Trifluralin#Microtubule Inhibition

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.{{cite journal |last1=Epp |first1=Jeffery B. |last2=Schmitzer |first2=Paul B. |last3=Crouse |first3=Gary D. |title=Fifty years of herbicide research: comparing the discovery of trifluralin and halauxifen-methyl |journal=Pest Management Science |date=4 July 2017|volume=74 |issue=1 |pages=9–16 |doi=10.1002/ps.4657 |pmid=28675627 |url=https://scijournals.onlinelibrary.wiley.com/doi/full/10.1002/ps.4657?saml_referrer#ps4657-bib-0019 |access-date=6 August 2024|url-access=subscription }} Application by incorporation into the top soil instead was eight times more potent.{{cite journal |last1=Anderson |first1=W. Powell |last2=Richards |first2=Anna Beth |last3=Whitworth |first3=J. Wayne |title=Trifluralin Effects On Cotton Seedlings |journal=Weeds |date=Jul 1967 |volume=15 |issue=3 |pages=224–227 |doi=10.2307/4041209 |jstor=4041209 |url=https://www.jstor.org/stable/4041209 |access-date=6 August 2024|url-access=subscription }} 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.

By 1968, trifluralin was internationally available, including Australia and New Zealand, and trifluralin was the 5th most used herbicide in the US, at {{convert|22,960,000|lbs|t}} by 1974.{{cite web |title=Pesticide Usage Survey of Agricultural, Governmental, and Industrial Sectors in the United States, 1974 |url=https://nepis.epa.gov/Exe/ZyPURL.cgi?Dockey=91012P4O.txt |website=epa.gov |publisher=EPA |date=1977}} The efficient post-emergent acetolactate synthase and ACCase inhibitors developed in 1980s significantly replaced trifluralin, though the trifluralin market has resurged, with weeds developing resistance to the post-emergents, and with rising no-till or low-till farming techniques.

Trifluralin was introduced to Latin America. It is used on sugarcane and soybean in Brazil, where {{convert|4.16|e6lb|t}} was used in 2019.

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.{{cite journal |last1=Gentner |first1=W. A. |title=Herbicidal Properties of Trifluralin Analogs |journal=Weeds |date=1966 |volume=14 |issue=2 |pages=176–178 |doi=10.2307/4040959 |jstor=4040959 }}

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.

Trifluralin, or other dinitroanilines, inhibits microtubule formation, by binding to tubulin proteins. Tubulin polymerises into microtubules, which make up the cellular cytoskeleton. Trifluralin binds to tubulin, and this misshapen 'herbicide complex' is incorporated into the growing microtubule, blocking further tubulin binding, and halting cell-division. It also depolymerises (splits) microtubules.{{cite journal |last1=Chen |first1=Jinyi |last2=Yu |first2=Qin |last3=Patterson |first3=Eric |last4=Sayer |first4=Chad |last5=Powles |first5=Stephen |title=Dinitroaniline Herbicide Resistance and Mechanisms in Weeds |journal=Frontiers in Plant Science |language=English |doi=10.3389/fpls.2021.634018 |date=25 March 2021|volume=12 |doi-access=free |pmid=33841462 |pmc=8027333 }}

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.

Due to the low solubility, high soil-adhesion and high volatility, dinitroaniline herbicides are absorbed into plants primarily via gaseous vapour.

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.

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.{{cite journal |last1=Busi |first1=Roberto |last2=Goggin |first2=Danica E |last3=Onofri |first3=Andrea |last4=Boutsalis |first4=Peter |last5=Preston |first5=Christopher |last6=Powles |first6=Stephen B |last7=Beckie |first7=Hugh J |title=Loss of trifluralin metabolic resistance in Lolium rigidum plants exposed to prosulfocarb recurrent selection |journal=Pest Management Science |date=December 2020 |volume=76 |issue=12 |pages=3926–3934 |doi=10.1002/ps.5993}} Some resistance mechanisms impose severe fitness cost on weeds, such as much reduced growth rate. Resistance has also been reduced experimentally by applying the organo-phosphate insecticide phorate, which reduces plants' production of the enzyme P450s, thus reducing metabolism of trifluralin in-plant.{{cite news |last1=Benjamin |first1=Cindy |title=Insecticide shown to reverse metabolic herbicide resistance |url=https://www.weedsmart.org.au/content/insecticide-shown-to-reverse-metabolic-herbicide-resistance/ |work=WeedSmart |date=2 February 2017 |language=en}}

Trifluralin is a Group D resistance class, (Aus), K1 or 3. (global or numeric){{cite web |title=Australia Herbicide Classification Lookup |url=https://hracglobal.com/tools/australia-classification-lookup/ |website=Herbicide Resistance Action Committee |language=en}}{{cite web |title=2024 HRAC Global Herbicide MOA Classification Master List |url=https://hracglobal.com/tools/2024-hrac-global-herbicide-moa-classification |website=Herbicide Resistance Action Committee |language=en}} Other Group D herbicides will experience resistance near identically.

