DEMETON-S-METHYL AND RELATED COMPOUNDS JMPR 1973
(DEMETON-S-METHYL, DEMETON-S-METHYL SULFOXIDE AND
DEMETON-S-METHYL SULFONE)
Explanation
One member of this family of compounds, oxydemeton-methyl
(Demeton-S-methyl sulfoxide), was reviewed at several previous
meetings (FAO/WHO, 1965b; 1968b; 1969b). On the basis of the studies
available at that time, primarily short-term studies, an acceptable
daily intake for man was estimated to be 0-0.0025 mg/kg/day (FAO/WHO,
1965b). When further considered at the 1967 meeting new data,
primarily a threegeneration reproduction study, was reviewed and the
ADI for man again reaffirmed to be 0-0.0025 mg/kg/day (FAO/WHO,
1968b). The 1968 joint meeting re-evaluated this compound and
concluded that the available information revealed that the toxicology
was not related to a single defined compound nor was there precise
knowledge of materials actually used in agricultural practice
(FAO/WHO, 1969b). Furthermore, no long-term data on any of the
substances belonging to this group were available for evaluation. That
meeting, therefore, recommended that the ADI as established at
previous meetings should no longer be considered valid. The further
work required to allow full assessment to be made included:
specifications of the compound or compounds in actual agricultural
use; studies to compare the metabolic fate in animals, plants and man;
investigation of the cholinesterase inhibition in man and adequate
long-term studies in two species. Portions of these requirements have
been met and the new work has been summarized combined with that
previously published and discussed in the following monograph
addendum.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
Biochemical aspects
Absorption, distribution and excretion
Studies on the absorption, distribution and excretion of the
demeton-methyl family of compounds is limited to a study on the oral
and subcutaneous administration of oxydemetonmethyl to mice. Within 15
hours following either oral or subcutaneous dosing at a level of 10
mg/kg, 97% of the administered dose was eliminated from the body
within 15 hours. There was no indication of the metabolic fate of the
compound in this study (Muhlmann and Tietz, 1956).
Information on identity and properties
Demeton-S-methyl
Chemical O, O-dimethyl-S-/2-(ethyl-thio)-ethyl/
name: phosphorothioate
Synonyms: Metasystox (i)
Metaisosystox
Bayer 18 436
25/154
E 154
Metilmerkaptofos teolovi (common name in USSR)
Structural O
formula CH3O "
\"
P-S-CH2-CH2-S-C2H5
/
CH3O
Empirical C6H15O3PS2
formula:
Appearance and Pale yellowish oily liquid with penetrating odour
odour: reminiscent of leeks
Molecular 230.3
weight:
Boiling point: 74°C at 0.05 mm Hg
92°C at 0.20 mm Hg
102°C at 0.4 mm Hg
118°C at 1.0 mm Hg
Vapour 1.2 x 10-4 mm Hg at 10°C
pressure: 3.6 x 10-4 mm Hg at 20°C
1.05 x 10-3 mm Hg at 30°C
2.9 X 10-3 mm Hg at 40°C
Volatility: 1.6 mg/m3 at 10°C
4.5 mg/m3 at 20°C
12.4 mg/m3 at 30°c
34.0 mg/m3 at 40°C
Specific 1.21 at 20°C
gravity: 4°
Solubility: Approx. 3300 mg/litre in water at room temperature;
readily soluble in most organic solvents; limited
solubility in petroleum ether
Minimum
purity: 90%
Impurities: O,O,S-trimethylthiophosphate max. 1.5%
O-methyl-S-2-(ethylmercapto)-ethylthiophosphate
max. 3.0%
2-ethylthioethylmercaptan max. 0.8%
bis(2-ethylthioethyl)-disulfide max. 0.8%
Various ionic components
(sulfonium compounds, max. 2.5%
anorganic salts altogether
Oligomeric alkyl(thio) max 1.0%
phosphates altogether
Water max. 0.4%
Oxydemeton-methyl
Chemical
name: O,O-dimethyl-S-/2-(ethyl-sulfinyl)-ethyl/phosphorothioate
Synonyms: Metasystox R
Demeton-S-methylsulfoxide
Bayer 21 097
R 2170
Metaisosystoxsulfoxide
Metilmerkaptofosoksid (common name in USSR)
Structural O O
formula CH3O " "
\" "
P-S-CH2-CH2-S-C2H5
/
CH3O
Empirical C6H15O4PS2
formula:
Appearance and Yellowish liquid, practically odourless
odour:
Molecular
weight: 246.3
Boiling point: 106°C at 0.01 mm Hg
Volatility: 0.09 mg/m3 at 20°C
0.3 mg/m3 at 30°C
0.7 mg/m3 at 40°C
Specific
gravity: 1.289 at 20°C
4°
Solubility: Miscible with water in any ratio; soluble in most
organic solvents, but practically insoluble in
petroleum ether
Minimum
purity: 90%
Impurities: Demeton-S-methyl max. 2.0%
Demeton-S-methylsulfone max. 2.0%
O,O,S-trimethylthiophosphate max. 1.5%
O-methyl-S-2-(ethylsulfinyl)ethylthio-phosphate
max. 1.2%
bis(2-ethylsulfinylethyl)-disulfide
max. 0.5%
Various ionic components max. 0.5%
(sulfonium compounds, etc.) altogether
Sodium- and ammoniumsulfate max. 0.8%
altogether
Oligomeric alkyl(thio)phosphates max. 0.5%
altogether
Water max. 1.0%
Demeton-S-Methylsulfone
Chemical
name: O,O-dimethyl-S-/2-(ethyl-sulfonyl)-ethyl/phosphorothioate
Synonyms: Metaisosystoxsulfon
Bayer 20 315
M 3/158
E 158
Structural O O
formula CH3O " "
\" "
P-S-CH2CH2-S-CH2CH3
/ "
CH3O O
Empirical C6H15O5PS2
formula:
Appearance and White to pale yellowish, microcrystalline;
odour: practically odourless
Molecular 262.29
weight:
Boiling point: 120°C at 0.03 mm Hg
144°C at 0.12 mm Hg
Vapour 0.5 × 10-3 mm Hg at 20°C
pressure: 1.6 × 10-5 mm Hg at 30°C
4.5 × 10-5 mm Hg at 40°C
Volatility: 0.072 mg/m3 at 20°C
0.22 mg/m3 at 30°C
0.60 mg/m3 at 40°C
Specific 1.416 at 20°C
gravity: 4°
Solubility: Miscible with water; soluble in most organic
solvents
Minimum 94%
purity:
Impurities: Oxydemeton-methyl max. 1.0%
Demeton-S-methyl max. 0.6%
O,O,S-trimethylthiophosphate max. 1.0%
"thiosulphoneacid" C2H5SO2C2H4-SO2SC2H4SO2C2H5
max. 0.4%
Oligomeric alkyl(thio)phosphates max. 1.0%
altogether
Various ionic components and max. 1.0%
traces ethylenechloride altogether
Water max. 1.0%
Metabolism
The metabolism of demeton-methyl in mammals has not been
investigated but the metabolism of the homologous diethyl esters have
been studied (see Disulfoton Working Paper). Results obtained in
studies with both compounds on plants seemingly justify analogously
extrapolating the results of animals experiments with demeton to
demeton-methyl.
With respect to demeton and its related compounds, it is known
that the thiono compound is very readily converted to the thiol form
(Fukuto and Metcalf, 1954). The rearrangement, particularly in polar
solvents, takes place at a taster rate for demeton-methyl than for
demeton. The required time in days for a 10% rearrangement in vitro
are as follows:
O
//
Days required for P=S to P conversion at:
\ \
O S
20°C 30°C 40°C
Demeton-S-methyl 104 26 8
Demeton 1 460 320 91
(Henglein and Schrader, 1955)
All studies undertaken with demeton revealed that the biochemical
mechanisms in mice, insects and plants were similar (March et al.,
1955). Major differences involved were concerned with rates of
metabolism and degradation; and, as expected rates were greater in the
mammal than in the insect and greater in the insect than in the plant.
The routes of metabolism and the metabolites formed were the same in
each case (oxidation of thioether of both isomers to the sulfoxide and
the sulfone). Although this mechanism has not been worked out for the
demeton-methyl family of compounds it is reasonable to assume that
metabolism will be analogous to that observed previously with the
demeton group.
Effects on enzymes and other biochemical parameters
Data are available on the cholinesterase inhibiting properties of
thiometon. In addition, based upon analogous work with disulfoton,
thiometon is a poor inhibitor of cholinesterase activity and when it
is converted to the phosphorothiolate, activity of cholinesterase will
be rapidly depressed. In one study, oxidation of demeton-S-methyl to
the sulfoxide and sulfone did not significantly increase the
inhibitory power. The I50 values for sheep erythrocyte cholinesterase
were 6.5 × 10-5, 4.1 × 10-5, and 2.3 × 10-5 M. for the sulfide,
sulfoxide and sulfone respectively (Heath and Vandekar, 1957).
In contrast, Wirth (1958) observed that demeton-S-methyl was a
more significant inhibitor of human blood serum cholinesterase. 150
values reported for demeton-S-methyl, oxydemeton-methyl and
demeton-S-sulfone were 1.65 x 10-6, 2.7 x 10-5, 4.3 x 10-5 M.
respectively.
Values of 4.66 and 5.10 (pI50) were recorded for thiometon with
RBC and serum cholinesterase respectively (Kimmerle and Lorke, 1968).
In vitro inhibition of cholinesterase was summarized in 1967
(FAO/WHO, 1968). It was suggested that demeton-S-methyl and
demeton-S-methyl sulfoxide (oxydemeton methyl) were essentially equal
in cholinesterase inhibiting properties with regard to sheep RBC
cholinesterase with an I50 value of 6.5 × 10-5 M. and 4.1 × 10-5 M.
respectively. Klimmer (1960) reported a substantial difference in rat,
brain cholinesterase inhibition between demeton-S-methyl and
oxydemeton-methyl with the 150 values being 9.52 × 10-5 M. and 1.43 ×
10-3 M. indicating that demeton-S-methyl is a more significant
inhibitor of cholinesterase in rat brain and following thioether
oxidation to demeton-S-methyl sulfoxide, cholinesterase depression is
significantly reduced. Owing to the pseudo unimolecular reaction
kinetics between organophosphates and cholinesterases. the
determinations of these values are rarely accurate. Furthermore, such
data given by different authors are not comparable in most instances,
since they depend on the time of incubation.
Subacute feeding studies were performed on rats with
demeton-S-methyl sulfoxide and demeton-S-methyl sulfone for the
purpose of comparing depression of cholinesterase activity. In a
preliminary study demeton-S-methyl sulfoxide was fed 50 ppm and the
demeton-S-sulfone was fed at 25 ppm for eight days. Both dietary
concentrations caused approximately the same degree of cholinesterase
activity depression in plasma and erythrocytes after four days of
feeding: the amount of inhibition was found to have increased still
more after eight days. In the main study, demeton-S-methyl sulfoxide
was fed at 50 and 100 ppm and demeton-S-methyl suffers was fed at 25
and 50 ppm for 21 days. In their effect on the cholinesterase activity
of plasma, erythrocytes and brain, both compounds behaved similarly at
the respected dietary concentrations with respect to both the time
cause and the intensity of depression. To obtain the same degree of
depression, demeton-S-methyl sulfone was administered at twice the
amount required for demeton-S-methyl sulfoxide. The lowest activity
was noted in plasma after 11-14 days and in erythrocytes after 14-18
days (Loser, 1972).
