UNITED NATIONS ENVIRONMENT PROGRAMME
INTERNATIONAL LABOUR ORGANISATION
WORLD HEALTH ORGANIZATION
INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 197
Demeton-S-methyl
The issue of this document does not constitute formal publication.
It should not be reviewed, abstracted, or quoted without the written
permission of the Manager, International Programme on Chemical Safety,
WHO, Geneva, Switzerland.
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.
Environmental Health Criteria 197
First draft prepared by Dr. A. Moretto, Institute of Occupational
Medicine, University of Padua, Italy
Published under the joint sponsorship of the United Nations
Environment Programme, the International Labour Organisation, and the
World Health Organization, and produced within the framework of the
Inter-Organization Programme for the Sound Management of Chemicals.
World Health Organization
Geneva, 1997
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WHO Library Cataloguing in Publication Data
Demeton-S-Methyl.
(Environmental health criteria ; 197)
1.Insecticides, Organophosphate - toxicity
2.Insecticides, Organophosphate - adverse effects
3.Environmental exposure 4.Occupational exposure
I.International Programme on Chemical Safety II.Series
ISBN 92 4 157197 7 (NLM Classification: WA 240)
ISSN 0250-863X
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CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR DEMETON-S-METHYL
PREAMBLE
ABBREVIATIONS
1. SUMMARY AND EVALUATION, CONCLUSIONS AND RECOMMENDATIONS
1.1. Summary and evaluation
1.1.1. Identity, physical and chemical properties, and
analytical methods
1.1.2. Sources of human and environmental exposure
1.1.3. Environmental transport, distribution and
transformation
1.1.4. Environmental levels and human exposure
1.1.5. Kinetics and metabolism
1.1.6. Effects on laboratory animals and in vitro
test systems
1.1.6.1 Single exposure
1.1.6.2 Short-term exposure
1.1.6.3 Long-term exposure
1.1.6.4 Skin and eye irritation and
sensitization
1.1.6.5 Reproduction, embryotoxicity and
teratogenicity
1.1.6.6 Mutagenicity and related end-points
1.1.6.7 Delayed neurotoxicity
1.1.6.8 Toxicity of metabolites
1.1.7. Mechanism of toxicity - mode of action
1.1.8. Effects on humans
1.1.9. Effects on other organisms in the laboratory
and field
1.2. Conclusions
1.3. Recommendations
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS
2.1. Identity
2.2. Physical and chemical properties
2.3. Conversion factors
2.4. Analytical methods
2.5. Formation of derivatives during storage
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1. Natural occurrences
3.2. Man-made sources
3.2.1. Production
3.2.2. Uses
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION
4.1. Transport and distribution between media
4.2. Abiotic and biotic transformation
4.2.1. Hydrolytic degradation
4.2.2. Photodegradation
4.2.3. Degradation in soil
4.2.4. Biodegradation in plants
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1. General population exposure
5.2. Occupational exposure during manufacture, formulation or
use
6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
6.1. Absorption, distribution and excretion
6.2. Metabolic transformation
7. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS
7.1. Single exposure
7.1.1. Oral
7.1.2. Inhalation
7.1.3. Dermal
7.2. Short-term exposure
7.2.1. Rat
7.2.2. Dog
7.3. Long-term exposure
7.3.1. Mouse
7.3.2. Rat
7.4. Skin and eye irritation and sensitization
7.4.1. Skin and eye irritation
7.4.2. Skin sensitization
7.5. Reproduction, embryotoxicity and teratogenicity
7.5.1. Reproduction
7.5.2. Embryotoxicity and teratogenicity
7.5.2.1 Rat
7.5.2.2 Rabbit
7.6. Mutagenicity and related end-points
7.6.1. DNA damage and repair
7.6.2. Mutation
7.6.3. Chromosomal effects
7.7. Delayed neurotoxicity
7.8. Toxicity of metabolites
7.9. Mechanism of toxicity - mode of action
7.10. Potentiation
8. EFFECTS ON HUMANS
8.1. General population exposure
8.2. Occupational exposure
8.2.1. Acute poisoning
8.2.2. Effects of short- and long-term exposure
9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD
9.1. Aquatic organisms
9.1.1. Algae
9.1.2. Invertebrates
9.1.3. Fish
9.2. Terrestrial organisms
9.2.1. Soil microorganisms
9.2.2. Invertebrates
9.2.3. Birds
9.2.4. Effects in field
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
10.2.1. Aquatic organisms
10.2.1.1 Acute risk
10.2.1.2 Chronic risk
10.2.2. Terrestrial organisms
10.2.2.1 Birds
10.2.2.2 Mammals
10.2.2.3 Bees
10.2.2.4 Earthworms
11. CONCLUSIONS AND RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH
AND THE ENVIRONMENT
12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
REFERENCES
RÉSUMÉ ET ÉVALUATION, CONCLUSIONS ET RECOMMANDATIONS
RÉSUMEN Y EVALUACION, CONCLUSIONES Y RECOMENDACIONES
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Environmental Health Criteria
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WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR DEMETON-S-METHYL
Members
Dr P.J. Abbott, Australia and New Zealand Food Authority
(ANZFA), Canberra, Australia
Dr K. Barabas, Department of Public Health, Albert Szent-Gyorgyi,
University Medical School, Szeged, Hungary
Dr A.L. Black, Woden, ACT, Australia
Professor J.F. Borzelleca, Pharmacology and Toxicology,
Richmond, Virginia, USA
Dr P.J. Campbell, Pesticides Safety Directorate, Ministry of
Agriculture, Fisheries and Food, Kings Pool, York,
United Kingdom
Professor L.G. Costa, Department of Environmental Health,
University of Washington, Seattle, USA
Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood,
Abbots Ripton, Huntingdon, Cambridgeshire, United Kingdom
Dr I. Dewhurst, Mammalian Toxicology Branch, Pesticides Safety
Directorate, Ministry of Agriculture, Fisheries and Food,
Kings Pool, York, United Kingdom
Dr V. Drevenkar, Institute for Medical Research and Occupational
Health, Zagreb, Croatia
Dr W. Erickson, Environmental Fate and Effects Division,
US Environmental Protection Agency, Washington, D.C., USA
Dr A. Finizio, Group of Ecotoxicology, Institute of Agricultural
Entomology, University of Milan, Milan, Italy
Mr K. Garvey, Office of Pesticide Programs (7501C),
US Environmental Protection Agency, Washington, D.C., USA
Dr A.B. Kocialski, Health Effects Division, Office of Pesticide
Programs, US Environmental Protection Agency,
Washington, D.C., USA
Dr A. Moretto, Institute of Occupational Medicine, University
of Padua, Padua, Italy
Professor O. Pelkonen, Department of Pharmacology and
Toxicology, University of Oulu, Oulu, Finland
Dr D. Ray, Medical Research Council Toxicology Unit, University
of Leicester, Leicester, United Kingdom
Dr J.H.M. Temmink, Department of Toxicology, Wageningen
Agricultural University, Wageningen, The Netherlands
Observers
Dr J.W. Adcock, AgrEvo UK Limited, Chesterford Park, Saffron,
Waldon, Essex, United Kingdom
Mr D. Arnold, Environmental Sciences, AgrEvo UK Ltd.,
Chesterford Park, Saffron Waldon, Essex, United Kingdom
Dr E. Bellet, CCII, Overland Park, Kansas, USA
Mr Jan Chart, AMVAC Chemical Corporation, Newport Beach,
California, USA
Dr H. Egli, Novartis Crop Protection AG, Basel, Switzerland
Dr P. Harvey, AgrEvo UK Ltd., Chesterford Park, Saffron Walden,
Essex, United Kingdom
Dr G. Krinke, Novartis Crop Protection AG, Basel, Switzerland
Dr A. McReath, DowElanco Limited, Letcombe Regis, Wantage,
Oxford, United Kingdom
Dr H. Scheffler, Novartis Crop Protection AG, Basel, Switzerland
Dr A.E. Smith, Novartis Crop Protection AG, Basel, Switzerland
Secretariat
Dr L. Harrison, Health and Safety Executive, Bootle, Merseyside,
United Kingdom
Dr J.L. Herrman, International Programme on Chemical Safety,
World Health Organization, Geneva, Switzerland
Dr P.G. Jenkins, International Programme on Chemical Safety,
World Health Organization, Geneva, Switzerland
Dr D. McGregor, Unit of Carcinogen Identification and Evaluation,
International Agency for Research on Cancer, Lyon, France
Dr R. Plestina, International Programme on Chemical Safety,
World Health Organization, Geneva, Switzerland
Dr E. Smith, International Programme on Chemical Safety,
World Health Organization, Geneva, Switzerland
Dr P. Toft, International Programme on Chemical Safety,
World Health Organization, Geneva, Switzerland
IPCS TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR DEMETON-S-METHYL
The Core Assessment Group (CAG) of the Joint Meeting on
Pesticides (JMP) met at the Institute for Environment and Health,
Leicester, United Kingdom, from 3 to 8 March 1997. Dr L.L. Smith
welcomed the participants on behalf of the Institute, and
Dr R. Plestina 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 demeton-S-methyl.
The first draft of the monograph was prepared by Dr A. Moretto,
Institute of Occupational Medicine, University of Padua, Italy.
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.
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
ACGIH American Conference of Governmental Industrial Hygienists
AChE acetylcholinesterase
ADI acceptable daily intake
a.i. active ingredient
BuChE butyrylcholinesterase
b.w. body weight
ChE cholinesterase
EC50 median effective concentration
GLC gas-liquid chromatography
HID highest ineffective dose
I50 concentration inhibiting 50% of the enzyme activity
i.p. intraperitoneal administration
i.v. intravenous administration
JMPR Joint Meeting on Pesticide Residues
Kd sorption coefficient
LC50 median lethal concentration
LD50 median lethal dose
LED lowest effective dose
LOEC lowest-observed-effect concentration
MRL maximum residue level
NT not tested
NTE neuropathy target esterase
NOAEL no-observed-adverse-effect level
NOEC no-observed-effect concentration
PEC predicted environmental concentration
RBC red blood cell
s.c. subcutaneous
SCE sister chromatid exchange
STS standard type of soil
TER toxicity-exposure ratio
TLC thin layer chromatography
TLV threshold limit value
TWA time-weighted average
1. SUMMARY AND EVALUATION, CONCLUSIONS AND RECOMMENDATIONS
1.1 Summary and evaluation
1.1.1 Identity, physical and chemical properties, and analytical
methods
Demeton-S-methyl, a pale yellow oily liquid with a penetrating
odour, is a systemic and contact organophosphate insecticide and
acaricide used to control Acarina, Thysanoptera, Hymenoptera and
Homoptera in fruits, cereals, ornamentals and vegetables. It has a
vapour pressure of 63.8 mPa at 20°C, is readily soluble in most
organic solvents, has a high water solubility of 3.3 g/litre at room
temperature and an octanol-water partition coefficient (log Pow) of
1.32. Demeton-S-methyl is stable in non-aqueous solvents.
Residual and environmental analyses are performed by extraction
with an organic solvent, followed by oxidation to the corresponding
sulfone. Measurement is then performed by gas chromatography, using a
phosphorus-specific detector.
