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

Absorption, Distribution and Excretion
Quickly and completely absorbed, rapidly distributed in the body and rapidly eliminated. The toxicokinetics and metabolism are not influenced by the route of administration, the dose level, pre-treatment, the site of label or the sex of animals.
In rats, thiamethoxam is absorbed rapidly and extensively, and is widely distributed, followed by very rapid elimination, mostly in the urine. The highest tissue concentrations are in skeletal muscle (10-15% of administered dose). Very low tissue residues were reported after 7 days. Within 24 hours, approximately 84-95% of the administered dose was excreted in urine, while 2.5-6% was excreted in the feces. Most was excreted as unchanged parent (70-80% of dose). ... Enterohepatic circulation is negligible.
Fifteen Tiflbm: MAG (SPF) mice/group were dosed with non-labeled thiamethoxam in diet for 29 days at 0, 100, 500, or 2500 ppm. Labeled thiamethoxam (10 mg/kg b.w.) was given by gavage to all groups on day 30, and again 72 hours later (non-labeled dietary treatments continued until termination). Mice were killed 6 hours after the second radio-labeled treatment. Investigators evaluated urine, feces, liver, plasma, and bile for radiolabel and metabolites. Regardless of dose, 58-76% of the first dose was found in urine and 24-36% of first dose in feces within 72 hours (accounting for 94-102% of administered dose). Six hours after the 2nd dose, liver contained about 0.9 to 1.5% of that dose, pooled bile from the gall bladders contained only 0.01 to 0.22% of that dose, and plasma contained 0.3 to 0.4% of that dose (no effect of pre-treatment for liver, bile, or plasma). Excreta and other samples showed no influence of dose on metabolite patterns. ...
Non-radiolabeled Thiamethoxam (purity >98%); Radiolabeled [Thiazol-2-(14)C] Thiamethoxam (Batch #Ko-73.1A and Ko-73.2A-1, specific activity 68.9 and 57.3 uCi/mg, respectively, purity of >97%) and [Oxadiazin-4-(14)C] Thiamethoxam (Batch Ko-75.2A-2 and Ko- 75.2A-3, specific activity of 87.0 and 84.6 uCi/mg, purity >96%) were administered to 4 or 5 Tif:RAI f (SPF) rats/sex/dose at 0.5 mg/kg, to 5 rats/sex at 0.5 mg/kg (after 14 days of unlabeled Thiamethoxam) and to 5 rats/sex at 0.5 or 100 mg/kg by oral gavage or iv. Three groups of 4 male Tiflbm:MAG (SPF) mice receiving [Thiazol-2-(14)C] Thiamethoxam for 14 days at 118 mg/kg to determine excretion and metabolic fate in mice. In rats, the dose was rapidly absorbed from the G.I. tract into the general circulation with maximum blood levels (tCmax (hr) achieved 1 to 4 hours independent of the radiolabel site, dose level or sex. Cmax ranged from 0.17 to 0.20 ppm (low dose) and 33 to 43 ppm (high dose) and levels declined rapidly (tCmax/2 about 8 hours). Bioavailability 0.6 to 0.8 (males) and 0.7 to 0.9 (females) indicated sizable oral absorption. Absorbed material was primarily excreted via the urine (approximately 90%) compared to about 4% in feces within 24 hours. The preponderance of fecal elimination originated from biliary excretion. Half-lives in all tissues ranged from 2 to 6 hours. Comparison of metabolite patterns in mice and rats indicated that the major metabolic pathways were similar.
In mice, approximately 72% of the administered dose was excreted in the urine and 19% was excreted in feces. Small but measurable amounts were detected in expired air (approximately 0.2% of dose). Parent (33-41% of administered dose) and 2 predominant metabolites: 8-12% and 9-18% of administered dose were found. These are the same structures that were most commonly observed in rat excreta; however, the proportions are quite different in mouse excreta. One additional significant metabolite (mouse R6) was isolated from feces samples. Between 30-60% of the administered dose was excreted as metabolites.