Liver function tests were performed at one and 24 hours and seven
days following an acute oral administration of 25 mg/kg of
demeton-S-methyl sulfone to rabbits. The Bromophthalein test and SGPT,
and SDH activity were not affected. As would be expected,
demeton-S-methyl sulfone is a cholinesterase inhibitor. Tests in rats
at a dose of 11.25 mg/kg and above resulted in approximately 50%
inhibition measured at three hours which maintained its inhibition
level through to three days following initial treatment (Kimmerle,
1966c).
Following oral administration of demeton-S-methyl and the
sulfoxide and sulfone, typical anticholinesterase symptoms were
observed. The durations of signs of poisoning were markedly longer
than after i.v. injection. Intravenous administration of these
compounds (except for the demeton-O-methyl) produced typical signs of
anticholinesterase poisoning in rats at doses close to the LD50. The
thionate (demeton-S-methyl), however, produced immediate
incoordination followed by accelerated respiration and weakness
lasting several hours. Lethal amounts of the thionate produced deep
anaesthesia with occasional jerking which lasted about 30 minutes.
Respiration then became more rapid until the animal died within one to
two hours. At no stage were typical anticholinesterase signs of
poisoning observed. A similar but weaker anaesthetic stage was
observed in rats injected IV with the thionate (demeton-S-methyl)
isomer. Signs of poisoning were of longer duration following oral
administration indicating a slower absorption from the gut (Heath and
Vandekar, 1957).
TOXICOLOGICAL STUDIES
Acute toxicity
Substance Animal Sex Route LD50 (mg/kg) Reference
Demeton-S-methyl Rat M & F Oral 35-85 Den-Dyke, Sanderson and
Noakes, 1970; Dubois and
Doull, 1955; DuBois and
Plzak, 1962; Heath and
Vandekar, 1957; Hecht,
1955; Kimmerle, 1966c; Kimmerle
1972; Klimmer, 1964;
Klimmer and Pfaff, 1955;
Writh, 1958; Klimmer, 1961
Guinea-Pig M Oral 110 DuBois and Doull, 1955;
Dubois and Plzak, 1962
Rabbit Oral ca. 20-50 Hecht, 1955
Cat Oral ca 5-10 Hecht, 1955
Dog Oral ca. 50 Hecht, 1955
Rat M & F i.p. 2-10 (techn.) Dubois and Doull, 1955;
Dubois and Plzak, 1962;
Hecht, 1955; Niessen et
al., 1963
27.5 (pure) Niessen et al., 1963
Guinea-pig i.p. 12.5 Dubois and Plzak, 1962
Acute toxicity (cont'd.)
Substance Animal Sex Route LD50 (mg/kg) Reference
Rat M i.v. 8.4 Niessen et al. 1963;
17.3 (pure) Nissen et al. 1963
Rat F i.v. 64.6 (pure?) Heath and Vandekar, 1957
Mouse i.v. 0.5-1.0 Hecht, 1955
6.8 (pure) Hecht, 1960
8.2 (techn.) Hecht, 1960
Mouse M i.v. 4.1 (techn.) Niessen et al., 1963
13.0 (pure) Niessen et al., 1963
Rat dermal 50-100 Ben-Dyke, Sanderson and
Noakes, 1970; Dubois,
1960; Klotzsche, 1964
Cat dermal 10-20 Hecht,1955
Oxydemeton-methyl Rat M & F Oral 30-85 Ben-Dyke, Sanderson and
Noakes, 1970; Dubois,
1955; DuBois and PIzak,
1962; Gaines, 1969;
Heath and Vandekar, 1957;
Hecht, 1955; Kimmerle,
1966c; Klimmer, 1960;
and Wirth, 1958
Guinea-pig Oral 120 DuBois, 1955; DuBois and
Plsak, 1962
Rabbit Oral 50-75 Hecht, 1955
Cat Oral 20-50 Hecht, 1955
Dog Oral 20-50 Hecht, 1955
Chickens Oral 35.0 DuBois, 1962b
Hens Oral ca. 100 ml. Kimmerle, 1961
Rat M & F i.p. 5.82-50 DuBois, 1955; DuBois and
Plzak, 1962; Hecht, 1955;
Klimmer, 1960
Mouse i.v. 8-12 DuBois and Plzak, 1962
Acute toxicity (cont'd.)
Substance Animal Sex Route LD50 (mg/kg) Reference
Guinea-pig i.p. 30 DuBois and and Plzak, 1982
Rat i.v. 47.2 Heath and Vandekar, 1957
Mouse i.v. 7.5-10 Hecht, 1955
Rat M & F Dermal 100-250 Ben.Dyke, Sanders and
Noakes; 1970; DeBois,
1960; Dubois and Plzak,
1962; Gaines, 1969; Hecht,
1955; Klimmer, 1960;
Klotzche, 1964
Cat Dermal >100 ccm. Hecht, 1955
Rat M Inhalation >1.32 mg/l Kimmerle and Lorke, 1968
1 h exposure
0.35 mg/l
4 h exposure
Dameton-S-methyl Rat M & F Oral 32.4-30 DuBois and Doull, 1955;
sulfone DuBois and Plzak, 1962;
Heath and Vandekar, 1957;
Hecht, 1955; Kimmerle,
1966c; Wirth, 1958
Mouse Oral 28.6 Kimmerle, 1966c
Guinea-pig Oral 258.0 Kimmerle, 1966c
Guinea-pig Oral 120.0 DuBois and Doull, 1955;
Rabbit Oral 40.0-50.0 Hecht, 1955; Kimmerle,
1966c
Hen Oral ca. 150 Kimmerle, 1966c
Cat Oral 25.0-50.0 Hecht, 1955; Kimmerle, 1966c
Dog Oral >30 Hecht, 1955; Kimmerle, 1966c
Rat M & F i.p. 17.5-25 DuBois and Doull, 1955;
DuBois and Plzak, 1962;
Hecht, 1955; Kimmerle, 1966c
Acute toxicity (cont'd.)
Substance Animal Sex Route LD50 (mg/kg) Reference
Guinea-pig i.p. 85 Kimmerle, 1966c
Hen i.p. 37.5-50 Kimmerle, 1966c
Rat M i.v. 23.7 Heath and Vandekar, 1957
Rat F i.v. 21.7 Heath and Vandekar, 1957
Mouse i.v. 21.7-25 Hecht, 1955; Kimmerle, 1966c
Mouse s.c. 21.8 Kimmerle, 1966c
Rat Dermal > 500 Hecht, 1955; Kimmerle, 1966c
Cat Dermal > 500 Hecht, 1955
Demeton-O-methyl Rat Oral 676 Heath and Vandekar, 1957
i.v. 216 Heath and Vandekar, 1957
Antidotal studies
Atropine and PAM were found to have a protective effect in rats
against the acute oral toxicity of oxydemeton-methyl and the sulfone.
Although PAM and atropine alone were both therapeutic, combinations of
both compounds did not Afford any greater protection to rats
(Kimmerle, 1966a, 1966b, 1966c; Lorke and Kimmerle, 1968; Dubois and
Plzak, 1962). On the other hand, atropine was not effective, either
alone or in combination with PAM when tested against demeton-S-methyl
(Kimmerle, 1966a; Lorke and Kimmerle, 1969; Klotzsche, 1964). Atropine
and PAM were found to be ineffective in protecting against the acute
toxic effects of oxydemetonmethyl in hens (Kimmerle, 1961).
Special studies
(a) Demeton-S-methyl
None available.
(b) Demeton-S-methyl Sulfoxide
Special studies on dermal toxicity
Two groups of five female rats each were administered 25 and 50
mg/kg daily by dermal application for 60 days. No mortality occurred
in either group over the period of time although the high dose group
exhibited signs of cholinergic stimulation in the first two weeks of
treatment. Continued treatment with oxydemeton-methyl to rats showed
that after prolonged exposure the animals developed a tolerance to the
acute signs of poisoning (DuBois, 1962a).
Oxydemeton-methyl was administered dermally to male and female
rats five days a week for three weeks at doses approximating one-fifth
of the LD50. A formulation of oxydemeton-methyl (Metasystox-R)
containing 2 lb active ingredient per gallon of formulation was used.
The acute dermal LD50 was approximately 112.5 mg/kg (450 mg
formulation/ kg) in both male and female rats. Male and female rats
given daily dermal exposures to this formulation exhibited a slight
inhibition of body weight gain and a marked inhibition of brain
cholinesterase activity. Repeated dermal exposure did not affect body
weight of various organs nor haematological values examined at the end
of this period (DuBois et al., 1966).
Histological examination of certain tissues revealed no changes
that could be attributed to the presence of oxydemeton-methyl as a
Metasystox-R formulation in the diet (Wren of al., 1968).
Special studies on mutagenicity
Groups of male mice (12 Charles River mice per group) were
administered oxydemeton-methyl by intraperitoneal administration at
levels of 0, 5, and 10 mg/kg. These animals were then mated with three
untreated virgin females per week for six consecutive weeks. The
females were sacrificed approximately one week after mating and the
ovaries and uterus examined for early resorption. The authors indicate
that pre-implantation losses for all groups were not affected by
oxydemeton-methyl administration and that the material did not cause a
"dominant-lethal" response. Data indicated that females mated to males
treated with 10 mg/kg after six weeks had a high number of early
resorption sites. During all other weeks the reproduction indices were
normal (Arnold et al., 1971).
Special studies on neurotoxicity
Adult hens administered oxydemeton-methyl orally at doses up to
the LD50 level showed no indications of delayed neurotoxic response
(Kimmerle, 1961).
Special studies on potentiation
Studies on the acute potentiation of oxydemeton-methyl in
combination with 15 other organophosphates and one carbamate
anticholinesterase agents administered simultaneously at one half of
the LD50 dose by intraperitoneal injection resulted in less than
additive acute toxicity. No evidence of potentiation of acute toxicity
was obtained by administration to rats of the pairs of compounds
(DuBois, 1961). Oral administration of demeton-S-methyl to male rats
in combination with phenamiphos (SRA-3886,
ethyl-4-(methylthio) m-tolyl-isopropyl-phosphoroamidate, Bay 68, 138,
NemacurR) resulted in no potentiation of the acute toxicity
(Kimmerle, 1972). Thiometon did not potentiate the acute toxicity of
formothion (FAO/WHO, 1970).
Special studies on reproduction
In a three generation reproduction study at oxydemetonmethyl
dietary levels of 0, 10, 25 and 50 ppm, groups of 10 males and 20
females of each generation, except the third filial, were maintained
through two successive matings. Second litter animals were used for
composing the succeeding generation groups. The third filial
generation was maintained only to weaning age. At 50 ppm in all
generations, the number of pregnancies and the number of young per
litter were significantly reduced. Histological examination of the
second filial generation animals disclosed only reduced oogenesis in
three of the 10 in the 50 ppm females, with no apparent effect at 25
ppm. 10 ppm was without effect on the number of pregnancies, the
number of young per litter, the number of surviving young up to 21
days and microscopic appearance of major organs. Erythrocyte
cholinesterase activity, expressed in percentage of controls, was
reduced to 83% in males and 67% in females in the third filial
generation, after 21 days; and in the second generation, after 27
weeks, to 83% in the males and to 61% in the females. Erythrocytic
cholinesterase activity was more consistently reduced, in proportion
to the test level, at the two higher levels. No gross abnormalities
nor effect on food consumption or body weight gain were seen at any
test level (reviewed in FAO/WHO, 1968).
