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Nitenpyram
Nitenpyram
Nitenpyram
Names
Preferred IUPAC name
(E)-N1-[(6-Chloropyridin-3-yl)methyl]-N1-ethyl-N′1-methyl-2-nitroethene-1,1-diamine
Other names
Capstar
Identifiers
3D model (JSmol)
8489488
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.162.838 Edit this at Wikidata
EC Number
  • 601-735-5
KEGG
UNII
  • InChI=1S/C11H15ClN4O2/c1-3-15(11(13-2)8-16(17)18)7-9-4-5-10(12)14-6-9/h4-6,8,13H,3,7H2,1-2H3/b11-8+
    Key: CFRPSFYHXJZSBI-DHZHZOJOSA-N
  • ClC1=CC=C(C=N1)CN(\C(=C\[N+](=O)[O-])\NC)CC
Properties
C11H15ClN4O2
Molar mass 270.72 g/mol
Appearance Pale yellow crystalline solid
Density 1.4 (g/mL)
Melting point 82 °C (180 °F; 355 K)
Hazards
GHS labelling:
GHS07: Exclamation mark
Warning
H302
P264, P270, P301+P312, P330, P501
Pharmacology
QP53BX02 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Nitenpyram is a chemical frequently used as an insecticide in agriculture and veterinary medicine. The compound is an insect neurotoxin belonging to the class of neonicotinoids which works by blocking neural signaling of the central nervous system. It does so by binding irreversibly to the nicotinic acetylcholine receptor (nACHr) causing a stop of the flow of ions in the postsynaptic membrane of neurons leading to paralysis and death. Nitenpyram is highly selective towards the variation of the nACHr which insects possess, and has seen extensive use in targeted, insecticide applications.

Known under the codename TI 304 during field testing starting in 1989, the compound's first documented commercial use was in 1995 under the name "Bestguard" as an agricultural insecticide.[1] Later, nitenpyram was expanded for use as a flea treatment by the Novartis company under the trade name "Capstar", with a subsequent FDA approval for non-food producing animals in October 2000. The current producer of nitenpyram itself is the Sumitomo chemical company. Nitenpyram continues to be used commercially, though data from market surveys indicate a significant decrease in the global usage compared to other insecticides or neonicotinoids.[2]

Due to its use as an insecticide and treatment of non-food producing animals, it was not deemed necessary to research the human toxicology during its main use, and, as such, not much is known about the details of nitenpyram's effects on humans. Looking at rat experiments however, the lethal amount of nitenpyram is quite high (on the order of grams) in mammals in general, whereas invertebrates will die with only micro or nanograms of the substance.[3][4]

Neonicotinoids, in general, have a low degradation rate when used for agricultural purposes, which allows for long-lasting protection of the crops against plant-sucking insects and indirectly the plant diseases these insects might carry.[1]

Structure

[edit]

Nitenpyram ( (E)-N-(6-Chloro-3-pyridylmethyl)- N-ethyl-N'-methyl-2-nitrovinylidenediamine) is an open-chain chloropyridyl neonicotinoid. Nitenpyram consists of a chloronicotinyl heterocyclic group common to all first generation neonicotinoids and a pharmacophore, the reactive group of the molecule. Nitenpyram possesses a nitroamine pharmacophore which is known to be the main reaction site in the binding of the compound to the nACh receptor, though the specificity of the reaction is not yet fully understood for neonicotinoids in general.[1] Due to its polar groups, nitenpyram is quite hydrophilic, with an extremely high water solubility.

Mechanism of action

[edit]

Though neonicotinoids are the largest group of insecticides used in today's agricultural world and prevalent in veterinary treatments, toxicity in general, e.g., genotoxicity and biotransformation, remains among the most controversial matters on the topic of neonicotinoids.[5] This is primarily due to the lack of concrete systematic work.[5] However, studies have been done on binding phenomena between neonicotinoids and proteins, serving as an indicator to its likely behavior in human physiological conditions.[6]

Nitenpyram, a synthetic, nicotine-related chemical (neonicotinoid), has an effect on the nicotinic acetylcholine receptors and, for this reason, is considered similar to nicotine (agonists). Nicotinic acetylcholine receptors are involved in the sympathetic and parasympathetic nervous systems, present on the muscle cells where the cells from the nervous systems and the muscle cells form synapses. Variations in nicotinic-acetylcholine-receptor-binding affinity persists between species.

Although nitenpyram is an agonist of nicotine for the nicotinic acetylcholine receptor, it has a much lower affinity for the nicotine acetylcholine receptor in mammals. For most insects nitenpyram is a very lethal compound. Nitenpyram will bind irreversibly to the nicotinic acetylcholine receptors, paralysing those exposed to the compound. Despite lower affinity levels, mammals can still get a nicotine poisoning response from too much neonicotinoids, hence it is of importance to provide the appropriate dose for a flea-infested pet and it's always best to consult a vet.

