Insecticide Synergists Research Articles

ChemInform Abstract: Pesticides and Phosphorus

More than 20 % of about 300 active ingredients of pesticides registered in Japan are phosphorus compounds. Although they are mainly insecticides including acaricides, organophosphorus fungicides and herbicides have recently been developed. Moreover, nematicides, rodenticides, plant growth regulators, insect chemosterilants, and insecticide synergists are also known. Majority of organophosphorus pesticides are P (V) oxyacid derivatives, carrying a phosphoryl or thiophosphoryl group. Phosphonium salts and trivalent phosphorus compounds are rather rare as pesticides. The role of phosphorus moiety in pesticides is 1) the principal in phosphorylation, 2) a leaving group in alkylation, 3) a carrier for other active moiety, and 4) an analogous group for the carboxyl group. In order to display a certain pesticidal activity, the compound should have a structure suitable for selectivity or affinity to the target organism and biomacromolecule.

ChemInform Abstract: Synthesis of New Analogues of Furapiole, a Potent Insecticide Synergist.

AbstractThe analogues (Ib), (Ic), (III) and (V) of the title compound (Ia) are synthesized as shown in the scheme.

Methylenedioxyphenyl complexes with microsomal cytochrome P-450: In vivo complex formation in rat liver and in midgut tissues of the Southern armyworm ( Spodoptera eridania)

The capacity of several methylenedioxyphenyl insecticide synergists to generate metabolite complexes with cytochrome P-450 was studied in midgut tissues of the Southern armyworm ( Spodoptera eridania). Examination of the NADH-reduced versus oxidized spectra from methylene-dioxyphenyl-induced midgut indicated that isosafrole, dihydrosafrole, and 4-ethoxy-1,2-methylenedioxybenzene generated metabolite complexes with a principal absorbance maximum at 427 nm and smaller absorbance maxima near 460 and 556 nm. Further studies with 2- n-heptylbenzimidazole showed that the complex between insect cytochrome P-450 and dihydrosafrole was unusually resistant to displacement. Initial rates of complex displacement in insect microsomes were found to be approximately an order of magnitude slower than those of the corresponding complexes in rat hepatic microsomes. Nevertheless, with the exception of the dihydrosafrole complex in insect microsomes, the “time to half-maximal displacement” parameter was found to be very similar for each complex. These findings indicate that the formation of dissociable complexes between cytochrome P-450 and the methylenedioxyphenyl metabolite occurs in both insect midgut and rat hepatic microsomes after in vivo exposure. From the present study it would appear that dihydrosafrole may constitute a useful probe to distinguish binding sites within insect and mammalian cytochrome P-450.

In vivo metabolism of nasally instilled dihydrosafrole [1-(3,4-methylenedioxyphenyl)propane] in dogs and monkeys

Nasal metabolism of inhaled material may influence its biological fate and toxicity. The purpose of this study was to investigate, in a noninvasive and qualitative manner, the in vivo nasal metabolic activity towards 1-(3,4-methylenedioxyphenyl)propane (dihydrosafrole). Dihydrosafrole was the compound of choice as a representative of the methylenedioxyphenyl compounds. Methylenedioxyphenyl compounds, inhaled as essences or insecticide synergists, have complex interactions with cytochrome P-450-dependent monooxygenases, causing both inhibition and induction. Clearance of dihydrosafrole and its metabolites from both the ethmoid (olfactory) and maxillary (respiratory) turbinate regions of Beagle dogs and Cynomolgus monkeys was examined. Nasopharyngeal mucus was collected at frequent intervals during periodic instillation of dihydrosafrole (and, for the dogs, 24 h after instillation). Blood, urine and feces were collected to examine dihydrosafrole clearance from the nose during instillations and up to 48 h after completion of the nasal instillations of [ 3H]dihydrosafrole. Analysis of mucus for dihydrosafrole metabolites was by HPLC. Most of the recovered radioactivity was in urine and blood samples over the first 24 h. Radioactivity was recovered from the nasopharyngeal mucus in both organic extractable and water soluble forms. HPLC of the organic extracts demonstrated that [ 3H]dihydrosafrole instilled in either turbinate region was metabolized to 2-methoxy-4-propylphenol, 2-methoxy-4-propenylphenol and 1-(3,4-methylenedioxyphenyl)propan-1-ol. A number of minor metabolites were produced in both species. One mucus sample from an ethmoid-instilled dog contained 1-(3,4-methylenedioxyphenyl)propene (isosafrole) as a metabolite. Results from this study indicate that interspecies, inter-individual, and inter-regional differences occur in the metabolism of nasally deposited dihydrosafrole in monkeys and dogs.

