INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 178
METHOMYL
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.
First draft prepared Dr M.L. Lithchfield, Arundel, United Kingdom
Published under the joint sponsorship of the United Nations
Environment Programme, the International Labour Organisation, and the
World Health Organization
World Health Organization
Geneva, 1996
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WHO Library Cataloguing in Publication Data
Methomyl
(Environmental health criteria ; 178)
1.Methomyl - toxicity 2.Insecticides, Carbamate
I.Series
ISBN 92 4 157178 0 (NLM Classification: WA 240)
ISSN 0250-863X
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CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR METHOMYL
1. SUMMARY
1.1. Identity, physical and chemical properties, and analytical
methods
1.2. Sources of human and environmental exposure
1.3. Environmental transport, distribution and transformation
1.4. Environmental levels and human exposure
1.5. Kinetics and metabolism in laboratory animals
1.6. Effects on laboratory mammals and in vitro test systems
1.7. Effects on humans
1.8. Effects on non-target organisms in the laboratory and field
1.9. Evaluation of human health risks and effects on the
environment
1.10. Conclusion
2. IDENTITY PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL METHODS
2.1. Identity
2.2. Physical and chemical properties
2.3. Conversion factors
2.4. Analytical methods
2.4.1. Sample preparation
2.4.2. Analytical determination
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1. Natural occurrence
3.2. Anthropogenic sources
3.2.1. Production processes and levels
3.2.2. Uses
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION
4.1. Transport and distribution between media
4.1.1. Water
4.1.2. Soil
4.1.3. Vegetation
4.2. Transformation
4.2.1. Biodegradation
4.2.2. Abiotic degradation
4.2.3. Bioaccumulation
4.3. Interaction with other physical, chemical or biological
factors
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1. Environmental levels
5.1.1. Water
5.1.2. Soil
5.1.3. Food crops
5.1.4. Other crops
5.1.5. Dairy products
5.1.6. Animal feed
5.2. General population exposure
5.2.1. Food
5.3. Occupational exposure
6. KINETICS AND METABOLISM IN LABORATORY ANIMALS
6.1. Absorption
6.2. Distribution
6.3. Metabolic transformation
6.4. Elimination and excretion
6.5. Retention and turnover
6.6. Reaction with body components
7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS
7.1. Single exposure
7.2. Short-term exposure
7.3. Long-term exposure
7.4. Skin and eye irritation; sensitization
7.4.1. Skin irritation
7.4.2. Eye irritation
7.4.3. Skin sensitization
7.5. Reproductive toxicity, embryotoxicity and teratogenicity
7.5.1. Embryotoxicity and teratogenicity
7.5.2. Reproduction studies
7.6. Mutagenicity
7.7. Carcinogenicity
7.8. Other special studies
7.8.1. Cholinesterase studies in vivo and in vitro
7.8.2. Neurotoxicity
7.8.3. Potentiation studies
7.8.4. Antidote studies
7.8.5. Other studies
7.9. Factors modifying toxicity
7.10. Mechanisms of toxicity - mode of action
8. EFFECTS ON HUMANS
8.1. General population
8.1.1. Accidental and suicidal poisoning
8.2. Adverse effects of occupational exposure
9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD
9.1. Microorganisms
9.2. Aquatic organisms
9.2.1. Algae
9.2.2. Fish
9.2.3. Other aquatic organisms
9.3. Terrestrial organisms
9.3.1. Terrestrial invertebrates
9.3.2. Birds
9.4. Field studies
10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
10.1. Evaluation of human health risks
10.2. Evaluation of effects on the environment
11. CONCLUSIONS AND RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH
12. FURTHER RESEARCH
13. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
REFERENCES
RESUME
RESUMEN
NOTE TO READERS OF THE CRITERIA MONOGRAPHS
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This publication was made possible by grant number 5 U01 ES02617-15
from the National Institute of Environmental Health Sciences, National
Institutes of Health, USA, and by financial support from the European
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WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR METHOMYL
Members
Dr T. Bailey, US Environmental Protection Agency, Washington DC, USA
Dr A.L. Black, Dept. of Human Services and Health, Canberra, Australia
Mr D.J. Clegg, Carp, Ontario, Canada
Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood, Abbots
Ripton, Huntingdon, Cambridgeshire, United Kingdom (Vice-Chairman)
Dr P.E.T. Douben, Her Majesty's Inspectorate of Pollution, London,
United Kingdom
Dr P. Fenner-Crisp, US Environmental Protection Agency, Washington DC,
USA
Dr R. Hailey, National Institute of Environmental Health Sciences,
National Institutes of Health, Research Triangle Park, USA
Ms K. Hughes, Environmental Health Directorate, Health Canada, Ottawa,
Ontario, Canada
Dr D. Kanungo, Central Insecticides Laboratory, Government of India,
Ministry of Agriculture & Cooperation, Directorate of Plant
Protection, Quarantine & Storage, Faridabad, Haryana, India
Dr L. Landner, MFG, European Environmental Research Group Ltd,
Stockholm, Sweden
Dr M.H. Litchfield, Melrose Consultancy, Denmans Lane, Fontwell,
Arundel, West Sussex, United Kingdom (Rapporteur)
Professor M. Lotti, Institute of Occupational Medicine, University of
Padua, Padua, Italy (Chairman)
Professor D.R. Mattison, University of Pittsburgh, Graduate School of
Public Health, Pittsburgh, PA, USA
Dr Jun Sekizawa, National Institute of Health Sciences, Tokyo, Japan
Dr Palarp Sinhaseni, Chulalongkorn University, Bangkok, Thailand
Dr Salah A. Soliman, King Saud University, Bureidah, Saudi Arabia
Dr M. Tasheva, National Centre of Hygiene, Medical Ecology and
Nutrition, Sofia, Bulgaria
Mr J.R. Taylor, Pesticides Safety Directorate, Ministry of Agriculture
Fisheries and Food, York, United Kingdom
Dr H.M. Temmink, Wageningen Agricultural University, Wageningen, The
Netherlands
Dr M.I. Willems, TNO Nutrition and Food Research Institute, Zeist, The
Netherlands
Observers
Dr R. Gardiner, GIFAP, Brussels, Belgium (Representative of GIFAP)
Dr B. Julin, Du Pont de Nemours (Belgium), Brussels, Belgium
(Representative of GIFAP)
Dr S.M. Kennedy, Du Pont de Nemours (Belgium), Brussels, Belgium
(Representative of GIFAP)
Dr Ronald L. Mull, Du Pont Agricultural Products, Wilmington, DE,
United States of America (Representative of GIFAP)
Secretariat
Ms A. Sundén Byléhn, International Register of Potentially Toxic
Chemicals, United Nations Environment Programme, Châtelaine,
Switzerland
Dr P. Chamberlain, International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland
Dr J. Herrman, International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland
Dr K. Jager, International Programme on Chemical Safety, World Health
Organization, Geneva, Switzerland
Dr P. Jenkins, International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland
Dr W. Kreisel, International Programme on Chemical Safety,
World Health Organization, Geneva, Switzerland
Dr M. Mercier, International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland
Dr M.I. Mikheev, Occupational Health, World Health Organization,
Geneva, Switzerland
Dr G. Moy, Food Safety, World Health Organization, Geneva, Switzerland
Mr I. Obadia, International Labour Office, Geneva, Switzerland
Dr R. Plestina, International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland (Secretary)
Dr E. Smith, International Programme on Chemical Safety, World Health
Organization, Geneva, Switzerland
Mr J. Wilbourn, International Agency for Research on Cancer, Lyon,
France
ENVIRONMENTAL HEALTH CRITERIA FOR METHOMYL
The Core Assessment Group (CAG) of the Joint Meeting on Pesticides
(JMP) met in Geneva from 25 October to 3 November 1994. Dr W. Kreisel,
Executive Director, welcomed the participants on behalf of WHO, and
Dr M. Mercier, Director, IPCS on behalf of the three IPCS cooperating
organizations (UNEP/ILO/ WHO). The CAG reviewed and revised the draft
monograph and made an evaluation of the risks for human health and the
environment from exposure to methomyl.
The first draft of the monograph was prepared by
Dr M.L. Litchfield, Arundel, United Kingdom. Extensive scientific
comments were received following circulation of the first draft to the
IPCS contact points for Environmental Health Criteria monographs and
these comments were incorporated into the second draft by the
Secretariat.
The fact that E.I. Du Pont de Nemours and Co. made available to
IPCS and the Core Assessment Group proprietary toxicological
information on their products is gratefully acknowledged. This
allowed the Group to make its evaluation on a more complete data base.
Dr R. Plestina and Dr P.G. Jenkins, both members of the IPCS
Central Unit, were responsible for the overall scientific content and
technical editing, respectively. The efforts of all who helped in the
preparation and finalization of the monograph are gratefully
acknowledged.
ABBREVIATIONS
ADI Acceptable Daily Intake
ALC Approximate Lethal Concentration
CAS Chemical Abstracts Service
CCPR Codex Committee on Pesticide Residues
EbC50 median effective concentration for inhibition of growth
based on comparison of areas under the growth curves after
"b" hours
ECD electron capture detector
FID flame ionization detector
FSD flame photometric detector selective for sulfur
GC gas chromatography
GLC gas-liquid chromatography
GOT glutamic oxaloacetic transaminase
GPT glutamic pyruvic transaminase
HPLC high performance liquid chromatography
ISO International Organization for Standardization
IUPAC International Union of Pure and Applied Chemistry
JMPR Joint FAO/WHO Meeting on Pesticide Residues
Kow octanol/water partition coefficient
LC50 median lethal concentration
LD50 median lethal dose
MATC maximum acceptable toxicant concentration
MHTA S-methyl- N-hydroxythioacetimidate (a metabolite of
methomyl)
mPa millipascal (7.5 × 10-6 mmHg)
MRL maximum residue limit
NOEC no-observed-effect concentration
P2S N-methyl-pyridium-2-aldoxime methane-sulphonate
(antidote)
PAM pyridine-2-aldoxime methiodiode (antidote)
RTECS Registry of Toxic Effects of Chemical Substances
TEAC tetraethylammonium chloride
TOCP tri- o-cresyl phosphate
TOD total oxygen demand
UV ultraviolet
1. Summary
1.1 Identity, physical and chemical properties, and analytical
methods
Methomyl is a white crystalline solid with a melting point of
77°C and a vapour pressure of 0.72 mPa (25°C). Its solubility in
water is 54.7 g/litre and its octanol/water partition coefficient
(Kow) is 1.24. It is stable in sterile water at pH 7, but is broken
down at higher pH values, the half-life being 30 days at pH 9 and
25°C.
