Synthetic Pyrethroids

Synthetic Pyrethroids are widely used insecticides with wide range from applications apart from agricultural, like household insecticides, veterinary use and medicinal use. Presentation here covers every possible aspect right from discovery to most recent development in the field of Pyrethroids.

1. Synthetic Pyrethroids A s eminar by Meet Patel - 13DYE1001

2. Table of Contents Synthetic Pyrethroids – Discovery, Classification and Structures Novelty of synthetic pyrethroids Synthesis Process Application of synthetic pyrethroids Mode of action Mechanism of metabolism Recent developments Current market

3. Synthetic Pyrethroids – Discovery, Classification and Structures

4. Discovery Pyrethroids insecticides are synthetic analogues of the naturally occurring insecticidal pyrethrins found in extract of Chrysanthemum cinerariaefolium. J. J. Schleier & R. K. Peterson, Green Trends in Insect Control, Ch. 3, Royal Society of Chemistry, 2011, 94-13

5. Timeline and classification Dr. Bhupinder Khambay, Pyrethroids Insecticides, Pesticide Outlook,13,2002,49-54

6. Structures Allenthrin Resmethrin Permethrin Cypermethrin 1 st generation synthetic pyrethroids 2 nd generation synthetic pyrethroids Type I Type II

7. Structural changes Etofenprox Kadethrin Protriefenbute Fenvalerate Dr. Bhupinder Khambay, Pyrethroids Insecticides, Pesticide Outlook,13,2002,49-54

8. Stereochemistry- type I The 1R conformations about the cyclopropane ring are considerably more toxic than the 1S isomers . Cis isomers Trans isomers

9. Stereochemistry- type II Pyrethroid Product Isomers Stereo - chemistry Cypermethrin Alpha 2 (1R)-cis , α S (1S)-cis, α R Beta 4 (1R)-cis , α S (1S)-cis, α R (1R)-trans, α S (1S)-trans, α R Cyhalothrin Lambda 2 (1R)-cis , α S (1S)-cis, α R Super 1 (1R)-cis, α S Type II All type II pyrethroids possess an additional chiral center at the α -C with the α S conformation considerably more toxic towards insects when compared to the α R conformation. * * * Table: Examples of commercial product based on isomers i. Pyrethroids, Agrochemicals Analysis Technical Note , C oresta March 2014 ii. Dr . Bhupinder Khambay, Pyrethroids Insecticides, Pesticide Outlook,13,2002,49-54

10. 2 . Novelty of synthetic pyrethroids

11. Toxicity profile Noritada Matsuo & Tatsuya Mori, Pyrethroids:From Chrysanthemumto Modern Industrial Insecticide, 2012, Ch.1 Insecticides LD 50 (mg /kg) Mammal (rat) Insects Ratio of selectivity Carbamate 45(15) 2.8(27) 16 Organophosphorus 67(83) 2.0(50) 33 Organochlorine 230(21) 2.6(26) 91 Pyrethroids 2000(27) 0.45(35) 4500 *Number of pesticides tested in parenthesis

12. Toxicity Data The Pesticides Manual, Twelfth edition Insecticide Oral LD 50 ( rats) (mg/kg) Dermal LD 50 (rats) (mg/kg) Chlorpyrifos 135-163 2000 (rabbit) Diazinon 300-400 >2150 Deltamethrin 531-5000 >2000 Cypermethrin 251-4123 >2400 (rabbit) Bioresmethrin 7070-8000 >10000 (female) Allenthrin 1100 (male) >2300

13. Toxicity to non-target insects Fish Bee i. Noritada Matsuo & Tatsuya Mori, Pyrethroids:From Chrysanthemumto Modern Industrial Insecticide, 2012, Ch.1 i. F. Antwi, V. P. Reddy, Toxicology effects of pyrethroids on non-target aquatic insects, Environmental Toxicology and Pharmacology, September 2015 Pyrethroids LC 50 Value Carp(ppm/48 h) Daphnid(ppm/3 h) Silafluofen >100 7.66 Etofenprox 5 40 Cycloprothrin 8 >10 Fenvalerate 0.00075 0.3 Permethrin 0.043 >10 Cyfluthrin 0.012 0.94 Tralomethrin 0.008 0.22 Fluvalinate 0.00048 0.298 Pyrethroid Acute Oral LD 50 ( μ g a.i./bee ) Acute Contact LD 50 ( μ g a.i./bee ) Bifenthrin 0.01 0.002 Cypermethrin 0.03 0.02 Deltamethrin 0.08 0.001 Permethrin 0.03 0.1

