of the extractable markers. At 8 and 24 hours, the total residues in the blood were only 30% and 1% of the peak (0.5 hour) level, respectively. The metabolic profiles (percentage of total radioactive residues at a given sampling time) for thiamethoxam, CGA 322704, CGA 265307, and CGA 330050 were 77.5%, 11.2%, and 1%, respectively. At 0.5 hours, they were 3.2 and 6.6, respectively; at 1 hour, they were 60.0, 15.7, 9.8, and 11.6, respectively; and at 8 hours, they were 39.5, 12.7, 30.4, and 9.0, respectively. For more complete metabolite/metabolite data on thiamethoxam (6 metabolites in total), please visit the HSDB record page.

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Biological Half-Life
The half-life in rat tissues is 2–6 hours.

[1]. Fate of thiamethoxam in mesocosms and response of the zooplankton community. Sci Total Environ. 2018 Oct 1;637-638:1150-1157.

[2]. Thiamethoxam impairs honey bee visual learning, alters decision times, and increases abnormal behaviors. Ecotoxicol Environ Saf. 2020 Apr 15;193:110367.

It has been reported that (4Z)-3-[(2-chloro-1,3-thiazolyl-5-yl)methyl]-5-methyl-N-nitro-1,3,5-oxadiazine-4-imine exists in Streptomyces canus, and relevant data are available. Thiamethoxam is a neonicotinoid insecticide, belonging to a class of neuroactive insecticides designed to mimic nicotine. Nicotine was discovered and used as an insecticide and rodenticide as early as the 17th century. Its effectiveness as an insecticide spurred the search for insecticidal compounds with less selective effects on mammals, ultimately leading to the discovery of neonicotinoid insecticides. Like nicotine, neonicotinoid insecticides bind to nicotinic acetylcholine receptors on cells. In mammals, nicotinic acetylcholine receptors are distributed in cells of the central and peripheral nervous systems. In insects, these receptors are limited to the central nervous system. Low to moderate levels of receptor activation cause nerve excitation, while high levels of activation overstimulate and block the receptors, leading to paralysis and death. Nicotine acetylcholine receptors are activated by the neurotransmitter acetylcholine. Acetylcholinesterase breaks down acetylcholine, thereby terminating signal transduction at these receptors. However, acetylcholinesterase cannot break down neonicotinoid insecticides, and their binding to receptors is irreversible. Because most neonicotinoid insecticides bind much more strongly to receptors on insect neurons than to those on mammalian neurons, these insecticides are far more toxic to insects than to mammals. The main reason for the low toxicity of neonicotinoid insecticides to mammals is the lack of charged nitrogen atoms at physiological pH. These uncharged molecules can penetrate the blood-brain barrier in insects, while the blood-brain barrier in mammals filters them out. However, some decomposition products of neonicotinoid insecticides are toxic to humans, especially the charged products. Due to their low toxicity and other favorable properties, neonicotinoid insecticides are among the most widely used insecticides in the world. Most neonicotinoid insecticides are readily soluble in water and decompose slowly in the environment, thus they can be absorbed by plants and provide insect protection during plant growth. Currently, neonicotinoid insecticides are used on crops such as corn, rapeseed, cotton, sorghum, sugar beets, and soybeans. They are also used on the vast majority of fruit and vegetable crops, including apples, cherries, peaches, oranges, berries, leafy greens, tomatoes, and potatoes. Multiple studies have shown that the use of neonicotinoid insecticides is associated with several adverse ecological impacts, including bee colony collapse (CCD) and a decline in bird populations due to reduced insect populations. This has led to the suspension or banning of these insecticides in Europe. A nitrooxazine and thiazole derivative is used as a broad-spectrum neonicotinoid insecticide. Mechanism of Action: A neonicotinoid acetylcholine receptor agonist that affects synapses in the insect's central nervous system. Thiamethoxam is a neonicotinoid insecticide that has not been found to be mutagenic in vitro or in vivo. However, when thiamethoxam was added to the diet of mice at concentrations of 500 to 2500 ppm for 18 months, the incidence of liver tumors in mice increased significantly. To determine the mechanism of liver tumor development observed at the end of the cancer bioassay, several dietary studies lasting up to 50 weeks have been