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Emamectin

Emamectin is a semi-synthetic macrocyclic derived from avermectins, a group of natural compounds produced by the soil bacterium , and is most commonly formulated as emamectin benzoate for practical applications. It targets the nervous systems of , particularly lepidopteran larvae, causing and death, and is valued for its translaminar activity that allows penetration into tissues. Developed by Merck & Co., Inc. as a second-generation , emamectin was first marketed in 1997 in countries including and , with U.S. Environmental Protection Agency (EPA) registration following in 1999 under product codes such as Proclaim and . Its consists primarily of a 9:1 mixture of the benzoate salts of 4"-epi-methylamino-4"-deoxyavermectin B1a and B1b, with a molecular formula of C56H81NO15 and low water solubility (approximately 0.024 g/L at pH 7). Emamectin exhibits moderate to mammals (oral LD50 of 50-76 mg/kg in rats) but is classified as highly toxic to bees (contact LD50 of 3.5 ng/bee) and aquatic (EC50 of 0.00004 mg/L). The compound's mode of action involves binding to glutamate-gated chloride channels in invertebrate nerve and muscle cells, increasing chloride ion influx, hyperpolarizing the cell membrane, and disrupting nerve signal transmission, which results in feeding cessation, paralysis, and eventual insect mortality within hours to days. In the environment, emamectin benzoate demonstrates low mobility in soil (Koc values of 25,363–730,000) and moderate persistence, with aerobic soil half-lives ranging from days to 193 days and photodegradation half-lives of 3.6–10.9 days in water. Emamectin is registered for use on a wide range of crops, including , , , leafy vegetables (e.g., , ), fruiting vegetables (e.g., peppers, tomatoes), and fruits (e.g., apples, pears), primarily against lepidopteran pests such as bollworms, diamondback moths, and leafrollers. In , it is applied via trunk injection (e.g., under the Tree-äge) to protect ash trees from larvae, providing systemic control for up to two years with minimal non-target impact when used appropriately. Its efficacy, combined with reduced application rates compared to earlier avermectins like , has made it a key tool in programs, though regulatory tolerances limit residues in harvested commodities to ensure consumer safety.

Chemical Identity

Molecular Structure

Emamectin is a semi-synthetic derivative of B1, also known as , specifically identified as 4"-deoxy-4"-epi-methylaminoavermectin B1. This modification involves the introduction of a methylamino group at the 4" position of the terminal sugar moiety, enhancing its insecticidal potency compared to the parent compound. Emamectin exists primarily as a of two homologues, emamectin B1a (>90%) and emamectin B1b (<10%), differing only in the alkyl substituent at the C-25 position (ethyl for B1a and methyl for B1b). It is commonly formulated as the benzoate salt, emamectin benzoate, for stability and application. The core structure of emamectin features a 16-membered macrocyclic lactone ring system characteristic of the avermectin family, comprising a polycyclic aglycone core in the southern hemisphere fused to a spiroketal ring and bearing an allylic hydroxyl group at C-5. Attached at the C-13 position is a disaccharide moiety in the northern hemisphere, consisting of two α-L-oleandrose units linked by a glycosidic bond, with the terminal oleandrose modified at the 4" position. Key functional groups include the lactone carbonyl, multiple hydroxyl groups (e.g., at C-3, C-5, and C-7), a trisubstituted double bond at C-22/23, and the distinctive 4"-methylamino group, which imparts basicity to the molecule. The molecular formula of the emamectin free base (B1a) is C49H75NO13, with a molecular weight of 886.1 g/mol, while the B1b homologue is C48H73NO13 (872.1 g/mol). For the benzoate salt form, the formula is C56H81NO15 (B1a benzoate, 1008.3 g/mol) or C55H79NO15 (B1b benzoate, 994.2 g/mol). Emamectin possesses multiple chiral centers, with the specified as (10E,14E,16E,22Z)-(1R,4S,5′S,6S,6′R,8R,12S,13S,20R,21R,24S), contributing to its diastereomeric and enantiomeric complexity. In comparison to , which has a hydroxyl group at the 4" position of the terminal oleandrose, emamectin features the epi-methylamino substitution (NHCH3 in place of OH), resulting in improved systemic activity and potency against lepidopteran pests. This alteration maintains the overall scaffold but shifts the electron density and hydrogen-bonding potential at the sugar terminus, optimizing interactions with target biological sites.

