FORMOTHION JMPR 1973
Explanation
Formothion was evaluated by the 1969 Joint Meeting (FAO/WHO,
1970). Toxicology studies were insufficient for establishing an
acceptable daily intake. Two-year studies in rats and dogs have been
completed and this information has been summarized in the present
monograph.
By the 1969 Joint Meeting temporary tolerances were recommended
for strawberries and blackcurrants but residue data on all other crops
were judged to be insufficient. A number of requirements were laid
down for further work or information on formothion.
The 1972 Joint Meeting (FAO/WHO, 1973) clarified a question
raised at the Sixth Session of the CCPR regarding the identity of the
compounds covered by the tolerances on strawberries and blackcurrants.
it was determined that, since the residues at harvest after use of
formothion were primarily dimethioate and omethoate, the temporary
tolerances recommended apply to these compounds, expressed as
dimethioate. It was also noted that tolerances for residues of
dimethioate in other fruits and vegetables would also apply to
residues resulting from use of formothion.
Information on certain of the requirements were received from the
manufacturer. Czechoslovakia, Australia and New Zealand also responded
with some information on current agricultural uses and national
tolerances in those countries.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
Toxicological studies
Acute toxicity
Species Route LD50 Reference
mg/kg
Rat Oral 218 Vorob'yeva and
Lapchenko, 1973
Mice Oral 83 "
Cat Oral 310 "
Short-term studies
Rat. Vorob'yeva and Lapehenko (1973) concluded that a daily dose
level of 0.83 mg/kg was a threshold level based on cholinesterase
depression. Daily doses above this level disturbed carbohydrate
metabolism, protein synthesis in the liver and caused changes in the
liver and heart such as fatty degeneration and dystrophy.
Dog. Groups of dogs (four male and four female beagle dogs per
group) were fed formothion in the diet at levels of 0, 40, 160 and 640
ppm for two years. The animals were between six and eight months of
age at the beginning of the study. The dogs were fed a standard dry
diet. Haematological examinations, clinical chemistry analyses and
urinalysis were perfumed periodically during the course of the study.
Ophthalmological and behavioural examinations were performed at
various times. At the conclusion of the study, gross and microscopic
examination of tissues and organs was performed. All dogs appeared
normal throughout the study with no changes in weight although there
was a slight reduction in food intake which appeared to be dependent
upon the dietary concentration of formothion. There were no apparent
effects in haematology, urinalysis or clinical chemistry with the
exception of cholinesterase depression. As was observed with rats, RBC
cholinesterase was the more sensitive parameter indicative of exposure
with the level of 160 ppm in the diet and above showing definitive
inhibition. Brain cholinesterase was unaffected at all dose levels
while liver cholinesterase was inhibited at 640 ppm in the diet. Gross
and histological examination of tissues in organs showed no evidence
of pathological change due to the incorporation of formothion in the
diet. (Klotzsche and Carpy, 1973)
Long-term studies
Rat. Groups of rats (35 male and 35 female Wistar rats per group)
were fed formothion in the diet at dosage levels of 0, 20, 80 and 320
ppm for two years. The study started with dose levels of 0, 10, 40 and
160 plat and after four weeks the doses were increased to 0, 20, 80
and 320 ppm. The animals were observed daily for mortality and
behavioural changes body weight and food consumption. Haematological
examination, chemical chemistry, including cholinesterase activity and
urinalysis were performed periodically. At the end of the two-year
period the surviving animals were sacrificed and gross pathology
performed on tissues and organs. Similar proportion of animals
survived until the end of the test in all groups. Abnormal behaviour,
slight tremors or muscle twitches, were observed in single rats at the
high dose between the third and the twelfth month of the study. Normal
behaviour was observed during the rest of the study. In the male
animals there was an impairment of growth which was significant during
the middle part of the study. This growth reduction appeared to have
disappeared somewhat during the last months of the study although
there was a gradual trend towards a reduction in growth as the dietary
dosage increases. This trend was not noted in females. There was no
significant difference in food intake in all groups of animals with a
slightly higher intake of food in the females at the high dose level.