Special studies on teratogenicity
Groups of 15 pregnant rabbits were administered oxydemeton-methyl
in doses of 0, 0.1 and 0.2 mg/kg from day 6 through day 18 of
gestation. Negative controls were treated with empty capsules and
positive controls were treated with 37.5 mg/kg/day of thalidomide. At
day 29 all animals were sacrificed and young were removed by caesarean
section, weighed and observed in an incubator for 24 hours. All young
were further observed by gross examination and by alizarin staining of
the bone.
No deaths or unusual reactions were noted in any of the females
nor was there any effect on weight gain that could be attributed to
the administration of oxydemeton-methyl to the animals. Fetal
mortality was not affected by oxydemeton-methyl and there were no
abnormalities observed among the fetuses from the low dose group. A
single incidence of talipes varus was observed which was believed to
have occurred spontaneously although it was not noted in the controls
of this test. Positive results were obtained with thalidomide
indicating the susceptibility of the strain of animals to teratogenic
effects. It is believed that administration of oxydemeton-methyl
during the susceptible period of gestation does not result in
teratogenic abnormalities in rabbits (Ladd et al., 1971).
(c) Demeton-S-methyl sulfone
Special studies on neurotoxicity
Following acute oral and intraperitoneal administration to hens,
demeton-S-methyl sulfone at levels up to and including 200 mg/kg did
not induce any neurotoxic effect in hens (Kimmerle, 1966c).
Demeton-S-methyl sulfone was found to be non-irritating to the
rabbit ear following in contact for 24 hours and after a seven-day
observation period. A small quantity of demeton-S-methyl sulfone
placed in conjunctival sack of rabbits produced a slight reddening of
the conjunctival but no change in the cornea. Constriction of the
pupil was noted (Kimmerle, 1966c).
Inhalation exposure
Groups of rats (10 males and 10 females per group) were exposed
for four hours daily for a period of 10 weeks (five exposures per
week) to concentrations of 0, 0.0068 and 0.017 mg/litre. Signs of
cholinergic stimulation were seen within two weeks at all
concentrations tested although no deaths occurred over the course of
this experiment. There was a significant decrease in body weight gain
over the course of the experiment although haematology was normal.
Urine examinations were normal as were the gross and microscopic
examinations of tissues and organs. Cholinesterase depression was
obvious in all groups with 50% depression being noted at the low
concentration (Kimmerle. 1966c).
Short-term studies
(a) Demeton-S-methyl
Rat. Groups of male rats (15 rats per group) wore orally
administered demeton-S-methyl daily for up to six months at doses of
0, 1, 5 and 10 mg/kg (Klimmer, 1961). Mortality was evident at 5 and
10 mg/kg and was absent at the lowest treatment level. Cholinergic
signs of poisoning evident at the beginning of the study became less
evident as the study progressed. No effects were noted at 1 mg/kg/day
(equivalent to administration of 10 ppm in the diet).
Groups of six male rats were fed demeton-S-methyl in the diet for
six months at levels of 0, 50, 100 and 200 ppm (Vandekar, 1958).
Cholinergic signs of poisoning were evident at the highest level at
the beginning of the study and lessened as time progressed. Depression
of cholinesterase activity was evident at all feeding levels. Growth
was depressed at 100 ppm. Gross and microscopic examination of tissues
showed no change attributed to the demeton-S-methyl in the diet.
Weanling male and female rats (Sprague-Dawley strain) Were fed
diets containing 0, 2, 5, 10 and 20 ppm demeton-S-methyl for three
months. Growth rate, food consumption, physical condition and
mortality were not effected at any of the feeding levels. Measurement
of serum and erythrocyte cholinesterase were performed at eight weeks
and at the end of the feeding period when all animals were sacrificed
for gross and microscopic tissue examination. There was no indication
of toxic effects at dietary levels of 10 ppm or less (Root and Doull,
1972).
(b) Demeton-S-methyl sulfoxide
Rat. In groups of 20 rats, administration of oxydemeton methyl by
mouth in doses of 5 ag/kg bw daily for three months caused no signs of
intoxication or pathological changes, and 10 mg/kg bw for 21 days
caused an inhibition of cholinesterase activity after four to six days
(reviewed by FAO/WHO, 1968).
Groups of six males and six females received oxydemeton-methyl
concentrations of 20 ppm or less in the diet for a period of 16 weeks:
no significant influence on growth-rate or food consumption was
observed. 10 ppm or less caused no significant depression of
erythrocyte cholinesterase activity. Gross and microscopic examination
of the tissues of rats revealed no indication of toxic effects except
for fatty changes in the livers of some of the rats fed 10 ppm and 20
ppm. 50 ppm for six months had no effect on weight gains in a group of
six rats and showed no pathological changes attributable to the action
of the compound. The brain and blood cholinesterase activity was
strongly inhibited. Concentrations of 100 and 200 ppm produced signs
of intoxication in the first three weeks of the experiment (Bar, 1963;
Vandekar, 1958; reviewed in FAO/WHO, 1968).
A group of 20 male rats were orally administered
oxydemeton-methyl daily five times per week for 75 days at a level of
5 mg/kg. Behaviour was not affected although growth was depressed. A
further study at 5 and 10 mg/kg for 21 days resulted in mortality at
10 mg/kg within one week. Cholinergic signs of poisoning observed in
the first week were not evident at the end of the study (Klimmer,
1960).
Groups of rats (six male and six female Sprague-Dawley strain
rats per group) were fed dietary levels of oxydemetonmethyl in the
diet at levels of 0, 2, 5, 10 and 20 ppm for a period of 16 weeks.
Behaviour, mortality, growth rate and food consumption data were
recorded over this 16 week period. At the conclusion of the experiment
gross and microscopic examination of tissues and organs and
cholinesterase determination of serum, erythrocyte, brain and
submaxillary gland were performed. Gross pathology, including absolute
organ weights and organ to body weight ratios was normal at all
feeding levels. Histological changes in the livers of rats fed the two
highest dietary concentrations consisted of vacuolization of the
cytoplasm of the hepatic cells in the periportal region. These changes
were apparent in some of the animals fed the control diet but were
more pronounced in the animals fed the two highest
oxydemeton-methyl-containing diets. The changes were less severe and
similar to the controls in the rats fed 2 and 5 ppm. Sections of the
liver of animals exhibiting these changes also were found to stain
positively for the presence of fat (with oil red, 0). Growth, food
consumption, behaviour and body weight changes were not noted during
the course of the study. Depression of cholinesterase activity in BBC
and brain were observed in both males and females at 20 ppm in the
diet. Serum and submaxillary gland cholinesterase appeared to be
unaffected in the study, although male submaxillary gland
cholinesterase activity was slightly depressed at the highest feeding
level.
A no-effect level in this study appears to be 5 ppm in the diet
based upon somatic effects noted on microscopic examination of liver
after 16 weeks. A level of 10 ppm in the diet had no effect on
cholinesterase activity (Doull et al., 1962).
Groups of rats (12 male and 12 female rats per group) were fed
diets containing oxydemeton-methyl for a period of 16 weeks at levels
of 0, 2, 5 and 10 ppm. Cholinesterase activity was also determined at
the end of the experiment in plasma, RBC, brain and submaxillary gland
(Root et al., 1967a). Gross and microscopic pathology was reported on
the following tissues: brain, liver, kidney, lymph node, spleen,
heart, lung, gonad, thymus, adrenal gland, urinary bladder, stomach,
duodenum, pancreas, jejunum. There was no effect on food consumption,
growth or survival in any of the levels examined. Haematology and
clinical chemistry were not affected although male rats receiving 10
ppm showed a slight decrease in blood glucose. Cholinesterase
depression measured at the conclusion of the study showed depression
of plasma cholinesterase at 10 ppm in both males and females.
Erythrocyte, brain and submaxillary gland inhibition cholinesterase
inhibition at 5 ppm in both males and females. A dietary level of 2
ppm was observed to be a no-effect level on cholinesterase. Gross and
histologic examination of the tissues of male and female rats
containing levels up to 10 ppm Metasystox-R for 16 weeks showed no
differences from the controls (Root et al,, 1967a; Hibbs and Nelson,
1967). in a separate study, groups of rats (12 males and 12 females
per group) were fed 0 and 20 ppm oxydemeton-methyl for 16 weeks (Root
and Meskauskas, 1968). Gross and microscopic analysis of the liver
showed no effects attributable to oxydemeton-methyl in the diet.
Groups of rats (12 male and 12 female) were fed oxydemeton-methyl
in the diet for 13 weeks at dietary concentrations of 0, 1, 1.5, 2,
30, 50 and 100 ppm.
Growth in animals fed 2 ppm and below was not affected by the
presence of oxydemeton-methyl in the diet. Food consumption was
reduced at 100 ppm and growth was reduced at 30 ppm and above. There
was no apparent mortality resulting from the incorporation of
oxydemeton-methyl in the diet. There was no effect on haematology and
blood chemistry and gross pathology was affected only at 100 ppm in
the diet. At this high level, organ weights were generally reduced
with the exception of the brain which was apparently unaffected., At
dietary levels of 1.5 ppm and above erythrocyte cholinesterase was
depressed slightly while plasma, brain and submaxillary gland
cholinesterase was depressed only at levels of 30 ppm and above.
There were no histological findings that could be attributed to
the presence of oxydemeton-methyl in the diet at levels up to and
including 100 ppm. A no-effect level in this study based upon
depression of cholinesterase was 1.0 ppm (Root of al., 1968; Wren and
Nelson, 1969).
Groups of rats (WISTAR strain SPF rats, 15 male and 15 female per
treatment group; 30 male and 30 female rats per control group) were
fed dietary concentrations of oxydemetonmethyl of 0, 1, 3, 25 and 125
ppm in the diet for 90 days.
Signs of cholinergic stimulation appeared within three weeks at
the 125 ppm dose level, continued to increase in severity after the
onset of the experiment, and gradually diminished. Food consumption
was low in the highest test group and this was reflected in the
reduced growth curve for both male and female which was significantly
depressed at this high feeding level. There was a slight increase in
mortality at the high dose level in males although the females
survived the entire test. There were no significant effects at levels
up to and including 125 ppm in the diet on clinical chemistry,
haematology, urinalysis, kidney function tests, blood, sugar or
cholesterol. Plasma cholinesterase was significantly depressed at 25
ppm in both males and females. Erythrocyte cholinesterase was
depressed in both males and females at 5 ppm in the diet. Gross
histological examination indicated a significantly lower organ weight
in several tissues (heart, lung, liver, spleen, kidney, adrenals, and
gonads in males and heart, thyroid and spleen of females at 125 ppm in
the diet). In females, the reduced organ weights when compared with
the reduced body weight resulted in a normal organ to body weight
ratio. In other tissues such as thymus, lung, liver, and kidneys the
size of which were not reduced the reduced body weight caused the
calculation to reflect an increased organ to body weight ratio. No
histological change was seen in the tissues examined which could be
attributed to the presence of oxydemeton-methyl in the diet (Vince and
Spicer, 1971). A no-effect level in this study was 1 ppm.
