WORLD HEALTH ORGANIZATION FOOD AND AGRICULTURE ORGANIZATION ORGANISATION MONDIALE DE LA SANTE ORGANISATION POUR L'ALIMENTATION ET L'AGRICULTURE VBC/PDS/DS/85.61 ORIGINAL: ENGLISH DATA SHEETS ON PESTICIDES No. 61 DEMETON-S-METHYL It must be noted that the issue of a Data Sheet for a particular pesticide does not imply endorsement of the pesticide by WHO or FAO for any particular use, or exclude its use for other purposes not stated. While the information provided is believed to be accurate according to data available at the time when the sheet was compiled, neither WHO nor FAO are responsible for any errors or omissions, or any consequences therefrom. The issue of this document does Ce document ne constitue pas une not constitute formal publication. Il ne doit faire publication. It should not be l'objet d'aucun compte rendu ou reviewed, abstracted or quoted résumé ni d'aucune citation sans without the agreement of the l'autorisation de l'Organisation Food and Agriculture des Nations Unies pour Organization of the United l'Alimentation et l'Agriculture Nations or of the World Health ou de l'Organisation Mondiale de Organization. la Santé. CLASSIFICATION: Primary use: Insecticide Secondary use: Acaricide Chemical group: Organophosphorus compound 1. GENERAL INFORMATION 1.1 COMMON NAME Demeton-S-methyl (ISO, BSI and JMAF; exception USSR - methyl- mercaptofos teolovy) 1.1.1 Identity IUPAC and CAS: S-2-ethylthioethyl O,O-dimethyl phosphorothiate CAS Reg. No.: 919-86-8 Molecular formula: C6H15O3PS2 Molecular weight: 230.3 Structural formula: 1.1.2 Synonyms AzotoxR; Bayer 18436; Bayer 21/116; Bayer 25/154; Campbell's DsMR; Demeton-S-methyl; Demeton-S-metile; DemetoxR; DuratoxR; Isometasystox; Isomethylsystox; Metaisoseptox; MetaisosystoxR; Metasystox iR; Methyl demeton thioester; Methyl isosystox; Methyl mercaptofos teolovy 1.2 SYNOPSIS Demeton-S-methyl is a broad spectrum, non-cumulative, systemic organophosphorus insecticide; a cholinesterase inhibitor with good contact and limited stomach action; highly toxic to mammals, other vertebrates and bees. Its toxicity is maintained after metabolism to the oxygen derivatives, i.e., sulfoxide and sulfone. 1.3 SELECTED PROPERTIES 1.3.1 Physical characteristics Demeton-S-methyl is a pale yellow oily liquid. It has a boiling point of 89°C at 0.15 mmhg; a density (d20) of 1.707; and a 4 refractive index (n20 ) of 1.5065. D 1.3.2 Solubility In water, 3.3 g/litre at 25°C, it is readily soluble in conventional organic solvents. 1.3.3 Stability Demeton-S-methyl has a half-life of 7.6 days in an ethanol-Ph 6 buffer solution (1:4) at 70°C. In aqueous solutions, Ph 1-5, it has a half-life of 88 days. The shelf-life is quite short yielding the highly toxic sulfonium compound. 1.3.4 Vapour pressure 4.79 x 10-5 Kpa (3.6 x 10-4 mmhg) at 20°C. 1.4 AGRICULTURE, HORTICULTURE AND FORESTRY 1.4.1 Common formulations These include emulsifiable concentrates of various concentrations in the range of 250 g a.i./kg. 1.4.2 Pests controlled Aphid vectors of vital diseases, whiteflies, leafhoppers, sawflies, red spider mites and other pests of garden crops, fruit and hops. 1.4.3 Use pattern It is recommended for use on alfalfa, almonds, apples, apricots, barley, beans, blackberries, broccoli, brussel sprouts, cabbage, cauliflower, celery, clover cotton, dewberries, eggplant, filberts, gooseberries, grapefruit, grapes, hops, lemons, lettuce, loganberries, muskmelons, nectarines, otas, oranges, peaches, pears, peas, pecans, peppers, pineapples, plums, potatoes, raspberries, sorghum, strawberries, sugar beets, walnuts, wheat, conifers and ornamentals. It is generally applied at 140-800 g/ha. 1.4.4 Unintended effects Demeton-S-methyl is phytotoxic to ornamentals, especially certain chrysanthemum cultivars; it is toxic to bees. 1.5 PUBLIC HEALTH USE No recommended use. 1.6 HOUSEHOLD USE No recommended use. 2. TOXICOLOGY AND RISKS 2.1 TOXICOLOGY - MAMMALS 2.1.1 Absorption Demeton-S-methyl may be absorbed from the gastrointestinal tract; through the intact skin; and by inhalation of spray mist and dusts. 