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Metabolism / Metabolites
The major biotransformation reaction is cleavage of the oxadiazine ring to form the corresponding nitroguanidine compound (i.e., chlothianidin, the regulated metabolite in plants and livestock).
In the in vivo study compared rat and mouse plasma metabolite levels after 1-week or 10-week dietary exposures of 3000 ppm in rats and 2500 ppm in mice (N = 5). Plasma thiamethoxam levels were 12 and 4 ug/mL in 1-wk and 10- wk mice, and 7 and 19 ug/mL in respective rats. In mice, it appeared that metabolic induction was progressing over that interval, as CGA 265307 (downstream metabolite of both CGA 322704 and CGA 330050) increased from 2 to 5 ug/mL. CGA 322704 levels in mice stayed about the same and CGA 330050 levels were marginally reduced during this interval. In rats, CGA 322704 ranged from 1.0 to 0.6 ug/mL. Other metabolite levels were exceedingly low in rats: CGA 265307 at 0.05 to 0.09 ug/mL, and CGA 330050 at 0.10 to 0.14 ug/mL. Liver microsomal fractions were prepared from mice, rats, and humans for in vitro studies of metabolism of thiamethoxam to metabolites. In all cases, mice had the most rapid metabolic rates (i.e. for metabolism of thiamethoxam to CGA 322704, thiamethoxam to CGA 330050, CGA 322704 to CGA 265307, and CGA 330050 to CGA 265307). Rats had slightly higher metabolic rates than humans for these reactions.
Two male Tiflbm: RAI (SPF) rats/group were dosed once with 100 mg/kg [Oxadiazin-4-(14)C] CGA 293343 by gavage. Sacrifices were 0.5, 1, 2, 4, 6, 8, or 24 hrs after dosing. Blood was collected to assess total residues and to identify major metabolites. A TLC radiochromatogram of whole blood extracts taken 4 hrs post-dosing revealed 1 strong peak, one much lesser peak, and very little label outside those areas. The corresponding HPLC radiochromatogram revealed 2 perceptible peaks: thiamethoxam and CGA 322704. At peak levels of thiamethoxam (6 hrs after dosing), 99.8% of radiolabel was extractible. Extractible residues other than thiamethoxam and two metabolites were 1.74% of label. Maximum concentrations were at 6 hr for thiamethoxam and its metabolites. Estimated t1/2 were 2 hrs for thiamethoxam, 4 hrs for CGA 322704, and 8 hrs for CGA 265307. During the period from 0.5 to 8 hrs post-dosing, "other" residues graduated from 0.3% to 2.2% of extractible label. At 24 hours, total residues in blood were only 2% of the peak [6 hr] levels. Metabolic profile (as % of total radioactive residues of a given sampling time) for thiamethoxam, CGA 322704, and CGA 265307, respectively were 94.6%, 5.0%, and (below quantifiable levels) at 1 hr; 81.9%, 15.0%, and 1.2% at 6 hrs; and 15.5%, 30.6%, and 17.6% at 24 hrs. CGA 330050, a significant metabolite in mice, was not detectable.
Six male Tiflbm: MAG (SPF) mice/group were dosed once with 100 mg/kg [Oxadiazin-4-(14)C] Thiamethoxam by gavage. Sacrifices were 0.5, 1, 2, 4, 6, 8, or 24 hrs after dosing. Blood was collected to assess total residues and to identify major metabolites. A TLC radiochromatogram of whole blood extracts taken 1 hr post-dosing revealed 3 strong peaks, with very little label outside those areas. One of the peaks represented 2 constituents, so that the HPLC radiochromatogram revealed 4 perceptible peaks. These were thiamethoxam (dominant peak), and three metabolites: CGA 322704, CGA 265307, and CGA 330050. During the first hour, about 1.5% to 2.9% of label was non-extractible, whereas residues other than thiamethoxam and the above metabolites were below levels of detection. Kinetics parameters for TCmax (hr) 0.5 for thiamethoxam, and 2 for the three metabolites, and estimated t1/2 (hr) were 3 hr (for thiamethoxam and all metabolites). During the period from 4-8 hrs post-dosing, "other" residues constituted about 5% of extractible label. At 8 and 24 hours, respectively, total residues in blood were only 30% and 1% of the peak (0.5 hr) levels. Metabolic profile (as % of total radioactive residues of a given sampling time) for thiamethoxam, CGA 322704, CGA 265307, and CGA 330050, respectively were 77.5, 11.2, 3.2, and 6.6 at 0.5 hrs; 60.0, 15.7, 9.8, and 11.6 at 1 hr; and 39.5, 12.7, 30.4, and 9.0 at 8 hrs.
For more Metabolism/Metabolites (Complete) data for Thiamethoxam (6 total), please visit the HSDB record page.

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Biological Half-Life
The half-life times from rat tissue ranged from 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.