Groups of weanling rats (six rats per group) were fed
oxydemeton-methyl in the diet at levels of 0, 1, 5 and 25 ppm for
seven days. At the end of one week the animals were sacrificed for the
measurement of the hydrolysis of tributyrin and diethyl succinate
(DES) by liver and serum and for the measurement of cholinesterase in
serum, liver, and brain. Dietary levels of oxydemeton-methyl producing
50% inhibition of aliesterase and cholinesterase over this one week
feeding period were obtained by analysis of a plot of the logarithm of
dietary concentration and inhibition of the respective enzymes.
Dietary level producing 50% inhibition of brain, liver, and serum
cholinesterase was 15, 28 and 20.5 ppm, respectively. Dietary level to
induce 50% inhibition of DES hydrolysis in liver and serum was 6.1 and
24.0 ppm respectively and for tributyrin hydrolysis in liver and serum
the values were 4.2 and >25 ppm respectively (Su et al., 1971).
Dog. Diets containing 0, 5, 10 and 20 ppm oxydemeton-methyl have
been fed to male and female beagle dogs for periods of 12 weeks. None
of these dose levels produced significant changes in food consumption
or body weight or gave rise to cholinergic signs. Levels of 10 ppm or
less did not cause significant inhibition of serum or erythrocyte
cholinesterase activity (Root et al., 1963; reviewed by FAO/WHO, 1965
as oxydemeton-methyl).
Groups of dogs (one male and one female per group) were fed
dietary levels of oxydemeton-methyl in the diet at levels of 0, 5, 10
and 20 ppm for 12 weeks. There was no change in food consumption or
body weight over the treatment period. Serum cholinesterase was
depressed at 20 ppm within one week to approximately 80% of normal and
remained at this level for the remainder of the study. Red blood cell
cholinesterase was continuously depressed from the beginning of the
study at 20 ppm in the diet and reached approximately a 30% inhibition
level after the 12-week period. In this study, the level of 20 ppm
reflected a minimal effect in cholinesterase of red blood cell in dogs
(Root et al., 1963).
Male and female beagle dogs were fed diets containing 0, 2, 5,
10, and 20 ppm demeton-S-methyl sulfoxide for three months.
Observations on growth rate, food consumption, physical activity and
mortality indicated no effects at any of the feeding levels.
Measurement of serum and erythrocyte cholinesterase were made weekly
in the dogs and it was found that no toxic effects in the animals at
levels of 10 ppm or less was observed. There was no effect on food
consumption, growth or survival over the 12-week feeding period. Male
and female dogs at 10 ppm showed a slight increase in SGPT activity
with no other effect noted on the haematological examination. There
appeared to be no significant somatic effects noted on gross or
histological examination. Plasma cholinesterase was unaffected at all
feeding levels while RBC brain and liver (especially in females)
cholinesterase was depressed significantly at 10 ppm in the diet. The
only apparent effect of oxydemeton in dogs is a slight RBC
cholinesterase depression and a more substantial decrease in esterases
activity of female brain and liver (Root et al., 1967; Root, 1969;
Root and Doull, 1972).
Two groups of four male and four female dogs were fed
oxydemeton-methyl in the diet for 12 weeks. One group was maintained
as a control and the second group of dogs was fed a dietary level of
50 ppm for three weeks, 75 ppm for three weeks, and 150 ppm for the
final six weeks. At a dietary level of 50 ppm for three weeks no gross
detectable cholinergic signs of poisoning were evident. The level when
raised to 75 ppm resulted in no overt signs of toxicity. However, upon
introduction of 150 ppm oxydemeton-methyl to the diet, severe signs of
cholinergic stimulation were evident resulting in death of one of the
four dogs. At the conclusion of the study, it was observed that at 150
ppm there was a significant and uniform reduction of liver
cholinesterase as well as brain cholinesterase in both sexes. Plasma
cholinesterase was depressed within the first week of the experiment
(at 50 ppm) to about 46% of normal at which level it remained
relatively constant for the entire feeding study. Erythrocyte
cholinesterase was continuously depressed at 50 ppm for the entire
three-week period of feeding after which it stabilized at a level
somewhat below 20% and was maintained at this level for the entire
duration of the experiment. Haematological values were slightly
altered in males by the presence of oxydemeton-methyl with the
clotting time being reduced and the SGPT activity being increased,
Similar effects were not noted in females on these two parameters. No
other clinical observations were observed to be abnormal. Gross
examination of various tissues and organs at the conclusion of the
study showed a decrease in spleen weight in both males and females; a
substantial increase in male thymus; a decrease in female thymus; an
increase in the thyroid gland in males and a decrease in females.
Microscopic examination of tissues of these animals showed no
significant changes, which could be attributed to the presence of
oxydemeton-methyl in the diet (Root et al., 1970; Wren, 1970).
Groups of dogs (four male and four female per group) were fed
oxydemeton-methyl for two years at dietary levels which varied from
0.5 to 150 ppm in the diet. Groups of four male and four female dogs
were fed a normal dry diet for this same period of time. The dietary
feedings levels were varied in all three groups of treatments with a
low level initiated at 0.5 ppm and fed for 29 weeks after which the
diet was switched to 1.0 ppm for weeks 30-43, and was increased to 2
ppm during weeks 43-77 after which it was raised to 4 ppm for weeks
7883 and then reduced to 2 ppm for the remainder of the study. The
level of 5 ppm in the diet was fed to the intermediate group for the
first 28 weeks after which it was raised to 10 ppm and the animals
maintained on this diet for the remainder of the two-year study. The
third group of animals (the highest dosed group) received 37.5 ppm for
the first 28 weeks after which the level was raised to 75 ppm for
weeks 29-77; 100 ppm for weeks 78-79; 125 ppm for weeks 80-83; 150 ppm
for weeks 84-88; and 100 ppm for weeks 89-104. There was no effect
over the two-year period on growth or food consumption. Behaviour of
animals at the highest dose level was abnormal at 125 ppm with signs
of poisoning being evident during the short period of time which they
were fed at this level and higher. There was no apparent signs of
cholinergic stimulation at 100 ppm. Haematological values, urinalysis
and clinical chemistry were all normal. No abnormalities were noted
with respect to organ weight data or organ to body weight or brain
weight ratios in all the test groups. There were no effects noted when
tissues of the animals were examined histologically.
Cholinesterase from various tissue sources was significantly
depressed in several of the groups over the period of this study.
Brain cholinesterase was significantly depressed in the highest group
while depression was not noted in the intermediate groups at levels up
to 10 ppm in the diet. Plasma cholinesterase was also inhibited in the
highest group and depressed in the intermediate group especially at
52 weeks and thereafter in the males. There was also a slight
depression noted in the females at this time period. There was no
apparent depression in either males or females at the 39-week interval
which might have been indicative of a dietary switch from 5 to 10 ppm
which took place in week 28. As week 39 was essentially normal, the
slightly depressed values noted in the 10 ppm level may not reflect a
true inhibition of plasma cholinesterase. At the lowest level fed
there was a slight depression especially in females at the 52, 78 and
104 weeks although again not coinciding with any dietary change. Red
blood cholinesterase was depressed in the highest group and was also
depressed in the intermediate group especially in males, at all
intervals tested. In females, depression was noted only at week 39 and
at each interval thereafter. There appear to be a significant drop at
both male and female BBC cholinesterase values, at week 39 which would
correspond to the change from 5 to 10 ppm in the diet. At the lowest
dose level there is a slight depression noted only at 104 weeks in
both males and females. This is presumably a reflection of the change
in dietary concentration to 4 ppm which took place at week 78. The
possibility exists that the effect of this concentration change would
be reflected only at week 104. 2 ppm is considered a no-effect level
in dog (Hartke et al., 1973).
(c) Demeton-S-methyl sulfone
Rat. Groups of rats (six male and six female WISTAR strain rats per
group) were orally administered demeton-S-methyl sulfone five days per
week for 10 weeks at dosage levels of 0, 1.3, 2.5, 5.0, 9.5 and 19
mg/kg. Behaviour and mortality were observed daily and growth and food
consumption were examined weekly. Mortality was observed at the two
highest dose levels with typical signs of cholinesterase depression
and cholinergic stimulation. In females, levels of 2.5 mg/kg and above
resulted in a reduction in growth while in males only the 5.0 mg/kg
were so reduced. There was no effect on the haematological values and
urine examination for protein, sugar, and sediment showed no
differences from the controls. Cholinesterase depression was obvious
at all feeding levels with the level of 1.3 mg/kg resulting in
approximately 50% depression. Over the course of the study, the enzyme
depression appeared to be maintained for five weeks after which there
was a further drop in activity which subsequently recovered to values
approximately 75% of normal. There was no effect on gross and
microscopic pathology in this study (Kimmerle, 1966c).
Groups of rats (14 males and 14 females per group) were fed
demeton-S-methyl sulfone in the diet at concentrations of 0, 2.5, 10
and 40 ppm for four to six months. Growth was recorded bi-weekly and
at the conclusion of the study cholinesterase activity in brain, RBC
and plasma were determined. No clinical signs of poisoning were
observed over the period of this study and food consumption and weight
gain were comparable to the controls. There was no apparent effect on
gross pathology as observed at the end of the feeding period and
cholinesterase depression in all tissues was obvious brain, plasma and
erythrocyte at 10 ppm. 2.5 ppm was judged to be a no-effect level in
this study (Klimmer, 1965).
Groups of rats (15 male and 15 female WISTAR rats per group, 30
male and 30 female rats were the control group) were fed
demeton-S-methyl sulfone in the diet at concentrations of 0, 1, 3, 10
and 30 ppm for three months.
Behavioural changes were observed in the animals fed 30 ppm in
the diet at the beginning of the experiment. These signs of poisoning
were reduced-as the experiment progressed. Food consumption in the
animals receiving 30 ppm was reduced as was the growth of males. At 10
ppm and below there was no effect on growth and mortality. There was
no apparent effect of demeton-S-methyl sulfone on clinical chemistry,
haematological values, urinalysis and kidney function tests.
Cholinesterase activity in plasma and erythrocyte was measured at 2,
4, 8 and 13 weeks and was observed to be inhibited at both 10 and 30
ppm in both sexes and marginally was depressed at 3 ppm and above in
both sexes. 1 ppm showed no effect on cholinesterase activity. Gross
examination of tissues and organs showed no indication of adverse
effect due to the compound in the diet. The no-effect level in this
experiment was 1 ppm in the diet based upon cholinesterase depression
(Loser, 1971b). Histological examination of the following tissues
showed no somatic effects of the compound (Newman and Urwin, 1972).
Long-term studies
(a) Demeton-S-methyl
None available.
