METHIDATHION JMPR 1975
Methidathion was evaluated by the Joint Meeting in 1972 (FAO/WHO,
1973). Further work was required to elucidate the formation of pigment
and the nature of the liver lesion which leads to increased serum
transaminase levels in dogs. It was considered desirable to have
metabolic studies in man to determine comparative degradation between
man and other species, a study to determine dose levels causing no
carboxylesterase (aliesterase) activity depression, and further
information on the fate of residues in storage and processing.
Since the 1972 Meeting, some additional residue information has
EVALUATION FOR ACCEPTABLE DAILY INTAKE
A re-evaluation of the histological slides of the liver tissue
from the original study in which dogs were treated for 104 weeks with
2, 4, 16 and 64 ppm methidathion (Johnston, 1967; Ferrell, 1973) has
been submitted by Ciba-Geigy Limited. Intrahepatic cholestasis was
observed in dogs fed 16 and 64 ppm methidathion. Neither degenerative
nor inflammatory changes were associated with this lesion.
Pigmentation occurred as bile-plugs in biliary ductules, or as
amorphous deposits in Kupffer cells or as lipofuscin in both hepatic
and Kupffer cells. Haemolysis was not detected. A minimal degree
lipofuscin pigmentation was also observed at 4 ppm and in the control
group. Mild irregular fatty changes of the hepatocytes with occasional
periportal histiolymphocytic infiltration of the liver were observed
in both treated and control animals (Hess, 1975).
In the two-year dog study at 64 ppm (1.6 mg/kg/day) it is
significant that the plasma enzyme and liver histology changes at 30
days of treatment were not increased after two years' treatment at
this dose. Furthermore, the serum enzyme changes at 16-19 weeks'
treatment at 64 ppm were reversible and returned to normal after three
weeks with no dosage.
It is well-known that a variety of drugs and chemicals produce
increases in plasma transaminases due to enzyme induction or increased
permeability of hepatocyte plasma membrane. Also many chemicals,
especially those which are highly lipophilic and are biliary excreted,
may compete with bilirubin and alkaline phosphatase for biliary
excretion, causing reversible elevations of plasma alkaline
phosphatase and bilirubin. The moderate hepatic accumulation of bile
pigment and lipid at the higher doses (16 and 64 ppm) would be in
keeping with these other observations.
Concern was expressed by the 1972 Joint Meeting with respect to
the hepatic lesions observed in a previously evaluated dog study.
Although no new data were provided, a re-evaluation and interpretation
was made of the liver damage previously noted in the original dog
study. Since no-effect levels were previously established for
cholinesterase inhibition in the rat, monkey and man, an acceptable
daily intake was established on the basis of the data in man.
Level causing no toxicological effect
Rat: 4 ppm in diet equivalent to 0.2 mg/kg bw.
Dog: 4 ppm in diet equivalent to 0.1 mg/kg bw.
Monkey: 0.25 mg/kg bw.
Man: 0.11 mg/kg bw.
ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN
0-0.005 mg/kg bw.
RESIDUES IN FOOD AND THEIR EVALUATION
The use patterns of methidathion in some countries were reported
to the Meeting and are summarized in Table 1.
TABLE 1. Use patterns of methidathion in some countries
Country Crops, (kg/ha) Insects (days)
Canada Potatoes 0.2 Colorado potato 14
Hungary Apples, apricots, 45-60g/ Mites, aphids, 28
peaches, pears, 100 moths, Colorado
potatoes litres potato beetle
The Netherlands* Apples, pears 0.6 Mites, aphids, 21
* Also used in tree nurseries.
RESIDUES RESULTING FROM SUPERVISED TRIALS
Residue levels of methidathion from supervised trials on apples
were reported from the Netherlands (Rijksinstituut, 1966). The data
are summarized in Table 2.