Wheat and triticale, if affected by trifluralin, display reduced root extension, increased number of seminal roots, increased root diameter and decreased root dry weight.{{cite journal |last1=Olson |first1=B. M. |last2=McKERCHER |first2=R. B. |title=WHEAT AND TRITICALE ROOT DEVELOPMENT AS AFFECTED BY TRIFLURALIN |journal=Canadian Journal of Plant Science |date=1 July 1985 |volume=65 |issue=3 |pages=723–729|doi=10.4141/cjps85-092 }}

Trifluralin has been banned in the European Union since 20 March 2008, primarily due to high toxicity to aquatic life.{{cite web | url = http://archive.pic.int/CH/Demo/embed/view_displayFRA.php?id=1186&back=viewB_FRAchems.php?sort=chemical | title = European Union - Final Regulatory Action }} Specifically, due to aquatic risk, the toxicity of trifluralin's metabolites to sediment-organisms, and potential consumer exposure for non-cereal crops. They also had concerns over the aquatic toxicity, "high" potential for bioaccumulation, "high persistence in soil" and a potential for long range movement in the wind.{{cite web |title=Trifluralin 2007.pdf |url=https://ec.europa.eu/food/plant/pesticides/eu-pesticides-database/start/screen/active-substances/details/178 |website=ec.europa.eu |publisher=European Commission |access-date=25 April 2025}}

The United Kingdom banned it under the same legislation.{{cite news |last1=Abram |first1=Mike |title=Withdrawn herbicide trifluralin to be used up by March 2009 |url=https://www.fwi.co.uk/arable/withdrawn-herbicide-trifluralin-to-be-used-up-by-march-2009 |work=Farmers Weekly |date=3 April 2007}} With IPU banned at the same time, few options were left for farmers to control black-grass.{{cite news |last1=Abram |first1=Mike |title=Trifluralin replacements trialled for blackgrass control |url=https://www.fwi.co.uk/news/trifluralin-replacements-trialled-for-blackgrass-control |work=Farmers Weekly |date=7 August 2008}}

Trifluralin is on the United States Environmental Protection Agency list of Hazardous Air Pollutants as a regulated substance under the Clean Air Act.{{cite web |title=Initial List of Hazardous Air Pollutants with Modifications |date=16 December 2015 |url=https://www.epa.gov/haps/initial-list-hazardous-air-pollutants-modifications |publisher=United States Environmental Protection Agency |access-date=16 December 2021}}

Trifluralin is typically sold as emulsifiable concentrate{{cite web |title=4Farmers Trifluralin 480 Infosheet |url=https://4farmers.com.au/wp-content/uploads/2021/04/Trifluralin-480.pdf |website=4farmers.com.au |publisher=4Farmers Australia}} or granules. Application rates vary, such as 0.8-3.0 L of 480 g/L formulation per hectare, typically diluted with water,{{cite web |title=4Farmers Trifluralin 480 Leaflet |url=https://4farmers.com.au/wp-content/uploads/2018/06/Trifluralin-480-leaflet.pdf |website=4farmers.com.au |publisher=4Farmers Australia |access-date=28 May 2024}} and other compatible herbicides, e.g. isoproturon, 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. This is to minimise volatilisation losses from trifluralin's relatively high vapour pressure.{{cite web |title=PRE-EMERGENT HERBICIDES FACT SHEET |url=https://grdc.com.au/__data/assets/pdf_file/0032/575069/GRDC_PreEmergentFS_2022_Final-approved-version.pdf |publisher=Grains Research and Development Corporation |date=2022}} Selectivity is possible even on susceptible crops, by sowing below the herbicide band, and shallower germinating weeds will be controlled. Stubble-cover reduces effectiveness, but a greater water rate offsets the effect. A test saw 53% control of ryegrass at 30 L/Ha become 78% control at 150 L/Ha. Droplet size did not affect the results, and a similar effect was seen with pyroxasulfone, despite large differences in adsorption and solubility.{{cite web |last1=Benjamin |first1=Cinda |title=How to improve pre-em herbicide efficacy in high stubble situations? |url=https://www.weedsmart.org.au/content/how-to-improve-pre-em-herbicide-efficacy-in-high-stubble-situations/ |website=WeedSmart |access-date=12 May 2025 |language=en}}