Physical and Chemical Properties

Emamectin benzoate is typically obtained as a to off-white crystalline , which facilitates its handling in solid formulations. This physical form contributes to its stability during storage and transport under ambient conditions. The compound exhibits a range of 141–146 °C, indicating moderate thermal stability before decomposition occurs above 148 °C in air. Its in is low and pH-dependent, measuring approximately 24 mg/L at pH 7 and 25 °C, which limits its mobility in aqueous environments but enhances its persistence on treated surfaces. In contrast, it shows high in solvents, such as acetone at 140 g/L and at 270 g/L (both at 25 °C), reflecting its lipophilic nature. Key physicochemical parameters include an (logP) of 5.0–5.7 at pH 7 and 20–25 °C, underscoring its strong affinity for and potential for in non-aqueous phases. The pKa values are 4.2 for the moiety and 7.6 for the group, influencing its and behavior across pH ranges. Emamectin benzoate demonstrates good under neutral to slightly acidic conditions (pH 5–8 at 25 °C), with half-life exceeding 19 weeks at pH 9; however, it degrades more readily in strong alkaline environments. Photolytic in yields a of 0.5–65 days at pH 7 and 25 °C, depending on intensity. Spectroscopic characteristics aid in its identification and . Ultraviolet-visible absorption shows a maximum at 245 nm (molar absorptivity approximately 37,000 L mol⁻¹ cm⁻¹ in neutral conditions), useful for analytical detection. (IR) and (NMR) spectra, including ¹H-NMR and ¹³C-NMR, confirm the molecular structure through characteristic peaks for avermectin-derived rings and the benzoate ester. Due to its inherent low aqueous , emamectin is commonly formulated as the benzoate to enhance dispersibility in products, such as emulsifiable concentrates or water-dispersible granules, improving efficacy in agricultural applications.
PropertyValue/DetailsConditionsSource
141–146 °C-
Water 24 mg/L 7, 25 °C
Acetone Solubility140 g/L25 °C
5.0–5.7 7, 20–25 °C
pKa ()7.625 °C
UV λ_max245 Neutral solution

Development and Production

Historical Development

Emamectin originated from the avermectins, a class of natural compounds isolated in the 1970s by Japanese microbiologist from the soil bacterium . These avermectins, particularly avermectin B1, served as the foundational scaffold for emamectin, which Merck & Co. researchers developed in the late 1980s through semi-synthetic modifications to enhance insecticidal potency and address emerging pest resistance issues. Key research milestones included the filing of a pivotal in 1987 by Merck chemist H. Mrozik and colleagues, resulting in US Patent 4,874,749 issued in 1989, which described the novel 4"-deoxy-4"-N-methylamino B1a/B1b structure as an effective agricultural . Initial commercial introductions occurred in 1997 in and under (following Merck's development), with US Environmental Protection Agency (EPA) approval for technical and end-use products granted in 1999. By 2000, emamectin benzoate was formulated as the insecticide Proclaim by (successor to Novartis crop protection), targeting lepidopteran pests in crops like . The development of emamectin was driven primarily by the need to counter resistance in lepidopteran pests, such as armyworms and moths, that had diminished the efficacy of earlier avermectin-based products in crop protection. Expansion into veterinary uses occurred in the late 1990s, including approvals for controlling sea lice (Lepeophtheirus salmonis) in salmon via in-feed treatments. Merck's team, led by innovators like H. Mrozik, played a central role in the semi-synthetic innovations that enabled emamectin's superior potency and systemic activity compared to parent avermectins. Global adoption followed EPA's 1999 endorsement, facilitating widespread use in programs across , , and by the early . As of 2025, major producers include and generic manufacturers in and .