1.1.2 Sources of human and environmental exposure
Prior to 1957, methyl-demeton was marketed as a mixture of
demeton-S-methyl and demeton-O-methyl isomers.
Demeton-S-methyl has been in use since 1957. It is formulated as
an emulsifiable concentrate and used as a spray on cereals, fruits,
ornamentals and vegetables. It is being replaced by oxydemeton-methyl,
which is a plant, soil and mammalian metabolite of demeton-S-methyl.
1.1.3 Environmental transport, distribution and transformation
Hydrolytic degradation of demeton-S-methyl depends on the pH of
the solution; at 22°C the half-life is 63 days at pH 4, 56 days at pH
7 and 8 days at pH 9. In soil, biodegradation is the primary route of
degradation. The half-life of demeton-S-methyl in soil is about 4 h.
However, after 24 h, oxydemeton-methyl still represents 20-30% of the
applied dose of demeton-S-methyl. The sorption coefficient (Kd) of
demeton-S-methyl in soil is 0.68 to 2.66, depending on the soil
composition.
Photolysis is not one of the major mechanisms of degradation of
demeton-S-methyl in the environment.
Metabolism in spring wheat is rapid and similar to that in soil
and mammals.
1.1.4 Environmental levels and human exposure
Primary exposure for the general human population is from
residues of demeton-S-methyl on food crops. The Joint FAO/WHO Meeting
on Pesticide Residues (JMPR) recommended acceptable daily intake (ADI)
is 0.0003 mg/kg body weight. This is a group ADI for demeton-S-methyl,
oxydemeton-methyl and demeton-S-methyl-sulfone, since the routine
analytical methods do not discriminate between these three compounds.
Excessive dermal exposure and absorption of demeton-S-methyl has
caused cholinergic toxicity in workers inadequately protected during
packaging of the concentrate formulation.
When volunteers engaged in a simulated spray activity with a
mixture of demeton-S-methyl and demeton-O-methyl (30 and 70%,
respectively) were exposed to 8.8-27 mg/m3 of the two active
ingredients combined, they experienced no adverse effects on plasma or
erythrocyte cholinesterase activities.
1.1.5 Kinetics and metabolism
Demeton-S-methyl is rapidly and almost completely absorbed from
the intestinal tract of rats and is uniformly (except for high
concentration in erythrocytes) distributed to body tissues. It is
rapidly metabolized and excreted via the urine. Blood concentration
decreases with an initial half-life of about 2 h. About 1% of the oral
dose is present in the body 24 h after treatment. The main metabolic
pathway of demeton-S-methyl in rats is the oxidation of the side
chain leading to the formation of the corresponding sulfoxide
(oxydemeton-methyl) and, to a lesser extent, after further oxidation,
to the sulfone. Another important metabolic route is O-demethylation.
1.1.6 Effects on laboratory animals and in vitro test systems
1.1.6.1 Single exposure
Demeton-S-methyl causes cholinergic toxicity. The LD50 values
for mammals range from 7 to 100 mg/kg body weight, depending on the
route of administration and species.
1.1.6.2 Short-term exposure
An early dietary study showed that rats fed demeton-S-methyl at
50 mg/kg diet had substantially reduced brain and erythrocyte
cholinesterase activity after 26 weeks of exposure. Cholinergic signs
were observed in rats fed 200 mg/kg diet during the first 5 weeks of
exposure.
In a one-year dietary study on dogs, a no-observed-adverse-effect
level (NOAEL) of 1 mg/kg diet (equal to 0.036 mg/kg body weight per
day) was established, based on effects on brain cholinesterase.
1.1.6.3 Long-term exposure
Mice were fed diets containing 0, 1, 15 or 75 mg/kg demeton-S-
methyl for 21 months. The NOAEL was found to be 1 mg/kg diet (equal to
0.24 mg/kg body weight per day) based on inhibition of brain
cholinesterase.
In rats fed diets containing 0, 1, 7 or 50 mg/kg demeton-S-
methyl, the NOAEL, based on inhibition of brain cholinesterase, was
1 mg/kg diet (equal to 0.05 mg/kg body weight per day).
No increased tumour incidence was found in either species.
1.1.6.4 Skin and eye irritation and sensitization
Demeton-S-methyl is a mild skin and eye irritant. Positive
results were obtained with the Magnusson and Klingman maximization
test in guinea-pigs. However, the Buehler epidermal patch test gave no
indication of skin sensitization, suggesting that sensitization should
not be a problem in the practical use of demeton-S-methyl.
1.1.6.5 Reproduction, embryotoxicity and teratogenicity
In a two-generation dietary rat study, demeton-S-methyl caused
reduced viability and body weight of pups (F1b generation only)
at a dose level of 5 mg/kg diet. The NOAEL was 1 mg/kg diet, equal to
0.07 mg/kg body weight per day.
Demeton-S-methyl was neither embryotoxic nor teratogenic in rats
and rabbits.
1.1.6.6 Mutagenicity and related end-points
Demeton-S-methyl induces point mutations in vitro. Chromosomal
effects have been demonstrated in vivo with commercial formulations
only. The available information is insufficient to permit an adequate
assessment of the genotoxic potential of demeton-S-methyl.
1.1.6.7 Delayed neurotoxicity
Demeton-S-methyl caused neither delayed polyneuropathy nor
inhibition of neuropathy target esterase (NTE) when tested in hens at
a level equal to the oral LD50.
1.1.6.8 Toxicity of metabolites
Two plant and mammalian metabolites of demeton-S-methyl
(i.e. oxydemeton-methyl and demeton-S-methylsulfone) are also
commercial pesticides and have been extensively studied. It has been
reported that the toxicological profile of these two compounds does
not significantly differ, either quantitatively or qualitatively, from
that of demeton-S-methyl.
1.1.7 Mechanism of toxicity - mode of action
Demeton-S-methyl is a direct cholinesterase inhibitor, and the
toxicity it causes is related to inhibition of acetylcholinesterase
(AChE) at nerve terminals. AChE inhibited by demeton-S-methyl
reactivates spontaneously with an in vitro half-life of about 1.3 h,
as expected for dimethyl phosphorylated AChE.
1.1.8 Effects on humans
A few cases of acute intoxication with cholinergic syndrome,
following suicide attempts, have been reported. Surviving patients,
including a pregnant woman, did not show delayed effects.
Following careless occupational exposure during packaging of
the commercial formulation, some workers developed cholinergic
toxicity which required pharmacological treatment. Absorption of
demeton-S-methyl was probably through the skin. Similarly, improper
working conditions may have caused excessive dermal absorption during
application of demeton-S-methyl in cotton fields.
1.1.9 Effects on other organisms in the laboratory and field
The 96-h EC50s for green algae range from 8 to 37 mg/litre. The
LC50s for a range of aquatic invertebrates range from 0.004 to
1.3 mg/litre. The toxicity for fish varies, with 96-h LC50 ranging
from 0.59 mg/litre for the rainbow trout to about 40 mg/litre for the
golden orfe, the goldfish and the carp.
The acute oral LD50 for the Japanese quail and the canary is
10-50 mg/kg body weight. In starlings, a single oral dose of 2 mg/kg
body weight caused 20% inhibition of brain AChE 3 h after treatment.
The LC50 of demeton-S-methyl in soil for earthworms is 66 mg/kg
for 14 days. The acute oral and contact LD50 for demeton-S-methyl are
0.21 and 0.6 µg/bee respectively. When used on winter wheat at the
suggested rate, demeton-S-methyl significantly reduced the number of
crop foliage invertebrates (mainly Empididae flies) but not the
number of soil surface entomophagous invertebrates.
1.2 Conclusions
Demeton-S-methyl is a highly toxic (class Ib of the WHO
classification) (WHO, 1996) organophosphorus ester insecticide. The
mechanism of toxicity is that of AChE inhibition at nerve terminals.
Exposure of the general population results mainly from residues
present in crop commodities.
With good work practices, hygienic measures and safety
precautions, the use of demeton-S-methyl during manufacture or
application should not cause adverse effects. Effects due to chronic
exposure are unlikely to occur.
Demeton-S-methyl does not persist in the environment and is not
accumulated by organisms. It has high acute toxicity to aquatic
invertebrates and is toxic to fish and birds, leading to high or
moderate risk factors for these organisms. However, significant field
kills of organisms have not been reported for the compound.
Precautions should be taken to minimize exposure of non-target
organisms (e.g., do not spray over water bodies, minimize exposure by
spray drift).
1.3 Recommendations
For the health and welfare of workers and the general population,
the handling and application of demeton-S-methyl should only be
entrusted to supervised and well-trained operators who follow the
required safety measures and good application practices.