2.1.2 Mode of action Demeton-S-methyl is a direct inhibitor of cholinesterase through phosphorylation of the esteratic site of the enzyme. Accumulation of acetylcholine at nerve synapses and myoneural junctions causes the toxic effects. Demeton-S-methyl and its oxidation products, the sulfoxide and the sulfone, are equally toxic. The thiono-isomer is less toxic than the thiolo-isomer. 2.1.3 Excretion products The metabolism and excretion of demeton-S-methyl have not been extensively studied in mammals. By extrapolation from the ethyl homologue demeton, metabolism should involve oxidation of the thioether to the sulfoxide and, more slowly, to the sulfone by liver microsomal enzymes. In mice 97% of demeton-S-methyl sulfoxide was eliminated within 15 hours of dosing (per oral or subcutaneous), mostly in urine. 2.1.4 Toxicity, single dose of demeton-S-methyl Oral LD50: Rat (H, F) 35-83 mg/kg bw; technical material Guinea-pig (M) 110 mg/kg bw; technical material Rabbit 20-50 mg/kg bw; technical material Cat 5-10 mg/kg bw; technical material Dog 50 mg/kg bw; technical material Dermal LD50: Rat 50-100 mg/kg bw; technical material Cat 10-20 mg/kg bw; technical material I.P. LD50; Rat (M, F) 2-10 mg/kg bw; technical material Rat (M, F) 27.5 mg/kg bw (pure) Guinea-pig 12.5 mg/kg bw; technical material I.V. LD50; Rat (M) 8.4 mg/kg bw; technical material Rat (M) 17.3 mg/kg bw (pure) Rat (F) 64.5 mg/kg bw (pure) Mouse (M) 4.1 mg/kg bw (purity unknown) Mouse (M) 13.0 mg/kg bw (pure) Oral LD50: Rat 676 mg/kg bw I.V. LD50; Rat 216 mg/kg bw Inhalation LC50: Rat 500 mg/m3/4 hours 2.1.5 Toxicity repeated doses Oral: Groups of male rats were given doses of 0, 1, 5 or 10 mg/kg bw for up to six months. Increased mortality was observed at the two highest doses only; no ill-effects were observed at 1 mg/kg/day. Dermal: No information available on demeton-S-methyl. Demeton-S-methyl sulfoxide, a metabolite, was administered to male and female rats for 60 days at dosage levels of 25 or 50 mg/kg bw. The animals on the highest dose only showed signs of increased cholinergic activity for the initial two weeks of treatment only. No other ill-effects were observed. Oxydemeton, a metabolite, was also administered to male and female rats, approximately one-fifth of the LD50, five days a week for three weeks. A slight reduction in body weight and a marked inhibition of brain cholinesterase activity were observed at the end of the study. No other ill-effects or changes in tissue histology could be attributed to oxydemeton treatment. Inhalation studies: Groups of male and female rats were exposed to the metabolite demeton-S-methyl sulfone at concentrations of 0, 0.0068 and 0.017 mg/litre for four hours a day, five days per week for a period of 10 weeks. Cholinesterase depression was marked and body weight gain was significantly depressed in all treatment groups; no other ill-effects were observed. Cumulation of compound: Demeton-S-methyl does not accumulate in body tissues. Cumulation of effect: Dermal and oral studies indicate that there is none. 2.1.6 Dietary studies Short-term: Groups of male rats were fed demeton-S-methyl at dietary levels of 0, 50, 100 or 200 mg/kg. Depression of cholinesterase activity was observed in all treatment groups; however, signs of cholinergic toxicity were evident at the highest dietary level only. Growth rates were depressed from 100 mg/kg (diet). There were no treatment-related changes in gross or microscopic anatomy. Groups of male and female weanling rats were maintained on diets containing 0, 2, 5, 10 or 20 mg/kg of demeton-S-methyl for three months. There were no signs of toxicity or laboratory findings that could be attributed to demeton-S-methyl at 10 mg/kg (diet) or less. Long-term: See section on Carcinogenicity. 