農薬とリン

More than 20 % of about 300 active ingredients of pesticides registered in Japan are phosphorus compounds. Although they are mainly insecticides including acaricides, organophosphorus fungicides and herbicides have recently been developed. Moreover, nematicides, rodenticides, plant growth regulators, insect chemosterilants, and insecticide synergists are also known. Majority of organophosphorus pesticides are P (V) oxyacid derivatives, carrying a phosphoryl or thiophosphoryl group. Phosphonium salts and trivalent phosphorus compounds are rather rare as pesticides. The role of phosphorus moiety in pesticides is 1) the principal in phosphorylation, 2) a leaving group in alkylation, 3) a carrier for other active moiety, and 4) an analogous group for the carboxyl group. In order to display a certain pesticidal activity, the compound should have a structure suitable for selectivity or affinity to the target organism and biomacromolecule.

Sorghum (Sorghum bicolor) Seed Safeners as Insecticide Synergists

Certain oximes, including cyometrinil [(Z)-α-(cyanomethoxy)iminobenzeneacetonitrile], CGA-92194 [N-(1,3-dioxolan-2-yl-methoxy)-iminobenzeneacetonitrile], 2-pyridinealdoxime-O-benzyl ether (PA-B), and 2-pyridinealdoxime-O-phenethyl ether (PA-PE), which are known to protect sorghum from chloroacetanilide herbicides, increased the toxicity of the insecticide propoxur (o-isopropoxyphenyl-methyl carbamate) to a resistant strain of housefly (Musca domesticaL.). Flurazole [5-thiazolecarboxylic acid, benzyl ester, 2-chloro-4-(trifluoromethyl)], a nonoxime protectant for grain sorghum, had less effect on the toxicity of propoxur than did the oximes. Metolachlor [2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-1-methylethyl)acetamide], which can be used as a herbicide in sorghum [Sorghum bicolor(L.) Moench.] only if the seed have been treated with a protectant, also increased the toxicity of propoxur to houseflies. Commercially available insecticide synergists increase insecticide activity by inhibiting NADPH-dependent microsomal mixed-function oxidase activity. Sorghum coleoptiles possessed the enzyme system necessary to oxidize aldrin (1,2,3,4,10,10-hexachloro-1,4,4a,5,8,8a-hexahydro-1,4-endo-exo-5,8-dimethanonaphthalene) to dieldrin (1,2,3,4,10,10-hexachloro-6, 7-epoxy-1,4,4a,5,6,7,8,8a-octahydro-1,4-endo-exo-5,8-dimethanonaphthalene), which is a standard test for oxidative metabolism in insects. Under the conditions of these tests, the aldrin epoxidase activity in sorghum coleoptiles was not affected by pretreatment with cyometrinil or flurazole.

Synergism of Insecticide Activity to Heliothis zea (Boddie) (Lepidoptera: Noctuidae) by Formanilides and Formamidines

The toxicities of binary mixtures of formanilides and formamidines with nine insecticides to Heliothis zea (Boddie) were investigated and compared to the toxicities of their individual components. The 21 formanilides were mono-, di-, or tri-substituted in the phenyl ring with chlorine, bromine, methyl, ethyl, nitro, or methoxy groups. The four N- ' aryl- N , N -dimethylformamidines were substituted in the phenyl moiety with 4-ethyl, 2-trifluoromethyl, 3,4-methylenedioxy, or 2,4,6-trimethyl. Toxicity of cypermethrin, permethrin, fenvalerate, methyl parathion, chlorpyrifos, carbaryl, methomyl, and endrin was appreciably enhanced by some of the formanilides and formamidines; however, the activity of profenofos was synergistic only with one of the formamidines. These and related formamidines and formanilides may have practical applicability as insecticide synergists.

The metabolism of insecticides: the role of monooxygenase enzymes.