It has been suggested that the normal weight gain in the high dosed
females was a result of the elevated food consumption at this level.
Increased clinical chemistry values were sporadic throughout the study
with increases primarily at the end of the study in BUN, SGPT and SAP.
These increases were not dose dependent. There was no apparent effect
of formothion on urinalysis. At the conclusion of the study the
average weight of the spleen in males was significantly decreased at
all dosage levels. This decrease was not noted in the females. There
were no histological abnormalities noted in the spleen which coincide
with the increased weight. There were no other abnormalities noted on
growth or histological examination of tissues in organs.
As with other organophosphate esters, cholinesterase was the most
sensitive indicator of exposure with the red blood cell cholinesterase
being somewhat more sensitive than the plasma. In both males and
females there was a slight depression of red blood cell cholinesterase
at 80 ppm in the diet and a more significant depression at 320 ppm in
the diet. Plasma cholinesterase depression was observed only at 320
ppm in the diet. On the basis of cholinesterase depression a marginal
effect was noted at 80 ppm in the diet with more definitive effects
being noted at 320 ppm in the diet especially regarding gross and
spleen weight in males. At 320 ppm in the diet brain cholinesterase
was significantly depressed with no apparent effect noted at the lower
dose.
On the basis of histological examination there was no evidence
that formothion given in the diet at levels of up to 640 ppm increased
the spontaneous tumour incidence in either dogs or rats (Klotzsche and
Carpy, 1973).
Comments
Two-year studies in rats and dogs, metabolism studies and
short-term studies in rats were available for consideration by the
present Meeting. Metabolism in plants has been shown to result in the
formation of dimethoate and formothion acid O.O dimethyl phosphoryl
acetic acid. Based on cholinesterase inhibition, no-effect levels of
20 and 40 ppm on the rat and dog respectively were observed in
two-year studies. No evidence of carcinogenic potential was observed
in the rat studies. An ADI for dimethoate was established (FAO/WHO,
1965) based on human studies, where 0.2 mg/kg bw/day was a noneffect
level. An ADI for formothion was established based on the studies in
the rat and the dog and on the experience of human exposure to
dimethoate.
TOXICOLOGICAL EVALUATION
Level causing no toxicological effects
Rat: 20 ppm in the diet equivalent to 1 mg/kg bw
Dog: 40 ppm in the diet equivalent to 1 mg/kg bw
Estimate of acceptable daily intake for man
0-0.02 mg/kg bw
RESIDUES IN FOOD AND THEIR EVALUATION
Comments on new information
1. As far as is known there is only one manufacturer. The technical
grade contains 95-96% formothion, the remainder being related
compounds.
2. No information was made available on animal metabolism or residues
in meat and milk; disappearance during storage, processing and
cooking; or data on residues in commodities moving in inter-state
commerce or in the total diet. In view of the fact that formothion is
completely transformed into dimethioate in plants and animals these
requirements were considered to be no longer necessary.
3. GLC method for regulatory purposes
The 1969 Joint Meeting noted the desirability of a GLC method
suitable for regulatory purposes. The basic manufacturer (Sandoz) has
provided an unpublished GLC method (identified CvH 6/70e) with
thermionic detection which simultaneously determines formothion,
dimethoate, and omethoate. The method is said to be applicable to the
determination of formothion residues in plant, material and soil. It
involves acetonitrile extraction and a florisil/charcoal column
clean-up. An optional petroleum ether/water and chloroform/water
partitioning step is included for samples with difficult clean-up
problems. Detector response varies about three-fold overall between
the three residue components. Formothion > dimethoate > omethoate,
with a limit of determination estimated to be about 0.03-0.1ppm for an
injection equivalent to about 10 mg sample. Recoveries for each
component at 0.1 and 1.0 ppm fortification levels were satisfactory
but it was not indicated what the fortified substrate was. The
multi-residue method of Storherr et. al. (1971) for organophosphorus
pesticides has been shown, in the meantime, to be applicable for use
as a regulatory method for dimethoate and omethoate.