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS
2.1 Identity
Chemical formula: C6H15O3PS2
Chemical structure:
O
"
CH3CH2SCH2CH2SP(OCH3)2
Relative molecular mass: 230.3
Common name: demeton-S-methyl
CAS chemical name: S-[2-(ethylthio)ethyl] O,O-dimethyl
phosphorothioate
IUPAC name: S-2-ethylthioethyl O,O-dimethyl
phosphorothioate
CAS registry number: 919-86-8
RTECS number: TG1750000
Common synonyms and AI3-24963; BAY 18436; Bayer 18 436;
trade names: Bayer 25/154; Demetox; DEP 836 349;
Duratox; ethanethiol,
2-(ethylthio)-S-ester with O,O-dimethyl
phosphorothioate; HSDB 6410;
Isometasystox; Isomethylsystox;
Metaisoseptox; Metaisosystox; Metasystox
(I); metasystox forte; Metasystox I;
Metasystox J; Metasystox 55; methyl
demeton thioester; methyl isosystox;
methyl-mercaptofos teolery;
methyl-mercaptofos teolovy (USSR);
methylmercaptofostiol (USSR); Mifatox;
O,O-dimethyl S-(2-(ethylthio)
ethylphosphorothioate; O,O-dimethyl
S-ethylmercaptoethyl thiophosphate;
O,O-dimethyl 2-ethylmercaptoethyl
thiophosphate, thiolo isomer;
phosphorothioic acid, O,O-dimethyl
S-(2-(ethylthio)ethyl) ester;
phosphorothioic acid,
S-(2-(ethylthio)ethyl) O,O-dimethyl
ester; S-(2-(ethylthio)ethyl);
dimethyl phosphorothiolate;
S-(2-(Ethylthio)ethyl) O,O-dimethyl
phosphorothioate (8CI)(9CI);
S-(2-(ethylthio)ethyl) O,O-dimethyl
phosphorothioate; S-(2-ethylthio)ethyl)
O,O-dimethyl phosphorothioate;
S-(2-ethylthioetyl)0,0-dimethyl
phosphorothioate; S-2-Ethylthioethyl-
dimethyl phosphorothioate; USP 2 571
989; 2-Ethylthioethyl dimethyl
phosphorothioate.
Formulations: EC (250 or 500 g a.i./litre), DSM
(Campbell), Metasystox55 (Bayer),
Mepatox (FCC),
EC (580 g/litre).
Purity: >90%
Impurities: O,O,S-trimethylthiophosphate (maximum of
1.5%)
O-methyl-S-2-(ethylmercapto)-ethylthioph
osphate (maximum of 3.0%)
2-ethylthioethylmercaptan max 0.8%
bis(2-ethylthioethyl)-disulfide (maximum
of 0.8%)
Various ionic components (sulfonium
compounds, organic salts) (total maximum
of 2.5%)
Oligomeric alkyl(thio) phosphates
(maximum of 1.0%)
Water (maximum of 0.1%)
2.2 Physical and chemical properties
Some relevant physical and chemical properties are summarized in
Table 1.
Table 1. Some chemical and physical properties of demeton-S-methyl
Physical state: oily liquid
Colour: pale yellow
Odour: penetrating, reminiscent of leeks
Boiling point 74°C at 6.65 Pa (0.05 mmHg)
92°C at 26.6 Pa (0.20 mmHg)
102°C at 53.2 Pa (0.40 mmHg)
118°C at 133 Pa (1.00 mmHg)
Vapour pressure: 21.3 mPa (1.6 × 10-4 mmHg) at 10°C
63.8 mPa (4.8 × 10-4 mmHg) at 20°C
193 mPa (1.45 × 10-3 mmHg) at 30°C
400 mPa (3.8 × 10-3 mmHg) at 40°C
Relative density at 20°C: 1.21
n-Octanol/water partition
coefficient: log Pow = 1.32
Solubility in water: 3.3 g/litre (at room temperature)
Solubility in organic readily soluble in most organic
solvents: solvents; limited solubility in
petroleum ether
Stability: hydrolysed by alkali and oxidized to the
sulfoxide (oxydemeton-methyl) and
sulfone (demeton-S-methylsulfone)
Half-life in water: 11 days at 37°C
Half-lives at 22°C: 63 days at pH 4
56 days at pH 7
8 days at pH 9
2.3 Conversion factors
1 ppm = 9.42 mg/m3 (at 25°C)
1 mg/m3 = 0.106 ppm
2.4 Analytical methods
Analytical methods for the determination of residues of the
demeton-S-methyl group (i.e. demeton-S-methyl, its sulfoxide and its
sulfone) are either identical or very similar.
Originally, colorimetric methods (i.e. determination of total
phosphorus) were used (FAO/WHO, 1993). Current methods are based on
GLC. In principle, these methods involve an oxidation step, using
potassium permanganate, to produce demeton-S-methylsulfone, which is
then determined with a thermoionic emission detector.
A GLC method (Wagner & Thornton, 1977) is suitable for
determining residues in plants, soil and water. The method is based on
the principle of oxidation described above, with variations depending
on the sample to be analysed. Before the oxidation step, maceration
with acetone is used for samples with a high fat or oil content. The
macerate and water samples are then extracted with chloroform or
dichloromethane. Since the analytical method involves the oxidation to
the sulfone, the determination is of demeton-S-methylsulfone, from
which the demeton-S-methyl residue can be calculated. The method was
used to determine residues in a wide range of crops with a minimum
recovery above 80%. The limit of determination depends upon the sample
and generally lies between 0.01 and 0.2 mg/kg. Another method, based
on similar principles, has been described for oxydemeton-methyl
residues in plant and animal tissues and in soil (Thornton et al.,
1977).
An alternative GLC method for sulfides (including demeton-S-
methyl), sulfoxides and sulfones has been proposed by Hill et al.
(1984), who reported that the use of acetone as a co-solvent during
potassium permanganate oxidation causes unpredictable (from negligible
to complete) loss of demeton-S-methyl. These authors used ethyl
acetate for extraction of organophosphorus compounds from fruit and
vegetable samples (Anonymous, 1977). The extracts were cleaned-up by
chromatography on a column of activated charcoal, magnesium oxide and
Celite. The compounds were eluted from the column using a mixture of
ethyl acetate, acetone and toluene. A mean recovery of >68% (mainly
>80%) was found for a number of organophosphorus sulfides, sulfoxides
and sulfones, that of demeton-S-methyl being 82.4±6.6% (mean ± SD,
n=10) when determined in lettuce.
Wilkins et al. (1985) reported the characterization of nearly
90 organophosphorus sulfides, sulfoxides and sulfones by gas
chromatography and mass spectrometry. Using similar experimental
conditions with three different mass spectrometers, the spectra
produced from a given compound were almost identical.
A TLC method for 10 different organophosphorus insecticides
(including demeton-S-methyl and demeton-S-methylsulfone) was reported
by Funk et al. (1989). This method has a limit of detection of
4-10 ng/spot.
2.5 Formation of derivatives during storage
Storage of "pure" demeton-S-methyl in the dark at room
temperature leads to the formation of sulfonium derivatives. This was
found to be associated with increased intravenous toxicity but not
oral toxicity (Heath & Vandekar, 1957). Hecht (1960) reported that the
oral toxicity in rat did not change if 4- or 24-hour-old aqueous
solutions of demeton-S-methyl were used.
The concentration in a water suspension of 1 g a.i./litre
decreased by about 50 and 75% after 7 and 28 days of storage
(apparently at 37°C), respectively (Hecht, 1960) (see also section
7.1).
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1 Natural occurrences
Demeton-S-methyl does not occur as a natural product.
3.2 Man-made sources
3.2.1 Production
In 1954, a reaction mixture containing demeton-S-methyl and
demeton-O-methyl (O-2-ethylthioethyl O,O-dimethyl phosphorothioate)
was introduced by Farbenfabrik Bayer AG (now Bayer AG) with the common
name of demeton-methyl. An improved manufacturing process led to the
introduction, in 1957, of demeton-S-methyl by Bayer AG. Information on
the global production is not available. It is formulated as an
emulsifiable concentrate.
3.2.2 Uses
Demeton-S-methyl is a systemic and contact insecticide and
acaricide used to control Acarina, Thysanoptera, Hymenoptera and
Homoptera on cereals, fruits, ornamentals and vegetables. It is
applied as an emulsifiable concentrate formulation mainly as a spray
and usually at a concentration of 0.025% a.i. (FAO/WHO, 1974). It has
been reported that most national registrations for demeton-S-methyl
should be transferred during the next few years to oxydemeton-methyl,
which has similar use and is applied at similar rates (FAO/WHO, 1993).
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION
4.1 Transport and distribution between media
The sorption behaviour of demeton-S-methyl and three other
organophosphorus pesticides in natural pond sediments was tested by
Froebe et al. (1989). Two different sediments were used, containing
9.3 and 6.2% organic matter, at pH 5.9 and 6.5, and a specific surface
area of 23.7 and 16.7 m2/g, respectively. The semi-quantitative
mineralogical composition was similar. For the four pesticides, their
sorption coefficients (Kd) followed the same sequence as their
lipophilicity (expressed as n-octanol/water coefficient). The
sorption efficiency for demeton-S-methyl was higher in the sediment
with a lower content of organic matter (Kd of 0.689 and 2.66,
respectively).
4.2 Abiotic and biotic transformation
4.2.1 Hydrolytic degradation
In water at 22°C demeton-S-methyl has a half-life of 63 days at
pH 4, 56 days at pH 7, and 8 days at pH 9. The main reactions are
demethylation in acid medium and hydrolysis of the phosphorus-ester
bond in basic medium (Krohn, 1984) (see also section 2.2).
4.2.2 Photodegradation
Demeton-S-methyl in aqueous solution does not absorb any light at
247 nm or longer wavelengths. Therefore, no direct photo-degradation
of demeton-S-methyl in the environment is to be expected
(Hellpointner, 1990). When solutions of demeton-S-methyl in water
(3.6-3.7 mg/litre) were irradiated for 8 h with a high-pressure
mercury vapour lamp, no photodegradation was detected. However, when
solutions were fortified with humic acid (10 mg/litre), the half-life
of photodegradation was
8 h (the degradation products were not identified). This suggests that
degradation by sensitized or indirect photolysis may also occur in the
environment (Wilmes, 1984).
4.2.3 Degradation in soil
The metabolism of demeton-S-methyl in soil is shown in Fig. 1.
The ability of microbial organisms to biodegrade demeton-S-methyl
sulfoxide was evaluated in a laboratory test and under aerobic
conditions using various species (Nocardia, Arthrobacter,
Corynebacter, Brevibacterium, Bacillus and Pseudomanas) and strains
(Ziegler et al., 1980). Almost all the organisms were able to degrade
the insecticide. The amount of insecticide degraded ranged between 65%
(Arthrobacter roseoparaffineus) and 99% (Pseudomonas putida) after
14 days of incubation. The biodegradation process led to the
production of several metabolites. In particular, P. putida and
Nocardia sp. during growth were able to metabolize almost completely
2 mmol/litre of demeton-S-methyl sulfoxide (99% and 98% respectively)
within 13 days. Three major metabolites, i.e., O-demethyl-demeton-S-
methyl, demeton-S-methyl sulfoxide and bis[2-ethylsulfinyl)ether]
disulfide, were found to be produced by Pseudomonas, whereas Nocardia
showed different pathways leading to the formation of different
metabolites, i.e., 2-(ethylsulfonyl)ethane sulfonic acid,
demeton-S-methyl sulfone and bis[2-(ethylthio)ethyl] disulfide. In
sterile controls about 48% of the parent compound remained after 20
days of incubation.
