Mancozeb

Mancozeb is a non-systemic, broad-spectrum contact fungicide from the ethylene bisdithiocarbamate (EBDC) chemical class, comprising coordination polymers of zinc(II) ion and manganese(II) ethylenebis(dithiocarbamate).^[1] It functions through multi-site disruption of fungal metabolism, providing protective action against foliar diseases on contact without systemic uptake into plants.^[2] Widely applied in agriculture to control pathogens such as potato blight, leaf spots, downy mildew, and rusts on crops including fruits, vegetables, nuts, and ornamentals, mancozeb has been a staple in integrated pest management due to its efficacy against diverse fungi.^[3][4] However, empirical studies indicate significant health risks from exposure, including hepatic toxicity, reproductive hazards, and potential contributions to neurological disorders via oxidative stress and metabolite ethylenethiourea (ETU).^[5][6][7] Environmentally, it poses high risks to birds, aquatic organisms, and non-target species, with evidence of endocrine disruption and bioaccumulation concerns.^[8] Despite these toxicities, regulatory assessments have weighed its agricultural utility against mitigated exposure scenarios in approved uses.^[9]

Chemical and Physical Properties

Molecular Structure and Composition

Mancozeb is a coordination polymer composed of manganese(II) and zinc(II) ions bound to ethylenebis(dithiocarbamate) ligands, forming a stable complex with the general formula (C₄H₆MnN₂S₄)ₓ(Zn)ᵧ, where the molar ratio of x to y is approximately 1:0.092.^[10] This polymeric structure arises from the bridging of dithiocarbamate groups between metal centers, enhancing its chemical stability compared to related compounds like maneb.^[11] The systematic IUPAC name for mancozeb is a coordination complex of manganese ethylenebis(dithiocarbamate), polymeric, with zinc salt, reflecting its hybrid metal composition.^[12] The core ligand, ethylenebis(dithiocarbamic acid), features two dithiocarbamate moieties (-NHC(S)SH) linked by an ethylene bridge (-CH₂CH₂-), which chelate the divalent manganese and zinc cations through sulfur atoms.^[1] This arrangement results in a repeating unit with an approximate molecular weight of 271.3 g/mol for the manganese-containing segment, though the full polymer lacks a defined molecular mass due to its extended network.^[11] In composition, mancozeb contains roughly equal parts of manganese and zinc ethylenebis(dithiocarbamates), often described empirically as C₈H₁₂MnN₄S₈Zn for dimeric representations in databases, but its true nature is that of an insoluble, grayish-yellow powder indicative of the polymeric solid.^[1] The metal ions, Mn²⁺ and Zn²⁺, are essential for the compound's fungicidal efficacy, as they facilitate multi-site interactions in target organisms while the organic ligand provides the dithiocarbamate functionality critical for biological activity.^[13]

Solubility, Stability, and Formulation Characteristics

Mancozeb demonstrates low aqueous solubility, approximately 6.2 mg/L at pH 7.5 and 25°C, rendering it practically insoluble in water under neutral conditions and limiting its mobility in soil and aquatic environments.^[14] This property contributes to its low bioaccumulation potential, as it exhibits minimal solubility in water and does not readily bioconcentrate in organisms.^[15] Solubility increases slightly under alkaline conditions but decreases in acidic media, where hydrolytic decomposition occurs.^[16] The compound remains stable under normal dry storage conditions but undergoes slow decomposition when exposed to heat, moisture, or acidic environments, with rapid hydrolysis to ethylenebis(dithiocarbamate) anions and eventual formation of ethylene thiourea (ETU).^[1] In analytical contexts, mancozeb solutions must be prepared fresh due to this hydrolytic instability, and it persists briefly in aerobic soils (half-lives of 1–13 days for ETU metabolite) but degrades under sunlight and microbial activity.^[17][18] Formulations of mancozeb are predominantly wettable powders (WP) or water-dispersible granules (WG), typically containing 75–80% active ingredient, which enhance dispersibility and suspensibility in water for foliar spray applications despite the parent compound's low solubility.^[19] These multi-site contact fungicides require immediate use post-mixing to mitigate degradation, with storage stability confirmed via accelerated tests (e.g., 54°C for 14 days) showing minimal breakdown in approved packaging.^[10][20] Compatibility with other pesticides is generally favorable in neutral suspensions but limited under acidic conditions.^[21]

