THIOMETON JMPR 1973
Thiometon was considered at the 1969 Joint Meeting (FAO/WHO,
1970b). At that time it was not possible to establish an acceptable
daily intake so no tolerances were recommended. Information was
provided on the nature and level of residues following the use of
thiometon.
Further information was required by the 1969 Joint Meeting before
tolerance could be established. Information was received on most of
these issues and the following monograph addendum summarizes its
evaluation by the Meeting.
IDENTITY
Chemical name - Thiometon
O,O-dimethyl-S-[2-(ethylthio)-ethyl phosphorodithioate
(C6H15O2PS3)
(MeO)2 P(S)-S-ET-S-ET (MW-246)
Appearance and solubility
Colourless oil with characteristic odour - slightly soluble in
water (0.2 mg/ml); and soluble in organic solvents
B.P. - 110°C at 0.1 mm Hg
V.P. 3 x 10-4 mm Hg at 20°C
Composition of technical Thiometon
Thiometon ca 95%
O-S-dimethyl S-((2-ethylthio)
ethyl) - phosphorodithioate ca 0.5 - 1.0%
2-6-dithia-octane ca 0.6 - 1.8%
3,6,7,10-tetrathia-dodecane ca 0.8%
3,6,9-trithia-undecane ca 1.6%
O-methyl S, S-di ((2-ethylthio)
- ethyl) -phosphorodithioate ca 1.6%
EVALUATION FOR ACCEPTABLE DAILY INTAKE
Biochemical aspects
Effects on enzymes and other biochemical parameters
Data are available on the cholinesterase inhibiting properties of
thiometon as reviewed in 1968 (FAO/WHO, 1969). Based upon analogous
work with dissolution, thiometon is a poor inhibitor of cholinesterase
activity and when it is converted to the phosphorothiolate, activity
of cholinesterase is rapidly depressed. 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 X 10-5, 4.1 x 10-5, and 2.3 x 10-5 M. for the
sulfide, sulfoxide and sulfone respectively (Health and Vandekar,
1957).
TOXICOLOGICAL STUDIES
Special studies on reproduction
Rat. Groups of 10 male and 10 female rats were fed thiometon in the
diet at 1 mg/kg/day to examine the effect of thiometon on reproduction
and fertility. After feeding for six months, animals were mated to
produce an F-1 generation and young from this F-1 generation were
chosen at weeks 10 and 17 for mating to produce an F-2A and F-2B
generation respectively. Reproduction indices recorded for the F-2A
and F-2B generation receiving 1 mg/kg/day were comparable with those
of the control animals. On the basis of what can be determined from
this unusually designed study, a dose of 1 mg/kg/day in the diet would
not have a substantial effect on reproduction (Klotzsche, 1972).
Acute toxicity
Substance Animal Sex Route LD50 (mg/kg) References
Thiometon Mouse M oral 66 Anon., 1969
F oral 62 Anon., 1969
Rat M oral 100-120 Anon., 1969;
Ben-Dyke,
Sanderson and
Noakes, 1970
F oral 120-125 Anon., 1969
Guinea-pig M oral 261 Anon., 1969
(cont'd)
Substance Animal Sex Route LD50 (mg/kg) References
Rabbit M oral 95 Anon., 1969
Rat M i.v. 27.5 Anon., 1969
F i.v. 35.5 Anon., 1969
Rat M i.p. 45.0 Anon., 1972
F i.p. 47.0 Anon., 1972
Rabbit M i.v. 22.0 Anon., 1969
Rat M dermal >1100 Klotzsche, 1964
Rat M oral pure 225 Klotzsche, 1958
compound
Rat M&F inhalation >60 mg/l Klotzsche, 1958
1h
Short-term studies
Rat. Groups of rats (15 male and 15 female WISTAR-strain rats per
group) were fed thiometon in the diet at concentrations of 0, 0.5, 2
and 5 ppm for four weeks. Cholinesterase activity in plasma and red
blood cell was examined at 1, 3, 7, 14, 21 and 28 days and brain
cholinesterase was examined on animals sacrificed at 14 and 28 days.