(b) Demeton-S-methyl sulfoxide
Rat. Groups of Charles River rats (35 males and 35 females per
group) were fed oxydemeton-methyl in the diet for 22 months at dose
levels which varied in the experimental design from 0 to 100 ppm. The
low dose group received 0.5 ppm for six months followed by 1 ppm for
three months, 2 ppm for eight months, 4 ppm for one month, and 2 ppm
for the two final months. The intermediate group received 5 ppm for
six months then 10 ppm for the remainder of the experiment. The high
dose group received 25 ppm for one month, 37.5 ppm for the second
month, 50 ppm for the next four months, 75 ppm for the next three
months, and then 100 ppm for the remainder of the study. Growth and
body weight was affected especially in males. Over the entire course
of the study growth in females was not significantly affected. Over
the course of the first six months, growth was depressed in males at
0.5 and 5 ppm in the diet and in the highest group which varied from
25 to 50 PPM. At six months, weight gain was depressed with the
controls gaining 427 g, the 0.5 ppm gaining 364 g, the 5 ppm gaining
350 g and the high group 309 g over this period. Data for females were
all similar to the controls. A comparison of the gain in weight over
months 10 to 17 where 2 ppm (the lowest group) was added to the diet
show the controls to have gained 104 g while the 2 ppm males gained
only 8 g. A plot of the average body weight data showed that there
were definitive effects on males at the lowest concentration in the
diet. At the conclusion of the 22-month study the total weight gain
data showed females to be unaffected while males appeared to be
significantly affected at the highest level and moderately affected at
the other two levels tested.
Haematological and urinalysis were normal and mortality over the
course of the study was not related to the oxydemeton in the diet.
Serum and alkaline phosphatase (SAP) activity in the high dose group,
the only group examined, was elevated sporadically principally in
females but does not appear to be related to the administration of
oxydemeton. No other clinical chemistry parameter was abnormal.
Cholinesterase depression was significant at the higher level in
both sexes in plasma, RBC, and brain tissues. At the intermediate
level, cholinesterase was significantly depressed again in the RBC and
brain and depression was observed in the plasma only at the conclusion
of the study. Cholinesterase was unaffected at the lower group level
in all tissues over the course of the whole study.
No differences were noted between the test and the control
animals on gross pathological examination. Kidney, liver and spleen
weights were decreased in males. Weight of the liver in males was
significantly reduced at the two highest feeding levels. The organ to
body weight ratios were unaffected although the organ to brain weight
ratios in the two highest groups were significantly reduced. In the
kidneys of males, the absolute organ weight was depressed at all
feeding levels as was the organ to brain weight ratio but not the
organ to body weight ratio. A reduced spleen weight of the male
animals on the highest and the lowest but not the intermediate level
was observed. Organ to body weight ratios were unaffected but organ to
brain weight ratios were similarly reduced. Gross effects were not
observed with any other tissues. Histopathological examination of all
tissues and organs showed no differences from the control. A no-effect
level of 2 ppm in the diet based on cholinesterase depression was
observed (Reyna et al., 1973),
(c) Demeton-S-methyl sulfone
None available.
Observations in man
In studies on volunteer subjects, the no-effect level determined
for oxydemeton-methyl after a 60-day period of administration was 0.05
mg/kg bw. An 0.4 mg/kg level caused depression of serum and
erythrocyte cholinesterase activity after a short time but no signs of
poisoning were seen. A single application of 1 mg/kg is tolerated
without affecting cholinesterase activity whereas 2 mg/kg inhibits the
enzyme (Doull, 1973).
Comments
Demeton-S-methyl and related compounds including
demeton-S-methyl sulfoxide (oxydemeton-methyl) and demeton-S-methyl
sulfone are alkylthioether dimethyl organophosphate esters
structurally analogous to demeton, the diethyl ester, and are
absorbed, distributed and metabolized in the same way as demeton in
various biological systems. The metabolism of these compounds, by
analogy with the diethyl esters, would result in oxidation of the
thioether to the sulfoxide and the sulfone. It has been suggested
that the sulfoxide, the major terminal residue in plants, is
responsible for the toxicological effects, Toxicological data
indicate that oxydemeton-methyl is not teratogenic to rabbits, not
mutagenic to mice and does not interfere with reproduction in rats.
None of these compounds induce delayed neurotoxic signs of poisoning
in hens nor do they potentiate the acute toxicity of other
anticholinesterase organophosphate or carbamate insecticides. The
thioether is the most active in vitro anticholinesterase agent
with the sulfoxide and the sulfone being less active. Short-term
studies with demeton-S-methyl in rat and dog resulted in a no-effect
level of 10 ppm in both species based on cholinesterase depression.
Similar studies with the sulfone indicate a marginal
anticholinesterase effect at 3 ppm with no effect noted at 1 ppm.
Short-term studies with demeton-S-methyl sulfoxide and two-year
studies in rats and dogs indicate a no-effect level of 2 ppm based
on cholinesterase depression in both species. Fatty degeneration
was seen in the liver but only in response to exposure at high dose
levels. A close of 0.05 mg/kg/day over a 60-day period was tolerated
in man with no evidence of cholinesterase depression. An ADI was
established on the basis of the long-term studies in animals and
observations in man.
TOXICOLOGICAL EVALUATION
Level causing no toxicological effect
Rat: 2 ppm in the diet equivalent to 0.1 mg/kg bw
Dog: 2 ppm in the diet equivalent to 0.05 mg/kg bw
Man: 0.05 mg/kg per-day
Estimate of acceptable daily intake for man
0-0.005 mg/kg*
* The total demeton-S-methyl, demeton-S methyl sulfoxide and
demeton-S-methyl sulfone should not exceed this figure.
RESIDUES IN FOOD AND THEIR EVALUATION
The three compounds are systemic insecticides used for the
control of aphids, scales, spider mites, sawflies, leafhoppers and
thrips. They are used in numerous crops, particularly cotton,
vegetables, potatoes, cereals, tobacco, hops and fruit.
Demeton-S-methyl and oxydemeton-methyl are marketed as emulsifiable
concentrate formulations in many countries of Europe, Asia, America,
Africa and Australia.
Demeton-S-methyl sulfone is marketed only in combination with
azinphos-methyl as a wettable powder formulation, practically only in
European countries.
Demeton-S-methyl products are registered in 31 countries,
oxydemeton-methyl products in 86 countries, and demeton-S-methyl
sulfone in 13 countries.
The usage on different crops is as follows:
Demeton-S- Oxydemeton- Demeton-S-
methyl methyl methylsulfone
Field Crop 55% 45% -
Vegetables 35% 40% 10%
including
potatoes
Fruit Crops 10% 15% 90%
including grapes
and citrus fruit
Pre-harvest treatment
Demeton-S-methyl and oxydemeton--methyl are usually applied in
concentration 0.025% a.i. and demeton-S-methyl sulfone as 0.015% a.i.
Depending on crops, the pesticides are applied one to five times in a
season. Recommended rates of application and safety intervals for
different crops are as follows.
Application rate Pre-harvest
Crop (a.i.) interval
Demeton-S-methyl
Fruit 500 g/ha 21 days
Vegetables 150-250 g/ha 14-21 days
Field crops generally 150-300 g/ha 21 days
Cotton 500 g/ha 14 days
Demeton-S-methyl
Sugar cane 200-400 g/ha 14 days
Maize 400-600 g/ha 14 days
Oxydemeton-methyl
Fruit 300-500 g/ha 21 days
Vegetables 150-600 g/ha 14-21 days
Field crops 150-600 g/ha 14-21 days
Demeton-S-methyl sulfone
Fruit 300 g/ha 21 days
Vegetables 100 g/ha 14-21 days
Post-harvest treatments
No recommended uses.
Other uses
All three compounds are recommended for the control of pest on
ornamentals.
Residues resulting from supervised trials
In biological systems, conversion constantly takes place
according to the following scheme:
demeton-S-methyl --> oxydemeton-methyl -->
demeton-S-methyl sulfone
Therefore, methods for the analysis of residues must determine
the following compounds:
after application of demeton-S-methyl: demeton-S-methyl +
oxydemeton-methyl +
demeton-S-methyl sulfone
after application of oxydemeton-methyl: oxydemeton-s-methyl sulfone +
demeton-S-methyl sulfone
after application of demeton-S-methyl sulfone: demeton-S-methyl
sulfone.
Residue data are available from supervised trials carried out in
different countries on food crops grown under various conditions. In
most cases normal dosage rates were applied in accordance with label
instructions. However, in some experiments higher dosages were also
included.
The data of the trials are summarized in Table 1. Those trials
carried out before the introduction of GLC wore analysed by the total
phosphorus method.
TABLE 1. TYPICAL RESIDUE RANGES RESULTING FROM RECOMMENDED APPLICATION
RATES AND FREQUENCIES OF APPLICATION OF DEMETON-S-METHYL,
OXYDEMETON-METHYL, AND DEMETON-METHYL SULFONE
Pre-harvest Residue Country/
Crop interval (ppm) number
of trials
Apples 14-28 n.d. - 1.3 GFR, USA/18
Pears 14-28 n.d. - 0.1 USA/7
0.2 - 0.6 GFR/1
Peaches 14-28 - 0.2 GFR/1
n.d. - 0.7 USA/3
14-21 0.5 -2.3 S.Afr/1
Plums 14-28 n.d. - 0.75 GFR, USA/4
Strawberries 14-28 n.d. - 0.6 USA/7
Blackcurrants 14-28 0.16 - 0.63 GFR/2
14 4.0 UK/1
Redcurrants 14-28 1.0 - 1.3 USA/2
Raspberries 14-28 0.1 - 0.6 USA/1
Grapes 14-28 0.05 - 2.7 USA/8
0.23 - 0.5 GFR/7
Citrus fruits 14-28 n.d. - 0.5 USA/9
(whole fruit)
Brassicas (cabbage, 21 n.d. - 0.45 GFR.S.Afr.
brussell sprouts, USA/26
cauliflower,
broccoli)
Lettuce 14 n.d. - <0.4 GFR, USA/10
14-21 0.05 - 0.5 USA/2
Beans, peas 14 n.d. - 0.3 S.Afr. USA/6
Pumpkins, watermelons, 7 n.d. - 0.2 USA/11
winter-squash n.d. - 0.3 USA/2
14 n.d. USA/11
Cantaloups 7-14 n.d. - 0.3 USA/1
Summer squash 7-25 n.d. - 0.6 USA/6
14-25 n.d. USA/11
Cucumbers 14 n.d. USA/6
Eggplants 1-21 n.d. - 0.2 USA/6
14 0.6 USA/1
Hops 21-35 n.d. - 0.8 GFR/5
Walnuts 21-47 n.d. USA/10
(meat)
Cotton-seed n.d. USA/2
Potatoes 3-108 n.d. GFR, Netherlands
USA/39
22-49 0.04 - 0.17 GFR/4
Sugar beet 7-63 n.d. GFR, USA/22
Pre-harvest Residue Country/
Crop interval (ppm) number
of trials
Turnips 7-14 n.d. USA/7
0.1 USA/1
21-28 n.d. USA/13
Cereals -including: 28 n.d. - 0.26 GFR, USA/22
Corn 31/32 0.02 - 0.08 GFR/6
Sorghum, 35-40 n.d. GFR, USA/18
Forage 14-28 n.d. - 3.2 GFR, USA/25
Sugar beet tops,
turnip tops,
sorghum forage,
corn fodder
Clover 21-28 2.4 - 5.0 USA/3
Alfalfa 21 n.d. - 5.5 USA/5
Fate of residues
In plants
No new data were available to amplify that summarized in 1968.