FATE OF RESIDUES
Dejonckheere and Kips (1974) studied the photodecomposition of
methidathion. Irradiation of methidathion was carried out with
ultraviolet light at a wavelength of 254 nm. The following products
were identified: amorphous sulfur, the oxygen analogue,
O,O,S-trimethyl phosphorodithioate, O,O,S-trimethyl phosphorothioate,
bis(2-methoxy-delta2-1,3,4-thiadiazolin-5-one-4yl) disulfide, and
1,3,4-oxadiazolidine-2,5-dione and S,S-methylenebis(O,O-dimethyl
Methidathion was fed to a Holstein cow at the 5 mg/kg level in
the ration for four days (St John and Lisk, 1974). Residues of intact
methidathion were not detected in milk, urine or faeces samples
collected throughout the feeding period and for six days thereafter.
In in vitro studies, methidathion was stable in rumen fluids for
periods up to eight hours. Analysis of urine showed the presence of
dimethyl phosphorodithioate and dimethyl phosphorothioate
representing, respectively, 2.74 and 3.58% of the total methidathion
dose. After 30 minutes' incubation with beef liver 10 000 × g
supernatant fraction, degradation of methidathion in three replicated
samples was 82, 86 and 74%.
In in vitro studies with rumen contents, Polan et al. (1969)
concluded that breakdown of methidathion was due to microbial activity
because neither boiled nor clarified rumen contents degraded the
compound. Methidathion disappeared rapidly from the intact rumen and
more than 80% of the original dose had disappeared within two hours.
It was concluded that microbial degradation of methidathion in the
rumen was of relatively little importance since absorption into the
bloodstream was so rapid.
TABLE 2. Residues of methidathion in apples, resulting from supervised trials
Mean residue, mg/kg (range in parenthesis), at interval, days,
Rate No. of after application
Crop (kg/ha) treatments 0 2 10-11 20-21 30-31
Apples 0.8 1 0.4 0.4 0.2 0.06 <0.05
(0.11- (0.21- (0.09- (<0.05-
0.63) 0.64) 0.28) 0.07)
1 0.9 0.3 0.15 0.1 0.07
(0.79- (0.28- (0.12- (0.08- (<0.05-
1.0) 0.37) 0.20) 0.15) 0.08)
Silage and hay were made from alfalfa and timothy that were
treated with methidathion at the rate of 1.12 kg/ha (Polan et al.,
1969). A logarithmic rate of degradation of methidathion occurred in
the silage and hay for 200 and 120 days, respectively.
Methidathion residues were not detected in either cured or
noncured tobacco grown on soils treated at rates of 0.28 to 2.24 kg/ha
(Townsend and Specht, 1975).
Methidathion residues ranged from 0.01 to 0.70 mg/kg in soils
from tobacco fields one month after treatment at rates of 0.28 to 2.24
kg/ha (Townsend and Specht, 1975). Residue levels ranged from about
0.01 to 0.15 mg/kg three months later. In another experiment it was
determined that three months after treatment (1.12 kg/ha)
approximately 2% of the applied methidathion remained in the soil.
RESIDUES IN FOOD IN COMMERCE OR AT CONSUMPTION
Hungary and France submitted to the Meeting analytical data on
residue levels of methidathion detected in food samples. The data are
summarized in Tables 3 and 4.
In Hungary 1974, 282 samples were analysed of which 16 contained
residues above the limit of determination of 0.02 mg/kg. Three potato
samples and one tomato sample had residues in excess of the temporary
tolerances of 0.02 and 0.1 mg/kg respectively, established at the 1972
Meeting (FAO/WHO, 1973).
In France during 1973-75, 74 food samples were analysed. Six
samples contained residues and all were within the temporary tolerance
established in 1972.
NATIONAL TOLERANCES REPORTED TO THE MEETING
Some further examples of national tolerances were reported to the
Meeting and are listed in Table 5.
