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Benomyl
Names
Preferred IUPAC name
1-(Butylcarbamoyl)-1H-1,3-benzimidazol-2-yl methylcarbamate
Other names
Benomyl
Identifiers
3D model (JSmol)
825455
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.037.962 Edit this at Wikidata
EC Number
  • 241-775-7
KEGG
RTECS number
  • DD6475000
UNII
UN number 3077 2757
  • InChI=1S/C14H18N4O3/c1-3-4-9-15-13(19)18-11-8-6-5-7-10(11)16-12(18)17-14(20)21-2/h5-8H,3-4,9H2,1-2H3,(H,15,19)(H,16,17,20) checkY
    Key: RIOXQFHNBCKOKP-UHFFFAOYSA-N checkY
  • InChI=1/C14H18N4O3/c1-3-4-9-15-13(19)18-11-8-6-5-7-10(11)16-12(18)17-14(20)21-2/h5-8H,3-4,9H2,1-2H3,(H,15,19)(H,16,17,20)
    Key: RIOXQFHNBCKOKP-UHFFFAOYAA
  • O=C(n1c2ccccc2nc1NC(=O)OC)NCCCC
Properties
C14H18N4O3
Molar mass 290.323 g·mol−1
Appearance white crystalline solid[1]
Odor acrid[1]
Melting point 290 °C (554 °F; 563 K) decomposes[1]
0.0004% (20 °C)[1]
Hazards
GHS labelling:[2]
GHS06: ToxicGHS07: Exclamation markGHS08: Health hazardGHS09: Environmental hazard
Danger
H315, H317, H335, H340, H360, H410
P203, P261, P264, P271, P272, P273, P280, P302+P352, P304+P340, P316, P317, P318, P319, P321, P332+P317, P333+P317, P362+P364, P391, P403+P233, P405, P501
Flash point noncombustible[1]
NIOSH (US health exposure limits):
PEL (Permissible)
 TWA 15 mg/m3 (total) TWA 5 mg/m3 (resp)[1]
REL (Recommended)
 none[1]
IDLH (Immediate danger)
 N.D.[1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Benomyl (also marketed as Benlate) is a fungicide introduced in 1968 by DuPont. It is a systemic benzimidazole fungicide that is selectively toxic to microorganisms and invertebrates (especially earthworms), but relatively nontoxic toward mammals.[3]

Due to the prevalence of resistance of parasitic fungi to benomyl, it and similar pesticides are of diminished effectiveness. Nonetheless, it is widely used.

Toxicity

[edit]

Benomyl is of low toxicity to mammals. It has an arbitrary LD50 of "greater than 10,000 mg/kg/day for rats". Skin irritation may occur through industrial exposure, and florists, mushroom pickers and floriculturists have reported allergic reactions to benomyl.[citation needed]

In a laboratory study, dogs fed benomyl in their diets for three months developed no major toxic effects, but did show evidence of altered liver function at the highest dose (150 mg/kg). With longer exposure, more severe liver damage occurred, including cirrhosis.[citation needed]

The US Environmental Protection Agency classified benomyl as a possible carcinogen. Carcinogenic studies have produced conflicting results. A two-year experimental study on mice has shown it "probably" causes an increase in liver tumours. The British Ministry of Agriculture Fisheries and Food took the view this was brought about by the hepatotoxic effect of benomyl.[citation needed]

In regards to occupational exposures to benomyl, the Occupational Safety and Health Administration has set a permissible exposure limit of 15 mg/m3 for total exposure over an eight-hour time-weighted average, and 5 mg/m3 for respiratory exposures.[4]

Birth defects

[edit]

In 1996, a Miami jury awarded US$4 million to a child whose mother was exposed in pregnancy to Benlate. The child was born with severe eye defects (clinical anophthalmia). The mother had been exposed to an unusually high dose of this compound through her exposure from a nearby farm, during pregnancy. An important issue in the case was the timing and magnitude of exposure.[citation needed]

In October 2008, DuPont paid confidential settlements to two New Zealand families whose children were born with various birth defects.[5] The mother of one of the children had been exposed to Benlate while working as a Christchurch parks worker before his birth.[6]

Environmental effects

[edit]

Benomyl binds strongly to soil and does not dissolve in water to any great extent. It has a half-life in turf of three to six months, and in bare soil, a half-life of six months to one year.[citation needed]

In 1991, DuPont issued a recall of its Benlate 50DF formula due to suspected contamination with the herbicide atrazine. In the wake of the recall, many US growers blamed Benlate 50DF for destroying millions of dollars' worth of crops. Growers filed over 1,900 damage claims against DuPont, mostly involving ornamental crops in Florida. Subsequent testing by DuPont determined the recalled product was not contaminated with atrazine. The reason for the alleged crop damage is unclear. The Florida Department of Agriculture and Consumer Services suggested Benlate was contaminated with dibutylurea and sulfonylurea herbicides.[citation needed]

After several years of legal argument, DuPont paid out about US$750 million in damages and out-of-court settlements. By 1993, a coalition of farm worker and environmental groups came together to form "Benlate Victims Against DuPont", a group which called for a nationwide boycott of DuPont products.[citation needed]

After carrying out tests, DuPont denied Benlate was contaminated with dibutylurea and sulfonylureas and stopped compensation pay-outs. In 1995, a Florida judge rejected a complaint from the Florida Department of Agriculture that had alleged such a link.[citation needed]