Synthesis and Preparation Methods

Emamectin benzoate production begins with the fermentation of the soil bacterium , which yields B1 as the primary precursor, consisting of approximately 90% B1a and 10% B1b. This natural process serves as the foundational step in industrial manufacturing, leveraging the microorganism's biosynthetic pathways to generate the macrocyclic structure essential for subsequent derivatization. The semi-synthetic transformation of avermectin B1 into emamectin benzoate involves selective modification at the C-4″ position. This multi-step process includes tosylation of the 4″-hydroxyl group to activate the site, followed by nucleophilic displacement through amination with methylamine, resulting in epimerization to form 4″-deoxy-4″-epi-(methylamino)avermectin B1 (MAB1), a mixture retaining the 90:10 ratio of B1a to B1b components. The final step entails salt formation by reacting MAB1 with benzoic acid to produce emamectin benzoate, enhancing its stability and solubility for formulation. Overall yields for this semi-synthetic sequence can exceed 78%, depending on optimization in reaction conditions and purification efficiency. In industrial-scale production, the process incorporates , such as (HPLC), for purification and isolation of intermediates and the final product, achieving recoveries of 61–100% in analytical validations. Research into modern variants includes biocatalysis, utilizing monooxygenases from bacterial strains to selectively oxidize to the 4″- intermediate, potentially improving efficiency and reducing chemical waste compared to traditional routes. Quality control adheres to FAO/WHO specifications, requiring emamectin benzoate purity of at least 950 g/kg, with the B1a benzoate component comprising no less than 900 g/kg and B1b benzoate not exceeding 70 g/kg. Analytical methods, including HPLC with or fluorescence detection, ensure compliance, with limits of quantification as low as 0.001–0.005 mg/kg and relative standard deviations of 9.6–13%.

Applications

Agricultural Uses

Emamectin benzoate serves as a key in crop protection, primarily targeting lepidopteran larvae such as the (Plutella xylostella), (Helicoverpa armigera), and (Spodoptera exigua) that damage vegetables, , and fruits. It is registered for use on crops including , tomatoes, , , , , , , apples, almonds, and walnuts, where it effectively controls foliage-feeding and fruit-boring pests. In , emamectin benzoate is applied via trunk injection, such as under the brand Tree-äge, to protect ash trees from (Agrilus planipennis) larvae. This systemic method provides control for up to two years with appropriate application. Common formulations include emulsifiable concentrates (e.g., 0.16 lb ai/gallon) and water-dispersible granules or soluble granules (e.g., 5% SG), which are applied via foliar sprays to achieve translaminar penetration and stomach toxicity, allowing the to move within plant tissues for prolonged pest exposure. Application rates typically range from 5 to 20 g per , enabling high efficacy at low doses; for instance, the LD50 for susceptible lepidopteran larvae like the cotton leafworm () is approximately 0.751 ng per larva. As a member of Group 6 (glutamate-gated activators), emamectin benzoate supports management through rotation with insecticides of different modes of action, reducing the risk of development in target pests. It integrates well into IPM programs for crops, where field trials demonstrate effective control against . Globally, emamectin benzoate is registered in at least 22 countries, including the , , , , , and members of the , for agricultural applications on fruits, vegetables, cereals, tree nuts, and oilseeds, reflecting its widespread adoption in systems.

Veterinary and Aquaculture Uses

Emamectin benzoate is widely used in for the control of sea lice infestations, particularly Lepeophtheirus salmonis, in salmonid species such as (Salmo salar). It is administered via in-feed formulations at doses of 50–100 µg/kg biomass per day for 7 consecutive days, providing systemic protection against all parasitic stages of the lice, from chalimus to adults. This treatment method allows for targeted delivery during the fish's feeding phase, minimizing handling stress in marine net pens. The of emamectin benzoate is notable for its rapid action, achieving 90–99% mortality of sea lice within 2–3 days post-treatment initiation, with sustained reductions in levels for several weeks due to its prolonged residue in tissues. In field trials, a single course has demonstrated over 85% overall against natural infestations, significantly lowering the incidence of epidermal damage caused by lice attachment. Dosing is typically limited to 1–3 treatments per production cycle, with current regulations specifying a zero-day period before to ensure residue levels remain below maximum limits, though earlier guidelines in some regions required 60–68 days based on temperature-dependent depletion studies. Since its commercial introduction around 2000, emamectin benzoate has become a cornerstone in sea lice management for the salmon industries in and , where it serves as a key alternative to organophosphates and pyrethroids due to its higher specificity and lower environmental persistence in sediments. In these regions, which dominate global production, routine integration of emamectin treatments has helped mitigate economic losses from lice-induced mortality and reduced fish quality, though resistance monitoring is now essential for sustained effectiveness.