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.{{cite journal | doi = 10.1021/es9912473 | title = Trifluralin Degradation under Microbiologically Induced Nitrate and Fe(III) Reducing Conditions | date = 2000 | last1 = Tor | first1 = Jason M. | last2 = Xu | first2 = Caifen | last3 = Stucki | first3 = Joseph M. | last4 = Wander | first4 = Michelle M. | last5 = Sims | first5 = Gerald K. | journal = Environmental Science & Technology | volume = 34 | issue = 15 | pages = 3148–3152 | bibcode = 2000EnST...34.3148T }}

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. It is extremely resistant to leaching, and shows little lateral soil movement. Repeated annual application shows steady and continuous decline in soil and does not accumulate, even applied well in excess of recommended rates.{{cite journal |last1=Parka |first1=S.J. |last2=Tepe |first2=J.B. |title=The Disappearance of Trifluralin from Field Soils |journal=Weed Science |date=Jan 1969 |volume=17 |issue=1 |pages=119–122|doi=10.1017/S0043174500031064 }}

Ultraviolet light can cause degradation. Trifluralin is stable to hydrolysis.

Trifluralin is safe for mammals and chickens, even in large amounts.{{cite journal |last1=Worth |first1=H. M. |last2=Anderson |first2=R. C. |title=The toxicity of trifluralin, Treflan, an herbicide, to mammals and chickens |journal=SWC |date=1965 |volume=18 |pages=711–712}} Mammals eliminate 85% after oral consumption within 72 hours. It is toxic to fish though: LC₅₀ for rainbow trout is 10-40 μg/L. Metabolism involves the thyroid; heavy and continuous exposure in rats can stress it via overstimulation.{{cite journal |last1=Saghir |first1=Shakil A. |last2=Charles |first2=Grantley D. |last3=Bartels |first3=Michael J. |last4=Kan |first4=Lynn H. L. |last5=Dryzga |first5=Mark D. |last6=Brzak |first6=Kathy A. |last7=Clark |first7=Amy J. |title=Mechanism of trifluralin-induced thyroid tumors in rats |journal=Toxicology Letters |date=30 July 2008 |volume=180 |issue=1 |pages=38–45 |doi=10.1016/j.toxlet.2008.05.019}}

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.{{cite journal |last1=Weichenthal |first1=Scott |last2=Moase |first2=Connie |last3=Chan |first3=Peter |title=A Review of Pesticide Exposure and Cancer Incidence in the Agricultural Health Study Cohort |journal=Environmental Health Perspectives |date=August 2010 |volume=118 |issue=8 |pages=1117–1125 |doi=10.1289/ehp.0901731|pmc=2920083 }} No association exists with lung cancer.{{cite journal |last1=Boulanger |first1=Mathilde |last2=Tual |first2=Séverine |last3=Lemarchand |first3=Clémentine |last4=Baldi |first4=Isabelle |last5=Clin |first5=Bénédicte |last6=Lebailly |first6=Pierre |title=0441 Exposure to dinitroanilines and risk of lung cancer (lc) by subtypes: results from the agrican cohort |date=August 2017 |pages=A140.1–A140 |doi=10.1136/oemed-2017-104636.365}} Trifluralin exposure can reduce cell apoptosis.{{cite journal |last1=Sarıgöl Kılıç |first1=Zehra |last2=Ündeğer Bucurgat |first2=Ülkü |title=The Apoptotic and Anti-Apoptotic Effects of Pendimethalin and Trifluralin on A549 Cells In Vitro |journal=The Turkish Journal of Pharmaceutical Sciences |date=2018 |doi=10.4274/tjps.94695|pmc=7227839 }}

