Environmental Health Criteria 90 Dimethoate

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Environmental Health Criteria 90

Dimethoate

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INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

ENVIRONMENTAL HEALTH CRITERIA 90

DIMETHOATE

This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organisation, or the World Health Organization.

Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization

World Health Orgnization Geneva, 1989

The International Programme on Chemical Safety (IPCS) is a joint venture of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization. The main objective of the IPCS is to carry out and disseminate evaluations of the effects of chemicals on human health and the quality of the environment. Supporting activities include the development of epidemiological, experimental laboratory, and risk-assessment methods that could produce internationally comparable results, and the development of manpower in the field of toxicology. Other activities carried out by the IPCS include the development of know-how for coping with chemical accidents, coordination of laboratory testing and epidemiological studies, and promotion of research on the mechanisms of the biological action of chemicals.

ISBN 92 4 154290 X

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already available.

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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR DIMETHOATE

1. SUMMARY

1.1. Identity, uses and analytical methods 1.2. Environmental concentrations and exposure 1.3. Effects on the environment 1.4. Kinetics and metabolism 1.5. Effects on experimental animals 1.6. Effects on man

2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

2.1. Identity 2.2. Physical and chemical properties 2.3. Analytical methods

3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE 3.1. Natural occurrence 3.2. Man-made sources 3.2.1. Industrial production 3.2.2. World production figures 3.2.3. Uses

4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

4.1. Transport and distribution between media 4.1.1. Air 4.1.2. Water 4.1.3. Soil 4.1.4. Plants 4.1.5. Disposal of wastes

5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

5.1. Environmental levels 5.1.1. Air, water, and soil 5.1.2. Food 5.2. Occupational exposure

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6. KINETICS AND METABOLISM

6.1. Absorption and distribution 6.2. Metabolic transformation 6.3. Elimination and excretion 6.3.1. Animal studies 6.3.2. Human studies

7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT

7.1. Microorganisms 7.2. Aquatic organisms

7.3. Terrestrial organisms 7.3.1. Honey-bees 7.3.2. Birds 7.3.3. Farm animals

8. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS

8.1. Single exposures 8.2. Skin and eye irritation 8.3. Repeated exposures 8.4. Reproduction studies 8.5. Teratogenicity 8.6. Mutagenicity 8.7. Carcinogenicity 8.8. Special studies 8.9. Factors modifying toxicity 8.10. Mechanisms of toxicity; mode of action

9. EFFECTS ON MAN

9.1. General population exposure 9.1.1. Poisoning incidents 9.1.2. Controlled human studies 9.2. Occupational exposure 9.2.1. Poisoning incidents 9.3. Early symptoms and treatment of poisoning

10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT

10.1. Toxicity of dimethoate 10.2. Human exposure 10.3. Evaluation of effects on the environment 10.4. Conclusions

11. RECOMMENDATIONS

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

REFERENCES

ANNEX I

WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR DIMETHOATE

Members

Dr L. Badaeva, All Union Scientific Research Institute of Hygiene and Toxicology of Pesticides, Polymers and Plastics, Kiev, USSR Dr J. Huff, National Institute of Environmental Health Sciences,

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Research Triangle Park, North Carolina, USA Dr S.K. Kashyap, National Institute of Occupational Health, Ahmedabad, India (Chairman) Dr J. Liesivuori, Institute of Occupational Health, Kuopio Regional Institute of Occupational Health, Kuopio, Finland Dr I. Ritter, Pesticides Division, Environmental Health Directorate, Department of National Health and Welfare, Tunney's Pasture, Ottawa, Ontario, Canada Dr A. Takanaka, Division of Pharmacology, National Institute of Hygienic Sciences, Tokyo, Japan (Vice-Chairman) Dr M. Tasheva, Institute of Hygiene & Occupational Health, Medical Academy, Sofia, Bulgaria (Rapporteur) Dr E.M. den Tonkelaar, National Institute of Public Health and Environment, Bilthoven, Netherlands (Rapporteur)

Secretariat

Dr K.W. Jager, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland (Secretary) Ms F. Ouane, United Nations Environment Programme, International Register of Potentially Toxic Chemicals, Palais des Nations, Geneva, Switzerland

NOTE TO READERS OF THE CRITERIA DOCUMENTS

Every effort has been made to present information in the criteria documents as accurately as possible without unduly delaying their publication. In the interest of all users of the environmental health criteria documents, readers are kindly requested to communicate any errors that may have occurred to the Manager of the International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland, in order that they may be included in corrigenda, which will appear in subsequent volumes.

* * *

A detailed data profile and a legal file can be obtained from the International Register of Potentially Toxic Chemicals, Palais des Nations, 1211 Geneva 10, Switzerland (Telephone No. 7988400 - 7985850).

ENVIRONMENTAL HEALTH CRITERIA FOR DIMETHOATE

A WHO Task Group on Environmental Health Criteria for Dimethoate met in Geneva from 11-15 May 1987. Dr K.W. Jager opened the meeting and welcomed the participants on behalf of the Manager of the IPCS and the heads of the three IPCS co- operating organizations (UNEP/ILO/WHO). The Group reviewed and revised the draft criteria document and made an evaluation of the risks for human health and the environment from exposure to dimethoate.

The first draft of this document and the second draft incorporating comments received from the IPCS contact points for Environmental Health Criteria Documents were prepared by Dr M. TASHEVA, Institute of Hygiene and Occupational Health, Medical Academy, Sofia, Bulgaria.

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The efforts of all who helped in the preparation and finalization of the document are gratefully acknowledged.

* * *

Partial financial support for the publication of this criteria document was kindly provided by the United States Department of Health and Human Services, through a contract from the National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA - a WHO Collab- orating Centre for Environmental Health Effects. The United Kingdom Department of Health and Social Security generously supported the cost of printing.

1. SUMMARY

1.1. Identity, Uses and Analytical Methods

Dimethoate is an organophosphorus insecticide with a contact and systemic action. It was introduced in 1956 and is produced in many countries for use against a broad range of insects in agriculture and also for the control of the housefly.

Dimethoxon, an oxygen analogue metabolite of dimethoate, appears to play a dominant role in its toxicity for insects and mammals. Dimethoxon itself is also used as an insecticide, known as omethoate.

Dimethoate is fairly soluble in water and highly soluble in most organic solvents. It is fairly stable in water and acid solution, and unstable in alkaline solution.

The analytical method of choice for its determination is gas chromatography with flame photometric detection.

1.2. Environmental Concentrations and Exposure

Hydrolytic degradation is the main inactivating pathway of dimethoate in the environment. In moist air, it is degraded photochemically to hydrolytic and oxidation products. The half- life of dimethoate in different plants is between 2 and 5 days. Degradation in soil is dependent on the type of soil, temperature, moisture, and pH level.

The general population is not normally exposed to dimethoate from air or water. Levels of residues in food are mainly below 1 mg/kg. Dimethoate was only detected infrequently in the latest reported total-diet studies (1982).

Occupational exposure to dimethoate, which may occur during manufacture, formulation, and use, is mainly through inhalation and dermal absorption. Higher occupational exposure may be observed in case of accident or as a result of incorrect handling.

1.3. Effects on the Environment

Dimethoate is not persistent in the environment. Its toxicity for aquatic organisms and birds has been reported to be

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moderate to high. However, it is very toxic for honey-bees.

1.4. Kinetics and Metabolism

Dimethoate is absorbed following ingestion, inhalation, and skin contact. It has been detected in the blood 30 min after oral administration. Accumulation in the tissues is not likely. The main metabolic pathways of dimethoate are oxidative desulfuration and hydrolysis. Hydrolytic metabolism predominates over oxidation in mammals, whereas the opposite is true in insects.

Dimethoxon (omethoate), which has been demonstrated in plants, insects, and mammals, seems to be the metabolite responsible for the toxic action of dimethoate. Dimethoate is degraded rapidly in the rat liver, but very little degradation occurs in other tissues. It is eliminated predominantly in the form of hydrolytic urinary products.

1.5. Effects on Experimental Animals

Dimethoate is moderately toxic; most oral LD50s in rats ranged from 150 to 400 mg/kg body weight. Signs of intoxication in the rat we2e observed`0.5-2 h after administration, and were typical of exposure to organophosphorus pesticides. Rat and dog erythrocyte-acetyl cholinesterase activity (AChE) is more susceptible to inhibition than plasma-cholinesterase (ChE). When rats were exposed to dimethoate at a concentration of 10 mg/m3 for 4 h, 40% inhibition of ChE activity was reported.

The acute dermal LD50 for dimethoate in rats is greater than 600 mg/kg. It is not irritating to the skin and only slightly irritating to the eye. No dermal sensitization data are available on dimethoate.

A dietary level of 5 mg dimethoate/kg is considered to be a no-observed-adverse-effect level in the rat on the basis of erythrocyte-cholinesterase depression. No effects were reported in rats exposed through inhalation to 0.01 mg dimethoate/m3 for 14 h/day for 3 months.

Dimethoate administered at 60 mg/litre drinking-water affected mating in 5 generations of mice tested.

Dimethoate did not appear to be teratogenic in experimental animals.

However, dimethoate was found to be mutagenic in a variety of in vitro and in vivo test systems.a

Long-term studies have been conducted on dimethoate administered orally to rats and mice and by intramuscular injection in rats. However, the available data are considered to be inadequate to assess the carcinogenic potential of the compound.b

------a On the basis of the results of new and published studies, the FAO/WHO Joint Meeting on Pesticide Residues (JMPR) have concluded that dimethoate is mutagenic in bacterial tests, but negative in mammalian cells and in vivo tests. b Since the Task Group met, the results of new long-term carcinogenicity studies on rats and mice have been submitted to the FAO/WHO Joint Meeting on Pesticide Residues. No

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indication of carcinogenicity was found.

1.6. Effects on Man

Several cases of suicidal and accidental poisoning by dimethoate have been reported. Some cases of occupational poisoning that have been reported have been the result of accidents or neglect of safety precautions. The lethal oral dose for human beings has been estimated to be in the range of 50-500 mg/kg body weight.

In human volunteers, an oral dose of 0.2 mg/kg body weight per day, for 39 days, did not produce any effects on whole-blood cholinesterase values. No skin irritation or ChE inhibition was observed after a 2-h dermal exposure to 2.5 ml of a 32% liquid formulation of dimethoate. There have been rare reports of skin sensitization to dimethoate.

Minimum safe re-entry periods after the application of dimethoate have been reported.

2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

2.1. Identity

Chemical structure:

Molecular formula: C5H12NO3PS2

Common name: dimethoate (accepted by BSI, ISO, ANSI, and JMAF); fosfamid (used in USSR)

Common trade names: Bi 58; Cygon; Dimethoate; Fosfamid; Fostion MM, Rogor; Perfekthion; Roxion

IUPAC name: O,O-dimethyl S-methyl-carbamoyl- methyl phosphorodithioate

CAS chemical name: Phosphorodithioic acid, O,O-dimethyl S-[2-(methylamino)-2-oxoethyl] ester (9CI)

CAS registry number: 60-51-5

RTECS registry number: TE1750000

Technical dimethoate is about 93-95% pure. The major impurities are O,O-dimethyl S-methylphosphorodithioate and O-O-S-trimethyl phosphorodithioate.

2.2. Physical and Chemical Properties

Pure dimethoate is a colourless crystalline solid with an odour of mercaptan. Technical dimethoate (about 93% pure) varies from off-white crystals to a grey semi-crystalline material. Some physical and chemical properties of dimethoate

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are given in Table 1.

Dimethoate is highly soluble in chloroform, methylene chloride, benzene, toluene, alcohols, esters, and ketones, slightly soluble in xylene, carbon tetrachloride, and aliphatic hydrocarbons, and fairly soluble in water.

