Trifluralin

Trifluralin[1]
Names
Preferred IUPAC name
2,6-Dinitro-N,N-dipropyl-4-(trifluoromethyl)aniline
Other names
Treflan; α,α,α-trifluoro-2,6-dinitro-N,N-dipropyl-p-toluidine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.014.936 Edit this at Wikidata
KEGG
UNII
  • InChI=1S/C13H16F3N3O4/c1-3-5-17(6-4-2)12-10(18(20)21)7-9(13(14,15)16)8-11(12)19(22)23/h7-8H,3-6H2,1-2H3 checkY
    Key: ZSDSQXJSNMTJDA-UHFFFAOYSA-N checkY
  • InChI=1/C13H16F3N3O4/c1-3-5-17(6-4-2)12-10(18(20)21)7-9(13(14,15)16)8-11(12)19(22)23/h7-8H,3-6H2,1-2H3
    Key: ZSDSQXJSNMTJDA-UHFFFAOYAB
  • [O-][N+](=O)c1cc(cc([N+]([O-])=O)c1N(CCC)CCC)C(F)(F)F
Properties
C13H16F3N3O4
Molar mass 335.283 g·mol−1
Appearance Yellow crystals
Density 1360 kg/m3 [2]
Melting point 46 to 47 °C (115 to 117 °F; 319 to 320 K)
Boiling point 139 to 140 °C (282 to 284 °F; 412 to 413 K) (at 4.2 mmHg)
0.0024 g/100 mL
Solubility in acetone >1000 g/L[2]
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
 Toxic to aquatic life
Lethal dose or concentration (LD, LC):
>5000 mg/kg (rat, oral)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Trifluralin is a common pre-emergent selective herbicide, a dinitroaniline. With about 14 million pounds (6,400 t) used in the United States in 2001,[3] and 3–7 million pounds (1,400–3,200 t) in 2012,[4] it is one of the most widely used herbicides. Trifluralin is also used in Australia,[5] and New Zealand,[6] previously in the EU. Introduced in 1964, Trifluralin was the first organofluorine compound used as an agrochemical.[7]

Trifluralin is generally applied to the soil to control annual grass and broadleaf weed species. It inhibits root development by interrupting mitosis and controls weeds as they germinate.[5][8] Trifluralin moves very little inside the plant, remaining in the roots.[9]

Technical grade trifluralin crystals

Discovery

Selective herbicides were unavailable in the 1950s to protect soybean and cotton (2,4-DNP could have been used but had to be exactingly applied lest it destroy the crops), so Lilly Research Laboratories screened ~2000 compounds from 1958 to 1980 blindly looking for a result. Trifluralin was initially thought a failure, yet the plots stayed free of weeds weeks later.[7] Application by incorporation into the top soil instead was eight times more potent.[10] Pre-plant soil incorporation was a new technique at the time. It is unclear why trifluralin's exotic 4-trifluoromethyl was tested so early (1960), before more common candidates such as fluoro, bromo, or iodo.[7]

By 1968, trifluralin was internationally available, including Australia and New Zealand,[6] and trifluralin was the 5th most used herbicide in the US, at 22,960,000 pounds (10,410 t) by 1974.[11]

Analogs

Related compounds show similar herbicidal properties. In a study of 16, trifluoromethyl (as trifluralin is) compounds proved more active pre-emergence, and methyl compounds more active post-emergence. Replacing trifluralin's two propyl groups (with ethyl, allyl or butyl) yielded lower pre-emergent activity in all cases; post-emergence activity was highest in ethyl, allyl combination analogs.[12]

Nitralin replaces the trifluroromethyl group with a methylsulfonyl. Benfluralin replaces the propyl-propyl groups with ethyl-butyl. Profluralin replaces one propyl group with cyclopropylmethyl. Profluralin and nitralin are mostly obsolete, but benfluralin is commercially used, though less so than trifluralin.

Mechanism and effects

Trifluralin inhibits tubulin formation,[5] by binding to tubulin, and when the resulting herbicide complex is built into the growing micro-tubule, it blocks further tubulin binding, halting growth.[13] It also depolymerises (splits) the microtubules.