There was no effect in this study on growth or behaviour. There was no
apparent effect on plasma cholinesterase in both males and females.
There was a slight effect observed in red blood cell cholinesterase in
both males and females at 5 ppm which was carried over to the
observations on brain cholinesterase at the two intervals examined. On
the basis of cholinesterase inhibition, the no-effect level in this
study would be 2 ppm in the diet although the 5 ppm effect was
marginal (Carpy, 1972).
Groups of rats (25 male and 25 female per group) were fed
thiometon in the diet at dose levels of 0, 5, 15 and 45 ppm for 90
days. Blood chemistry including plasma and erythrocyte cholinesterase
were examined at 4, 8, and 13 weeks. At the conclusion of the study
the animals were sacrificed and gross pathology performed on the
following tissues: heart, kidney, spleen, adrenal, testes, and liver.
Mortality was apparently observed in this study at 45 ppm in the diet
after the fourth week. Clinical chemistry values were unaffected at
any level in both males and females and the gross pathological
examination of tissues showed no differences from controls. Plasma
cholinesterase in males and females was significantly reduced at
15 ppm in the diet. Red blood cell cholinesterase activity was
significantly depressed at 15 ppm in the diet and was slightly
affected at 5 ppm. An apparent no-effect level in this study based
upon cholinesterase depression would be 5 ppm in the diet (Klotzsche,
1971).
Dog. Groups of beagle dogs (four male and four female dogs per
group) were fed thiometon in a standard diet (NAFAG - 164) for 90
days. The dietary concentrations of 0, 10, 20 and 40 ppm in the diet
corresponded to an actual intake of 0.35, 0.65 and 1.40 mg
thiometon/kg/day.
There were no effects noted in food consumption, growth or
behaviour of the animals over the 90-day period. Results of the
haematology, clinical chemistry and urinalysis wore normal. Gross and
histological examinations showed no differences from the controls.
Plasma cholinesterase depression was evident in the study with a
slight effect being noted at 40 ppm in both males and females
primarily at the end of the 90 day feeding interval. Brain
cholinesterase was unaffected at dose levels up to and including 40
ppm in the diet while red blood cell cholinesterase was inhibited
significantly at 20 ppm and above. A no-effect level of 10 ppm based
upon red blood cell cholinesterase depression is considered to be the
most sensitive parameter examined (Klotzsche and Carpyl 1973).
Comments
Thiometon, like the diethyl ester, disulfoton, is an alkyl
thioether dimethyl organophosphorus ester of moderately acute
toxicity. No information from metabolic studies in animals or from
observations in man are available. In a previous evaluation (FAO/WHO,
1970b) an ADI was not established. Short term studies in rats and dogs
have indicated no-effect levels, based on cholinesterase depression,
at 5 ppm and 10 ppm in the diet, respectively. A reproduction study in
rats was negative at a dosage level of 1 mg/kg. The results of
long-term studies are not available. The analogy with cliaulfoton
suggests that thiometon should be metabolized to the sulfoxide and
sulfone of the dithioate ester and to demeton-S-methyl, but evidence
that this is so is not available. On the basis of the short-term
studies with thiometon a temporary ADI for man was established.
TOXICOLOGICAL EVALUATION
Level causing no toxicological effects
Rat: 5 ppm in the diet, equivalent to 0.25 mg/kg bw
Dog: 0.35 mg/kg bw/day
Estimate of temporary acceptable daily intake for man
0-0.005 mg/kg bw.
RESIDUES IN FOODS AND THEIR EVALUATION
Data is available on supervised trials from Czechoslovakia, the
Netherlands, United Kingdom and South Africa.
The dosages applied and the residues found in the various
commodities are listed in Table 1.