2.1.7 Supplementary studies of toxicity Carcinogenicity: Short-term dietary studies in rats have not shown a carcinogenic potential for demeton-S-methyl. Two-year rat studies with demeton-S-methyl sulfoxide have also not produced evidence of carcinogenic activity for that compound at dietary levels as high as 100 mg/kg. Mammalian mutagenicity and reproductive studies show no supportive evidence for an oncogenic role. Mutagenicity: Demeton-S-methyl has shown some mutagenic potential in non-mammalian systems at 5 mg/plate in an E. coli and an S. typhimurium plate test and in a Drosophila melanogaster nondisjunction test. In mammalian systems, however, the sulfoxide analogue was not mutagenically active in a mouse dominant lethal assay (5 and 10 mg/kg bw). Teratogenicity: Pregnant female rabbits were given oral doses of oxydemetonthalidomide at 0, 0.1 and 0.2 mg/kg bw from days 6 to 18 of gestation; a thalidomide positive control was also carried out. No clear treatment-related embryotoxic or teratogenic effects were observed nor were there any ill-effects observed among the does. Reproduction: No clear treatment-related adverse effects were observed in rats in a three-generation study at dosage levels of 10- 50 mg/kg (diet), although cholinesterase depression was produced. At 50 mg/kg (diet) the number of pregnancies and litter size were significantly reduced. Neurotoxicity: Demeton-S-methyl sulfone did not produce any delayed neurotoxic effects at doses up to and including 200 mg/kg bw. 2.1.8 Modifications of toxicity No evidence of acute potentiation was observed when oxydemeton- methyl was given in pairs with 15 other organophosphorus compounds, at one-half the LD50 dose, to male rats. 2.2 TOXICOLOGY - MAN 2.2.1 Absorption route Demeton-S-methyl or related compounds may be absorbed from the gastrointestinal tract; through the intact skin; and by inhalation of spray mist or dusts. 2.2.2 Dangerous doses Single: Not known. Repeated: Not known. 2.2.3 Observations on occupationally exposed workers Over 700 cases of poisoning are known, including three fatalities which followed a one-week exposure in an agricultural spray programme. Lack of good personal hygiene was implicated as a cause. All others apparently recovered without sequelae, most after atroprine therapy and/or withdrawal from contact. 2.2.4 Observations on exposure of the general population A group of teenagers and children living adjacent to a spray area were found to have depressed cholinesterase levels. The depression was attributed to air-borne contamination. 2.2.5 Observations on volunteers The no-effect level for oxydemeton-methyl was found to be 0.05 mg/kg bw after a 60-day period of administration. 0.4 mg/kg bw caused depression of serum and erythrocyte cholinesterase after several days but no signs of poisoning. A single application of 1 mg/kg bw was tolerated without affecting cholinesterase activity, whereas a 2 mg/kg bw single dose inhibited the enzyme. 2.2.6 Reported mishaps There have been several cases of suspected suicide. A 60-year- old man drank two liqueur glasses of demeton-S-methyl with two bottles of beer. Conventional treatment was given in hospital within two hours though there were no signs of toxicity at that time. In addition, the patient was treated for chronic illnesses. At 60 hours numbness developed, followed by diarrhoea at 72 hours and he died of cardiac failure at 81 hours post-administration. No laboratory findings were reported. A 65-year-old male ingested 15 ml of a mixture of demeton-S-methyl (25%) and benzene methyl chloride; there were no clinical signs of toxicity upon admission to hospital. After 32 hours his condition deteriorated; signs and symptoms were consistent with anticholinesterase poisoning. Given conventional treatment, he appeared to be recovering but died nine days later of a pulmonary embolus. A farmer drank 90 ml of a 70% a.i. solution of demeton-S- methyl. Hospitalized within 30 minutes with the usual signs and symptoms of anticholinesterase poisoning, he responded well to conventional treatment including gastric lavage, recovering completely. A 26-year-old male injected demeton-S-methyl into his upper arm at a rate of 44.6 mg/kg; surgical drainage released some of the fluid. The patient survived a protracted illness with conventional treatment. 2.3 TOXICOLOGY - NON-MAMMALIAN SPECIES Fish, LC50 (96 hours);1 Cyprinus carpio 40-60 mg/litre Scardinius erythrothalmis 30-40 mg/litre Idis 20-40 mg/litre Carassius duratus 20-40 mg/litre 1 Data supplied by manufacturer. 