Cellular biology

[edit]

Benomyl is used in molecular biology to study the cell cycle in yeast; in fact, the name of the protein class "Bub" (Bub1, etc.) comes from their mutant in which budding was uninhibited by benomyl. Benomyl acts by depolymerizing microtubules.[7] Benomyl is also useful in the laboratory because it is selectively toxic to most members of the Ascomycota, whereas members of the Basidiomycota are largely resistant.[8]

References

[edit]

Further reading

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Benomyl

View on Grokipedia
from Grokipedia
Benomyl is a synthetic developed by E.I. du Pont de Nemours and Company and introduced in 1968 for protecting agricultural crops against fungal diseases caused by Ascomycetes and . It functions systemically, with the parent compound rapidly hydrolyzing in and soils to its active metabolite , which inhibits fungal by binding to β-tubulin and disrupting assembly. Widely applied as a foliar spray, , or soil drench on fruits, , nuts, and field crops, benomyl provided effective broad-spectrum control but contributed to the development of resistance in target pathogens due to its single-site . Despite its utility in boosting crop yields, benomyl exhibited selective toxicity toward non-target organisms, including high sensitivity in earthworms and aquatic species like and , stemming from its persistence in (half-life up to several months under certain conditions) and moderate mobility. In mammals, it displayed relatively low (EPA category IV), though subchronic inhalation exposure caused respiratory irritation, and its metabolite raised concerns over potential reproductive and developmental effects in laboratory animals. These empirical risks, alongside detections in and field impacts on beneficial , prompted regulatory scrutiny; the U.S. EPA canceled registrations by 2003, the never approved it under modern standards, and similar bans followed in and elsewhere due to inadequate risk mitigation outweighing benefits. ceased production around 2001 amid these pressures and litigation over alleged off-target plant damage, marking the decline of benomyl despite its historical role in advancing systemic technology.

Chemical Properties

Molecular Structure and Synthesis

Benomyl has the molecular formula C₁₄H₁₈N₄O₃ and a molar mass of 290.32 g/mol. Its systematic name is methyl N-[1-(butylcarbamoyl)-1H-benzimidazol-2-yl]carbamate. The molecule features a benzimidazole ring system, with the 2-position substituted by a methyl carbamate group (-NHCO₂CH₃) and the 1-nitrogen bearing a butylcarbamoyl substituent (-CONH(CH₂)₃CH₃). This arrangement of functional groups enables its role as a systemic fungicide precursor to active metabolites. Benomyl is prepared by reacting carbendazim (methyl 1H-benzimidazol-2-ylcarbamate) with n-butyl isocyanate. The reaction occurs in an aprotic solvent such as dichloromethane, with addition of the isocyanate to the deprotonated carbendazim, often facilitated by a base like triethylamine, followed by stirring at room temperature and purification by filtration and washing. This method yields the 1-substituted benzimidazole derivative characteristic of benomyl.

Physical Characteristics and Stability

Benomyl is a white crystalline solid with a faint acrid and molecular formula C14H18N4O3, corresponding to a of 290.3 g/mol. Its is approximately 1.16 g/cm³, and it exhibits low volatility with a below 5.0 × 10-6 Pa at 25°C. Benomyl decomposes upon heating without a defined , with decomposition observed above 300°C or as low as 140°C under certain conditions. It has very low in , ranging from 2 mg/L at pH 7 and 20°C to 3.6 mg/L at pH 5 and 24°C, rendering it essentially insoluble under neutral to acidic aqueous conditions. Regarding stability, benomyl remains stable under dry storage conditions with exclusion of moisture, but it readily hydrolyzes in aqueous environments to form (methyl 1H-benzimidazol-2-ylcarbamate), its primary degradation product. This decomposition occurs rapidly in regardless of exposure, with photolysis playing a negligible role in its breakdown; half-lives in sterile are short, often on the order of hours to days depending on and . Formulated products are stable when protected from humidity, but aqueous suspensions or solutions lead to conversion to , which itself has limited persistence in and due to further microbial degradation.

Mechanism of Action

Biochemical Interactions

Benomyl exerts its primary biochemical effect through its rapid to , the that binds specifically to β-tubulin subunits in fungal cells, thereby inhibiting . This binding occurs at a distinct site on β-tubulin, near but not identical to the colchicine-binding domain, with key interaction residues including at position 198 (E198) and nearby such as those at positions 200 and 246. Mutations at these sites, such as E198A or L246F, disrupt the binding affinity, conferring resistance to benomyl and its derivatives in various fungal species. The interaction destabilizes dimers, preventing their assembly into functional essential for intracellular transport and structural integrity. studies demonstrate that benomyl inhibits polymerization with an of approximately 70-75 μM using mammalian brain as a proxy, though fungal tubulins exhibit higher sensitivity due to evolutionary differences in binding pocket architecture. This binding is non-covalent and reversible, but sustained exposure leads to accumulation of unpolymerized , amplifying the disruption. Binding assays with radiolabeled confirm reduced affinity in resistant β-tubulin variants from fungi like and . Beyond , benomyl induces secondary via generation, though this is downstream of the primary microtubule-targeted interaction and not directly mediated by tubulin binding. No significant interactions with α-tubulin or other major cytoskeletal proteins have been reported, underscoring the specificity to β-tubulin as the dominant biochemical target.