In animals
When 3 ppm oxydemeton-methyl in green forage was supplied to
dairy cattle, practically no residues (40.01 ppm) were found in brain,
heart, liver, kidney, steak and fat after a four-week feeding. When
fed 12 ppm in forage for the same period the heart contained up to
0.04 ppm, brain up to 0.03 ppm and steak up to 0.06 ppm. When fed 30
ppm for seven days the following residues were determined:
liver - n.d.
fat - 0.04 ppm
kidney - 0.09 ppm
heart - 0.11 ppm
brain - 0.18 ppm
In four-week feeding studies with cows, when 3 ppm oxydemetonmethyl
was applied to the ration the residue levels in milk was lower than
0.01 ppm. Likewise the feeding of 9 ppm in the ration produces less
than 0.02 ppm residues in milk (Chemagro report 35556, 35557).
No residues could be detected (below 0.001 ppm) in eggs of hens
fed rations containing 5 ppm oxydemeton-methyl for four weeks. The
muscle and fat of these hens was also free of residues (below 0.01
ppm). Giblets contained 0.01 ppm-0.02 ppm (Chemagro Report 27469,
27470).
In soil and water
Stability of oxydemeton-methyl in three soil types was studied.
When 10 ppm was applied 0.05 ppm was found after 15 days. In another
experiment residue levels decreased from 2 ppm to n.d. - 0.1 ppm after
four weeks and later no residues were detectable.
The effect of oxydemeton-methyl on microbial populations was
studied (Houseworth and Tweedy, 1972). The pesticide when added to two
types of soil at rates of 50 and 250 ppm no effect on soil
microorganism populations could be shown over a 56-day period.
Studies on leaching, adsorption and stability in water (Flint et
al., 1970) showed that 3% of the applied chemical was recovered in run
off water from sandy loam, silt loam and high organic silt loam over a
period of five weeks.
Leaching studies indicated that the compound leaches 30 cm into
silt loam, and high organic silt loam following 580 mm and 1350 mm of
rainfall, whereas sandy loam soil showed minimal retention of
oxydemeton. The half-life of this compound in pond water outdoors at
an average temperature of 29°C and pH 7 was 3.7 days.
Fate of residues in storage, processing and cooking
In sugar beet processing and corn oil deodorization, residues of
oxydemeton-methyl, including demeton-methyl sulfone, decreased very
markedly (Katague, 1967; Thornton, 1970b).
When apples were processed into juice and pomace, 49% of the
initial residues were lost (Chemagro Report 38890).
Residues on oranges, resulting from application of
oxydemeton-methyl, did not decrease significantly following a
commercial washing procedure. However, all the processed orange
products were free of residues (Olson, 1966).
Exposure to SO2 or sun-drying did not result in losses of
residues in peaches and prunes (Chemagro Report 21596, 21600). Washing
of tomatoes simulating commercial preparation for market did not
remove any significant amount of the residue (Thornton, 1973).
Residues present on and in grapes after application of
oxydemeton-methyl are not reduced during processing into the must and
wine (Bayer AG, Leverkusen, Internal Report 328/67, 329/67, 348/67,
349/67).
During frozen storage at about -20°C, oxydemeton-methyl residues
remain unchanged for long periods as was shown for alfalfa, apples,
cabbage, green oat forage and raspberries (Chemagro Report 11573).
Residues in food moving in commerce
Out of 30 lettuce samples of German origin, one sample contained
more than 1.0 ppm of demeton-S-methyl sulfone. Out of 91 apple samples
of German origin, four contained residues of "demeton-methyl", viz.
less than 0.1 ppm in three samples, and 0.1-0.5 ppm in one sample
(Krause and Kirchhoff, 1969).
In a survey of fruits and vegetables for organophosphorus
insecticides carried out in 1967 in the United Kingdom, a total of 349
samples were analysed. One out of five blackcurrant samples contained
0.95 ppm, one out of 15 cherry samples contained 2.36 ppm, one out of
seven radish samples contained 0.07 ppm of demeton-S-methyl. No
demeton-methyl residues were found in any of the other samples (Dickes
and Nicholas, 1968).
In another study conducted in the United Kingdom, 184 samples of
raspberries and strawberries, of which 19 were treated with
demeton-S-methyl, were analysed for residues. All the 19 samples of
raspberries and strawberries that had been treated with
demeton-S-methyl were found to be free of residues (Findlay, 1972).
The following results were provided by the New Zealand Ministry
of Agriculture:
A. RANDOM SAMPLING AT RETAIL LEVEL
Demeton-S-methyl
Crop residue levels
1968 Apples and pears 1 sample in 11 Less than 0.1 ppm
1971 Leaf vegetables 1 sample in 57 Less than 0.01 ppm
1971 Root vegetables 2 samples in 32 Less than 0.01 ppm
1971 Strawberries 1 sample in 7 Less than 0.01 ppm
B. RESIDUES IN CROPS KNOWN TO BE TREATED WITH DEMETON-S-METHYL
Crop Residue levels
1970 Apples 1 sample N.D.
1972 Strawberries 1 sample Less than 0.005 ppm
Methods of residue analysis
Advances have been made in the development of methods for the
analysis of demeton-methyl compounds since the evaluation in 1968.
The basis of most methods is the oxidation of residues containing
demeton-S-methyl and oxydemeton-methyl to the sulfone, which can then
be determined by GLC. If permanganate is used as the oxidizing agent
there is usually no transformation of P = S to P = O, so it is
possible to distinguish between P = S sulfone and P = O sulfone. This
permits conclusions to be drawn as to whether the residues present
result from the application of demeton-S-methyl products or from the
use of thiometon products. The same is true for demeton-S and
disulfoton. These sulfone pairs may be clearly separated on a 1 m
column packed with 10% DC-200 + 1% QF-1 on 80/100 mesh Gas Chrom Q at
195°C (Wagner, 1973). The following retention times are obtained:
demeton-S-methyl sulfone 3.75 min
thiometon sulfone 4.75 min
demeton-S-sulfone 5.0 min
disulfoton sulfone 6.15 min
The determination of oxydemeton and demeton-S-methyl sulfone in
lettuce and sugar beets is described by Thornton and Olson (1971). A
sensitive GLC method for all the three compounds in sorghum foliage
and wheat plants is described by Thornton and Anderson (1968) who
reports a limit of determination of 0.05 ppm.
Determination of oxydemeton and metabolite residues in
cotton-seed and walnuts is described by Olson (1971a) Limit of
determination of the method for these crops is 0.01 ppm.
No interferences were observed by Olson (1971b) and Thornton
(1970c), Thornton and Olson (1971) when all organophosphorus
pesticides registered in the United States of America were examined.
If so, they could be resolved by the standard or alternate procedures.
A GLC procedure for residues in poultry and eggs is described by
Thornton (1970a).
The determination of oxydemeton-methyl and other phosphorus
compounds in the soil is described by Olson (1970b). Limit of the
method - 0.1 ppm.
A multi-residue scheme for organophosphorus pesticides residue
analyses in total diet samples was described by Abbot et al. (1970).
It included three different extraction and clean-up procedures for
seven commodity groups. Thirty-one pesticides and some of their
metabolites (among them demeton-S-methyl and demeton-S-methyl) were
recoverable by this method with a limit of determination of
approximately 0.01 ppm for most compounds.
National tolerances and safety intervals
Unless otherwise stated, the given tolerance levels and safety
intervals apply to both demeton-S-methyl (I) and oxydemeton-methyl
(II).
Safety
Country Crop Tolerance interval
in ppm in days
Australia Fruit, vegetables, cereals 0.5
General 21 (I)
Austria General 35
Belgium Fruit, vegetables excl. 0.4
potatoes
General 28
Denmark General except lettuce, 28 (II)
spinach and other short
season crops
Finland General except vegetables 35 (II)
France General except vegetables 21 (II)
and strawberries
Germany, Fruit, vegetables, field 21
Federal crops incl. fodder crops,
Republic of application under glass
generally
Vegetables excl. carrots, 0.4a
fruit, sugar beets
Cereals, potatoes 0.2a
Other food crops 0.05a
(cont'd)
Safety
Country Crop Tolerance interval
in ppm in days
Hungary General 0.5 30 (I)
Italy General 0.4b 20
Korea Fruit, vegetables, 30 (I)
potatoes, tobacco, fodder
crops
Morocco General except vegetables 21 (I)
Netherlands General 0.4a
Potatoes 0.1a
Fruit incl. soft fruit, 28
beans, peas, brassicas,
potatoes
New Zealand General from Oct.-March 0.4 21
General from April-Sept. 0.4 35
Norway General 28 (I)
Poland Fruit, vegetables, legumes 30 (II)
(no vegetables), root
crops and other field
crops
Fruit, vegetables, legumes 42 (I)
(no vegetables), root
crops and other field crops
Apples, pears, plums Apply up to
14 days post
blossom
Sweet cherries, currants, Established
gooseberries, garden by time of
strawberries, raspberries application
Fruit and vegetables 0.4
Portugal General 35 (II)
South General 2.0
Africa Beans, crucifers generally 10
Brussels sprouts 14
Fruit, potatoes, tomatoes 21
Cueurbits 21 (II)
Brinjals, peppers 14 (I)
Kafir corn, onions, wheat, 21 (I)
groundnuts, cotton, maize
(cont'd)
Safety
Country Crop Tolerance interval
in ppm in days
Spain Cereals, sugar beets 30 (II)
Cotton 35 (II)
Fruit Apply only
up to petal
fall or
post-harvest
(II)
Sweden General 28
Switzerland Leafy and fruiting 0.4b
vegetables, legumes, fruit
crops, grapes, hops
Fruit, grapes, sugar beets 42 (II)
Field beans Before
flowering
begins (II)
USSR Fruits 0.7 (I)
Fodder 1.0
United Wheat, barley 14 (I)
Kingdom Mangold, fodder beets 10 (I)
(for clamping)
Fodder crops generally 21 (I)
All other crops 21 (I)
United Fruits, general 1.0
States Melons, pears 0.3
of America Vegetables, general 1.0
Potatoes 0.1
Sugar beets 0.3
Sugar beets tops 0.5
Turnips 0.3
Winter squash 0.3
Pumpkins 0.3
Cotton seed 0.1
Walnuts 0.3
Alfalfa (green) 5.0
Alfalfa (hay and chaff) 11.0
Clover (green) 5.0
Clover (hay and chaff) 11.0
Corn fodder and forage 3.0
(cont'd)
Safety
Country Crop Tolerance interval
in ppm in days
Corn grain, fresh corn 0.5
incl. sweet corn (kernels,
plus cob with husk
removed)
Yugoslavia Fruit, grapes, field 28 (II)
crops, hops
a Sum of demeton-S-methyl (I), oxydemeton-methyl (II) and
demeton-S-methylsulfone (III) calculated as demeton-S-methyl (I).
b Total as demeton-S-methyl (I).