Historical Development

Discovery and Synthesis

Mancozeb was developed by the Rohm and Haas Company in the early 1960s as a broad-spectrum contact fungicide, representing a coordination complex that combines the manganese-based maneb and zinc-based zineb to mitigate limitations such as phytotoxicity and thermal instability observed in the individual precursors. This innovation aimed to leverage the fungicidal strengths of both metals while enhancing overall product stability and performance against fungal pathogens. The compound achieved industrial production in 1961 and was registered for agricultural use in 1962, marking a significant advancement in dithiocarbamate chemistry for crop protection.^[22][23][24] The synthesis of mancozeb involves a multi-step process starting with the reaction of ethylenediamine and carbon disulfide in aqueous solution to form the disodium salt of ethylenebis(dithiocarbamic acid). This intermediate is then treated with manganese chloride or sulfate to yield maneb, the manganese ethylenebis(dithiocarbamate) polymer. To produce mancozeb, purified maneb is subsequently complexed with a zinc salt, such as zinc sulfate, under alkaline conditions, resulting in a polymeric structure with approximately 20% manganese and 2.6% zinc content. The reaction is typically conducted at controlled temperatures to prevent decomposition, followed by filtration, washing, and drying to obtain the technical-grade product.^[25][21][26]

Commercial Introduction and Widespread Adoption

Mancozeb, a coordination product of zinc ion and manganese ethylenebis(dithiocarbamate), was commercially introduced in 1962 by Rohm and Haas Company as a broad-spectrum protectant fungicide.^[27] This followed the development of earlier ethylenebis(dithiocarbamate) (EBDC) compounds like maneb, with mancozeb representing an improved formulation combining manganese and zinc for enhanced stability and efficacy.^[28] Initial registrations targeted agricultural applications, particularly for foliar sprays on crops susceptible to fungal diseases such as downy mildew and leaf blight.^[29] Its widespread adoption accelerated in the 1960s and 1970s due to several advantageous properties, including multi-site mode of action that minimized resistance development, compatibility in tank mixes with other pesticides, and cost-effectiveness relative to emerging systemic fungicides.^[27] By the 1980s, mancozeb had become a cornerstone in integrated disease management for high-value crops like potatoes, tomatoes, grapes, and apples, where it provided reliable control against oomycetes and foliar pathogens.^[27] Global usage expanded rapidly in regions with intensive horticulture, such as Europe, North America, and Asia, supported by its low application rates (typically 1-2 kg/ha) and favorable environmental persistence as a contact protectant.^[11] The fungicide's market dominance persisted into the late 20th century, with annual global production exceeding thousands of tons by the 1990s, driven by its role in preventing yield losses estimated at 20-50% from unmanaged fungal infections in solanaceous and cucurbit crops.^[27] Adoption was further bolstered by regulatory approvals in major markets, including the U.S. EPA's reregistration under tolerance reassessments, affirming its utility despite scrutiny over metabolites like ethylenethiourea (ETU).^[30] Today, it remains integral in developing agricultural economies, though phasedowns in some regions reflect evolving residue limits.^[31]

Mechanism of Action

Biochemical Interactions with Fungi

Mancozeb, an ethylene bisdithiocarbamate (EBDC) fungicide, interacts biochemically with fungi primarily by disrupting sulfhydryl (-SH)-dependent enzymatic processes essential for cellular metabolism. Upon contact, it binds to thiol groups in fungal enzymes, inactivating those involved in respiration, energy production, and nucleic acid synthesis within the cytoplasm and mitochondria. This multi-site inhibition prevents spore germination and mycelial growth by halting key metabolic pathways, including ATP synthesis via complex formation with metal-containing enzymes such as those with manganese or zinc cofactors.^[4][32][33] The fungicide's dithiocarbamate moiety decomposes to release ions that chelate metal ions in fungal enzyme active sites, further impairing oxidative phosphorylation and glycolysis. Studies indicate that exposure inhibits fungal dehydrogenase activities, leading to accumulation of toxic intermediates and cellular energy depletion. For instance, in Phytophthora infestans, mancozeb reduces mycelial respiration rates by up to 70% within hours of application, correlating with disrupted electron transport chains.^[22][1] This broad enzymatic interference, classified as Fungicide Resistance Action Committee (FRAC) group M, targets non-specific sites across fungal species, minimizing single-point resistance evolution while ensuring protective, contact-based efficacy against pathogens like Alternaria spp. and Botrytis cinerea. Empirical assays confirm no curative translocation, with activity confined to surface-bound fungal structures.^[34][2]