In a laboratory study, biodegradation of demeton-S-methyl was
investigated in two different standardized soils (S1, and S2) with
different characteristics particularly in terms of organic matter
content and cation exchange capability (Wagner et al., 1985). The
study was conducted under aerobic and anaerobic conditions with
sterile controls and using 14C-labelled demeton-S-methyl. One day
after the start of the test no parent compound could be detected.
After 63 days under aerobic conditions 54% (S1) and 34% (S2) of the
14C activity applied was eliminated as 14CO2, indicating a higher
activity in the soil with higher organic matter content and cation
exchange capability. Various metabolites were isolated and identified
(Fig. 1). Under anaerobic conditions 0.5% (S1) and 1.1% (S2) of the
14C activity applied was eliminated as 14CO2, and there was a
predominance of the metabolites O-demethyl-demeton-S-methyl and
demeton-S-methyl sulfoxide. The half-lives of demeton-S-methyl were
approximately 5 h in the non-sterile soil and 70 h in the sterile test
control.
4.2.4 Biodegradation in plants
The metabolic behaviour of ethylene-1-14C demeton-S-methyl in
spring wheat (Schirokko variety) was investigated in a greenhouse test
(Wagner & Oehlmann, 1987). The distribution of the 14C radioactivity
in the wheat matrix was determined at 3, 14, 42 and 60 days after
application of demeton-S-methyl during crop stage 0 (flowering), and
the isolated biotransformation products were analysed by spectroscopy.
The composition of the applied spray was 241.5 µCi ethylene-1-14C
demeton-S-methyl (corresponding to about 0.5 kg a.i./hectare as
opposed to a use rate of 0.15 kg a.i./hectare) in 2 ml benzene plus
1 drop emulsifier Np10 plus 20 ml water. The majority of the applied
radioactivity was found in the wheat straw (about 85% of total
radioactivity corresponding to 10.3 mg a.i. equivalents/kg, 60 days
after application), while the amount in the kernels at harvest was
substantially smaller (0.7 mg a.i. equivalents/kg). About 0.5 mg a.i.
equivalents/kg could not be extracted with water and organic solvents,
and 24% of the 14C activity could not be extracted from the straw
using solvents of different polarity. Only a minor portion of the a.i.
was detected 3 days after application. Identified metabolites were
O,O-dimethyl-S-[2-(ethylsulfonyl)-ethyl]-thiophosphate (11.7% of
recovered radioactivity at 60 days), O,O-dimethyl-S-[2-
(ethylsulfonyl)-ethyl]-thiophosphate (9.8% of recovered radioactivity
at 60 days), 2-ethylsulfonyl-ethanesulfonic acid (8.2% of recovered
radioactivity at 60 days), S-(2-(ethylsulfonyl)-ethyl)-thiophosphate
(5.2% of recovered radioactivity at 60 days), 1-(ethylsulfinyl)-2-
(methylsulfinyl)-ethane (8.9% of recovered radioactivity at 60 days),
and 2-ethylsulfinylethanol (5.1% of recovered radioactivity at 60
days). Additional biotransformation products occurred to a minor
extent (<0.2%) in the kernels only.
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1 General population exposure
Data on residues in crops resulting from the use of demeton-S-
methyl have been summarized by FAO/WHO (1974). Maximum residue limits,
varying from 0.01 to 1 mg/kg, have been recommended for a range of
commodities. These residue limits were previously expressed as
demeton-S-methyl but now as oxydemeton-methyl, and are common for
demeton-S-methyl, oxydemeton-methyl and demeton-S-methylsulfone
(see section 2.4). More updated values referring to the use of
oxydemeton-methyl have been reported by FAO/WHO (1993). Data on
residue levels in meat and milk from cows, and in chickens, eggs and
fish have been reported for oxydemeton-methyl in the same document
but not for demeton-S-methyl. Some data are also available for
demeton-S-methylsulfone (FAO/WHO, 1993). The JMPR recommended a group
ADI of 0-0.003 mg/kg body weight for demeton-S-methyl,
oxydemeton-methyl and demeton-S-methyl sulfone (FAO/WHO, 1990).
5.2 Occupational exposure during manufacture, formulation or use
When Metasystox (30% demeton-S-methyl, 70% demeton-O-methyl) was
sprayed with a hand-held nebulizer, the concentration of the two
active ingredients combined was 8.8-27 mg/m3 of ambient air (Klimmer
& Pfaff, 1955; see also section 8.2.2).
The ACGIH proposed a very conservative TLV/TWA for methyl-demeton
of 0.5 mg/m3 with the "skin" notation (ACGIH, 1993). The "skin"
notation indicates that dermal absorption is likely to occur and
therefore adequate protective equipment should be used.
6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
6.1 Absorption, distribution and excretion
Absorption, distribution and excretion of (ethylene-1-14C)-
demeton-S-methyl (93% radiochemical purity) were studied in SD SPF
rats. Male rats (n=5 per group) were given a single oral dose of 0.1,
0.5, 5 or 10 mg/kg body weight or a single intravenous dose of 0.5 or
1 mg/kg body weight of radio-labelled compound. Female rats (n=5)
received a single oral dose of 0.5 mg/kg body weight. Total
radioactivity recovery was 90-100% in each animal. The authors
reported that kinetic parameters did not change with dose or sex;
therefore, only data on male rats given 5 mg/kg orally have been
reported. Absorption after oral administration was rapid (peak blood
concentration was reached within one hour) and almost complete (98-99%
of the administered radioactivity was, in fact, eliminated through the
urine). The blood concentration decreased with a half-life of about
2 h during the first 6 h and then with a half-life of about 6 h for
the next 48 h. The half-life thereafter was even longer. The
radioactivity associated with erythrocytes accounted for almost all of
the blood radioactivity found 24 h or more after dosing. The half-life
of urinary elimination was 2-3 h during the first 24 h and 1.5 days
thereafter. Elimination through faeces and exhaled air accounted for
0.5-2% and about 0.2% of the applied dose, respectively. Except for
erythrocytes, radioactivity was distributed rather uniformly in
various body tissues and organs. At 2, 24 and 48 h after dosing, the
radioactivity remaining in the body was about 60%, 1% and 0.5% of the
administered dose, respectively. At 10 days, radioactivity was almost
undetectable in most organs except in the erythrocytes. In a separate
experiment, whole-body autoradiography indicated some localized
accumulation of radioactivity in the pineal gland, thyroid and some
glands of the genital tract (Cowper's gland, seminal vesicle,
accessory genital gland). When the labelled compound (0.5 mg/kg body
weight) was administered into the duodenum of rats with cannulated
bile ducts, it was shown that about 3% of the radioactivity was
excreted into the bile in the first 24 h (Weber et al., 1978).
6.2 Metabolic transformation
The proposed metabolic pathway of demeton-S-methyl in rats
is shown in Fig. 2. This was derived from the analysis of urine
samples of SD rats given a single oral dose of 5 or 10 mg/kg of
(ethylene-1-14C)-demeton-S-methyl. Urine samples were collected
for 8 or 24 h after dosing and there was a 92% or 96% recovery,
respectively, of the applied dose. The main metabolic route was
oxidation of the side chain leading to the formation of the
corresponding sulfoxide oxydemeton-methyl, and to a lesser extent,
after further oxidation, the sulfone; O-demethylation was also an
important route. Neither glucuronide nor sulfate conjugates were found
(Ecker, 1978; Ecker & Cölln, 1983).
7. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS
7.1 Single exposure
Demeton-S-methyl causes cholinergic toxicity. The acute toxicity
data are reported in Table 2.
Heath & Vandekar (1957) and Vandekar (1958) showed a significant
increase in intravenous but not oral toxicity after storage of
demeton-S-methyl ("pure") at room temperature in the dark. This was
associated with the formation of sulfonium derivatives, which have a
lower oral toxicity, possibly because of poor absorption.
Dilution with water also increased the intravenous toxicity, and
this was again associated with the formation of sulfonium derivatives.
The maximum toxicity of a 1 mg/ml suspension kept at 35°C for one day
was about 30 times the initial toxicity (the LD50 decreased from
about 60 to about 2 mg/kg in rats) (Heath & Vandekar, 1957). Similar
results were obtained with commercial Metasystox (70% demeton-O-
methyl, 30% demeton-S-methyl) (see also section 2.2.)
7.1.1 Oral
Following oral dosing with demeton-S-methyl performed on a very
small number of animals (one per dose level), one rabbit given
50 mg/kg died within 2 h, while the dose of 20 mg/kg caused symptoms
but the animal recovered. A cat given 10 mg/kg died after 2 days,
while the dose of 5 mg/kg caused signs that were reversible and
animals recovered (few details given) (Hecht, 1955).
Single oral doses (180 mg/kg) of metasystox, containing 25%
demeton-S-methyl, were administered to seven male buffalo calves
(10-12 months of age). Signs of poisoning appeared 15 to 35 min later.
Two calves were treated repeatedly with atropine (1.5 mg/kg body
weight, i.v.), D-tubocurarine (0.1 mg/kg body weight, i.v.) and
glucose (3-4 mg/kg body weight, i.v.). Another two calves were treated
repeatedly with atropine (1.5 mg/kg body weight, i.v.), gallamine
(1 mg/kg body weight, i.v.) and glucose (3-4 mg/kg body weight, i.v.)
Three calves were not treated. All calves displayed typical
cholinergic signs. Treatments delayed but did not prevent death, which
occurred in about 2 h in calves not treated with antidotes and in
about 23 h in calves treated with antidotes (Mitra et al., 1978).
7.1.2 Inhalation
The LC50 (4 h of exposure) for Wistar rats was found to be 310
and 210 mg/m3 for males and females, respectively (Flucke & Pauluhn,
1983).