Appraisal
Since the evaluation of the oxydemeton-methyl in 1965, 1967,
1968, further data have become available on the following compounds:
I - demeton-S-methyl;
II - oxydemeton-methyl; and
III - demeton-S-methyl sulfone.
which are systemic organophosphorus insecticides and acaricides used
individually for pre-harvest treatment of a wide range of crops in
many countries.
One to five applications are recommended at rates ranging from
0.1-0.6 kg/ha depending on the crop.
Compounds II and III are also the oxidative metabolites of
demeton-S-methyl. Following treatments with either compounds I or II,
the residues in the crops consist of oxidized derivatives of compounds
I and/or II.
Residue data were available from the United States of America,
Germany, United Kingdom, South Africa and Netherlands from supervised
trials on fruit, vegetables, field crops and fodder, and on the
feeding of animals. Information on the fate of residues in storage and
processing of some crops was available as was information on the fate
of residues in soil and pond water. Data on residues in foodstuffs
moving in commerce were also considered.
Available multi-residue gas-chromatographic procedures are
suitable for regulatory purposes but it is essential to oxidize all
components of the residue to compound III (sulfone) in order to
increase the accuracy.
RECOMMENDATIONS
Tolerances
The following recommendations are based on pre-harvest intervals
of 14-28 days.
Animal foodstuffs (green) 5 ppm
" " (dry) 10 ppm
Currants (red and black), grapes 2 ppm
Apples, peaches, plums 1 ppm
Blackberries, citrus fruits, gooseberries, 0.5 ppm
lettuce, pears, raspberries, strawberries,
summer squash
Beans, broccoli, brussels sprouts, 0.2 ppm
cabbage, cantaloupes, cauliflower,
cereals, cucumbers, eggplants, peas,
potatoes, pumpkins, raw cereals,
watermelons, winter squash
Cotton-seed, sugar beets, turnips 0.1 ppm
Eggs, fat and meat of cattle, 0.05* ppm
sheep, pigs, poultry, milk and milk
products, nuts (kernal)
These tolerances are to apply to the sum of the residues of
demeton-S-methyl, oxydemeton-methyl, and demeton-S-methyl sulfone,
determined as the sulfone and calculated as demeton-S-methyl.
FURTHER WORK OR INFORMATION
Desirable
1. Studies to elucidate fatty degeneration in liver at high doses.
2. Information on residues in animal tissues from the feeding of
demeton-methyl group compounds, in the form of plant residues, to
domestic animals other than cows and chickens.
* At or about the limit of determination.
REFERENCES
Abbott, D.C., Crisp, S., Tarrant, K. R. and Tatton, J. O'G. (1970)
Organophosphorus pesticide residues in the total diet. Pestic. Sci,
1: 10-13
Anderson, C.A. (1962) Colorimetric determination of DI-SYSTON and
SYSTOX residues in plant material. Chemagro Report No. 8544
Arnold, D., Keplinger, M.D. and Fancher, O.E. (1971) "Mutagenic Study
with Meta-Systox R 50% Technical in Albino Mice". Unpublished report
from Industrial Biotest & Laboratories Inc.
Bayer AG (1973) - Leverkusen - Pflanzenschutz AT, Biol. Forschung,
Institut for Rückstandsanalytik. Unpublished reports filed with FAO
Ben-Dyke, R. Sanderson, D.M. and Noakes, D.N. (1970) "Acute Toxicity
Data for Pesticides (1970)". World Review of Pest Control, 9:
119-127
Bowman, M.C., Beroza, M. and Gentry, C.R. (1969) GLC determination of
residues of disulfoton, oxydemetomethyl, and their metabolites in
tobacco plants. J.A.O.A,C. 52: 157-162
Chemagro Corporation, Kansas City, U.S.A. (1963/73) Unpublished
research reports filed with FAO
Dickes, G.J. and Nicholas, P.V. (1968) A survey of fruits and
vegetables for organochlorine and organophosphorus insecticides. J.
Assoc. Publ. Analysts, 6: 60-66
Doull, J., Vesselinovitch, D., Cowan, J., Root, M., Meskauskas, J.
and Fitch. (1972) Subacute Oral Toxicity of Metasystox-R to Rats.
Unpublished report from Univ. of Chicago
Doull, J. (1973) Personal communication submitted by Bayer A. G.
DuBois, K.P. and Doull, J. (1955) "The Acute Toxicity of P=O
Meta-Systox, P=O Meta-Systox Sulfoxide and P=O Meta-Systox Sulfone to
Mamais". Unpublished report from the Univ. of Chicago
DuBois, K.P. (1960) "The Dermal Toxicity of Meta-Systox R and
Meta-Systox I to Rats. Unpublished from the Univ. of Chicago
DuBois, K.P. & Plzak, G.J. (1962) Toxicol. Appl. Pharmacol. 4: 621.
(Cited in FAO/WHO, 1965)
DuBois, K.P. (1961) "The Acute Toxicity of Meta-Systox R in
Combination with Other Anticholinesterase Agents". Unpublished report
from the Univ. of Chicago
DuBois, K.P. (1962a) "Effect of Repeated Daily Dermal Application of
Meta-Systox R to Rats". Unpublished report from the Univ. of Chicago
DuBois, K.P. (1962b) "Acute Oral Toxicity of Meta-Systox R to
Chickens". Unpublished report from the Univ. of Chicago
DuBois, K.P., DiGiacomo, R., Root, M, Meskaukas, J. and Doull, J.
(1966) Subacute Dermal Toxicity of a Meta-Systox R Formulation to
Rats. Unpublished report from the Univ. of Chicago
EPPO Pesticide Residue Analysis. (1964) Recommended Methods. European
Plant Protection Organisation, Avenue des Champs-Elysées, Paris
FAO/WHO (1965b) Evaluation of the Toxicity of Pesticide Residues in
Food. FAO Meeting Report PL/1965/10/1. WHO/Food Add./27.65
FAO/WHO (1967b) 1967 Evaluations of Some Pesticide Residues in Food.
FAO/PL: 1967/m/11/1. WHO/Food Add./68.30
FAO/WHO (1969b) 1968 Evaluations of Some Pesticide. Residues in Food.
FAO/PL: 1968/./9/1. WHO/Food Add./69.35
FAO/WHO (1970b) 1969 Evaluation of Some Pesticide Residues in Food.
FAO/PL: 1969/m/17/1. WHO/Food Add./70.38
Findlay, E. (1972) Pesticide residues in foodstuffs in Great Britain.
Pesticide residues in raspberries and strawberries. Pestie. Sci. 3:
169-174
Flint, D.R., Church, D.D. and Shaw, H.R. (1970) Soil studies with
META-SYSTOX-R. Chemagro-Report No. 28 140
Fukuto, T.R. and Metcalf, R.L. (1954) Isomerization of ß-
ethylmercaptoethyl diethyl thionophosphate (Systox). J. Amer. Chem.
Soc. 76: 5103-5106
Fukuto, T.R., Metealf, R.L., March, R.B. and Maxon, M.G. (1955)
Chemical behaviour of Systox isomers in biological systems. J. Econ.
Entomol. 48: 347-354
Fukuto, T.R., Wolff III, J.P. Metcalf, R.L. and March, R.B. (1956)
Identification of the sulfoxide and sulfone plant metabolites of the
thiol isomer of Systox. J. Econ. Entomol. 49: 147-151
Fukuto, T.R., Wolff III, J.P., Metealf, R.L. and March, R.B. (1957)
Identification of the sulfone plant metabolite of the thiono isomer of
Systox. J. Econ. Entomol. 50: 399-401
Hartke, K., Burtner, B.R., Kennedy, G.L. jr, and Keplinger, M.L.
"Two-year Chronic Oral Toxicity Study with Meta-Systox R in Beagle
Dogs". Unpublished study from Industrial Bio-Test Laboratory, Inc.
Hartley, G.S. (1952) The anomaly of Systox. World Crops 4: 397
Heath, D.F. and Vandekar, M. (1957) "Some Spontaneous Reactions of
//-Dimethyl S-Ethylthioethyl Phosphorothiolate and Related Compounds
in Water and on Storage, and their Effects on the Toxicological
Properties of the Compounds." Biochem. Journ. 67: 187-201
Heath, D.F., Lane, D.W.J. and Park, P.O. (1955) The decomposition of
some organophosphorus insecticides and related compounds in plants.
Royal Soc. London Philos. Transactions 239B: 191-214
Hecht, G. (1955) "Verigeichende Prufung der Praparate 25/154, R 2170
and M 3/158". Unpublished report submitted by Bayer A.G.
Hecht, G. (1960) "Toxikologische Untersuchung mit Mota-Systox (i)/
Vortrag, gehalten in Tokyo, Korinkaku, am 20.10. 1960". Unpublished
report submitted by Bayer A.G.
Henglein, A. and Schrader, G. (1935) Zur Kenntnis der
Isomerie-Ersheinungen bei den System-Insektiziden "Systox" and
"Meta-Systox". Z. Naturforsch, 10b: 12-19
Hibbs, C.M. and Nelson, D.L. (1967) "Histologic Evaluation of
Meta-Systox R Treated Rats". Unpublished report submitted by Bayer
A.G.
Houseworth, L.D. and Tweedy, B.G. (1972) Effect of META-SYSTOX-R on
microbial populations. Chemagro-Report No. 34 991
Houseworth, L.D. and Tweedy, B.G. (1973) Report on parent leaching
studies for METASYSTOX-R. Chemagro-Report No. 37 181
Joint Demeton-Methyl Residues Panel. (1962) The determination of
demeton-methyl residues in fruits and vegetables. Analyst, 87:
485-492
Katague, D.B. (1967) The effect of processing on META-SYSTOX-R
residues in sugar beets. Chemagro-Report No. 20 686
Kimmerle, G. (1961) "Protective action of FAM against R 2170 poisoning
and neurotoxic effect of R 2170". Unpublished report submitted by
Bayer A.G.
Kimmerle, G. (1963) "Meta-Systox (i)". Unpublished report submitted by
Bayer A.G.
Kimmerle, G. (1966a) "E 154 (88, 5%)/Antidetwirkung". Unpublished
report submitted by Bayer A.G.
Kimmerle, G. (1966b) "Metasystox R/Antidotwirkung (Ht-Nr. 3653)".
Unpublished report submitted by Bayer A.G.
Kimmerle, G. (1966c) "Toxicological Studies on Active Ingredient Saver
20 315". Unpublished report submitted by Bayer A.G.
Kimmerle, G. (1972) "Acute Toxicity of ERA 3886 in Combination with S
276 and with E 154 in Rats". Unpublished report submitted by Bayer
A.G.
Kimmerle, G. and Lurks, D. (1968) "Toxicology of insecticidal
organophosphates". Fflanzenschutz-Nachrichten Bayer 1/68, 21: 111-142
Klimmer, O.R. (1960) "Opinion on the toxicity of the substance 'R
2170' of Farbenfabriken Bayer A.G." Unpublished report from the Pharm.
Institut der Universitat, Bonn
Klimmer, O.R. (1961) "Gutachten uber die chronische orale Toxizitat
von Metasystox der Farbenfabriken Bayer A.G., Leverkusen". Unpublished
report from the Pharm. Institut der Universitat, Bonn
Klimmer, O.R. (1964) "Bestimmung der akuten oralen Toxizitat von
Metasystox M". Unpublished report from the Institut der Universitat,
Boon
Klimmer, O.R. (1965) "Insecticide BAYER 20 315/Toxicological Studies".
