Imidacloprid

Chemical Properties

Imidacloprid is a white solid crystal or powder under ambient conditions and have a low volatility (U.S. EPA, 2010; HSDB, 2006, 2012b).

History

Imidacloprid was discovered in 1984 at Nihon Bayer Agrochem in Japan by screening novel synthetic compounds for a high affinity to the insect nicotinic AChRs receptors, but with low toxicity to vertebrate species (Kagabu, 1997). Its molecule includes the insecticidal N-(3- pyridinyl)methyl group of nicotine and a nitroimine moiety. Because of their structural similarity to nicotine, imidacloprid and related insecticides (acetamiprid, thiacloprid, thiamethoxam and nitenpyram) were termed neonicotinoids (Tomizawa and Yamamoto, 1993). Nicotine possesses only modest insecticidal activity and is not stable for use in the field for crop protection. Imidacloprid has greater insecticidal activity than nicotine, and its stability is suitable for field use. Both the neonicotinoids and nicotinoids act as agonists at the nAChR. The principal differences between the two classes of compounds are that the nicotinoids are ionized at physiological pH and selective for the mammalian nAChR; whereas the neonicotinoids are not ionized and more selective for the insect nAChR. The selectivity of the neonicotinoids toward insects relative to mammals reflects the fundamental differences in the subunit combination and pharmacological profiles between the nAChR in insects and mammals (for review see Tomizawa and Casida, 2003).

Uses

Imidacloprid is the active ingredient in AdvantageTM used to control fleas in dogs and cats (HSDB, 2006). Clothianidin is the major metabolite of thiamethoxam and both compounds are registered for use as insecticides. Widespread use increased greatly in the 1990s as alternatives to organophosphosphorus and carbamate insecticides because of their much lower mammalian toxicity and resistance developed to other pesticides. Imidacloprid has become the most widespread insecticide used in the world.

A neonicotinoid; the active ingredient in certain neuro-active insecticides. Reports show that when exposed to neonicotinid pesticides honeybees have probelms returnign home after foraging and bumble bee colonies grow poorly and produce fewer queens.

Uses

The four neonicotinoids are acetamiprid (l),imidacloprid (2), nitenpyram (3) and thiamethoxam (4) (IS0 draft proposal name). They are potent broad spectrum insecticides possessing contact, stomach and systemic activity. The structures are given below and consist of substituted aromatic heterocyclic rings: 6-chloropyridinyl for acetamiprid, imidacloprid and nitenpyram and 3-chlorothiazole for thiamethoxam. Each compound has a methylene bridge, to a cyclic nitroguanidine moiety in imidacloprid and thiamethoxam, to a cyanoamidine in acetamiprid or to a diaminonitroethylene group in nitenpyram. The terminal group for all compounds is a strong electron-withdrawing substituent on an ethene or imino group.
These insecticides are used for foliar and soil application but imidacloprid also has a very high usage as a seed treatment. They have low rates of application: for example thiamethoxam is typically applied to foliage at rates of only 2.5-50 g ha^-1. The neonicotinoids are polar, nonvolatile solids with high water solubilities and they are non-ionised at pH values typically found in the environment. The insecticides are not readily hydrolysed. Their polar nature makes them potentially mobile in soil but this is mitigated by their low rates of application and, for acetamiprid and nitenpyram, short persistence. hnidacloprid and thiamethoxam are sufficiently persistent to be used as soil treaments. All the insecticides are efficiently translocated in plants and are effective systemic agents against sucking pests.

Preparation

Reduction of 2-chloro-5-pyridinecarbonyl chloride (8) to 2-chloro-5-hydroxymethylpyridine (9) was carried out by excess NaBH4 in water, which was converted to the chloride (10) by SOCl2 . Imidacloprid was obtained by the coupling reaction of 10 with 2-nitroiminoimidazolidine (11) in acetonitrile with potassium carbonate as base. This method was successfully applied to the synthesis of [3H]imidacloprid (12) using NaB[3H]4 as the tritium source (40).
Technical production starts with the Tschitschibabin reaction of 3-methylpyridine giving 2-amino-5-methylpyridine (14), which is transformed to the chloride (15) by the Sandmeyer reaction in the presence of hydrogen chloride. A successive operation of chlorination of the methyl group to 10 and the subsequent substitution of the active chloride with ethylene diamine to 16 are carried out without isolation of the intermediates. The final product is produced by ring formation with nitroguanidine. This multistep process affords the product at a purity of >95% (41).

Definition

ChEBI: The E-isomer of imidacloprid.

Health Hazard

Imidacloprid is rapidly and almost completely absorbed (>92%) from the gastrointestinal tract of rats, and is eliminated from the organism rapidly and completely, with no indication of bioaccumulation of the parent compound or its metabolites (WHO, 2001). Similarly, thiamethoxam has relatively low solubility in nonpolar organic solvents and its octanol/water partition coefficient suggests that accumulation in fatty tissues is unlikely to occur (U.S. EPA, 2010).