Multi-Site Activity and Resistance Profile

Mancozeb functions as a multi-site fungicide, classified by the Fungicide Resistance Action Committee (FRAC) under Group M03, which encompasses dithiocarbamates that inhibit multiple essential enzymes in fungal cells. Its primary biochemical interactions involve binding to sulfhydryl groups on enzymes located in the cytoplasm and mitochondria, thereby disrupting critical processes such as cellular respiration, ATP synthesis, lipid metabolism, and nucleic acid production.^[2][27] This non-specific, broad interference affects diverse fungal taxa, including Ascomycetes, Basidiomycetes, Deuteromycetes, and Oomycetes, conferring protective activity against spore germination and mycelial growth without systemic penetration into plant tissues.^[27][4] The multi-site nature of mancozeb's action inherently lowers the probability of resistance evolution, as simultaneous mutations across multiple independent targets are statistically improbable for fungal populations.^[2][27] Unlike single-site inhibitors (e.g., FRAC Groups 1, 7, or 11), which can select for targeted genetic adaptations, mancozeb's profile shows minimal documented resistance cases globally since its introduction in the 1960s, with no widespread failures attributed to inherent fungal adaptation.^[27][4] Isolated reports of reduced sensitivity, such as in certain Alternaria strains, typically involve cross-effects from overuse of unrelated chemistries rather than direct selection against mancozeb.^[35] In resistance management strategies, mancozeb is routinely integrated into rotations or tank mixtures with single-site fungicides to dilute selective pressure on those modes of action, enhancing overall program durability.^[36][2] Regulatory assessments, including those by the U.S. Environmental Protection Agency, affirm its low-resistance-risk status, supporting its continued recommendation for prophylactic applications in high-disease-pressure scenarios.^[37] This profile underscores mancozeb's role as a foundational protectant in integrated pest management, where adherence to label rates and application timings further minimizes any potential shifts in pathogen sensitivity.^[4][36]

Agricultural Applications

Target Crops and Pathogens

Mancozeb is applied to diverse agricultural crops, including potatoes, tomatoes, apples, pears, grapes, cereals, peanuts, and various fruits, vegetables, nuts, and ornamentals, primarily to prevent and control foliar fungal infections.^[1][10] In potatoes, it targets late blight caused by the oomycete Phytophthora infestans and early blight from Alternaria solani.^[2][4] On tomatoes, mancozeb manages similar blights (Phytophthora infestans and Alternaria solani) along with leaf spot diseases.^[3][4] Apple and pear scab, induced by Venturia inaequalis, is effectively suppressed in pome fruits.^[3] Grapes benefit from mancozeb treatments against downy mildew (Plasmopara viticola), a key oomycete pathogen in viticulture.^[38] In cereals and ornamentals such as roses, it controls rust diseases, while broader leaf spot and blight issues affect peanuts and other field crops.^[4][3] Its multi-site mode of action enables efficacy across ascomycetes, oomycetes, basidiomycetes, and deuteromycetes, though registration varies by region and ongoing regulatory reviews may limit uses, such as proposed restrictions on grapes.^[39][40]

Application Methods and Dosage Guidelines

Mancozeb is applied primarily through foliar sprays to achieve protective coverage on plant surfaces, using ground boom sprayers, airblast equipment, or aerial application where permitted, with volumes adjusted to ensure uniform deposition without excessive runoff.^[41] Applications should commence preventively before disease onset or at the first signs of infection, repeating at intervals of 7 to 14 days depending on rainfall, humidity, and disease pressure, with shorter intervals during high-risk periods.^[42] Spray mixtures are prepared by adding the product to water under agitation, often incorporating adjuvants like spreaders or stickers for improved adhesion on waxy leaves, and applications are best timed for early morning or evening to minimize volatilization and phytotoxicity under high temperatures.^[43] Dosage rates vary by formulation (e.g., 80% WP, 750 g/kg WG, or flowable concentrates), crop, target pathogen, and regional regulations, typically ranging from 1.5 to 3 kg active ingredient per hectare per application for wettable powders.^[44] For potatoes against early and late blight, labels specify 2-3 kg/ha of 80% WP, applied in 200-400 liters of water per hectare, with a seasonal maximum not exceeding 20-30 kg/ha depending on jurisdiction.^[45] In tomatoes for foliar diseases like early blight, rates of 3 pounds (1.36 kg) mancozeb per acre (equivalent to approximately 3.36 kg/ha) are recommended, using up to 100 gallons (378 liters) spray volume per acre for full canopy coverage.^[46] For beans targeting anthracnose and rust, 1.5 kg/ha or 300 g per 100 liters water is standard, repeated every 7-10 days.^[44] Pre-harvest intervals (PHI) must be observed, such as 5-7 days for most vegetables and up to 14 days for fruits, to minimize residues, with annual application limits like 16.8 pounds (7.6 kg) mancozeb per acre in certain U.S. regions to comply with tolerance levels.^[47] Compatibility with other pesticides should be tested via jar tests, as mancozeb's multi-site mode supports tank-mixing but may require pH adjustments to avoid precipitation.^[42] Users must adhere to label-specific restrictions, including groundwater advisory zones and buffer requirements near water bodies, to mitigate environmental drift.^[4]

