“These two volumes are a mine of information … useful works of reference that can be thoroughly recommended …”–Angewandte Chemie, International Edition, Vol 40, No 8, April 17, 2001, p 1548

Metabolic Pathways of Agrochemicals Part 2: Insecticides and Fungicides

By Terry R. Roberts, David H. Hutson

The Royal Society of Chemistry

Copyright © 1999 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85404-499-3

Contents

Introduction, xxi,
Physico-chemical Data and Abbreviations, xxiii,
INSECTICIDES, 1,
Carbamates, 3,
Macrocyclic insecticides, 79,
Neonicotinoids, 105,
Nereistoxin precursors, 127,
Organochlorine insecticides, 139,
Organophosphorus insecticides, 187,
Organotin insecticides, 523,
Oxime and Oxyimidothioate carbamates, 535,
Phenylpyrazoles, 573,
Pyrethroids, 579,
Miscellaneous insecticides, 727,
INSECT GROWTH MODULATORS, 793,
Benzoylureas, 795,
Diacylhydrazines, 817,
Juvenile hormone mimics, 823,
INSECT PHEROMONES, 851,
INSECTICIDE SYNERGISTS, 865,
NEMATICIDES, 873,
RODENTTCIDES, 895,
FUNGICIDES, 937,
Alkylenebis(dithiocarbamate)s, 939,
Anilinopyrimidines, 961,
Antibiotics, 975,
Aromatic hydrocarbon derivatives, 985,
Azoles and analogues, 1011,
Benzimidazoles, 1105,
Carboxamides, 1139,
Dicarboximides, 1155,
Dimethyldithiocarbamates, 1175,
Dinitrophenols, 1189,
Guanidines, 1199,
Methyl isothiocyanate and precursors, 1211,
Morpholines, 1225,
Organophosphorus fungicides, 1239,
Phenoxyquinolines, 1263,
Phenylamides, 1269,
Phenyl carbamates, 1283,
Phenylpyrroles, 1289,
Pyrimidines, 1299,
Pyrimidinyl carbinols, 1313,
Strobilurin analogues, 1327,
N-Trihalomethylthio derivatives, 1343,
Miscellaneous fungicides, 1375,
PLANT ACTIVATORS, 1453,
Index of Common Names, 1463,
Index of Chemical Names, 1466,
Index of CAS Registry Numbers and Common Names, 1472,

CHAPTER 1

Insecticides

Carbamates

Overview

Carbamate esters are used extensively as insecticides on a wide range of crops and some are of low enough acute toxicity to mammals to be used for veterinary purposes. Carbaryl has also been used in shampoos for humans. By modern standards the compounds are used at quite high rates of application in the field, for example carbaryl is applied at about 0.25-2.0 kg ha-1.

Fourteen aryl N-methylcarbamate compounds are described. Eight are simple phenyl carbamates with alkyl, alkoxy and thioalkyl substituents. Commercial trimethacarb consists of two trimethyl isomers. Propoxur is noteworthy in having a substituent with some similarity to an open chain analogue of carbofuran. Five compounds (bendiocarb, benfuracarb, carbaryl, carbofuran, carbosulfan) have fused-ring structures. Bendiocarb differs from carbofuran by substituting a methylene group with an oxygen atom. Thus, hydroxylation and subsequent oxidation and conjugation at the 3-position is not possible in bendiocarb. Benfuracarb and carbosulfan are sulfenylated pro-insecticides that are precursors of carbofuran. N-Sulfenylated pro-insecticides generally show lower mammalian toxicity, better residual insecticidal activity and lower phytotoxicity and are more lipophilic than their parent compounds. However, they also show less systemic activity in plants and are less stable on storage. Carbaryl is an otherwise unsubstituted naphthyl compound with possibilities for metabolic hydroxylation at a number of positions on the aryl rings. Hence, it forms many and diverse metabolites. Pirimicarb is basic and differs structurally from the other compounds in having a heterocyclic aromatic ring and by being an N,N-dimethylcarbamate. It probably has a dimethyl moiety because monomethyl derivatives of heterocyclic carbamates tend to hydrolyse too quickly under alkaline conditions. Formetanate has an atypical basic unsaturated dimethylaminomethyl-eneamino substituent. Quatemisation of an amine in the 3-position on an aromatic ring, such as those in pirimicarb or formetanate, also tends to enhance the anti-acetylcholinesterase activity compared with uncharged analogues.