Dinitroanilines hit microtubules in plants and protists, but not animals, nor fungi, nor carrots, whose microtubules, even in purified form in laboratory work, are unaffected.[13]

Resistance

Resistance, where evolved, can be through mutated α- or β-tubulin, particularly common in protists. This resistance is especially hard to evolve for weeds to tubulin disrupting herbicides because both α-tubulin and β-tubulin must mutate, as imbalance between their expressions is potentially lethal. Non-target-site resistance is usually though increased metabolism of trifluralin. Mobility-related mechanisms are not effective as minimal movement in the weed is needed to prevent germination.[13]

Resistance has been shown to devolve under repeated application of prosulfocarb on lolium rigidum (ryegrass). Supposedly, the mechanism of prosulfocarb-resistance is inverse to trifluralin resistance, requiring lower metabolism of herbicide, rather than greater. Therefore, when growing resistance for with one mechanism, the weeds undo their resistance to the other.[14] Some resistance mechanisms impose severe fitness cost on weeds, such as much reduced growth rate.[13]

Trifluralin is a Group D resistance class, (Aus),[15] K1 or 3. (global or numeric)[16][17] Other Group D herbicides will experience resistance near identically.

Symptoms

Wheat and triticale, if affected by trifluralin, display reduced root extension, increased number of seminal roots, increased root diameter and decreased root dry weight.[18]

Environmental regulation

Trifluralin has been banned in the European Union since 20 March 2008, primarily due to high toxicity to aquatic life.[19] The United Kingdom banned it under the same legislation.[20] With IPU banned at the same time, few options are left for controlling black-grass.[21]

Trifluralin is on the United States Environmental Protection Agency list of Hazardous Air Pollutants as a regulated substance under the Clean Air Act.[22]

Application

Trifluralin is typically sold as emulsifiable concentrate[15] or granules.[2] Application rates vary, such as 0.8-3.0 L of 480 g/L formulation per hectare, typically diluted with water,[5] and other compatible herbicides, e.g. isoproturon,[2] to be sprayed in one go.

Trifluralin must be incorporated into soil within 24 hours of sowing, or in some cases sooner. Various methods achieve this; most involve machinery set to 5-13 cm deep.[5] This is to minimise volatilisation losses from trifluralin's relatively high vapour pressure.[23] Selectivity is possible even on susceptible crops, by sowing below the herbicide band, and shallower germinating weeds will be controlled.[5]

Environmental behavior

Trifluralin breaks down into many products as it degrades, ultimately being incorporated into soil-bound residues or converted to carbon dioxide (mineralized). Among the more unusual behaviors of trifluralin is inactivation in wet soils. This has been linked to transformation of the herbicide by reduced soil minerals, which in turn had been previously reduced by soil microorganisms using them as electron acceptors in the absence of oxygen. This environmental degradation process has been reported for many structurally related herbicides (dinitroanilines) as well as a variety of explosives such as TNT and picric acid.[24]

Trifluralin has a long half-life in soil of ~180 days, but it is accepted at high application rates because of its low soil mobility and high volatility.[7] It is extremely resistant to leaching, and shows little lateral soil movement.[2] Repeated annual application shows steady and continuous decline in soil and does not accumulate, even applied well in excess of recommended rates.[25]

Ultraviolet light can cause degradation. Trifluralin is stable to hydrolysis.[2]

Health Effects

Trifluralin is safe for mammals and chickens, even in large amounts.[26] Mammals eliminate 85% after oral consumption within 72 hours. It is toxic to fish though: LC50 for rainbow trout is 10-40 μg/L.[2] Metabolism involves the thyroid; heavy and continuous exposure in rats can stress it via overstimulation.[27]

Cancer

There is discussion of trifluralin being carcinogenic. Some studies have shown links, such as a 1986 study of three non-hodgkin lymphoma cases. A later, larger study found no significant relation. A review study examined trifluralin against kinds of cancer, finding no link except to colon cancer, which was found in only one studied cohort. Research on humans remains unconvincing, but EPA animal toxicity data "supports the possible carcinogenicity" of trifluralin.[28] No association exists with lung cancer.[29] Trifluralin exposure can reduce cell apoptosis.[30]