Use patterns
TABLE 1
Treatment PHI National
Country Crop rate (ai) (days) tolerance
ppm
Czechoslovakia Fruits 0.05% 28 0.1a
Cherries 0.05% 18 0.5a
TABLE 1 (Cont'd.)
Treatment PHI National
Country Crop rate (ai) (days) tolerance
ppm
Oats 250g/ha 21 -
New Zealand Lettuce )
)
Brassicas )
)
Potatoes )
6.4 oz/acre ) 14 1
Carrots )
)
Celery )
Australia Citrus -
tree fruits
Grapes 14 -
a Proposed national tolerances as dimethioate.
Residue data on crops from supervised trials
Additional data from trials on citrus, small grains and their
straws, lettuce and radish are available. No formothion was found at
any time under the conditions of the test on samples other than
citrus. Dimethoate and omethoate were found on the leafy vegetable and
root parts for two to three weeks. No residues were detected in grain
at any time. A summary of the data on grains, lettuce and radishes are
shown in Table 2.
The data on citrus from supervised trials in Israel show that
residues of formothion per se are present for as long as 62 days and
that these might approximate 0.2 ppm at harvest under good
agricultural practices (fifteen-day pre-harvest interval). Residues of
dimethoate and omethoate (total) at the same interval after treatment
averaged 0.62 ppm (max. 1.25 ppm), well within the tolerance
recommended for dimethoate residues in citrus at the 1967 Meeting (2
ppm). On the basis of these data a tolerance of 0.2 ppm formothion
would be appropriate.
Fate of residues
In plants
A new 14C metabolism study for formothion on bean plants has
become available (Sauer, 1972). In general, it confirms previous
information on the fate of formothion residues, i.e. rapid
transformation to dimethoate, omethoate and O,O-dimethyl
dithiohosphoryl acetic acid. Further metabolic products are
O,O-dimethyl dithiophosphoric acid; and bis
(O,O-dimethyl-thiophosphoryl) disulfide.
The formothion was labelled in two positions, as was dimethoate,
which was studied for comparison purposes. The study reinforces
conclusions of the 1972 Joint Meeting that the residues arising from
the use of either formothion or dimethoate, are in fact, identical.
In soil and water
An unpublished report (Sandoz, 1969) on degradation in soil and a
similar report on fate in water (Sandoz, 1972) were also made
available. Degradation in both soil and water was rapid. The rate of
degradation in water increased with pH.
TABLE 2
Maximum residues at end of interval
Pre-harvest
Crop Dosage interval Formothion Dimethoate Dimethoxon
% ai (days) (ppm)
Barley
Grain 0.5 59 nda nd nd
straw 0.5 73 nd nd nd
lettuce 0.05 7 nd 3.3 0.70
14 nd 0.12 0.12
21 nd 0.01 0.03
Radish 0.07 0 nd 5.9 0.06
(roots) 1 nd 5.1 0.06
3 nd 0.17 0.02
7 nd 0.03 0.01
14 nd 0.01 0.01
Wheat
Grain 0.05 56 nd nd nd
straw 0.05 56 nd nd nd
plant 0.05 0 nd 1.2 nd
7 nd 0.04 0.03
14 nd nd nd
28 nd nd nd
a nd = non-detected
Appraisal
Temporary tolerances were recommended by the 1969 Joint Meeting
for strawberries and blackcurrants with the stipulation that certain
additional information on residue chemistry be required and that
certain other information would be desirable. The basic manufacturer
has responded directly to two of the requirements as indicated below.
Response to the other requirements was limited to statements that
information available on dimethoate residues fulfils the requirements
for formothion.
The Sixth Session of the Codex Committee on Pesticide Residues
requested clarification as to whether the 1969 tolerances applied to
formothion or to the primary metabolite dimethoate. The 1972 JMPR
clarified the recommended formothion tolerance as applying to residues
of dimethoate and omethoate resulting from the use of formothion. It
was also noted by the 1972 Meeting that the previously recommended
tolerances for dimethoate on citrus, tree fruits, tomatoes, peppers,
and vegetables would apply to residues resulting from use of
formothion.