Nitenpyram itself and its metabolites, apart from 6-chloronicotinic acid, have not been through in-depth toxicological investigations.[7] Similarly genotoxicity effects remain ambiguous. 6-chloronicotinic acid, according to a research group, is non-carcinogenic and is not considered a developmental toxicant.[6]

Metabolism

[edit]

The literature on the biotransformation of nitenpyram has been scarce. However, some studies have been conducted.[6] Toxicokinetic studies have shown that human intestinal caco-2 cell line can absorb imidacloprid at a very high rate of efficiency.[6][7] The compound completely absorbs (>92%) from the gastrointestinal tract, rapidly distributes from the intravascular space to the peripheral tissues and organs, like the kidney, liver and lungs, proceeding biotransformation. Vets and pet owners have reported the effect of nitenpyram on flea-infested pets starting within 30 minutes after administering the neonicotinoid.[8]

Nitenpyram has been reported to metabolize into 6-chloronicotinic acid.[6]

Nitenpyram in mice metabolizes into nitenpyram-COOH, nitenpyram-deschloropyridine, desmethyl-nitenpyram, nitenpyram-CN, and nitenpyram-deschloropyridine derivatives.[7] The nitenpyram metabolites have not been through in-depth study. However, these metabolites can undergo oxidation reactions like the cyano group into a carboxylic group.[7] 6-chloronicotinic acid can make hydrogen bonds with the hydrogen atom of amino groups.

Cytochrome P450 enzymes in humans could generate some metabolites with greater toxicity than the parent compound, certified to cause tumors in combination with nitrates and induce genetic damage.[9] A precautionary approach to anything understudied would be advised, until the biotransformation is better and its effects are better studied and understood.

Synthesis

[edit]

Nitenpyram is synthesized in a multistage reaction.[10] The precursor compound of this reaction is 2-chloro-5-chloromethylpyridine, which is also used in the preparation of other neonicotinoids such as imidacloprid. The reaction of this compound undergoes three reaction steps.

First step, 2-chloro-5-chloromethylpyridine reacts with ethylamine on its phase boundary acquiring the molecule N-ethyl-2-chloro-5-pyridylmethyl amine.

Synthesis can then proceed with a condensation reaction (step 2), adding the solvents dichloromethane and trichloronitromethane will yield the intermediate N-ethyl-2-chloro-5-pyridylmethyl amine with an additional nitroethylene group.

In the last step methylamine is added and reacts with the intermediate, replacing the pharmacophore chloride group, obtaining nitenpyram as the final end product.

Derivatives

[edit]

Being a first generation neonicotinoid, nitenpyram has been subject to a variety of modifications to its original structure, to either increase the effectiveness or specificity of the compound. One such variation is on the configuration of the reactive group/pharmacophore, from cis (E) to trans (Z) configuration.[11] It has been shown that this type of modification can substantially increase the affinity of nitenpyram to bind to the insect nACh receptor, allowing for more directed and ecologically friendly pest control. Changes to these compounds could also help circumvent the growing resistance in nitenpyram.

Toxicology

[edit]

Invertebrates

[edit]

In a 2015 study, neonicotinoids toxicity was tested on the egg parasitoid trichogramma. Nitenpyram specifically was found to have the lowest toxicity, making it useful in IPM (integrated pest management) treatment.[2]

In 2015, researchers conducted a study on the toxicity of nitenpyram on the earthworm E.fetida. E.fetida is a common earthworm, which is partly responsible for the natural aeration of soil, including agricultural soil. In a 14-day exposure period, the Toxicity in LC50 of nitenpyram on e.fetida was found to be 4.34 mg/kg soil, showing an inhibition of cellulase activity and damage to the epidermal cells and gut cells. This, however, was significantly less toxic than similar insecticides such as imidacloprid, thiacloprid and clothianidin, making nitenpyram a viable substitute for many other neonicotinoids used.

Ecologic effects of nitenpyram on bee populations is under controversy, as contradicting studies show the presence of nitenpyram in honey bees and their honey, while others do not detect nitenpyram at all.[12][13] This, however, may be due to the decrease in usage of nitenpyram, as the global market share has been steadily decreasing.

Nitenpyram is also commonly used in the elimination of and protection from mosquitoes. Specifically, the toxicity of nitenpyram on Culex quinquefasciatus or the southern house mosquito was tested. The LC50 of the compound was found to be 0.493 ug/ml.

Vertebrates

[edit]

Aquatic animals

[edit]

In a study a 60-day chronic toxicity test was conducted on Chinese rare minnows (Gobiocypris rarus) as a general fish model.[14] Of the neonicotinoids tested (imidacloprid, nitenpyram, and dinotefuran), nitenpyram was shown to not have much genotoxic effects or adversely affect the immune system, either through short or chronic exposure in comparison to the other compounds.

In a similar study, nitenpyram was shown to have adverse effects on the DNA of Zebrafish.[15] Enzymes inhibiting the formation of reactive oxygen species (ROS) were severely affected, causing oxidative DNA damage increasing with chronic exposure.