Biological and Pharmacological Activity

Mechanism of Action

Emamectin benzoate, a semi-synthetic of , primarily exerts its insecticidal and antiparasitic effects by to glutamate-gated channels (GluCl) in the nervous systems of . This activates the channels, leading to an influx of ions into the neurons, which causes hyperpolarization of the and disrupts normal impulse transmission. The result is of the affected organism, preventing feeding and ultimately leading to death. In addition to its action on GluCl, emamectin benzoate modulates gamma-aminobutyric acid (GABA)-gated channels, further enhancing conductance and contributing to the overall disruption of excitatory in target pests. The semi-synthetic modification of the structure increases its potency by 10- to 100-fold compared to parent avermectins like , allowing for lower effective doses while maintaining the core . Emamectin's selectivity for over mammals arises from its low affinity for mammalian receptors and its exclusion from the by the blood-brain barrier, minimizing neurotoxic effects in higher vertebrates. In agricultural applications, its translaminar movement through plant leaf tissues facilitates targeted delivery to pests feeding on treated foliage, enhancing without systemic throughout the plant. Resistance to emamectin benzoate in populations often develops through target-site in the , such as the A309V substitution in the , which reduces channel sensitivity to the compound and confers cross-resistance to related avermectins. Recent studies (as of 2024) have identified additional like G315E and G323D in pests such as Plutella xylostella and frugiperda, contributing to high-level resistance (up to 11,000-fold in some cases).

Metabolism and Environmental Fate

Emamectin undergoes rapid metabolism in mammals primarily through oxidative processes involving N-demethylation and , followed by conjugation, mediated by enzymes. In rats, following oral administration, approximately 55-74% is absorbed, with a of 20-51 hours at low doses (0.5 mg/kg body weight) and 35-36 hours at higher doses (20 mg/kg body weight). occurs rapidly, with over 90% of the dose eliminated within 72 hours, predominantly in (approximately 80-90%) and minimally in (about 1%). In and , emamectin exhibits similar oxidative , including N-demethylation and formation of hydroxylated derivatives, though to a lesser extent than in mammals. on foliage is significant under sunlight exposure, with a time for 50% loss (DT50) of approximately 0.5-4 days, leading to rapid breakdown at the surface. In , such as lepidopteran larvae, involves comparable I oxidations, contributing to the compound's short persistence within target organisms. Recent (2024) highlights sublethal effects from chronic low-dose exposure, including reduced , longevity, and reproductive rates in beneficial like parasitoids, underscoring broader ecological impacts. In the environment, emamectin demonstrates moderate persistence in soil, with aerobic DT50 values ranging from 5-34 days under dark conditions and 5-19 days under irradiated conditions, indicating some susceptibility to light-enhanced degradation. Its mobility in soil is low due to strong adsorption, with organic carbon partition coefficients (Koc) exceeding 25,000, preventing significant leaching. In aquatic systems, the half-life in water is less than 1 day under photolytic conditions, though it extends to 3-13 days in the dark; the compound readily binds to sediments, reducing bioavailability in the water column and resulting in sediment half-lives of 2-4 weeks. As of 2024-2025, concerns over environmental persistence and toxicity in aquaculture settings have led to proposed but delayed restrictions in regions like Scotland, due to impacts on non-target aquatic organisms and sediment accumulation. Key degradation products include the 8,9-Z (formed via photo-isomerization) and N-demethyl emamectin (AB1a), along with hydroxylated and conjugated forms such as 24-OH-MAB1a; these metabolites are generally less persistent and, in many cases, exhibit reduced compared to the parent compound, though the 8,9-Z retains significant activity. Polar photodegradates and derivatives also form, comprising up to 85% of total applied radioactivity in photolysis studies.