Table 2. LD50 of demeton-S-methyl for various species and different routes of administration
Species Sex Observation Route Purity LD50 Vehicle References
(strain) period (mg/kg
(days) body weight)
Mouse M 3 oral ? 17 ? Klimmer & Pfaff (1955)
Mouse ? 7 i.v. ? 7 water Hecht (1960)
Rat F 1 oral "pure" 63 ? Heath & Vandekar (1957)
Vandekar (1958)
Rat M 3 days minimum oral ? 40 ? Klimmer & Pfaff (1955)
Rat ? ? oral ? 35 ? Hecht (1955)
Rat M 14 oral 25% formulation 33 water Klimmer (1964)
(Wistar)
Rat M ? oral 86-89% 57-64 Lutrol 9 Klimmer (1964)
(Sprague-
Dawley)
Rat M & F 14 oral 50% formulation 64-65 water Flucke & Pauluhn (1983)
(Wistar)
Rat M 7 oral 50% formulation 129 water Edson (1960)
(Wistar)
Rat M 14 oral 90% formulation 44 cremophor EL Flucke & Kimmerle (1977)
(Wistar)
Table 2. (con't)
Species Sex Observation Route Purity LD50 Vehicle References
(strain) period (mg/kg
(days) body weight)
Rat F 10 oral ? 80 ethanol (20%) DuBois & Doull (1955)
(Sprague- and DuBois & Plzak (1962)
Dawley) propylene
glycol (80%)
Rat M & F 14 i.p. ? 7.5 ethanol (20%) DuBois & Doull (1955)
(Sprague- and propylene DuBois & Plzak (1962)
Dawley) glycol (80%)
Rat ? ? i.p. formulation 10 water Hecht (1960)
Rat ? ? dermal ? 85 ? Edson (1960)
Rat M 14 dermal 50% formulation 71 none Flucke & Pauluhn (1983)
(Wistar)
Rat F 14 dermal 50% formulation 45 none Flucke & Pauluhn (1983)
(Wistar)
Rat ? 7 dermal technical 100-200 none Hecht (1960)
Rat ? 7 dermal 25% formulation about 10 none Hecht (1960)
Rat F 1 i.v. "pure" 65 ? Heath & Vandekar (1957)
Vandekar (1958)
Table 2. (con't)
Species Sex Observation Route Purity LD50 Vehicle References
(strain) period (mg/kg
(days) body weight)
Guinea- M 10 oral ? 110 ethanol (20%) Du Bois & Doull (1955)
pig and propylene
glycol (80%)
Guinea- M 14 i.p. ? 12.5 ethanol (20%) Du Bois & Plzak (1962)
pig and propylene
glycol (80%)
When rats (n=2) and mice (n=4) were exposed for 1 h to 1, 2.5 or
5 g/m3 of demeton-S-methyl (alcohol solution), all mice died whereas
rats displayed signs but recovered (few experimental details given)
(Hecht, 1955).
Rats (n=20) were exposed for 8 h to nebulized demeton-S-methyl
(0.5 g/m3 of air), which was obtained from a 25% emulsifiable
commercial formulation diluted 1:250 (0.1% final concentration of
active ingredient). None of the animals died or showed overt
cholinergic signs. Erythrocyte cholinesterase activity, determined in
three animals immediately after the end of exposure, was reduced by
70%. When purified active ingredient was used, lower erythrocyte
cholinesterase inhibition (60%) was found under the same experimental
conditions. This was paralleled by an increased rat LD50 (from 10 to
27.5 mg/kg i.p.) (Hecht, 1960).
7.1.3 Dermal
Doses of 20 or 100 mg/kg demeton-S-methyl applied to the shaved
skin of two cats caused death. A dose of 10 mg/kg caused mild signs;
very few details were given (Hecht, 1955).
7.2 Short-term exposure
7.2.1 Rat
Groups of six male rats (strain not specified) were fed
demeton-S-methyl at levels of 0, 50, 100 or 200 mg/kg diet in
the diet (equivalent to 0, 5, 10 and 20 mg/kg body weight per day,
respectively) for 6 months. Cholinergic signs (slight tremors and
fasciculations) were observed at the highest dose-level during the
first 5 weeks of the study. Brain and erythrocyte cholinesterase
activities were reduced at 50 mg/kg diet (by about 80 and 88%,
respectively), 100 mg/kg diet (by about 85 and 92%) and 200 mg/kg diet
(by about 90 and 94%) groups. Body weight gain was depressed at 100
and 200 mg/kg diet. Gross microscopic examination of tissues (liver,
kidney and adrenals) showed no treatment-related changes (Vandekar,
1958).
Groups of 30-day-old female Holtzman rats were fed dietary
levels of 0, 1, 5 or 25 mg/kg diet of demeton-S-methyl (purity not
reported) for 1 week. At termination, serum, liver and brain
acetylcholinesterase (n=3) and liver and serum aliesterase (n=3) with
diethylsuccinate and tributyrin as substrates activities were
measured. Interpolated dietary levels producing 50% inhibition were
15-28 mg/kg diet for acetylcholinesterase, 4-6 mg/kg diet for liver
aliesterase and about 25 mg/kg diet for serum aliesterase, equivalent
to 1.5-2.8, 0.4-0.6 and 2.5 mg/kg body weight per day, respectively
(Su et al., 1971).
7.2.2 Dog
In a one-year study, pure-bred beagle dogs (n=6 animals of each
sex per group) were fed 0, 1, 10 or 100 mg a.i./kg diet (day 1-36) or
50 mg a.i./kg diet (day 37-termination) of demeton-S-methyl (52.2% in
xylene). Haematological, blood biochemical and urinalysis parameters
were determined during pretest period and at months 1, 2, 3, 4, 5, 6,
8, 10, 12. Hearing tests and ophthalmoscopic examinations were
performed once in the pretest period and at months 3, 6 and 12 of
treatment. At termination animals were killed for pathology, and
determination of organ weights, brain cholinesterase activity, hepatic
cytochrome P-450 and triglyceride contents and N-demethylase
activity were carried out.
All animals survived the study. Diarrhoea and vomiting were
observed in all animals, most frequently in the high-dose group: these
animals also showed reduced food consumption before the dose was
reduced to 50 mg/kg diet. The mean daily compound intake was found to
be 0.036, 0.36 and 4.6/1.5 mg/kg body weight at 1, 10 and 100/50 mg/kg
diet, respectively. Body weight was similar in all groups. No
alterations were observed in the hearing test and ophthalmoscopic
examination. Haematological, blood chemistry (excluding cholinesterase
activities) and urinalysis parameters and organ weights at termination
were not significantly altered by any of the treatments. Hepatic
biochemical parameters were not altered by any of the treatments. No
treatment-related gross pathology alterations were found. However,
multifocal slight/moderate atrophy and/or hypertrophy of proximal
renal tubules was demonstrated in three males and three females of the
high-dose group. Plasma cholinesterase activity was reduced as
compared to controls by 20-30% and 5-20% in males and females,
respectively, at 10 mg/kg diet, and by 45-65% (males) and 50-70%
(females) at 50 mg/kg diet. Erythrocyte cholinesterase activity was
reduced by 25-35% and 30-45% in males and females, respectively, at
10 mg/kg diet. A higher inhibition was found at 50 mg/kg diet, where
inhibition was 80-90% and 55-65% in males and females, respectively.
Brain cholinesterase activity was reduced by 25% in males at 10 mg/kg
diet and by 64% (males) and 15% (females) at 50 mg/kg diet. Based on
effects on brain cholinesterase activity, the NOAEL was 1 mg/kg diet,
equal to 0.036 mg/kg body weight per day (Bathe, 1983).
7.3 Long-term exposure
7.3.1 Mouse
A long-term carcinogenicity study was conducted in NMRI mice
(70 animals of each sex per group) that were given demeton-S-methyl
(about 50% in xylene) mixed into the feed with approximately 10 mg/kg
diet of groundnut oil at concentrations of 0, 1, 15 or 75 mg a.i./kg
diet, or xylene (75 mg/kg diet). Groups were subdivided into two
subgroups: one (n=20) was terminated at 12 months, the second one was
terminated at 21 months.
Animals in the high-dose group had a lower (significantly lower
during the first 4 weeks only) food consumption and a reduced (about
10% throughout the study in males only, and at the beginning in
females) body weight. The mean daily intake of demeton-S-methyl was
(males/females): 0.24/0.29, 3.47/4.18, 17.81/20.0 mg/kg body weight
at 1, 15, 75 mg/kg diet, respectively. Clinical signs due to
cholinesterase inhibition were not observed. Mortality at 21 months
was (males/females) 16/30, 13/34, 17/35, 16/35 and 16/32% in the
control, low-, mid-, high-dose and xylene groups, respectively.
Haematological and clinical chemical parameters were not affected by
the treatment except plasma urea (lower than control in the high-dose
males) and plasma and erythrocyte cholinesterase activities. Plasma
cholinesterase activity was significantly decreased in mid- (by
63-74%) and high-dose (by 91-97%) groups. Erythrocyte cholinesterase
activity was only slightly reduced in the mid- and high-dose groups.
Brain cholinesterase activity (n=10 per group) was reduced in
high-dose groups (in males by 70% and in females by 59%) and in the
mid-dose group (in males by 44% and in females by 38%). Histological
examination did not reveal an increased incidence of neoplastic and
non-neoplastic lesions in treated groups. Based on inhibition of brain
cholinesterase, the NOAEL was 1 mg/kg diet, equal to 0.24 mg/kg body
weight per day (Schmidt & Bomhard, 1988).
7.3.2 Rat
Wistar rats (60 animals of each sex per group) were given
demeton-S-methyl (about 50% in xylene mixed into the feed with
approximately 10 mg/kg of groundnut oil) at concentrations of 0, 1, 7
or 50 mg a.i./kg diet, or 50 mg/kg diet of xylene. Groups were
subdivided into two subgroups; one (n=10) was terminated at 12 months,
the second one was terminated at 24 months.
