PESTICIDE RESIDUES IN FOOD - 1984
Sponsored jointly by FAO and WHO
EVALUATIONS 1984
The monographs
Data and recommendations of the joint meeting
of the FAO Panel of Experts on Pesticide Residues
in Food and the Environment and the
WHO Expert Group on Pesticide Residues
Rome, 24 September - 3 October 1984
Food and Agriculture Organization of the United Nations
Rome 1985
DIMETHOATE
Explanation
Dimethoate was evaluated by the Joint Meetings in 1965, 1966 and
1967 (FAO/WHO, 1965, 1967 and 1968). The ADI (0.02 mg/kg bw/day was
derived from a study in humans where the NEL of 0.2 mg/kg bw/day was
based on plasma cholinesterase depression. Animal studies comprised
essentially short-term studies (rat, 15 weeks and 6-12 months; dog, 13
weeks), and a three-generation, two-litter per generation,
reproduction study in mice. Several studies have been obtained through
open literature and are summarized in this monograph addendum.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOCHEMICAL ASPECTS
Effects on Enzymes and Other Biochemical Parameters
Dimethoate significantly inhibited the active transport of
glucose though the isolated intestine of the mouse (Guthrie, Shah &
Moreland, 1980).
TOXICOLOGICAL STUDIES
Special Studies on Reproduction
Mice
Five generations of CD-1 mice were maintained on a diet
containing 60 ppm of Dimethoate in drinking water. Dimethoate
treatment significantly altered reproductive performance as indicated
by reduced mating success and longer gestation period. At birth,
litter size or weight were not reduced, but pup mortality increased
significantly with treatment. Growth rate of the pups was generally
lower than that observed for controls. Dimethoate did not show
teratologic potential or adverse effects on organ weights or histology
(Budreau & Singh, 1973).
Special Studies on Teratogenicity
Rat
Groups of pregnant female rats were administered 0, 3, 6, 12 or
24 mg/kg bw of Dimethoate daily from days 6 to 15 of gestation. The
dams were killed on day 22 of gestation; the uterine content was
removed, the carcass weighed, the number of corpora lutea was
determined, and the animals were necropsied. The foetuses were weighed
and examined for viability and external malformations. Live foetuses
were studied for skeletal development and visceral anomalies. Maternal
weight decreased significantly in the 24 mg/kg group. Clonic spasms
and muscular tremors were seen in females treated with 24 mg/kg. Mean
foetal weight was not reduced in treated groups. Dimethoate treatment
(12 and 24 mg/kg) was associated with an increased number of litters
with abnormal foetuses and foetuses with wavy ribs. No effect was seen
at a dose of 6 mg/kg bw of formulated product, equal 2.84 mg/kg of
Dimethoate (Khera, et al., 1979).
Cat
Teratogenic effects were studied in four groups of 17 cats each,
which were mated and treated with Cygon-4E, a commercial insecticide
containing 47.3 percent Dimethoate, in single daily doses of 0, 3, 6
or 12 mg/kg bw on days 14 to 22 of pregnancy. The cats were necropsied
on day 43 of pregnancy. Foetuses were removed, weighed, and examined
for external malformations. The total number of anomalous foetuses in
the 12 mg/kg group was higher, but not statistically different from
that of controls. The only treatment-related malformation observed at
this dose was forepaw polydactyly in eight of the 39 foetuses. A dose
relationship was not established, due to the limited response and the
common occurrence of this anomaly in the cat population. It is
suggested that 6 mg/kg of Cygon-4E, or 2.84 mg/kg of Dimethoate be
considered a no-effect level (Khera 1979).
Special Studies on Mutagenicity
See Table 1.
Special Studies on Carcinogenicity
Mouse
Groups of B6C3F1 mice (50 males and 50 females/group) were fed
diets containing Dimethoate (technical grade, 90-100 percent purity)
at levels of 250 or 500 ppm for 60 to 80 weeks. Following the exposure
period, mice were returned to control diets until they were sacrificed
at 94 weeks. The matched control group consisted of seven male and ten
female mice. The doses were selected after 1 000 and 500 ppm, used in
a preliminary study, appeared too toxic. All animals were observed for
signs of toxicity and body weights recorded. Tissues and organs from
almost all animals in the study were subjected to histopathological
examinations.
In the first year of the study the average weight gain in all
groups except the low-dose female group was less than that of the
matched controls. In the second year the average gain in weight in the
treated groups was generally similar. Tremors and hyperexcitability
were observed in both sexes.
During the second year of the study adverse clinical signs were
observed in all treatment groups. Animals surviving at termination
were generally in very poor physical condition. The Dimethoate
treatment had no apparent effect on survival rates. Several non-
neoplastic proliferative or inflammatory conditions occurred with
approximately equal frequency in control and Dimethoate-treated mice.