14. Toxicity to humans Technical Report, Louise Hénault-Ethier, Canadian Association of Physicians for the Environment, 2016 Acute toxicity Chronic toxicity Eye irritation Change in immunity Mouth Ulcer Potential carcinogenicity Irritation in nasal cavity Non-specific symptoms Tremors Thyroid inactivity Paraesthesia & Cutaneous reactions Estrogenic & anti-androgenic activities Coma , convulsions & Death Neurotoxicity

15. Toxicity to humans – Case studies Case study 1 In a single case report, a 28-year-old man who applied some 1.5g permethrin in cream from neck to toe and did not wash for about 10 hours developed severe torticollis and inability to tilt his head to the left. This persisted unchanged for 24 hours and no cause other than the pesticide was identified. Case study 2 Of 12 workers who sprayed lambda Cyhalothrin indoors,11 complained of nasal irritation and six of throat irritation. Case study 3 A 45-year-old man died 3 hours after eating beans and cheese prepared using Cypermethrin 10% instead of oil. He developed symptoms within a few minutes, including prolonged vomiting, tenesmus, diarrhea, convulsions, coma. Death followed respiratory arrest . A. Vale, Poisoning due to Pyrethroids, Toxicological Reviews, February, 2005

16. Toxicity to environment Noritada Matsuo & Tatsuya Mori, Pyrethroids:From Chrysanthemumto Modern Industrial Insecticide, 2012, Ch.1 Isomerization Homolytic cleavage

17. Synergists Synergists are typically non toxic compounds at the dosage applied, but which enhance the toxicity of the active pesticide ingredients. Methylenedioxyphenyl synergists, such as piperonyl butoxide , are thought to suppress primarily oxidative detoxification by inhibiting enzymatic action of CYP enzyme within the insect. C. Pasa, L. Arlian, M. Morgan, R. Gunning, L. Rossiter, D. Holt, S. Walton, S. Beckham, J. McCarthy, Synergists in Pyrethroid-Resistant Scabies Mites , PLOS journal of neglected tropical diseases , January 2009, Volume 3, Issue 1 Treatment Sensitive mites Resistant mites Permethrin 4 15 Permethrin + PBO 4 4 Permethrin + DEF 3.5 6 Permethrin + DEM 2 3

18. 3 . Synthesis Process

19. Synthesis of chrysanthemic acid Trans-chrysanthemic acid First industrial process and its still used with better catalysts giving specifically 1R isomer which has more insecticidal activity. Professor Dr. Bernd Schaefer, Natural Products in the Chemical Industry, Springer-Verlag Berlin Heidelberg 2014, 704-723

20. Isomerization of chrysanthemic acid Thionyl chloride Lewis acid,150 ° to 170° C Cis : Trans = 45:55 Cis : Trans = 18.8:81.2 Cis : Trans ratio in the product depends on L ewis acid we use. Process for isomerization of a cyclopropane carboxylic acid, US 4008268 A, Sumitomo Chemical Company, 15 Feb 1977

21. Mechanism of Isomerization Dr. Klaus Naumann , Chemistry of Plant Protection, Ch. - Synthetic Pyrethroid Insecticides: Chemistry and Patents, 1990

22. Getting 1R isomer i. MeOH, H 2 O ii. Acid hydrolysis A process for the production of 1r pyrethroid esters,   WO 2003053905 A1, Syngenta Limited, Jul 3, 2003 Major product

23. Synthesis of GAMMA Cyhalothrin Three step synthesis:- Chlorinating acid derivative Esterification Epimerizing the diastereoisomeric mixture PRODUCTION PROCESS OF GAMMA-CYHALOTHRIN, Indian Patents: 219118, SYNGENTA LIMITED, Publication Date 06-Jun-2008 http:// www.allindianpatents.com/patents/219118-production-process-of-gamma-cyhalothrin (S )- α - cyano-3-phenoxybenzyl (Z)-(1R,3R)-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate

24. Chlorination Chlorinating agent Solvent, T b of solvent

25. Esterification C yanide source Solvent O rganic base 0°C and 20°C. D iastereoisomeric mixture of Cyhalothrin isomers

26. Epimerizing the diastereoisomeric mixture D iastereoisomeric mixture of Cyhalothrin isomers Solvent, -10°C to 10°C   S ource of cyanide / tertiary amine / a seed of gamma- C yhalothrin gamma-Cyhalothrin and a diastereomer ratio of 95:5. Second and third step can be done in a single reactor without any isolation but we need to compromise with yield. PRODUCTION PROCESS OF GAMMA-CYHALOTHRIN, Indian Patents: 219118, SYNGENTA LIMITED, Publication Date 06-Jun-2008 http:// www.allindianpatents.com/patents/219118-production-process-of-gamma-cyhalothrin

27. Formulations Pyrethroid Formulation Permethrin Emulsifiable concentrate (100-500 g a.i/l) Wettable powders (100-500 g/kg) Aerosol conc. & Fumigants ( household use) Cypermethrin Emulsifiable concentrate (25-200 g/l) ULV concentrates (10-50 g/l) Deltamethrin Emulsifiable concentrate (25 g a.i/l) Granules (0.5 g/kg) Wettable powders (25 g/l) Bioresmethrin Aerosol concentrates (1 g/l) Ready to use liquid (for oil/water based sprays, 2.5 g/l) The Pesticides Manual, Twelfth edition

28. 4 . Applications of synthetic pyrethroids

29. Agricultural applications Pyrethroids Insects Crops Bifenthrin Beetles, aphids, moths, locust, lice, houseflies Beans, cereals, corn, cotton, melons Cypermethrin Cockroaches, flies, moths, mosquitoes Cotton, onions, pears, peaches Deltamethrin Aphids, bollworms, caterpillars, cicadas Alfalfa, beet, maize, cotton potatoes, soyabean Fluvalinate Leafhoppers, thrips spider mites, moths Cereals, cotton, tobacco, apples Permethrin Ants, termites, lice, weevils, Cotton, lettuce, wheat, tomatoes

30. Other applications i. A.J . Thatheyus, A.Deborah Gnana Selvam, Synthetic Pyrethroids: Toxicity and Biodegradation, App. Eco. & Env . Sci., 2013, Vol. 1 , 33-36 ii http ://www.anapsid.org/pyrethroids.html

31. 5 . Mode of action

32. Mode of Action

33. Symptoms Mammalian intoxication by type I pyrethroids causes symptoms characterized by tremor i.e. T-class, exaggerated startle response, and hyperexcitability. Intoxication by type II pyrethroids results in burrowing and pawing behavior, followed by salivation and coarse tremor, which evolves into choreoathetosis (involuntary movement and writhing ). This second type of poisoning is referred to as CS-class . Some pyrethroids, such as fenpropathrin and cyphenothrin can result in symptoms from both T and CS-class, thus are called TS-class. i. E. Wakeling , A. Neal & W. Atchison, Pesticides-Advances in Chemical and Botanical Pesticides, Ch. 3 ii. Technical Report, Louise Hénault-Ethier, Canadian Association of Physicians for the Environment, 2016

34. Resistance to pyrethroids A major contributory factor is that pyrethroids exhibit cross-resistance to DDT , which is thought to act at the same binding site on the voltage-gated sodium channel. Dr. Bhupinder Khambay, Pyrethroids Insecticides, Pesticide Outlook,13,2002,49-54

35. 6 . Mechanism of metabolism

36. Metabolic pathways Hideo Kaneko, Pyrethroids: Mammalian Metabolism and Toxicity, J. Agric. Food Chem. 2011,59,2786–2791

37. Ester hydrolysis Hideo Kaneko, Pyrethroids: Mammalian Metabolism and Toxicity, J. Agric. Food Chem. 2011,59,2786–2791 Trans isomer Cis isomer

38. Oxidation i. Hideo Kaneko, Pyrethroids: Mammalian Metabolism and Toxicity, J. Agric. Food Chem. 2011,59,2786–2791 ii. Junshi Miyamoto, Degradation, Metabolism and Toxicity of Synthetic Pyrethroids, EHP, 1976, vol. 14,15-28 (1RS, trans)- tetramethrin Deltamethrin (1R, trans)- resmethrin (1R, tans)- phenothrin