Trifluralin on mammalian ovaries (tested in mice, at 150 mg/kg/day) showed no effect on oocyte quality, but may induce a stress response in ovarian somatic cells. Fertility was unaffected. Levels of pRb stayed unchanged, though trifluralin raised levels of p53, a tumor suppressing gene, by 2.5 times. The additional p53 appeared not to increase rates of apoptosis.[31]

Food

Due to trifluralin's high vapour pressure, food residue is reduced in processing, especially in high temperature processes, such as in the mashing of beer.[32]

Medical Use

Trifluralin can be used as ointment to treat Leishmaniasis welts on the skin. It, and other dinitroanilines, are tubulin-binding agents with selective antileishmanial properties, leishmania being the parasite causing the disease, which killed 60,000 people in 2001. Research into expanding's trifluralin's medical use is stymied by its low water solubility and easy sublimation. Trifluralin analogues have been tried, and some show greater efficacy than miltefosine; all trifluralin analogues have the benefits of being non-hemolytic and lower cell toxicity.[33]

Trifluralin also has anti-malarial properties and accumulates in parasite-infected erythrocytes, though low solubility makes effective administration of trifluralin difficult.[34] Treatment of Toxoplasma gondii and cryptosporidiosis is effective but limited due to solubility.[35][36] Liposome-administered trifluralin has been used to treat leishmania in dogs successfully.[37]

Tradenames and lists

  • Trifluralin
  • Treflan
  • Trilin
  • Trust
  • Tri-4
  • Edge
  • Snapshot (formulation of isoxaben and trifluralin)

Commercial formulations have included trifluralin mixtures with: linuron, napropamide, metribuzin, clomazone,tebutam, bromoxynil and ioxynil, isoproturon, terbutryn, trietazine, neburon and isoxaben.[2]

Crops trifluralin is used in include: Wheat, barley, cotton, triticale, rye, sunflowers, sugar cane, peas, canola, safflower, peanuts, tobacco, pigeon peas, lupins, lucerne, linseed, legume seed, strawberry, lentils, faba beans, chickpeas, cowpeas, lablab, mung beans, borlotti beans, red beans, adzuki beans,[5] citrus fruit, lettuce, capsicums, tomatoes, artichokes, onions, garlic, brassicas, sugar beet, parsnips, carrots or soya.[2]

