Nitenpyram

Last updated
Nitenpyram
Nitenpyram Formula V1.svg
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 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 601-735-5
KEGG
PubChem CID
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
AppearancePale yellow crystalline solid
Density 1.4 (g/mL)
Melting point 82 °C (180 °F; 355 K)
Hazards
GHS labelling:
GHS-pictogram-exclam.svg
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).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

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.

Contents

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

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

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

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

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.

Firstreaction nitenpyram synthesis.png

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.

Secondreaction nitenpyram synthesis.png

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

Thirdreaction nitenpyram synthesis.png

Derivatives

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

Invertebrates

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

Aquatic animals

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

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

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

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

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

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

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.

Related Research Articles

<span class="mw-page-title-main">Insecticide</span> Pesticide used against insects

Insecticides are pesticides used to kill insects. They include ovicides and larvicides used against insect eggs and larvae, respectively. Acaricides, which kill mites and ticks, are not strictly insecticides, but are usually classified together with insecticides. The major use of Insecticides is agriculture, but they are also used in home and garden, industrial buildings, vector control and control of insect parasites of animals and humans. Insecticides are claimed to be a major factor behind the increase in the 20th-century's agricultural productivity. Nearly all insecticides have the potential to significantly alter ecosystems; many are toxic to humans and/or animals; some become concentrated as they spread along the food chain.

<span class="mw-page-title-main">Imidacloprid</span> Chemical compound

Imidacloprid is a systemic insecticide belonging to a class of chemicals called the neonicotinoids which act on the central nervous system of insects. The chemical works by interfering with the transmission of stimuli in the insect nervous system. Specifically, it causes a blockage of the nicotinergic neuronal pathway. By blocking nicotinic acetylcholine receptors, imidacloprid prevents acetylcholine from transmitting impulses between nerves, resulting in the insect's paralysis and eventual death. It is effective on contact and via stomach action. Because imidacloprid binds much more strongly to insect neuron receptors than to mammal neuron receptors, this insecticide is more toxic to insects than to mammals.

<span class="mw-page-title-main">Chlorfenvinphos</span> Chemical compound

Chlorfenvinphos is an organophosphorus compound that was widely used as an insecticide and an acaricide. The molecule itself can be described as an enol ester derived from dichloroacetophenone and diethylphosphonic acid. Chlorfenvinphos has been included in many products since its first use in 1963. However, because of its toxic effect as a cholinesterase inhibitor it has been banned in several countries, including the United States and the European Union. Its use in the United States was discontinued in 1991.

Pesticides vary in their effects on bees. Contact pesticides are usually sprayed on plants and can kill bees when they crawl over sprayed surfaces of plants or other areas around it. Systemic pesticides, on the other hand, are usually incorporated into the soil or onto seeds and move up into the stem, leaves, nectar, and pollen of plants.

<span class="mw-page-title-main">Fipronil</span> Chemical compound

Fipronil is a broad-spectrum insecticide that belongs to the phenylpyrazole chemical family. Fipronil disrupts the insect central nervous system by blocking the ligand-gated ion channel of the GABAA receptor and glutamate-gated chloride (GluCl) channels. This causes hyperexcitation of contaminated insects' nerves and muscles. Fipronil's specificity towards insects is believed to be due to its greater binding affinity for the GABAA receptors of insects than to those of mammals, and for its action on GluCl channels, which do not exist in mammals. As of 2017, there does not appear to be significant resistance among fleas to fipronil.

<span class="mw-page-title-main">Phosmet</span> Organophosphate non-systemic insecticide

Phosmet is a phthalimide-derived, non-systemic, organophosphate insecticide used on plants and animals. It is mainly used on apple trees for control of codling moth, though it is also used on a wide range of fruit crops, ornamentals, and vines for the control of aphids, suckers, mites, and fruit flies.

Neonicotinoids are a class of neuro-active insecticides chemically similar to nicotine, developed by scientists at Shell and Bayer in the 1980s.

<span class="mw-page-title-main">Spinosad</span> Medication

Spinosad is an insecticide based on chemical compounds found in the bacterial species Saccharopolyspora spinosa. The genus Saccharopolyspora was discovered in 1985 in isolates from crushed sugarcane. The bacteria produce yellowish-pink aerial hyphae, with bead-like chains of spores enclosed in a characteristic hairy sheath. This genus is defined as aerobic, Gram-positive, nonacid-fast actinomycetes with fragmenting substrate mycelium. S. spinosa was isolated from soil collected inside a nonoperational sugar mill rum still in the Virgin Islands. Spinosad is a mixture of chemical compounds in the spinosyn family that has a generalized structure consisting of a unique tetracyclic ring system attached to an amino sugar (D-forosamine) and a neutral sugar (tri-Ο-methyl-L-rhamnose). Spinosad is relatively nonpolar and not easily dissolved in water.

