Overview
The triazole compound propiconazole (Pcz), 1-[[2-(2,4- dichlorophenyl)-4-propyl-1, 3-dioxolan-2-yl]methyl]-1,2,4-triazole, is a kind of triazole fungicide (Fig. 1). It is used extensively in a variety of applications. It is used on grasses grown for seed, mushrooms, corn, wild rice, peanuts, almonds, sorghum, oats, pecans, apricots, peaches, nectarines, plums and prunes. On cereals it controls diseases caused by Erysiphe graminis, Leptosphaeria nodorum, Pseudocerosporella herpotrichoides, Puccinia spp., Pyrenophora teres, Rhynchosporium secalis, and Septoria spp.
[1, 2, 3] .
Wheat crops are among the commodities most heavily treated with fungicides in the United States, and propiconazole comprises approximately 90% of this application
[4]. Propiconazole is soluble in water at a concentration of 110 mg/L, and concentrations as high as 24 mg/L have been reported in waters receiving runoff from agricultural endeavors using the fungicide
[5].
It can act as a potent inhibitor of BR biosynthesis as has been found that it has inhibitory effect on hypocotyl elongation of cress plants (Lepidium sativum)
[6]. This inhibitory effect of Pcz was reversed by co-application with brassinolide. Based on the Pcz structure additional BR inhibitors, such as 2RS, 4RS-1-[2-(4- trifluoromethylphenyl)-4-n-propyl-1, 3-dioxolan-2-ylmethyl]-1H- 1,2,4-triazole, were identified
[6]. On the other hand, Pcz has been commercially used as fungistat (BannerMaxx, Syngenta) against a broad range of phytopathogenic fungi. Its fungistatic mode of action is the same as that of Ucz and Pac, blocking of lanosterol 14R-demethylase (CYP51A1)
[7, 8]. Pcz has also been studied extensively for its toxicity on plants, animals, humans, and the environment
[9, 10]. Here we present a molecular genetic analysis of Pcz’s effects on Arabidopsis and maize seedlings.
Figure 1 the chemical structure of propiconazole
Application
Triazole fungicides are used as clinical drugs and agricultural pesticides useful for the treatment and protection of corns, fruits, and other plants
[11-13]. It is a systemic fungicide with a broad range of activity and a wide range of agricultural cropping applications. It can be used for controlling the fungi diseases caused by Erysiphe graminis; Leptosphaeria nodorum; Pseudocerosporella herpotrichoides; Puccinia spp.; Pyrenophora teres; Rhynchosporium secalis; Septoria spp. It can be used at various plants such as Mushrooms; Corn; Wild rice; Peanuts; Amonds; Sorghum; Oats; Pecan; Fruit including apricots, plums, prunes, peaches & nectarines
[14].
Administration method
For the treatment of Powdery midew of grape, Anthracnose of grape, Anthrax, White rot, spray 25% EC 4000-6000 times mixed with water; For the treatment of Altermaria leaf spot and Venturia inaequalis of apple and pear, spray 25% EC 5000-6000 times mixed with water. For the treatment of Leaf spot and necrosis of peanuts, spray 25% EC 2500-4000 times mixed with water. For the treatment of leaf spot of bananas, spray 25% EC 1500 times mixed with water. For the treatment of Anthrax of Watermelon, Powdery mildew of water-melon, and Leaf spot of watermelon, spray 25% EC 4000-6000 times mixed with water. For the treatment of leaf spot of corn, spray 25% EC 1500 times mixed with water. For the treatment of powdery mildew of wheat, ornamental rust of wheat, spray 25% EC 4000-6000 times mixed with water. For the treatment of Bakanae disease of rice, dip in the seed mixed with water 1000 times for 2 to 3 days
[15].
Mode of action
Propiconazole's mode of action is demethylation of C-14 during ergosterol biosynthesis (through inhibiting the activity of 14a-demethylase as detailed below), and leading to accumulation of C-14 methyl sterols. The biosynthesis of these ergosterols is critical to the formation of cell walls of fungi. This lack of normal sterol production slows or stops the growth of the fungus, effectively preventing further infection and/or invasion of host tissues. Therefore, propiconazole is considered to be fungistatic or growth inhibiting rather than fungicidal or killing [2].