Dimethoate is fairly stable in water and acid solution, at room temperature, and unstable in alkaline solution (Table 1). Heating converts it to the O,S-dimethyl phosphorodithioate.

Table 1. Some physical and chemical properties of dimethoate ------

Relative molecular mass 229.2

Odour threshold 0.010 mg/m3

Melting point 45-52.5 °C

Boiling point 107 °C at 0.05 mmHg 86 °C at 0.01 mmHg

Vapour pressure (25 °C) 8.5 x 10-6 mmHg

Volatility 1.107 mg/m3

Specific gravity 1.281 (compared to water)

Partition coefficient n-octanol/water 5.959

Solubility in water (21 °C) up to 39 g/litre

Half-life: in aqueous media at pH 2-7, relatively stable at pH 9, 50% loss in l2 days ------

2.3. Analytical Methods

A review of the detection methods for dimethoate in treated crop plants has been presented by De Pietri-Tonelli et al. (1965). The procedures reported are based on colorimetry, column, paper, and thin-layer chromatography, paper electro- phoresis, gas chromatography, and radiometry. Bioassay techniques and autoradiographic procedures can also be applied. High-performance thin-layer chromatography has been proposed by Hauck & Amadori (1980) as a new potential for the determination of dimethoate.

The Codex Committee on Pesticide Residues has listed recommended methods for the determination of dimethoate residues (FAO/WHO 1986) and various methods used in the determination of dimethoate are summarized in Table 2.

A personal air sampler to measure vapours and aerosols of dimethoate at low concentrations has been described by Hill & Arnold (1979).

Table 2. Methods for the determination of dimethoate ------Sample type Method of detection Comments Detection li ------

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Soil gas-liquid chromato- 1-20 ng graphy/phosphorus detection

Soil thin-layer chromato- 50-mg soil samples; ex- 0.1 mg/kg; graphy; gas-liquid traction with chloroform 0.05 mg/kg chromatography/thermionic detection

Water thin-layer chromato- 200-ml sample; extraction 0.5 µg; graphy; gas-liquid with chloroform 5 ng chromatography/thermionic detection or electron capture detection

Wheat plants gas chromatography/ suitable for determina- 0.02 mg/kg flame photometric tion of dimethoate and detection dimethoxon (omethoate) residues in field wheat plants

Plants colorimetry enzymatic pig liver 1 µg dimetho powder used as ChE source; more sensitive by converting into 50 ng ometho oxidation product

Fruits and gas-liquid chromato- extraction with methyl 0.02 mg/kg vegetables graphy/thermionic chloride detection

Fruits and colorimetry 250 g of sample; extrac- 5 µg (0.1 mg vegetables tion with chloroform

Asparagus gas chromatography extraction with 0.002 mg/kg nitrogen/phosphorus/ ethyl acetate (fresh weigh detection ------

Table 2. (contd). ------Sample type Method of detection Comments Detection li ------

Vegetables gas chromatography/ 25 g of sample; extrac- 0.008 mg/kg (snap bean) electron affinity tion with methylene detection chloride; oxygen analogue could not be detected at a 1:1 ratio; detectable at 10 parts oxygen to 1 part dimethoate

Food stuffs high-performance suitable for pesticide 0.3 mg/kg liquid mixtures; the method can chromatography also be used for air samples

Honey thin-layer chromato- extraction with hexane 0.1 mg/kg graphy and chloroform

Honey, nectar, gas chromatography/ extraction with benzene 0.1 ng in ne and pollen flame photometric 0.5 ng in po samples detection

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Milk gas chromatography/ samples heated at 60 °C 0.001 mg/kg flame photometric in water bath for 20 min detection to facilitate precipi- tation; extraction with methylene chloride

Animal tissues thin-layer chromato- dimethoate and dimethoxon graphy (omethoate) can be detected 25 days after death of the animal

Skin and respir- gas chromatography/ suitable for field 0.01 µg/samp ator pads flame photometric studies; pads placed in detection individual 30-ml glass bottles, each containing 10 ml benzene

Technical gas-liquid chromato- - - material and graphy/flame ionization formalizations detection ------3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

3.1. Natural Occurrence

Dimethoate does not occur as a natural product.

3.2. Man-made Sources

3.2.1. Industrial production

Dimethoate was first described by Hoegberg & Cassaday (1951) and was introduced on the market in 1956.

3.2.2. World production figures

Dimethoate is manufactured in many countries, but data on the world production of dimethoate are not available.

3.2.3. Uses

Dimethoate formulations are widely used as contact and systemic insecticides against a broad range of insects and mites and is applied at 0.3-0.7 kg active ingredient/ha on numerous crops: fruits (apples, citrus, bananas, mangoes), vegetables (beans, broccoli, cabbage, cauliflower, pepper, potatoes, spinach, tomatoes), wheat, alfalfa, cotton, tobacco, ornamentals, olives, sunflower, and others (Worthing & Walker, 1983).

Dimethoate is also used for the indoor control of house- flies. For residual treatment, 10-25 g/litre formulations are used (0.046-0.5 g active ingredient/m2) (WHO, 1984). The dose of dimethoate for outdoor fly control is 224 g active ingredient/ha (WHO, 1984).

Dimethoate is also applied as a systemic insecticide for control of cattle grubs (Worthing & Walker, 1983).

The oxygen analogue of dimethoate, dimethoxon, is also used as insecticide and is known under the common name of omethoate.

Formulations of dimethoate include emulsifiable concen-

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trates, wettable powders, and granules. There is also a formulation for ultra low volume application.

4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

4.1. Transport and Distribution Between Media

4.1.1. Air

Air concentrations of dimethoate were measured under hot climatic conditions at a distance of 300 m from a sprayed area. Concentrations on the day of spraying ranged from 0.061 to 0.142 mg/m3, but decreased during the next 4 days to 0.004-0.014 mg/m3. At a distance of 1500 m, dimethoate was not detected on either the day of treatment or during the days that followed (Madzhidov, 1970).

Dimethoate is an intermediate product in the hydrolysis of the pesticide formothion (Melnikov et al., 1977; Bolotnyi et al., 1978). After use, formothion is found in the air the day of spraying and dimethoate during the following days up to the 10th day.

In moist air, dimethoate is degraded photochemically to hydrolytic and oxidation products (Melnikov et al., 1977).

4.1.2. Water

Aqueous solutions of dimethoate are fairly stable. The compound is rapidly hydrolysed in alkali (pH 11): about 50-57% of dimethoate degrades to water-soluble material in ´ h, 68% in 1 h, and 87% in 2 h. The predominant degradation product is desmethyl dimethoate (49.3%) (Brady & Arthur, 1963). Hydrolysis is catalyzed by heavy metal ions, such as Cu++, Fe+++, and Mn++ (Sanderson & Edson, 1964).

The degradation pathways of dimethoate in air and water under environmental conditions are presented in Fig. 1.

4.1.3. Soil

The half-life of dimethoate after application at approximately 1 kg/ha in sandy loam soil, was approximately 4 days during drought conditions and 2.5 days after moderate rainfall (Bohn, 1964). Following 3 applications, dimethoate did not leach more than 7.5 cm below the surface of the soil.

Getzin & Rosefield (1968) studied the persistence of dimethoate in non-sterile, autoclaved, and gamma-radiation- sterilized Orissa soils. Two weeks after application, the degradation of dimethoate was 18% in the autoclaved soil, 20% in irradiated soil, and 77% in non-sterile soil. The half-life of dimethoate ranged from approximately 9 to 11 days under non- sterile conditions and from 16 to 18 days under sterile conditions (Sahu & Pattanaik, 1980).

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Different factors may affect the accumulation and degradation of dimethoate in soil, such as the soil type, the numbers and type of microorganisms present in soil, the environmental temperature, the pH level, the amount of pesticide applied, and the degree of evaporation (El Beit et al., 1977a,b, 1978). The persistence of dimethoate was greater in heavy than in light soil. At pH 4.2, the pesticide was stable for nearly 19 days; at pH 11, it degraded within 20 h. The amount of dimethoate in soil increased when higher concentrations were applied. El Beit et al. (1977a) reported that soil microorganisms played little part in the degradation of dimethoate.

4.1.4. Plants

When applied to plants, dimethoate was rapidly absorbed and decomposed, both on the surface and within the plant, by hydrolysis and oxidation (Menzie, 1969; Melnikov et al., 1977). The half-life of dimethoate in the different plants varied between 2-5 days (Melnikov et al., 1977). Dimethoate completely disappeared after 15-30 days, depending on the plant species and the climatic conditions. Decomposition in plants and the hydrolysis of dimethoate increased with temperature (Atabaev, 1972).

The dissipation of dislodgeable residues of dimethoate is best characterized by two first-order kinetic processes. The half-life values were 2.2 days in the 1 to 10-day period and 7.0 days in the 10 to 49-day period (Hadjidemetriou et al., 1985).

4.1.5. Disposal of wastes

Hydrolytic decomposition is the main way to inactivate dimethoate. By adding lime (1-2 kg calcium oxide/m3 water) to waste waters from agricultural centres, dimethoate was fully inactivated in 45 min (Winkler & Muller, 1979).

During pyrolysis, approximately 50% decomposition of dimethoate occurred at 500 °C with the formation of O,O-dimethyl-

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S,S-dithionpyrophosphate; decomposition was complete at 1100 °C (Rosvaga, 1983).

5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

5.1. Environmental Levels

5.1.1. Air, water, and soil

No studies have been reported on levels in air, water, or soil under actual conditions of use and various environmental conditions.

5.1.2. Food

When a combination of dimethoate and omethoate (dimethoxon) was given to cows in dosages of 1 and 0.1 mg/kg body weight, respectively, for 14 days, only residues of the metabolite omethoate were observed in the milk (0.004-0.125 mg/kg). Three days after the application, neither compound could be detected. When dosages of 0.5 mg dimethoate/kg and 0.05 mg omethoate/kg were given for 14 days or when corn silage containing 1-7 mg dimethoate/kg (resulting in dosages of 0.06-0.36 mg/kg body weight) was given for 28 or 42 days, no residues were detected in the milk (Beck et al., 1968).

Harvest residues found in many crops 1-3 weeks after spraying with dimethoate, during the first years of application in the United Kingdom (1957-58), were below 2 mg/kg (Chilwell & Beecham, 1960).

The dimethoate content of apples was 0.03-0.07 mg/kg, 75 days after an application of 0.72 kg active ingredient/ha (Atabaev & Stepovaya, 1966).

The pulp of lemon and orange fruit treated with dimethoate did not show any residues at a detection level of 0.01 mg/kg, 60 days after application (Iwata et al., 1979).

Residues of dimethoate do not concentrate in wine. Analysis of seven different Californian wines indicated levels of less than 0.03 mg/litre (Kawar et al., 1979).

No residues were found in grapes, 29 days after treatment with 0.1-0.15% dimethoate applied at the rate of 1400 litre/2 ha (Grigorashvili & Dzhibladze, 1965).

A number of studies on residues of dimethoate found through- out the world have been reported in a review by De Pietri- Tonelli et al. (1965). The residues were most frequently below 1 mg/kg. Dimethoate residues found in various agricultural products in India are reported in Khan & Bhaskar Dev (1982).

Dimethoate was not found in total-diet samples studied in England and Wales during 1966-67 (Abbott et al., 1970). According to other authors, dimethoate was also not found in the total diets of adults and infants during 1975-79 (Johnson et al., 1981a,b, 1984a,b; Podrebarac, 1984a,b; Gartrell et al., 1985a,b,c). Market-basket surveys carried out in 1976-78 in the Netherlands showed only omethoate residues in a small number of fruits (De Vos et al., 1984). In the USA, dimethoate and omethoate have been identified in about 5% of samples of fruits and vegetables (Duggan et al., 1983).