The analytical procedure for the determination of methomyl in
different samples is extraction followed by clean-up and analysis by
HPLC or GLC. In some cases methomyl is converted to its oxime
derivative or a fluorophore derivative (post-column) prior to
analytical determination.
1.2 Sources of human and environmental exposure
Methomyl is produced by reacting S-methyl N-hydroxythio-
acetimidate (MHTA) in methylene chloride with gaseous methyl
isocyanate at 30-50°C. It is a carbamate insecticide used on a wide
range of crops throughout the world. Crops protected include fruit,
vines, hops, vegetables, grain, soya bean, cotton and ornamentals.
Indoor uses include the control of flies in animal houses and dairies.
The main formulations are water soluble powders and water
miscible liquids, which are diluted with water for ground or aerial
spraying of crops. Typical active ingredient rates are 0.15 to
1.0 kg/ha. The main sources of human exposure are during the
preparation and application of these products and from the ingestion
of crop residues in foodstuffs (see section 5.3.1.4).
1.3 Environmental transport, distribution and transformation
In laboratory studies, methomyl adsorbs poorly to soil. Weak
adsorption to clay minerals, particularly illite, has been
demonstrated; adsorption to soil organic matter is 50 times greater
but still relatively weak. Hardly any desorption of bound residue is
seen. With these characteristics, methomyl would be expected to be
mobile in soil.
Under natural environmental conditions, abiotic degradation of
methomyl by hydrolysis or photolysis is slow or absent.
Aerobic degradation in soil is about twice as fast as anaerobic
degradation. Reported half-lives of methomyl in soil vary from a few
days to more than 50 days; dry conditions delay breakdown. In
practice in the field most applications should lead to a half-life of
around one week.
In field conditions, methomyl does not leach to levels below 20
to 30 cm into the soil and does not contaminate ground water.
When 14C-methomyl is applied to plant leaves it is absorbed but
not translocated to other parts of the plant. When applied to the
root system it is absorbed into the plant where the principle residue
component is methomyl itself. Volatile breakdown products are CO2
and acetonitrile. The remainder of the activity is incorporated into
natural plant components such as lipids and Krebs cycle acids and
sugars. The half-life of methomyl in plant foliage is a few days.
There was no evidence for accumulation of methomyl in rainbow
trout exposed to the compound for 28 days in a flow-through system.
1.4 Environmental levels and human exposure
Methomyl levels are likely to be either very low or undetectable
(< 0.02 mg/litre) in ground water on the evidence of analyses of
various water sources after the application of the compound at
recommended rates.
Low residue levels of methomyl are present in food and other
crops at harvesting, the levels depending upon factors such as the
applied rate, time interval after the last application and the type of
crop. The residue is composed primarily of methomyl.
Residues of methomyl in dairy products are either undetectable or
very low. Lactating cows given methomyl by capsule at a rate
equivalent to 80 mg/kg in their feed for 28 days showed no detectable
residues of methomyl or the metabolite MHTA in milk or tissues
(< 0.02 mg/kg). No methomyl was detected in eggs or tissues of
laying hens given 1 or 10 mg/kg in the diet for 4 weeks.
In total diet or individual food analyses in the USA, the
concentrations of methomyl in sample surveys were either undetectable
or very low. Residue levels are further reduced by processes such as
washing, peeling and cooking.
Re-entry exposure studies, specifically for California desert
conditions, showed that, when workers returned to vineyards where
dislodgeable foliar residues had fallen to 0.1 µg/cm2, the highest
exposure occurred on the upper body and head during grape girdling and
on the upper body and hands during raisin harvesting. Harvesting and
packing table grapes resulted in the lowest exposure. Inhalation
exposure was minimal.
After methomyl was sprayed on cucumber and tomato plants, ambient
air concentrations in the greenhouse ranged up to 4.7 µg/m3 on the
day after spraying. Three and 7 days after spraying, breathing zone
methomyl concentrations ranged up to 14.5 and 0.7 µg/m3,
respectively. Hand-wash methomyl values ranged from 10 to 322 µg
per h work in a greenhouse. This indicated that dermal exposure was a
more important route of exposure than inhalation and that re-entry
intervals should be based on dermal exposure data.
1.5 Kinetics and metabolism in laboratory animals
The absorption, metabolism and excretion of methomyl after oral
administration to rats are very rapid, the processes being completed
within a few days. When rats were given radiolabelled methomyl
(5 mg/kg body weight), 54% of the dose was excreted in urine and 2-3%
in faeces within 7 days, and 34% in expired air within 5 days. After
7 days, 8-9% of the 14C dose remained in the tissues and carcass,
which was incorporated into endogenous constituents. The highest
concentration of radioactivity was in the blood (representing 2% of
the dose).
The major metabolic components in expired air of rats were carbon
dioxide and acetonitrile in the ratio of about 2:1. The major
metabolite in urine was the mercapturic acid derivative of methomyl,
which was equal to 17% of the dose. Neither methomyl nor its oxime
derivative was detected.
The proposed metabolic pathway includes displacement of the
S-methyl grouping by glutathione followed by enzymic transformation
to give the mercapturic acid derivative. Another pathway is by
hydrolysis to give MHTA, which is rapidly broken down to carbon
dioxide. A further possible route is conversion of syn-methomyl (the
insecticidal form) to its anti-isomer, which undergoes hydrolysis,
rearrangement and elimination reactions to give acetonitrile.
Methomyl is similarly metabolized in the monkey, except that the
mercapturic acid derivative is a minor component in the urine.
The penetration of 14C-methomyl was estimated to be 85% within
one hour after dermal application in acetone to mice. At that time 3%
of the dose had appeared in blood, 5% in liver and 13% had been
excreted. Within 8 h the total excretion was 54.5%.
The rapid breakdown and elimination of methomyl in the rat,
together with its lack of accumulation in tissues, are comparable to
that seen in ruminants.
Methomyl is completely broken down when cows or goats are dosed.
No methomyl or its oxime derivative was detected in milk or tissues.
It was shown that the compound was metabolized and incorporated into
natural constituents of milk and liver.
No nitrosomethomyl was detected when 14C-methomyl was incubated
under simulated stomach conditions with sodium nitrite in a cured meat
macerate.
1.6 Effects on laboratory mammals and in vitro test systems
Methomyl has high acute oral toxicity, with an oral LD50 in the
rat of 17-45 mg/kg body weight. It is also highly toxic to rats by
the inhalation route, with a 4-h LC50 of 0.26 mg/litre in aerosol
form. Dermal toxicity is very low, with the LD50 exceeding
2000 mg/kg body weight in the rabbit (intact skin) and > 1000 mg/kg
body weight in the rat (abraded skin). Signs of acute toxic action
are those expected of a cholinesterase inhibitor and include among
others profuse salivation, lacrimation, tremor and pupil constriction.
Recovery from the effects was rapid. No gross pathological effects
due to treatment were seen in the organs examined. Methomyl is not a
skin irritant or sensitizer and is a mild eye irritant.
Repeated dietary administration over longer periods did not lead
to accumulation or increase in toxic effect. Rats and dogs fed diets
containing methomyl up to 250 mg/kg and 400 mg/kg in the diet,
respectively, for 13 weeks did not show any toxic signs or mortality.
Rats fed at the 250 mg/kg level showed small decreases in body weight
gain, lower haemoglobin levels and moderate erythroid hyperplasia in
the bone marrow. The NOEL in rats was 50 mg/kg in the diet
(equivalent to 3.6 mg/kg body weight per day). Rabbits given repeated
dermal applications of methomyl at doses up to 500 mg/kg body weight
per day for 21 days showed hyperactivity and depressed plasma and
brain cholinesterase activity at the top dose. The NOAEL was 50 mg/kg
body weight per day in this study.
Long-term studies were carried out on rats at methomyl
dietary levels of 0, 50, 100 or 400 mg/kg and on mice at 0, 50, 75 or
200 mg/kg. Effects on rats at the top dose included depressed body
weight gain and lowered haemoglobin and haematocrit values. The NOEL
was 100 mg/kg in the diet, equivalent to 5 mg/kg body weight per day.
In the study in mice, an increased mortality rate and decreased
haemoglobin and red blood cell counts were seen at the two higher dose
levels. The NOEL was 50 mg/kg in the diet, equivalent to 8.7 mg/kg
body weight per day. In a 2-year toxicity study in dogs (0, 50, 100,
400 or 1000 mg/kg in the diet), clinical signs of toxicity were noted
in some animals at the top dose together with slight to moderate
anaemia. The NOEL was 100 mg/kg in the diet, equivalent to 3 mg/kg
body weight per day.
There was no evidence of treatment-related increases in tumour
incidences in 2-year studies on rats and mice, indicating that
methomyl is not carcinogenic. It was not genotoxic in bacterial or
mammalian cells in vitro and was negative in tests for primary DNA
damage in bacterial and mammalian cells in vitro and in an in vivo rat
bone marrow chromosomal study. It showed cytogenetic potential in
human lymphocytes in vitro, as shown by increases in micronuclei and
chromosome aberrations. Methomyl did not produce embryotoxic or
teratogenic effects in rats or rabbits at doses up to 400 mg/kg in the
diet or 16 mg/kg body weight per day by gavage, respectively, at which
levels toxic effects were present in the dams. In a 3-generation
reproduction study in rats at dose levels of 50 or 100 mg/kg in the
diet (equivalent to 5 or 10 mg/kg body weight per day) methomyl did
not affect fertility, gestation or lactation indices and there were no
treatment-related gross abnormalities.
Methomyl did not show delayed neurotoxicity after single or
repeated administration. Rats fed 800 mg/kg in the diet showed
significant depression of blood cholinesterase activity only in the
early stages of a 5-month study. In a 28-day dietary study, brain
cholinesterase activity was only slightly depressed at this dose
level. This indicated the rapid reversibility of methomyl-inhibited
cholinesterase activity in the animals during the feeding periods. In
vitro, human erythrocyte cholinesterase activity was six times more
sensitive to the inhibitory action of methomyl than that of the rat,
although the rates of spontaneous reactivation were similar.
Atropine was shown to be the most consistently effective antidote
for methomyl poisoning based upon the results of studies in several
species.