Sterol 14a-demethylase is a key enzyme for the fungal ergosterol biosynthesis. Inhibition of Sterol 14a-demethylase causes not only depletion of ergosterol but also accumulation of 14-methylsterols in fungal cells [16]. Since 14-methylsterols are unfavourable sterols for bio-membranes, inhibition of 14a-demethylase) seriously impairs the membrane function by the synergistic effects of ergosterol depletion and 14-methylsterol accumulation. Hence, Sterol 14a-demethylase inhibitors are an important class of antifungal agents, and a number of azole derivatives have been put to practical use as the potent antifungal medicines and agrochemicals of this class.
Propiconazole is also a potent inhibitor of Brassinosteroids biosynthesis. Brassinosteroids (BRs) are poly-hydroxylated steroidal hormones with profound effects on several physiological plant responses. They are involved in regulating cell elongation and division, vascular differentiation, photomorphogenesis, leaf angle inclination, seed germination, stomata development, as well as suppression of leaf senescence and abscission [17-22]. Studies showed that several steps of BR biosynthesis are mediated by cytochrome P450 monooxygenases (P450s) [23]. Triazole compounds have been shown to inhibit P450s, one of the largest and most ubiquitous groups of plant enzymes that catalyze oxidative processes in life systems [24].
Toxicity and environmental issue
Propiconazole (PCZ) is among the most heavily used in agriculture [25]. Triazole fungicides have a shorter half-life and lower bioaccumulation than organochlorine pesticides, but detrimental effects on the aquatic ecosystem may arise from spray drift or surface run-off after rainfall [11]. They have been reported to undergo transformation to secondary metabolites in terrestrial mammals [12, 26].
Acute toxicity
The acute toxicity to mammals for propiconazole technical are an acute oral LD50 for rats of 1,517 mg/kg and 1,344 mg/kg for rabbits. The acute dermal LD50 for rabbit was reported to be >4,000 mg/kg. Propiconazole was considered a slight irritant in rabbit skin and eye irritation studies. A skin sensitization study in guinea pigs demonstrated no allergic effect (2). The acute toxicity to mammals for the formulated products Orbit 3.6E, Tilt 3.6E and Banner 1.1E was as follows: acute oral LD50 for rats of 1,310 mg/kg. The acute dermal LD50 for rabbit was reported to be >5,010 mg/kg. The formulated products were considered a moderate irritant in rabbit skin and eye irritation studies. A skin sensitization study in guinea pigs resulted in the formulated product being considered a sensitizer [2, 27]. EPA toxicologists have recommended that the developmental No-ObservedEffect-Level (NOEL) of 30 mg/kg/day from the rat developmental toxicity study be used for acute dietary risk calculations. The lowest-effect-level (LEL) of 90 mg/kg/day is based on the increased incidence of unossified sternebrae, rudimentary ribs, and shortened or absent renal papillae.
Chronic effect
In two-year feeding studies in mice, the NOEL was established at 100 ppm. Significant increases were noted in the incidence of spontaneous liver tumors (benign) observed in male mice at the highest feeding level only. In two-year rat feeding studies, the no-effect-level was established at 100 ppm. There were no tumors in the rat at any feeding level. In one-year feeding studies in dogs, the NOEL was established at 250 ppm, the highest level tested (2). Based on the available chronic toxicity data, EPA has established the RfD for propiconazole at 0.013 mg/kg/day. This RfD is based on a 1 year dog feeding study with a NOEL of 1.25 mg/kg/day and an uncertainty factor of 100. The uncertainty factor of 100 was applied to account for inter-species extrapolation and intra-species variability. Mild irritation of the gastric mucosa was the effect observed at the LEL of 6.2 mg/kg/day [28]. A 21-day subchronic dermal toxicity test in rabbits found after 3 weeks (15 applications) moderate skin irritation to be the only effect following applications of propiconazole at 1000 mg/kg/day [2].