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The use of additional procedures for the determination of organophosphates resulted in the identification of dimethoate in adult and infant total-diet samples in 1980-82 (Gartrell et al., 1985d, 1986a,b). However, the intakes (0.001 µg/kg body weight per day) were far below the FAO/WHO acceptable daily intake (ADI) (see section 12).

5.2. Occupational Exposure

Immediately after the use of dimethoate in greenhouses, Stroy (1983) determined levels of 0.01-0.42 mg/m3 in the air, 3.6-9.3 mg/kg in the plants, and 0.98-1.75 mg/kg in the soil.

Dimethoate content in greenhouse air has been analysed at different times after spraying; at 0 time the measured amount was 0.66 mg/m3, at 2.5 h it was 0.38 mg/m3, at 5 h dimethoate content was 0.21 mg/m3, at 10 h it was 0.07 mg/m3 and at 20 h it was 0.01/m3 (Zolotnikova & Zotov, 1978).

The exposure to dimethoate of tractor drivers using airblast units during treatment of citrus trees was investigated by Carman et al. (1982). Dermal exposure was measured by placing ethyleneglycol-treated gauze patches on the shoulders, upper arms, and knees of the drivers. An emulsifiable concentration (EC) formulation of dimethoate containing 0.009 kg/litre was applied at the rate of 16 822 litre/ha using an open tractor, a cab unit with both side windows open, and a cab unit with the windows closed. Under these conditions, the patches attached to the driver absorbed mean deposits of 2.5, 1.5, and < 0.01 µg dimethoate/cm2 per h, respectively. The corresponding average air concentrations were 10(sic), 48, and 2 µg of dimethoate/m3.

Procedures for determining foliar residues and to establish the safe re-entry times for some insecticides were reported by Knaak (1980) and Knaak et al. (1980). A safe level of dimethoate on foliage of 53 µg/cm2 was calculated using the results of dermal-dose ChE-response studies in male rats.

Minimum safe re-entry periods for dimethoate were estimated to be 3 days in greenhouses, and 7 days in tobacco fields, after application by tractor, or 5 days after application by plane (Kaloyanova-Simeonova & Izmirova-Mosheva, 1983). No ChE inhibition in serum or subjective complaints of workers picking dimethoate-treated tobacco leaves were established at a concentration of 1 mg/kg on the surface of the plant.

Copplestone et al. (1976) studied the exposure to dimethoate of 8 spraymen, 1 mixer, and 2 supervisors in the Sudan. The percentage of toxic dosea received per day, calculated on the basis of a 4-h working day, varied from 0.02% to less than 0.001% for individual spraymen. No ChE depression was found in any of the men.

The highest concentration of dimethoate, measured in the work-place air of a dimethoate-producing factory in Italy, was 0.050 mg/m3 (Armeli et al., 1967).

The respiratory and dermal exposure to dimethoate of applicators was determined for greenhouse workers. The respiratory and dermal exposures were 0.034 mg/h and 30 mg/h, respectively. The hands of the operators were the most affected parts of the body, accounting for 63-92% of the total exposure

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(Adamis et al., 1985).

------a Percentage toxic dose per day or h (WHO, 1982). This is calculated from these indices adapted from the method of Durham & Wolfe (1962) using the formula:

Dermal exposure (mg/day or h) + respiratory exposure (mg/day or h) x 10 if measured ------x 100 Dermal LD50 mg/kg (rat) x 70

6. KINETICS AND METABOLISM

6.1. Absorption and Distribution

Panshina & Klisenko (1962) checked the blood levels of dimethoate in cats and rats after single oral doses of 50, 75, or 200 mg/kg in the cat and 300 mg/kg in the rat. The determinations were carried out 15, 30, 60, 90, 120, and 180 min after dosing. Dimethoate was detected in the blood of cats and rats after 30 min, and reached a maximum level after 60-90 min. Nearly 80% of the dimethoate in the blood was found in the erythrocytes; only 15-20% was found in the serum. With repeated daily oral intake of dimethoate at doses of 20 mg/kg or 10 mg/kg, the maximum blood level occurred on the 5-10th day of the study.

The same pattern in blood levels was observed with repeated inhalation of dimethoate for 4 h/day over 3 months, at a mean concentration of 5 mg/m3 air. Dimethoate was detected in blood from the second day and reached its maximum by the 7-10th day.

Daily application of 50 mg dimethoate/kg on the skin of rabbits resulted in a maximum concentration in the blood at about the third day (Kundiev, 1979).

When dimethoate was applied to the skin of rats for 1, 2, 4, 12, or 24 h in a single dose of 560 mg/kg, the maximum concentration in the skin was reached after 12 h of exposure and was correlated with the maximum inhibition of ChE activity in the serum and liver. The concentrations of dimethoate in the blood, liver, and kidney were maximal after 2 h of exposure (Baranova et al., 1986).

6.2. Metabolic Transformation

The ester and amide groups of dimethoate are cleaved in reactions that vary with the organism and that contribute to the selective toxicity of the compound.

The results of in vitro and in vivo studies showed that the

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main metabolic pathways of dimethoate were hydrolysis and oxidation (Hassan et al., 1969; Lucier & Menzer, 1970; North & Menzer, 1972).

Santi & Giacomelli (1962) studied the metabolic fate of dimethoate in olives. P=O derivative and degradation products, such as phosphoric and/or methylphosphoric acid, were found.

The presence of the oxygen analogue dimethoxon (omethoate) has been demonstrated in insects, plants, and mammals; it appears to be the metabolite responsible for the toxic action of dimethoate (Brady & Arthur, 1963; Hassan et al., 1969; Lucier & Menzer, 1970). The highest levels of this metabolite were found in insects, particularly in those highly susceptible to dimethoate. The oxygen analogue was produced in larger quantities in insects than in rats. The enzymes mediating the hydrolysis of the carboxyamide bond are much less effective in insects than in mammals (Mikhailov & Shterbak, 1983).

It has been shown that cleavage of dimethoate by rats and cows occurs initially at the C-N bond to produce the carboxy derivative (Dauterman et al., 1959; Hassan et al., 1969). A second hydrolytic pathway involves an esterase action on the S-C bond (Hassan et al., 1969).

Oxidative metabolism of dimethoate predominated over hydrolytic metabolism in the cell culture system. In the whole rat, the opposite was true. Metabolism of dimethoate in human embryonic lung cells was much the same as metabolism in rats (North & Menzer, 1972). In vitro and in vivo studies showed that dimethoate is biotransformed to the P=O analogue via the liver cytochrome P-450 system (Kaloyanova et al., 1984). Concentrations of 0.1-10 mmol dimethoate/litre led to a linear decrease in the rates of N-demethylation and P-hydroxylation. Similarly, in microsomes from rats treated with dimethoate in vivo, increased activity of desulfuration (140%, P < 0.01), and decreased activity of hydroxylation and demethylation were seen (Mitova et al., 1986).

In vivo studies on mice showed dimethoate toxicity to be markedly increased by phenobarbital pre-treatment, as a result of induction of hepatic microsomal enzymes including the mixed function oxidases responsible for the conversion of P=S to P=O (Menzer & Best, 1968).

It has been found that, while dimethoate undergoes rapid degradation in the rat liver, very little occurs in other tissues (lung, muscle, pancreas, brain, spleen, blood). The ability of the liver to degrade dimethoate in various species decreased in the order: rabbit > sheep > dog > rat > cattle > hen > guinea-pig > mouse > pig. For the hen, cattle, mouse, sheep, and rat there was a reasonably good straight-line relationship between the LD50 values and the degradation ability of the liver (Uchida et al., 1964).

After administration of 32P-dimethoate to rats, dimethoate, dimethoxon, dimethoate carboxylic acid, dimethylphosphoro- dithioate, dimethylphosphorothioate, dimethylphosphate, mono- methylphosphate, phosphorothioate, formate, and N-methyl 2- glucuronate acetamide were found in the urine (Hassan et al., 1969). Data on the metabolism of dimethoate in plants and animals have been reviewed by Menzie (1969, 1974, 1978, 1980).

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6.3. Elimination and Excretion

6.3.1. Animal studies

About 45% of the 32P-dimethoate administered orally at 50 mg/kg to rats was excreted in the urine, while only 5.8% was eliminated in the faeces, 72 h after treatment (Brady & Arthur, 1963). The values in rats after dermal application were 30.6% and 6.5%, respectively. More than 95% of the 32P materials in the urine and faeces after oral or dermal administration in rats were hydrolytic products, as determined by chloroform/water partition coefficients.

Twenty-four h after ip and oral administration of dimethoate to rats at doses of 0.25, 2.5, or 25 mg/kg, dimethylphosphoro- dithioate, dimethylphosphorothioate, and dimethyl phosphate were detected in the urine at concentrations of 12-14%, 11-15%, and 12-13%, respectively (Riemer et al., 1985). Neither the route of exposure nor the dose had any influence on the types of metabolite formed.

About 87-90% of an oral dose of 10 mg dimethoate/kg was eliminated in the urine of cattle at the end of 24 h. The same percentage of an intramuscular dose of 10 mg/kg was excreted after 9 h. Only 3.7-5% of the oral dose and about 1.1% of the intramuscular dose were eliminated in the faeces after 72 h and 24 h, respectively (Kaplanis et al., 1959).

6.3.2. Human studies

In human beings, 76-100% of radioactivity was reported to be excreted in the urine, 24 h after oral dosing with 32P- dimethoate (Sanderson & Edson, 1964).

7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT

7.1. Microorganisms

The addition of dimethoate to soil at 10 or 100 mg/kg did not result in significant differences in the number of bacteria solubilizing tricalcium phosphate or in the number of bacteria mineralizing calcium glycerophosphate, but an increase in the population of phospholipase-producing organisms solubilizing lecithin occurred (Congregado et al., 1979). At 10 mg/kg, an increase in carbon dioxide production occurred for 2 weeks after treatment, followed by a decrease to control levels. At 100 mg/kg, the increase in carbon dioxide output was slower and longer.

7.2. Aquatic Organisms

A number of LC50s have been determined for various aquatic organisms (Table 3).

The median tolerance limit of the fresh-water teleost, Channa punctatus for dimethoate is 20.5 mg/litre (Anees, 1975). Exposure for 24 h, 96 h, or 14 days to dimethoate concentrations of 10.8, 8.0, or 5.0 mg/litre, respectively, produced moderate vacuolation of the liver and a high degree of cytoplasmic granulation, which developed for up to 96 h of exposure. The 14-day exposure added little in the way of vacuolation or granulation (Anees, 1978a). The haematological response to dimethoate included reduced erythrocyte counts and haemoglobin

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concentration, and an elevated mean corpuscular haemoglobin and colour index indicating that the insecticide exerted an effect similar to the production of anaemia (Anees, 1978b).

The signs of the toxicity of dimethoate in fish (Channa punctatus) included jumping, erratic movement, imbalance, and death (Dikshith & Raizada, 1981a; Dikshith, 1986).

Verma et al. (1978) determined the TLm values of dimethoate for Channa gachua for 24, 48, 72, or 96 h to be 5.2, 5.0, 4.6, or 4.5 mg/litre, respectively. The safe concentration of dimethoate calculated on the basis of TLm values was approximately 1.4 mg/litre.

Dimethoate inhibited AChE activity in the brain, liver, and muscle of some fresh-water teleosts (Channa gachua and Cirrhina mrigala), exposed to sublethal concentrations of 35% EC formulation (0.9-2.4 and 0.6-1.6 mg/litre, respectively) (Verma et al., 1979).