Mammals

[edit]

The Oxford University chemical safety data documents an LD50 toxicology test on rats, both male and female, where doses are recorded as 1680 mg and 1575 mg per kg body weight respectively.[3] As such, the overdose limits for humans and animals are quite high, reaching into grams, and the compound is seen as safe for daily use for animals. Human consumption is not recommended, though no side effects of indirect exposure (such as eating treated plants) are known to occur.

Degradation

[edit]

In the hope to understand neonicotinoid degradation in various types of water, an interesting find was made.[16] In testing ground water, surface water and finished drinking water, researchers found degradation of nitenpyram was occurring primarily in the drinking water, which was attributed to hydrolysis of the compound. Some of these degradation products are thought to have toxic properties in non-target organisms, though the actual toxicities are not known. Nitenpyram is also degraded under the effect of UV light, suggesting that exposure to the sun will also degrade the compound into various degradation products.

Veterinary applications

[edit]

Nitenpyram tablets, brand name Capstar,[17] are used to treat flea infestations in cats and dogs.[18] After oral administration of the tablet the drug is readily and quickly absorbed into the blood. If a flea bites the animal it will ingest with the blood the nitenpyram. The effect of nitenpyram can be observed half an hour after the administration. At this time a high concentration in the plasma can be detected and the first fleas dislodge from the pet host. A study showed that six hours after application the infestation of fleas on decreased by 96.7% for dogs and 95.2% for cats.[17][19] The adult fleas present on the hosts are severely interrupted, hence, egg production is reduced. Eggs are not directly affected by nitenpyram, only after they come out. Administering nitenpyram might have to be repeated or continued until the pest infestation has subsided. The half life of nitenpyram is around eight hours. Thus, 24 hours after treatment roughly 100% of the adult fleas were killed. Between 24 hours and 48 hours the efficacy is highly decreased and after 72 hours no effect could be shown anymore in studies.

Side effects

[edit]

One observed side effect is itchiness, suspected to be from the fleas dislodging. In the five hours after the treatment it was observed that cats were grooming themselves more, i.e. scratching, biting, licking, and twitching. This will stop when the fleas have either flagged or have died.[17] Other reported side effects are hyperactivity, panting, lethargy, vomiting, fever, decreased appetite, nervousness, diarrhea, difficulty breathing, salivation, incoordination, seizures, pupil dilation, increased heart rate, trembling and nervousness.[20] In other studies no adverse effects were observed.[19]

Agricultural applications

[edit]

Being one of the first generation neonicotinoids, nitenpyram has seen extensible commercial use since its introduction, including pest control in agriculture. While the development of newer generation nicotinoids has caused a decrease in its use, a Worldwide Integrated Assessment (WIA) report still judged it as an ecologically viable treatment in pest control projects such as Integrated Pest management (IPM). This is due to its lower toxicity and high uptake in plants in relation to soil as opposed to other commercially used neonicotinoids.[21]

Nitenpyram has been used on many commercial crops, such as cotton and corn,[21][22] and can be applicated in various ways. Commonly used techniques are dusting and seed treatment. Seed treatment allows for a long lasting immunity to insects damaging the crops. The use of nitenpyram has been shown to be highly effective in protecting crops, as it is generally less toxic for non-target organisms, while killing off crop-destroying insects. While usage is still common, unlike other neonicotinoids, the global market share for nitenpyram seems to decrease based on product sale data from 2003, 2005, 2007 and 2009.[22][5] The reason for this is not yet fully understood, as other first generation neonicotinoids do not seem to follow the same trend, and nitenpyram is known to be less toxic to non-target organisms as compared to the compounds of the same generation.

However, the decrease of use could possibly be explained through the formation of resistance in various insect species.[22][23] In a study conducted on nine commonly used nicotinoids, nitenpyram was found to have the greatest increase in resistance of the group within brown planthoppers, a common agricultural pest, between 2011 and 2012. A substantial increase of resistance was also found in Aphis gossypii or the cotton aphid, as compared to other compounds such as imidacloprid.

Side effects

[edit]

Due to its use on pollen carrying plants, nitenpyram has been linked to a decrease in population of pollinators such as honey bees, wild bees and butterflies.[5] Other non-target organisms, such as earthworms, are also reported to be negatively affected by nitenpyram. Plants themselves do not seem to have a negative response, as they do not possess nicotine nACh receptors.

References

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Nitenpyram

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from Grokipedia
Nitenpyram is a synthetic utilized in and to target pests, most prominently for the swift elimination of adult fleas (Ctenocephalides felis and C. canis) on dogs and cats. With the C11H15ClN4O2, it operates as a by competitively binding to nicotinic receptors in the postsynaptic membranes of neurons, disrupting nerve impulse transmission and inducing rapid paralysis and mortality. In companion animal treatments, such as the oral tablet formulation sold under brand names like Capstar, nitenpyram achieves significant flea kill-off within 30 minutes of administration, though it lacks ovicidal or larvicidal activity against flea eggs or larvae. Its favorable safety profile extends to pregnant, lactating, and breeding animals, with minimal mammalian due to poor penetration of the blood-brain barrier and rapid excretion. In agricultural settings, it controls sucking pests like and through systemic action, often formulated as technical concentrates or in combination products.