1.7 Effects on humans
Reports on accidental and suicidal poisonings with methomyl
provide some information on effect levels and recovery. Three out of
five victims of accidental poisoning from a contaminated meal died
within 3 h of the ingestion. It was estimated that the victims had
consumed about 12-15 mg methomyl/kg body weight. A 31-year-old woman
and her 6-year-old son, both of whom died as a result of deliberate
poisoning, showed concentrations of methomyl in the liver of 15.4 and
56.5 mg/kg, respectively. The estimated doses were 55 mg/kg body
weight for the mother and 13 mg/kg body weight for the son. Six hours
after ingesting approximately 2.25 g methomyl, a woman's blood
contained .6 mg methomyl/kg. Methomyl could not be detected 22 h
after ingestion, when the woman was recovering.
A pesticide operator, who did not take any precautions when
mixing a powdered methomyl formulation for spraying vegetables,
displayed poisoning symptoms within one hour and showed a blood
cholinesterase activity 40% of normal after 12 h, with recovery to 80%
of normal activity within 36 h. Other operators, following the
recommended precautions, did not show any symptoms or effects on red
blood cell or plasma cholinesterase activity during activities with
the aerial application of methomyl.
1.8 Effects on non-target organisms in the laboratory and field
Methomyl showed no effects on soil fungal or bacterial
populations, nitrification or dehydrogenase activity when applied at
recommended rates.
An NOEC for algal growth of 6.5 mg/litre was established for
methomyl in laboratory studies.
Methomyl is moderately to highly toxic to fish, the 96-h LC50
values being in the range of 0.5-2 mg/litre for a variety of species.
In a longer-term (21 days) study the LC50 for fingerling trout was
1.3 mg/litre methomyl when tested as a Lannate 20L (21.5% methomyl)
formulation. In an early- life-stage toxicity study over 28 days with
fathead minnows, the MATC was estimated to be > 57 and < 117 µg/litre.
In acute toxicity tests with other aquatic organisms, Daphnia
magna was one of the most susceptible species to methomyl, the 48-h
LC50 being 0.032 mg/litre. In a 21-day study on the survival,
growth and reproductive capacity of Daphnia magna, the maximum
acceptable toxicant concentration for methomyl was > 1.6 and
< 3.5 µg/litre.
Methomyl is toxic to honey-bees, the reported contact LD50
being 1.29 µg/bee and the oral LD50 0.2 µg/bee.
The acute toxicity of methomyl has been assessed in several bird
species, typical acute oral LD50 values being 10 mg/kg body weight
for pigeons and 34 mg/kg body weight for Japanese quail. It is
relatively less toxic by the dietary route, the 8-day dietary LC50
being 1100 mg/kg methomyl in the diet for bobwhite quail and
2883 mg/kg methomyl in the diet for mallard ducks. In 18-to 20-week
one-generation studies, the NOEC was 150 mg/kg methomyl in the diet in
bobwhite quail and mallard ducks.
No effects were seen on bobwhite quail when they were exposed to
serial spray applications of methomyl at recommended rates. Two
studies on wild bird populations, after methomyl was sprayed over
forest land or hop fields at recommended rates, did not reveal any
apparent changes in bird activity and caused no treatment-related
effect or mortality. Fat deposits of song birds in treated forests
were reduced relative to controls; this was considered to be an
indirect effect through reduction in insect food.
1.9 Evaluation of human health risks and effects on the environment
Methomyl is a carbamate cholinesterase inhibitor with a
well-known mechanism of toxic action. It is particularly toxic by the
acute oral and inhalation routes in animal studies, but it has low
dermal toxicity. Acute toxic signs in animals are typical of those of
a cholinesterase inhibitor. The reversibility of acute toxic action
is rapid, with survivors showing quick recovery from toxic signs and
reversal of cholinesterase inhibition in the blood and brain. The
quick recovery from toxic effects is due to the rapid reversibility of
methomyl-inhibited cholinesterase, which is facilitated by the rapid
clearance of the compound from the body. Data from accidental and
intentional human poisonings show that the level of acute methomyl
toxicity in humans is similar to that found in laboratory animals.
Because of the rapid reversibility of the action of methomyl
during periods of feeding, acute toxic signs and blood cholinesterase
inhibition were rarely seen in dietary studies. The most consistent
findings in longer-term studies at the higher dietary levels were
decreases in body weight gain in rodents and reduced red blood cell
indices in rodents and dogs. There was no evidence for carcinogenic
potential from three long-term studies in rodents. The compound was
negative in in vitro genotoxicity tests that investigated several
end-points, but methomyl showed cytogenetic potential in human
lymphocytes. It was negative in an in vivo rat bone marrow
chromosomal study.
NOELs were identified in each of the long-term animal studies,
based upon depression of body weight gain and red blood cell indices.
These were 5 mg/kg body weight per day in rats, 8.7 mg/kg body weight
per day in mice and 3 mg/kg body weight per day in dogs. In the
absence of any marked species differences in toxic effect in these
studies, the NOEL in the dog of 3 mg/kg body weight per day should be
used for the purpose of human risk estimation.
The adsorption of methomyl to soil is low to moderate with hardly
any desorption. Aerobic degradation in soil (with a half-life of
around one week) is about twice as fast as anaerobic degradation.
Application of methomyl to plant leaves results in rapid
absorption of about half the amount applied (the other half being
adsorbed), and there is no indication of translocation. Absorbed
methomyl concentrations in food crops decline rapidly to about 5%
within one week.
Several aquatic invertebrates, and particularly daphnids, are
very sensitive to methomyl with LC50 values in the order of 10 to
100 µg/litre.
Fish, both freshwater and estuarine, are less sensitive, the
LC50 values ranging from 0.5 to 7 mg/litre. Given the low
persistence of methomyl and its relatively low acute toxicity to fish,
the risk is expected to be low.
At recommended application rates, methomyl does not adversely
affect microbial activity in temperate soil.
Methomyl is classified as highly toxic to honey-bees with a
topical LD50 of around 0.1 µg/bee.
Acute oral LD50 values for various bird species range between
10 and 40 mg/kg body weight. Dietary LC50 values (5 days) range from
1100 to 3700 mg/kg diet. Methomyl poses an acute risk to birds,
particularly from granules; dietary intake from contaminated food is
not expected to kill birds.
The high acute toxicity of methomyl to laboratory mammals
indicates a similar hazard to wild mammals.
1.10 Conclusion
Considering the qualitative and quantitative characteristics of
methomyl toxicity, the Task Group concluded that 0.03 mg/kg body
weight per day will probably not cause adverse effects in humans by
any route of exposure.
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL METHODS
2.1 Identity
Chemical structure:
O
"
CH3-C=N-O-C-NH-CH3
'
S - CH3
Used in the syn-isomer form
Molecular formula: C5H10N2O2S
Relative molecular mass: 162.2
ISO common name: methomyl
IUPAC chemical name: S-methyl- N-[(methyl-carbamoyl)oxy]
thio-acetimidate
CAS chemical name: methyl N[[(methyl-amino)carbonyl]
oxy] ethanimidothioate
CAS registry number: 16752-77-5
RTECS number: AK 2975000
Synonyms: metomil, mesomil, OMS 1196
Trade names Flytek (Zoecon), Golden Fly Bait
(manufacturers and (Sorex), Lannate (Du Pont), Methomex
suppliers): (Makhteshim), Methomyl (various),
Nudrin (Shell), Pillarmate (Pillar)
Technical product purity: > 98% w/w
Technical product S-methyl- N-hydroxy-thioacetimidate
impurities: (0.2%), 1,3-dimethylurea (0.4%)
2.2 Physical and chemical properties
The physical properties of methomyl are listed in Table 1.
Table 1. Physical properties of methomyl (Silveira, 1990)
Physical state crystalline solid
Colour white
Odour slight sulfurous
Melting point 77°C
Vapour pressure 0.72 mPa (at 25°C)
Henry's Law constant 2.1 × 10-11 atm-m3/mole
Octanol-water partition coefficient 1.24
(Kow)
Solubility:
water 54.7 g/litre
toluene 30 g/litre
isopropanol 220 g/litre
ethanol 420 g/litre
acetone 720 g/litre
methanol 1000 g/litre
Methomyl is stable at temperatures up to 140°C. It is not
sensitive to impact, but dusts may form explosive mixtures in air.
The autoignition temperature is 265°C. Methomyl is stable to
sunlight; it does not decompose when exposed for 120 days. It is
stable in sterile buffered water at 25°C (at pH 5 or 7 no breakdown
occurred within 30 days), but it is increasingly decomposed with
increasing pH and temperature. The half-life in water at pH 9 is 30
days. Methomyl at concentrations of 10 or 100 mg/litre in water is
decomposed by artificial sunlight with half-lives of 5.5 and 2 days,
respectively. Methomyl itself is not corrosive but aqueous solutions
may be mildly corrosive to iron (Silveira, 1990). Irradiation of
methomyl in aqueous solution at 254 nm for 10 h gave rise to
acetonitrile (40%), dimethyl disulfide (30%), acetone (15%) and
N-ethylideneme-thylamine (5%); the rest was unidentified products
(Freeman & Ndip, 1984).
2.3 Conversion factors
1 ppm = 6.62 mg/m3
1 mg/m3 = 0.151 ppm
2.4 Analytical methods
Analytical methods for the detection and determination of
methomyl in a variety of substrates are shown in Table 2. In general,
methomyl is extracted from the sample followed by clean-up and HPLC or
GLC analysis. In some cases the methomyl is converted to its oxime
derivative or a fluorophore derivative (post-column) prior to
analytical determination.
2.4.1 Sample preparation
Solid samples are extracted with organic solvents followed by
solvent partition and then, usually, a column clean-up. Water samples
are mainly submitted directly to solid phase extraction.
2.4.2 Analytical determination
The cleaned-up samples are submitted to either HPLC or GLC
analysis, in some cases after conversion to the oxime derivative.
HPLC analysis is coupled with UV detection, sometimes after conversion
to a fluorescent derivative. GLC detection is provided by FID, FSD,
ECD or microcoulometric detectors. A GC-mass spectrometric detection
method has been described (Brodsky, 1991).