In summary, it can be said that advances have been made in understanding the range and significance of monooxygenase reactions involving insecticides in both target and non-target species and that some specific aspects emerge that should command the attention of insecticide toxicologists and others in the immediate future. The role of co-oxidation of insecticides during prostaglandin synthesis has just emerged as an issue but, if we can extrapolate from other xenobiotics (126), we can predict with some confidence that it will assume major proportions. It is also apparent that both activation and detoxication reactions are catalyzed by the FAD-containing monooxygenase and that many of these reactions were formerly attributed to the cytochrome P-450-dependent monooxygenase system. Since any particular substrate may be oxidized by either or both of these two routes, it is essential that studies be conducted to define their relative contributions to xenobiotic oxidation in microsomal preparations and ultimately in vivo. The area of interactions and the mechanisms behind them is also of importance, from the public health point of view in the case of multiple exposures, and from the practical viewpoint in the case of insecticide synergists. While the above aspects are not the only ones of future importance, they should contribute to the ultimate goal of insecticide toxicology: practical, safe use of chemicals for the control of insect pests.

Self-catalyzed destruction of insect cytochrome [formula omitted

Incubation of housefly microsomes with 1-aminobenzotriazole (ABT) resulted in a considerable loss of cytochrome P-450 as measured by its dithionite-reduced CO-difference spectrum. This cytochrome P-450 loss was strictly dependent on NADPH, and was dependent also on both incubation time and ABT concentration. An abnormal porphyrin was isolated from housefly microsomes incubated with ABT and NADPH. Its electronic absorption spectrum was identical to that of an authentic NN- aryl- bridged protoporphyrin IX, a result which suggests that cytochrome P-450 loss was due to self-catalyzed covalent modification of the prosthetic haem group. A cytochrome P-450 monooxygenase activity, aldrin epoxidation, was inactivated by ABT in vitro according to pseudo-first order kinetics typical of suicide substrates. ABT had no detectable toxicity in vivo, but synergized the toxicity of a carbamate insecticide to houseflies. 2-Iso propyl-4- pentenamide , ethynylcyclohexanol, and substituted phenyl propynyl ethers (the latter are known insecticide synergists) cause similar in vitro loss of cytochrome P-450. The amounts of cytochrome P-450 destroyed by these compounds depend on the strain of houseflies (insecticide-resistant or susceptible) and on whether the insects are pretreated with phenobarbital. Cytochrome P-450 induced by phenobarbital in resistant flies appeared to be the most sensitive to these suicide substrates. This suggests that self-catalyzed destruction of cytochrome P-450 is isozyme-selective in the house fly.

Absorption Distribution and Excretion of Piperonyl Butoxide in Rats

The tissue distribution and excretion of an insecticide synergist, piperonyl butoxide (PB), after oral and intravenous administration in male rats were investigated by the use of gas chromatography. After the oral administration of PB (250mg/kg), 2.35% of the dose was excreted in feces, whereas none was detected in the 48hr urine. Maximum plasma concentration of PB was attained 5hr after the administration, and the PB concentrations in brain, testis, liver and adipose tissue were higher than the plasma concentration at that time, Some PB remained in the plasma but none remained in the liver, brain and kidney 24hr after the administration; however, the accumulation of PB in the adipose tissue was remarkable and PB was observed even after 96hr.After the intravenous administration of PB (250mg/kg), PB concentrations in the tissues were higher than those after the oral administration except in the liver, and the amount of PB in the lung was very large, being much higher than that in the adipose tissue.

Delayed neuropathy in hen by the insecticide synergist O-n-propyl O-(2-propynyl) phenylphosphonate (NIA-16388) and other phenylphosphonate esters.

O-n-Propyl O-(2-propynyl) phenylphosphonate (NIA-16388), which has been recommended for use as insecticide synergist, was synthesized and tested for acute and neurotoxicities in hens. The 24-h LD50 value of this compound in the hen was found to be about 340 mg/kg. Hens treated with this compound at 400 mg/kg with atropine sulfate as an antidote developed clear clinical signs of delayed neurotoxicity 12-17 d after single oral treatment. The signs of neurotoxicity gradually progressed from ataxia through paralysis. Biochemical tests indicated that at the tested dose level of this compound, the level of hen-brain neurotoxic esterase (NTE) was inhibited in vivo to less than 10% of the normal level 1 d after treatment. These clinical and biochemical signs of neurotoxicity are supported by histopathological findings. Degenerative lesions of axons were observed in the NIA-treated group of hens. The lesions in the spinal cord were seen most frequently and most prominently in the lateral columns, although they sometimes were observed in other areas, e.g., in the anterior columns (especially in thoracic and lumbar sections). Generally, the lesions were more apparent in the longitudinal sections than in the cross-sections. Two other phenylphosphonate derivatives, O-ethyl S-benzyl phenylphosphonothioate (ESBP) and O-methyl O-(4-benzylidenylphenylhydrazone) phenylphosphonothioate, were also synthesized and tested for neurotoxicity to hens. The LD50 values for these two compounds in the hen were more than 1000 mg/kg. No signs of delayed neuropathy were detected in hens given either ESBP or the hydrazone compound at single oral doses of 1000 mg/kg.