3. FOR REGULATORY AUTHORITIES - RECOMMENDATIONS ON REGULATION OF COMPOUND 3.1 RECOMMENDED RESTRICTIONS ON AVAILABILITY (For definition of categories, see the Introduction to Data Sheets) Liquid formulations of 20.0% and over, Category 2 Other liquid formulations, Category 3 There are no solid formulations available. 3.2 TRANSPORTATION AND STORAGE All formulations - Should be transported and stored in clearly labelled impermeable containers under lock and key, secure from access by children and other unauthorized persons. No food or drink should be stored in the same compartment. 3.3 HANDLING All formulations - Full protective clothing (see section 4.1.3) should be used by those handling the compound. Adequate washing facilities should be available at all times during the handling and should be close to site of handling. Eating, drinking and smoking should be prohibited during handling and before washing after handling. 3.4 DISPOSAL AND/OR DECONTAMINATION OF CONTAINERS All formulations - Containers must be either burned or crushed and buried below topsoil. Care must be taken to avoid subsequent contamination of water sources. Decontamination of containers in order to use them for other purposes should not be permitted. 3.5 SELECTION, TRAINING AND MEDICAL SUPERVISION OF WORKERS All formulations - Pre-employment medical examination of workers necessary. Workers suffering from hepatic or renal disease should be excluded from contact. Pre-employment and periodic cholinesterase tests for workers desirable. Special account should be taken of the workers' mental ability to comprehend and follow instructions. Training of workers in techniques to avoid contact essential. 3.6 ADDITIONAL REGULATIONS RECOMMENDED IF DISTRIBUTED BY AIRCRAFT All formulations: Pilots and loaders should have special training in application methods and early symptoms of poisoning, and must wear a suitable respirator. Use of flagmen not recommended. Flagmen, if used, should wear protective clothing and be located well away from the dropping zone. 3.7 LABELLING All formulations: "DANGER - POISON" (skull and cross-bones insignia) Demeton-S-methyl is an organophosphorus compound which inhibits cholinesterase. It is highly toxic. Contact with the skin, inhalation of dust or spray, or swallowing may be fatal. Wear protective gloves, clean protective clothing, and a respirator of the organic-vapour type when handling this material. Bathe immediately after work. Ensure that containers are stored under lock and key. Empty containers must be disposed of in such a way as to prevent all possibility of accidental contact with them. Keep the material out of reach of children and well away from foodstuffs, animal feed and their containers. In case of contact, immediately remove contaminated clothing and wash the skin thoroughly with soap and water; for eyes, flush with water for 15 minutes. If poisoning occurs, call a physician. Atropine sulfate and pralidoxime are specific antidotes; repeated doses may be necessary. Artificial respiration also may be needed. 3.8 RESIDUES IN FOOD Maximum residue levels - Maximum residue levels have been recommended by the Joint FAO/WHO Meeting on Pesticide Residues. 4. PREVENTION OF POISONING IN MAN AND EMERGENCY AID 4.1 PRECAUTIONS IN USE 4.1.1 General Demeton-S-methyl is an organophosphorus pesticide of high toxicity. It penetrates the intact skin and is also absorbed by inhalation and from the gastrointestinal tract. Repeated exposure may have a cumulative effect on cholinesterase levels. Most formulations should be handled by trained personnel wearing protective clothing. 4.1.2 Manufacture and formulation - TLV No information. Closed systems and forced ventilation may be required to reduce, as much as possible, the exposure of workers to the chemical. 