Table 2. Methods for the determination of methomyl
Sample type Sample preparation Analytical method Limit of Reference
extraction/clean-up detection
Technical methomyl Reverse phase HPLC 254 nm UV detector not applicable Du Pont (1982)
and formulations
Plant, animal or Extract (ethyl acetate), add water, GLC with 0.02 mg/kg Pease & Kirkland
soil residues evaporate, acidify, extract & discard S-microcoulometer detector (25 g sample, (1968); Leitch &
(hexane), extract (chloroform), concentrate, or flame photometric 93% recovery) Pease (1973)
derivatize by alkaline hydrolysis detector
Crop residues extract (acetonitrile), partition (hexane), HPLC, UV detector at 0.02 mg/kg Clark & Kennedy
Florisil clean-up 233 nm (10 g sample, (1990)
98% recovery)
Non-fatty matrix extract (methanol), 3-step solvent partition HPLC, post column < 0.05 mg/kg Labare (1990)
residues Celite/charcoal column clean-up, derivatization, fluorescent (150 g sample,
concentrate, filter detector at 254 nm 89% recovery)
Vegetables Homogenized (20 g sample) with HPLC/UV µg/kg range Ivie (1980)
methylene chloride. Clean-up 10 ml of the (µ Baudpac C18 column)
extract by passing through SEP-PAK silica
cartridge. Wash with 2 ml CH2Cl2. Elute
with CH2Cl2:CH3OH (1:1 v/v). Evaporate
eluate to dryness. Redissolve in 1 ml of
CH3CN:H2O(1:1 v/v)
Table 2 cont'd).
Sample type Sample preparation Analytical method Limit of Reference
extraction/clean-up detection
Body fluids derivatize by alkaline hydrolysis, extract GC/chemical ionization 0.01 mg/kg Miyazaki et al.
(ethyl acetate), concentrate, convert to mass spectroscopy (2 g sample, (1989)
trimethysilyl ether derivative 95% recovery)
Soil samples extracted with ethyl acetate; HPLC, UV detector at 0.020 mg/kg Kennedy (1989)
filtered; evaporated to 5 ml; silica gel 233 nm (5 ml sample,
clean-up used when cleaner extract 94-102%
needed for HPLC recovery)
Groundwater extract (solid phase adsorbent), elute HPLC, UV detector < 0.1 µg/litre Batelle (1991)
(acetonitrile), concentrate (1 litre sample,
53-62%
recovery)
Well water Filter, automated sample injection, HPLC, flurometric detector at 1 µg/litre Hill et al. (1984)
post-column alkaline hydrolysis and 230 nm excitation and (0.5 ml sample,
conversion to a fluorophore 418 nm emission cut-off 95% recovery)
filter
Drinking-water as above as above 0.7 µg/litre Foerst & Moye
(0.4 ml sample, (1985)
90% recovery)
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1 Natural occurrence
Methomyl does not occur naturally in the environment.
3.2 Anthropogenic sources
3.2.1 Production processes and levels
Methomyl is produced by reacting S-methyl- N-hydroxythio-
acetimidate (MHTA) in methylene chloride with gaseous methyl
isocyanate at 30-50°C. The unreacted MHTA is recovered and the
remaining reaction product is subjected to solvent exchange into water
followed by crystallization and centrifugation. The ensuing wet cake
is dried to give technical methomyl (Council of the European
Communities, 1991).
The worldwide production has been estimated to be less than 7000
tonnes (SRI, 1988).
There are no data available on possible releases to the
environment from production processes and transportation.
3.2.2 Uses
Methomyl was introduced as an insecticide in 1966. It is used
for the control of a large variety of insects on a wide range of crops
throughout the world. It is particularly active on many lepidopterous
insects. It acts by direct contact and following ingestion, through
the stomach. Treated crops include fruit, vines, hops, vegetables,
grain, soya beans, cotton and ornamentals. Indoor uses include the
control of flies in animal houses and dairies.
A global estimate of the amount of methomyl used annually for the
above purposes is not available. However, the annual amount used in
the USA was estimated to be approximately 1300 tonnes in 1987 and
1992. The major crops treated in that country are sweet corn, apples,
lettuce, soya beans, peanuts, tomatoes, cotton, corn, alfalfa, and
grapes, accounting for nearly 80% of the total amount used (US EPA,
1988; Gianessi & Puffer, 1992).
The main formulated products are water-soluble powders (25-90%
methomyl) and water-miscible liquids (12.5-29% methomyl). These
products are diluted with water and applied by ground or aerial spray
equipment. Typical methomyl concentrations in the spray solutions are
200-500 mg/litre. Typical active ingredient rates are 0.15-1.0 kg/ha
although higher rates, up to 2 kg/ha, may be used for some purposes.
Repeat applications, as directed on the label, may be required to
maintain control of insect infestations. Examples of crops treated
and methomyl use rates for the USA and Australia are given by FAO/WHO
(1990a,b). Methomyl formulations are compatible in use with many
other insecticides and fungicides, and combined formulations are
registered and available for use in many countries. Methomyl is often
used with one or more other products in a tank-mix. Possible
potentiation by other cholinesterase inhibitors should be considered
when assessing the safety of use of the tank-mix formulations.
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION
4.1 Transport and distribution between media
4.1.1 Water
The transference of methomyl from greenhouse plants to soil and
to water was assessed on chrysanthemums, grown three times per annum,
with methomyl applied over a 6-month period at 1-week to 2-month
intervals at a rate of 1.4 kg/ha. The three soils investigated were
frequently irrigated and the drainage water was collected at a depth
of 0.8 m. The adsorption isotherms for the three soils indicated that
the adsorption of methomyl was weak to moderate. The concentration of
methomyl in the drainage water was undetectable (< 0.1 µg/litre) in
60% of the samples and was below 1 µg/litre in the remainder (Leistra
et al., 1984).
Methomyl was applied at a high rate of 2.2 kg/ha to a loamy sand
soil on a farm site with a 10% slope. No methomyl was detected
(< 0.01 mg/litre) at the base of the site after a total of about
80 mm of natural and artificial rain had fallen on the site over a
period of 15 days (Harvey & Pease, 1973).
14C-Methomyl was applied at a very high rate of 5 kg/ha to
cylinders (38 cm deep) containing a fine sand soil or a loamy sand
soil. No radioactivity was found in the eluate collected after the
columns had been subjected to heavy rain (Harvey & Pease, 1973).
In natural waters, pesticides can be photochemically degraded by
direct (the pesticide absorbs sunlight) and indirect (other chemicals
in the water absorb sunlight, and transfer the energy to the
pesticide) mechanisms. Current regulatory studies only address the
direct mechanism, and thus neglect an important degradative process.
This can result in unrealistically high estimates of persistence of a
pesticide in surface water.
These data would suggest that any methomyl residues present in
agricultural waters would be rapidly degraded, and that methomyl would
not be expected to have an impact on non-target aquatic organisms.
4.1.2 Soil
Batch equilibrium studies were carried out with 14C-methomyl on
two sandy loams and two silt loams. Aqueous solutions containing
0.2-6 mg methomyl/litre of were mixed with the soils and shaken for
24 h. A separate study was also undertaken on each soil using TLC.
Methomyl was shown to be weakly adsorbed on one of the silt loams
(Ka=1.4), and poorly adsorbed on the other three soils. Desorption
was related to soil organic matter content and indicated that methomyl
is not readily desorbed. In the TLC assessment the Rf values
(0.46-0.82) indicated methomyl as Class 4 (mobile) on a sandy loam and
Class 3 (intermediate mobility) on the other three soils (Priester,
1984).
A silty clay loam, a silt loam and two sandy loams were made up
as slurries and spread on TLC plates. Methomyl and a minor soil
metabolite, S-methyl- N-hydroxy-thioacetimidate (MHTA) were applied
at 1 µg/spot and the plates developed. Methomyl and its metabolite
were considered to be very mobile, with Rf values of 0.64-0.79 and
0.86-0.93, respectively, in the four soils (US EPA, 1988).
In a field study on a sandy loam in California, methomyl was
applied to cabbage by back-pack sprayers at a very high rate of
10 kg/ha (single application). Samples of the soil were taken at 0
and 6 h and then at intervals from 3 to 272 days after application.
Analysis showed that methomyl residues remained mostly in the top
15 cm of soil with deepest penetration into the 15-30 cm layer after
48 cm rainfall/irrigation. On this basis the mobility of methomyl was
considered to be low to moderate under field conditions in this soil
(Kennedy, 1989).
In another field study on a soil characterized as a loam and silt
loam, methomyl was applied to cabbage by back-pack sprayers at the
high rate of 4.4 kg/ha (single application). Soil samples were taken
at 0 and 6 h and then at intervals over a 91-day period after
application. Methomyl residues were found only in the top 15 cm of
soil after 28 cm rainfall/irrigation. On this basis methomyl was
considered to be of low mobility in these field conditions (Kennedy,
1991).
Cox et al. (1993) studied methomyl adsorption to 14 soils from
southern Spain. These varied in pH from 5.3 to 7.9, in percentage of
organic matter from 0.59 to 2.5%, in cation exchange capacity from 4.2
to 28.5, and in the percentage of clay minerals. The methomyl
concentration in soil and water components following shaking for 24 h
was measured by HPLC. Simple and multiple regression analysis was
used to evaluate which factors affected methomyl adsorption. Soils
were equilibrated with both 20 and 50 µM methomyl (high purity); there
was no significant difference between concentration at the same
soil/solution ratio, indicating poor affinity of methomyl for the
soils. Both simple and multiple regression indicated soil organic
matter, clay content and clay minerals, methomyl in soil and illite
content as the major features of soil affecting adsorption of
methomyl. Further studies examined adsorption to individual soil
components. Humic acid showed by far the highest affinity for
methomyl with Kd values 50 times greater than for clay minerals.
Montmonillonites showed a similar Kd to illite in these studies,
contrary to findings with whole soils. The authors suggest, on the
basis of maturation studies, that adsorption to clay may occur in the
interlamellar space of the minerals.
4.1.3 Vegetation
When 14C-methomyl was applied to the surface of tobacco plant
leaves the compound was absorbed in the leaf but not translocated to
other parts of the plant (Harvey & Reiser, 1973).
In a study by Fung et al. (1978), each tobacco seedling received
250 ml of water containing 500 µg methomyl/litre (equivalent to about
0.5 kg active ingredient per hectare of 17 000 plants) after
transplantation. The concentration of methomyl peaked at 15 mg/kg in
the leaves and at 2.5 mg/kg in the growing tips 2 weeks after
treatment. Subsequently, the concentration decreased, which could be
explained almost entirely by growth dilution. At 9 weeks after
transplantation, the plants were sprayed with a solution of 500 mg
methomyl/litre. Three weeks after this (i.e. 12 weeks after
transplantation), another similar application was made. Some plants
received an additional application of 250 ml of a 500 mg
methomyl/litre solution on each side of the row of plants.
Concentrations increased sharply after these treatments and dropped
afterwards: levels in the leaves of plants with both foliar
application peaked at 9 and 6 mg/kg; levels in leaves which received
foliar and root applications peaked at 18 and 11 mg/kg. Part of the
decrease after application could again be explained by growth
dilution. It appears, therefore, that translocation of methomyl from
roots to leaves can occur (Fung et al., 1978).