Efficacy and Benefits

Disease Control Outcomes

Mancozeb exhibits protectant efficacy against a range of fungal and oomycete pathogens, with field trial outcomes varying by crop, disease pressure, and application regimen, typically achieving 60-80% control for blights and mildews when applied preventively at rates of 800-3,000 g active ingredient per hectare.^[22] Against late blight (Phytophthora infestans) on potatoes, multiple studies report average control of 73% ± 22%, with one field assessment yielding 72.8% protection under moderate disease incidence.^[22][2] Efficacy against the same pathogen on tomatoes averages 61% ± 26%, while downy mildew (Plasmopara viticola) on grapevines reaches 79% ± 22%.^[22] In a 2014 greenhouse trial evaluating four strains of P. infestans (Blue 13, Pink 6, Green 33, Orange), mancozeb at 1,500 g/ha reduced necrotic foliage across all genotypes via standardized area under disease progress curve (stAUDPC) metrics, outperforming metalaxyl (ineffective against Blue 13) and fluazinam (weaker against Green 33), confirming its utility against diverse pathogen populations.^[48] For early blight (Alternaria solani), outcomes are more modest, with 36% ± 20% control on potatoes and 43% ± 20% on tomatoes, reflecting its contact-only action under high spore loads.^[22] Outcomes in cereals like rice show limitations; in vitro tests against blast (Pyricularia oryzae) yielded a low EC₅₀ of 0.25 ppm, but field applications provided suboptimal control (<30% for dirty panicle disease) relative to systemic options like azoxystrobin-triazole mixtures, attributable to poor redistribution and curative deficits.^[49] Mixtures with single-site fungicides often enhance overall performance, as mancozeb's multi-site inhibition delays resistance and boosts protectant coverage, sustaining yields in high-value crops like potatoes and grapes.^[22][2]

Economic and Productivity Impacts

Mancozeb's broad-spectrum fungicidal activity contributes to agricultural productivity by mitigating yield losses from fungal diseases, with studies indicating general fungicide applications, including mancozeb, can increase crop yields by approximately 17% through disease suppression.^[50] In silage maize, mancozeb treatments enhanced fresh matter yield by 36.6% in low-dose applications and 9.07% in high-dose applications relative to untreated controls, demonstrating direct productivity gains via improved plant health and reduced pathogen pressure.^[51] In fruit crops such as apples and pears, mancozeb delivers high economic benefits by facilitating resistance management against other fungicides, enabling consistent disease control and preserving marketable yields that would otherwise decline due to pathogen evolution.^[52] Moderate benefits extend to cucurbits, tomatoes, peppers, and mangoes, where its multi-site mode of action supports integrated pest management, reducing the need for costlier alternatives and maintaining output stability.^[52][37] The fungicide's affordability enhances economic returns for producers, with mancozeb exhibiting high profit probability in foliar disease control due to its low application costs despite variable efficacy levels compared to single-site options.^[53] This cost-effectiveness underpins its role in global crop protection, reflected in a market size exceeding $1.8 billion as of 2023, driven by demand for reliable yield protection amid rising disease pressures.^[54] In soybean production, for example, mancozeb bolsters pathogen control, correlating with elevated overall productivity and farmer profitability.^[31]

Toxicology and Human Health Effects

Acute and Subchronic Toxicity Data

Mancozeb demonstrates low acute toxicity in mammals across standard exposure routes. In rats, the oral median lethal dose (LD50) exceeds 5,000 mg/kg body weight, indicating practical non-toxicity following single ingestion.^[55][56] Dermal LD50 values similarly surpass 2,000 mg/kg, with no significant absorption or systemic effects observed in rabbits during acute skin exposure tests.^[15][57] Inhalation LC50 in rats is greater than 5 mg/L air (4-hour exposure), classifying it as minimally toxic via respiratory route.^[58][57] Mancozeb is mildly irritating to eyes and skin in rabbits but does not cause sensitization or corrosivity.^[59] Subchronic toxicity studies, typically 90-day dietary or inhalation exposures, identify the thyroid gland, liver, and hematopoietic system as primary targets in rodents and dogs. In a 90-day dog feeding study, the no-observed-adverse-effect level (NOAEL) was established at 3 mg/kg body weight per day, with elevated serum cholesterol and mild regenerative anemia observed at higher doses (approximately 15 mg/kg/day).^[60] In rats, a 90-day dietary study reported a NOAEL of 6.8 mg/kg body weight per day, based on reduced body weight gain, decreased thyroxine (T4) levels, and thyroid follicular hypertrophy at 27.5 mg/kg/day.^[10] Liver effects, including oxidative stress, elevated transaminases, and histopathological changes such as hepatocellular degeneration, emerged in male Wistar rats dosed subchronically at 500-1,000 mg/kg diet, linked to reactive oxygen species generation.^[61] Inhalation subchronic studies in rats confirmed low systemic toxicity, with a NOAEL of 0.05 mg/L (6 hours/day, 5 days/week) and minor thyroid alterations at higher concentrations.^[62] These findings align with mancozeb's goitrogenic properties, attributable to its ethylene thiourea (ETU) metabolite, though direct mancozeb exposure predominates in short-term effects.^[63] No immunotoxic or neurotoxic effects were evident below these NOAELs in subchronic assays.^[63]