Hair loss (up to 50% of females) and diarrhoea (up to 50% of
males) were observed significantly more frequently in the animals of
the high-dose group. Body weight was reduced in mid-dose males (by
5-10%) and in both males (by 10-20%) and females (by 5%) in the
high-dose group. Food consumption was similar in all groups. The mean
daily intake of demeton-S-methyl was (males/females): 0.05/0.06,
0.31/0.41, 2.59/3.09 mg/kg body weight at 1, 7 and 50 mg/kg diet,
respectively. Mortality at 24 months was (males/females) 12/26, 10/20,
10/20, 4/26 and 8/24% in the control, low-, mid-, high-dose and xylene
groups, respectively. Haematological and clinical chemical parameters,
except for cholinesterases, measured at months 6, 12, 18 and 24, were
unaffected by the treatments. Plasma and erythrocyte cholinesterase
activities, measured at months 3, 6, 12 and 24, were significantly
decreased in groups given 7 mg/kg diet (plasma cholinesterase by
30-56%, erythrocyte cholinesterase by 12-31%) or 50 mg/kg diet (plasma
cholinesterase by 75-92%, erythrocyte cholinesterase by 20-44%). Brain
cholinesterase activity (measured at 12 and 24 months) was reduced in
the high-dose group (by 67-75%) and in the mid-dose group (by 15-47%).
A statistically significant decrease in brain cholinesterase activity
(33%) was observed in males given 1 mg/kg diet at 24 months but not at
12 months. The toxicological significance of this finding is not
clear; it should also be noted that brain cholinesterase activity at
7 mg/kg diet was higher than at 1 mg/kg diet and that plasma
cholinesterase and erythrocyte cholinesterase activities were not
inhibited at either of these dose levels. Histological examination did
not reveal an increased incidence of neoplastic lesions in treated
groups. Increased incidence of retinal atrophy (78% of males, 92% of
females as compared to 36-63% and 61-70% in the other groups) and
keratitis (44% of males, 22% of females as compared to 4-12% and 0-2%,
respectively, in the other groups) was observed at 50 mg/kg diet. The
retinal atrophy mainly affected the fundus, unilaterally or
bilaterally, and occurred in either the inner corneal layer, the inner
and outer layers, or all layers of the retina. Based on inhibition of
brain cholinesterase, the NOAEL was considered to be 1 mg/kg diet,
equal to 0.05 mg/kg body weight per day (Schmidt & Westen, 1988).
7.4 Skin and eye irritation and sensitization
7.4.1 Skin and eye irritation
Demeton-S-methyl (commercial formulation, 50% of active
ingredient) was applied (0.5 ml) to the shaved skin of three New
Zealand white rabbits on a 2.5 × 2.5 cm cellulose dressing for 4 h.
Mild erythema and oedema were observed, which generally disappeared
after 3 days (Flucke & Pauluhn, 1983). A 52.5% solution of
demeton-S-methyl in xylene produced slight skin and eye irritancy in
New Zealand white rabbits, but this was attributed to the solvent
(Thyssen, 1981).
A commercial formulation of demeton-S-methyl (50%) was instilled
(0.1 ml) either undiluted or as a 0.5% aqueous dilution into the
conjunctival sac of one eye of groups (n=3) of New Zealand white
rabbits. Treated eyes were washed with physiological solution after
24 h. No signs of eye irritation were observed in rabbits treated with
the 0.5% aqueous solution. The undiluted formulation caused severe
lacrimation and miosis on application. Mild corneal opacity and
discrete redness and oedema of conjunctivae were observed and
recovered in about 7 days (Flucke & Pauluhn, 1983).
7.4.2 Skin sensitization
The skin-sensitizing potential of demeton-S-methyl was assessed
by the Magnusson and Kligman maximization test with Freund's adjuvant
on guinea-pigs (n=20, Bor:SPF, DHPW strain). The concentrations of
demeton-S-methyl (96.3% purity, average of three determinations) used
were: 0.1% for the intra-dermal induction, 10% for the topical
induction and the first challenge, and 1% for the second challenge.
All twenty animals reacted positively to the 1st challenge (controls
4/10), and 16 reacted positively to the 2nd challenge (controls 3/10).
The results indicate that demeton-S-methyl has a skin-sensitizing
potential (Heimann, 1987a).
In another study, the Buehler epidermal patch test was used on
guinea-pigs (n=12, Bor: SPF, DHPW strain). The concentrations of
demeton-S-methyl (95.6% purity, average of three determinations) used
were 10% for topical induction (once a week for 3 weeks) and the first
challenge, and 20% for the second challenge. The results indicate that
demeton-S-methyl does not have a skin-sensitizing potential under
these conditions (Heimann, 1987b).
It is concluded that demeton-S-methyl might have some
skin-sensitizing potential, but this is of no relevance in practice.
7.5 Reproduction, embryotoxicity and teratogenicity
7.5.1 Reproduction
A standard two-generation study (two litters/generation) was
conducted in SPF rats (BOR:WISW) (10 males and 20 females) that were
given demeton-S-methyl at 0, 1, 5 or 25 mg/kg diet (Eiben et al.,
1984). The compound was used as a pre-mix in xylene (about 50%). Rats
in an extra control group were given xylene at 25 mg/kg diet.
In the F0 generation, none of the animals died. No treatment-
related signs were observed in any animal. Body weight gain was
reduced in males (by 10%) and in some females at 25 mg/kg diet. Food
intake was also reduced (by 7%) in high-dose males. Fertility index
was not affected by treatment. At 25 mg/kg diet, the viability of pups
was reduced; it was 89% and 85% in first and second matings,
respectively. Lactation index was also reduced in the high-dose group
(85-92%), the control value being 98-99%. Body weight at birth was
comparable in all groups, but body weight gain was significantly
reduced (by 8-10%) in pups fed 25 mg/kg diet.
In the F1b generation, one female was found dead in the 5-mg/kg
diet group and one in the 25-mg/kg diet group; one male and one female
in one of the 25-mg/kg diet litters also died. Autopsy did not reveal
treatment-related alterations. No treatment-related signs were
observed in any animal. Body weight gain was reduced at times in
low-dose males and consistently in mid- and high-dose and xylene-
treated males when compared to untreated animals. When compared to
xylene-treated animals (which were 5-15% lighter than untreated
animals), however, only males of the high-dose group had a
significantly reduced (by about 15%) body weight gain. Females of the
high-dose and xylene groups had a reduced (by about 10%) body weight,
compared to controls, the former being at times lighter weight than
the latter. Fertility index was not significantly affected. The number
of pups born was reduced in the high-dose group and the viability of
pups was also reduced in the mid- and high-dose groups in a
dose-related manner (82-88% and 47-67% of controls, respectively).
No compound-related malformation was found in animals of any of
the treatment groups. Demeton-S-methyl intake, as calculated in the
F0 generation, was found to be (female data in parentheses): 0.07
(0.08), 0.32 (0.39) and 1.71 (1.90) mg/kg body weight per day in the
low-, mid- and high-dose groups, respectively, and xylene intake was
1.66 (1.96) mg/kg body weight per day. Based on the viability of pups
and body weight in the F1b generation, the NOAEL was 1 mg/kg diet,
equal to 0.07 mg/kg body weight per day (Eiben et al., 1984).
7.5.2 Embroytoxicity and teratogenicity
7.5.2.1 Rat
Groups (n=25) of fertilized female rats (BAY:FB 30 strain) were
given daily (0, 0.3, 1 or 3 mg/kg body weight orally) demeton-S-methyl
(from a 52.6% solution in xylene) dissolved in corn oil from day 6 to
15 of gestation. At day 20 of gestation, pups were delivered by
caesarean section. Fetuses were weighed, sexed, inspected for external
abnormalities and examined for visceral and bone malformations. No
alteration of physical appearance or behaviour was observed in any
group. All animals survived until the caesarean section. Body weight
gain was reduced (by 13%) in the high-dose group. The numbers of live
fetuses and resorptions, fetal weight, number of fetuses with
malformations and number of implants were comparable in all groups. No
treatment-related visceral or skeletal abnormalities were observed
(Renhof, 1985).
7.5.2.2 Rabbit
A formulation of demeton-S-methyl (52.2% a.i. in xylene) was
administered by gavage to mated chinchilla hybrid rabbits (n=15-16) on
gestation days 6 to 18 at dose levels of 0, 3, 6 and 12 mg/kg body
weight per day. Caesarean sections were performed on gestation day 28.
There were no mortalities. In the high-dose group, diarrhoea was
observed in all animals after 4 to 10 days of treatment. Beginning 1
to 2 h after dosing, it persisted for 6 to 24 h. In the high-dose
group, mean food consumption was decreased by 7% during gestation days
6 to 18 and by 17% during gestation days 19 to 24 when compared to
controls. This was associated with decreased mean body weight gain
(-7%). There were no abortions and no relevant differences between
test and control groups in the numbers of implantations per dam, pre-
implantation losses, post-implantation losses, resorptions, living and
dead fetuses or sex ratios. A decrease in mean fetal body weight,
compared to the mean control weight, of 6.6% was observed in the
high-dose group. There was no treatment-related increase in gross,
skeletal or visceral malformations (Becker, 1983).
7.6 Mutagenicity and related end-points
A summary of the studies conducted to assess mutagenicity of
demeton-S-methyl is given in Table 3.
7.6.1 DNA damage and repair
Demeton-S-methyl did not induce DNA damage in the Pol test on
Escherichia coli either with or without metabolic activation.
7.6.2 Mutation
Increased mutation rates were observed in the Ames test and in
the mouse lymphoma forward mutation assay both with and without
metabolic activation.
7.6.3 Chromosomal effects
In in vivo tests, no SCEs were found in the bone marrow of
Chinese hamsters treated with high doses of demeton-S-methyl.
Bone marrow micronucleus and dominant lethal tests on mice
treated with demeton-S-methyl gave negative results. Chromosomal
aberrations were found in the bone marrow of Syrian hamsters treated
with a commercial formulation of demeton-S-methyl.
It is concluded that the available information is insufficient to
permit an adequate assessment of the genotoxic potential of
demeton-S-methyl.
7.7 Delayed neurotoxicity
Adult Leghorn hens (n=20) were given two doses of 100 mg a.i./kg
body weight (approximately equal to the LD50) of demeton-S-methyl
(51.2% in xylene) by gavage. The second dose was given 21 days
after the first one. Positive control animals (n=5) received
tri- ortho-cresyl phosphate (TOCP) (375 mg/kg body weight by gavage).
