Thiamethoxam

History

Thiamethoxam was developed by Ciba-Geigy (now Syngenta) in 1991 and launched in 1998; a patent dispute arose with Bayer which already had patents covering other neonicotinoids including imidacloprid and clothianidin. In 2002 the dispute was settled, with Syngenta paying Bayer $120 million in exchange for worldwide rights to thiamethoxam.

Synthesis

Thiamethoxam was first prepared by chemists at Ciba Geigy in 1991. S-Methyl-N-nitro-isothiourea is treated with methylamine to give N-methyl nitroguanidine. This intermediate is used in a Mannich reaction with formaldehyde in formic acid to give 3-methyl-4-nitroimino-1,3,5-oxadiazinane. In the final step, the heterocycle is N-alkylated with a thiazole derivative to give a mixture of E and Z isomers of the final product. :[[File:Thiamethoxam synthesis v2.svg|upright=2]]

Mechanisms of action

Thiamethoxam is a broad-spectrum, systemic insecticide, which means it is absorbed quickly by plants and transported to all of its parts, including pollen, where it acts to deter insect feeding. An insect can absorb it in its stomach after feeding, or through direct contact, including through its tracheal system. The compound gets in the way of information transfer between nerve cells by interfering with nicotinic acetylcholine receptors in the central nervous system, and eventually paralyzes the muscles of the insects.

Syngenta asserts that thiamethoxam improves plant vigor by triggering physiological reactions within the plant, which induce the expression of specific "functional proteins" involved in various stress defense mechanisms of the plant allowing it to better cope under tough growing conditions, such as "drought and heat stress leading to protein degradation, low pH, high soil salinity, free radicals from UV radiation, toxic levels of aluminum, wounding from pests, wind, hail, etc, virus attack".

Toxicity

The selective toxicity of neonicotinoids like thiamethoxam for insects versus mammals is due to the higher sensitivity of insects' acetylcholine receptors. The Food and Agriculture Organization (FAO) of the U.N. assessed thiamethoxam as "moderately hazardous to humans (WHO class III)", because it is harmful if swallowed. It found it to be no skin or eye irritant, and not mutagenic in any in vitro and in vivo toxicology tests.

FAO described thiamethoxam as non-toxic to fish, daphnia and algae, mildly toxic for birds, highly toxic to midges and acutely toxic for bees. In bioassays of aquatic organisms, fish, aquatic primary producers, mollusks, worms, and rotifers are often largely insensitive to thiamethoxam concentrations found in surface waters, but insects, such as chironomid larvae are especially susceptible.

Sublethal doses of thiamethoxam metabolite clothianidin (0.05–2 ng/bee) have been known to cause reduced foraging activity since at least 1999, but this was quantified in 2012 by RFID tagged honeybees. Doses of equal or more than 0.5 ng/bee caused longer foraging flights.

Regulation and use

United States

Thiamethoxam has been approved for use in the US as an antimicrobial pesticide, wood preservative and as a insecticide; it was first approved in 1999. It is still approved for use in a wide range of crops.

On September 5, 2014 Syngenta petitioned the EPA to increase the legal tolerance for thiamethoxam residue in numerous crops. It wanted to use thiamethoxam as a leaf spray, rather than just a seed treatment, to treat late to midseason insect pests.

The estimated annual use of the compound in US agriculture is mapped by the US Geological Service and showed an increasing trend from its introduction in 2001 to 2014 when it reached 1420000 lb. However, use from 2015 to 2019 dropped sharply following concerns about the effect of neonicotinoid chemicals on pollinating insects. In May 2019, the Environmental Protection Agency revoked approval for a number of products containing thiamethoxam as part of a legal settlement. However, certain formulations continue to be available.

Neonicotinoids banned by the European Union

In 2012, several peer reviewed independent studies were published showing that several neonicotinoids had previously undetected routes of exposure affecting bees including through dust, pollen, and nectar; that sub-nanogram toxicity resulted in failure to return to the hive without immediate lethality, the primary symptom of colony collapse disorder; and showing environmental persistence in agricultural irrigation channels and soil. However, not all earlier studies carried out before 2014 have found significant effects. These reports prompted a formal peer review by the European Food Safety Authority, which stated in January 2013 that neonicotinoids pose an unacceptably high risk to bees, and that the industry-sponsored science upon which regulatory agencies' claims of safety have relied on may be flawed and contain several data gaps not previously considered. In April 2013, the European Union voted for a two-year restriction on neonicotinoid insecticides. The ban restricts the use of imidacloprid, clothianidin, and thiamethoxam on crops that attract bees.

In February 2018, the European Food Safety Authority published a new report indicating that neonicotinoids pose a serious danger to both honey bees and wild bees. In April 2018, the member states of the European Union decided to ban the three main neonicotinoids (clothianidin, imidacloprid and thiamethoxam) for all outdoor uses.

Other countries

Thiamethoxam is approved for a wide range of agricultural, viticultural(vineyard), and horticultural uses.

Emergency use

In January 2021 the UK allowed this pesticide to be used to save sugar beet plants in danger of damage from beet yellows virus which is transmitted by aphids. However, due to lower levels of this disease than was expected, it was announced in March 2021 that the conditions for emergency use had not been met. The UK made similar decisions in 2022, 2023, and 2024 but in these three years the predicted incidence level of yellow virus was met, and in March 2024 it was announced that the use of Cruiser SB (a pesticide which contains thiamethoxam) would be allowed for a third consecutive year.