Effects on Fungal Cells

Benomyl exerts its antifungal effects primarily through its metabolite carbendazim, which binds selectively to β-tubulin in fungal cells, inhibiting the polymerization of tubulin dimers into microtubules. Microtubules are essential cytoskeletal components required for intracellular transport, maintenance of cell shape, and formation of the mitotic spindle during nuclear division. This binding disrupts microtubule assembly without significantly affecting already polymerized microtubules, leading to the collapse of dynamic microtubule networks. The inhibition of microtubule function arrests fungal cells in the stage of , preventing segregation and . In filamentous fungi, this manifests as suppressed hyphal tip growth, abnormal branching patterns, and the formation of multinucleate compartments due to failed nuclear migration and division. Hyphal elongation is particularly impaired because guide vesicle transport to the apex, and their disruption halts the polarized deposition of materials. At the cellular level, benomyl exposure induces in fungal cells, exacerbating damage through accumulation, which further compromises membrane integrity and enzymatic functions. Resistance to benomyl often arises from point mutations in the β-tubulin gene (e.g., at codons or ), reducing affinity and allowing microtubule polymerization to proceed. These effects are concentration-dependent, with effective inhibition occurring at micromolar levels that spare most plant tubulins due to sequence differences.

History and Development

Discovery and Early Research

Benomyl, chemically methyl [1-[(butylamino)carbonyl]-1H-benzimidazol-2-yl]carbamate, was synthesized and developed by chemists at in the mid-1960s as part of a screening program for systemic s capable of broad-spectrum control of fungal pathogens. This effort targeted compounds that could be absorbed and translocated within plants, addressing limitations of earlier contact fungicides like dithiocarbamates. DuPont's agricultural products department identified benomyl's potential after evaluating its degradation to the carbendazim, which provided enhanced persistence and efficacy. The compound was first registered and introduced commercially in 1968 under the trade name Benlate, marking it as the inaugural for agricultural use. Early laboratory and greenhouse studies conducted by researchers in 1966–1967 demonstrated benomyl's systemic uptake via roots and foliage, with translocation to untreated plant parts occurring within hours of application. These experiments revealed its selective toxicity to fungi through disruption of assembly, inhibiting nuclear division in pathogens such as and powdery mildew species (Erysiphe spp.), while showing minimal at recommended doses of 0.5–1 kg per . Initial absorption and metabolism assays, using radiolabeled benomyl on crops like and apples, confirmed rapid conversion to in plant tissues, with residues detectable up to 14 days post-application. Field trials initiated in 1967 across the and validated benomyl's curative and protective effects against Ascomycete diseases, achieving 80–95% control of foliar pathogens in fruits, , and ornamentals, outperforming non-systemic alternatives in humid conditions. By 1969, peer-reviewed publications from DuPont-affiliated studies reported its efficacy against soil-borne fungi like , expanding its scope beyond foliar applications to treatments. These findings, disseminated in journals such as Phytopathology, underscored benomyl's role in advancing technology toward single-site, targeted modes of action, though early observations hinted at risks of resistance development in high-pressure pathosystems.

Commercial Introduction and Adoption

Benomyl, marketed primarily under the Benlate by E.I. du Pont de Nemours and Company (), was commercially introduced in 1968 as a systemic . This marked a significant advancement in agricultural , as benomyl represented one of the earliest broad-spectrum systemic agents capable of being absorbed by and translocated to protect against fungal infections internally. Initial formulations included 50% wettable powders, which facilitated foliar applications on crops such as fruits, , and ornamentals. Adoption accelerated rapidly following its U.S. registration in 1970, with expanding marketing to over 50 countries by the mid-1970s, driven by its efficacy against diverse pathogens including , Botrytis, and powdery mildews. Farmers valued its protective and curative properties, which allowed for fewer applications compared to contact fungicides, contributing to higher yields in intensive cropping systems; for instance, it became a staple in , , and turf management. By the early 1970s, benomyl had supplanted many older protectant fungicides in commercial agriculture due to its versatility and lower use rates, with global usage peaking in the 1980s before resistance and regulatory pressures emerged. A dry flowable formulation (Benlate DF) was launched in 1987 to improve handling and reduce dust, further boosting adoption among growers despite early reports of in sensitive crops. Its widespread integration into programs reflected empirical evidence of yield protections, such as 20-50% reductions in disease incidence in treated fields, though overuse in systems later prompted concerns over fungal resistance development.

Agricultural Applications

Targeted Crops and Diseases

Benomyl, a systemic , was applied to a broad spectrum of agricultural commodities, including pome fruits (apples and pears), stone fruits (peaches, nectarines, plums, apricots, cherries), nuts (almonds, pistachios, walnuts, pecans), berries (strawberries, raspberries, blueberries), grapes, , bananas, (tomatoes, celery, cucumbers, eggplants, carrots, , peppers), field crops (, , beans, corn), pineapples, mangoes, turf, ornamentals, and mushrooms, primarily as foliar sprays, seed treatments, or soil drenches to suppress fungal infections. Among the targeted diseases were (Venturia inaequalis) and powdery mildew on apples and pears; powdery mildew (Erysiphe necator) and Botrytis bunch rot (Botrytis cinerea) on grapes; anthracnose (Colletotrichum spp.) and common on strawberries and other berries; bloom diseases (e.g., shot hole, brown rot) on almonds and stone fruits; and blights on vegetables like tomatoes (early blight, Septoria ) and celery; Fusarium head blight (scab) on wheat; and dollar spot, brown patch, and on turf. The following table summarizes select examples of major crop-disease pairings where benomyl demonstrated efficacy prior to widespread resistance development and regulatory restrictions:
Crop CategorySpecific CropsKey Diseases Controlled
Pome FruitsApples, pearsScab (Venturia inaequalis), powdery mildew
GrapesGrapesPowdery mildew, Botrytis bunch rot
BerriesStrawberries, raspberriesAnthracnose, leaf spot
NutsAlmonds, pistachiosBloom diseases, fungal blights
VegetablesTomatoes, celeryEarly blight, leaf spots, fungal pathogens
Turf/OrnamentalsTurf grasses, ornamentalsDollar spot, brown patch, powdery mildew
These applications often involved rates of 0.125–1 lb active ingredient per acre, with pre-harvest intervals varying from 1 day (tomatoes) to 4 weeks (fruits and nuts), reflecting its role in both preventive and curative control strategies.