Residues of the synergist S-421 in human milk collected from the Tokyo metropolitan area.

S-421, 1,1'-Oxybis(2,3,3,3-tetrachloropropane), is a synergist for pyrethroid insecticides against sanitary insects such as mosquitos, houseflies and cockroaches (HAYASHI 1969). In a previous paper we reported on the identification of the synergist present in human milk samples collected in the Tokyo metropolitan area (MIYAZAKI et al. 1981), but not the method for the determination of S-421 residues. Therefore, we investigated the analytical method, and then examined the residual levels in human milk samples. As a result, a gas chromatographic method for residual organochlorine pesticides was found to be applicable to the synergist in human milk. The synergist was detected at relatively low levels in most human milk samples, and also found to be in use in some of commercial insecticide formulations. These results suggested that the presence of the synergist residue in human milk may be due to the use of these formulations containing the synergist.

Inactivation of hepatic cytochrome p-450 by a 1,2,3-benzothiadiazole insecticide synergist

Inactivation of hepatic cytochrome p-450 by a 1,2,3-benzothiadiazole insecticide synergist

Interaction of antioxidants with ozone and herbicide stress.

Antioxidants are compounds used to prevent the reactions of organic materials with molecular oxygen. Antioxidants are used to protect foods and other products from discoloration and spoilage, thus sodium benzoate is added to bread to prolong its shelf life. Other antioxidants such as piperonyl butoxide (..cap alpha..-(2-(2-butoxyethoxy)ethoxy)-4,5-methylenedioxy-2-propyltoluene) and sesamex (a component of sesame oil) are used as insecticide synergists. Both of these compounds are potent microsomal mixed function oxidase (m.f.o.) inhibitors and when applied in combination with certain insecticides increase the insecticide's potency by decreasing the rate at which insects can detoxify the insecticides. In plants, EDU (N-(2-(2-oxo-1-imidazolidiny)ethyl)-N-phenylurea has been reported to protect pinto beans (Phaseolus vulgaris L.) and piperonyl butoxide to protect tobacco (Nicotiana tabacum L.) from ozone injury. The purpose of this study was to a) evaluate the antioxidants EDU, piperonyl butoxide, and n-propyl gallate, as protectants against ozone injury in navy bean, and b) to determine if these antioxidants could function as herbicide synergists just as piperonyl butoxide functions as an insecticide synergist.

Pesticides as inducers of hepatic drug-metabolizing enzymes—I. Mixed function oxidase activity

1. 1. Sixteen pesticides, one carcinogen (3-methylcholanthrene), one cotton defoliant, two drugs (phenobarbital and chloral hydrate) and two insecticide synergists (piperonyl butoxide and sesamex) were administered to adult male mice by different routes in order to evaluate the inductive effects of pesticides on hepatic drug metabolizing enzymes. 2. 2. Of the experimental insecticides screened, TH-6042 (a substituted pyrazoline) showed the highest level of induction of cytochrome P-450 (>3-fold) and also significant increases in O-demethylation of p-nitroanisole and N-demethylation of aminopyrine. 3. 3. Maximum induction was generally achieved when compounds were administered orally for each of 3 days.

Pesticides as inducers of hepatic drug-metabolizing enzymes—II. Glutathione S-transferases

1. 1. The effects of 16 pesticides, 1 carcinogen (3-methylcholanthrene), 2 drugs (phenobarbital and chloral hydrate), 2 insecticide synergists (piperonyl butoxide and sesamex) and 1 cotton defoliant on mouse hepatic GSH S-aryl, S-aralkyl, or S-epoxide transferase activities were investigated. 2. 2. With most chemicals tested, the induction was less than 2-fold while TH-6042, a substituted pyrozolone insecticide, and phenobarbital caused up to 2 and 4-fold induction, respectively. 3. 3. The results indicate that inductive effects are dose dependent, vary with the route of administration and are selective with regard to different GSH S-transferase activities.