<span class="mw-page-title-main">Clothianidin</span> Chemical compound

Clothianidin is an insecticide developed by Takeda Chemical Industries and Bayer AG. Similar to thiamethoxam and imidacloprid, it is a neonicotinoid. Neonicotinoids are a class of insecticides that are chemically similar to nicotine, which has been used as a pesticide since the late 1700s. Clothianidin and other neonicotinoids act on the central nervous system of insects as an agonist of nAChR, the same receptor as acetylcholine, the neurotransmitter that stimulates and activating post-synaptic acetylcholine receptors but not inhibiting AChE. Clothianidin and other neonicotinoids were developed to last longer than nicotine, which is more toxic and which breaks down too quickly in the environment.

<span class="mw-page-title-main">Acetamiprid</span> Chemical compound

Acetamiprid is an organic compound with the chemical formula C10H11ClN4. It is an odorless neonicotinoid insecticide produced under the trade names Assail, and Chipco by Aventis CropSciences. It is systemic and intended to control sucking insects (Thysanoptera, Hemiptera, mainly aphids) on crops such as leafy vegetables, citrus fruits, pome fruits, grapes, cotton, cole crops, and ornamental plants. It is also a key pesticide in commercial cherry farming due to its effectiveness against the larvae of the cherry fruit fly.

<span class="mw-page-title-main">Thiamethoxam</span> Chemical compound

Thiamethoxam is the ISO common name for a mixture of cis-trans isomers used as a systemic insecticide of the neonicotinoid class. It has a broad spectrum of activity against many types of insects and can be used as a seed dressing.

<span class="mw-page-title-main">Dinotefuran</span> Chemical compound

Dinotefuran is an insecticide of the neonicotinoid class developed by Mitsui Chemicals for control of insect pests such as aphids, whiteflies, thrips, leafhoppers, leafminers, sawflies, mole cricket, white grubs, lacebugs, billbugs, beetles, mealybugs, and cockroaches on leafy vegetables, in residential and commercial buildings, and for professional turf management. Its mechanism of action involves disruption of the insect's nervous system by inhibiting nicotinic acetylcholine receptors.

<span class="mw-page-title-main">Thiacloprid</span> Chemical compound

Thiacloprid is an insecticide of the neonicotinoid class. Its mechanism of action is similar to other neonicotinoids and involves disruption of the insect's nervous system by stimulating nicotinic acetylcholine receptors. Thiacloprid was developed by Bayer CropScience for use on agricultural crops to control of a variety of sucking and chewing insects, primarily aphids and whiteflies.

<span class="mw-page-title-main">Sulfoxaflor</span> Chemical compound

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<span class="mw-page-title-main">Phantasmidine</span> Chemical compound

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<span class="mw-page-title-main">Novaluron</span> Chemical compound

Novaluron, or (±)-1-[3-chloro-4-(1,1,2-trifluoro-2-trifluoro- methoxyethoxy)phenyl]-3-(2,6-difluorobenzoyl)urea, is a chemical with pesticide properties, belonging to the class of insecticides called insect growth regulators. It is a benzoylphenyl urea developed by Makhteshim-Agan Industries Ltd.. In the United States, the compound has been used on food crops, including apples, potatoes, brassicas, ornamentals, and cotton. Patents and registrations have been approved or are ongoing in several other countries throughout Europe, Asia, Africa, South America, and Australia. The US Environmental Protection Agency and the Canadian Pest Management Regulatory Agency consider novaluron to pose low risk to the environment and non-target organisms and value it as an important option for integrated pest management that should decrease reliance on organophosphorus, carbamate and pyrethroid insecticides.

<span class="mw-page-title-main">Desnitro-imidacloprid</span> Chemical compound

Desnitro-imidacloprid is a metabolite of the insecticide imidacloprid, a very common insecticide and the most important member of the class of insecticides called neonicotinoids, the only significant new class of insecticides to be developed between 1970 and 2000. While imidacloprid has proved highly selective against insects, the desnitro- version is highly toxic to mammals, due to its agonist action at the alpha4beta2 nicotinic acetylcholine receptor (nAChR) in the mammalian brain, at least as demonstrated in experiments involving mice.

<span class="mw-page-title-main">Nereistoxin</span> Chemical compound

Nereistoxin is a natural product identified in 1962 as the toxic organic compound N,N-dimethyl-1,2-dithiolan-4-amine. It had first been isolated in 1934 from the marine annelid Lumbriconereis heteropoda and acts by blocking the nicotinic acetylcholine receptor. Researchers at Takeda in Japan investigated it as a possible insecticide. They subsequently developed a number of derivatives that were commercialised, including those with the ISO common names bensultap, cartap, thiocyclam and thiosultap.