Chronic Exposure Risks and Epidemiological Evidence

Chronic exposure to mancozeb in animal studies primarily targets the thyroid gland, leading to hypothyroxinemia, goiter, and histopathological changes such as follicular cell hypertrophy and hyperplasia in rats at dietary doses exceeding 100 mg/kg/day.^[60] The metabolite ethylenethiourea (ETU), formed both as a degradation product and in mammalian metabolism, exacerbates these effects and induces thyroid follicular cell adenomas and carcinomas in rats, as well as hepatocarcinomas and mammary gland tumors in long-term rodent bioassays.^{[64] [65]} The U.S. Environmental Protection Agency (EPA) classifies ETU as a probable human carcinogen based on these findings, though mancozeb itself shows limited direct genotoxicity and relies on a nonlinear reference dose for chronic thyroid risk assessment due to the absence of a clear mode of action for carcinogenicity at low doses.^[66] Reproductive and developmental toxicity emerges in chronic rodent studies, with mancozeb causing dose-related gonadal damage, reduced fertility, and increased teratogenic outcomes like neural tube defects when maternal toxicity is evident; males exhibit significant testicular atrophy and sperm abnormalities after prolonged exposure.^{[67] [68]} Oxidative stress mechanisms, including reactive oxygen species generation and mitochondrial dysfunction, underlie broader systemic effects such as hepatic and renal damage observed in subchronic-to-chronic exposures.^[69] Epidemiological evidence in humans remains limited and associative rather than definitively causal, with studies on agricultural workers showing elevated urinary ETU levels correlating with thyroid hormone disruptions and oxidative biomarkers like advanced oxidation protein products.^{[70] [71]} A systematic review of dithiocarbamate fungicides, including mancozeb, identified potential links to reproductive outcomes such as reduced semen quality and spontaneous abortions in exposed populations, though confounders like co-exposures to other pesticides and lifestyle factors complicate attribution.^{[72] [73]} No large-scale cohort studies demonstrate clear increases in cancer incidence directly attributable to mancozeb, and EPA dietary risk assessments for chronic exposure conclude margins of exposure exceed thresholds for concern under registered uses, albeit with ongoing monitoring for ETU residues.^[66]

Occupational and Dietary Exposure Assessments

Occupational exposure assessments for mancozeb primarily evaluate dermal and inhalation routes during handler activities such as mixing, loading, application, and post-application re-entry into treated fields.^[4] In field studies involving vineyard workers applying mancozeb, median skin deposition was measured at 125 μg per application, with an absorbed dermal dose of 0.9 ng/kg body weight when personal protective equipment (PPE) was used, indicating low systemic uptake under controlled conditions.^[74] The U.S. Environmental Protection Agency (EPA) conducted a 2024 occupational exposure assessment for registration review, focusing on handler and re-entry scenarios across crops like grapes, and identified elevated post-application risks for re-entry workers, prompting a proposal to cancel mancozeb uses on grapevines due to potential exceedance of safety thresholds without enhanced mitigation.^[75][76] Biological monitoring via urinary ethylenethiourea (ETU), a key mancozeb metabolite and exposure biomarker, has been used in studies of greenhouse farmers, confirming dermal absorption dynamics and the effectiveness of preventive measures like gloves in reducing oxidative stress markers.^[77] Dietary exposure assessments account for residues of mancozeb and its metabolite ETU in treated commodities, using field trial data, market basket surveys, and probabilistic models to estimate population-level intakes.^[9] The EPA's 2023 acute, chronic, and cancer dietary risk assessments for the ethylene bisdithiocarbamate (EBDC) group, including mancozeb, incorporated anticipated residues and found acute exposures below levels of concern (LOC) for the general U.S. population, with chronic food-only exposures representing less than 1% of the chronic population adjusted dose (cPAD) for most subgroups.^[66][78] However, the European Food Safety Authority (EFSA) peer review in 2020 identified potential acute dietary intake concerns for ETU in high-consumption scenarios like table grapes, exceeding the acute reference dose (ARfD) for certain consumer groups based on maximum residue levels (MRLs).^[8] Aggregate chronic risks, factoring in ETU's probable carcinogenicity, were deemed acceptable under EPA tolerances established in 2013, with dietary contributions forming the primary non-occupational pathway but remaining below reference doses when aligned with good agricultural practices.^[78][66]