Flammability and Explosibility

Not classified

Mechanism of action

Imidacloprid is a neurotoxic insecticide, which belongs to the class of the neonicotinoid pesticides. Imidacloprid is registered to control insect pests on agricultural and nursery crops, structural pests and parasites on companion animals.
Imidacloprid is an agonist of the nicotinic acetylcholine receptor (nAChR) at the neuronal and neuromuscular junctions in insects and vertebrates. It is structurally and functionally related to nicotine. The toxicity of imidacloprid is largely due to interference of the neurotransmission in the nicotinic cholinergic nervous system. Prolonged activation of the nAChR by imidacloprid causes desensitization and blocking of the receptor, and leads to incoordination, tremors, decreased activity, reduced body temperature and death. Presently, there is no specific antidote, which acts as an antagonist to the effects imidacloprid.

Pharmacokinetics

Imidacloprid is quickly absorbed by the oral route and rapidly distributed in nearly all organs and tissues. In rats, the oral absorption was estimated as 92-99%. Imidacloprid degrades to a large number of metabolites formed by multiple pathways. The same, or similar metabolites are found in rats, goats and hens. Based on structural considerations, the following metabolites may be of toxicological significance: 6-chloronicotinic acid, imidazolidine 4- and 5- hydroxy compounds, olefinic imidacloprid, desnitro-imidacloprid and the nitrosoimine compound. Metabolites were excreted primarily in the urine as glutathione and glycine conjugates of mercaptonicotinic acid and hippuric acid. Imidacloprid or its metabolites penetrated the blood-brain barrier. The parent compound and some of its metabolites have been detected in milk, meat of goats and hens, and eggs. Pharmacokinetic studies were not available for a direct determination of the rate of absorption from dermal and inhalation routes.

Pharmacology

Imidacloprid is a nitroguanidine compound and belongs to the nitromethylene family of chemicals. Themode of action of imidacloprid involves interference with neurological transmission in insects by binding to the postsynaptic nicotinic acetylcholine receptors. Imidacloprid is available as a spot-on treatment for cats and dogs for flea control, and, following application, it distributes throughout the skin within 6 h (Bayer, 1996). It is not absorbed systemically by the animal, and its adulticidal activity is by contact with fleas.
Imidacloprid, besides its agricultural use, is also used for the control of subterranean pests and pet ectoparasites.

Metabolic pathway

The photolytic degradation of imidacloprid in different conditions yields diversified degradation products as indicated in the pathways. Photolysis in water gives 6- chloronicotinaldehyde, N-methylnicotinic acid amide, 1- (6-chloro-3-pyridinyl)methyl-2-imidazolinone and 6-chloro-3-pyridylmethylethylenediamine which are identified as main degradates together with a complex mixture of degradation products. On the surface of the tomato plant, four of the 14 metabolites are identified. In tobacco smoke, five degradates are detected, and in field soils, four metabolites are identified from the treated sugarbeet. As for the mammalian metabolites, the pathways are drawn tentatively by the author (see Klein145).

Metabolism

Acute oral LD₅₀ for rats: ca. 450 mg/kg

Degradation

The hydrolysis of imidacloprid was investigated to US EPA guidelines. [¹⁴C]Imidaclopridw as added to sterile aqueous buffer solutions at pH 5,7 and 9 and incubated at 25 °C in the dark for up to 30 days. Analysis was by HPLC and TLC methods. No products of hydrolysis were found at pH 5 or 7. Some imidacloprid (7%) degraded at pH 9 (DT₅₀ 355 days) and two products were detected. The major product was not identified but may have resulted from a small transformation of the imidazole ring. The minor product was the cyclic urea (2) as shown in Scheme 1.
The photodegradation of imidacloprid in aqueous buffer at pH 7 was investigated to US EPA guidelines. The UV spectrum of imidacloprid has a maximum at 269 nm. Solutions were irradiated with a xenon lamp (8.9-9.5 μW cm^-2) for up to 2 hours at 23-24.5 °C. Samples were analysed by TLC, HPLC and MS. Control samples were protected from irradiation. The DT₅₀ for photolysis of imidacloprid was 57 minutes. No volatile products were produced but a large number of photoproducts were formed. A further study was done using a high initial concentration of imidacloprid so that photoproducts could be identified. Nine products were identified as shown in Scheme 1. The five major products were the cyclic guanidine derivative (3), the cyclic urea (2), an olefinic cyclic guanidine (4) and the fused ring products (5) and (6). These products together accounted for 48% of the applied radiocarbon after 2 hours of irradiation, when 23% of the applied imidacloprid remained. The proposed routes of aqueous photolysis were via loss of the nitro group followed by oxidation and piecemeal degradation of the imidazoline ring affording the minor products 7,8,9,10 and 11 as shown in Scheme 1(PSD, 1993).

Toxicity evaluation

Acute toxicity of imidacloprid was examined via the oral route in rats and mice, and via the inhalation and dermal routes in rats. Mice appeared to be more sensitive to the acute oral toxicity of imidacloprid than rats. In mice, the median oral lethal doses (LD50) ranged between 131-168 mg/kg (Category II oral toxicant). Imidacloprid was classified as Category III dermal toxicant, Category IV inhalation toxicant and Category IV eye and skin irritant. An acute (single dose) oral exposure of rats and mice to imidacloprid caused clinical signs characteristic for nicotine intoxication, such as incoordination, tremors, spasms and respiratory difficulties. Other symptoms included decreased motility and lethargy. The same clinical signs were observed in rats following a 4-hour exposure to imidacloprid via the inhalation route.