A sandy loam soil was treated with 14C-methomyl at a rate of
4.4 kg/ha and, 30-120 days later, cabbage, red beet and sunflower
seeds were sown and the plants grown to maturity. Thirty days after
treatment the soil contained 26% of the original methomyl whereas
after 120 days it contained only 8%. All crops, sown at 30 or 120
days, contained only very small residues of methomyl and/or
metabolites, equivalent to 0.01 mg/kg or less at harvest (Harvey,
1978).
4.2 Transformation
4.2.1 Biodegradation
In a study by Harvey (1972a), 14C-methomyl (1 mg/litre) in
river water (pH 6.3) was exposed for 8 weeks from JulySeptember in the
USA. The compound degraded with a half-life of about one week. The
initial degradation product was MHTA followed by breakdown to carbon
dioxide, which accounted for 65% of the original radioactivity after 8
weeks. The S-oxide of MHTA was also detected in small amounts. At
termination, 9% of the original activity was present in sediment and
the biological film on the walls of the container.
Laboratory studies were carried out on a non-sterile silt loam at
its natural pH of 4.7 and at an adjusted pH of 7.9; an alkaline soil
(pH 7.9) was also evaluated. All soils were treated with
14C-methomyl at a high rate equivalent to 4.4-6.1 kg/ha and the
breakdown was assessed over 42 days. Methomyl degraded (52-69%) in 42
days, carbon dioxide (31-45%) being the main decomposition product.
Small amounts of MHTA (1-2%) were present in the soil at termination.
It was shown that the 14CO2 could be reincorporated into soil
organic matter (Harvey & Pease, 1973) (J. Harvey, Jnr (1976):
supplement to "Decomposition of methomyl in soil"; personal
communication by Du Pont to IPCS, dated 28 July 1976).
Under field conditions the decomposition of methomyl was more
rapid, with a 71% loss from a silt loam soil within one month; none
was detected after one year. MHTA was present in trace amounts at 1
and 3 months but was not present at one year. Most of the residual
application was found in the top 75 mm of soil, and none was found
below 200 mm. Decomposition was rather more rapid in fine sand and
loamy sand soils (Harvey & Pease, 1973).
When applied at a concentration of 4.1 mg/kg to a microbially
active loam soil (equivalent to a very high rate of 9 kg/ha),
14C-methomyl was metabolized with a half-life of approximately
11 days. The decomposition followed first-order kinetics and the main
end product was 14CO2 (Zwick & Malik, 1990a). These results were
in agreement with the studies described above and with other aerobic
soil metabolism studies conducted on soils of high or low organic
matter content and various pHs (Harvey, 1972b; 1977a,b).
Dissipation studies of methomyl in loam soils in California and
Mississippi resulted in half-lives of 8 weeks and 5 days, respectively
(Kennedy, 1989; 1991). In addition to differences in temperature,
field moisture differences during the experiment seem largely
responsible for these differences in half-life, because adjusting
field moisture of the California soil to 75% of its capacity in the
laboratory reduced the half-life to 11 days (Kennedy, 1991). Field
moisture conditions greatly decrease the air content of the soil. In
anaerobic soils it has been shown that ferrous ions facilitate the
rapid degradation of methomyl (Bromilow et al., 1986).
Methomyl is also degraded under anaerobic soil conditions. An
alkaline soil with low organic matter content was incubated with
methomyl (4.1 mg/kg) aerobically for 14 days and then anaerobically
for 60 days. The half-life under anaerobic conditions was
approximately 14 days and 14CO2 was a major break-down product,
equivalent to 23.4% of the applied activity during the 60 days of
anaerobic incubation. Unextractable activity was 30% of the total at
7 days and 24% after 60 days of anaerobic treatment. Most of this was
associated with soil organic matter (Zwick & Malik, 1990b).
Anaerobic degradation (Eh 80-310 mV) was studied in samples of
sand, loamy sand and fine sand, taken from below the soil water table
at four locations in the Netherlands (Smelt et al., 1983). In each
case, methomyl was incubated at 10°C and when pH was between 7.4 and
7.7 the half-life was less than 0.2 day (one hour after the start of
the experiment, 38-63% of the applied dose was recovered, and after
24 h, 0.15-5% of the applied dose was recovered. When the fine sand
sample was incubated at 10°C and pH 5.0, methomyl could be detected
for 3 days, and the rate of decrease corresponded to a half-life of
7 h.
The role of microbial action was shown by perfusing two soil
samples (fine sandy loam at pH 6.1 and fine sandy clay loam at pH 5.87
with organic matter content in both of 2.1-2.3%) with methomyl
solution (6 mg/litre) with and without sodium azide (Fung & Uren,
1977). The contribution of adsorption or dissipation of methomyl from
solutions was small when compared with that of microbial
transformation. The latter amounted to 25-45% in 42 days after a lag
phase of 7-14 days. When previously perfused soil was re-exposed to
fresh methomyl solution, 60-75% was lost in 42 days without any lag
phase.
The metabolic fate of methomyl has been investigated in tobacco,
corn and cabbage (Harvey & Reiser, 1973). Tobacco was grown from
seedlings, and when the plants were 18 cm high the roots were treated
with 14C-methomyl (10 mg/litre solution). Cabbage (42 days old) and
corn (28 cm high) plants were treated with 14C-methomyl via foliar
application. Each plant was placed in a glass metabolism apparatus
for radioactivity measurement of volatile products and plant material.
Tobacco absorbed 20-25% of the available activity over a 4-week
period. One quarter of this was retained in plant tissue and the
remainder volatilized. The principal component of plant tissue
activity was methomyl. The volatile components were carbon dioxide
and acetonitrile in equal proportions. Of the applied activity, 47%
was lost from the growing shoots of young corn as volatile components
within 10 days. This was composed of CO2 and acetonitrile in the
ratio of 1:4. One week after treatment of cabbage leaves, 20% of the
activity was lost as CO2 and acetonitrile in equal proportions. The
extracts of the treated plants were investigated for the presence of
three possible metabolites, MHTA and the S-oxide and S,S-dioxide
derivatives of methomyl. There was no evidence for the presence of
these compounds. The only terminal residue specifically detected was
methomyl. The remainder of the radioactivity was incorporated into
natural plant components such as lipids and Krebs cycle acids and
sugars.
The biodegradation of methomyl was also studied in corn and
cabbage under field conditions after the application of the
radiolabelled compound. The outer leaves of cabbage contained most of
the radioactive residue of which a small proportion (3-4%) was
identified as methomyl. In corn, the outer portions contained most of
the radioactive residue with about 2 mg methomyl/kg being present
(Harvey & Reiser, 1973).
The half-life of methomyl was determined in cotton leaves sampled
during periods without rainfall after a single application at
0.75 kg/ha, the maximum label rate. The foliar half-life was
estimated to be between 0.6 and 2.2 days, with an average of 1.1 days
(Eble & Tomic, 1991). Bull (1974) applied radiolabelled
14C-methomyl to leaves of tobacco in aqueous solution. Almost half
of the applied methomyl penetrated the leaves within the first few
hours. Surface residues were largely lost within 48 h and the parent
compound was the only radioactive component of the unabsorbed dose.
The absorbed methomyl was degraded within 8 days (mostly within 48 h).
No S-oxide, S,S-dioxide or oxime derivatives were found in the plants,
the methomyl being degraded to acetonitrile and CO2. After methomyl
was applied directly to tobacco leaves, its half-life was 3-7 days
(Harvey & Reiser, 1973). Studies describing the decline of
dislodgeable foliar residues on various crops are reviewed in
section 5.3.
4.2.2 Abiotic degradation
When a 3% solution of methomyl in distilled water was stored for
168 days, 90% of the compound was recovered at the end of the period.
The remainder was recovered as MHTA (Harvey, 1967).
The hydrolysis of methomyl was studied at pH 5, 7 and 9, at
concentrations of 10 and 100 mg/litre, and at 25°C. The compound was
stable for 30 days at pH 5 and 7 but broke down at pH 9 with a
half-life of about 30 days. The hydrolysis product was MHTA
(Friedman, 1983).
The photolysis of methomyl was studied at initial concentrations
of 10 and 100 mg/litre and at pH 5 under UV light. Methomyl
photolysed rapidly at both concentrations with a half-life of 2-3 days
at 100 mg/litre. The principal photo-product was acetonitrile
(Harvey, 1983).
In a study by Swanson (1986), 14C-methomyl was applied to a
thin layer of a silt loam soil on glass plates and exposed to natural
sunlight for 30 days at 24-28°C. The compound decomposed with an
estimated half-life of 34 days. The principal decomposition product
was acetonitrile. Duplicate preparations, kept in the dark, did not
decompose.
Methomyl degraded rapidly in slightly alkaline solution (pH 8.85)
with a chlorine/methomyl ratio of 10. The degradation rate increased
with increasing temperature, increasing chlorine concentration, and
decreasing pH. The reaction rate with free chlorine was 1000-fold
faster than with chloramine. Methomyl degraded to acetic acid,
methanesulfonic acid and dichloromethylamine after forming methomyl
sulfoxide and N-chloromethomyl (Miles & Oshiro, 1990). Mason et al.
(1990) also reported that the removal of methomyl can be effectively
achieved by some disinfectants (Cl2, O3) but not by ClO2.
4.2.3 Bioaccumulation
Rainbow trout were exposed to 0.075 and 0.75 mg methomyl per
litre in a flow-through test system for up to 28 and 21 days,
respectively, and then placed in clean water (pH 7.3, total hardness
25 mg CaCO3/litre at 18°C). At the higher concentration, fish
tissue contained 0.36-0.45 mg methomyl/kg during the exposure period
and, at the lower concentration, 0.04-0.07 mg/kg. Within one day of
depuration the methomyl tissue levels fell to below 0.02 mg/kg in both
exposure groups. There was therefore no indication of bioaccumulation
of methomyl in these studies (Sleight, 1971).
4.3 Interaction with other physical, chemical or biological factors
When 14C-methomyl was incubated with a rumen microorganism
culture at a level of 1 mg/kg and at 38°C for 24 h, 90% was
metabolized to a volatile component which was identified as
acetonitrile by gas chromatography. Less than 0.1% of the total
activity was recovered as methomyl or MHTA (Belasco, 1972b).
No nitrosomethomyl was detected (< 1 µg/kg) when 14Cmethomyl
(1 mg/kg) was incubated under simulated stomach conditions (pH 2) with
sodium nitrite (16-20 mg/kg) in a macerate of cured meat for 1 or 3 h
at 37°C (Han, 1975).