History and Development

Discovery and Commercialization

Nitenpyram, a , emerged from research initiated in the early at Nihon Tokushu Noyaku Seizo K.K. (now Bayer CropScience K.K.), building on the lead compound nithiazine discovered by Shell Development Company. In the mid-, the company filed numerous patents for neonicotinoid structures, selecting nitenpyram for further development due to its rapid insecticidal action and favorable mammalian safety profile compared to earlier candidates. Field testing began in 1989 under the codename TI-304, demonstrating efficacy against pests like through enhanced binding to insect nicotinic acetylcholine receptors, addressing resistance issues with prior such as organophosphates. The compound's first commercial application occurred in 1995 in as Bestguard, targeting hop aphids and other sucking pests in , marking an early milestone in deployment for crop protection. This agricultural introduction capitalized on nitenpyram's quick knockdown effect, enabling systemic uptake in for control of resistant populations. By the late 1990s, licensing agreements expanded its scope; Animal Health (now ) commercialized it for veterinary use as Capstar tablets, launched around 2000 for rapid elimination of adult fleas on dogs and cats. Subsequent formulations broadened agricultural applications to , , and orchards against aphids, whiteflies, and , driven by empirical data on its selectivity and speed over conventional pesticides.

Chemical Properties

Molecular Structure and Synthesis

Nitenpyram possesses the molecular formula C11H15ClN4O2 and a of 270.72 g/mol. Its IUPAC name is (E)-N-[(6-chloropyridin-3-yl)methyl]-N-ethyl-N'-methyl-2-nitroethene-1,1-diamine. The molecule features a central 2-nitroethene-1,1-diamine core, with one nitrogen substituted by an and a (6-chloropyridin-3-yl)methyl group, and the other by a . This nitromethylene subgroup, characterized by the =CH-NO2 functionality, defines its classification within neonicotinoids and contributes to selective binding at insect nicotinic acetylcholine receptors. Synthesis of nitenpyram typically proceeds via multi-step routes from pyridine precursors, emphasizing chlorination and condensation reactions for industrial scalability. One established method begins with 2-chloro-5-chloromethylpyridine, which undergoes nucleophilic substitution with ethylamine to form N-ethyl-(6-chloro-3-pyridyl)methanamine. This intermediate then condenses with a nitroethene precursor, such as a derivative of N-methyl-2-nitro-1,1-ethenediamine, to construct the key nitro-methylene linkage under controlled conditions to favor the E-isomer and achieve high yields. Alternative routes initiate from 1,1,1,2-trichloroethane to build the nitroethene chain, followed by coupling with the pyridylamine, optimizing for cost-effective production with minimal byproducts. These processes highlight efficient atom economy and adaptability for large-scale manufacturing.

Physical and Chemical Characteristics

Nitenpyram appears as a white to pale yellow crystalline solid. Its melting point ranges from 83 to 84 °C, facilitating handling in solid formulations during manufacturing. The compound exhibits high solubility, approximately 840 g/L at 25 °C, which supports its formulation into aqueous solutions but requires consideration for precipitation in concentrated preparations. This solubility contrasts with lower values in organic solvents, influencing extraction and purification processes. The (log Kow) of -0.64 at 25 °C indicates hydrophilic character, promoting mobility in aqueous environments and limiting potential in lipophilic matrices. is negligible at 1.1 × 10-6 mPa (20 °C), ensuring low volatility and minimal airborne exposure risks during storage and application. measures approximately 1.40 g/cm³ at 26 °C, aiding in calculations for industrial packaging. Nitenpyram demonstrates chemical stability under neutral to mildly acidic conditions, with no significant at 3–7 (DT50 >1 year at 25 °C), but undergoes degradation via at alkaline 9 (DT50 ≈ 2.9 days at 25 °C). This pH-dependent stability necessitates neutral buffering in formulations to prevent breakdown during prolonged storage or use in variable environmental conditions. Thermal stability extends to 150 °C without , supporting processes like or .
PropertyValue
Molecular formulaC11H15ClN4O2
Molecular weight270.72 g/mol
(predicted)417 °C
pKa (strongest basic)≈3.5

Mechanism of Action

Nitenpyram acts as an at postsynaptic nicotinic receptors (nAChRs) in the of , binding to the acetylcholine recognition site and triggering an influx of cations such as sodium, which causes of the neuronal membrane. This persistent activation—unlike the transient response elicited by endogenous , which is quickly hydrolyzed by —leads to overstimulation, desensitization of the receptors, blockage of neural transmission, paralysis, and insect death typically within hours. Electrophysiological assays confirm that nitenpyram's agonist potency derives from its structural mimicry of , with specific interactions at the receptor's orthosteric site stabilizing an open-channel state. The compound's selectivity for invertebrate nAChRs stems from evolutionary differences in receptor subunit composition; insect nAChRs, composed of diverse alpha-like subunits (e.g., α1–α8), possess binding pockets more accommodating to neonicotinoids' nitroimine or nitromethylene pharmacophores, whereas mammalian nAChRs exhibit lower affinity due to conserved neuronal subtypes with mismatched geometries. Radioligand binding studies demonstrate nitenpyram's (Ki) in the low nanomolar range for insect receptors, orders of magnitude higher than for counterparts, minimizing cross-toxicity. This differential binding affinity, validated through structure-activity relationship analyses, underscores the causal basis for its safety profile in mammals.