35—THE CROSS-RESISTANCE OF DIELDRIN-RESISTANT CLOTHES-MOTH SPECIES TO OTHER MOTHPROOFING AGENTS

A procedure is described for measuring the resistance of textile pests to mothproofing agents. By this method, dieldrin-resistant wild strains of Tinea metonella and Tineola bisselliella are shown to have acquired no resistance or only very little resistance to the commonly used industrial mothproofing agents. T. metonella require much higher concentrations of these mothproofing agents for their control than T. bisselliella. The high dieldrin-resistance in wild strains of T. metonella is substantially reduced in the presence of the insecticide synergist, piperonyl butoxide.

Preparation of a porphyrin-iron-carbene model for the cytochrome P 450 complexes obtained upon metabolic oxidation of the insecticide synergists of the 1,3-benzodioxole series

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTPreparation of a porphyrin-iron-carbene model for the cytochrome P 450 complexes obtained upon metabolic oxidation of the insecticide synergists of the 1,3-benzodioxole seriesD. Mansuy, J. P. Battioni, J. C. Chottard, and V. UllrichCite this: J. Am. Chem. Soc. 1979, 101, 14, 3971–3973Publication Date (Print):July 1, 1979Publication History Published online1 May 2002Published inissue 1 July 1979https://doi.org/10.1021/ja00508a048RIGHTS & PERMISSIONSArticle Views272Altmetric-Citations79LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (400 KB) Get e-Alerts Get e-Alerts

Carcinogenesis Bioassay of Technical-Grade Piperonyl Butoxide in F344 Rats2

The insecticide synergist piperonyl butoxide--alpha-[2-(2-butoxyethoxy)ethoxy]-4,5-methylenedioxy-2-propyltoluene--was tested for carcinogenicity in inbred F344 rats in a 2-year study employing doses of 10,000 and 5,000 ppm of the compound administered continuously in the feed. Although a statistically significant dose-related increase in the incidence of lymphoreticular neoplasia was associated with administration of the compound to females, the incidence of that class of neoplasm was higher in control males than in treated males. The finding of statistical significance in one sex is not considered by itself to constitute sufficient evidence of a biologic effect to justify an indictment of carcinogenic action. However, inasmuch as the chief use of this substance is to alter the in vivo metabolism of other chemicals, its possible role as a cocarcinogen should be carefully considered in any risk-benefit evaluation aimed at setting policies regarding its uses.

Metabolism of a synthetic juvenile hormone (JH-I) in two strains of the grain weevil, Sitophilus granarius

The metabolism of topically applied 14-C juvenile hormone (JH-I) was compared in adult insecticide-susceptible and pyrethrin-resistant grain weevils, Sitophilus granarius and in newly ecdysed pupae of the susceptible strain. The half-lives of JH-I in susceptible and resistant insects were approximately 3 hr and 2 1 2 hr respectively in adults and 4 hr in the pupae. The insects produced three major metabolites which co-chromatographed with known JH-I metabolites and were thus tentatively identified as the 1-carboxy acid, the 10,11-diol and the corresponding acid-diol. The two strains showed differences in the metabolic emphasis of JH-I degradation. In the susceptible strain, the 1-carboxy acid was the major metabolite whereas in the pyrethrin-resistant strain the acid-diol predominated. Pre-treatment with piperonyl butoxide (PB) or SKF 525A delayed degradation of JH-I in both strains and greatly reduced acid-diol production in the resistant strain. In the pupae, PB increased the persistence of JH-I by 4 to 5 fold, and over 40% of the applied JH-I remained intact after 24 hr. Some similar effects were noted with SKF 525A. By contrast, the esterase (and penetration) inhibitor triorthocresyl phosphate (TOCP) had little effect on the metabolism of JH-I in either strain. An investigation of the effect of PB on the distribution of topically-applied JH-I indicated that this insecticide synergist delayed penetration of JH-I from the surface into the cuticle and also from the cuticle into the internal tissue. This is, however, unlikely to be the only factor involved in reducing the rate of JH-I metabolism.