References

References

1. Pesticide Properties Database. "Thiamethoxam". University of Hertfordshire.
2. PubChem Database. (2022-01-15). "N-[3-[(2-chloro-1,3-thiazol-5-yl)methyl]-5-methyl-1,3,5-oxadiazinan-4-ylidene]nitramide".
3. "Compendium of Pesticide Common Names". [[British Crop Production Council.
4. (2018-02-28). "Neonicotinoids: risks to bees confirmed {{!}} EFSA".
5. (2013). "Conclusion on the peer review of the pesticide risk assessment for bees for the active substance clothianidin". EFSA Journal.
6. US EPA, OCSPP. (2022-06-16). "EPA Finalizes Biological Evaluations Assessing Potential Effects of Three Neonicotinoid Pesticides on Endangered Species".
7. Carrington, Damian. (2018-04-27). "EU agrees total ban on bee-harming pesticides". The Guardian.
8. Milman, Oliver. (2022-03-08). "Fears for bees as US set to extend use of toxic pesticides that paralyse insects". The Guardian.
9. (October 2001). "Chemistry and biology of thiamethoxam: a second generation neonicotinoid". Pest Management Science.
10. (February 2001). "The discovery of thiamethoxam: a second-generation neonicotinoid". Pest Management Science.
11. West, Bob. (13 February 2002). "Syngenta Settles Patent Dispute with Bayer".
12. (2006). "Synthesis and Properties of Thiamethoxam and Related Compounds". Zeitschrift für Naturforschung B.
13. (21 June 2000). "FAO Specifications and Evaluations for Agricultural Pesticides: Thiamethoxam".
14. Syngenta. (2006). "Thiamethoxam Vigor Effect".
15. (2012). "Mammalian Toxicology of Insecticides". The Royal Society of Chemistry.
16. (February 2019). "The risk of neonicotinoid exposure to shrimp aquaculture". Chemosphere.
17. (February 2023). "Environmental occurrence, toxicity concerns, and biodegradation of neonicotinoid insecticides". Environmental Research.
18. (October 2017). "Comprehensive characterization of the acute and chronic toxicity of the neonicotinoid insecticide thiamethoxam to a suite of aquatic primary producers, invertebrates, and fish: Thiamethoxam acute and chronic aquatic toxicity". Environmental Toxicology and Chemistry.
19. (11 January 2012). "RFID Tracking of Sublethal Effects of Two Neonicotinoid Insecticides on the Foraging Behavior of Apis mellifera". PLOS ONE.
20. EPA Dec 21, 2011 [https://www.regulations.gov/document/EPA-HQ-OPP-2011-0581-0002 Thiamethoxam Summary Document Registration Review Initial Docket] Entire docket is available [https://web.archive.org/web/20140914044636/http://iaspub.epa.gov/apex/pesticides/f?p=CHEMICALSEARCH:31:0::NO:1,3,31,7,12,25:P3_XCHEMICAL_ID:4032 here]
21. [https://web.archive.org/web/20140914005505/http://ecfr.gpoaccess.gov/cgi-bin/text-idx?SID=2cec0a45ea0d311fb60cd0ea25baf029&node=se40.24.180_1565&rgn=div8 §180.565 Thiamethoxam; tolerances for residues.]
22. Syngenta. "Actara Insecticide".
23. (5 September 2014). "Receipt of Several Pesticide Petitions Filed for Residues of Pesticide Chemicals in or on Various Commodities". Federal Register.
24. (15 September 2014). "Syngenta Stands Firm On Neonicotinoids". American Chemical Society.
25. US Geological Survey. (2021-10-12). "Estimated Annual Agricultural Pesticide Use for thiamethoxam, 2019".
26. (3 September 2013). "EPA Actions to Protect Pollinators".
27. (21 May 2019). "EPA Curbs Use of 12 Bee-Harming Pesticides". [[Bloomberg News.
28. (29 April 2013). "Scientific opinions differ on bee pesticide ban". BBC News.
29. EFSA. (2012). "Assessment of the scientific information from the Italian project 'APENET' investigating effects on honeybees of coated maize seeds with some neonicotinoids and fipronil". EFSA Journal.
30. "Bees & Pesticides: Commission goes ahead with plan to better protect bees".
31. Damian Carrington, [https://www.theguardian.com/environment/2018/feb/28/total-ban-on-bee-harming-pesticides-likely-after-major-new-eu-analysis "Total ban on bee-harming pesticides likely after major new EU analysis"], ''[[The Guardian]]'', 28 February 2018 (page visited on 29 April 2018).
32. Damian Carrington, [https://www.theguardian.com/environment/2018/apr/27/eu-agrees-total-ban-on-bee-harming-pesticides "EU agrees total ban on bee-harming pesticides "], ''[[The Guardian]]'', 27 April 2018 (page visited on 29 April 2018).
33. (3 March 2021). "BBC News - UK allows emergency use of bee-harming pesticide". BBC News.
34. (4 March 2024). "Emergency pesticide authorisation to protect sugar beet crop conditionally approved".
35. "Defra's Chief Scientific Adviser's advice on the use of Cruiser SB for sugar beet in 2024".