Environmental Fate and Ecotoxicology

Degradation and Persistence in Soil and Water

Mancozeb exhibits very low persistence in soil, with laboratory aerobic DT₅₀ values ranging from 0.017 to 0.159 days under typical conditions.^[63] Degradation occurs primarily through microbial processes in non-sterile soils, leading to rapid mineralization of degradates to carbon dioxide, while no such mineralization is observed in sterile conditions.^[79] Key degradates include ethylenethiourea (ETU, DT₅₀ 0.1–15.3 days), ethylenebis(isothiocyanate) sulfide (EBIS, DT₅₀ 0.1–0.42 days), ethyleneurea (EU, DT₅₀ 0.5–8 days), and others, with ETU being the major persistent metabolite.^{[63] [18]} Adsorption to soil is moderate, with K_oc values of 363–2334 mL/g, limiting leaching potential despite ETU's higher mobility (K_d ≈ 0.76 L/kg).^[11] In water, mancozeb displays similarly low persistence, with hydrolysis half-lives of approximately 1–2 days across pH 4–9 at 25°C and aquatic metabolism DT₅₀ values of 0.5–3.8 days under aerobic or anaerobic conditions.^{[18] [11]} It remains stable to aqueous photolysis but degrades via hydrolysis and microbial activity to EBIS (maximum 31% applied radioactivity), ETU (up to 52%), and EU (up to 43%), all of which show low persistence in water-sediment systems (water phase DT₅₀ ≈ 0.2 days).^{[63] [11]} ETU persists longer in water (aerobic DT₅₀ 4–30 days; anaerobic 10–30 days) and is stable to hydrolysis and photolysis, contributing to potential runoff contamination due to its high water solubility (≈20 g/L).^[18] Factors such as pH, temperature, and microbial activity influence degradation rates, with faster breakdown observed in neutral to alkaline conditions and aerobic environments.^[11]

Effects on Non-Target Organisms

Mancozeb exhibits high acute toxicity to fish, with a 96-hour LC₅₀ of 0.074 mg/L reported for rainbow trout (Oncorhynchus mykiss).^[11] Chronic exposure also poses significant risks, evidenced by a 21-day NOEC of 0.0022 mg/L for the same species.^[11] Similarly, aquatic invertebrates such as Daphnia magna show high sensitivity, with a 48-hour EC₅₀ of 0.073 mg/L and a 21-day NOEC of 0.0073 mg/L.^[11] European Food Safety Authority (EFSA) assessments conclude a high risk to aquatic organisms across most agricultural uses, except potatoes with a 20-meter buffer zone mitigation.^[8] In terrestrial vertebrates, mancozeb demonstrates low acute oral toxicity to birds, with an LD₅₀ exceeding 2000 mg/kg body weight in mallard ducks (Anas platyrhynchos), but moderate chronic effects, including a 21-day NOEL of 18.8 mg/kg body weight per day.^[11] Wild mammals exhibit low acute toxicity (LD₅₀ >5000 mg/kg in rats) yet face high long-term risks from representative uses in crops like wheat and grapevines per EFSA evaluations.^[11][8] For pollinators, mancozeb shows low oral acute toxicity to honeybees (Apis mellifera), with an LD₅₀ exceeding 110 μg per bee, though contact LD₅₀ values above 85.3 μg per bee indicate moderate contact risk; chronic risks to adults and larvae remain high according to EFSA.^[11][8] Non-target arthropods experience high in-field risks across uses.^[8] Soil invertebrates display variable sensitivity. Earthworms (Eisenia foetida) show moderate acute toxicity, with a 14-day LC₅₀ exceeding 299.1 mg/kg dry weight soil and a chronic NOEC of 20 mg/kg dry weight soil.^[11] However, collembolans (Folsomia candida) and enchytraeids (Enchytraeus crypticus) exhibit greater vulnerability in certain soils, such as Oxisol, where LC₅₀ values are 54.43 mg active ingredient per kg for collembolan survival and 6.97 mg/kg for enchytraeid survival, with reproduction EC₅₀s of 2.72 mg/kg and 3.56 mg/kg, respectively; effects are less pronounced in Ultisol.^[80] EFSA identifies high chronic risks to soil macroorganisms from outdoor applications.^[8] Mancozeb likely induces endocrine disruption in non-target organisms through thyroid-mediated pathways, primarily via its ethylenethiourea (ETU) metabolite, as determined in amphibian studies.^[8]