References

  1. ^ Merck Index, 11th Edition, 9598.
  2. ^ a b c d e f g h i Tomlin, Clive (1994). The Pesticide Manual Incorporating the Agrochemicals Handbook (Tenth ed.). State Library of Western Australia: The Royal Society of Chemistry. p. 1025. ISBN 0-948404-79-5.
  3. ^ 2000-2001 Pesticide Market Estimates, United States Environmental Protection Agency
  4. ^ "Pesticides Industry Sales and Usage 2008 – 2012 Market Estimates" (PDF).
  5. ^ a b c d e f g "4Farmers Trifluralin 480 Leaflet" (PDF). 4farmers.com.au. 4Farmers Australia. Retrieved 28 May 2024.
  6. ^ a b "Application for Approval to Import or Manufacture GF-1981 for Release" (PDF). 24 Mar 2010.
  7. ^ a b c d Epp, Jeffery B.; Schmitzer, Paul B.; Crouse, Gary D. (4 July 2017). "Fifty years of herbicide research: comparing the discovery of trifluralin and halauxifen-methyl". Pest Management Science. 74 (1): 9–16. doi:10.1002/ps.4657. PMID 28675627. Retrieved 6 August 2024.
  8. ^ Grover, Raj; Wolt, Jeffrey D.; Cessna, Allan J.; Schiefer, H. Bruno (1997). "Environmental Fate of Trifluralin". Reviews of Environmental Contamination and Toxicology. Vol. 153. pp. 1–64. doi:10.1007/978-1-4612-2302-3_1. ISBN 978-1-4612-7492-6. PMID 9380893.
  9. ^ Moreland, D. E.; Farmer, F. S.; Hussey, G. G. (1 October 1972). "Inhibition of photosynthesis and respiration by substituted 2,6-dinitroaniline herbicides: I. Effects on chloroplast and mitochondrial activities". Pesticide Biochemistry and Physiology. 2 (3): 342–353. Bibcode:1972PBioP...2..342M. doi:10.1016/0048-3575(72)90039-9.
  10. ^ Anderson, W. Powell; Richards, Anna Beth; Whitworth, J. Wayne (Jul 1967). "Trifluralin Effects On Cotton Seedlings". Weeds. 15 (3): 224–227. doi:10.2307/4041209. JSTOR 4041209. Retrieved 6 August 2024.
  11. ^ "Pesticide Usage Survey of Agricultural, Governmental, and Industrial Sectors in the United States, 1974". epa.gov. EPA. 1977.
  12. ^ Gentner, W. A. (1966). "Herbicidal Properties of Trifluralin Analogs". Weeds. 14 (2): 176–178. doi:10.2307/4040959. JSTOR 4040959.
  13. ^ a b c d Chen, Jinyi; Yu, Qin; Patterson, Eric; Sayer, Chad; Powles, Stephen (25 March 2021). "Dinitroaniline Herbicide Resistance and Mechanisms in Weeds". Frontiers in Plant Science. 12. doi:10.3389/fpls.2021.634018. PMC 8027333. PMID 33841462.
  14. ^ Busi, Roberto; Goggin, Danica E; Onofri, Andrea; Boutsalis, Peter; Preston, Christopher; Powles, Stephen B; Beckie, Hugh J (December 2020). "Loss of trifluralin metabolic resistance in Lolium rigidum plants exposed to prosulfocarb recurrent selection". Pest Management Science. 76 (12): 3926–3934. doi:10.1002/ps.5993.
  15. ^ a b "4Farmers Trifluralin 480 Infosheet" (PDF). 4farmers.com.au. 4Farmers Australia.
  16. ^ "Australia Herbicide Classification Lookup". Herbicide Resistance Action Committee.
  17. ^ "2024 HRAC Global Herbicide MOA Classification Master List". Herbicide Resistance Action Committee.
  18. ^ Olson, B. M.; McKERCHER, R. B. (1 July 1985). "WHEAT AND TRITICALE ROOT DEVELOPMENT AS AFFECTED BY TRIFLURALIN". Canadian Journal of Plant Science. 65 (3): 723–729. doi:10.4141/cjps85-092.
  19. ^ "European Union - Final Regulatory Action".
  20. ^ Abram, Mike (3 April 2007). "Withdrawn herbicide trifluralin to be used up by March 2009". Farmers Weekly.
  21. ^ Abram, Mike (7 August 2008). "Trifluralin replacements trialled for blackgrass control". Farmers Weekly.
  22. ^ "Initial List of Hazardous Air Pollutants with Modifications". United States Environmental Protection Agency. 16 December 2015. Retrieved 16 December 2021.
  23. ^ "PRE-EMERGENT HERBICIDES FACT SHEET" (PDF). Grains Research and Development Corporation. 2022.