Efficacy Data and Yield Impacts

Benomyl demonstrated substantial efficacy in controlling fungal diseases such as Septoria brown spot in soybeans, with field studies indicating that yield responses varied based on the number and timing of applications; multiple foliar applications often reduced disease severity and enhanced yields more effectively than single treatments under moderate to high disease pressure. In related trials on soybeans, benomyl applications suppressed anthracnose and Phomopsis seed rot, yielding an additional increase of approximately 300 kg/ha beyond potassium fertilization alone. However, efficacy and yield benefits were genotype-dependent, with some indeterminate and determinate soybean cultivars showing no significant response to benomyl under varying Septoria brown spot conditions. In trials conducted in southeast from 1973 to 1975, single timed sprays of benomyl effectively curbed foliar pathogens, while programs involving two or more applications produced greater mean yield increases, typically outperforming untreated controls by reducing disease progression during key growth stages. For sheath blight in , sequential applications of benomyl following significantly lowered disease severity and boosted yields in three of four field evaluations, highlighting its role in integrated under endemic conditions. In canola, aerial applications of benomyl markedly decreased sclerotinia stem rot incidence in cultivars like Altex and , correlating with preserved yield potential in central Alberta fields. Yield impacts were most pronounced under high disease incidence, where benomyl's systemic action prevented yield losses of 10-30% attributable to unchecked fungal infections, though results diminished in low-pressure environments or with emerging resistance; for instance, early adoption in the 1960s-1970s U.S. field tests confirmed broad-spectrum protectant and curative effects across pathogens, translating to consistent harvest gains in fruits, , and cereals when applied preventively. Overall, documented yield uplifts ranged from 0.3 to 0.74 t/ha in responsive scenarios, underscoring benomyl's value prior to regulatory shifts, albeit with variability tied to environmental factors and application precision.

Regulatory Status

Initial Approvals and Global Usage

Benomyl was first registered as a by the (EPA) in 1969, following its introduction by E.I. du Pont de Nemours and Company (DuPont) in 1968 as a systemic under the trade name Benlate. This approval enabled its initial commercial use in the for controlling fungal diseases on crops such as fruits, , and ornamentals, marking it as one of the early benzimidazole-class fungicides to gain regulatory clearance. Globally, benomyl achieved widespread registration in over 50 countries by the and , reflecting its adoption for agricultural applications on more than 70 crop types, including cereals, , grapes, bananas, and plantation crops. Annual worldwide usage reached approximately 1,700 tonnes by the early 1990s, positioning it as a dominant product in the market, where it reportedly accounted for a substantial share of global sales prior to heightened regulatory scrutiny. Its systemic properties and broad-spectrum efficacy against fungal pathogens facilitated extensive application in both developed and developing agricultural sectors, particularly for foliar sprays, seed treatments, and soil drenches. Usage patterns varied by region, with higher volumes in countries reliant on export-oriented farming, such as those producing bananas and other tropical fruits, where benomyl's role in disease management supported yield stability amid prevalent fungal threats. In many jurisdictions, initial approvals emphasized its low to mammals (classified as EPA IV), which contributed to its rapid global proliferation before long-term health and environmental data prompted reevaluations.

Restrictions, Bans, and Phasing Out

In the United States, the Environmental Protection Agency (EPA) issued a cancellation order for all benomyl registrations on August 8, 2001, following DuPont's voluntary request for cancellation on April 18, 2001, due to concerns over potential risks to human health, including reproductive and developmental toxicity, and environmental contamination. Existing stocks were permitted for use until depleted, with tolerances for residues in food revoked by September 2002, effectively phasing out the from agricultural applications. In the , benomyl was not approved under Regulation (EC) No 1107/2009, with inclusion in I of Directive 91/414/EEC lapsing by , 2003, after highlighted its carbendazim's as toxic to reproduction (category 1B) and aquatic life. Temporary derogations were granted in some member states, such as until 2004, for essential uses, but overall authorization expired, leading to a continent-wide ban on sales and use. Australia prohibited the supply and use of benomyl-containing products after December 6, 2006, as determined by the Australian Pesticides and Veterinary Medicines Authority (APVMA), citing insufficient evidence of safety margins for dietary and occupational exposure risks. In , benomyl was banned for manufacture, import, and use via notification S.O. 3951(E) on August 8, 2018, amid broader restrictions on pesticides linked to hazards. followed suit in 2018, including benomyl in a list of eight banned pesticides to address and suicide-related concerns. Globally, bans and restrictions in developed nations stem primarily from benomyl's rapid conversion to , which exhibits , endocrine disruption, and persistence in soil and , prompting phase-outs despite prior widespread approval. While prohibited in the , , , and increasingly in , residual use persists in some developing countries where alternatives are limited, though international pressure via has lowered maximum residue levels toward default limits of quantification.