39. Hydrophilic Conjugation Thiocynates conjugates Sulfonic acid conjugates Kaneko , H. Pyrethroid chemistry and metabolism, Hayes ’ Handbook of Pesticide Toxicology, 3rd ed ., 2010; Ch.76 . Hydrophilic conjugates are often found as glucuronides, sulfates, or amino acid conjugates . But in few pyrethroids other conjugates are also formed like

40. Lipophilic Conjugates Hideo Kaneko, Pyrethroids: Mammalian Metabolism and Toxicity, J. Agric. Food Chem. 2011,59,2786–2791

41. Metabolism of Cyhalothrin Glucuronide Glucuronide Glycerides Sulfate Kaneko , H. Pyrethroid chemistry and metabolism, Hayes ’ Handbook of Pesticide Toxicology, 3rd ed ., 2010; Ch.76 .

42. 7 . Recent developments

43. Discovery of Silafluofen H igh insecticidal activity and low mammalian toxicity, this compound features low fish toxicity, chemical stability under sunlight, in the soil and under alkaline environments. Acute oral toxicity for rat (LD 50 ): >5,000 mg/kg Acute dermal toxicity for rat (LD 50 ): >5,000 mg/kg Fish toxicity for carp (LC 50 after 48 hours): >100 ppm Y. Katsuda, Y. Minamite, and C. Vongkaluang , Development of Silafluofen-Based Termiticides in Japan and Thailand, December 2011

44. Discovery of Metofluthrin N. MATSUO, K. UJIHARA, Y. SHONO, T. IWASAKI, M. SUGANO, Discovery and Development of a Novel Pyrethroid Insecticide Metofluthrin (SumiOne®, Eminence®), SUMITOMO KAGAKU, vol. 2005-II. Compound Recovery rate(%) Metofluthrin 98.2 Empenthrin 82.7 d - Allenthrin 6.9 Prallenthrin 11.2 Photo stability Compound Culex pipiens Adese albopictus Metofluthrin 0.0015 0.00047 d - Allenthrin 0.038 0.023 Prallenthrin 0.0056 0.0050 D-tetramethrin 0.0096 0.0036 permethrin 0.0028 0.0012 LD 50 ( μ g/ female adult)

45. Properties of metofluthrin N. MATSUO, K. UJIHARA, Y. SHONO, T. IWASAKI, M. SUGANO, Discovery and Development of a Novel Pyrethroid Insecticide Metofluthrin (SumiOne®, Eminence®), SUMITOMO KAGAKU, vol. 2005-II. Efficacy Acute toxicity to mammals Species Route Lethal dose Rat Oral >2000 mg/kg Rat Dermal >2000 mg/kg Rat Inhalation Male: 1960 mg/ m 3 Female: 1080 mg/m 3 Dog Oral >2000 mg/kg Compound Conc. (%w/w) No. of mosquitoes Pretreatment After treatment Reduction% Metofluthrin 0.005 210 18 93 Transfluthrin 0.03 187 26 88 d - Allenthrin 0.3 188 27 88

46. 7 . Current Market & Future Scope

47. Current Market Pyrethroids account for up to 17% of global insecticide sales – a market worth more than $7Bn each year . Extermination Vegetal Farming Domestic Animal Farming Technical Report, Louise Hénault-Ethier, Canadian Association of Physicians for the Environment, 2016 http:// www.foodsecurity.ac.uk/research/impact/pyrethroids.html

48. Problems faced by Pyrethroids J. J. Schleier & R. K. Peterson, Green Trends in Insect Control, Ch. 3, Royal Society of Chemistry, 2011, 94-13

49. Alternatives to Pyrethroids Silicon dioxide provides an effective and safer control against household and pet animal pests. Bollcure – a biopesticides can be used on cotton. Biopesticides derived from vegetable oil can be used in grain protection. Alternative to Pyrethroids are Biopesticides A. Singh, A. Khare, A. P. Singh, Use of Vegetable Oils as Biopesticide in Grain Protection, J. of Fertilizers & Pesticides, January 25, 2012

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