Regulatory Status and History

Initial Approvals and Safety Evaluations

Mancozeb, a coordination complex of zinc and manganese with ethylenebis(dithiocarbamate) ligands, was first registered for pesticidal use in the United States in 1962 by Rohm and Haas as a broad-spectrum protectant fungicide superior to its precursors maneb and zineb.^{[22] [2]} Initial U.S. regulatory evaluations under pre-EPA frameworks (via the U.S. Department of Agriculture and later the Federal Insecticide, Fungicide, and Rodenticide Act) deemed it acceptable based on submitted data demonstrating low acute mammalian toxicity, including rat oral LD50 values greater than 5,000 mg/kg body weight, indicating minimal risk from single exposures.^[60] Dermal LD50 exceeded 5,000 mg/kg, with primary effects limited to mild skin and eye irritation, leading to its classification as slightly toxic and approval for agricultural applications on crops such as potatoes, tomatoes, and turf.^[11] The Joint FAO/WHO Meeting on Pesticide Residues (JMPR) conducted its inaugural evaluation of mancozeb in 1967, assessing toxicological profiles, residue dynamics, and use patterns reported since its 1961 introduction.^{[81] [26]} This review incorporated manufacturer-submitted studies showing rapid decomposition in soil and plants to ethylenethiourea (ETU) and other metabolites, but with low bioaccumulation potential and no evidence of significant genotoxicity or carcinogenicity in short-term assays available at the time.^[81] JMPR noted mancozeb's contact-only mode of action, lacking systemic uptake in mammals, which supported its safety for pre-harvest applications, though no acceptable daily intake (ADI) was established initially due to limited chronic data; subsequent reviews in 1970 and 1974 refined this to an ADI of 0.03 mg/kg body weight based on thyroid effects in dogs.^[82] In Europe, initial approvals occurred at the national level in the mid-1960s, with widespread registration across member states by the 1970s under pre-harmonized directives, reflecting similar reliance on acute toxicity and efficacy data without early emphasis on long-term endocrine or reproductive risks later identified via ETU.^[11] These evaluations prioritized empirical evidence of efficacy against foliar diseases like late blight and downy mildew, with safety margins derived from no-observed-adverse-effect levels (NOAELs) in subchronic rodent studies exceeding 100 mg/kg/day, justifying tolerances and worker exposure limits.^[26] Regulatory decisions at approval privileged causal evidence from controlled exposure tests over speculative hazards, enabling global adoption despite precursors' limitations.^[22]

Restrictions, Bans, and Ongoing Reviews

In the European Union, the approval of mancozeb was not renewed following a review by the European Food Safety Authority, culminating in Commission Implementing Regulation (EU) 2020/2087 on December 14, 2020, which cited concerns over its reprotoxicity category 1B classification and endocrine-disrupting properties for non-target organisms.^[83] EU member states were required to withdraw authorizations for plant protection products containing mancozeb by July 4, 2021, effectively banning its use from February 2021 onward, with maximum residue limits (MRLs) subsequently reduced or set to default levels.^[84] In the United Kingdom, following Brexit, the Health and Safety Executive (HSE) conducted an independent review and proposed withdrawal of mancozeb's approval in January 2024, determining it failed to meet safety criteria under retained EU regulations, primarily due to genotoxicity and developmental toxicity risks.^[85] Existing stocks may be used or disposed of until October 2025, with full revocation anticipated at the end of the 2025 growing season, though a three-month extension from the January 31, 2024, expiry was under consideration.^[86] The United States Environmental Protection Agency (EPA) maintains mancozeb's registration but initiated a periodic review under the Federal Insecticide, Fungicide, and Rodenticide Act, issuing a proposed interim decision on July 17, 2024, that recommends canceling its use on grapes due to unacceptable post-application risks to workers and handlers, as well as prohibiting on-farm seed treatments.^[87] Public comments on these proposals were solicited through September 2024, with final decisions pending further evaluation of ecological risks and mitigation options; no full ban has been enacted, but restrictions target high-exposure scenarios.^[76] Globally, mancozeb remains approved in countries like India, Brazil, and Ecuador for key crops such as bananas and potatoes, where alternatives are limited, prompting WTO trade concerns over EU MRL reductions impacting exports.^[88] EU firms continue exporting mancozeb despite domestic bans, with 2024 notifications exceeding prior years, highlighting regulatory divergences rather than uniform international restrictions.^[89]