Human Health Effects

Acute and Chronic Toxicity Studies

Acute toxicity studies indicate low mammalian for benomyl via oral and dermal routes. The acute oral LD50 in rats exceeds 5000 mg/kg body weight, while the acute dermal LD50 in rabbits also surpasses 5000 mg/kg. Benomyl causes mild, reversible eye in rabbits but no primary skin . The acute LC50 in rats is greater than 2 mg/L air. Benomyl metabolizes rapidly to , its primary toxic metabolite, which exhibits slightly higher dermal toxicity (EPA Toxicity Category III) but remains low for oral exposure (Category IV). In humans, acute exposures primarily manifest as dermal and , the most common health effect reported among agricultural workers. No severe acute systemic poisonings have been widely documented, consistent with the low LD50 values from . Chronic and subchronic toxicity studies in and dogs identify principal effects on the , including , aspermatogenesis, and reduced sperm motility, observed at doses as low as 50-250 mg/kg/day over 1-2 years. Additional findings include liver hypertrophy, thyroid follicular cell hypertrophy, and bone marrow in multiple species. represents the most sensitive route, with subchronic rat studies showing irritation and degeneration at concentrations around 50-200 mg/m³. These effects occur via microtubule disruption, a mechanism shared with . Long-term studies provide mixed evidence on carcinogenicity; some mouse assays reported increased liver tumors, but subsequent peer reviews questioned their validity due to histopathological re-evaluations. The U.S. EPA has noted sufficient evidence for developmental and reproductive concerns in animals but classifies overall chronic risks based on no-observed-adverse-effect levels (NOAELs) around 5-15 mg/kg/day for reproductive endpoints. Human epidemiological data remain limited, with occupational exposures linked mainly to rather than systemic chronic effects.

Reproductive and Developmental Concerns

Benomyl, which rapidly metabolizes to in mammals, exhibits primarily targeting the in animal models. In male rats dosed orally with 30-90 mg/kg/day benomyl, histopathological changes included stage-specific sloughing of germ cells from seminiferous tubules, leading to reduced production and . These effects occur at doses causing moderate systemic toxicity and are mediated by disruption of signaling, as demonstrated by blockade with flutamide, an , which prevented carbendazim-induced reproductive malformations such as and vaginal pouch formation in male offspring. Developmental toxicity studies in rats and rabbits identified skeletal and visceral malformations at maternally toxic doses exceeding 15 mg/kg/day, including exencephaly, fused sternebrae, and reduced fetal weight, though no effects were observed below maternal LOAELs in multi-generation reproduction assays. In vitro exposure of rat and human embryos to benomyl concentrations above 10-12 μM induced gross dysmorphogenesis and impaired yolk sac circulation, suggesting direct teratogenic potential independent of maternal metabolism. Three-generation rat studies at up to 400 mg/kg/day showed no adverse effects on female reproduction or lactation but confirmed male-specific impairments in spermatogenesis and offspring viability. Mechanistically, interferes with assembly, disrupting meiotic and mitotic divisions essential for , while also exhibiting anti-androgenic activity that alters during critical fetal windows. In placental cell models, benomyl and at micromolar levels reduced viability and induced , indicating potential risks to trophoblast function and embryonic implantation, though epidemiological data linking occupational exposure to or birth defects remain inconclusive. Regulatory assessments by the EPA classify benomyl as a potential reproductive toxicant based on these findings, contributing to its phase-out, with no-observed-adverse-effect levels (NOAELs) for around 6-10 mg/kg/day in . risks are deemed low at typical environmental exposures below 0.01 mg/kg/day, per dietary residue modeling.

Environmental Impacts

Degradation and Persistence

Benomyl undergoes rapid in aqueous and environments, primarily degrading to its major , (also known as MBC), with half-lives typically ranging from 2 hours in water to 19 hours in under aerobic conditions. This initial transformation occurs via cleavage of the butylcarbamoyl side chain, independent of light exposure, as photolysis plays a negligible role in its breakdown. , in turn, exhibits greater stability and is the primary determinant of benomyl's environmental persistence, further degrading through microbial activity into minor products such as 2-aminobenzimidazole and eventually to bound residues or complete mineralization. In , demonstrates moderate to high persistence, with aerobic DT50 values (time to 50% dissipation) varying from 19 days to several months depending on , microbial population, and conditions; for instance, half-lives of 51.3 days in sandy soils and up to 6-12 months on bare soil have been reported. Anaerobic conditions extend persistence, with DT50 values reaching 25 months in water-sediment systems, while factors like higher , neutral , and fertilizer amendments (e.g., reducing to 18 days) can accelerate microbial degradation. In aquatic environments, benomyl's conversion to occurs swiftly (DT50 <1 day under aerobic conditions), but the metabolite persists longer, with half-lives of 2 months aerobically and up to 25 months anaerobically in water, contributing to potential groundwater contamination risks due to moderate mobility in certain soils. Overall, soil microorganisms drive the primary degradation pathways, though persistence is influenced by application rates and environmental variables, leading to detectable residues for extended periods post-application.