Animals were pretreated with atropine (100 mg/kg body weight
intramuscularly 10 min before the dose of demeton-S-methyl and
50 mg/kg body weight subcutaneously 6 h later). Surviving animals
received atropine (30 mg/kg s.c.) 24, 30 and 48 h later. At the second
dose, atropine treatment was suspended after 24 h. Hens treated with
demeton-S-methyl had signs of cholinergic toxicity. The recovery
started on day 3 and by day 8 all treated animals, except for one,
were free of signs. After the second dose, the recovery started on day
2 and by day 5 all treated animals were free of signs. One animal died
after the second treatment and surviving animals did not develop
neurological deficits. TOCP-treated animals showed locomotor
Table 3. Studies on mutagenicity of demeton-S-methyl
Test Organism Purity Results LED or HIDa Reference
-S9 +S9
Microorganisms
Pol assay Escherichia coli p3478, 93% - - 10 000 µg/plate Herbold (1983a)
W3110
Reverse Salmonella typhimurium unknown + n.t. 5 µg/plate Hanna & Dyer (1975)
mutation TA1530, TA1535, his C117,
his G46
E. coli WP2, WP2 uvra, unknown + n.t. 5 µg/plate Hanna & Dyer (1975)
CM561, CM571, CM611, WP67,
WP12,
S. typhimurium TA98, TA100, 50.2% ++ 300 µg/plate Herbold (1979)
TA1535, TA1537 (formulation)
S. typhimurium TA98, TA100, >98% ++ 20 µg/plate Herbold (1980a)
TA1535, TA1537
Saccharomyces cerevisiae 53.1% -- 1062 µg/ml Hoorn (1982)
S138 S211ý (formulations
in xylene)
Insects
Recessive Drosophila melanogaster unknown + 80 mg/kg diet Hanna & Dyer (1975)
lethal
Table 3. (con't)
Test Organism Purity Results LED or HIDa Reference
-S9 +S9
Cultured mammalian cells
Mutation, tk Mouse lymphoma L5178Y cells 94% ++ 50 µg/ml Cifone (1984)
locus
Mammals in vivo
Bone marrow NMRI mouse >98% - 2 × 5 mg/kg b.w. Herbold (1980b)
micronucleus oral
SCE in bone Chinese hamster 94% - 20 mg/kg b.w. oral Herbold (1983b)
marrow
Chromosomal Syrian hamster, female 50% + 2 mg/kg b.w. i.p. Dzwonkowska & Hübner (1986)
aberration (commercial)
Dominant NMRO mouse >98% - 5 mg/kg b.w. oral Herbold (1980c)
lethal
a LED = lowest effective dose; HID = highest ineffective dose
impairment beginning on day 10. Histological examination showed
moderate axonal degeneration in peripheral nerves and medulla in
TOCP-treated animals but not in demeton-S-methyl-treated or solvent
control animals (Flucke & Kaliner, 1988).
Neuropathy target esterase (NTE), the target for organophosphate-
induced delayed neuropathy, was not inhibited in hen brain and
spinal cord 1, 2 and 7 days after treatment with demeton-S-methyl
(80 mg a.i./kg body weight) by gavage. Positive controls (TOCP at
100 mg/kg body weight) showed NTE inhibition (> 90%) in both brain
and spinal cord (Flucke & Eben, 1988).
7.8 Toxicity of metabolites
Two plant and mammalian metabolites of demeton-S-methyl (namely
oxydemeton-methyl and demeton-S-methylsulfone) have been studied
extensively, since they are also the active ingredient of commercial
pesticides. According to the JMPR, the toxicity of the two compounds
does not differ substantially, either qualitatively or quantitatively,
from that of demeton-S-methyl (FAO/WHO, 1990).
7.9 Mechanism of toxicity - mode of action
Demeton-S-methyl is a direct cholinesterase inhibitor and
it causes signs and symptoms of the cholinergic syndrome. The
in vitro I50 (30 min, 37°C) for sheep erythrocyte cholinesterase
was 6.5 × 10-5 mol/litre. The I50 of oxydemeton-methyl and
demeton-S-methylsulfone were of the same order of magnitude
(2.7 × 10-5 and 4.3 × 10-5 mol/litre, respectively). The half-life
of recovery of acetylcholinesterase activity after inhibition by
demeton-S-methyl was 1.3 h, as expected from a dimethyl phosphorylated
acetylcholinesterase (Heath & Vandekar, 1957).
The 1973 JMPR (FAO/WHO, 1974) reported that rat brain
cholinesterase was more sensitive to in vitro inhibition by demeton-
S-methyl than by oxydemeton-methyl (I50 values of 9.52 × 10-5 and
1.43 × 10-3 mol/litre, respectively; time of incubation, temperature
and pH not reported). It was also reported that demeton-S-methyl was a
more potent inhibitor of human serum cholinesterase (no details
given).
Data on in vivo inhibition of plasma cholinesterase and
erythrocyte and brain cholinesterase are reported in section 7.2 and
7.3.
7.10 Potentiation
Male Wistar rats (160-180 g body weight) were given trichlorfon
(98.6% purity) and demeton-S-methyl (90% purity) in combination by
gavage. The amount of compound in the mixture was proportional to its
oral LD50 (302 mg/kg body weight for trichlorfon and 44 mg/kg body
weight for demeton-S-methyl) in order to obtain equitoxic doses. The
resulting toxicity was additive (LD50 of the mixture was 223 mg/kg
body weight against expected 173 mg/kg body weight) (Flucke &
Kimmerle, 1977).
Similarly, an additive effect was obtained when demeton-S-methyl
was given in combination with phenamiphos (ethyl-4-(methylthio)
m-tolyl-isopropyl-phosphoroamidate). The experimental LD50 of the
mixture was 55 mg/kg body weight while that estimated from the
individual LD50s was 50 mg/kg body weight (Kimmerle, 1972).
8. EFFECTS ON HUMANS
8.1 General population exposure
A 31-year old woman attempted suicide with an unknown amount
("1 or 2 mouthfuls") of Metasystox I (25% demeton-S-methyl). On
admission to hospital she was comatose, sweating and salivating,
and had pin-point pupils. She stayed in the Intensive Care Unit for 15
days where she was treated with atropine (up to 97 mg per day, 550 mg
in 14 days). Oximes (2-PAM) were only given on day 1 (0.5 + 0.25 +
0.25 g) and there was no apparent clinical improvement. On admission,
plasma and erythrocyte cholinesterase activities were less than 10% of
normal control values. The patient was discharged on the 30th day with
normal plasma cholinesterase values; erythrocyte cholinesterase
activity was still below the normal values (about 65%), but had
recovered a month later (Barr, 1966).
A case of acute poisoning in a 5-month pregnant woman has been
described (Carrington da Costa et al., 1982). A 41-year-old woman
attempted suicide by ingesting Metasystox, which resulted in an
estimated intake of 12 g methyl demeton (it should be noted that in
the report Metasystox was said to contain methyl-demeton and not
oxydemeton-methyl as the commercial name implies). On admission, 3.5 h
after poisoning, blood cholinesterase (it was not specified whether
pseudo- or acetylcholinesterase) was 10% of normal values. The patient
became comatose 12 h after admission. She was treated with atropine,
obidoxime and haemoperfusion 72 h after hospitalization. Artificial
ventilation was required on the 4th day of hospitalization. The
patient was discharged after 24 days and 4 months later she delivered
a healthy female child.
In a fatal suicidal case with a commercial formulation of
demeton-S-methyl, the concentration of the compound was measured in
several organs. It was estimated that death occurred about 6 h after
poisoning. Highest demeton-S-methyl levels were found in the proximal
small intestine (166 mg/kg of tissue); in brain, kidney and muscles,
the levels were 30-80 mg/kg; lowest concentrations were found in liver
(7 mg/kg tissue) and blood (7-16 mg/litre). Metabolites were not
measured (Schludecker & Aderjan, 1988).
In the United Kingdom in 1991 there were five cases of poisoning
by demeton-S-methyl and in 1994 three cases, none of which were fatal
(personal communication by G. Volans, Medical Toxicology Unit, London,
to the IPCS, dated 15 January 1996).
Hegazy (1965) reported three cases of suspected poisoning with
demeton-S-methyl in children (6-14 years of age) exposed in a recently
sprayed field and 1 case after ingestion of contaminated feed.
Symptoms were mild and the patients recovered fully. Serum
cholinesterase determinations gave ambiguous results.
8.2 Occupational exposure
8.2.1 Acute poisoning
A worker inadvertently exposed to demeton-S-methyl (no details)
was monitored for about 100 days. Plasma cholinesterase activity was
always within the normal values of the laboratory. However, if the
activity on day 40 and 100 is considered as the normal value for this
worker, then a 30% inhibition occurred 2-3 days after exposure. The
activity recovered with an half-life of about 10 days. Erythrocyte
cholinesterase activity was below the normal value for about 40 days.
When calculated on the activity of day 100, a 60% inhibition was found
up to day 10. The activity recovered with a half-life of about 35 days
(Lewis et al., 1981).
Two workers in a chemical packaging company, whose job it was to
fill a concentrate of demeton-S-methyl (500 g/litre of xylene) into
one-litre containers using a weight-triggered bottle-filling machine
for 3 to 4 h, were admitted to hospital because of organophosphate
poisoning and were treated with atropine. Cholinesterase measurement
made 14 days after exposure (1 worker) showed inhibited erythrocyte
cholinesterase, but the plasma cholinesterase activity was within the
normal range. In the second worker, whose symptoms lasted for 3 days,
erythrocyte cholinesterase activity was below the normal value 5 weeks
after exposure. These workers wore gloves, overalls and boots, but
frequent spillage was reported. Normal clothing had been left under
the filling apparatus and apparently was contaminated. The filling
system was changed by housing the filling machine in a fume cupboard
and by providing new protective garments and changing room facilities.
One more worker was admitted to the hospital and treated with atropine
because of organophosphate poisoning. This occurred on the morning
after a day spent fitting the infill seal and screwing on the tops
of cans. He had reduced erythrocyte and plasma cholinesterase
(erythrocyte > plasma) activities for several days after exposure.
Another worker showed a sharp drop in erythrocyte and plasma
cholinesterase activities associated with abdominal cramps, which
resolved in about 5 days. Another worker had depressed erythrocyte and
plasma cholinesterases activities without complaining of any adverse
effect. It was concluded that absorption of demeton-S-methyl was
through the skin because of penetration of the protective clothing
used or because this clothing was not worn properly. It should be
noted that the active ingredient was dissolved in xylene, which is
known to attack rubber and plastics, making the penetration of gloves
possible (Jones, 1982).