Table 3. Summary of acute toxicity values for aquatic organisms ------Species LC50 (mg/litre) Refer 24-h 48-h 72-h 96-h ------Rainbow Trout 20 - - 8.5 (Salmo gairdneri)

Rainbow Trout - - - 6.2 (Salmo gairdneri)

Long-nosed killifish 1.0 - - (Fundulus similis)

Saccobranchus fossilis 5.14 4.80 4.67 4.57

Channa punctatus 68 54 - 47

Scud 0.9 0.4 - - (Gammarus lacustris)

Scud - - - 0.20 (Gammarus lacustris)

Red Crayfish - 1.0 - - (Procambarus clarkii)

Stonefly - 0.14 - - (Pteronarcys california)

Stonefly - - - 0.043 (Pteronarcys california)

Unspecified insect 0.51 - - -

Bluegill ------Dalela et al. (1979) reported that acute (5-h) and short- term (up to 32 days) exposure of the fish, Channa gachua, to dimethoate at 6.2 mg/litre and 1.5 mg/litre, respectively, produced histological changes in the gills. On acute exposure,

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there was erosion at the distal end of the gill filaments and loss of cell membrane. With exposure to a concentration of 1.5 mg/litre, the basement membrane started separating, and the damage to the gill was found to be more significant with increasing exposure time, with vacuolization occurring after 32 days.

The exposure of the fish Heteropneustes fossilis to a dimethoate concentration of 10 mg/litre led to an increased level of glycogen by the end of the second week in both the liver and the kidney, and to a slight decrease in the protein contents at the end of the eighth day (Awasthi et al., 1984). A sharp rise in the activity of succinate dehydrogenase in both organs was noted during the first two weeks of this study.

The estimated 48- and 72-hour TLm values for zebrafish Brachydanio rerio embryos, exposed to dimethoate, were 940 mg/litre and 259 mg/litre, respectively (Roales & Perlmutter, 1974). Dimethoate retarded the development of embryos as expressed by lack of heartbeat and little movement at 24 h.

Dimethoate at a concentration of 0.05 mg/litre produced morphological changes in the melanophores of Bufo melano- stictus tadpoles and an increase in pigmented areas of the skin (Pandey & Tomar, 1985).

Dimethoate had a very low toxicity for some aquatic organisms in Sudan, such as Oreochromis niloticus, Gambusia affinis, Pseudagrion spp., Crocothemis erythraea, and Lanistes carinatus. Under laboratory conditions, it did not kill any animal at concentrations lower than 80 mg/litre (Karim et al., 1985).

The toxicity of dimethoate for 11 freshwater species was studied by Slooff & Canton (1983). The results are summarized in Table 4. The relative susceptibility tests indicated that Daphnia magna was the organism most sensitive to dimethoate, while the microorganisms P.fluorescens, M.aeruginoso, and S.pannonicus were generally less sensitive indicators of toxicity. The susceptibility of aquatic species to a chemical may vary by more than two-three orders of magnitude. The data demonstrate that the sublethal criteria studied were not necessarily the most sensitive toxicological criteria.

7.3. Terrestrial Organisms

7.3.1. Honey-bees

The oral LD50 for the honey-bee (Apis mellifera L) ranges from 93 to 150 ng per bee (Jaycox, 1964; Lord et al., 1968; Stevenson, 1968; Barker et al., 1980). The contact LD50 is 98-120 ng per bee (Stevenson, 1968).

Table 4. Fresh-water species susceptibility to dimethoate ------Type of Test species Lifestage Exposure Test condition organism time Temper- Test (days) ature methods ------Bacteria (Pseudomonas fluorescens) log-phase 0.3 22 ± 2 Static

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Cyano Bluegreen bacteria log-phase 4 23 ± 2 Static bacteria (Microcystis aeruginosa)

Algae Green Algae log-phase 4 23 ± 2 Static (Scenedesmus pannonicus)

Plant Lemna minor - 7 25 ± 1 Static growth rate

Crustacean Water flea (Daphnia magna) 1 day 21 19 ± 1 Semi- static

Insect Mosquito (Culex pipiens) 1st 25 27 ± 1 Semi- instar static

Coelente- Hydrozoan (Hydra oligactis) budless 21 18 ± 1 Semi- rate static Mollusc Giant Pond Snail 5 months 40 20 ± 1 Semi- (Lymnaea stagnalis) static egg 7 20 ± 1 Semi- static

Fish Guppy (Poecilia Reticulata) 3-4 weeks 28 23 ± 1 Semi- Viviparous static

Fish Japanese Ricefish eggs 40 23 ± 2 Semi- (Oryzias latipes) oviviparous static

Amphibian Xenopus laevis 2 days 100 20 ± 1 Semi- static

------From: Slooff & Canton (1983).

Dimethoate was only slightly repellent to foraging honey- bees. The self-limiting dose for foraging was 20-25 times the lethal oral dose (2.9-3.9 µg/bee vs 150 ng/bee). This can be interpreted on the basis of 5% absorption by foraging bees, while 95% is passed on to the colony. Thus, systemic insecticide in nectar may also pose a threat to the rest of the colony when brought back to the hive (Waller et al., 1979).

Residual toxicity has been supported by several observations. Nectar from plants sprayed with 0.1% dimethoate was lethal for honey-bees for at least 2-3 days (Jaycox, 1964) or 10 days (Barker et al., 1980). Waller et al. (1984) also showed the possible toxic levels of residues in the nectar for up to 10 days after treatment of lemon trees with dimethoate at a rate of 1.12 kg of ai per ha. The high bee mortality observed, immediately after treatment, was attributed to dimethoate residues on the plant surface.

7.3.2. Birds

The acute toxicity studies of dimethoate for birds are summarized in Table 5.

a Table 5. Acute oral LD50 of dimethoate for birds (mg/kg) ------

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Species Sex Pure Laboratory Technical Liquid grade grade formulation ------Hen F 50 40 30 25

Pheasant M 15 - 20 15 20 25

Duck F - > 40 - -

Sparrow M/F - - - 22

Blackbird M/F - - - 26 ------a From: Sanderson & Edson (1964).

Hens did not show any evidence of delayed neurotoxicity (Sanderson & Edson, 1964; Gaines, 1969; Francis et al., 1985).

The effect of dimethoate on esterase levels following the oral dosing of pheasants and following long-term feeding to pheasants and pigeons was investigated by Bunyan et al. (1968, 1969). Dimethoate inhibited brain-alpha-naphthyl acetate esterase more than brain-cholinesterase and triacetin esterase in acute studies.

A characteristic of dimethoate was the elevation of phenyl benzoate esterase levels, showing that after initial liver damage, dimethoate is able to induce certain enzymes.

7.3.3. Farm animals

The acute oral LD50s for several farm animals are summarized in Table 6.

No visible signs of intoxication were seen in horses receiving dimethoate orally at doses of 25 or 50 mg/kg. Single doses of dimethoate at 40 mg/kg were effective in removing Gasterophilus spp. from infected horses, but toxic signs appeared in animals treated with higher levels of 60-80 mg/kg (Jackson et al., 1960).

Table 6. Acute oral LD50 for farm animals ------Species LD50 (mg/kg Reference body weight) ------Horse > 50 Jackson et al. (1960)

Sheep 80 Hewitt et al. (1958a,b)

Cattle 70 Hewitt et al. (1958a,b) ------

Mild signs of intoxication occurred in sheep at 75 mg/kg, including slight salivation, lachrymation, transitory diarrhoea, rhinitis, and anorexia. Doses lower than 15 mg/kg were essen- tially asymptomatic in calves. The data with dimethoate indicate an appreciable margin of safety between the lowest dose that kills first instar Hypoderma lineatum (5 mg/kg), and the doses that produce mild toxicity (15-20 mg/kg), or severe, reversible toxicity (40 mg/kg) (Hewitt et al., 1985b).

Fetcher (1984) described cases of suspected dimethoate intoxication in cattle grazing on pasture that had been sprayed

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6 weeks earlier. There was a predominance of nicotinic signs and a poor response to atropine treatment. Chemical analysis of liver, kidney, and brain tissue did not reveal any organophosphorus compounds or metabolites. Whole blood-ChE was depressed in 3 out of 14 animals.

After spraying barns (for calves) and pigsties with dimethoate, only 16-29% of the initial concentration still persisted after 8 weeks. Nevertheless, the animals showed a decrease in ChE (Müller & Reinhold, 1973).

8. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS

A more complete treatise on the effects of organophosphorus insecticides, especially their short- and long-term effects on the nervous systems, can be found in the WHO Environmental Health Criteria document entitled EHC 63: Organophosphorus Insecticides, a General Introduction (WHO, 1986a).

8.1. Single Exposures

The acute oral and dermal LD50s of dimethoate for several animal species are summarized in Tables 7 and 8 (all LD50s are expressed as active ingredient).

Signs, characteristic of organophosphorus intoxication, were observed in the rat 0.5-2 h after oral administration of dimethoate (Sanderson & Edson, 1964). They included muscular fibrillation, salivation, lachrymation, urinary incontinence, diarrhoea, respiratory distress, prostration, gasping, coma, and death (WHO, 1986a).

Oral LD50 values for rats, which were measured in 13 studies, ranged from 150 to 680 mg/kg body weight. The purity and formulation of the compounds used were not stated in most of the reports. Oral LD50s were determined of 60-140 mg/kg body weight for mice, 200 mg/kg body weight for hamsters, 350-600 mg/kg body weight for guinea-pigs, 280-500 mg/kg body weight for rabbits, and 100 mg/kg body weight for cats. Administration of 100 mg/kg body weight to dogs did not result in mortality. The World Health Organization based its classification of dimethoate as moderately hazardous on an acute oral LD50 in the rat of 150 mg/kg body weight (WHO, 1986b).

The dermal LD50s for rats were found to range between 500 and 1150 mg/kg body weight, and were of about the same order of magnitude as the oral LD50s or slightly higher (Table 8).

Data on LD50s after parenteral administration were given by Sanderson & Edson (1964). The values were comparable with those for ip, sc, and iv administration. In the rat, the values for ip administration varied between 175 and 325 mg/kg body weight and were also of the same order of magnitude as the oral LD50s.

The inhalation LC50 has not been estimated, but, in a 4-h inhalation study on rats, Panshina (1963b) did not find any signs of intoxication with exposure to dimethoate at 20 mg/m3 air, 40% cholinesterase inhibition at 10 mg/m3, and no effects at 2 mg/m3. Visible signs of intoxication were observed in cats at concentrations of 50-80 mg/m3. At 20 mg/m3, cholinesterase inhibition was found to be 10-66%, while at 2-8 mg/m3, it was 7-56%. No effects were seen at 1.5 mg/m3 (Panshina, 1963b).

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Table 7. Acute oral LD50 of dimethoate in experimental animals ------Species Sex Material tested LD50 (mg/kg Reference body weight) ------Rat M 32% emulsifiable 247 Edson & Noakes (1960) solution

Rat M/F technical 185 - 245 West et al. (1961)

Rat 230 Panshina (1963a)

Rat technical 172 Panshina (1963a)

Rat M/F pure 500 - 680 Sanderson & Edson (1964)

Rat M/F laboratory 280 - 356 Sanderson & Edson grade (1964)

Rat M/F technical 180 - 336 Sanderson & Edson (32-40% w/v) (1964)

Rat M/F liquid formul- 150 - 400 Sanderson & Edson ation (20% ai) (1964)

Rat M/F wettable powder 280 - 300 Sanderson & Edson (1964)

Rat pure 250 Atabaev & Stepovaya (1966)

Rat M/F produced 1962 215 - 245 Gaines (1969)a (43.5%)

Rat pure 200 - 300 Ben-Dyke et al. (1970)

Rat 250 - 265 Melnikov (1974)

Mouse 99% pure 140 Hewitt et al. (1958b)

Mouse pure 135 Panshina (1963a)

Mouse technical 125 Panshina (1963a)

Mouse F pure 60 Sanderson & Edson (1964)

------a Lower figures (20-30 mg/kg body weight) have been reported by the same author for a material produced in 1959.