Carbamates act as substrates for acetylcholinesterase and initially form a reversible Michaelis-like reversible complex. Once formed, the complex transfers the carbamoyl group to the active serine in an analogous mechanism to that of the natural substrate acetylcholine where the acetate group is transferred. However, the carbamoylated enzyme is hydrolysed (decarbamoylated) very slowly with a typical half-life for most cholinesterases measured in hours so that the enzyme is effectively irreversibly inhibited. In general, the decarbamoylation rates for N,N-dimethylcarbamates (e.g. pirimicarb) are slower than for N-methylcarbamates. These reactivation rates are, however, much faster than those of organophosphorus-inhibited acetylcholinesterases in which dephosphorylation rates are measured in days, weeks or even longer. It is generally considered that the high affinity of carbamates for cholinesterase and the pseudo-irreversible inhibition via carbamoylation of the active site are responsible for their toxicity.

The carbamates are only moderately strongly sorbed to soils but some may be leachable. They are fairly rapidly degraded in soil and so are non-persistent, the compounds being hydrolysed and oxidised and forming bound residues. Almost all of the described compounds are of intermediate lipophilicity such that they have good systemic activity in plants, being translocated from roots to shoots via the xylem vessels. Pirimicarb is an aphicide with favourable selectivity towards beneficial insects such as ladybirds. This selectivity may partly arise from the systemicity of the compound. Benfuracarb and carbosulfan are too lipophilic to be well translocated in plants, however, they are converted to carbofuran which is itself systemic. Carbaryl also has applications for the fruit thinning of apples.

A major monograph on the chemistry, biochemistry and toxicology of carbamates was written by Kuhr and Dorough (1976) and the metabolism of carbamate insecticides was extensively surveyed by Cool and Jankowski (1985). More information has been published on carbaryl and carbofuran than for the other compounds. A combination of hydrolysis, oxidation and conjugation governs the biological fate of carbamate esters. Early studies concentrated on hydrolysis (which produces a phenol) as the major initial reaction, but later it was discovered that oxidation and conjugation are often more important. Thus, the hydrolytic stability of the esters may be greater than perhaps expected. Rates of hydrolysis may be faster in mammals than in plants or insects and this difference may contribute to selective action. Important oxidation reactions include hydroxylation, epoxidation, N-dealkylation and sulfoxidation. Hydroxylation may take place on the carbamate N-methyl group, on an alkyl substituent or on the aromatic ring itself. A benzylic carbon, as for example in carbofuran, is particularly susceptible to hydroxylation. Often the metabolites formed in plants, mammals and insects are similar and differ only in the nature of the conjugates. Conjugation occurs after the initial hydrolysis or oxidation of the insecticide. Metabolites are conjugated as glucuronides in mammals and as glycosides in plants and insects. Sulfates are more common in mammals but phosphates are found in insects. All are capable of conjugation with amino acids. Two glutathione conjugates of carbaryl and their mercapturic acid derivatives were found in mammals but the mercapturic acids were not confirmed by chemical methods of analysis.

Bendiocarb

Uses Bendiocarb is a contact and ingested insecticide with some systemic activity in crop plants. It is active against many public health, industrial and storage pests such as Formicidae, Blattodae, Culicidae, Muscidae and Siphonaptera.

Metabolic pathways

Pathways of bendiocarb metabolism in mammals include hydrolysis to the benzodioxol-4-ol, hydroxylation of the phenyl ring, hydroxylation at the N-methyl moiety and conjugation. Extensive pathways reported for the structurally related carbofuran are not reported for bendiocarb partly because hydroxylation and subsequent oxidation and conjugation at the 3-position is not possible in bendiocarb although it is a major pathway for carbofuran. No information is available for the metabolism of bendiocarb in plants.

Chemical degradation

Bendiocarb undergoes base-catalysed hydrolysis but is more stable in neutral or acidic conditions. The products of hydrolysis are 2,2-dimethyl-l,3-benzodioxol-4-ol (2), methylamine and CO2. Its DT50 at pH 7 and 25 °C is 4 days (PM).