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1 Environmental levels
5.1.1 Water
In 60% of drain water samples from greenhouses containing treated
plants in an area south of The Hague, The Netherlands, methomyl could
not be detected (< 0.1 µg/litre). In the remaining 40% samples its
concentration was < 1 µg/litre (Leistra et al., 1984).
Out of 22 404 wells sampled and analysed for methomyl in the US
EPA pesticide monitoring programme, 85 showed detectable methomyl
concentrations within the range of trace to 20 µg/litre, i.e. within
the lifetime health advisory figure of 200 µg/litre (US EPA, 1991).
After a cedar swamp had been sprayed with Lannate LV formulation
(29% a.i.) at a rate of 0.28 kg methomyl/ha, no methomyl could be
detected (< 0.02 mg/litre) in surface water at any time between 1 and
58 days after treatment (Du Pont, 1978).
5.1.2 Soil
Soil samples taken from a tobacco farm in Maryland, USA, after a
single application of methomyl (Lannate 90% a.i.; 13.4 kg/ha)
contained 0.6 mg methomyl/kg at 0-15 cm depth after 8 days. At a
depth of 15-30 cm, 0.1 mg/kg was detected after 17 days. No methomyl
(< 0.02 mg/kg) was detected after 47 days at either level. Lannate
is applied as an incorporation to a depth of 10 cm (Pease, 1968).
Levels of methomyl in soil after an upland forest and a cedar
swamp had been sprayed with Lannate LV at a rate of 0.28 kg
methomyl/ha were either very low (< 0.07 mg/kg) or undetectable
(< 0.02 mg/kg). No residues were detected (< 0.02 mg/kg) at an
application of half the above rate (Du Pont, 1978).
5.1.3 Food crops
Methomyl is used as a broad spectrum insecticide on many food
crops, hence low residues may be present at harvesting. The amount of
residue at harvest depends upon factors such as the application rate,
time interval between the last application and harvest, and the type
of crop. The residue is composed mainly of methomyl itself. The
residue levels expected in food crops at harvest can be derived from
the numerous supervised trials which have been carried out on many
crops in countries worldwide (FAO/WHO, 1988a,b; 1990a,b). Pre-harvest
intervals are also set on the basis of the results of supervised
trials, e.g. 7 days for lettuce and onions in USA, 1 day for brassicas
and tomatoes in Australia (FAO/WHO, 1990a,b).
The decline of methomyl residues on food crops after application
was demonstrated by the field treatment of broccoli followed by
harvesting at intervals thereafter. The results of treatment at
0.55 kg/ha (6 applications) are shown in Table 3 (Du Pont, 1973).
Table 3. The decline of surface and absorbed methomyl residues in
broccoli (Du Pont, 1973)
Days after treatment Residue (mg/kg)
1 1.0
3 0.15
7 0.04
10 0.02
Similar examples of the decline of methomyl residues have been
shown for lettuce and cauliflower (Braun et al., 1980), celery (Braun
et al., 1982), wheat (Du Pont, 1973; FAO/WHO, 1988a,b) and tomatoes
(FAO/WHO, 1990a,b).
Treated food crops processed after harvesting generally do not
show a concentration of methomyl residues in the processed fractions.
Unwashed whole oranges were found to contain 0.96 mg/kg at harvest and
0.88 mg/kg after washing. The dried peel contained 2.8 mg/kg whereas
the pulp, juice, cold process oil and molasses contained no detectable
residue (< 0.02 mg/kg). Similarly, tomatoes analysed after harvest
contained 0.38 mg/kg while the processed fractions, wet pomace, dry
pomace, juice and puree contained < 0.02 mg/kg (Kennedy & Hay, 1991a;
Marxmiller & Hay, 1991). Mint oil produced from the distillation of
methomyl-treated plants and wine produced from treated grapes
contained no detectable residues (< 0.04 and < 0.02 mg/kg,
respectively) of methomyl (Kiigemagi et al., 1973; Brodsky, 1991).
5.1.4 Other crops
Environmental levels of methomyl on treated crops such as cotton
and tobacco may be deduced from supervised trials.
After 14 applications of methomyl at 0.5 kg/ha and two at the
high rate of 1.65 kg/ha, cotton contained 0.17 mg methomyl/kg 15 days
after the last application. Processed fractions showed < 0.02 mg/kg
in oil, 0.065 mg/kg in meal and 0.14 mg/kg in hulls (Kennedy & Hay,
1991b).
The residue levels in tobacco leaves immediately after the
application of methomyl at the recommended rate of 0.56 kg/ha were 44
and 88 mg/kg at two sites in the USA. After five days these levels
had dropped to 0.7 and 1.4 mg/kg. Approximately 96% of the methomyl
was lost during flue-curing (Leidy et al., 1977).
5.1.5 Dairy products
There are no reports of methomyl residues in dairy produce.
Groups of lactating cows (three/group) were dosed methomyl by
capsule at a rate equivalent to 8, 24 or 80 mg/kg in their feed for
28 days. Milk collected during the dosing period and tissues taken at
termination contained no detectable residues of methomyl or its
metabolite MHTA. Acetonitrile was detected in the milk of cows dosed
with methomyl at 8 mg/kg, the milk concentration of acetonitrile
reaching a plateau of 0.04-0.1 mg/kg by day 4. This component was
also present in liver (0.08 mg/kg) and kidney and muscle (0.04 mg/kg)
at this dose level. Acetamide concentrations in milk and tissue of
cows dosed with 80 mg/kg were the same as those found in control
animals. Radiolabel assessment showed that the acetamide derived from
methomyl was < 1% of the total dose (Powley, 1991). In another study,
methomyl was fed to cows at 2 or 20 mg/kg in feed and no methomyl
(< 0.02 mg/kg) was detected in milk over a 30-day period nor in meat
tissue at termination (Du Pont, 1967).
The 14C-residue in milk was equivalent to 0.13 mg/kg 4 days
after two goats had been fed 14C-methomyl at 8 mg/kg diet. Methomyl
itself could not be detected. Total 14C-residues in a range of
tissues were very low (< 0.001-0.003 mg/kg) (Osman et al., 1983).
5.1.6 Animal feed
Some indication of methomyl residues expected in those portions
of treated crops used for animal feed can be deduced from the
following studies. Methomyl concentrations were 0.35 mg/kg in forage,
0.14 mg/kg in cannery waste and < 0.02 mg/kg in kernels from sweet
corn treated with methomyl at 0.9 kg/ha and harvested 9 days after the
last of four applications (Harvey & Yates, 1967). Methomyl residues
on sweet corn forage harvested immediately after the last of nine
foliar applications at 0.5 or 1 kg/ha were 0.15-0.60 mg/kg and
0.2-0.72 mg/kg, respectively (US EPA, 1988). The residues on samples
of wheat straw taken 7 days after foliar application of 0.55 kg
methomyl/ha were < 0.02-6.5 mg/kg, and after 14-18 days they were
< 0.02-0.8 mg/kg (US EPA, 1988).
5.2 General population exposure
Information available on general population exposure is limited
and derives primarily from only one country. More complete exposure
information via various routes specific to regions and countries is
required to assess the risk of occupational exposure and intake of
residues.
5.2.1 Food
The market baskets collected for the US FDA total diet study
prior to 1991 consisted of 234 food items. Of these, a total of 72
items (69 adult foods, 2 baby foods and water) were analysed by
methodology known to be capable of determining methomyl. Methomyl was
detected only in 11 food items collected from 1987 to April 1991 (20
market basket studies): watermelon, pear, strawberries, grapes,
cantaloupe, raisins, lettuce, celery, cauliflower, cucumber, and green
sweet peppers. The levels detected in these food samples ranged from
trace to 0.630 mg/kg, well below the tolerances established by US EPA
(US FDA, 1993a).
The total number of domestic and imported food samples analysed
by methodology known to be capable of determining methomyl in US FDA
regulatory monitoring programmes during the period 1988-1992 was 7765.
Of these, methomyl residues were detected only in 112 samples. Four
samples were found to be violative: one domestic sample of strawberry
(4.53 mg/kg) and one imported cantaloupe (0.28 mg/kg) exceeded the
USA tolerances and there were two imported samples for which no USA
tolerances have been established (okra, 0.05 mg/kg and pepino,
0.46 mg/kg) (US FDA, 1993b).
Residues in foodstuffs are reduced by domestic processing such as
washing, peeling and cooking. For example, 50-90% of methomyl
residues on celery was removed by trimming (FAO/WHO, 1986). Methomyl
residues declined by 70-93% in tomatoes, peas or cabbage after 30 min
cooking in boiling water in open containers (Holt, 1971). Methomyl
was added to spinach puree to give a concentration of 50 mg/kg and
then processed in closed cans for 40 min at 122°C. No methomyl was
detected (< 0.05 mg/kg) at the end of this period (Niven, 1971).
Methomyl has not been detected in wine or mint oil prepared from
crops previously treated with methomyl (see section 5.1.3).
No methomyl could be detected (< 0.02 mg/kg) in eggs or tissues
of laying hens given 1 or 10 mg methomyl/kg diet for 4 weeks (Sherman,
1972).
5.3 Occupational exposure
A series of studies was carried out to determine worker re-entry
times after the application of methomyl to grape vines in California,
USA (Dong et al., 1992; Reeve et al., 1992). These studies were
specific to the desert conditions found in California and should not
be compared to studies on other crops or in other climates. Methomyl
was applied at different times of the growing season at 1 kg/ha and
the dislodgeable foliar residues were measured at time intervals after
application to estimate how long it would take to reach the desired
level of 0.1 µg/cm2 on the leaves. Under desert conditions with
water supplied only by furrow or drip irrigation, it was found that it
required about 5 days to reach this level in June, when grape girdling
was carried out, and about 10 days in September, at harvesting
(Powley, 1989, 1990a,b).
A worker re-entry study was undertaken to estimate exposure after
entry into vineyards when dislodgeable foliar residues had fallen to
0.1 µg methomyl/cm2 or less. Each worker wore ankle length tights
(except raisin grape harvesters) and long sleeved T-shirt, both worn
under normal work clothes. Each wore a personal air sampling pump and
two patches were attached to work hats. Sample patches were worn on
the thigh and ankle on the normal work clothes by most workers during
girdling operations. Work continued for 3-4 h. Methomyl exposure
when girdling field grapes ranged from 315-1214 µg/h with highest
values on the upper body and head. Exposure was highest to the upper
body and hands of raisin harvesters where overall daily exposure was
463-865 µg/h. Harvesting and packing table grapes resulted in the
lowest methomyl exposures of 219 and 102 µg/h, respectively.