Table 7. (contd). ------Species Sex Material tested LD50 (mg/kg Reference body weight) ------

Mouse F technical 60 Sanderson & Edson (1964)

Hamster M laboratory grade 200 Sanderson & Edson (1964)

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Guinea- M/F pure 550 Sanderson & Edson pig (1964)

Guinea- M/F laboratory grade 600 Sanderson & Edson pig (1964)

Guinea- M/F technical 350 - 400 Sanderson & Edson pig (1964)

Guinea- M/F liquid formul- 350 - 370 Sanderson & Edson pig ation (1964)

Rabbit M/F pure 500 Sanderson & Edson (1964)

Rabbit M/F laboratory grade 450 Sanderson & Edson (1964)

Rabbit M/F technical 300 Sanderson & Edson (1964)

Rabbit M/F liquid formul- 283 Sanderson & Edson ation (1964)

Cat technical 100 Panshina (1963a) ------

8.2. Skin and Eye Irritation

A single dose of 300 mg technical dimethoate/kg body weight did not cause skin irritation in male and female rabbits (Dikshith & Raizada, 1981b).

In a study by West et al. (1961), dimethoate did not have any irritant effect on the rabbit eye after introduction of 10 mg of dry material into the conjunctival sac. However, in a personal communication (1986), the US EPA suggested that dimethoate had a slight irritant effect on the eye.

8.3. Repeated Exposures

The effects on experimental animals of repeated oral or inhalation exposure to dimethoate are summarized in Tables 9 and 10.

In the various studies, which ranged from 5 1/2-12 months in duration, inhibition of cholinesterase (ChE) in the erythrocytes was a more sensitive indicator of exposure to dimethoate than ChE inhibition in plasma. ChE activity in the brain was measured in one study only.

Table 8. Acute dermal LD50 of dimethoate in experimental animals ------Species Sex Material tested LD50 (mg/kg Reference body weight ------Rat M 32% emulsifiable 1120 Edson & Noakes (1960) solution

Rat liquid formula- 700 - 1150 Sanderson & Edson tion (24-h) (1964)

Rat wettable powder 500 (24-h) Sanderson & Edson

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(1964)

Rat M/F produced 1962 610 Gaines (1969)a

Rat M 32% w/v emulsifi- 770 - 1090 Noakes & Sanderson able solution (24-h) (1969)

Rat M 32% w/v emulsi- > 1100 (4-h) Noakes & Sanderson fiable solution (1969)

Guinea-pig liquid formula- 965 West et al. (1961) tion (46%)

Guinea-pig wettable powder 995 West et al. (1961) (25%)

Rabbit not specified 600 Melnikov (1974) ------a Lower figures (55-61 mg/kg body weight) have been reported by the same author for a material produced in 1959.

In a study by West et al. (1961), no effects were observed on ChE inhibition in rats administered dimethoate in the diet at 32 mg/kg. In their first study (12 months) on rats, Sanderson & Edson (1964) observed inhibition of ChE in erythrocytes at 50 mg/kg diet, but not at 10 mg/kg. In the second study (5 1/2 months), inhibition of ChE in erythrocytes was found at both 20 and 10 mg/kg, but not at 5 mg/kg. The studies of Atabaev (1972) did not show any inhibition of blood-ChE in rats administered a

40% formulation of dimethoate at 0.5-1 mg/kg body weight, corresponding to 0.2-0.4 mg dimethoate/kg body weight. From all available data on the rat, a dietary level of dimethoate of 5 mg/kg, corresponding to 0.25 mg/kg body weight, can be considered as the no-observed-adverse-effect level.

From limited studies on the dog (West et al., 1961), it can be concluded that a level of 10 mg dimethoate/kg diet, corresponding to 0.25 mg/kg body weight, does not result in ChE depression in erythrocytes.

ChE inhibition was not observed in an inhalation study in which rats were exposed for 14 h/day, over 3 months, to 0.01 mg dimethoate/m3 (measured concentration) (Kaloyanova et al., 1968).

Table 9. The effects on experimental animals of repeated exposure to dimethoate ------Species Purity Dose Duration Effects ------Rat technical 50, 100, or 200 35 days no mortality; no signs (95%) mg/kg diet of intoxication

Rat technical 2, 8,or 32 mg/kg 3 months no mortality; no ChE (95%) diet inhibition

Rat technical 15 mg/kg (oral) 6 months 100% inhibition of ChE in serum and erythrocytes; approximately 85% inhibition in brain

Rat technical 30 mg/kg (oral) 6 months death of 3 out of 5 animals

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Rat technical 60 mg/kg (oral) 6 months death of all animals

Rat (M) laboratory 10 mg/kg diet 12 months no inhibition of ChE in grade erythrocytes or plasma

Rat (M) laboratory 50 mg/kg diet 12 months marked inhibition of grade ChE in erythrocytes

Rat (M) laboratory 200 mg/kg diet 12 months marked toxic effects; grade reduced rate of weight gain; inhibition of approximately 70% and 100 ChE in plasma and eryth cytes, respectively

Rat laboratory 800 mg/kg diet 12 months severe toxic effects grade (1 week) (cholinergic effect: weakness, weight loss after a few days); the pesticide was withdrawn after one week; complet recovery in 10 - 14 day

Rat (M) technical 20 or 10 mg/kg 5 1/2 months 50 and 40% inhibition (weanling) diet of ChE in erythrocytes, respectively ------

Table 9. (contd). ------Species Purity Dose Duration Effects ------

Rat (M) technical 5 mg/kg diet 5 1/2 months no inhibition of ChE (weanling)

Rat 40% formula- 13 mg/kg body 4 months one rat died on the tion weight (oral) 35th day

Rat 40% formula- 50 mg/kg body 4 months 3 rats died on the 7th tion weight (oral) day, 2 died on the 8th day, and one died on th 70th day

Rat 40% formula- 0.5 - 1 mg/kg 6 months no effect on ChE tion (oral)

Rat 40% formula- 5 mg/kg body 6 months AChE inhibition in tion weight (oral) blood in the first 2 months (approximately 50%)

Dog technical 2 or 10 mg/kg 13 weeks no inhibition of ChE diet

Dog technical 50 mg/kg diet 13 weeks slight depression of ChE in erythrocytes

Cat technical 10 mg/kg body 3 months death in 2 out of 4 weight (oral) animals

Cat technical 20 mg/kg body 3 months death in 2 out of 3 weight (oral) animals

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Cat 40% formula- 0.5 - 1 mg/kg 3 months no effect on ChE tion body weight (oral)

Cat 40% formula- 2 mg/kg body 3 months reduced body weight in tion weight (oral) the first 2 months (16 - 32%); recovery at the third month ------

Table 10. Inhalation toxicity - repeated exposure ------Species Concentration Duration Effects (mg/m3) Daily exposure Number of (h) months ------Rat 2 ? 2 no visible signs of int ication; 26% inhibition AChE in blood at the en the study

Cat 1.5 ? 1.5 no visible signs of int cation; 40-72% inhibiti of AChE in blood at the of the study

Rat in a miniature greenhouse (0.6 m3; temperature no blood-ChE inhibition 21-30 °C); plants sprayed with 5 ml of 0.5% aqueous formulation in the course of 28 days

Rat and 4.50 8 3 inhibition of ChE; leuk guinea-pig ocytosis

Rat 0.05 14 3 inhibition of ChE in bl only in the first month inhibition of brain- an liver-AChE; morphologic alterations in the neur

Rat 0.01 14 3 no changes observed

Rat 0.495 24 3 inhibition of ChE and changes

Rat 0.049 24 3 inhibition of ChE

Rat 0.003 24 3 no detectable changes

------8.4. Reproduction Studies

One reproduction study on mice has been reported in the literature (Budreau & Singh, 1973). In this 5-generation study, initial groups of 14 female and 10 male mice received dimethoate in the drinking-water at 60 mg/litre for a period of one month, prior to mating. A comparable control group was included in the study. Animals receiving dimethoate showed a significant ( P < 0.05) reduction in mating performance (expressed as pro- portion of females with deliveries to females mated), which ranged from 33 to 61%, varying with litter and generation. Similarly, reproduction time (measured as number of days elaps-

Page 27 of 58 Dimethoate (EHC 90, 1989)

ing from first day of mating to day of delivery) was significantly ( P < 0.01) increased in all first litters of all 5 generations examined, but unaffected in all second litters. The biological relevance of this observation is unclear. Litter size and average weight at birth were not affected by treatment. Although the mean weights of treated pups were not significantly lower, the growth rate was consistently lower in treated pups compared with that in the controls.

A 3-generation reproduction study using technical dimethoate (98.3%) was carried out on mice. Information sup- plied by the US EPA indicated that there were no effects on reproduction and teratogenicity at a dimethoate level of 50 mg/kg (US EPA, personal communication, 1986). Details of this study were not available.

8.5. Teratogenicitya

Intraperitoneal administration of 40 mg dimethoate/kg body weight, given as a single dose on the day of mating or on the 9th day of gestation, or given for the first 14 days of gestation in mice, caused a high incidence of embryonal loss (Scheufler, 1975).

Cygon 4E (containing 47.3% dimethoate) was given to female rats by intubation from the 6th to the 15th day of gestation at dose levels of 3, 6, 12, or 24 mg/kg body weight. The 24 mg/kg dose was toxic for the dams (8 out of 20 dams manifested clonic spasms and muscular tremors during the treatment period, 7 recovered, and one died on the 16th day of pregnancy). Doses of 12 and 24 mg/kg were associated with an increase ( P < 0.05) in the numbers of anomalous litters (each having at least one anomalous fetus) and wavy-ribbed fetuses. The 3 and 6 mg/kg doses (equal to 1.42-2.84 mg dimethoate/kg) did not produce any evidence of teratogenicity or embryotoxicity in the rats (Khera et al., 1979).

------a A further teratogenicity study on the rat (Edwards et al., 1984) was submitted to the FAO/WHO Joint Meeting on Pesti- cide Residues (JMPR) in 1987. Although fetotoxicity was observed, there were no teratogenic effects (FAO/WHO, 1987).

Cygon 4E (47.3% dimethoate) was given to cats in gelatin capsules at doses of 3, 6, or 12 mg/kg on the 14th-22nd days of pregnancy. At the levels tested, the compound did not produce any effects on the incidence of pregnancy. In the 12 mg/kg group, forepaw polydactily was observed in 8 out of 39 fetuses. Cygon 4E at 3 or 6 mg/kg (1.42-2.84 mg dimethoate/kg) did not produce any effects (Khera, 1979). (The effect observed in Khera's investigations may be due to the other components in the formulation).

Courtney et al. (1985) reported that dimethoate administered orally was not teratogenic in CD-1 mice at dose levels of 10 or 20 mg/kg body weight, and that these levels were not lethal to the dams. The two highest dose levels of 40 and 80 mg/kg produced maternal toxicity.

8.6. Mutagenicity

A variety of in vivo and in vitro mutagenicity tests have been carried out with dimethoate, the results of which are given in Table 11.

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Negative mutagenicity results were reported by Degraeve et al. (1984) for commercial mixtures of insecticides containing dimethoate. Two formulations were tested: dimethoate + fenitrothion (dose 60 mg/kg body weight, corresponding to 9 mg/kg of each) and dimethoate + malathion + methoxychlor (dose 100 mg/kg body weight corresponding to 9.5 mg dimethoate/kg). A single ip injection did not induce chromosome aberrations in bone marrow cells, spermatogonia, or primary spermatocytes of the mouse. No significant increases in pre- or post-implantation fetal lethality were observed in a dominant lethal mutation assay.

Alkylation by dimethoate at the N-7 position of guanine in DNA has been investigated (Dedek et al., 1984). Male mice (strain AB Jena/Halle, random bred) were injected ip with 14C- methyl-labelled dimethoate at a dose of 0.35 mmol/kg. The extent of methylation was in the range of 1-10 µmol N- 7 methylguanine/mol guanine; the values in the kidneys were higher than those in the liver. The excretion half-life of N- 7 methylguanine was 23-160 h.