Some additional information on methidathion was presented to the
Meeting on the following: use patterns in some countries; a supervised
trial on apples in the Netherlands; identification of
photodecomposition products; fate in a cow; degradation in hay, silage
and rumen; residues in tobacco and in soil from a tobacco field; data
from food samples in Hungary and France. Of the 282 food samples
analysed in Hungary, methidathion residues in three potato samples and
in one tomato sample exceeded the temporary tolerances recommended at
the 1972 Meeting. Further examples of national tolerances were
TABLE 3. Residue levels of methidathion in food inspection samples
in Hungary, 1974
No. of samples containing
residues in range (mg/kg)
Crop analysed <0.02* 0.02-0.1 0.1-0.2
Apples 129 124 4 1
Apricot 3 2 - 1
Cabbage 9 8 1 -
Carrot 2 2 - -
Cauliflower 2 2 - -
Cherry 4 4 - -
Sour cherry 2 - - 2
Cucumber 1 1 - -
Grape 4 4 - -
Onion 41 41 - -
Parsley 9 9 - -
Peach 28 28 - -
Pear 6 6 - -
Plum 3 - 1 2
Potato 33 30 - 3
Tomato 6 5 - 1
* Limit of determination of the method.
TABLE 4. Residue levels of methidathion in food samples in France,
No. of No. of samples
Crop analysed detectable residues Residue, mg/kg
Apple 27 1 0.03
Pear 38 1 0.07
Brussels sprouts 5 1 0.011
Cherry 1 - -
Orange 1 1 0.018
Lemon 1 1 1.9
Mandarin orange 1 1 0.25
TABLE 5. National tolerances reported to the Meeting
Country Commodity Tolerance
Hungary General 0.2
South Africa Citrus fruits (whole) 2
All food products 0.5
Apples, pears 0.3
Apricots, grapes, peaches, plums 0.2
USA Alfalfa, alfalfa hay, clover, 6
clover hay, grass, grass hay
Grapefruit, oranges, lemons, 2
sorghum fodder and forage
Sunflower seeds 0.5
Cottonseed, potatoes, sorghum, grain 0.2
Peaches, pecans, walnuts 0.05*
Yugoslavia General 0.1
* Negligible residues.
The additional data confirm the original evaluation and as an ADI
has been allocated, the temporary tolerances recommended at the 1972
Meeting are confirmed as maximum residue limits.
The temporary tolerances recommended at the 1972 Joint Meeting
(FAO/WHO, 1973) are confirmed as maximum residue limits.
FURTHER WORK OR INFORMATION
As FAO/WHO, 1973a, p. 45, excluding item 1.
Dejonckheere, W. P. and Kips, R. H. (1974) Photodecomposition of
methidathion. J. Agr. Food Chem, 22:959-968.
Ferrell, J. F. (1973) Experimental Pathology Laboratories Inc.,
Herndon, Virginia, USA. Report to Dr G. L. Rolofson, Agricultural
Division, Ciba-Geigy Corporation, Ardsley, NY. April 25, 1973.
Hess, R. (1975) Nature of the liver changes observed in a two year
feeding study in dogs. Unpublished report from the
Toxicology/Pathology Dept., Ciba-Geigy, submitted to the World Health
Organization by Ciba-Geigy Ltd., Basle, Switzerland.
Johnston, C. D. (1967) G.S. 13 005. Safety evaluation by two year
feeding studies in rats and dogs. Unpublished report from the Woodard
Research Corporation, submitted to the World Health Organization by
Ciba-Geigy Ltd., Basle, Switzerland.
Polan, C.E., Sandy, R. A. and Huber, J. T. (1969) Degradation of
Supracide in hay silage, and the rumen. J. Dairy Sci., 52:1296-1299.
Rijksinstituut voor de Volksgezonheid, (1966) Bilthoven, The
Netherlands (unpublished data).
St John, L. E. and Lisk, D. J. (1974) Feeding studies with Supracide
in the dairy cow. Bull. Environ. Contamin. Toxicol., 12:594-598.
Townsend, L. R. and Specht, H. B. (1975) Organophosphorus and
organochlorine pesticide residues in soils and uptake by tobacco
plants. Can. J. Plant Sci., 55:835-842.