Controversies and Debates

Scientific Disputes on Risk Assessment

Scientific disputes surrounding mancozeb's risk assessment primarily revolve around its metabolite ethylenethiourea (ETU), which forms upon degradation and exhibits thyroid-disrupting effects in rodents. Animal studies demonstrate that oral administration of mancozeb or ETU induces thyroid follicular cell adenomas and carcinomas in rats at doses exceeding 10 mg/kg body weight per day, alongside liver tumors in mice, prompting concerns over genotoxic and non-genotoxic mechanisms.^[28] However, the human relevance of these findings is contested, as epidemiological data from cohorts like the Agricultural Health Study show no consistent association with thyroid cancer (only 5 cases observed in exposed farmers) or other malignancies, attributing rodent-specific outcomes to sustained thyroid-stimulating hormone (TSH) elevation not replicated in human physiology due to differences in iodide organification and clearance.^[28] Regulatory classifications highlight these interpretive divides. The U.S. Environmental Protection Agency (EPA) deems ETU a probable human carcinogen (Group B2) based on animal evidence but regulates mancozeb through exposure limits, concluding low overall cancer risk via non-linear dose-response models that account for threshold effects below human exposure levels.^{[64] [9]} In contrast, the European Food Safety Authority (EFSA) classifies mancozeb as a Category 1B carcinogen (presumed human carcinogen) under Regulation (EC) No 1107/2009, citing insufficient margins of safety and data gaps, which contributed to non-renewal of approval in 2021 despite no in vivo genotoxicity in mammals.^[90] The International Agency for Research on Cancer (IARC) assigns ETU and related ethylene bisdithiocarbamates (EBDCs) to Group 3 (not classifiable as to human carcinogenicity), reflecting limited human evidence and mechanistic uncertainties.^{[91] [28]} Further contention arises over endocrine disruption and reproductive toxicity. EFSA identifies mancozeb as likely meeting endocrine disruption criteria for non-target organisms and potentially humans, based on thyroid hormone perturbations and developmental anomalies in rat pups at maternal doses around 62.5 mg/kg/day, though peer reviews note uncertainties in extrapolating to low-dose human exposures.^{[90] [8]} Critics argue that precautionary interpretations overestimate risks, as human biomarkers (e.g., urinary ETU levels <0.1 mg/L in applicators) fall below no-observed-adverse-effect levels (NOAELs) from chronic studies (5 mg/kg/day for developmental effects), and mode-of-action analyses indicate thresholds inapplicable at environmental doses.^[28] These debates underscore tensions between hazard-based (e.g., EU) and risk-based (e.g., EPA) frameworks, with calls for re-evaluation emphasizing species-specific metabolism and lack of positive human epidemiology.^[28]

Alternatives and Transition Challenges

Alternatives to mancozeb primarily include other contact fungicides, systemic options, and biological agents, often requiring integration into resistance management programs due to mancozeb's unique multi-site mode of action (FRAC group M3) that minimizes resistance development.^[36] Chemical replacements such as chlorothalonil (FRAC M5), ziram, or captan serve as broad-spectrum protectants for crops like grapes and vegetables, though chlorothalonil faces its own restrictions in regions like the EU.^[92] For late blight control in potatoes and tomatoes, alternatives like oxathiapiprolin, dimethomorph, fluopicolide + propamocarb, or combinations of Zorvec (oxathiapiprolin), Ranman (cyazofamid), and Revus (mandipropamid) have shown superior efficacy in trials, providing 83.9% disease protection compared to mancozeb's 72.8%.^[2] In viticulture, difenoconazole, azoxystrobin, boscalid + pyraclostrobin, or strobilurins (FRAC group 11) and triazoles (group 3) like Cevya or Flint offer targeted control but demand alternation to prevent resistance.^[93] Biological options, such as Seican (based on Bacillus amyloliquefaciens), target fungi and mites in bananas without residues, though efficacy varies by application timing and environmental conditions.^[94] Transitioning from mancozeb presents significant challenges, including gaps in broad-spectrum protection and heightened fungicide resistance risks from over-reliance on single-site alternatives.^[31] Mancozeb's role in mixtures extends the durability of systemic fungicides by reducing selection pressure, and its absence could accelerate resistance in pathogens like Phytophthora infestans, as evidenced by documented sensitivity reductions to multi-site inhibitors.^[95] In eastern U.S. grape production, growers report openness to change but highlight the lack of affordable, equally effective replacements, with trials showing variable performance of copper, captan, or biologics under high-disease pressure.^[38] Economic impacts include 20-30% higher program costs and potential yield losses from incomplete disease control, particularly in potatoes where mancozeb's low-cost, persistent coverage is unmatched.^[96] Regulatory timelines exacerbate issues; EU bans since 2022 force rapid shifts, while U.S. EPA proposals for cancellation in grapes due to worker exposure risks demand stockpiling or reformulation, straining supply chains.^[76] Integrated pest management emphasizing cultural practices, resistant varieties, and precise monitoring is recommended but requires farmer education and infrastructure investment to mitigate efficacy shortfalls.^[2]