4.1.3 Mixers and applicators When opening the container and when mixing, protective impermeable boots, clean overalls, gloves and respirator should be worn. Mixing, if not mechanical, should always be carried out with a paddle of appropriate length. When spraying tall crops or during aerial application, a face mask should be worn as well as an impermeable hat, clothing, boots and gloves. The applicator should avoid working in spray mist and avoid contact with the mouth. Particular care is needed when equipment is being washed after use. All protective clothing should be washed immediately after use, separate from other laundry, including the insides of gloves. Splashes must be washed immediately from the skin, or eyes, with large quantities of water. Before eating, drinking or smoking, hands and other exposed skin should be washed. 4.1.4 Other associated workers (including flagmen in aerial operations) Persons exposed to the compound and associated with its application should wear protective clothing and observe the precautions described above in section 4.1.3 under "Mixers and applicators". 4.1.5 Other populations likely to be affected With good application practice, subject to section 4.2 below, other persons are not likely to be exposed to hazardous amounts of the compound. 4.2 ENTRY OF PERSONS INTO TREATED AREAS Unprotected persons should be kept out of tall crops for four days and out of other crops for 24 hours after application. 4.3 DECONTAMINATION OF SPILLAGE AND CONTAINERS Residues in containers should be emptied in a diluted form into a deep pit, taking care to avoid groundwaters. The empty container may be decontaminated by rinsing two or three times with water and scrubbing the sides. An additional rinse should be carried out with 5% sodium hydroxide solution which should remain in the container overnight. Impermeable gauntlets should be worn during this work and a soakage pit should be provided for the rinsings. Decontaminated containers should not be used for food or drink. Spillage of the compound and its formulations should be removed by washing with 5% sodium hydroxide solution and then rinsing with large quantities of water. 4.4 EMERGENCY AID 4.4.1 Early symptoms of poisoning Early symptoms of poisoning may include excessive sweating, headache, weakness, giddiness, nausea, vomiting, hypersalivation, stomach pains, blurred vision, slurred speech and muscle twitching. Later there may be convulsions and coma. 4.4.2 Treatment before person is seen by a physician; if these symptoms appear following exposure The person should stop work immediately, remove contaminated clothing and wash the affected skin with soap and water, if available, and flush the area with large quantities of water. If swallowed, and if the person is conscious, vomiting should be induced. In the event of collapse, artificial resuscitation should be given, bearing in mind that, if mouth-to-mouth resuscitation is used, vomit may contain toxic amounts of pesticide. 5. FOR MEDICAL AND LABORATORY PERSONNEL 5.1 MEDICAL DIAGNOSIS AND TREATMENT IN CASES OF POISONING 5.1.1 General information Demeton-S-methyl is an organophosphorus pesticide of moderate mammalian toxicity which is active against a variety of agricultural and public health pests. It is readily absorbed from the gastrointestinal tract; through the intact skin; and by inhalation. It is converted in vivo to the oxygen derivatives which inhibit cholinesterase. It does not accumulate in body tissues. 5.1.2 Symptoms and signs Initial symptoms of poisoning may include excessive sweating, headache, weakness, giddiness, nausea, hypersalivation, vomiting, stomach pains, blurred vision, slurred speech and muscle twitching. More advanced symptoms of poisoning may be convulsions, coma, loss of reflexes and loss of sphincter control. 5.1.3 Laboratory The most important finding is reduction of activity of blood cholinesterases. Urinary levels of organic phosphorus containing metabolites may also be used as a measure of exposure. Neither method is specific for the compound. 