<span class="mw-page-title-main">Flupyradifurone</span> Chemical compound

Flupyradifurone is a systemic butenolide insecticide developed by Bayer CropScience under the name Sivanto. Flupyradifurone protects crops from sap-feeding pests such as aphids and is safer for non-target organisms compared to other insecticides. Sivanto was launched in 2014 since it obtained its first commercial registration in central America. Insecticide Resistance Action Committee (IRAC) classified Flupyradifurone as 4D subset (butenolide) and it is the first pesticide in the butenolide category. It was approved by European Union in 2015.

References

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  4. ↑ Pubchem. "Nitenpyram". pubchem.ncbi.nlm.nih.gov. Retrieved 2018-03-21.
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  10. ↑ CNpatent 102816112],曾挺, 陈华, 陈共华, 潘光飞, 浙江禾本科技有限公司,"Method for preparing pesticide nitenpyram",published 2012-09-13
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  12. ↑ Codling, Garry; Naggar, Yahya Al; Giesy, John P.; Robertson, Albert J. (2018-03-01). "Neonicotinoid insecticides in pollen, honey and adult bees in colonies of the European honey bee (Apis mellifera L.) in Egypt". Ecotoxicology. 27 (2): 122–131. doi:10.1007/s10646-017-1876-2. ISSN   0963-9292. PMID   29143171. S2CID   3917697.
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  16. ↑ Noestheden, Matthew; Roberts, Simon; Hao, Chunyan (2016-07-15). "Nitenpyram degradation in finished drinking water". Rapid Communications in Mass Spectrometry. 30 (13): 1653–1661. Bibcode:2016RCMS...30.1653N. doi:10.1002/rcm.7581. ISSN   1097-0231. PMID   27321854.
  17. 1 2 3 Rust, MK; Waggoner, MM; Hinkle, NC; Stansfield, D; Barnett, S (September 2003). "Efficacy and longevity of nitenpyram against adult cat fleas (Siphonaptera: Pulicidae)". Journal of Medical Entomology. 40 (5): 678–81. doi: 10.1603/0022-2585-40.5.678 . PMID   14596282.
  18. ↑ Wismer, Tina; Means, Charlotte (March 2012). "Toxicology of newer insecticides in small animals". Veterinary Clinics of North America: Small Animal Practice. 42 (2): 335–347. doi:10.1016/j.cvsm.2011.12.004. PMID   22381183.
  19. 1 2 Dobson, P.; Tinembart, O.; Fisch, R. D.; Junquera, P. (2000-12-16). "Efficacy of nitenpyram as a systemic flea adulticide in dogs and cats". The Veterinary Record. 147 (25): 709–713. ISSN   0042-4900. PMID   11140929.
  20. ↑ "CAPSTAR Novartis (nitenpyram)" (PDF). datasheets.scbt.com. 2 April 2014. Retrieved 12 June 2019.
  21. 1 2 Furlan, Lorenzo; Pozzebon, Alberto; Duso, Carlo; Simon-Delso, Noa; Sánchez-Bayo, Francisco; Marchand, Patrice A.; Codato, Filippo; Bijleveld van Lexmond, Maarten; Bonmatin, Jean-Marc (2018-02-25). "An update of the Worldwide Integrated Assessment (WIA) on systemic insecticides. Part 3: alternatives to systemic insecticides". Environmental Science and Pollution Research International. 28 (10): 11798–11820. doi: 10.1007/s11356-017-1052-5 . ISSN   1614-7499. PMC   7921064 . PMID   29478160.
  22. 1 2 3 Pisa, Lennard; Goulson, Dave; Yang, En-Cheng; Gibbons, David; Sánchez-Bayo, Francisco; Mitchell, Edward; Aebi, Alexandre; van der Sluijs, Jeroen; MacQuarrie, Chris J. K. (2017-11-09). "An update of the Worldwide Integrated Assessment (WIA) on systemic insecticides. Part 2: impacts on organisms and ecosystems". Environmental Science and Pollution Research International. 28 (10): 11749–11797. doi: 10.1007/s11356-017-0341-3 . ISSN   1614-7499. PMC   7921077 . PMID   29124633.
  23. ↑ Sabatino, Leonardo; Scordino, Monica; Pantò, Valentina; Chiappara, Elena; Traulo, Pasqualino; Gagliano, Giacomo (2013). "Survey of neonicotinoids and fipronil in corn seeds for agriculture". Food Additives & Contaminants. Part B, Surveillance. 6 (1): 11–16. doi:10.1080/19393210.2012.717969. ISSN   1939-3229. PMID   24786619. S2CID   6769499.
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