Pharmacokinetics

Absorption, Metabolism, and Excretion

Nitenpyram is rapidly and nearly completely absorbed after in mammals, with peak plasma concentrations occurring within 1.21 hours in dogs (Cmax ≈ 4787 ng/mL) and 0.63 hours in cats. The compound exhibits high due to this swift gastrointestinal uptake, facilitating quick systemic distribution for ectoparasite control in veterinary applications. In dogs and cats, the plasma elimination is short at approximately 2.8–3 hours and 7.7–8 hours, respectively, which limits prolonged exposure and tissue accumulation. Hepatic metabolism occurs primarily through enzymes, converting nitenpyram into polar metabolites that undergo conjugation. These metabolites are excreted mainly via , with elimination completing within 48 hours post-dosing; in dogs, only about 3% of the dose is excreted unchanged, underscoring efficient and low potential. In hematophagous insects like fleas, nitenpyram is absorbed rapidly upon ingestion from host blood, achieving systemic distribution and neurotoxic effects within minutes to hours, aligning with its fast-acting adulticide profile. Mammalian metabolism proceeds more rapidly than in target , where via analogous P450 pathways is slower or less efficient, contributing to the compound's selective window and safety margin for vertebrate hosts.

Environmental Degradation

Nitenpyram exhibits stability to under neutral conditions, with no significant degradation observed at 7 and 20°C, contrasting with base-catalyzed at 9 where the DT50 is approximately 696 days at 25°C. In natural waters at 7 and 25°C, the hydrolytic extends to about 415 days, indicating limited aqueous persistence under typical environmental ranges. Photodegradation occurs readily under UV and solar irradiation in aqueous solutions, with kinetics showing pseudo-first-order decay and formation of transformation products such as nitroso and hydroxy derivatives. Exposure to sunlight in deionized water or soil leads to significant breakdown, accelerated by UVB wavelengths compared to UVA, though overall rates depend on matrix effects like soil organic content. In , aerobic predominates, yielding a DT50 of 1–15 days under conditions, driven by microbial activity that mineralizes the compound to CO2 and bound residues. This short persistence differentiates nitenpyram from more recalcitrant neonicotinoids like (DT50 up to 156 days), reflecting its polar structure favoring biotic transformation over abiotic stability. Sorption to is moderate, with an estimated Koc of 1600, indicating low leaching potential and reduced risk of relative to highly mobile pesticides (Koc <500). Equilibrium adsorption in loess soils occurs within 4 hours, influenced by organic carbon and clay content, further limiting vertical migration. Field dissipation studies report minimal residues post-application, such as 0.01–0.54 mg/kg in kiwifruit 7–21 days after spraying, and trace levels in cabbage and below regulatory thresholds, supporting rapid environmental clearance without accumulation in crops or runoff waters. These data challenge broad claims of neonicotinoid persistence, as nitenpyram's empirical fate—short soil DT50 and low mobility—evidences lower carryover risks in agronomic settings.

Applications

Veterinary Applications

Nitenpyram is administered orally in tablet form, primarily under the brand name Capstar, to provide rapid control of adult flea infestations (Ctenocephalides felis and Ctenocephalides canis) on dogs and cats. This application targets active infestations by killing adult fleas shortly after ingestion, aiding in the immediate relief of symptoms associated with heavy flea burdens, such as skin irritation leading to dermatitis. Approved by the FDA in 2000 for non-food-producing animals, its adoption in veterinary practice expanded in the early 2000s as part of integrated flea management strategies. The standard dosing regimen is a minimum of 1 mg/kg body weight, administered once daily as needed when adult fleas are observed, for dogs and cats weighing at least 2 pounds (0.9 kg) and older than 4 weeks. Tablets are available in 11.4 mg (for animals 2-25 pounds) and 57 mg (for dogs 25.1-125 pounds) strengths, with administration directly by mouth or concealed in food to ensure compliance during infestations. In clinical settings, veterinarians often recommend its use alongside monthly preventives lacking adulticidal activity to address breakthrough infestations, thereby supporting overall parasite control programs that minimize environmental flea reservoirs. Veterinary protocols emphasize nitenpyram's role in scenarios requiring swift adult flea elimination, such as in multi-pet households or shelters with high infestation risks, where it helps prevent secondary issues like flea allergy dermatitis exacerbations or blood loss contributing to anemia in severe cases. Since its commercialization, real-world applications in companion animal clinics have integrated it into protocols for prompt intervention, particularly for young animals where long-acting topicals may not yet be suitable. It lacks activity against flea eggs or larvae, necessitating complementary environmental treatments and preventives for comprehensive management.