(4Z)-3-[(2-chloro-1,3-thiazol-5-yl)methyl]-5-methyl-N-nitro-1,3,5-oxadiazinan-4-imine has been reported in Streptomyces canus with data available.
Thiamethoxam is a neonicotinoid insecticide, which is a class of neuro-active insecticides modeled after nicotine. Nicotine was identified and used as an insecticide and rat poison as early as the 1600’s. Its effectiveness as an insecticide spurred a search for insecticidal compounds that have selectively less effect on mammals, which led to the discovery of neonicotinoids. Neonicotinoids, like nicotine, bind to nicotinic acetylcholine receptors of a cell. In mammals, nicotinic acetylcholine receptors are located in cells of both the central and peripheral nervous systems. In insects these receptors are limited to the CNS. While low to moderate activation of these receptors causes nervous stimulation, high levels overstimulate and block the receptors causing paralysis and death. Nicotinic acetylcholine receptors are activated by the neurotransmitter acetylcholine. Acetylcholine is broken down by acetylcholinesterase to terminate signals from these receptors. However, acetylcholinesterase cannot break down neonicotinoids and the binding is irreversible. Because most neonicotinoids bind much more strongly to insect neuron receptors than to mammal neuron receptors, these insecticides are selectively more toxic to insects than mammals. The low mammalian toxicity of neonicotinoids can be explained in large part by their lack of a charged nitrogen atom at physiological pH. The uncharged molecule can penetrate the insect blood–brain barrier, while the mammalian blood–brain barrier filters it. However, Some neonicotinoid breakdown products are toxic to humans, especially if they have become charged. Because of their low toxicity and other favorable features, neonicotinoids are among the most widely used insecticides in the world. Most neonicotinoids are water-soluble and break down slowly in the environment, so they can be taken up by the plant and provide protection from insects as the plant grows. Neonicotinoids are currently used on corn, canola, 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. The use of neonicotinoids has been linked in a range of studies to adverse ecological effects, including honey-bee colony collapse disorder (CCD) and loss of birds due to a reduction in insect populations. This has led to moratoriums and bans on their use in Europe.
A nitro-oxazine and thiazole derivative that is used as a broad spectrum neonicotinoid insecticide.

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Mechanism of Action
Agonist of the nicotinic acetylcholine receptor, affecting the synapses in the insect central nervous system.
Thiamethoxam, a neonicotinoid insecticide, which is not mutagenic either in vitro or in vivo, caused an increased incidence of liver tumors in mice when fed in the diet for 18 months at concentrations in the range 500 to 2500 ppm. A number of dietary studies of up to 50 weeks duration have been conducted in order to identify the mode of action for the development of the liver tumors seen at the end of the cancer bioassay. Both thiamethoxam and its major metabolites have been tested in these studies. Over the duration of a 50-week thiamethoxam dietary feeding study in mice, the earliest change, within one week, is a marked reduction (by up to 40%) in plasma cholesterol. This was followed 10 weeks later by evidence of liver toxicity including single cell necrosis and an increase in apoptosis. After 20 weeks there was a significant increase in hepatic cell replication rates. All of these changes persisted from the time they were first observed until the end of the study at 50 weeks. They occurred in a dose-dependent manner and were only observed at doses (500, 1250, 2500 ppm) where liver tumors were increased in the cancer bioassay. There was a clear no-effect level of 200 ppm. The changes seen in this study are consistent with the development of liver cancer in mice and form the basis of the mode of action. When the major metabolites of thiamethoxam, CGA322704, CGA265307, and CGA330050 were tested in dietary feeding studies of up to 20 weeks duration, only metabolite CGA330050 induced the same changes as those seen in the liver in the thiamethoxam feeding study. It was concluded that thiamethoxam is hepatotoxic and hepatocarcinogenic as a result of its metabolism to CGA330050. Metabolite CGA265307 was also shown to be an inhibitor of inducible nitric oxide synthase and to increase the hepatotoxicity of carbon tetrachloride. It is proposed that CGA265307, through its effects on nitric oxide synthase, exacerbates the toxicity of CGA330050 in thiamethoxam treated mice.
Thiamethoxam was shown to increase the incidence of mouse liver tumors in an 18 month study; however, thiamethoxam was not hepatocarcinogenic in rats. Thiamethoxam is not genotoxic, and, given the late life generation of mouse liver tumors, suggests a time-related progression of key hepatic events that leads to the tumors. These key events were identified in a series of studies of up to 50 weeks that showed the time-dependent evolution of relatively mild liver dysfunction within 10 weeks of dosing, followed by frank signs of hepatotoxicity after 20 weeks, leading to cellular attrition and regenerative hyperplasia. Metabolite CGA330050 was identified as generating the mild hepatic toxicity, and metabolite CGA265307 exacerbated the initial toxicity by inhibiting inducible nitric oxide synthase. This combination of metabolite-generated hepatotoxicity and increase in cell replication rates is postulated as the mode of action for thiamethoxam-related mouse liver tumors. The relevance of these mouse-specific tumors to human health was assessed by using the framework and decision logic developed by ILSI-RSI. The postulated mode of action was tested against the Hill criteria and found to fulfill the comprehensive requirements of strength, consistency, specificity, temporality, dose-response, and the collective criteria of being a plausible mode of action that fits with known and similar modes of action. Whereas the postulated mode of action could theoretically operate in human liver, quantitation of the key metabolites in vivo and in vitro showed that mice, but not rats or humans, generate sufficient amounts of these metabolites to initiate the hepatic toxicity and consequent tumors. Indeed, rats fed 3000ppm thiamethoxam for a lifetime did not develop hepatotoxicity or tumors. In conclusion, the coherence and extent of the database clearly demonstrates the mode of action for mouse liver tumorigenesis and also allows for 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.)