TABLE 1 - Special Studies on Mutagenicity
Test system Test object Concentration Purity Results Reference
of dimethoate used
5-methyl tryptophan E. coli 1 - 6.10-3 M not indicated positive Mohn, 1973
resistant mutation during 60 min.
assay
host-mediated mouse; 3 equal oral doses of not indicated positive Rani, Reddi & Reddy,
assay S. typhimurium 155 mg/kg body weight 1980
S. typhimurium injected,
collected, and plated
sister-chromatid Chinese hamster 0, 10, 20, 40, and 80 94% positive in SCE; Chen, et al.,1981
exchange; cell ovary cells µg/ml + 10 picograms/ml positive in cell
cycle delay V79 of 5-bromo deoxyuridine cycle delay
(BUdR)
micronucleus test mouse; bone 2 equal oral doses of not indicated positive Rani, Reddi & Reddy,
marrow 51.7 mg/kg b.w. at 1980
24-h interval
human cells human Chang 50 - 500 µg/ml 99.8% cytotoxic in Gabliks & Friedman,
in vitro liver and HeLa both cell lines; 1965
cells ID50 = 170 µg/ml
(liver cells)
ID50 = 200 µg/ml
(HeLa cells)
human cells human HeLa 2.0-300 µg/ml 99.8% cytotoxic in Gabliks, 1965a
in vitro cells minimal toxic
dose = 20 µg/ml
human cells human HeLa 2.0 -300 µg/ml 99.8% treated cells Gabliks, 1965b
in vitro (up to cells more susceptible
108 days exposure) to poliovirus
infection
The most commonly occurring neoplasm in male mice was hepatocellular
carcinoma and malignant lymphoreticular tumours in female mice but
there was no significant difference in the incidence of tumours among
the Dimethoate-treated mice and their controls (Nat. Canc. Inst.,
1976).
Rat
Groups of Osborne-Mendel rats (50 males and 50 females/group)
were fed diets containing Dimethoate (technical grade, 90-100 percent
purity) at time-weighted average levels of 155 or 310 ppm (male rates)
and 192 or 384 ppm (female rats) for 80 weeks, and then returned to
control diets until they were sacrificed at 114 weeks. The matched
control group consisted of ten male and ten female rats. Pooled
control groups from other studies were also considered. The initial
treatment levels (250 or 500 ppm) were selected after a six-week study
showed weight depression in male and female rats fed 250 or 500 ppm,
while all rats receiving 1 000 ppm died. As the initial treatment
levels were toxic, levels for treated rats were lowered for the
varying treatment periods indicated in Table 2. All animals were
observed for signs of toxicity and body weights were recorded. Tissues
and organs of almost all animals in the study were subjected to
histopathological examinations. Cholinergic signs of toxicity were
evident in treated animals. Early in the study tremors and
hyperexcitability were observed in both male and female rats. In
general there appeared to be a dose-related depression in both low-
and high-dose groups. Adverse clinical signs in all treatment groups
were noted with frequent incidence during the second year of the
study. Animals that survived to termination were generally in poor
physical condition. At termination there appeared to be a dose-related
mortality with Dimethoate (58 and 51 percent survival to 115 weeks for
males and females, respectively). However the significance of this
observation is not clear, since survival was lowest in the male
matched and pooled control group. Numerous inflammatory, degenerative
and proliferative lesions, commonly seen in aged rats, occurred with
approximately equal frequency in treated and control animals. Several
non-neoplastic lesions occurred more frequently in treated rats than
in controls, but were generally not dose-related. The pituitary and
thyroid were the most common primary sites of neoplasia in both
treated and control rats but there was no significant increase in the
incidence of tumours between the treated and control groups (Nat.
Canc. Inst., 1976).
Acute Toxicity
The acute toxicity of Dimethoate to rats via oral and dermal
routes is summarized in Table 3.
TABLE 2. Design of Dimethoate Chronic Feeding Study in Rats and Mice
Initial Dimethoate Time on Study Time-Weighted
No. of in Diet Treated Untreated Average Dose
Animals (ppm) (weeks) (weeks) (ppm)
(a) (b) (c) (d)
RATS
Male
Matched Control 10 0 0 114
Low 50 250 19 155
125 61
0 34-35
High 50 500 19
250 61 310
0 33-34
Female
Matched Control 10 0 0 114
Low 50 250 43
125 37 192
0 33-34
MICE
Male
Matched Control 10 (e) 0 0 94
Low 50 250 69 250
0 24
High 50 500 60 500
0 34
Female
Matched Control 10 0 0 94
Low 50 250 80 250
0 13
High 50 500 80 500
0 14
TABLE 2. (continued)
(a) All animals were 35 days of age when placed on test.
(b) Initially 1 000 and 500 ppm of Dimethoate were fed to mice of each sex; these doses were
too toxic, however, and the mouse study was terminated and restarted as shown in the table.
(c) When diets containing Dimethoate were discontinued, treated rats and their matched controls
were fed plain feed diets (without corn oil) for 8 weeks, then control diets (2 percent
corn oil added) for an additional 25 to 27 weeks. Mice received the control diet until
termination.