To fish
Fish exposed to fungicides in the environment exhibit a variety of biochemical changes, including those in the antioxidant defense system and other biochemical indices [25]. Long-term exposure to PCZ results in significantly increased ROS in fish brain, indicating severe oxidative stress. PCZ induced ROS formation can oxidize most cellular constituents, such as DNA, proteins, and lipids, causing damage to molecules, resulting in reduced enzymatic activity and affecting cellular integrity. Moreover, PCZ can cause inhibition of Na+–K+ATPase in fish brain after long-term exposure probably disturbed the Na+–K+ pump, resulting in the limitation of Na+–K+-ATPase synthesizing capability.
References
- Worthing, C. R., ed. 1983. The pesticide manual: A world compendium. Croydon, England: The British Crop Protection Council.
- Technical Information Bulletin for Propiconazole Fungicide. Ciba-Geigy. Greensboro, NC. 15 pp.
- W. T. Thomson. 1997. Agricultural Chemicals. Book IV: Fungicides. 12th edition. Thomson Publications, Fresno, CA.
- Garry VF, Schreinemachers D, Harkins ME, Griffith J. 1996. Pesticide appliers, biocides, and birth defects in rural Minnesota. Environ Health Perspect 104:394–399.
- Mortensen SR, Johnson KA, Weisskop CP, Hooper MJ, Lacher TE, Kendall RJ. 1998. Avian exposure to pesticides in Costa Rican Banana plantations. Bull Environ Contam Toxicol 60:562–568.
- Sekimata K, Han SY, Yoneyama K, Takeuchi Y, Yoshida S, et al. (2002) A specific and potent inhibitor of brassinosteroid biosynthesis possessing a dioxolane ring. J Agric Food Chem 50: 3486 3490.
- Yoshida Y, Aoyama Y (1991) Sterol I4a-demethylase and its inhibition: structural considerations on interaction of azole antifungal agents with lanosterol 14a-demethylase (P-45014DM) of yeast. Biochem Soc Trans 19: 778–782.
- Wiggins TE, Baldwin BC (1984) Binding of azole fungicides related to dichlobutrazol to cytochrome P450. Pest Sci 14: 206–209.
- Li Z, Zlabek V, Velisek J, Grabic R, Machova J, et al. (2011) Multiple biomarkers responses in juvenile rainbow trout, Oncorhynchus mykiss, after acute exposure to a fungicide propiconazole. Environ Toxicol DOI: 10.1002/ tox.20701.
- Thorstenson CW, Lode O (2001) Laboratory degradation studies of bentazone, dichlorprop, MCPA, and propiconazole in Norwegian soils. J Environ Qual 30: 947–953.
- Konwick BJ, Garrison AW, Avants JK, Fisk AT. 2006. Bioaccumulation and biotransformation of chiral triazole fungicides in rainbow trout (Oncorhynchus mykiss). Aquatic Toxicol 80:372–381.
- Chen PJ, Moore T, Nesnow S. 2008. Cytotoxic effects of propiconazole and its metabolites in mouse and human hepatoma cells and primary mouse hepatocytes. Toxicol Vitro 22:1476–1483.
- Li ZH, Randak T. 2009. Residual pharmaceutically active compounds (PhACs) in aquatic environment—Status, toxicity and kinetics: A review. Vet Med 52:295–314.
- https://sitem.herts.ac.uk/aeru/ppdb/en/Reports/551.htm
- http://www.udpf.com/pz2b7acb4-cz69c79f-propiconazole-25-ec.html
- Van den Bossche, H. (1985) in Current Topics in Medical Mycology (McCinnis, M. K. ed.), vol.1, pp. 3 13-345, Springer-Verlag, New York
- Azpiroz R, Wu Y, LoCascio JC, Feldmann KA (1998) An Arabidopsis brassinosteriod-dependent mutant is blocked in cell elongation. Plant Cell 10: 219–230.