Agricultural Applications

Nitenpyram functions as a systemic insecticide in agricultural crop protection, primarily applied via foliar sprays to control sucking pests including aphids, whiteflies, , and leafhoppers on rice, vegetables, fruits, and glasshouse crops. These applications leverage its rapid uptake and translocation within plant tissues, providing protection to both treated foliage and new growth. Typical dosages range from 10-75 g active ingredient per hectare, depending on crop and formulation, such as 15-75 g/ha for foliar use on rice. Introduced during the expansion of neonicotinoid insecticides in the mid-1990s, nitenpyram has been incorporated into integrated pest management strategies, particularly in Asia, where it offers an alternative to organophosphates and contributes to yield protection by mitigating pest-induced losses. Its use supports higher crop outputs in rice paddies, vegetable fields, and orchards by enabling timely interventions against piercing-sucking insects that vector diseases and reduce photosynthesis. Regulatory approvals are prominent in Asian markets, with maximum residue limits established for commodities like rice and vegetables, often at or below 0.5 mg/kg to align with safety standards. Adoption in Western agriculture remains restricted, reflecting broader neonicotinoid limitations.

Efficacy Data

Performance in Pest Control

In veterinary trials, oral nitenpyram administration has consistently achieved over 95% mortality of adult fleas (Ctenocephalides felis) on infested dogs and cats within 6 to 8 hours. For example, experimental studies reported 96.7% efficacy in dogs and 95.2% in cats at six hours post-treatment, with fleas rapidly detaching from hosts prior to death. In controlled infestations, 100% mortality of fleas present on treated cats was observed immediately upon host contact, alongside near-complete suppression of flea egg production for up to 48 hours. These outcomes were replicated in multi-clinic field evaluations, yielding 98.6% efficacy in dogs and 98.4% in cats against natural infestations. Agricultural field trials demonstrate nitenpyram's effectiveness against sucking pests, with seed or granular treatments providing 80-100% population reduction for 7-14 days. In cotton seedling tests, nitenpyram seed coatings at 10 mg per seed achieved superior control of mirid bugs (Apolygus lucorum) compared to other neonicotinoids, maintaining low pest densities through early growth stages. Granular applications similarly prevented outbreaks of aphids (Aphis gossypii) and plant bugs (Apolygus lucorum), with residue analyses confirming sustained uptake and pest suppression over two weeks. High control efficiencies, up to 95% in field settings, were noted against aphids in treated crops. The compound's rapid kill supports resistance management by interrupting reproduction cycles, as short exposure leads to immediate adult mortality and reduced oviposition in pests. Longitudinal data from repeated veterinary treatments show progressive infestation declines, minimizing opportunities for resistant strain selection. In agriculture, this translates to fewer applications needed for sustained control, with cost-benefit evaluations highlighting economic advantages through lower input costs and reduced crop damage from pests like aphids and mirids.

Comparative Advantages

Nitenpyram exhibits a notably faster onset of action against fleas compared to other neonicotinoids such as and alternatives like or cythioate, achieving 100% efficacy in cats within 3 hours and near-complete kill (99.1%) in dogs by the same timeframe, with full efficacy by 8 hours. In contrast, reaches only 82.8% efficacy within 8 hours under similar conditions. This rapid knockdown, often within 30 minutes for fleas, stems from its systemic absorption and quick binding to insect nicotinic acetylcholine receptors, providing immediate relief in veterinary flea infestations where slower-acting topicals delay control. Its selectivity for insect over mammalian nicotinic receptors—approximately 3500-fold greater affinity for insect alpha-4beta-2 subtypes—confers a wide safety margin, with acute mammalian LD50 values exceeding those of carbamates by factors often >1000:1 in insect-to-mammal ratios for neonicotinoids broadly. This contrasts with carbamates' narrower therapeutic indices due to acetylcholinesterase inhibition affecting both insects and vertebrates more indiscriminately, enabling nitenpyram's use at lower doses (e.g., 1 mg/kg orally in pets) without comparable vertebrate toxicity. In resistance-prone populations, nitenpyram demonstrates empirical efficacy against strains showing cross-resistance to or pyrethroids, as its distinct receptor binding evades common metabolic resistance mechanisms in fleas and sucking pests like . Slower alternatives, such as , exhibit higher failure rates in such scenarios due to shared resistance pathways among neonicotinoids, underscoring nitenpyram's utility in integrated management where rapid, targeted kill reduces selection pressure. Its shorter residual activity, typically 24-48 hours, further minimizes prolonged environmental exposure compared to persistent pyrethroids.