In summary, dimethoate has been found to be mutagenic in both in vitro and in vivo assays.a ------a After this statement was written, new well-performed negative mutagenicity studies were submitted to the FAO/WHO Joint Meeting on Pesticide Residues (JMPR) in 1987 including an in vitro mutation assay on Chinese hamster ovary cells (Johnson et al., 1985), a dominant lethal test in mice (Becker, 1985), a micronucleus test in mice (Sorg, 1985), and a metaphase analysis assay in rat bone marrow cells (San Sebastian, 1985). On the basis of these new studies and the published studies, the JMPR concluded that dimethoate is mutagenic in bacterial tests, but negative in mammalian cells and in vivo tests (FAO/WHO, 1987).

Table 11. Mutagenicity tests ------Tests Concentration of Results dimethoate used ------Escherichia coli 1 - 6.10-3 mmol 5-methyltryptophane resistan K-12/gal Rs mutation -positive

Escherichia coli Up to 5000 µg/plate positive WP2 hcr

Escherichia coli Minimum mutagenic positive WP2 & WP2uvrA- concentration 47 nmoles/ml

Salmonella typhimurium negative TA 98, 100, 1535, 1537, 1538

Salmonella typhimurium Up to 5000 µg/plate positive with and without TA 100 activation

Salmonella typhimurium Up to 5000 µg/plate negative TA 98, 1535, 1537, 1538

Salmonella typhimurium 5 - 200 µg/plate positive at all doses, mutag

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TA 100 (base pair subst.) increased with liver microsom

Saccharomyces cerevisiae 7 doses, 40 - 100 mmol induction of mitotic gene conversions

Schizosaccharomyces pombe 1.3 - 131 mmol negative ade 6 (LD50 50 mmol)

Chinese hamster ovary 20,40 & 80 µg/ml sister chromatid exchange inc cells V79 10 µg/ml negative

Rat hepatocytes culture 47 nmol/ml negative unscheduled

SV-40 transformed human 100 & 1000 umol positive unscheduled DNA synthesis

Drosophila melanogaster 1 mg/kg (feeding) negative

------

Table 11. (contd). ------Tests Concentration of Results dimethoate used ------Drosphila melanogaster adult inj. ip 0, 10, increase in sex-linked 20 mg/kg body weight recessive lethals at 10 mg/kg not at 20 mg/kg

Drosophila melanogaster adult feeding 0, negative 10 mg/kg; larval negative feeding 0, 20 mg/kg

Host-mediated assay mouse 3 equal oral doses positive - mutation factor of Salmonella typhimurium of 155 mg/kg 3.44 ( P < 0.05)

Dominant lethal mutation acute 10 mg/kg ip negative assay mice strain Q 7 weeks 0.6 mg/litre drinking-water, equivalent to 0.093 mg/kg body weight

Dominant lethal test 30 & 60 mg/kg body negative - AB Jena Halle mice 5 x 6 mg/kg body weight ip DBA mice 3 x 18 mg/kg body weight ip

Micronucleus test - 2 equal doses of a significant increase in mice - bone marrow 51.7 mg/litre drink- frequency of polychromatic ing-water at 24-h erythrocytes with micronuclei intervals -0.85% (controls 0.28%)

Chromosome abnormalities 50 and 100 mg/kg body positive mice - bone marrow weight

Mice - bone marrow 20 mg/kg body weight no abnormalities ip

Mice - bone marrow 60 mg/kg body weight increase in number of mitosis ip aberrations

Syrian golden hamsters 16, 32, 80, or increase in number of chromat

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Mesocricetus auratus 160 mg/kg body weight and chromosomal breaks ip single (no dose-response relationshi ------8.7. Carcinogenicity

Two carcinogenicity studies, reported by Gibel et al. (1973), are summarized below.

Rat: Groups of 40, 10-week-old Wistar rats were intubated with 0 (control), 5, 10, or 30 mg dimethoate/kg body weight (twice weekly) for the life span. The mean life spans were 743, 518, 511, and 627 days at 0, 5, 15, and 30 mg/kg body weight, respectively. No malignant tumours were observed in the 36 control animals. In test groups, malignant tumours occurred in 2/26, 3/25, and 4/20 rats, respectively, at the 3 dose levels. At 5 mg/kg body weight, a reticulosarcoma of the spleen with metastases and a malignant reticuloma were observed. At 15 mg/kg body weight, a sarcoma of the colon, a reticulosarcoma of the spleen (with pancreatic metastases) and a hepatocellular carcinoma occurred. At 30 mg/kg body weight, a liver fibrosarcoma, a malignant reticuloma and two reticulosarcomas of the spleen were noted. Three, 7, 5, and 2 benign tumours were noted, respectively, in the controls and at 5, 15, and 30 mg/kg body weight (Gibel et al., 1973).

Rat: Groups of 40, ten-week-old Wistar rats were injected im with 15 mg dimethoate/kg body weight (twice weekly) or with isotonic saline until spontaneous death occurred. The mean life spans were 711 and 570 days in the saline and dimethoate-treated animals, respectively. No malignant tumours occurred in the saline-treated group, but 4/35 animals developed benign tumours. In the dimethoate group, 6/30 rats had malignant tumours (a spleen reticulosarcoma, a spleen fibrosarcoma, an ovarian alveolar sarcoma, a liver hepatocellular carcinoma, a malignant reticuloma, and a soft tissue spindle-cell sarcoma) and 5/30 had benign tumours. The first malignant tumour (a splenic fibrosarcoma) was noted after 410 days (Gibel et al., 1973).

Dimethoate (technical grade, 90-100% pure) was given in the feed to Osborne Mendel rats and to B6C3F1 mice. Groups of 50 male and 50 female rats (10 animals in each control group) received "time-weighted average doses" of 155 or 310 mg/kg for male rats and 192 or 384 mg/kg for female rats. After 80 weeks, all groups received control diets, and the studies were concluded at week 114.

Groups of 50 male and 50 female B6C3F1 mice were given dimethoate in the diet at concentrations of 0 (10 "matched" controls), 250, or 500 mg/kg for 60-69 weeks (males) or for 80 weeks (females). The studies were ended after 94 weeks. Tremors and hyperexcitability were observed in exposed animals; rats and mice that survived to termination were generally in poor condition. Survival was reduced in the high-dose groups of rats. Several non-neoplastic lesions occurred more frequently in dimethoate-exposed animals. No increases in neoplasia were reported to be associated with dimethoate administration, for any of the organs or tissues examined histologically (NCI-1977).

These studies are not considered adequate to determine properly the presence or absence of a carcinogenic response, largely because of the shorter than usual duration of exposures, the poor condition of the animals, and changes in exposure concentrations.a

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8.8. Special Studies

The action of dimethoate on the immune system was studied in mice and rats by Tiefenbach & Lange (1980). A single dose of 75 mg dimethoate/kg (route not specified) decreased the lymphocyte count to 50% of the pre-exposure value and increased the neutrophile granulocytes. After 72 h, these changes returned to normal. A reduction in the thymus cortex with disrupted lymphocytes, and a reduction in the number of rosette- forming cells were observed.

When administered to rats at 5-30 mg/kg body weight orally or 15 mg/kg im, twice a week, until death, dimethoate caused hyperplasia in the bone marrow, mainly in granulocytopoiesis (Stieglitz et al., 1974). The authors interpreted the changes in the haematopoietic system of the rats as a direct haematological effect of dimethoate.

The effects of dimethoate on the heart were investigated in rabbits (Mahkambaeva, 1971), and guinea-pigs and rats (Nadmaiteni & Marosi, 1983). After oral administration of 150 mg dimethoate/kg to rabbits, the effects observed included bradycardia and increased atrio-ventricular and intraventricu- lar conductance, with complete recovery after 4-7 days. In rats and guinea-pigs, a dose-effect relationship was established for heart rate disturbances, and atrio-ventricular block. An electron-microscopic study of the myocard did not reveal any changes. The ip doses that were tested ranged from 500 to 1500 mg/kg body weight.

------a After the Task Group met, new well-performed long-term/ carcinogenicity studies in rats and mice were submitted to the FAO/WHO Joint Meeting on Pesticide Residues (JMPR) in 1987. No indication for carcinogenicity was found. In the mouse study, the lowest dose of 25 mg/kg produced decreased body weight, decreased cholinesterase activity in erythrocytes, and also slight extramedullary haematopoiesis in the spleen (Hellwig, 1986a). Administration of dimethoate to rats for 2 years (Hellwig, 1986b) also resulted in a decrease in body weight, decreased cholinesterase activity in erythrocytes and the brain, and slight anaemia. No effects were observed at 1 mg/kg (0.05 mg/kg body weight) (FAO/WHO, 1987).

In anaesthetized guinea-pigs treated with lethal doses of dimethoate, cardiac failure and serious ECG disturbances developed in the early phase of intoxication. The toxic cardiac phenomena appeared to be unrelated to the degree of cholinesterase inhibition, but were correlated with the myocardial dimethoate concentration. Cardiac failure and mortality were first observed at a level of about 110 µg/g, while a level of 221 µg/g resulted in death in all cases. The present investigation refers to the direct effect of dimethoate on the myocardium, independent of its anticholinesterase action (Marosi et al., 1985a,b).

8.9. Factors Modifying Toxicity

The acute toxicity of dimethoate was not affected by the dietary content of protein (Boyd & Muis, 1970). The oral LD50 was 147 mg/kg for male albino rats fed for 28 days from weaning on a diet containing 3.5% protein as casein and, in controls maintained on a diet containing 26% casein at 152 mg/kg. Other

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groups maintained on a diet that contained 24% protein from various plant and animal sources were apparently less susceptible to dimethoate (LD50, 358 mg/kg). Dimethoate was given to rats orally for 10 weeks at a dose of 10 mg/kg in diets containing 90, 160, or 240 g protein/kg (Gontzea & Gorcea, 1977). The high-protein (240 g) diet diminished the adverse effects of dimethoate on the growth of the rats and lessened its anticholinesterase activity in plasma, total blood, brain, and liver.

A marked increase in the toxicity of dimethoate was noted in male and female mice after pre-treatment with phenobarbital and with chlorinated hydrocarbons (DDT and dieldrin) (Menzer & Best, 1968; Menzer, 1970). The toxicity of dimethoate was increased from an ip LD50 of 198 mg/kg body weight to 58.5 mg/kg by pre-treatment of mice for 3 days with sodium phenobarbital.

Liquid formulations of technical dimethoate in the solvents, 2-methoxy- and 2-ethoxyethanol, showed increased toxicity after storage. After storage for 7 months in England and 9 months under tropical conditions, the oral LD50 for the rat decreased to 30-40 mg/kg and 15 mg/kg, respectively (from an initial 150-250 mg/kg). The most toxic conversion product was O,O-dialkyl S-(N-methylcarbamoylmethyl) phosphorothioate with an oral LD50 for the rat of 1 mg/kg (Casida & Sanderson, 1961).

8.10 Mechanisms of Toxicity; Mode of Action

The mode of action of organophosphorus insecticides is decribed in WHO (1986a). They act principally by inhibition of acetyl cholinesterase (AChE) at the cholinergic synapses.

Dimethoxon (omethoate), a metabolite of dimethoate, is 75-100 times more potent than dimethoate in inhibiting AChE, suggesting that this metabolite plays a dominant role in mammalian toxicity (Hassan et al., 1969). The LD50 of omethoate in rats is 25-28 mg/kg body weight (FAO/WHO, 1979); it is about 10 times more toxic than dimethoate.