Unpublished report from the Pharm. Institut der Universitat, Bonn
Klimmer, O.R. and Pfaff, W. (1955) "Untersuchungen uber die Toxicitat
des neuen Kontaktinsekticides 0,0
Dimethyl-thiophosphorsaure-o-(ß-S-athyl)-athylester ('Metasystox')".
Arzmeim.-Forsch, 5: 584-587
Klotzsche, C. (1964) "Zur toxikologischen Prufung neuer insecticider
Phosphorsaureester". Int. Arch. f. Gewerbepath, u. Gewerbehyg. 21:
92-106
Krause, Ch. and Kirchhoff, J. (1969) Organophosphatruckstande auf
Marktproben von Obst und Gemuse sowie auf Getreideerzeugnissen.
Nachrichtenbl. Dtsch. Pflanzenschutzdienstes, 21: 81-84
Ladd, R., Jenkins, D.H., Keplinger, M.L. and Fancher, O.E. (1971)
"Teratogenic Study with Meta-Systox R 50% Technical in Albino
Rabbits".
Laws, E.Q. and Webley, D.J. (1959) Determination of demeton methyl
residues in plant material. Analyst, 84: 28-32
Loeffler, W.W. (1963) Colorimetric determination of METASYSTOX R
residues in plant material. Chemagro-Report No. 11 476
Unpublished report from Industrial Biotest Laboratories Inc.
Lorke, D. and Kimmerle, G. (1969) "The Action of Reactivators in
Phosphoric-Acid-Ester Poisoning". Naunym Schmiedebergs Arch. Pharmak.
exp. Path. 263: 237
Loser, E. (1971a) "R 2170 (Metasystox R Active Ingredient)/Subchronic
Toxicological Studies on Rats". Unpublished report submitted by Bayer
A.G.
Loser, E. (1971b) "E 158 (metaisosystoxulfone)/Subchronic
Toxicolological Studies on Rats". Unpublished report submitted by
Bayer A.G.
Loser, E. (1972) "Metasystox R (R 2170) - Metaisosystoxsulfone, (E
158)/Vergleichende Untersuchungen zur Cholinesterase-Hemung bei
Ratten", Unpublished report submitted by Bayer A.G.
March, R.E., Metcalf, R.L., Fukuto, T.R. and Maxon, M.G. (1955)
Metabolism of Systox in the white mouse and American cockroach. J.
Econ. Entomol. 48: 355-363
Metcalf, R.L., Fukuto, T.R., March, R.B. and Stafford, E.M. (1956) The
systemic behaviour of Systox thiol isomer sulfoxide and methosulfate
in plants. J. Econ. Entomol. 49: 738-741
Metealf, R.L., March, R.B., Fukuto, T.R. and Maxon, M. (1954) The
behaviour of Systox-isomers in bean and citrus plants. J. Econ.
Entomol. 47: 1045-1055
Metcalf, R.L., March, R.B., Pukuto, T.R. and Maxon, M.G. (1955) The
nature and significance of Systox residues in plant material. J. Econ.
Entomol. 48: 364-369
van der Merve, J.H. and Taylor, W.B. (1971) Gas chromatographic
determination of demeton-S-methyl residues in plant material.
Pflanzenschutz-Nachrichten Bayer, 24: 259-264
Mühlmann, R. and Tietz, H. (1956) "Das chemische Verhalten von
Methylisosystox in der lebenden Pflanze und das sich daraus ergebende
Rusk-standsproblem. Hofchen-Briefe, 9: 116-140
Mühlmann, R. and Schrader, G, (1957) Hydrolyse der insektiziden
Phosphorsaureester. Z. Naturforsch, 12b: 196-209
New Zealand Ministry of Agriculture. (1973) Information reported to
FAO
Newman, A.J. and Urwin, C. (1972) "Pathology Report of E 158 Rat
Study". Unpublished report from the Huntingdon Res. Centre, England
Niessen, H., Tietz, H., Hecht, G. and Kimmerle, G. (1963) "Uber
Vorkonmen von Sulfoniumverbindungen in Metasystox (i) und Metasystox R
und ihre physiologische Wirkung". Arch. f. Tox. 20: 44-60
Olson, T.J. (1966) The effect of processing on META-SYSTOX-R residues
in oranges and orange products. Chemagro-Report No. 18 586
Olson, T.J. (1969) A confirmatory gas chromatographic procedure for
META-SYSTOX-R residue analysis. Chemagro-Report No. 23 999; plus
Addendum Chemagro-Report No. 28 504 (1970)
Olson, T.J. (1970a) A study of the possible interferences of other
pesticides with the analytical method for METASYSTOX-R on crops.
Chemagro-Report No. 21 463
Olson, T.J. (1970b) Determination of DASANIT, GUTHION, META-SYSTOX-R3
NEXACUR and TRICHLORFON in soil by thermionic emission gas
chromatography. Chemagro-Report No. 27 835
Olson, T.J. (1971a) Determination of META-SYSTOX-R residues in
cottonseed and walnuts by thermionic emission gas chromatography.
Chemagro-Report No. 21 590
Olson, T.J. (1971b) An interference study for the META-SYSTOX-R
residue method for crops. Chemagro-Report No. 30 957
Reyna, N.F,, Kennedy, G.L. jr and Keplinger, N.L. (1973) "22 Month
Chronic Oral Toxicity Study with Metasystox-R in Albino Rats".
Unpublished report from Industrial Biotest Laboratories, Inc.
Root, M., Cowan, J. and Doull, J. (1963) "Determination of the Safe
Dietary Level for Metasystox-R in Dogs". Unpublished report from the
University of Chicago
Root, M., Meskauskas, J., Kinoshita, F., Flynn, M. and Grohs, D.
(1967a) "Subacute Oral Toxicity of Metasystox-R to Male and Female
Rats". Unpublished report from the University of Chicago
Root, M. and Meskauskas, J. (1968) "Addendum to a Report on Subacute
Oral Toxicity of Metasystox-R to Male and Female Rats". Unpublished
report from the University of Chicago
Root, M., Meskauskas, J., Kinoshita, F., Flynn, M. and Grohs, D.
(1967b) "Subacute Oral Toxicity of Metasystox-R to Male and Female
Dogs". Unpublished report from the University of Chicago
Root, M. (1969) "Addendum to Subacute Oral Toxicity of Metasystox-R to
Male and Female Dogs". Unpublished report from the University of
Chicago
Root, M.. Meskauskasy J., Kinoshita, F., Flynn, M. and Kompf, C.
(1968) "Subacute Oral Toxicity of Metasystox R to Male and Female
Rats". Unpublished report from the University of Chicago
Root, M., Meskauskas, J., Kinoshita, F. and Flynn, M. (1970) "Subacute
Oral Toxicity of Metasystox-R to Male and Female Dogs". Unpublished
report from the University of Chicago
Root, M.S. and Doull, J. (1972) "Comparative Subacute Oral Toxicity of
Some Organic Phosphates in Rats and Dogs". (5th Annual Meeting - 29
June 1972 - reviewed by abstract only)
Su, M.Q., Kinoshita, F.K., Frawley, J.P. and DuBois, K.P. (1971)
"Comparative Inhibition of Aliesterase and Cholinesterase in Rats Fed
Eighteen Organophosphorus Insecticides". Toxicol. and Appl. Pharm.
20: 241-249
Thomas, W.D.E. (1956) The behaviour of systemic insecticides in
plants. A survey of results obtained with 32-P labelled Schradan and
demeton-S. J. Sci. Food Agric. 9: 565-573
Thomas, W.D.E., Bennett, S.H. and Lloyd-Jones, C.P. (1955) The
absorption, breakdown and systemic behaviour in plants of
32-P-labelled demeton S. Ann. Appl. Biol. 43: 569-593
Thomas, W.D.E. and Glynne Jones, G.D. (1955) The systemic properties
of diethyl-S-2-(ethylthioethyl) phosphorothiolate (demeton-S) with
reference to the contamination of nectar. Ann. Appl. Biol. 43:
182-191
Thornton, J.S. (1970a) A confirmatory gas chromatographic procedure
for META-SYSTOX-R in poultry and eggs. Chemagro-Report No. 27 085
Thornton, J.S. (1970b) Effect of the oil doodorization process on
residues of METASYSTOX-R and METASYSTOX-R sulfone in corn oil
(Simulated). Chemagro-Report No. 27 638
Thornton, J.S. (1970c) A study of the possible interferences of other
pesticides with the analytical method for META-SYSTOX-R on crops. I.
Test for the compounds registered on mint. Chemagro-Report No. 29 063
Thornton, J.S. (1973) Effect of washing on residues in tomatoes
treated with METASYSTOX-R. Chemagro-Report No. 37 332
Thornton, J.S. and Anderson, C.A. (1968) Determination of residues of
Di-Syston and metabolites by thermionic emission flame gas
chromatography. J. Agr. Food Chem. 16: 895-898
Thornton, J.S. and Olson, T.J. (1971) Determination of META-SYSTOX-R
residues in lettuce and sugar beets by thermionic emission gas
chromatography. Chemagro-Report No. 21 000
Thornton, J.S. and Yoksh, R.M. (1970) Determination of META-SYSTOX-R
residues in poultry tissues and eggs by thermionic emission flame gas
chromatography. Chemagro-Report No. 27 004
Tietz, H. and Frehse, H. (1960) Methods zur Bestimmung von Rückstanden
der systemischen Insektizide der Metasystox Gruppe in pflanzlichem
Material. Hofeben-Briefe, 13, 212-221
Vandekar, M. (1958) "The Toxic Properties of Demeton-Methyl
(Metasystox) and Some Related Compounds". Brit. J. Industr. Med. 15:
158-167 (Cited in FAO/WHO, 1965, 1968)
Vince, A.A. and Spicer, J.F. (1971) "Pathology Report on R 2170
(Metasystox-R active substance) Sub-Chronic Toxicological Studies in
Rats". Unpublished report from the Huntingdon Res. Centre
Wagner, K. (1973) Unpublished. Bayer A.G., Pflanzenschutz AT, Biol.
Forschung, Institut fur Ruckstandsanalytik
Wirth, W. (1958) "Zur Wirkung System-insecticider Phosphorsaure Ester
in Warmbluter-Stoffwechsel". Naunyn SchmiedebergIs Arch. exp. Path. u.
Pharmak. 234: 352-363
Wren, D.B. and Nelson, D.L. (1969) "Histologic Evaluation of
Metasystox-R Treated Rats". Unpublished report from the Chemagro
Corporation, submitted by Bayer A.G.
Wren, W.B. (1970) "Microscopic Findings in the Tissues of Male and
Female Dogs Administered Metasystox-R Orally (subacute toxicity) 150
ppm". Unpublished report submitted by Bayer A.G.
Wren, W.B., Hibbs, C. and Nelson, D.L. (1968) "Subacute Dermal
Toxicity of the Metasystox-R Formulation to Rats, Histologic
Evaluation of Metasystox-R Treated Rats". Unpublished report from
Chemagro Corporation, submitted by Bayer A.G.