TABLE 1. RESIDUE DATA PROM SUPERVISED TRIALS
(Thiometon expressed as the sum of thiometon, thiometon-sulfoxide and
thiometon-sulfone)
Crop or Rate of Pre-harvest and Residue Country
product application interval/day. in ppm.*
Apples 1.25 g/tree 0 0.71 Czechoslovakia
2 0.63
6 0.70
9 0.06
13 0.13
(multi-treatment)
2.5 g/tree 0 0.84 Czechoslovakia
4 0.38
7 0.71
13 0.30
21 0.22
0.5 kg/ha 0 0.62 United Kingdom
1 0.52
3 0.4
21 <0.01
Barley (grain) 0.250 kg/ha 28 <0.01
(straw) 42 <0.01 Netherlands
Bean 0.125 kg/ha 7 0.13 South Africa
14 0.1
Brussels sprouts 0.5 kg/ha 1 2.0
0 2.5 United Kingdom
3 0.21
21 <0.01
(cont'd)
Crop or Rate of Pre-harvest and Residue Country
product application interval/day. in ppm.*
Cabbage 0.4 kg/ha 1 1.6 Czechoslovakia
1 0.13
15 <0.01
0.4 kg/ha 1 1.78 Czechoslovakia
8 <0.01
15 <0.01
2 x 0.4 kg/ha 1 4.08 Czechoslovakia
8 0.19
15 0.02
0.5 kg/ha 0 2.1
3 0.32
7 0.06
10 0.09
Carrots 0.5 kg/ha 21 0.03 United Kingdom
Corn 0.125 kg/ha 28 0.05 South Africa
Hops 0.5 kg/ha 17 0.15 United Kingdom
Lettuce 0.33 kg/ha 0 1.3 United Kingdom
1 0.3
3 0.11
21 <0.01
0.5 kg/ha 0 2.52
3 0.36
7 0.09
10 0.02
16 <0.01
Lettuce (glasshouse) 0.5 kg/ha 0 3.02
7 2.25
11 1.62
18 0.69
22 0.43
25 0.11
Peas (including pod) 0.5 kg/ha 21 <0.01 United Kingdom
Potatoes 0.5 kg/ha 21 <0.01 United Kingdom
0.25 ka/ha 27 <0.05 South Africa
(cont'd)
Crop or Rate of Pre-harvest and Residue Country
product application interval/day. in ppm.*
Red peppers 2 kg/ha 0 0.56
(glasshouse) 2 0.38
4 0.29
7 0.31
9 0.18
Strawberries 0.5 kg/h. 0 0.43 United Kingdom
(GLC)
1 0.23
3 0.08
21 <0.01
Sweet cherries 0.06 kg/tree 7 0.83
12 0.09
16 0.125
20 0.16
Tomatoes 0.025% spray 7 <0.05 South Africa
Wheat (grain) 0.25 kg/h. 56 <0.01
(straw) 56 <0.01 Netherlands
Sugar beet 0.5 kg/ha 0 2.2 United Kingdom
(leaves) 1 2.7
3 0.26
7 0.02
14 <0.01
21 <0.01
0.5 kg/ha 0 2.6 United Kingdom
1 1.9
3 1.3
7 0.08
14 <0.01
21 <0.01
Information on national tolerances available to the Meeting is
set out in Table 2.
TABLE 2. NATIONAL TOLERANCES
Country Product Tolerance
Belgium Fruits, vegetables 0.5
Potatoes 0.05
Hungary General 0.5
Netherlands Fruit, vegetables 0.5
Potatoes 0.05
New Zealand 0.00
Poland Vegetables, fruits 0.5
South Africa General 2
Switzerland Fruits 0.3
Potatoes 0.05
USSR Fruits 0.5
Methods of residue analysis
For the analysis of the parent compound and its oxidative
metabolites TLC and GLC methods and available (Huntington, 1969) and
(Sandoz, 1972). The limits of determination of the methods are 0.02
ppm and 0.01 ppm respectively.
The sample is extracted with acetonitrile. The extract is treated
with potassium permangamate and subjected to clean-up by partition
between water and methylene chloride/petroleum ether (1/9).
By this oxidation procedure residues of thiometon, its sulfoxide
and sulfone are determined together as thiometon sulfone. This allows
a faster and more accurate analysis. Residues of the oxygen analogue
and its sulfoxide add sulfone are likely to be too low to
significantly affect the accuracy of the analysis.