9. EFFECTS ON MAN

9.1 General Population Exposure

9.1.1 Poisoning incidents

Cases of both accidental and suicidal poisoning have been reported with dimethoate. Hayes (1982) has reviewed the human toxicity and poisoning cases.

Nagler et al. (1980) described a case of attempted suicide of a 34-year-old female who ingested 10 g dimethoate. Half an hour after admission to the hospital, the serum-dimethoate level was 2340 mg/litre. Combined haemoperfusion and haemodialysis were applied and, after 18 h, dimethoate was no longer detected in the serum.

A severe case of poisoning after ingestion of approximately 20 g dimethoate was reported by Köppel et al. (1986). On admission, the 52-year-old man was comatose with unmeasurable pseudo-cholinesterase (< 200 U/litre). He had been admitted 2 h after ingestion and received, every 20 min, an injection of 20 mg atropine. Two haemoperfusions with activated charcoal and amberlite were performed, and atropine was given by infusion up to day 12. Twenty-five days after admission, he was discharged, fully recovered.

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De Reuck et al. (1979) presented a case of a patient who died on the 9th day after dimethoate poisoning with an atypical central neurological disorder. The neuropathological findings, which were similar to those observed in severe forms of Wernicke's encephalopathy, included severe haemorrhagic necrosis of the walls of the ventricles. The authors suggested that the increased level of acetylcholine in the brain had led to thiamine depletion in the regions of predilection of Wernicke's encephalopathy.

Many other cases of human dimethoate poisoning, some of which were fatal, have been reported, but the information given was insufficient (Molphy & Rathus, 1964; Masiak & Olajossy, 1973; François & Verbraeken, 1977; Demeter & Heyndrickx, 1978; Ebel & Karyofilis, 1978; Areekul et al., 1981; Wehran & Hammer, 1984; Bolgar et al., 1985; Le Blanc et al., 1986; Senanayake & Karalliedde, 1987).

On the basis of a number of cases, the oral lethal dose for human beings was estimated to be of the order of 50-500 mg/kg body weight (Gosselin et al., 1984).

Trinh van Bao et al. (1974) reported an increase in the frequency of breaks and stable chromosome aberrations in 2 patients who died after dimethoate intoxication.

Thirty firemen, exposed to dimethoate in the air as a result of an accident in a dimethoate-manufacturing plant, developed symptoms of intoxication (Larripa et al., 1979, 1983). Peripheral blood lymphocytes from 20 of these workers were examined for the frequency of sister chromatid exchanges, 2 months after the accident. The frequencies were 9.2 ± 0.2 for the exposed and 8.5 ± 0.2 for unexposed persons ( P < 0.05). Dicentric chromosomes and a low frequency of chromatid breaks were found in 2 exposed workers. It is not certain to what the firemen were exposed besides dimethoate.

9.1.2 Controlled human studies

The results of a number of studies in which human volunteers, without occupational exposure to organophosphates, were given dimethoate, are summarized in Table 12. From these studies it can be concluded that repeated doses of up to 0.2 mg/kg body weight did not inhibit cholinesterase activity in the blood.

9.2 Occupational Exposure

9.2.1 Poisoning incidents

One of the first cases of poisoning with dimethoate (Rogor) in agriculture was described by Muratore et al. (1960). A 28- year-old-farmer, who reportedly had worn protective rubber clothing and equipment, had sprayed olive trees with dimethoate the day before he was hospitalized. The man began to experience profound weakness, faintness, and somnolence, followed by attempts to vomit, chills, and profound prostration on the day he was hospitalized. His general condition was found to be serious; his pulse was weak, he exhibited pronounced myosis, vomited and sweated profusely, and had pronounced inhibition of cholinesterase activity. Treated with large doses of atropine (20 mg on day 2, 12 mg on day 3, and 5 mg until day 9), prednisone, analgesics, and penicillin, he recovered.

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A case of poisoning in a woman working in agriculture and exposed to dimethoate in the field, 2 days after spraying, was reported by Asatryan (1971). Within 3-3.5 h after beginning work, the woman noted an unpleasant odour recognized as dimethoate. She developed headache, dry cough, dyspnoea, nausea, vomiting and was admitted to hospital in a somnolent state with muscular fibrillations and an asthmatic component. After treatment with saline solution, glucose, caffeine, atropine, and insulin, the state of acute intoxication was overcome. Allergic symptoms were treated with dimedrol.

Contact allergy due to dimethoate was reported in a 53- year-old female. She had a positive skin test (Pambor & Bloch, 1985).

Table 12. Controlled human studies ------Number Sex Route of Dose/day Duration of Results of Admini- exposure subjects stration ------20 oral 0.04 mg/kg 4 weeks absence of toxic effects or blood-ChE inhibition

2 oral 0.13 mg/kg; 21 days absence of blood-ChE 0.26 mg/kg inhibition

5 M oral 0.25 mg/kg single dose absence of toxic effects or ChE inhibition

50 dermal 32% liquid form- 2-h patch absence of skin irritation ulation, up to test and ChE inhibition 2.5 ml

12 M/F oral 5 mg (0.068 28 days no significant change in mg/kg body weight)

9 M/F oral 15 mg (0.202 39 days no significant change in mg/kg body weight)

8 M/F oral 30 mg (0.434 57 days inhibition of ChE by the mg/kg body weight)

6 oral 45 mg (0.587 45 days inhibition of ChE (35%) mg/kg body weight) 6 M/F oral 60 mg (1.02 14 days inhibition of ChE (21%) mg/kg body weight) ------Female greenhouse workers working with dimethoate were reported to have a high percentage of specific leukocyte agglomeration, a raised index of lymphoblastic transformations, and antibodies against dimethoate (Zolotnikova & Somov, 1978; Zolotnikova, 1980). With increasing duration of work, progress- ive sensitization towards the pesticide was observed.

On the basis of epidemiological observations and of dermal testing of workers with a 1-2% solution of dimethoate, Jung (1979) concluded that the index of sensitization was very low for dimethoate and that general intoxication might occur, but rarely contact eczema.

9.3 Early Symptoms and Treatment of Poisoning

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Initial symptoms of poisoning may include sweating, headache, weakness, giddiness, nausea, vomiting, stomach pains, blurred vision, slurred speech, and muscle twitching (WHO, 1986a). Arrhythmias and cardiac failure have been reported (Kiss & Fazekas, 1983; Marosi et al., 1985a,b; Duval et al., 1986). The most important diagnostic finding is inhibition of blood-cholinesterase activity. For a full discussion of the clinical picture and treatment of organophosphate insecticide poisoning, see WHO (1986a). The section on treatment is presented in the annex to this publication.

In all cases of clinical poisoning with dimethoate and other organophosphorus insecticides, it is essential to maintain general surveillance and cholinesterase and cardiac monitoring for at least 4 days, and longer if necessary, and to adapt general supportive and specific therapy in accordance with the findings.

Data on the effects of oxime reactivators in dimethoate poisoning are contradictory, some indicating that they may have a negative effect on cholinesterase inhibition (Sanderson & Edson, 1959; Durham & Hayes, 1962; Molphy & Rathus, 1964; Erdmann et al., 1966; Zech et al., 1966; Ebel & Karyofilis, 1978; Sterri et al., 1979). It is therefore suggested, that if oxime reactivators are indicated, these should be used with caution and under close supervision.

Haemoperfusion may be effective in the early stages of dimethoate poisoning (Okonek 1976, 1977; Okonek et al., 1976; Pach et al., 1977; Nagler et al., 1980).

10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT

10.1. Toxicity of Dimethoate

Dimethoate is moderately toxic. Most oral LD50s in the rat ranged from 150-400 mg/kg body weight. The dermal LD50 in the rat was greater than 600 mg/kg body weight. Dimethoate is not irritating to the skin, but may be slightly irritating to the eye.

It can be absorbed following ingestion, inhalation, and skin contact. It is readily metabolized and excreted and does not accumulate in the body. Dimethoxon (omethoate), the oxygen analogue found in plants, insects, and mammals, is about 10 times more toxic and is a more potent inhibitor of cholinesterase activity than dimethoate.

Signs of intoxication from exposure to dimethoate are those typical of organophosphorus pesticides. Inhibition of erythrocyte-cholinesterase is the most sensitive indicator of exposure to dimethoate and may indicate toxicity. A dietary level of 5 mg dimethoate/kg, equivalent to 0.25 mg/kg body weight, is considered to be a no-observed-adverse-effect level in the rat.a

A 5-generation reproduction study in mice given drinking- water containing dimethoate at 60 mg/litre resulted in decreased mating success and increased reproduction time in all generations. On the basis of available data on experimental animals, dimethoate is not considered to be a teratogen.

Dimethoate is considered mutagenic in a variety of in vitro

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and in vivo test systems.b Long-term studies have been conducted involving oral administration in rats and mice and im injection in rats. However, the available data are considered

------a FAO/WHO (1987) concluded that a dietary level of 1 mg/kg, equivalent to 0.05 mg/kg body weight is the no-observed- adverse-effect level in the rat. b After this statement was written, new well-performed negative mutagenicity studies were submitted to the FAO/WHO Joint Meeting on Pesticide Residues (JMPR) in 1987 including an in vitro mutation assay on Chinese hamster ovary cells (Johnson et al., 1985), a dominant lethal test in mice (Becker, 1985), a micronucleus test in mice (Sorg, 1985), and a metaphase analysis assay in rat bone marrow cells (San Sebastian, 1985). On the basis of these new studies and the published studies, the JMPR concluded that dimethoate is mutagenic in bacterial tests, but negative in mammalian cells and in vivo tests (FAO/WHO, 1987). to be inadequate to assess the carcinogenic potential of dimethoate.c

10.2. Human Exposure

Air and water are negligible sources of exposure to dimethoate for the general population. Residues found in food are generally below the acceptable daily intake (ADI) set by the FAO/WHO Joint Meeting on Pesticide Residues (JMPR) (See section 12).

Whole blood-cholinesterase was not inhibited in human volunteers given oral doses of 0.2 mg dimethoate/kg body weight for 39 days.

Several cases of suicidal or accidental poisoning due to ingestion of dimethoate have been reported.

Occupational exposure to dimethoate, principally through inhalation and the skin, may occur during its manufacture, formulation, and use, and cases of poisoning as a result of accident or neglect of safety precautions have been reported. The oral lethal dose for human beings has been estimated to be in the range of 50-500 mg/kg body weight.

Skin sensitization due to dimethoate has been observed in some cases.

10.3. Evaluation of the Effects on the Environment

Dimethoate is rapidly hydrolysed and does not persist in the environment. The toxicity of dimethoate for aquatic organisms and birds is moderate to high. It is very toxic for honey-bees.

------c After the Task Group met, new well-performed long-term/ carcinogenicity studies in rats and mice were submitted to the FAO/WHO Joint Meeting on Pesticide Residues (JMPR) in 1987. No indication for carcinogenicity was found. In the mouse study, the lowest dose of 25 mg/kg produced decreased body weight, decreased cholinesterase activity in erythro-

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cytes, and also slight extramedullary haematopoiesis in the spleen (Hellwig, 1986a). Administration of dimethoate to rats for 2 years (Hellwig, 1986b) also resulted in a decrease in body weight, decreased cholinesterase activity in erythrocytes and the brain, and slight anaemia. No effects were observed at 1 mg/kg (0.05 mg/kg body weight) (FAO/WHO, 1987).

10.4. Conclusions

1. Under proper conditions of use, exposure of the general population to dimethoate is negligible.

2. When appropriate safety precautions are observed, exposure to dimethoate during manufacture, formulation, use, and disposal should not pose an unacceptable human health hazard.

3. Dimethoate is rapidly degraded and not persistent in the environment. Care must be taken not to expose honey-bees, fish and aquatic organisms, and birds.