(d) Time-weighted average dose = Sigma (dose in ppm x no. of days at that dose)
Sigma (no. of days receiving each dose)
(e) Examination at necropsy subsequently revealed that 3 of 10 mice designated as male matched
controls were females.
TABLE 3. Acute Toxicity of Dimethoate in Animals
Species Sex Route Purity LD50 Reference
Rat m/f oral 97.6-99% 540-600 Dal Re &
mg/kg Vola Gera
1980
Rat m/f dermal 97.6-99% >7 000 Dal Re &
mg/kg Vola Gera
1976
COMMENTS
The last evaluation of Dimethoate was conducted in 1967, when an
ADI of 0-0.02 mg/kg bw was derived from a no-effect level in humans of
0.2 mg/kg/day for plasma cholinesterase. Since that time several
studies on the toxicology of Dimethoate have been published and have
now been reviewed to supplement the data on short-term rat and dog.
toxicology studies and a mouse three-generation study used in previous
toxicological evaluations.
A five-generation study of Dimethoate in mice showed decreased
success in mating, longer reproduction time and increased pup
mortality, but no teratogenic potential. Teratogenicity studies with
Dimethoate-formulated products enabled no-effect levels to be
established for rats and cats (2.8 mg Dimethoate/kg bw).
Dimethoate was shown not to be oncogenic in mouse and rat
studies, but was mutagenic in a number of in vivo and in vitro
short-term tests.
The meeting was informed that several additional toxicological
studies are in progress and will be available by 1987. In the absence
of a complete data base for this compound the ADI was replaced by a
temporary ADI at a lower level.
Level Causing no Toxicological Effect
Rats: 5 ppm in the diet, equivalent to 0.25 mg/kg bw
Humans: 0.2 mg/kg bw/day
Estimate of Temporary Acceptable Daily Intake for Humans
0 - 0.002 mg/kg bw
FURTHER WORK OR INFORMATION
Required (by 1987)
1. Submission of the on-going toxicological studies sponsored
by the "Dimethoate Task Force".
2. A dog study of at least six months' duration.
Desirable
Observations in humans.
REFERENCES
Budreau, C.H. & Singh, R.P. Effect of Fenthion and Dimethoate on
1973 reproduction in the mouse. Toxicol. Appl. Pharmacol. 26:
29-38.
Chen, H.H., Hsueh, J.L., Sirianni, S.R. & Huang, C.C. Induction of
1981 Sister-Chromatid exchanges and Cell Cycle Delay in cultured
mammalian cells treated with eight organophosphorous
pesticides. Mutat. Res. 88: 307-316.
Dal Re, V. & Vola Gera, F. Determination of the acute dermal toxicity
1976 of technical Rogor. Report from Centro Ricerche
Antiparassitari, Montedison, Italy, submitted by Farmoplant,
Italy to WHO. (Unpublished)
Dal Re, V. & Vola Gera, F. Acute oral toxicity of technical Rogor
1980 samples recently produced in albino rats. Report from Centro
Ricerche Antiparassitari, Montedison, Italy, submitted by
Farmoplant, Italy to WHO. (Unpublished)
Gabliks, J. Responses of cell cultures to insecticides II. Chronic
1965a toxicity and induced resistance. Proc. Soc. Expt. Biol. Med.
120: 168-171.
Gabliks, J. Responses of cell cultures to insecticides III. Altered
1965b susceptibility to Poliovirus and Diptheria toxin. Proc. Soc.
Expt. Biol. Med. 120: 172-175.
Gabliks, J. & Friedman, L. Responses of cell cultures to insecticides
1965 I. Acute toxicity to human cells. Proc. Soc. Expt. Biol.
Med. 120: 163-168.
Guthrie, F.E., Shah, P.V. & Moreland, D.E. Effects of pesticides on
1980 active transport of glucose through the isolated intestine
of the mouse. J. Agric. Food Chem. 22: 3.
Khera, K.S. Evaluation of Dimethoate (Cygon 4E) for teratogenic
1979 activity in the cat. J. Environ. Pathol. Toxicol. 2:
1283-1288.
Khera, K.S., Whalen, C., Trivett, G. & Angers, G. Teratogenicity
1979 studies on pesticidal formulations of Dimethoate, Diuron and
Lindane in rats. Bull. Environ. Contam. Toxicol. 22:
522-529.
Mohn, G. 5-methyl tryptophan resistance mutations in Escherichia Coli
1973 K-12. Mutat. Res. 20: 7-15.
National Cancer Institute. Bioassay of Dimethoate for possible
1976 carcinogenicity. NCI-CG-TR-4 DHEW Publication No. (NIH)
77-80.
Rani, M.V.U., Reddi, O.S. & Reddy, P.P. Mutagenicity studies involving
1980 Aldrin, Endosulfan, Dimethoate, Phosphamidon, Carbaryl and
Ceresan. Bull. Environ. Contam. Toxicol. 25: 277-282.