The working party was informed that Sandez Ltd is at present the
only manufacturer. That company has furnished statements of
composition for two BC formulations which permits a calculation that
the technical product contains 95-96% formothion.
A thermionic - GLC method capable of measuring simultaneously
formothion, dimethoate, and omethoate was submitted by Sandoz. It is
as yet unpublished. Dimethoate and omethoate are also detected by a
multi-residue method for organophosphate pesticides, suitable for
regulatory purposes.
The requested information on animal metabolism and residues in
meat or milk; disappearance in storage, processing, and cooking; and
occurrence in commodities in commerce and total diet studies were not
directly provided but in view of the recommendation of the 1969
Meeting that the residues following the use of formothion are
dimethoate and omethoate (except for citrus), it would appear
unnecessary to pursue these requirements further.
Information has been made available to FAO on new national
tolerances and approved uses on certain fruits, vegetables, and grains
In Australia, New Zealand and Czechoslovakia. There are no adequate
data from supervised trials corresponding to these uses. In any event
the interpretation that dimethoate tolerances apply to residues
arising from the use of formothion would obviate the need to extend
the present tolerances to specific crops which are covered by
tolerances for dimethoate and omethoate.
Citrus presents an exception to the pattern of terminal residues
resulting from the use of formothion. Formothion residues per se
exist for considerable periods after treatment of citrus. Data
indicate that a tolerance of 0.2 ppm for the parent compound would be
necessary under good agricultural practices including a pre-harvest
interval of 15 days.
RECOMMENDATIONS
The following tolerance is recommended for formothion per se
Tolerance ppm Interval on which
recommendations
are based (days)
Citrus 0.2 15
The residue should be measured and expressed as formothion.
Residues of dimethoate and omethoate occurring simultaneously should
be determined separately and expressed as dimethoate.
The previously recommended tolerances for residues of dimethoate
and omethoate from use of formothion on strawberries and blackcurrants
are also recognized under the heading dimetboate along with
recommended tolerances for dimethoate and omethoate residues on
citrus, tree fruits, tomatoes, peppers, and vegetables resulting from
the use of either dimethoate or formothion.
FURTHER WORK OR INFORMATION
Desirable
1. A survey of current uses of both formothion and dimethoate on
crops on which either pesticide may be used with a view to making
recommendations for common tolerances.
2. Additional studies to show whether the residues of formothion per
se will occur on crops, particularly olives.
REFERENCES
FAO/WHO. (1965b) Evaluation of the toxicity of pesticide residues in
food. FAO Meeting Report, No. PL/1965/10/1; WHO/Food Add./27.65
FAO/WHO. (1970) 1969 Evaluations of some pesticide residues in food.
FAO/PL: 1969/M/17/1, WHO/FOOD ADD./70.38
FAO/WHO. (1973) 1972 Evaluation of some pesticide residues in food
AGP: 1972/M/9/1, WHO Pesticide Residues Series, No. 2
Klotzsche, C. and Carpy, S. (1973) Formothion, two-year feeding study
in rats and dogs. Unpublished report from Sandoz Chemical Company
Sandoz. (1969) Formothion degradation in soil. Report CvH 9/69,
unpublished report of Sandoz Agrochemical Research, Basle, Switzerland
Sandoz. (1972) The behaviour of formothion in water at different pH
values. Unpublished report of Sandoz Agrochemical Research, Basle,
Switzerland
Sauer, H.H. (1972) Fate of formothion on bean plants in the
greenhouse. J. Agr. Food Chem.,.20, No. 3, 578-583
Storherr, R.W., Ott, P. and Watts, R.R. (1971) A general method for
organophosphorus pesticide in non-fatty foods. J.A.O.A.C., 54:
513-516
Vorob'yeva, N.M. and Lapehenko, V.S. (1973) Toksikologicheskaya
Kharakteristika Novogo Pesticida Antio. Farmakol. Toksikol. 6: 104-7
See Also:
Toxicological Abbreviations
Formothion (FAO/PL:1969/M/17/1)
Formothion (WHO Pesticide Residues Series 2)