Effects on Ecosystems and Wildlife

Benomyl rapidly degrades to its primary metabolite carbendazim (MBC) in environmental compartments, which exhibits greater persistence in soil due to strong adsorption to organic matter, with half-lives ranging from weeks to months depending on conditions. This persistence contributes to bioaccumulation risks in soil ecosystems, where carbendazim disrupts microbial activity and inhibits fungal populations essential for nutrient cycling. In laboratory studies, benomyl and carbendazim demonstrated selective toxicity to invertebrates, particularly earthworms, with LC50 values indicating moderate to high sensitivity; for instance, exposure reduced earthworm reproduction and survival in tropical soil tests at concentrations as low as 10 mg/kg. Aquatic ecosystems face significant risks from benomyl runoff, as it is algicidal and acutely toxic to fish and macroinvertebrates in controlled settings, with 96-hour LC50 values for freshwater species often below 1 mg/L for carbendazim. Microcosm experiments revealed that carbendazim applications at environmentally relevant levels (e.g., 3-10 µg/L) altered water quality, slowed particulate organic matter decomposition, and reduced macroinvertebrate abundance, potentially cascading to affect higher trophic levels. Fifty-three acute toxicity tests confirmed benomyl's harm to aquatic animals, including fish and invertebrates, underscoring the need to prevent surface water contamination to avoid lethal and sublethal effects on populations. For terrestrial wildlife, benomyl and carbendazim show low acute toxicity to birds, with LD50 values exceeding 2100 mg/kg and LC50 >5000 ppm in dietary studies, classifying them as practically non-toxic to avian species. However, indirect effects may arise through alteration, such as reduced prey availability from declines, though field surveys on treated fields reported no observed adverse impacts on birds or mammals. Overall, while direct toxicity is minimal, benomyl's disruption of communities and aquatic food webs poses broader threats to and function.

Resistance and Alternatives

Development of Fungal Resistance

Fungal resistance to benomyl, a benzimidazole fungicide that disrupts microtubule assembly by binding to β-tubulin, primarily develops through point mutations in the β-tubulin gene (benA or tub2), which reduce the fungicide's affinity for its target site. These genetic alterations confer low to high levels of resistance, often with cross-resistance to related compounds like carbendazim and thiophanate-methyl, due to benomyl's degradation into methyl benzimidazol-2-yl carbamate (MBC). Selection pressure from repeated applications accelerates fixation of these mutations in populations, as sensitive strains are eliminated, leaving resistant variants to proliferate. While efflux pumps or overexpression mechanisms contribute in some cases, target-site mutations predominate, classifying benzimidazoles as high-risk for resistance under Fungicide Resistance Action Committee guidelines. The first documented resistance to benzimidazoles emerged in , within a year of benomyl's commercial introduction, initially in fungal pathogens exposed to MBC precursors. By , resistant isolates had been reported across at least 16 fungal genera, including key plant pathogens, correlating with widespread field failures in disease control. In crops like , resistance in Colletotrichum spp. and stem-end rot fungi was evident by , with isolates showing markedly reduced sensitivity after seasons of prophylactic spraying. varied by region and pathogen; for instance, surveys of Botrytis cinerea isolates from agricultural settings revealed 62.7% resistance to benomyl at 2 μg/mL concentrations. In Sclerotinia sclerotiorum, field isolates from 13 U.S. sites in 2001 exhibited EC50 values exceeding 200 mg/L, compared to <8 mg/L for sensitive strains, linking resistance to prior benomyl use. Resistance persistence post-exposure underscores its stability, with mutants retaining fitness in benomyl-free environments, though some incur costs like reduced virulence or sporulation under stress. In Monilinia fructicola, resistant populations endured for years after fungicide withdrawal, necessitating integrated management shifts. Common mutations, such as those at codons 6, 198, or 200 in β-tubulin, recur across species like Colletotrichum acutatum and Elsinoë fawcettii, enabling rapid dissemination via spores. By the 1980s, such adaptations prompted regulatory scrutiny and alternation strategies, as unchecked use in high-pressure systems like greenhouses amplified resistant subpopulations. Empirical monitoring via EC50 assays and remains essential for tracking, given the pathogen's adaptability and agriculture's reliance on repeated applications.

Contemporary Substitutes and Legacy Use

Following the phase-out of benomyl in regions such as the United States and European Union due to regulatory restrictions initiated around 2001–2002, agricultural producers have adopted alternative fungicides targeting similar fungal pathogens, including species of Ascomycota and Basidiomycota. Effective substitutes include triazole-class compounds like tebuconazole, which demonstrated comparable efficacy to benomyl in controlling cercospora leaf spot on crops such as turnip greens in field trials conducted in the southeastern U.S. Strobilurin fungicides, such as azoxystrobin, have also served as replacements for managing foliar diseases in fruits, vegetables, and nuts, offering systemic action with lower resistance risk when rotated properly. Copper-based protectants, including copper hydroxide and basic copper sulfate, provide contact activity as non-systemic options, though they require more frequent applications and can accumulate in soil. Integrated pest management strategies increasingly incorporate microbial biofungicides, such as those based on Trichoderma spp. or Bacillus subtilis, as environmentally preferable alternatives to synthetic benzimidazoles like benomyl. These biological agents suppress soilborne and foliar pathogens through antagonism and induced plant resistance, with studies showing efficacy against diseases previously targeted by benomyl, albeit sometimes requiring combination with cultural practices for . Resistance management protocols emphasize rotating chemical classes—e.g., combining demethylation inhibitors (triazoles) with succinate dehydrogenase inhibitors—to mitigate the fungal resistance that diminished benomyl's utility by the late 1990s. Benomyl's legacy persists in developing countries where regulatory oversight is less stringent, with ongoing agricultural applications reported in regions reliant on export crops despite international bans. For instance, production and use continue in parts of and , contributing to detectable residues of its primary metabolite, , in imported commodities. In the U.S., existing stocks were depleted by 2002 following voluntary cancellation by manufacturers, but historical soil persistence has led to sporadic detections in and from legacy sites. Global market analyses indicate niche demand for benomyl equivalents, though phase-outs have shifted volumes toward alternatives, with total usage declining amid scrutiny from bodies like the . Efforts to enforce maximum residue limits, such as the European Parliament's 2024 rejection of proposed tolerances for benomyl at the limit of quantification, underscore ongoing challenges from non-compliant imports.