conducted. These studies tested thiamethoxam and its major metabolites. In the 50-week thiamethoxam dietary feeding study in mice, the earliest changes observed were within one week, namely a significant decrease in plasma cholesterol (up to 40%). After 10 weeks, signs of hepatotoxicity appeared, including single-cell necrosis and increased apoptosis. After 20 weeks, hepatocyte proliferation was significantly increased. All these changes persisted from the first observation until the end of the 50-week study. These changes were dose-dependent and observed only at doses (500, 1250, and 2500 ppm) that increased the incidence of liver tumors in the cancer bioassay. No significant effect was observed in the 200 ppm dose group. The changes observed in this study are consistent with the development and progression of liver cancer in mice and form the basis of the mechanism of action of thiamethoxam. In a 20-week feeding trial, the major metabolites of thiamethoxam, CGA322704, CGA265307, and CGA330050, were tested. The results showed that only the liver changes induced by the metabolite CGA330050 were the same as those observed in the thiamethoxam feeding experiment. This leads to the conclusion that thiamethoxam, metabolized to CGA330050, is hepatotoxic and hepatocarcinogenic. Furthermore, the metabolite CGA265307 was also confirmed to be an inhibitor of inducible nitric oxide synthase and to enhance the hepatotoxicity of carbon tetrachloride. The study indicated that CGA265307, through its effect on nitric oxide synthase, exacerbated the toxicity of CGA330050 in mice treated with thiamethoxam. An 18-month study showed that thiamethoxam increased the incidence of liver tumors in mice; however, thiamethoxam did not show hepatocarcinogenicity in rats. Thiamethoxam is not genotoxic, and considering that mouse liver tumors typically appear later in life, this suggests that key liver events leading to tumorigenesis may involve time-related progression. A series of studies lasting up to 50 weeks identified these key events, showing relatively mild hepatic dysfunction within 10 weeks of administration, followed by significant hepatotoxicity after 20 weeks, ultimately leading to cell death and regenerative proliferation. The metabolite CGA330050 was identified as the source of mild hepatotoxicity, while the metabolite CGA265307 exacerbated the initial toxicity by inhibiting inducible nitric oxide synthase. The combination of hepatotoxicity from these metabolites with increased cell proliferation is considered the mechanism of action for thiamethoxam-associated mouse liver tumors. The relevance of these mouse-specific tumors to human health was assessed using the framework and decision logic developed using ILSI-RSI. The proposed mechanism of action met the Hill criteria for strength, consistency, specificity, timeliness, and dose-response, and is consistent with known and similar mechanisms of action, making it a plausible mechanism. Although the hypothesized mechanism of action theoretically may act in the human liver, quantitative analysis of key metabolites in vivo and in vitro indicates that these metabolites produced in mice (rats or humans) are sufficient to induce hepatotoxicity and subsequent tumor formation. In fact, rats fed 3000 ppm thiamethoxam for life did not develop hepatotoxicity or tumors. In conclusion, the coherence and completeness of this database clearly reveal the mechanism by which thiamethoxam induces liver tumors in mice, and lead to the conclusion that thiamethoxam does not pose a carcinogenic risk to humans.

C8H10CLN5O3S

291.71

291.019

153719-23-4

Thiamethoxam-d3;1294048-82-0

5485188

Crystalline powder
Light brown granules

1.7±0.1 g/cm3

485.8±55.0 °C at 760 mmHg

139.1°

247.6±31.5 °C

0.0±1.2 mmHg at 25°C

1.725

-1.16

0

6

2

18

352

0

ClC1=NC([H])=C(C([H])([H])N2/C(=N/[N+](=O)[O-])/N(C([H])([H])[H])C([H])([H])OC2([H])[H])S1

NWWZPOKUUAIXIW-FLIBITNWSA-N

InChI=1S/C8H10ClN5O3S/c1-12-4-17-5-13(8(12)11-14(15)16)3-6-2-10-7(9)18-6/h2H,3-5H2,1H3/b11-8-

(NZ)-N-[3-[(2-chloro-1,3-thiazol-5-yl)methyl]-5-methyl-1,3,5-oxadiazinan-4-ylidene]nitramide

Adage 5FS; Adage

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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 (~342.81 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (7.13 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 (7.13 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 20.8 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: ≥ 2.08 mg/mL (7.13 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.)