- Yamamoto R, Demura T, Fukuda H (1997) Brassinosteroids induce entry into the final stage of tracheary element differentiation in cultured Zinnia cells. Plant Cell Physiol 38: 980–983.
- Neff MM, Nguyen SM, Malancharuvil EJ, Fujioka S, Noguchi T, et al. (1999) BAS1: a gene regulating brassinosteroid levels and light responsiveness in Arabidopsis. Proc Natl Acad Sci U S A 96: 15316–15323.
- Wada K, Marumo S, Ikekawa N, Morisaki M, Mori K (1981) Brassinolide and homobrassinolide promotion of lamina inclination of rice seedlings. Plant Cell Physiol 22: 323–325.
- Sasse JM, Smith R, Hudson I (1995) Effect of 24-epibrassinolide on germination of seeds of Eucalyptus camaldulensis in saline conditions. Proc Plant Growth Regul Soc Am 22: 136–141.
- Kim TW, Michniewicz MM, Bergmann DC, Wang ZY (2012) Brassinosteroid inhibits stomatal development by releasing GSK3-mediated inhibition of a MAP kinase pathway. Nature, Epub 2012/02/ 07.
- Fujioka S, Yokota T (2003) Biosynthesis and metabolism of brassinosteroids. Annu Rev Plant Biol 54: 137–164.
- Mizutani M, Ohta D (2010) Diversification of P450 genes during land plant evolution. Annu Rev Plant Biol 61: 291–315.
- Egaas, E., Sandvik, M., Fjeld, E., Kallqvist, T., Goksoyr, A., Svensen, A., 1999. Some effects of the fungicide propiconazole on cytochrome P450 and glutathione Stransferase in brown trout (Salmo trutta). Comp. Biochem. Physiol. C: Toxicol. Pharmacol. 122, 337–344.
- Sun, G.B., Thai, S.F., Tully, D.B., Lambert, G.R., Goetz, A.K., Wolf, D.C., Dix, D.J., Nesnow, S., 2005. Propiconazole-induced cytochrome P450 gene expression and enzymatic activities in rat and mouse liver. Toxicol. Lett. 155, 277–287.
- Technical Paper. Banner: A Turf Fungicide. Ciba-Geigy. Greensboro, NC. 21 pp.
- U.S. Environmental Protection Agency. Propiconazole; Pesticide Tolerances for Emergency Exemptions. Federal Register Document 96-29020. November 12, 1996.
Description
Propiconazole is a mixture of four stereoisomers and was first
developed in 1979 by Janssen Pharmaceutical of Belgium.
Chemical Properties
Colorless solid or a yellow thick liquid.
Odorless. Commercial product is available as an emulsifi-
able concentrate. Physical and toxicological properties may
be affected by carrier solvents in commercial formulations.
Chemical Properties
normally provided as a yellow liquid
Uses
Labelled Propiconazole (P770100). Systemic foliar fungicide. Agricultural fungicide.
Uses
Propiconazole is a triazole-based fungicide that is used to
control fungi in agriculture, on turf, and in wood.
Uses
Agricultural fungicide.
Production Methods
The commercial production of propiconazole involves a multi-step chemical synthesis that typically begins with ethanone-1-(2,4-dichlorophenyl), which undergoes condensation with 1,2-pentanediol to form a dioxolane intermediate. This intermediate is then brominated in dichloromethane to produce a bromomethyl derivative, which finally undergoes nucleophilic substitution with a sodium triazole salt in dimethyl sulfoxide at elevated temperatures to yield propiconazole.
Production Methods
Commercial production of trans-propiconazole mirrors the standard industrial synthesis of propiconazole but incorporates additional controls to enrich the trans isomer pair (2R,4S / 2S,4R). The core process begins with formation of the dioxolane intermediate from 2,4 dichloroacetophenone, followed by coupling with a 1,2,4 triazole derivative, steps well documented in propiconazole manufacturing literature. To obtain the trans enriched material, producers apply stereoselective crystallisation or controlled catalytic conditions during the dioxolane forming and triazole coupling stages, minimising formation of the cis isomers. Final purification removes unreacted intermediates and separates the desired trans isomer mixture, yielding technical grade trans propiconazole suitable for formulation.