Appraisal
Since the 1969 Joint Meeting some additional data have become
available on residue levels in a variety of commodities after
supervised trials.
Taking into consideration the residue data that was available in
1969 and additional information obtained from supervised trials
recommendations were made for residual limits in potatoes, raw
cereals, sugar beet and some fruits and vegetables based on a
pre-harvest interval of 28 days.
No information was provided on residues in commodities in
commerce, fate in processing and cooking or residues in meat or milk.
The information available indicates that residues of the oxygen
analogue together with its sulfoxide and sulfone are unlikely to
exceed 10% of the total residue.
RECOMMENDATIONS
Residues are to be determined as thiometon sulfone and expressed
as thiometon.
Temporary tolerances
Apples, cherries (sweet),
grapes, pears,
peaches, plums, strawberries
Beans, lettuce,
peas, peppers,
tomatoes, hops (dry) 0.5
Carrots, potatoes,
sugar beets,
raw cereals (including maize) 0.05
FURTHER WORK OR INFORMATION
Required (before June 1976)
1. Long-term studies to investigate chronic toxicity in at least one
species.
2. Metabolism studies in plants and animals.
3. Adequate data from supervised trials, using sensitive gas-liquid
chromatography methods, on crops (including those for which temporary
tolerances are recommended but excluding those at or about the limit
of determination) in order that the temporary tolerances can be
confirmed and additional residue limits recommended.
Desirable
1. Data on the rate of disappearance of residues during storage.
processing, and cooking.
2. Information on the nature and level of residues in meat, milk, and
eggs, following the feeding of residues of thiometon in the ration.
3. Data on the residue level in commodities moving in commerce.
REFERENCES
Anon. (1969) Thiometon, toxicological investigations. Unpublished
report from Sandoz submitted by Sandoz Ltd., Basle
Anon. (1972) Thiometon, toxicological investigations. Unpublished
report from Sandoz submitted by Sandoz Ltd., Basle
Bátora, V. et al. (1968) Studies on the persistence of thiometon
sulfoxide residues in some vegetables and fruits. Agrochemia, 8, 5
Carpy, S. (1972) Thiometon, 28 Tage-Futterungsversuch an
Ratten-Bestimmungen der Cholinesteraseaktivitat. Unpublished report
Agro-Department Forschung, Sandoz Chemical Company, submitted by
Sandoz Ltd
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
Huntingdon. (1969) Huntingdon Research Centre, England, report No.
2752
Klotzsche, C. (1958) Thiometon, ein neuer systemischer
Phosphorsäureester. Mitteilungen aus dam Gebiet der
Lebensmitteluntersuchung und Hygiene, 49: 72-77
Klotzsche, C. (1964) Zur toxikologischen prufung neuer insecticider.
Phosphorsäureester. Int. Arch. f. Gewerbepath, u. Gewerbehyg., 21:
92-106
Klotzsche, C. (1971) Thiometon 90-Tage-Futterungs-Versuchmit Ratten.
Unpublished report by Agro-Department Forschung, Sandoz Chemical
Company, submitted by Sandoz Ltd
Klotzsche, C. (1972) Thiometon, 3-Generationenversuch an Ratten.
Unpublished report from Agro-Department Forschung, Sandoz Chemical
Company, submitted by Sandoz Ltd
Klotzsche, C. and Carpy, S. (1973) Thiometon 90-Day Feeding Study in
Dogs. Unpublished report from Agro- Department Forschung, Sandoz
Chemical Company, submitted by Sandoz Ltd
Listopadova, E. and Laska, P. (1971) Thiometon residues in cabbage
following Intration spray. Ochr. rostl. (Praha), 7(2): 113-120
Sandoz. (1972) Report CVH 1/72
See Also:
Toxicological Abbreviations
Thiometon (ICSC)
Thiometon (FAO/PL:1969/M/17/1)
Thiometon (Pesticide residues in food: 1976 evaluations)
Thiometon (Pesticide residues in food: 1979 evaluations)