11. RECOMMENDATIONS

1. Figures relating to the current production and use of dimethoate should be made available.

2. Studies are necessary on dermal sensitization by dimethoate.

3 Data are required on the absorption and disposition of dimethoate from different routes of exposure.

4. Long-term toxicology and carcinogenicity studies should be carried out on laboratory animals.a

5. More research is required to investigate the in vivo mutagenic effects of dimethoate.a

6. Reproduction and teratology studies should be carried out.a

7. Epidemiological studies on persons engaged in the manufacture and professional use of dimethoate should be considered, and workers should be monitored for exposure to dimethoate and for potential adverse health effects.

8. Cleaning and disposal of contaminated equipment, clothing, and containers should be in accordance with recommended procedures.

9. Further work is necessary to establish safe re-entry periods under different conditions of use.

10. Acute toxicity studies should be carried out on formulations in which dimethoate is mixed with other active ingredients.

11. The role of oxime reactivators in the treatment of human poisoning by dimethoate, should be clarified.

12. Information should be obtained concerning the changes in toxicity, due to impurities, that can arise in pesticides as a consequence of different manufacturing processes, the

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use of formulating ingredients, and improper storage.

------a Several of these studies were later submitted to the FAO/WHO Joint Meeting on Pesticide Residues in 1987. See previous footnotes for sections 8.5, 8.6 and 8.7.

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

Dimethoate was evaluated by the Joint Meeting on Pesticide Residues (JMPR) in 1963, 1965, 1966, 1967, 1970, 1973 (evaluation of the related compound formothion), 1977, 1978, 1984, and 1987 (FAO/WHO, 1964, 1965, 1967, 1968, 1971, 1974, 1978, 1979, 1985, 1987).

The estimate of an acceptable daily intake (ADI) for man for dimethoate is 0-0.01 mg/kg body weight, based on the no- observed-adverse-effect level in man of 0.2 mg/kg body weight per day, and in the rat of 1 mg/kg diet, equivalent to 0.05 mg/kg body weight (FAO/WHO, 1987).

A data sheet on dimethoate has been issued by WHO in the series "Data Sheets on Pesticides" (WHO/FAO, 1980).

In the WHO Recommended Classification of Pesticides by Hazard, technical dimethoate is classified as moderately hazardous, when handled in accordance with instructions (WHO, 1986b).

The IRPTC (1982) has issued a review on dimethoate, in its series "Scientific Reviews of Soviet Literature on Toxicity and Hazards of Chemicals".

REFERENCES

ABBOTT, D.C., CRISP, S., TARRANT, K.R., & TATTON, J.O'G. (1970) Pesticide residues in the total diet in England and Wales, 1966- 67. III. Organophosphorus pesticide residues in the total diet. Pestic. Sci., 1: 10-13.

ABRAMOVA, J.I. & BOLTUSHKINA, L.A. (1968) [Safety action of several vitamins in poisoning with organophosphorus insecticides.] In: [Hygiene and toxicology of pesticides and the clinical picture of intoxications,] Vol. 6, Kiev, Zdorovye Publishers, pp. 448-452 (in Russian).

ADAMIS, Z., ANTAL, A., FUZESI, I., MOLNAR, J., NAGY, L., & SUSAN, M. (1985) Occupational exposure to organophosphorus insecticides and synthetic pyrethroids. Int. Arch. occup. environ. Health, 56: 299-305.

AHMED, F.E., HART, R.W., & LEWIS, N.J. (1977) Pesticide induced DNA damage and its repair in cultured human cells. Mutat. Res., 42: 161-174.

AKORONKO, S.L. & GIRENKO, D.B. (1977) [Methods of estimating fosfamid in soil using chromatographic methods.] In: [ Methods of determination of micro-quantities of pesticides in foods, feed, and the environment,] Moscow, Kolos, pp. 118-120 (in Russian).

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(1980) Reentry research: Establishment of safe pesticide levels on foliage. Bull. environ. Contam. Toxicol., 24: 796-804.

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SAHU, D. & PATTANAIK, M. (1980) Persistence of rogor in some Orissa soils. Indian J. agric. Sci., 50(6): 505-507.

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SANDERSON, D.M. & EDSON, E.F. (1964) Toxicological properties of the organophosphorus insecticide dimethoate. Br. J. ind. Med., 21: 52-64.

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SAN SEBASTIAN, J.R. (1985) In vivo bone marrow cytogenetics rat metaphase analysis. PH 315-AC-001-84, Dimethoate CL 12880. (Unpublished report dated 29 August 1985 from Pharmakon Research International, Inc. Waverly, Pennsylvania 18471).

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SENANAYAKE, N. & KARALLIEDE, W. (1987) Neurotoxic effects of organophosphorus insecticides. An intermediate syndrome. New Engl. J. Med., 316(13): 761-763.

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ANNEX I. TREATMENT OF ORGANOPHOSPHATE INSECTICIDE POISONING IN MAN (From EHC 63: Organophosphorus Insecticides - A General Introduction)

All cases of organophosphorus poisoning should be dealt with as an emergency and the patient sent to hospital as quickly as possible. Although symptoms may develop rapidly, delay in onset or a steady increase in severity may be seen up to 48 h after ingestion of some formulated organophosphorus insecticides.

Extensive descriptions of treatment of poisoning by organophosphorus insecticides are given in several major references (Kagan, 1977; Taylor, 1980; UK DHSS, 1983; Plestina, 1984) and will also be included in the IPCS Health and Safety Guides to be prepared for selected organophosphorus insecti-

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cides.

The treatment is based on:

(a) minimizing the absorption;

(b) general supportive treatment; and

I.1 Minimizing the Absorption

When dermal exposure occurs, decontamination procedures include removal of contaminated clothes and washing of the skin with alkaline soap or with a sodium bicarbonate solution. Particular care should be taken in cleaning the skin area where venupuncture is performed. Blood might be contaminated with direct-acting organophosphorus esters, and, therefore, inaccurate measurements of ChE inhibition might result. Extensive eye irrigation with water or saline should also be performed. In the case of ingestion, vomiting might be induced, if the patient is conscious, by the administration of ipecacuanha syrup (10-30 ml) followed by 200 ml water. This treatment is, however, contraindicated in the case of pesticides dissolved in hydrocarbon solvents. Gastric lavage (with addition of bicarbonate solution or activated charcoal) can also be performed, particularly in unconscious patients, taking care to prevent aspiration of fluids into the lungs (i.e., only after a tracheal tube has been placed).

The volume of fluid introduced into the stomach should be recorded and samples of gastric lavage frozen and stored for subsequent chemical analysis. If the formulation of the pesticide involved is available, it should also be stored for further analysis (i.e., detection of toxicologically relevant impurities). A purge to remove the ingested compound can be administered.

I.2 General Supportive Treatment

Artificial respiration (via a tracheal tube) should be started at the first sign of respiratory failure and maintained for as long as necessary.

Cautious administration of fluids is advised, as well as general supportive and symptomatic pharmacological treatment and absolute rest.

I.3 Specific Pharmacological Treatment

I.3.1 Atropine

Atropine should be given, beginning with 2 mg iv and given at 15 to 30-min intervals. The dose and the frequency of atropine treatment varies from case to case, but should maintain the patient fully atropinized (dilated pupils, dry mouth, skin flushing, etc.). Continuous infusion of atropine may be necessary in extreme cases and total daily doses up to several hundred mg may be necessary during the first few days of treatment.

I.3.2 Oxime reactivators

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Cholinesterase reactivators (e.g., pralidoxime, obidoxime) specifically restore AChE activity inhibited by organophosphates. This is not the case with enzymes inhibited by carbamates. The treatment should begin as soon as possible, because oximes are not effective on "aged" phosphorylated ChEs. However, if absorption, distribution, and metabolism are thought to be delayed for any reasons, oximes can be administered for several days after intoxication. Effective treatment with oximes reduces the required dose of atropine. Pralidoxime is the most widely available oxime. A dose of 1 g pralidoxime can be given either im or iv and repeated 2-3 times per day or, in extreme cases, more often. If possible, blood samples should be taken for AChE determinations before and during treatment. Skin should be carefully cleansed before sampling. Results of the assays should influence the decision whether to continue oxime therapy after the first 2 days.

There are indications that oxime therapy may possibly have beneficial effects on CNS-derived symptoms.

I.3.3 Diazepam

Diazepam should be included in the therapy of all but the mildest cases. Besides relieving anxiety, it appears to counteract some aspects of CNS-derived symptoms, which are not affected by atropine. Doses of 10 mg sc or iv are appropriate and may be repeated as required (Vale & Scott, 1974). Other centrally acting drugs and drugs that may depress respiration are not recommended in the absence of artificial respiration procedures.

I.3.4 Notes on the recommended treatment

I.3.4.1 Effects of atropine and oxime

The combined effect far exceeds the benefit of either drug singly.

I.3.4.2 Response to atropine

The response of the eye pupil may be unreliable in cases of organophosphorus poisoning. A flushed skin and drying of secretions are the best guide to the effectiveness of atropinization. Although repeated dosing may well be necessary, excessive doses at any one time may cause toxic side-effects. Pulse-rate should not exceed 120/min.

I.3.4.3 Persistence of treatment

Some organophosphorus pesticides are very lipophilic and may be taken into, and then released from, fat depots over a period of many days. It is therefore quite incorrect to abandon oxime treatment after 1-2 days on the supposition that all inhibited enzyme will be aged. Ecobichon et al. (1977) noted prompt improvement in both condition and blood-ChEs in response to pralidoxime given on the 11th-15th days after major symptoms of poisoning appeared due to extended exposure to fenitrothion (a dimethyl phosphate with a short half-life for aging of inhibited AChE).

I.3.4.4 Dosage of atropine and oxime

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The recommended doses above pertain to exposures, usually for an occupational setting, but, in the case of very severe exposure or massive ingestion (accidental or deliberate), the therapeutic doses may be extended considerably. Warriner et al. (1977) reported the case of a patient who drank a large quantity of dicrotophos, in error, while drunk. Therapeutic dosages were progressively increased up to 6 mg atropine iv every 15 min together with continuous iv infusion of pralidoxime chloride at 0.5 g/h for 72 h, from days 3 to 6 after intoxication. After considerable improvement, the patient relapsed and further aggressive therapy was given at a declining rate from days 10 to 16 (atropine) and to day 23 (oxime), respectively. In total, 92 g of pralidoxime chloride and 3912 mg of atropine were given and the patient was discharged on the thirty-third day with no apparent sequelae.

REFERENCES TO ANNEX I

ECOBICHON, D.J., OZERE, R.L., REID, E., & CROCKER, J.F.S (1977) Acute fenitrothion poisoning. Can. Med. Assoc. J., 116: 377- 379.

KAGAN, JU.S. (1977) [ Toxicology of organophosphorus pesticides,] Moscow, Meditsina, pp. 111-121, 219-233, 260-269 (in Russian).

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WARRINER, R.A., III, NIES, A.S., & HAYES, W.J., Jr (1977) Severe organophosphate poisoning complicated by alcohol and turpentine ingestion. Arch. environ. Health, 32: 203-205.

See Also: Toxicological Abbreviations Dimethoate (HSG 20, 1988) Dimethoate (ICSC) Dimethoate (FAO Meeting Report PL/1965/10/1) Dimethoate (FAO/PL:CP/15) Dimethoate (FAO/PL:1967/M/11/1) Dimethoate (JMPR Evaluations 2003 Part II Toxicological) Dimethoate (AGP:1970/M/12/1) Dimethoate (Pesticide residues in food: 1983 evaluations) Dimethoate (Pesticide residues in food: 1984 evaluations) Dimethoate (Pesticide residues in food: 1984 evaluations) Dimethoate (Pesticide residues in food: 1987 evaluations Part II Toxicolog Dimethoate (Pesticide residues in food: 1996 evaluations Part II Toxicolog

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