Production Methods
Commercial production of cis-propiconazole mirrors the standard industrial synthesis of propiconazole but incorporates additional controls to enrich the cis isomer pair (2R,4S / 2S,4R). The core process begins with formation of the dioxolane intermediate from 2,4 dichloroacetophenone, followed by coupling with a 1,2,4 triazole derivative, steps well documented in propiconazole manufacturing literature. To obtain the cis enriched material, producers apply stereoselective crystallisation or controlled catalytic conditions during the dioxolane forming and triazole coupling stages, minimising formation of the trans isomers. Final purification removes unreacted intermediates and separates the desired cis isomer mixture, yielding technical grade cis propiconazole suitable for formulation.
Definition
ChEBI: Propiconazole is the cyclic ketal obtained by formal condensation of 1-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone with pentane-1,2-diol. A triazole fungicide, it is used commercially as a diastereoisomeric mixture on soft fruit (including apricots, peaches, nectarines, plums and prunes), nuts (including peanuts, pecans and almonds), mushrooms, and grasses grown for seeds. It has a role as a xenobiotic, an environmental contaminant, an EC 1.14.13.70 (sterol 14alpha-demethylase) inhibitor and an antifungal agrochemical. It is a member of triazoles, a cyclic ketal, a dichlorobenzene, a conazole fungicide and a triazole fungicide.
General Description
Yellowish odorless liquid. Non corrosive. Used as a fungicide.
Reactivity Profile
A triazole derivative.
Flammability and Explosibility
Not classified
Agricultural Uses
Fungicide: Used to control fungi on a broad range of crops and turf. Used on ornamentals, range land and rights-of-way to prevent and control powdery mildew and fungi on hardwoods and conifers.
Trade name
ALAMO®; BANNER®; BENIT®; BREAK®; BUMPER®; CGA-64250®; CGA-92710 F®; DESMEL®; FIDIS®; JUNO®; MANTI® S; MAXX®; NOVEL®; ORBIT®; PRACTIS®; PROPIMAX®; RADAR®; RESTORE®; SPIRE®; STRATEGO® (trifloxystrobin + propiconazole); TASPA®; TILT®; WOCOSIN®
Potential Exposure
Propiconazole is a triazole fungicide
used to control fungi on a broad range of crops and turf.
Used on ornamentals, range land and rights-of-way to pre-
vent and control powdery mildew and fungi on hardwoods
and conifers.
Environmental Fate
Routes and Pathways, and Relevant Physicochemical Properties
Log Kow＝3.72
Solubilities: 47 g l1 in n-hexane; completely miscible with
ethanol, acetone, toluene, and octanol; soluble in most organic
solvents; in water ＝ 100 mg l
-1 at 25°C
Henry's law constant＝ 4.1×10
-9 atm-cu mmol
-1 at
25°C
Partition Behavior in Water, Sediment, and Soil
Terrestrial Fate
Propiconazole penetrates the terrestrial environment in its
function as a fungicide for a variety of crops. In the terrestrial
environment, propiconazole is presented to be slightly persistent
to persistent. Biotransformation is an important route of
transformation for propiconazole, with major transformation
products being 1,2,4-triazole and compounds hydroxylated at
the dioxolane moiety. Phototransformation on soil or in air is not important for propiconazole transformation. Propiconazole
appears to have medium to low mobility in soil. It has the
potential to reach ground water through leaching, especially in
soils with low organic matter content. Propiconazole is typically
detected in the upper soil layers, but transformation
products were detected deeper in the soil profile.