5.1.4 Treatment If the pesticide has been ingested, unless the patient is vomiting, rapid gastric lavage should be performed using 5% sodium bicarbonate if available. For skin contact, the skin should be washed with soap and water. If the compound has entered the eyes, they should be washed with large quantities of isotonic saline or water. Persons without signs of respiratory inefficiency but with manifest peripheral symptoms should be treated with 2-4 mg of atropine sulfate by intravenous injection and 1000 mg pralidoxime chloride or 250 mg of toxogonin (adult dose) by slow intravenous injection. More atropine may be given as needed. Persons with severe intoxication, with respiratory difficulties, convulsions and unconsciousness should immediately be given atropine and a reactivator. In such severe cases, 4-6 mg of atropine sulfate should be given initially followed by repeated doses of 2 mg at 5-10 minute intervals. Diazepam may be given to control convulsions. The patient's condition including respiration, blood pressure, pulse frequency, salivation and convulsions should be carefully observed as a guide to further administration of atropine. If the patient is cyanotic, oxygen should be given at the same time as atropine sulfate. The airways should be kept free and artificial resuscitation should be applied if required, preferably by mechanical means. If necessary, intubation should be performed. Contraindicated are morphine, barbiturates, phenothiazine, tranquillizers and central stimulants of all kinds. Pralidoxime and toxogonin alone are not regarded as effective antidotes in organophosphorus poisoning. In cases of severe poisoning, when administered early, pralidoxime may be used to relieve nicotinic effects. 5.1.5 Prognosis If the acute toxic effect is survived and adequate artificial resuscitation has been given if needed, the chances of complete recovery are good. However, in very severe cases, particularly if artificial resuscitation has been inadequate, prolonged anoxia may give rise to permanent brain damage. 5.1.6 References of previously reported cases Demeton-S-methyl has been implicated in a number of cases of pesticide poisoning. Barr, A.M. (1964) M. J. Aust., 1, 792-796 Tilsner, V. (1966) Vergiftung Argtliche Fosch., 20, 272-273 United Kingdom Ministry of Agriculture, Fisheries and Food (1969) Report on the use of poisonous substances in agriculture and on the worker and of the Agriculture Regulations during 1969 Hegazy, M. R. (1965) Br. J. Med., 22, 230-235 Khasanor, V. K. & Li, A. P. (1970) Med. Zh. Uzb., 7, 12-13 Readhead, I. H. (1968) Lancet, 1, 686-688 5.2 SURVEILLANCE TESTS Normal Action Symptomatic Test level* level* level* Plasma cholinesterase 100% 50% variable Whole blood or erythrocyte cholinesterase 100% 70% usually 40% 5.3 LABORATORY METHODS 5.3.1 Detection and assay of compound Thin-layer chromatography and gas-liquid chromatography methods have been used to analyse demeton-S-methyl in technical products and in its formulations. Analysis of residues in plant and animal tissues gas chromatography and flame photometry methods. Boshoff, P. R. & Pretorium, V. (1979) J. Agric. Food Chem., 27(3), 626 Brinkman, U. & De Vries, G. (1979) Chromatog., 161(1), 167 CIPAC HANDBOOK (1970) Vol. 1, p. 312 Fysh, R. R. & Jones, L. V. (1980) Forensic Toxicol., Eur. Meet. Int. Assoc. Forensic Toxicol., pp. 189-203 Hild, J. & Thief, H. P. (1978) Z. Lebensom. Unters. Forsch., 166(1), 9 Laws, E. Q. & Webley, D. J. (1959) Analyst (London), 84, 28 MacDougal, D. (1964) Anal. Methods Pestic. Plant Growth Regulators Food Adit., 2, 295 Ramsay, J. D. et al. (1980) J. Chromatogr., 184(2), 185 Stan, H. J. (1977) Z. Lebensom. Unters. Forsch., 164(3), 153 Start, H. J. et al. (1977) Fresenius 'Z'. Anal. Chem., 287(4-5), 271 Tietz, H. & Frehse, H. (1960) Hoefchen-Briefe (Eng. Edition), 3, 212 * Expressed as percentage of pre-exposure activity. Van der Merwe, J. H. & Taylor, W. B. (1977) Pflanzenschutz- Nachr. (Amer. Edition), 24, 259 Wagner, K. & Thorton, J. S. (1977) Pflanzenschutz-Nachr., 30(1), 1 5.3.2 Other tests in case of poisoning Levels of cholinesterase in the blood, particularly plasma, provide the most useful diagnosis of poisoning. Michel, N. O. (1949) J. Lab. Clin. Med., 34, 1564-1568 Ellman, G. L. et al. (1961) Biochem. Pharmacol., 7, 88-95 Measurement of urine metabolites may also be determined in order to give an indication of exposure. For methods, see section 5.3.1, "Detection and assay of compound".
See Also: Demeton-s-methyl (PIM 760)