Toxicology

Effects on Invertebrates

Nitenpyram demonstrates high potency against target invertebrates, particularly fleas (Ctenocephalides felis), where blood concentrations of 0.5–0.9 ppm achieve 100% mortality of feeding adults within 15–30 minutes and sustain near-complete kill for 24 hours post-exposure. This rapid knockdown stems from its action as a nicotinic acetylcholine receptor agonist, disrupting neural transmission in insects. Against aphids and related hemipterans, nitenpyram exhibits strong selectivity and toxicity due to affinity for insect-specific receptor subtypes, with effective field application rates around 30 g active ingredient per hectare for aphid control. For non-target invertebrates like honey bees (Apis mellifera), is moderate, with an oral LD50 of approximately 138 ng per , higher than that of many other neonicotinoids such as (around 40 ng/). Sublethal exposures, such as chronic low doses (3–300 μg/L over 14 days), can induce , altering metabolic , immunity, and potentially behavior, though these effects are primarily documented in settings. Nitenpyram's short systemic duration (24–48 hours efficacy against fleas) and rapid elimination may limit accumulation and chronic exposure risks in field scenarios, contrasting with more persistent neonicotinoids. Resistance to nitenpyram has emerged in laboratory-selected strains, such as a 164-fold increase in the (Nilaparvata lugens) after 42 generations of selection, linked to enhanced detoxification enzymes like P450s. Field populations of (Bemisia tabaci) show moderate to high resistance in up to 48% of sampled groups, associated with fitness costs including reduced and . Compared to broad-spectrum organophosphates or pyrethroids, resistance development appears slower in s like nitenpyram due to targeted , though cross-resistance with other neonicotinoids occurs via shared metabolic pathways. Field studies specific to nitenpyram report no isolated population declines in pollinators attributable solely to its use, amid broader controversies over neonicotinoid impacts.

Effects on Vertebrates

Nitenpyram demonstrates low acute mammalian , with oral LD50 values ranging from 1575 to 1680 mg/kg body weight in . In chronic studies, the (NOAEL) was established at 53.7 mg/kg/day over two years in , with the primary observable effect being reduced body weight gain and no indications of , carcinogenicity, or developmental . Similar NOAEL values of approximately 60 mg/kg/day were reported in one-year studies, underscoring selective due to rapid hepatic and in vertebrates, which limits accumulation. Aquatic vertebrates exhibit minimal sensitivity, evidenced by 96-hour LC50 values exceeding 1000 mg/L in and low factors of approximately 3 in , enabling swift elimination and reducing chronic exposure risks. This profile contrasts with higher sensitivity in embryonic models like , where LC50 values around 143 mg/L were noted, but adult data support low hazard under typical environmental concentrations. In companion animals, nitenpyram is generally well-tolerated at therapeutic doses for flea control, with reported adverse events primarily mild and transient, such as , , hyperactivity, or increased salivation, often linked to massive flea mortality rather than inherent . Serious effects like seizures or decreased activity occur rarely and predominantly at overdoses exceeding recommended levels by several fold, with post-marketing surveillance indicating a favorable margin relative to acute mammalian LD50 thresholds.

Environmental Impact

Persistence and Bioaccumulation

Nitenpyram demonstrates low environmental persistence in , with a degradation (DT50) ranging from 1 to 15 days across various soil types under aerobic conditions. This rapid breakdown, driven primarily by , contrasts sharply with persistent organic pollutants exhibiting DT50 values of months or years, thereby minimizing long-term soil accumulation and subsequent trophic transfer to higher organisms. In water, hydrolytic stability is greater, with an estimated of 150 to 320 days at environmentally relevant levels, though under natural sunlight reduces this to approximately 3.7 hours in clear systems. Bioaccumulation potential is negligible, as evidenced by an estimated bioconcentration factor (BCF) of 3 in , well below thresholds of concern (e.g., BCF >1000) used in regulatory assessments. This low value aligns with nitenpyram's hydrophilic nature (log Kow = -0.66) and is consistent with Guideline 305 predictions for substances with minimal partitioning, which often waive empirical testing for low-accumulation compounds. Primary metabolites, such as those formed via nitroimine reduction or cleavage, exhibit reduced toxicity compared to the parent compound, further limiting risks in aquatic and terrestrial food webs. Kinetic models incorporating these parameters indicate restricted uptake across trophic levels, with field dissipation studies in treated agricultural soils confirming residues falling below detectable limits (typically <0.01 mg/kg) within weeks post-application.