Environmental Persistency
Propiconazole is persistent and relatively immobile in most
soil and aqueous environments. Propiconazole degradation in
the aquatic environment appears to be dependent solely on
aqueous photolysis. In the soil, propiconazole dissipation
appears to be dependent on binding to soil organic matter
content. The average half-life in soils ranges from months to
a year.
Propiconazole is expected to biodegrade in the environment.
The estimated half-life of propiconazole in aerobic soils
is about 40–70 days, and in aerobic waters is about 25–85 days.
Based on monitoring data and field tests, propiconazole has an
estimated half-life of about 60–96 days in typical soils. No
hydrolysis of propiconazole at environmentally relevant pH
has been observed.
Propiconazole degrades into triazole compounds, which
may still be toxic. Decomposition of propiconazole by heating
may release toxic gases.
Metabolic pathway
The numerous metabolites of propiconazole are
identified from rat urine and feces. Major sites for
enzymatic attack are the propyl side chain and the
cleavage of the dioxane ring. The 2,4-dichlorophenyl
ring is attacked in various ways including the formation of a cyclohexadiene ring system, hydroxylation,
replacement of the chlorine substituent by a hydroxy
group, and introduction of a methylthio group. The
1,2,4-triazole ring is oxidatively attacked, leading to
hydroxy derivatives. The vast majority of the alcoholic
and phenolic metabolites are excreted as sulfuric acid
and glucuronic acid conjugates. The major metabolic
pathway in mice is via cleavage of the dioxane ring.
Photolysis causes cleavage of the C1-triazole bond of
propiconazole, liberating 1,2,4-triazole as the major
product. Six more degradation products are identified
which are not included in the mammalian metabolites.
Shipping
UN3082 Environmentally hazardous substances,
liquid, n.o.s., Hazard class: 9; Labels: 9-Miscellaneous
hazardous material, Technical Name Required. UN3077
Environmentally hazardous substances, solid, n.o.s., Hazard
class: 9; Labels: 9-Miscellaneous hazardous material,
Technical Name Required.
Degradation
Photolysis of propiconazole (1) in hexane and methanolic solutions
irradiated with a high-pressure mercury lamp gave a mixture of products
2-8 (Scheme 1) (Dureja et al., 1987). The major product isolated was 1,2,4-
triazole (7). A monodechlorinated product (5) was formed in hexane. The
dioxolane ring was cleaved in methanol under these conditions.
Sunlight irradiation on a sandy loam soil surface for 48 days degraded
80% of the applied material and a DTs0 of about 12 days on soil was
derived through further rate studies. 1,2,4-Triazole (7) was the major
product identified after exposing a thin layer of propiconazole, coated as
a thin film, inside a Pyrex flask to sunlight for one month.
Toxicity evaluation
Propiconazole mode of action is demethylation of C-14
during ergosterol biosynthesis and leading to accumulation of
C-14 methyl sterols. The biosynthesis of these ergosterols is
critical to the formation of cell walls of fungi. This lack of
normal sterol production slows or stops the growth of the
fungus, effectively preventing further infection and/or invasion
of host tissues. Therefore, propiconazole is considered to
be fungistatic or growth inhibiting rather than fungicidal or
killing.
Incompatibilities
The triazoles are sensitive to heat,
friction, and impact. Sensitivity varies with the type
substitution to the triazole ring. Metal chelated and halogen
substitution of the triazol ring make for a particularly heat
sensitive material. Azido and nitro derivatives have been
employed as high explosives. No matter the derivative
these materials should be treated as explosives
Waste Disposal
Consult with environmental
regulatory agencies for guidance on acceptable disposal
practices. Contact a licensed disposal facility about surplus
and nonrecyclable solutions. Burn in a chemical incinerator
equipped with an afterburner and scrubber. Extra care must
be exercised as the material in an organic solvent is highly
flammable. In accordance with 40CFR165, follow recom-
mendations for the disposal of pesticides and pesticide con-
tainers. Containers must be disposed of properly by
following package label directions or by contacting your
local or federal environmental control agency, or by con-
tacting your regional EPA office. Incineration or permanga-
nate oxidation.