Degradation in soils

Bendiocarb (1) was rapidly degraded in soil (half-life in the range 1-10 days) by hydrolytic cleavage of the methyl carbamate group to form the benzodioxol-4-ol (2). This was metabolised further by oxidation to polar compounds and soil-bound residues. There was considerable mineralisation of the phenyl ring to CO2. In soil sorption studies some bendiocarb was also hydrolysed to the benzodioxol-4-ol (2). The rate of degradation of bendiocarb increased with soil pH (PM).

Metabolism in plants

No published information is available.

Metabolism in animals

[2-14C-benzodioxol]Bendiocarb was applied topically to adults or larvae of southern com rootworm (Diabrotica undecimpunctata). Bendiocarb was taken up rapidly by the insects. The adults excreted a larger proportion of the applied radioactivity (17%) than the larvae within 4 hours. The benzodioxol-4-ol (2) was the predominant metabolite in adults but its polar conjugates were major metabolites in larvae (Hsin and Coats, 1987).

Bendiocarb was eliminated almost completely in mammals as sulfate and glucuronide conjugates of the benzodioxol-4-ol (2) (PM). [2-14C-benzodioxol]Bendiocarb was administered to rats in com-oil and to male human volunteers in gelatine capsules. Urine, faeces and tissue samples taken from rats were extracted and analysed by LSC, TLC and GC-MS. Some human urine samples were hydrolysed with acid, β-glucuronidase or sulfatase. The benzodioxol-4-ol (2) was determined in human urine by a mass fragmentographic method (Adcock and Challis, 1981). Bendiocarb was rapidly and extensively absorbed and completely metabolised. In man >99% and in rat >86% of the administered dose was excreted in the urine within 24 hours. Faecal excretion from the rat was minor (3-8% of applied radioactivity) and about 2% was excreted as 14CO2. The major pathway in both species (>95% in man) was cleavage of the carbamate ester group to yield, in man, the benzodioxol-4-ol (2), mainly as sulfate and glucuronide conjugates. Small amounts of conjugates of the N-hydroxymethyl derivative (3) were also found in early samples in man. Metabolism in rat was more complex with the formation of small amounts of conjugates of the the N-hydroxymethyl derivative (3) and several minor metabolites thought to be ring-hydroxylated derivatives of bendiocarb (4) and the benzodioxol-4-ol (5) (Challis and Adcock, 1981). The metabolic pathways are shown in Scheme 1.

Benfuracarb

Uses Benfuracarb is a contact and ingested insecticide. It is used to control insect pests in citrus, maize, rice, sugar beet and vegetables. It is active against Chrysomelidae, Elateridae, Aphididae, Lissorhoptrus oryzophilus and Plutella xylostella.

Mode of action Benfuracarb is a cholinesterase inhibitor.

Metabolic pathways

Benfuracarb was developed as a pro-insecticide that utilises the lability of the N-sulfenyl group to generate carbofuran. Benfuracarb is degraded in soil to carbofuran which is degraded by hydrolysis in flooded conditions. In plants and mammals, N-S bond cleavage occurs to form carbofuran which is subsequently hydrolysed and oxidised at the 3-position.

Chemical degradation

Benfuracarb is stable in neutral and weakly basic media but unstable in strongly acidic or basic conditions. It is degraded by sunlight (PM). A methanolic solution of unlabelled benfuracarb was coated on a glass plate or applied to soil on a plate and irradiated with a high pressure Hg lamp (125 W). Details not given were the emission spectrum of the lamp, the experimental sample temperatures and the irradiation periods. After irradiation, samples were analysed by TLC methods. The methanol solution turned a deep brown on irradiation and four major and three minor products were formed (see Scheme 1). The major products were a cleavage product (2), the phenol (5) and carbofuran (6). Minor amounts of the dimeric compounds 3 and 4 were detected. On soil, three photoproducts were the phenol (5), carbofuran (6) and the cleavage product (7). On a glass surface four products were the phenol (5), carbofuran (6) and the cleavage products 2 and 7. No products of oxidation were reported (Dureja et al., 1990).

Degradation in soils

Benfuracarb is degraded (DT50 4-28 hours) in soil to carbofuran (6). In flooded conditions the carbofuran is hydrolysed to the phenol (5) (PM). Carbofuran was a major metabolite of benfuracarb in soil (Mori et al., 1987).