  24. ^ Tor, Jason M.; Xu, Caifen; Stucki, Joseph M.; Wander, Michelle M.; Sims, Gerald K. (2000). "Trifluralin Degradation under Microbiologically Induced Nitrate and Fe(III) Reducing Conditions". Environmental Science & Technology. 34 (15): 3148–3152. Bibcode:2000EnST...34.3148T. doi:10.1021/es9912473.
  25. ^ Parka, S.J.; Tepe, J.B. (Jan 1969). "The Disappearance of Trifluralin from Field Soils". Weed Science. 17 (1): 119–122. doi:10.1017/S0043174500031064.
  26. ^ Worth, H. M.; Anderson, R. C. (1965). "The toxicity of trifluralin, Treflan, an herbicide, to mammals and chickens". SWC. 18: 711–712.
  27. ^ Saghir, Shakil A.; Charles, Grantley D.; Bartels, Michael J.; Kan, Lynn H. L.; Dryzga, Mark D.; Brzak, Kathy A.; Clark, Amy J. (30 July 2008). "Mechanism of trifluralin-induced thyroid tumors in rats". Toxicology Letters. 180 (1): 38–45. doi:10.1016/j.toxlet.2008.05.019.
  28. ^ Weichenthal, Scott; Moase, Connie; Chan, Peter (August 2010). "A Review of Pesticide Exposure and Cancer Incidence in the Agricultural Health Study Cohort". Environmental Health Perspectives. 118 (8): 1117–1125. doi:10.1289/ehp.0901731. PMC 2920083.
  29. ^ Boulanger, Mathilde; Tual, Séverine; Lemarchand, Clémentine; Baldi, Isabelle; Clin, Bénédicte; Lebailly, Pierre (August 2017). "0441 Exposure to dinitroanilines and risk of lung cancer (lc) by subtypes: results from the agrican cohort": A140.1–A140. doi:10.1136/oemed-2017-104636.365. {{cite journal}}: Cite journal requires |journal= (help)
  30. ^ Sarıgöl Kılıç, Zehra; Ündeğer Bucurgat, Ülkü (2018). "The Apoptotic and Anti-Apoptotic Effects of Pendimethalin and Trifluralin on A549 Cells In Vitro". The Turkish Journal of Pharmaceutical Sciences. doi:10.4274/tjps.94695. PMC 7227839.
  31. ^ Cecconi, Sandra; Rossi, Gianna; Carta, Gaspare; Di Luigi, Gianluca; Cellini, Valerio; Canipari, Rita; Buccione, Roberto (April 2013). "Effects of trifluralin on the mouse ovary". Environmental Toxicology. 28 (4): 201–206. doi:10.1002/tox.20711.
  32. ^ Kaczyński, Piotr; Iwaniuk, Piotr; Hrynko, Izabela; Łuniewski, Stanisław; Łozowicka, Bożena (June 2024). "The effect of the multi-stage process of wheat beer brewing on the behavior of pesticides according to their physicochemical properties". Food Control. 160: 110356. doi:10.1016/j.foodcont.2024.110356.
  33. ^ Esteves, M. A.; Fragiadaki, I.; Lopes, R.; Scoulica, E.; Cruz, M. E. M. (1 January 2010). "Synthesis and biological evaluation of trifluralin analogues as antileishmanial agents". Bioorganic & Medicinal Chemistry. 18 (1): 274–281. doi:10.1016/j.bmc.2009.10.059. PMID 19926293.
  34. ^ Naughton, Julie Ann; Hughes, Ruth; Bray, Patrick; Bell, Angus (15 April 2008). "Accumulation of the antimalarial microtubule inhibitors trifluralin and vinblastine by Plasmodium falciparum". Biochemical Pharmacology. 75 (8): 1580–1587. doi:10.1016/j.bcp.2008.01.002. PMID 18291349.
  35. ^ Benbow, John W.; Bernberg, Erin L.; Korda, Anna; Mead, Jan R. (February 1998). "Synthesis and Evaluation of Dinitroanilines for Treatment of Cryptosporidiosis". Antimicrobial Agents and Chemotherapy. 42 (2): 339–343. doi:10.1128/aac.42.2.339. PMC 105410. PMID 9527782.
  36. ^ Endeshaw, Molla M.; Li, Catherine; Leon, Jessica de; Yao, Ni; Latibeaudiere, Kirk; Premalatha, Kokku; Morrissette, Naomi; Werbovetz, Karl A. (1 September 2010). "Synthesis and evaluation of oryzalin analogs against Toxoplasma gondii". Bioorganic & Medicinal Chemistry Letters. 20 (17): 5179–5183. doi:10.1016/j.bmcl.2010.07.003. PMC 2922421. PMID 20675138.
  37. ^ Marques, C.; Carvalheiro, M.; Pereira, M. A.; Jorge, J.; Cruz, M. E. M.; Santos-Gomes, G. M. (1 October 2008). "Efficacy of the liposome trifluralin in the treatment of experimental canine leishmaniosis". The Veterinary Journal. 178 (1): 133–137. doi:10.1016/j.tvjl.2007.07.016. PMID 17855131.
  • Trifluralin in the Pesticide Properties DataBase (PPDB)