Safety and Toxicology

Toxicity Profiles

Emamectin benzoate exhibits moderate to mammals via the oral route, with an LD50 of 76-88 mg/kg body weight in rats, classifying it as Toxicity Category II according to EPA criteria. It shows no evidence of carcinogenicity, as evidenced by the absence of tumor increases in long-term studies, leading to an EPA classification of "not likely to be carcinogenic to humans." Similarly, assays, including Ames tests and chromosomal aberration studies, indicate no mutagenic potential. The compound is a severe eye irritant, categorized as Toxicity Category I by the EPA, capable of causing and conjunctival redness in rabbits that may persist for several days. In chronic exposure scenarios, emamectin benzoate demonstrates neurotoxic potential at elevated doses due to its effects on chloride ion channels, similar to its insecticidal mechanism. A 1-year oral study in dogs established a (NOAEL) of 0.25 mg/kg/day, based on the onset of clinical signs such as tremors, , and reduced motor activity at higher doses. These neurotoxic effects, including and changes in motor activity, were consistently observed across multiple mammalian species in subchronic and chronic studies, with degeneration in the noted histopathologically at doses exceeding the NOAEL. Emamectin benzoate poses significant risks to non-target organisms, particularly pollinators and aquatic species. It is highly toxic to bees, with an acute contact LD50 of 0.0027 µg/bee, rendering it highly hazardous to honey bee populations through direct exposure or residue contact. Aquatic invertebrates are also extremely sensitive, as demonstrated by a 48-hour EC50 of 1 µg/L for Daphnia magna immobilization, indicating potential for widespread impacts in freshwater ecosystems. In contrast, avian toxicity is moderate, with acute oral LD50 values of 76 mg/kg in mallard ducks and 264 mg/kg (95% CI: 201-329 mg/kg) in bobwhite quail, suggesting some risk to birds under high exposure conditions. Human exposure to emamectin benzoate primarily occurs through dermal contact during agricultural handling, though via this route is low at approximately 1.6% in mammalian models. Oral and exposures are less common but can arise from accidental or spray drift. A 2024 review documented cases of human poisoning, primarily from , resulting in symptoms such as , respiratory distress, gastrointestinal issues, and ; treatment is supportive, with no specific . Occupational risks, including potential neurotoxic symptoms from repeated dermal or exposure, are effectively mitigated through the use of such as gloves, long-sleeved clothing, and respirators, as recommended in EPA risk assessments. The compound's rapid contributes to its relatively low persistence in biological systems, reducing cumulative exposure concerns.

Regulatory Status and Environmental Impact

Emamectin benzoate was first registered as a by the U.S. Environmental Protection Agency (EPA) in 1999, establishing tolerances for residues on various crops ranging from 0.01 to 1.0 to ensure . Examples include 0.02 for the vegetable, fruiting, group 8-10 and 1.0 for the leafy greens subgroup 4-16A, reflecting assessments of dietary exposure risks. In the , the (EFSA) has reviewed and set maximum residue levels (MRLs) for emamectin between 0.01 and 0.5 mg/kg across commodities such as fruits, vegetables, and teas, based on alignments and consumer risk evaluations. For applications, regulatory frameworks impose restrictions on emamectin benzoate use to curb resistance development in sea lice, including dosage limits and treatment intervals mandated by bodies like the Scottish Environment Protection Agency (SEPA). Risk assessments classify emamectin benzoate as moderately hazardous (WHO Class II), indicating potential health concerns from acute exposure while emphasizing safe handling protocols. Environmental monitoring focuses on in aquatic species, with factors (BCF) in fish typically below 100, such as 82 L/kg measured in bluegill sunfish (Lepomis macrochirus), supporting low chronic accumulation risks under regulated conditions. Environmental concerns with emamectin benzoate center on its persistence in sediments and effects on non-target organisms, though leaching potential remains low due to strong binding and limited mobility when applied per label guidelines. It exhibits high toxicity to aquatic invertebrates, causing mortality in non-target species such as spot prawns (Pandalus platyceros) at environmentally relevant concentrations from effluents. Mitigation strategies include establishing buffer or mixing zones around farms to dilute discharges and protect benthic communities, as outlined in SEPA's interim environmental quality standards limiting sediment concentrations to 272 ng/kg dry weight. Recent developments post-2020 underscore gaps in sustainability, with reviews documenting resistance in sea lice populations on Pacific salmon farms, driven by repeated exposures and prompting calls for integrated pest management alternatives. Emamectin benzoate is prohibited under certain organic standards, including the Soil Association's certification for salmon aquaculture, to avoid synthetic chemical residues in labeled products. Emerging research also links its application to pollinator declines, revealing elevated risk quotients (e.g., 591.4 for bees) in wetland agricultural areas, highlighting needs for broader ecological impact studies.

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