Inhalation exposure was minimal (Merricks, 1990).
It should be emphasized that the rate of decay of methomyl in the
Californian studies described above is not representative of the
situation in grape culture in other areas of the world or for other
crops, as, due to irrigation and other cultural practices, Californian
grape vines are quite large and have lush foliage which maximizes
exposure. Methomyl does not hydrolyse readily in the hot dry
desert-like conditions and this gives rise to atypical transfer rates.
Dislodgeable foliar residue from cotton plants was the subject of
three studies in Arizona, USA (Cahill et al., 1975; Ware et al, 1978,
1980). In each case, methomyl was applied at 0.55 kg/ha and leaf
samples were taken for analysis of dislodgeable residues up to 96 h
after. In each study the methomyl residues had declined to 0.1 µg/cm2
or less within 48 h.
Dislodgeable foliar residues were determined after spraying mint
to estimate possible exposure to workers moving irrigation pipes.
After spraying methomyl at l kg/ha from the air, dislodgeable residues
were 1.5 µg/cm2 at 4 h and 0.32 µg/cm2 at 48 h, and, after
applying 2 kg/ha, residues were 2.3 µg/cm2 at 4 h and 0.6 µg/cm2 at
48 h (Kiigemagi & Deinzer, 1979).
A pilot study was undertaken in Thailand with a methomyl 90%
soluble powder formulation to assess the use of food dyes as markers
for pesticide exposure. Pesticide operators prepared and sprayed the
diluted methomyl formulation containing the dyes on low (broccoli,
chinese kale), medium (tobacco) or tall (citrus) crops with knapsack
or high pressure power sprayers. Measurement of dye content of the
outer garments showed that exposure occurred mainly to the lower body
and legs when spraying low crops and mainly to the upper body and arms
when spraying tall crops. Some correlation was shown between the
amounts of methomyl and dye deposited on the outer garments. However,
the number of participants (two per group) was too small to draw
definite conclusions, and more work needs to be done to establish
these correlations (Ambridge, 1992).
Methomyl was not detected in air samples from the working zones
of operators during normal closed transfer, mixing-loading operations.
During application, methomyl air concentrations of up to 7.5 µg/m3
were found in applicator working zones (Knaak et al., 1980).
In order to establish a post-application re-entry interval for
workers employed in greenhouse operations, methomyl dislodgeable
foliar residue data were collected from rose foliage. It was shown
that after a single high rate of application of 3.2 kg/ha it took
nearly 5 days for the dislodgeable residue to decline to the required
level of 0.1 µg/cm2. It was estimated that for the application rate
of 1 kg/ha, the highest normally used for rose treatment, a re-entry
interval of 48 h would be required (Oswald et al., 1991).
The concentration of methomyl in greenhouse air was measured
directly by an atmospheric pressure chemical ionization mass
spectrometer system. The atmosphere was monitored during spraying of
roses and for 26 h thereafter. Samples taken at head height during
spraying showed methomyl levels of about 33.1-39.7 µg/m3 (5-6 ppb).
A few hours later, at the end of the day's operations, concentrations
were about 19.9-26.5 µg/m3 (3-4 ppb). When monitoring resumed the
following morning the air concentrations were still at about the same
level indicating that methomyl, deposited in aerosol droplets on the
roses, had not fully evaporated (Williams et al., 1982).
Ambient air and breathing zone samples were analysed in four
greenhouses 1 day before and 7 days after methomyl was sprayed on
cucumber and tomato plants. Ambient air methomyl concentrations
ranged up to 4.7 µg/m3 on the first day after spraying. Three and
seven days after spraying, breathing zone methomyl concentrations
ranged up to 14.5 and 0.7 µg/m3, respectively. Hand-wash methomyl
values ranged from 10 to 322 µg/h of work in a greenhouse. The
authors considered that dermal exposure, as indicated by the hand-wash
data, was a more important factor than air exposure and that re-entry
intervals should be set according to information derived from the
former (Boleij et al., 1991).
Ambient air in a pesticide storage building was monitored over a
3-h period using high volume air samplers and absorption on XAD-4 or
XE-340 resins. Methomyl was stored in the building as a liquid
concentrate along with other pesticide formulations. The average
methomyl air concentration over the sampling period was 13.7 ng/m3.
This represents a value of 0.18 µg/m3 when converted to a 40-h
working week and can be compared with the ACGIH TLV of 2500 µg/m3
(Yeboah & Kilgore, 1984).
6. KINETICS AND METABOLISM IN LABORATORY ANIMALS
The term 14C-methomyl in this section refers to
S-methyl-[1-14C]-N-[(methylcarbamoyl)oxy] thioacetimidate, unless
otherwise stated.
6.1 Absorption
The absorption of 14C-methomyl was very rapid after oral dosing
of 5 mg/kg to male or female rats. About 80% of the activity was
excreted within 24 h as metabolic products in urine and expired air.
Only 2-3% was found in faeces (Harvey et al., 1973; Hawkins et al.,
1991).
A similar pattern was seen in the cynomolgus monkey following a
single 5 mg/kg oral dose. More than 60% of the dose was eliminated in
expired air and urine within 24 h as metabolic products. Only about
3% of the dose was found in faeces over a period of 168 h after dosing
(Hawkins et al., 1992).
In an assessment of dermal penetration, 14C-methomyl was
applied in acetone to a 1 cm2 shaved area of skin of mice (7-8 weeks
old) at a rate of 1 mg/kg. The mice were then placed in metabolism
chambers and killed for radioactivity measurements at intervals up to
48 h. Within 5 min, 14C activity was detected in blood and liver.
In 60 min, 2.9% of the original 14C dose was present in blood, 5%
was in the liver, and 12.9% had been excreted (urine plus CO2 plus
faeces). Very little methomyl remained at the application site after
60 min, when penetration was estimated to be approximately 85%. The
half-life, as a measure of penetration rate, was approximately 13 min
(Shah et al, 1981).
6.2 Distribution
After 5 mg 14C-methomyl/kg had been dosed orally to five male
and five female rats, 8-9% of the initial activity was found in the
tissues and carcass 7 days later. The highest concentration of
activity was found in blood (2 mg/kg equivalents) with a distribution
of 3-4 mg/kg in red cells and 0.7-0.9 mg/kg in plasma. The
radioactivity concentrations were lower in other tissues (< 1 mg per
kg). As a proportion of the original dose, blood contained
approximately 2%, liver 0.4%, gastrointestinal tract 0.6% and other
individual tissues < 0.1% each. There was no significant difference
in distribution between males and females (Hawkins et al., 1991).
14C activity was distributed among a range of tissues after two
rats had been fed 200 mg methomyl/kg diet for 8 days and then given
5 mg 14C-methomyl/kg orally. Of the 14C dose, 9% was found in the
tissues and carcass within one day and 10% within 3 days (Harvey et
al., 1973).
When cynomolgus monkeys were given a single oral dose of 5 mg
14C-methomyl/kg, approximately 5% of the radioactivity was retained
in the tissues after 168 h. The highest concentrations of activity
were in the liver (0.7-0.9 mg/kg equivalents), fat (0.4-0.7 mg/kg
equivalents) and kidney (0.4-0.5 mg/kg equivalents). Lower
concentrations found in other tissues were generally higher than blood
levels of 0.1-0.2 mg/kg equivalents (Hawkins et al., 1992).
One hour after the dermal applications of 14C-methomyl to mice
(see section 6.1), 2.9% of the dose was present in blood, 5% in liver
and 56% in the remaining carcass. After 8 h the distribution was 6.1%
in blood, 3.3% in liver, 3.8% in the gastro-intestinal tract and
smaller amounts (< 1%) in other individual tissues. The remaining
carcass contained 15% of the original dose (Shah et al., 1981).
6.3 Metabolic transformation
In an initial investigation, two male rats were fed a diet
containing 200 mg methomyl/kg for 8 days, followed by intra-gastric
intubation of 1.2 mg 14C-methomyl (=5 mg/kg). One male rat was
treated similarly except that the 14C-methomyl was given after 19
days. Urinary and volatile metabolite identification was carried out
1 or 3 days after the 14C dose. Volatile products, trapped in
caustic soda solution or in cold traps, were identified as carbon
dioxide and acetonitrile, the latter confirmed by mass spectroscopy.
Countercurrent distribution of the urine showed that nearly all the
radioactivity was present as polar material. Methomyl, its
S,S-dioxide and MHTA were not detected. The methomyl S-oxide could
not be detected by TLC (Harvey et al., 1973).
A more detailed study (Hawkins et al., 1991), with five male and
five female rats receiving single oral doses of 14C-methomyl
(5 mg/kg), confirmed that the expired metabolites (over 120 h) were
carbon dioxide (22%) and acetonitrile (12%). The radioactive
components of the 0-24 h urine were separated by reverse phase HPLC,
ion partition chromatography and TLC. The major metabolite in urine
was identified by NMR and mass spectroscopy as the mercapturic acid
derivative of methomyl, equivalent to about 17% of the 14C-dose.
There were 10 minor components which included, on tentative
identification, acetonitrile, acetate and methomyl oxime sulfate.
Methomyl, MHTA and the anti-isomer form of methomyl were not detected.
Metabolic pathways for methomyl in the rat include the
displacement of the S-methyl moiety by glutathione and enzymic
transformation to give the mercapturic acid derivative. Another
pathway involves hydrolysis to give MHTA which is rapidly
broken down to carbon dioxide (Fig. 1).
Another proposed pathway involves the conversion of the
syn-isomer of methomyl (the insecticide form) to its anti-isomer. The
latter has been shown to produce acetonitrile as the main volatile
metabolite when given orally to rats (see section 6.4). It is
proposed that the anti-isomer hydrolyses to the anti-MHTA,
which then undergoes a Beckmann re-arrangement and elimination
reaction to form acetonitrile (Huhtanen & Dorough, 1976).
It is also likely that certain metabolic products such as
acetonitrile undergo further reactions, with the carbon components
being incorporated into natural body constituents such as fatty acids,
neutral lipids and glycerol, as shown in ruminants (see section
4.2.1).
It is probable that two of the main metabolic pathways also
operate in the monkey. When an oral dose of 14C-methomyl
(5 mg/kg body weight) was given to cynomolgus monkeys, the
major metabolites were CO2 (32-38%) and acetonitrile (4-7%) in the
expired air. These were derived, presumably, by the same processes as
described for the rat above. A combination of HPLC and TLC
characterized 18 radioactive metabolites in urine, with no metabolite
representing more than 4% of the dose. Small amounts of acetonitrile,
acetate, acetamide and MHTA sulfate were among the products found.