Effects on Non-Target Species

Nitenpyram demonstrates sublethal effects on pollinators, including disruption of honey bee gut microbiota, which can impair metabolic homeostasis and immune function following exposure. Laboratory studies indicate toxicity to non-target insects like bees at concentrations relevant to agricultural applications, though field exposure via crop residues or pet flea treatment waste remains debated due to rapid metabolism and low persistence in the environment. Specific residues of nitenpyram in honey or bee products are infrequently detected at levels causing verified colony-level impacts, with no empirical evidence linking it directly to colony collapse disorder, unlike broader neonicotinoid associations. Aquatic non-target species exhibit variable sensitivity, but nitenpyram displays low acute toxicity to key invertebrates such as Daphnia magna, with a 48-hour EC50 exceeding 10,000 mg/L, far above typical environmental concentrations. Runoff dilution and the compound's short in further reduce risks to ecosystems, though chronic low-level exposure could affect sensitive macroinvertebrate communities in undiluted scenarios. For vertebrate , including birds, dietary risks from nitenpyram appear negligible, as s in this class generally have high LD50 values (>200 mg/kg body weight) for avian species, limiting acute even from contaminated or . Empirical field data and meta-analyses on neonicotinoid use show no specific between nitenpyram application and measurable declines in or populations, countering generalized alarmism about systemic harm.

Controversies and Regulatory Debates

Scientific Disputes on Risks

Scientific disputes regarding nitenpyram's risks center on discrepancies between findings and field observations, particularly for impacts. Laboratory studies have demonstrated to honeybees at doses as low as 0.003 μg/bee, with sublethal effects on foraging behavior and larval development observed under controlled exposures. However, field trials reconciling these with real-world applications reveal minimal population-level harm, attributing lab to unrealistic dosing that exceeds typical environmental concentrations by orders of magnitude; critiques emphasize that extrapolating sublethal lab metrics to field irrelevance overlooks dilution, degradation, and behavioral avoidance in natural settings. Pet ectoparasiticide runoff concerns, often generalized from topical neonicotinoids, face scrutiny for nitenpyram's : as an oral systemic agent with rapid kill within hours and hepatic yielding short biological half-lives (under 24 hours in mammals), it produces negligible persistent residues compared to spot-on formulations. Empirical monitoring of waterways near high density areas detects neonicotinoids at parts-per-trillion levels, below thresholds for chronic aquatic , challenging claims of widespread from veterinary use; proponents of exaggerated risks cite lab assays on but ignore nitenpyram's rates (predicted 150–320 days in sterile , accelerated in biotic matrices) and low application volumes. Debates on resistance development highlight overuse in continuous agricultural spraying fostering metabolic and target-site mutations in pests like whiteflies, with up to 100-fold tolerance reported after repeated exposures. Yet, from targeted, pulse-dosing protocols in veterinary contexts show sustained without rapid resistance buildup, favoring integrated over prohibitions that could elevate reliance on broader-spectrum alternatives; empirical resistance monitoring underscores that intermittent use mitigates selection pressure more effectively than blanket restrictions.

Policy Responses and Critiques

In the , restrictions on insecticides implemented since 2018 primarily targeted agricultural applications of substances like , , and due to concerns over declines, but these measures have indirectly influenced scrutiny of related compounds like nitenpyram used in veterinary products. Nitenpyram, approved for oral control in companion animals under products like Capstar, remains authorized for indoor veterinary use by the , with no outright ban as of 2025. However, environmental advocacy groups such as Action Network have called for extending prohibitions to pet medicines containing neonicotinoids, citing 2023 studies detecting residues in waterways from excreted veterinary doses, potentially harming aquatic invertebrates at concentrations exceeding predicted environmental levels. These demands argue for a precautionary approach prioritizing ecosystem protection over localized benefits. Critiques of such proposed veterinary curbs emphasize empirical gaps in linking low-dose pet applications to verifiable ecological damage, given nitenpyram's rapid metabolism and short environmental half-life of hours to days, which limits persistence compared to banned agricultural neonics. Veterinary industry representatives, including the National Office of Animal Health (NOAH), contend that evidence for pollution-driven harms remains unsubstantiated, as monitored exposure levels from companion animal treatments do not correlate with observed population declines, and restrictions could exacerbate infestations transmissible to humans and , increasing disease vectors like . A cost-benefit reveals that curtailing access to fast-acting options like nitenpyram—effective within 30 minutes against fleas—might drive reliance on slower or more persistent alternatives, potentially yielding net environmental drawbacks without proportional gains in . In contrast, regulatory approvals in the United States and prioritize efficacy and targeted risk data, with the FDA and EPA permitting nitenpyram in over-the-counter pet products based on assessments showing minimal human or non-target exposure under labeled use. Asian markets, including and where nitenpyram originated, continue expansive authorization for both veterinary and limited agricultural applications, supported by market growth projections to USD 250 million globally by 2033, reflecting confidence in its safety profile derived from pharmacodynamic studies. Broader critiques of restrictions, informed by ex-post economic evaluations, highlight such as 4-9% yield reductions in EU oilseed rape post-2013 bans, equating to annual losses exceeding €900 million, alongside shifts to older pyrethroids or organophosphates with higher profiles, questioning whether pollinator safeguards justify forgone productivity and . These analyses underscore that regulatory decisions overly reliant on correlation-based environmental claims, rather than causal exposure-response data, may amplify costs without commensurate benefits, a principle applicable to veterinary extensions where pet health imperatives—preventing and allergies in millions of animals—outweigh speculative aquatic risks.

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