8.2.2 Effects of short- and long-term exposure
Three volunteers without any protective equipment were exposed
for two consecutive days to Metasystox (30% demeton-S-methyl, 70%
demeton-O-methyl) while spraying with a hand-held nebulizer. Exposure
lasted for 3 and 6 h on the first and second days, respectively. The
concentrations of the active ingredient (isomers not separated) were
8.8-27 mg/m3 of ambient air. Plasma and erythrocyte cholinesterase
activities measured up to 14 days after exposure did not show
significant decreases when compared to pre-exposure values (Klimmer &
Pfaff, 1955).
Volunteers, wearing overalls but not mask protection, were
exposed to metasystox (30% demeton-S-methyl, 70% demeton-O-methyl)
while spraying in a greenhouse. They used the splash method
(0.03-0.05% a.i.), the low volume (0.5% a.i.) or the high volume spray
method (0.05% a.i.) for 5 to 25 min. There was no effect on plasma or
erythrocyte cholinesterase activity measured after exposure (Klimmer &
Pfaff, 1958).
Six workers engaged in hop cultivation using Metasystox I
(reported to contain demeton-O-methyl instead of demeton-S-methyl as
the commercial name implies) were monitored. They sprayed up to
2400 litres of a 0.1% solution (in water) of the insecticide in one
day. Protective clothing and masks were not always used. No
significant inhibition of blood acetyl cholinesterase was observed at
the end of exposure or 1 or 2 days later. One subject, who was exposed
twice, showed a 29% decrease in blood acetyl cholinesterase after the
second exposure. No signs or symptoms were observed in these workers
(Winkler & Arent, 1970).
The medical department of a company reported no adverse effect in
workers employed in the formulation of demeton-S-methyl from 1967 to
1984 (Faul, 1984).
Agricultural workers exposed to demeton-S-methyl for 3
consecutive days were monitored. Pre-and post-exposure urinary levels
of the metabolite dimethyl phosphorothiolate potassium salt (DMPThK),
and plasma and whole blood cholinesterase activities were measured.
Exposed subjects were divided into three groups according to their
job, i.e. mixers (n=7), sprayers (n=6) and others (n=7) not directly
involved in handling the pesticide. Higher levels of DMPThK were
found in mixers, with a medium value of 83 µg/litre and a range of
0-822 µg/litre (neither corrected for creatinine nor for urine
volume). Sprayers had a mean value of 30 µg/litre (limit of detection)
and a range of 0-208 µg/litre; the other subject had a mean value of
30 µg/litre and a range of 0-100 µg/litre. Whole blood cholinesterase
activity was not affected by the exposure, while plasma cholinesterase
activity was slightly (about 10%, statistically significant) reduced
when compared to pre-exposure levels in mixers. However, no
correlation was found between DMPThK levels and plasma cholinesterase
activity (Vasilic et al., 1987).
Hegazy (1965) reported a study of 121 spraymen exposed to
Meta-isosystox during spraying of cotton fields in Egypt. The spraymen
applied Meta-isosystox at a rate of 0.5 litres of concentrate in
400 litres of spray per 4200 m2 mainly by hand-operated knapsack
sprayers, or in a few cases by high-pressure motor-powered sprayers
with a large tank connected by a long hose to a multi-nozzled
spray-boom. Sprayers were not involved in chemical mixing. Workmen
washed exposed body parts with soap and water after spraying. Working
clothes were removed at the end of the day, but the clothes may not
have been washed before re-use. Not all workers used protective
clothing and masks. None of the workers were re-exposed to
Meta-isosystox after the onset of symptoms. Serum cholinesterase
activity estimates were performed within 24 h after the onset of
symptoms in some patients and after the cessation of symptoms in some
others. In most cases they were repeated 2-3 times at various
intervals up to 40 days from the onset of symptoms. In general, the
serum cholinesterase activity in spraymen underwent a marked initial
fall, followed by a rise to above-normal levels after about 30-40
days. Signs and symptoms of toxicity in spraymen occurred after 1-18
days of exposure, with a mean time of 3 days. These consisted of
gastrointestinal disturbances (58% of total), dizziness (23%),
persistent general weakness and fatigue (19%), respiratory
manifestations (16%), headache (16%), sweating, salivation or
lacrimation (12%), tremors of outstretched hands, intention tremors,
ataxia (4.1%), exaggerated superficial and deep reflexes (5.8%),
hiccough (2.5%), muscular fasciculations (2.5%), or had apparently
resolved (30%), at the first determination of serum cholinesterase
activity (Hegazy, 1965).
9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD
9.1 Aquatic organisms
9.1.1 Algae
Table 4 reports the results obtained when different
formulations of demeton-S-methyl were tested on the green alga
Scenedesmus subspicatus (Heimbach, 1985a, 1990b).
9.1.2 Invertebrates
The acute toxicity of demeton-S-methyl for molluscs and
crustaceans is given in Table 5.
The lowest concentration tested on the water flea Daphnia
magna (10 µg a.i./litre) caused toxic effects (Heimbach, 1985b,c). A
21-day exposure test on water flea reproduction produced a NOEC of
> 5.6 µg a.i./litre (Heimbach, 1990d). A study performed with a
27.3% emulsifiable concentrate formulation (Heimbach, 1985c) yielded
a NOEC of 3.7 µg/litre (equal to 1 µg a.i./litre) and a LOEC of
11.7 µg/litre (equal to 3.1 µg a.i./litre).
Using a commercial formulation of metasystox, the 96-h LC50 for
the lammellibranch mollusc Paphia laterisulca was 2 µg/litre (Akarte
et al., 1986) and that for the freshwater prawn Donax cuneatus was
4 µg/litre (Muley et al., 1987).
9.1.3 Fish
Table 6 indicates the toxicity of demeton-S-methyl for fish.
9.2 Terrestrial organisms
9.2.1 Soil microorganisms
In a study conducted in silty sand soil or loamy silt soil
with doses of demeton-S-methyl up to 5 times those recommended
(2 litres/hectare of a 27% emulsifiable concentrate formulation),
no influence on soil respiration or nitrification in soil was found
(Anderson, 1989; Blumenstock, 1989).
9.2.2 Invertebrates
When demeton-S-methyl was mixed with an artificial soil where
earthworms (Eisenia foetida) were kept for 14 days, the LC50 was
241 mg/kg of dry substrate of the commercial formulation (a 25%
emulsifiable concentrate), corresponding to 60 mg a.i./kg (Heimbach,
1990a).
Table 4. Effect of demeton-S-methyl on the green alga Scenedesmus subspicatusa
Specification of test EC50 (mg a.i./litre) NOEC LOEC Duration Conditions
substance (mg/litre) (mg/litre) (h)
Increase of Growth rate
biomass
Technical 97.3% purity 8 22 1 3 96 pH 7.8 - 8.5
23 °C
EC formulationb 37 >100 18 32 96 pH 7.6 - 10.4
(27.3% a.i.) 23 °C
Pre-solutionc 13 37 1 10 96 pH 7.7 - 8.5
xylene (53.7% a.i.) 22 °C
a From: Heinbach (1985a, 1990b)
b Tests performed with the blank formulation gave the same results as the highest tested concentration.
c No test with the blank pre-solution was performed.
Table 5. Acute toxicity of demeton-S-methyl for molluscs and crustaceans
Species Specification of test Temperature LC50 Duration of Reference
substance (°C) (mg/litre) exposure
(h)
Mollusc commercial formulation ? 0.0042 96 Akarte et al. (1986)
(Paphia laterisulca)
Water flea (Daphnia magna) technical (96.7%) 20 ± 1 >0.1 24 Heimbach (1985b)
0.023 48
pre-solution in xylene 20 ± 1 >0.1 24 Heimbach (1985c)
(53.7%) formulation 0.022 48
Clam (Donax cuneatus) commercial formulation 25-28.5 0.0064 96 Muley et al. (1987)
Prawn (Macrobrachium lamerrii) commercial formulation 27 ± 2 1.3 72 Mary et al. (1986)
Table 6. Toxicity of demeton-S-methyl for fish (96-h exposure)
Species Mass and length Temperature LC50 (mg/litre) Reference
(°C)
Rainbow trout (Onchorhyncus mykiss) 4.0 - 5.5 cm 16 4.5 Grau (1985a)
1.0 - 1.5 g (52.7% of a.i.)
6.4 ± 1.0 cm 15±2 0.59 Grau (1990c)
3.0 ± 0.6 g (69.5% of a.i.)
6.9 ± 1.1 cm 15±2 6.44 Grau (1990a)
3.5 ± 1.6 g (27.3% of a.i.)
Golden orfe (Leuciscus idus melamotus) 6.0 - 7.5 cm 21 43 Grau (1985b)
2.5 - 4.2 g (52.7% of a.i.)
6.4 ± 0.6 cm 21±2 23.2 Grau (1990b)
2.5 ± 0.6 g (27.3% of a.i.)
Goldfish (Carassius auratus) 6 cm 18 20-40 Hermann (1974a)
1.5 g (28.1% of a.i.)
Carp (Cyprinus carpio) 6 cm 18 40-60 Hermann (1974b)
1.6 g (28.1% of a.i.)
Scardinius erythrophthalmus 6 cm 18 30-40 Hermann (1974c)
1.3 g
Cirrhana mrigala (larvae) 51 ± 3 mg 20 1.45 Verma et al. (1984)
Demeton-S-methyl was applied on fields of winter wheat by
fixed-wing aircraft using conventional boom-and-nozzle equipment.
The applied amount was 245 g a.i. per hectare at a volume rate of
20 litres/hectare. Samples of the soil surface and crop foliage fauna
were collected 1-2 times before and 4-5 times after application from a
treated field and from a control untreated field. The number of crop
foliage but not of soil surface entomophagus invertebrates was reduced
soon after application of demeton-S-methyl. Empididai (dance flies)
was the only group to be significantly reduced in numbers by
demeton-S-methyl. Predatory Coleoptera (beatles) (Carabidae and
Staphylinidae), Araneae (spiders) and predatory Diptera (flies)
(except Empididae) were not affected by demeton-S-methyl. Among the
ephytophagus fauna, cereal aphids markedly declined in number soon
after application, but a rapid inc