References

  1. https://www.sciencedirect.com/topics/medicine-and-dentistry/benomyl
  2. https://pubchem.ncbi.nlm.nih.gov/compound/Benomyl
  3. https://sitem.herts.ac.uk/aeru/ppdb/en/Reports/66.htm
  4. https://pmc.ncbi.nlm.nih.gov/articles/PMC10975326/
  5. https://www.epa.gov/system/files/documents/2022-07/benomyl-memo-2021.pdf
  6. https://www.inchem.org/documents/hsg/hsg/hsg81_e.htm
  7. http://extoxnet.orst.edu/pips/benomyl.htm
  8. https://pmc.ncbi.nlm.nih.gov/articles/PMC7175046/
  9. https://www.federalregister.gov/documents/2002/01/15/02-958/benomyl-cancellation-order
  10. https://ec.europa.eu/food/plant/pesticides/eu-pesticides-database/start/screen/active-substances/details/447
  11. https://www.apvma.gov.au/chemicals-and-products/chemical-review/listing/benomyl
  12. https://www.beyondpesticides.org/assets/media/documents/pesticides/factsheets/Benomyl.pdf
  13. https://www.chemspider.com/Chemical-Structure.26771.html
  14. https://webbook.nist.gov/cgi/inchi/InChI%253D1S/C14H18N4O3/c1-3-4-9-15-13%2819%2918-11-8-6-5-7-10%2811%2916-12%2818%2917-14%2820%2921-2/h5-8H%252C3-4%252C9H2%252C1-2H3%252C%28H%252C15%252C19%29%28H%252C16%252C17%252C20%29
  15. https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/benomyl
  16. https://www.scribd.com/presentation/444646466/Synthesis-of-Benomyl-from-2-butene
  17. http://www.osha.gov/chemicaldata/298
  18. https://www.chemicalbook.com/ChemicalProductProperty_EN_CB3204052.htm
  19. https://www.inchem.org/documents/icsc/icsc/eics0382.htm
  20. https://www.chemicalbook.com/ProductChemicalPropertiesCB3204052_EN.htm
  21. https://www.cdpr.ca.gov/wp-content/uploads/2024/10/benomyl.pdf
  22. https://www.inchem.org/documents/jmpr/jmpmono/v073pr04.htm
  23. https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/benomyl
  24. https://www.nature.com/articles/s41598-018-25336-5
  25. https://pubs.acs.org/doi/10.1021/bi801136q
  26. https://pmc.ncbi.nlm.nih.gov/articles/PMC5940828/
  27. https://pubmed.ncbi.nlm.nih.gov/15157098/
  28. https://www.sciencedirect.com/science/article/abs/pii/S0006295208006291
  29. https://www.apsnet.org/publications/phytopathology/backissues/Documents/1992Articles/Phyto82n11_1348.pdf
  30. https://www.sciencedirect.com/science/article/abs/pii/0048357587900800
  31. https://pubmed.ncbi.nlm.nih.gov/19049291/
  32. https://www.ftb.com.hr/images/pdfarticles/2004/April-June/42-83.pdf
  33. https://apsjournals.apsnet.org/doi/10.1094/PHYTO-08-15-0186-R
  34. https://www.annualreviews.org/doi/pdf/10.1146/annurev.py.24.090186.000355
  35. https://pubmed.ncbi.nlm.nih.gov/2128007/
  36. https://www.mdpi.com/1420-3049/29/6/1218
  37. https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/benzimidazole-fungicide
  38. https://apsjournals.apsnet.org/doi/pdf/10.1094/PHP-2008-0418-01-RV
  39. https://www.inchem.org/documents/ehc/ehc/ehc148.htm
  40. https://www.apsnet.org/edcenter/apsnetfeatures/Pages/Fungicides.aspx
  41. https://archive.epa.gov/pesticides/chemicalsearch/chemical/foia/web/pdf/099101/099101-096.pdf
  42. https://extension.okstate.edu/fact-sheets/fungicide-resistance-management.html
  43. https://www.apsnet.org/publications/phytopathology/backissues/Documents/1981Articles/Phyto71n04_438.PDF
  44. https://acsess.onlinelibrary.wiley.com/doi/abs/10.2134/agronj1985.00021962007700040029x
  45. https://acsess.onlinelibrary.wiley.com/doi/abs/10.2134/agronj1989.00021962008100060001x
  46. https://ui.adsabs.harvard.edu/abs/1989AgrJ...81..847C/abstract
  47. https://bsppjournals.onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-3059.1977.tb01968.x
  48. https://www.apsnet.org/publications/plantdisease/backissues/Documents/1987Articles/PlantDisease71n03_222.pdf
  49. https://www.researchgate.net/publication/233310979_Efficacy_of_aerial_application_of_benomyl_and_iprodione_for_the_control_of_sclerotinia_stem_rot_of_canola_rapeseed_in_central_Alberta