Metabolism in plants

[14C-ring]Benfuracarb was painted on to the primary leaves of bush bean plants (10 days old) or the cotyledons of cotton plants (13 days old) or applied to com seedlings. In a further study, radiolabelled benfuracarb was injected into the stems of bean plants and com seedlings to overcome the poor absorption of the compound into com leaves. At intervals up to 10 days, plant tissues were extracted and analysed by 2-D TLC methods. Metabolites were identified by co-chromatography with authentic standards. Metabolism of benfuracarb was similar in all three plant species (see Scheme 2) and occurred mainly by N-S bond cleavage, oxidation, hydrolysis and conjugation. The first main step was cleavage of the N-S bond to form carbofuran (6). Carbofuran was oxidised to 3-hydroxycarbofuran (10). Other oxidised products, isolated as plant conjugates, were carbofuran phenol (5) and the 3-hydroxy- and 3-keto-phenols (8 and 9). Appreciable amounts of 3-hydroxy- and 3-keto-benfuracarb (11 and 12) were also detected. After stem injection into com plants, benfuracarb was rapidly metabolised. The principal metabolite was carbofuran (6) but 3-hydroxycarbofuran (10) (free and conjugated) later became equally abundant. The 3-ketophenol (9) was also obtained as a major metabolite after 10 days. Minor metabolites observed after foliar application to bean and cotton plants (but not in stem-injected corn) included 3-hydroxy-benfuracarb (11), 3-keto-benfuracarb (12) and some unidentified compounds (Tanaka et al., 1985).

Similar results were obtained from a previous study of the metabolism of [14C-carbonyl]benfuracarb in cotton plants where the fate of the ring moiety and formation of phenolic products could not be confirmed. [14C-carbonyl]Benfuracarb was topically applied to the base of cotton leaves and by stem injection. Again, the major metabolites were carbofuran (6) and its 3-hydroxy derivative (10) (free and conjugated) whilst 3-ketocarbofuran (14) was a minor product. Other metabolites (13, 15 and 16) were formed in minor proportions by hydroxylation at the N-methyl group. A dimeric product similar to 4 (Scheme 1) was probably an artefact formed in acidic conditions on a TLC plate (Umetsu et al., 1985).

Metabolism in animals

The N-S bond of sufenylated methylcarbamates is susceptible to thiolytic cleavage by attack at the sulfur atom by sulfhydryl-containing agents in biological tissue (Chiu et al., 1975). [14C-ring]Benfuracarb was applied topically to houseflies. Flies were extracted and analysed at intervals up to 24 hours. Penetration of applied radioactivity was rapid and extensive (65% of that applied). Pathways of metabolism were similar to those for plants (Scheme 2). Principal reactions in the housefly were N-S bond cleavage, oxidation, hydrolysis and conjugation. Benfuracarb was readily decomposed to form carbofuran which was in turn oxidised at the 3-position and at the N-methyl group. These oxidised metabolites became conjugated. Major metabolites were carbofuran (6) and 3-hydroxy-carbofuran (10) (free and conjugated). All other metabolites were of minor importance. Minor metabolites were N-hydroxymethyl-carbofuran (13), 3-keto-carbofuran (14), 3-hydroxy-carbofuran phenol (8), 3-hydroxy-N-hydroxymethyl-carbofuran (15), 3-keto-N-hydroxymethyl-carbofuran (16) and several minor unidentified products. Small amounts of polysulfides of bis-carbofuran and of the isopropyl(ethoxycarbonyl-ethyl)amine were detected but may have been formed during extraction or on TLC plates and are not included in Scheme 2 (Usui and Umetsu, 1986).

Benfuracarb was metabolised rapidly and almost completely excreted in the urine and faeces of rats within 7 days. Major metabolites found in the faeces were carbofuran (6), carbofuran phenol (5), 3-hydroxy-carbofuran (10), the 3-hydroxyphenol (8) and the 3-ketophenol (9) (PM). β-Glucuronide conjugates of these metabolites were eliminated in the urine.

(Continues…)Excerpted from Metabolic Pathways of Agrochemicals Part 2: Insecticides and Fungicides by Terry R. Roberts, David H. Hutson. Copyright © 1999 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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