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.{{cite journal |last1=Cecconi |first1=Sandra |last2=Rossi |first2=Gianna |last3=Carta |first3=Gaspare |last4=Di Luigi |first4=Gianluca |last5=Cellini |first5=Valerio |last6=Canipari |first6=Rita |last7=Buccione |first7=Roberto |title=Effects of trifluralin on the mouse ovary |journal=Environmental Toxicology |date=April 2013 |volume=28 |issue=4 |pages=201–206 |doi=10.1002/tox.20711}}

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.{{cite journal |last1=Kaczyński |first1=Piotr |last2=Iwaniuk |first2=Piotr |last3=Hrynko |first3=Izabela |last4=Łuniewski |first4=Stanisław |last5=Łozowicka |first5=Bożena |title=The effect of the multi-stage process of wheat beer brewing on the behavior of pesticides according to their physicochemical properties |journal=Food Control |date=June 2024 |volume=160 |pages=110356 |doi=10.1016/j.foodcont.2024.110356}}

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.{{cite journal |last1=Esteves |first1=M. A. |last2=Fragiadaki |first2=I. |last3=Lopes |first3=R. |last4=Scoulica |first4=E. |last5=Cruz |first5=M. E. M. |title=Synthesis and biological evaluation of trifluralin analogues as antileishmanial agents |journal=Bioorganic & Medicinal Chemistry |date=1 January 2010 |volume=18 |issue=1 |pages=274–281 |doi=10.1016/j.bmc.2009.10.059 |pmid=19926293 |url=https://www.sciencedirect.com/science/article/pii/S0968089609009948|url-access=subscription }}

Trifluralin also has anti-malarial properties and accumulates in parasite-infected erythrocytes, though low solubility makes effective administration of trifluralin difficult.{{cite journal |last1=Naughton |first1=Julie Ann |last2=Hughes |first2=Ruth |last3=Bray |first3=Patrick |last4=Bell |first4=Angus |title=Accumulation of the antimalarial microtubule inhibitors trifluralin and vinblastine by Plasmodium falciparum |journal=Biochemical Pharmacology |date=15 April 2008 |volume=75 |issue=8 |pages=1580–1587 |doi=10.1016/j.bcp.2008.01.002|pmid=18291349 }} Treatment of Toxoplasma gondii and cryptosporidiosis is effective but limited due to solubility.{{cite journal |last1=Benbow |first1=John W. |last2=Bernberg |first2=Erin L. |last3=Korda |first3=Anna |last4=Mead |first4=Jan R. |title=Synthesis and Evaluation of Dinitroanilines for Treatment of Cryptosporidiosis |journal=Antimicrobial Agents and Chemotherapy |date=February 1998 |volume=42 |issue=2 |pages=339–343 |doi=10.1128/aac.42.2.339|pmid=9527782 |pmc=105410 }}{{cite journal |last1=Endeshaw |first1=Molla M. |last2=Li |first2=Catherine |last3=Leon |first3=Jessica de |last4=Yao |first4=Ni |last5=Latibeaudiere |first5=Kirk |last6=Premalatha |first6=Kokku |last7=Morrissette |first7=Naomi |last8=Werbovetz |first8=Karl A. |title=Synthesis and evaluation of oryzalin analogs against Toxoplasma gondii |journal=Bioorganic & Medicinal Chemistry Letters |date=1 September 2010 |volume=20 |issue=17 |pages=5179–5183 |doi=10.1016/j.bmcl.2010.07.003|pmid=20675138 |pmc=2922421 }}

Liposome-administered trifluralin has been used to treat leishmania in dogs successfully.{{cite journal |last1=Marques |first1=C. |last2=Carvalheiro |first2=M. |last3=Pereira |first3=M. A. |last4=Jorge |first4=J. |last5=Cruz |first5=M. E. M. |last6=Santos-Gomes |first6=G. M. |title=Efficacy of the liposome trifluralin in the treatment of experimental canine leishmaniosis |journal=The Veterinary Journal |date=1 October 2008 |volume=178 |issue=1 |pages=133–137 |doi=10.1016/j.tvjl.2007.07.016|pmid=17855131 }}

• 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.

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, citrus fruit, lettuce, capsicums, tomatoes, artichokes, onions, garlic, brassicas, sugar beet, parsnips, carrots or soya. Trifluralin has had a huge market to control black-grass, but the weed was not listed on the label as being susceptible.{{cite news |title=What should be on the label? {{!}} NIAB |url=https://www.niab.com/news-views/blogs/what-should-be-on-the-label |access-date=12 January 2025 |work=www.niab.com |date=3 Feb 2012}}

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