  50. https://www.bcpc.org/wp-content/uploads/2022/07/BCPC-Insecticide-and-Fungicide-Conference-1969-Vol-II-p298-405.pdf
  51. https://www.sciencedirect.com/science/article/abs/pii/S1161030118305240
  52. https://acsess.onlinelibrary.wiley.com/doi/abs/10.2135/cropsci1986.0011183X002600020029x
  53. https://nepis.epa.gov/Exe/ZyPURL.cgi?Dockey=2000E7YC.TXT
  54. https://nepis.epa.gov/Exe/ZyPURL.cgi?Dockey=P100B5NA.txt
  55. https://www.fao.org/fileadmin/user_upload/IPM_Pesticide/JMPR/Evaluations/1998/benomyl.pdf
  56. https://www.federalregister.gov/documents/2001/08/08/01-19572/benomyl-cancellation-order
  57. https://www.cdpr.ca.gov/wp-content/uploads/2024/10/2001023.pdf
  58. https://ppqs.gov.in/sites/default/files/list_of_pesticides_which_are_banned_refused_registration_and_restricted_in_use_01.07.2021.pdf
  59. https://kathmandupost.com/health/2024/12/09/nepal-bans-three-more-pesticides-to-tackle-growing-suicide-cases
  60. https://pubmed.ncbi.nlm.nih.gov/10668211/
  61. https://pubmed.ncbi.nlm.nih.gov/15371226/
  62. https://www.tandfonline.com/doi/abs/10.1080/15287390490486833
  63. https://www.sciencedirect.com/science/article/abs/pii/S0890623805000699
  64. https://www.sciencedirect.com/science/article/pii/0041008X75902215
  65. https://www.sciencedirect.com/science/article/pii/027205909090055O
  66. https://www.sciencedirect.com/science/article/abs/pii/S0273230014000981
  67. https://academic.oup.com/endo/article/145/4/1860/2878538
  68. https://pubmed.ncbi.nlm.nih.gov/25530041/
  69. https://www.inchem.org/documents/jmpr/jmpmono/v95pr19.htm
  70. https://www.researchgate.net/publication/277952485_The_role_of_soil_microorganisms_in_reducing_the_half-life_of_fungicide_Benomyl_as_influenced_by_some_selected_organic_and_inorganic_fertilizers
  71. https://www.sciencedirect.com/science/article/abs/pii/S0045653500001843
  72. https://pmc.ncbi.nlm.nih.gov/articles/PMC6536136/
  73. https://pubmed.ncbi.nlm.nih.gov/17713810/
  74. https://www.researchgate.net/publication/12629835_Impact_of_the_Fungicide_Carbendazim_in_Freshwater_Microcosms_I_Water_Quality_Breakdown_of_Particulate_Organic_Matter_and_Responses_of_Macroinvertebrates
  75. https://www.waterboards.ca.gov/water_issues/programs/tmdl/records/state_board/2013/ref4102.pdf
  76. https://pmc.ncbi.nlm.nih.gov/articles/PMC309941/
  77. https://apsjournals.apsnet.org/doi/10.1094/PHYTO-10-22-0370-KD
  78. https://www.researchgate.net/publication/249303700_First_Report_of_Resistance_to_Benomyl_Fungicide_in_Sclerotinia_sclerotiorum
  79. https://www.frac.info/media/jtafagre/monograph-1.pdf
  80. https://www.science.org/doi/10.1126/science.aap7999
  81. https://jag.journalagent.com/ias/pdfs/IAS_2_3_168_171.pdf
  82. https://www.apsnet.org/publications/plantdisease/backissues/Documents/1982Articles/PlantDisease66n12_1185.PDF
  83. https://bsppjournals.onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-3059.1988.tb02089.x
  84. https://apsjournals.apsnet.org/doi/10.1094/PDIS.2001.85.11.1206C
  85. https://www.sciencedirect.com/science/article/pii/026121949090162Z/pdf?md5=6a8f7d4e0e63e2b178797ea92fbdf073&pid=1-s2.0-026121949090162Z-main.pdf
  86. https://www.sciencedirect.com/science/article/abs/pii/S1087184507000679
  87. https://www.researchgate.net/publication/241048584_First_report_of_benomyl_resistance_in_Elsinoe_fawcettii_in_New_Zealand_citrus_orchards
  88. https://pmc.ncbi.nlm.nih.gov/articles/PMC10662737/
  89. https://journals.ashs.org/downloadpdf/view/journals/hortsci/40/5/article-p1324.pdf?pdfJsInlineViewToken=878644052%3BinlineView=true
  90. https://www.researchgate.net/publication/236974348_Alternatives_to_Benomyl_for_Management_of_Cercospora_Leaf_Spot_on_Turnip_Greens
  91. https://pmc.ncbi.nlm.nih.gov/articles/PMC10917481/
  92. https://www.qyresearch.com/reports/1326930/benomyl
  93. https://agrinfo.eu/book-of-reports/maximum-residue-levels-for-benomyl/
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