The mercapturic acid derivative of methomyl (a major rat urinary
metabolite) accounted for about 1% of the dose. The presence of these
minor metabolites are presumably the result of extensive metabolism of
primary metabolites (Hawkins et al., 1992).
A lactating cow was dosed twice daily by capsule for 28 days
with 14C-methomyl at a rate equivalent to 8 mg/kg in feed. Milk
samples were collected each day and selected tissues were taken within
24 h of the last dose. Radioactivity appeared in milk within one day
and reached a plateau of 0.5 mg/kg (equivalents) within 6 days. This
activity was mostly due to the reincorporation of the radiolabel into
fatty acids, lactose and other acetate derived products. No methomyl
or MHTA was detected; acetonitrile accounted for about 25% of the
radioactivity. The liver showed the greatest concentration of
radioactivity, equivalent to 9.23 mg/kg; kidney contained only
2.01 mg/kg and there were lower concentrations in fat and muscle. No
methomyl was detected in tissue; most of the radioactivity was
considered to be the result of reincorporation of the radiolabel as
acetate into natural constituents (Monson & Ryan, 1991).
A lactating goat was given 14C-methomyl by capsule, twice a
day, for 10 days at a dose rate equivalent to 20 mg/kg in feed. Milk,
blood, urine and faeces were sampled daily and selected tissues taken
within one day of the last dose. No methomyl or the metabolite MHTA
was detected in any of the samples. Approximately 16% and 7% of the
activity was excreted in urine and faeces, respectively, and about 8%
appeared in the milk and 17% in expired air. The milk activity
reached a plateau after 3 days and was equivalent to approximately
2 mg/kg. At this time the lactose component contained about 11-13% of
the milk activity. Hexane extracts, containing the triglyceride
components, contained 26-37% of the milk activity and the casein
component 8-9%. This indicates that methomyl had been completely
broken down and incorporated into natural constituents of milk.
Acetonitrile was identified as a volatile metabolite in milk and blood
(Harvey, 1980).
The examination of the liver fractions showed that the
radio-activity derived from methomyl was found in glycerol,
glycerol-3-phosphate, fatty acids, neutral lipids and insoluble
protein. This indicates a metabolic pathway via acetonitrile and
acetate into the natural occurring constituents in the liver. The
breakdown of methomyl and distribution of metabolic products in the
liver was shown to be similar in the cow (Monson, 1989).
Acetonitrile, CO2 and reincorporation products derived from
acetate found after the application of methomyl to plants (section
4.2.1) are similar to those identified in the above animal studies.
The proposed metabolic pathway for methomyl in animals is shown
in Fig. 1.
6.4 Elimination and excretion
Rat and monkey studies show that methomyl is very rapidly
metabolized and eliminated, the processes being largely completed
within 24 h.
Rats fed 200 mg methomyl/kg in diet and then given 5 mg
14C-methomyl/kg orally (see section 6.3 for detail) showed a 50%
elimination of 14C in expired air in 3 days in the form of carbon
dioxide and acetonitrile in the proportion of 1:2. Urinary excretion
of 14C was 27% in one day (Harvey et al, 1973).
In a more detailed study, where male and female rats were given
5 mg 14C-methomyl/kg orally (see section 6.3), approximately 53% of
the radioactivity was excreted in urine over 7 days, 45% of the dose
being excreted in the first 6 h. Faecal excretion contributed only
2-3% over 7 days. The other major path of elimination (over 5 days)
was via expired air as carbon dioxide (22% of dose) and acetonitrile
(12% of dose). Of this, 18% of the dose was expired as CO2 within
6 h and 10% as acetonitrile in 24 h. Overall, most of the
radiolabelled dose (80%) had been eliminated in 24 h with an estimated
half-life of 5 h. There was no obvious difference in the amount or
rate of excretion between males and females. The single oral dose
given to these animals (5 mg/kg) produced mild clinical signs of
cholinesterase inhibition which disappeared within 2 h of dosing
(Hawkins et al., 1991).
When methomyl was radiolabelled on the carbonyl group, the
elimination of 14CO2 was very rapid and equivalent to about 85% of
the oral dose in male and female rats. When the labelling was at the
- 14C=N group, the overall elimination in expired air in 24 h was
30% in the form of CO2 and acetonitrile (in the proportion of 2:1).
When 14C-MHTA was administered in the same way the expired component
was mainly 14CO2, equivalent to 22% of the dose. The anti-isomer
of methomyl mainly produced acetonitrile in the expired air,
equivalent to 28% of the dose given orally to rats. Rats given the
anti-MHTA by intraperitoneal injection produced ten times more
acetonitrile than those given the syn-MHTA. The urine from rats
treated orally with 14C-methomyl or MHTA contained 25-35% of the
radioactivity over a 24-h period (Huhtanen & Dorough, 1976).
In monkeys given 5 mg 14C-methomyl/kg orally, approximately 32%
of the dose was excreted in urine in 7 days, with 34% as CO2 and 5%
as acetonitrile in the expired air. Most of this was excreted in the
first 24 h. Faecal excretion amounted to only 3-4% (Hawkins et al.,
1992).
After dermal application of 14C-methomyl to mice (see section
6.1), the total excretion (urine plus CO2 plus faeces), as a
proportion of the applied dose, was 0.2% in 15 min, 12.9% in 60 min
and 54.5% in 480 min (Shah et al., 1981).
6.5 Retention and turnover
The absorption, metabolism and excretion of methomyl in the rat
are very rapid. No methomyl can be detected within the tissues or
excretory products within a few hours of dosing. Most of the dose is
eliminated within 24 h with an estimated half-life of 5 h (Hawkins et
al., 1991). Metabolic products, mainly in urine and expired air, are
also eliminated rapidly; tissue concentrations are very small and
lower than blood levels. There is no evidence for accumulation in
tissues. A similar picture exists for the metabolism of methomyl in
ruminant species.
6.6 Reaction with body components
Methomyl is a potent direct inhibitor of acetylcholinesterase in
both insects and mammals. The carbamylated enzymes undergo rapid
spontaneous reactivation (see section 7.8.1).
7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS
7.1 Single exposure
The results of the single exposure of technical methomyl by the
oral, dermal and inhalation routes in various species are shown in
Table 4.
Methomyl is very toxic by the oral route. In the rat, the signs
of toxicity are those expected from a cholinesterase inhibitor and
include profuse salivation, lacrimation, tremor, abnormal posture,
pupil constriction, diarrhoea and prostration. At lethal doses the
rats died within hours. Survivors began to recover within several
hours and had fully recovered within days. No compound-related
changes were seen in organs subjected to histopathological
examination.
The acute dermal toxicity of methomyl is very low. No deaths
occurred in rats or rabbits at the doses shown in Table 4. The
compound has high toxicity by the inhalation route in the rat, with
affected animals showing typical signs of cholinesterase inhibition.
No target organ effect was seen upon histopathological examination.
An LD50 of approximately 8 mg/kg was obtained when methomyl was
injected intraperitoneally in rats (Dashiell, 1972).
The acute oral toxicity of methomyl formulations is in proportion
to the amount of a.i. present and, therefore, they are less toxic than
methomyl itself (Table 5). The same pattern is seen with the results
of acute inhalation studies. The signs of toxicity in the oral and
inhalation studies are those shown by the active ingredient. The
dermal toxicity of the formulations is very low.
Ocular toxicity was shown by a solid formulation containing 92.4%
methomyl when 10 mg was introduced into rabbits' eyes. Typical
anticholinesterase effects were seen up to 20 min after treatment,
including pupillary constriction of the treated eyes, incoordination,
tremors and profuse salivation. All of the effects had disappeared by
the next day (Sarver, 1991g).
7.2 Short-term exposure
Six male rats were given methomyl in peanut oil by gavage at a
dose of 5.1 mg/kg body weight per day, 5 times per week for 2 weeks.
The signs of toxicity were the same as those exhibited in acute oral
studies (section 7.1) but they regressed during the second week of
dosing. All animals survived, and there were no compound-related
histopathological changes (Kaplan & Sherman, 1977).
Table 4. Acute toxicity of technical grade methomyl
Species Sex Route Vehicle Testa Result Reference
Rat M oral peanut oil LD50 17 mg/kg Sherman (1966)
Rat F oral peanut oil LD50 23.5 mg/kg Sherman (1968a)
Rat M oral water LD50 45 mg/kg Trivits (1979)
Rat M oral water LD50 34 mg/kg Sarver (1991a)
Rat F oral water LD50 30 mg/kg Sarver (1991a)
Rat M dermal water LD50 abraded skin > 1000 mg/kg Morrow (1972)
Rat M inhalation aerosol 4-h ALC 0.30 mg/litre Foster (1966a)
Rat M inhalation vapour 4-h ALC 0.04 mg/litre Foster (1966b)
Rat M inhalation spray 4-h LC50 0.45 mg/litre Hornberger
(1967)
Rat M/F inhalation aerosol 4-h LC50 0.258 mg/litre Panepinto
(1991a)
Rabbit M oral acetone/ ALD 30 mg/kg Sherman (1968c)
peanut oil
Table 4. (cont'd).
Species Sex Route Vehicle Testa Result Reference
Rabbit M/F dermal water LD50 intact skin > 2000 mg/kg Sarver (1991b)
Dog M oral capsule ALD 20 mg/kg Sherman (1968d)
Guinea-pig M oral acetone/ ALD 15 mg/kg Kaplan &
peanut oil Sherman (1977)
Monkey M/F oral water ALD 40 mg/kg Kaplan &
Sherman (1977)
a ALC = approximate lethal concentration; ALD = approximate lethal dose
Table 5. Acute toxicity of some methomyl formulations
Formulation Species Route Vehicle LD50 (mg/kg) or LC50 Reference
(% a.i.) (mg/litre)a
Lannate 40 SP rat oral water 61 (male) Sarver (1992a)
(41.6%) 73 (female)
Lannate 20 L rat oral methanol 129 Lheritier (1991a)
(21.5%)
Lannate 12.5 L rat oral water 208 Sarver (1991c)
(12.7%)
Lannate 40 SP rabbit dermal (intact skin) water > 2000 Sarver (1992b)
(41.6%)
Lannate 20 L rat dermal (intact skin) methanol > 4000 Lheritier (1991b)
(21.5%)
Lannate 40 SP rat inhalation (4 h) aerosol 0.66 Kelly (1992)
Lannate 20 L rat inhalation (4 h) aerosol 1.3 Jacks