DIMETHOATE
EXPLANATION
Dimethoate was evaluated for acceptable intake by the JMPR in
1963 and was also reviewed in 1965, 1966, 1967 and 1984 (Annex 1,
FAO/WHO, 1964, 1965a, 1967a, 1968a, 1985a). In the absence of a
complete data base the 1984 JMPR meeting replaced the ADI of
0-0.2 mg/kg bw. (established at the 1967 meeting, based on a no
observed effect level in humans of 0.2 mg/kg/day for plasma
cholinesterase) by a temporary ADI at a lower level
(0-0.002 mg/kg bw.). The following investigations were 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 month's duration.
The on-going studies have become available and have been
summarized in this monograph addendum.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOLOGICAL DATA
Toxicological Studies
Special studies on carcinogenicity
See under long-term studies
Special studies on teratogenicity
Rats
Groups of 25 pregnant female rats (CrL: COBS CD (SD) BR strain)
received 0, 3, 6 and 18 mg dimethoate (purity 97.3%)/kg bw. by gavage
from day 6-15 of gestation. The fetuses were delivered by caesarian
section on day 20 of pregnancy. The dams were observed daily for
clinical signs, mortality and body weight. The number of corpora
lutea, implantations and live and dead fetuses were recorded. The
fetuses were counted and weighed and examined for visceral and
skeletal abnormalities.
Salivation and hair loss was observed in females at all dose levels.
Females of the highest dose group also had brown facial staining,
small rounded feces (also at 6 mg/kg bw.), hypersensitivity, body
tremors and unsteady gait. Body weight gain and food consumption were
significantly reduced. No malformations were found. There was no
obvious indication of an adverse effect of dimethoate treatment on
mean incidences of both visceral and skeletal anomalies, although at
all dosages an unspecific increase was observed relative to control
values (which were, however, lower than concurrent control values in
recent preceding studies) (Edwards et al., 1984)
Rabbits
Groups of 16 pregnant female rabbits received 0, 10, 20 and 40 mg
dimethoate (purity 97.3%)/kg bw. in 1% methylcellulose by gavage on
day 7-19 of gestation. The fetuses were delivered by caesarian section
on day 29 of pregnancy. The dams were observed daily for clinical
signs, mortality and body weight. The number of corpora lutea,
implantations and live and dead fetuses were recorded. The fetuses
were weighed and sexed and examined for visceral and skeletal
abnormalities.
Muscle tremors, an unsteady gait, and a increased incidence of
animals showing cold ears after dosing and abnormal feces were
observed at 40 mg/kg. During dosing body weight gain and food
consumption were significantly reduced at 40 mg/kg. A slightly lower
body weight gain was observed at 20 mg/kg, while at 10 mg/kg mean
weight gain was higher. Fetal weight was significantly decreased at
40 mg/kg, with a tendency at 20 mg/kg bw. Teratogenic effects were not
observed (Edwards et al., 1984).
Special studies on mutagenicity
Dimethoate was not mutagenic in the studies considered in this
monograph addendum (see table 1).
Special studies on skin sensitization
Technical dimethoate (97.3% purity) was not a skin sensitizer in
guinea pigs when rested by the patch technique (Buehler test)
(Madison, 1984).
Long-term studies
Mice
Groups of 50 male and 50 female B6 C3 F1 mice were fed diets
containing 0, 25, 100 and 200 ppm dimethoate (purity > 96.71%) for
778 weeks. Satellite groups of 10 male and 10 female mice were fed
diets containing dimethoate at the same dietary levels and sacrificed
after 51 weeks of treatment. Observations included clinical signs,
mortality, body weight, food consumption, hematology and
cholinesterase activities (only after 51 weeks) in plasma and
erythrocytes. Organs were weighed and comprehensive histopathology was
performed (from the satellite animals only those dying intercurrently
or sacrificed in a moribund state).
Retarded growth was observed in males at all dose levels during
the first months of the study and in females at 200 ppm in the
beginning. Towards the end of the study the body weights of the
females at all dose levels were significantly increased. At all dose
levels cholinesterase activity in plasma as well as in erythrocytes
was significantly decreased in both sexes (at 25 ppm only 10 to 30%
respectively in both sexes). The inhibition was greater for
cholinesterase in erythrocytes in all cases. Absolute as well as
relative ovary weight were significantly decreased in females of all
dose groups at termination of the study. Other changes in organ
Table 1. Special studies on the mutagenicity of dimethoate
Type of test Test object Concentration Purity Results References
of dimethoate
In vitro
CHO/HGPRT Chinese 1000 µg up to 97.3% Negative Johnson et al.,
mutation assay hamster 3500 µg/ml 1984
(with and without ovary
metabolic
activation)
In vivo
Dominant lethal NMRI mice 5, 10 and 20 mg/kg 96.89% Negative Becker, 1985
test (administered (1)
orally, 5 days)
Micronucleus CD-1 mice 55 mg/kg 97.3% Negative Sorg, 1985
test (administered i.p. (1)
twice 24 hr apart)
dissolved in
0.9% saline
Metaphase Rat bone i.p. 15, 75 97.3% Negative San Sebastian,
analysis assay marrow cells & 150 mg/kg (1) 1985
(1) Positive control yielded positive results
weights were not consistent or dose related and are probably induced
by the higher body weight at all dose levels (especially in females).
At histopathology hepatocellular vacuolization was observed in males
and females at 200 and 100 ppm. Extramedullary hematopoiesis in the
spleen was observed in males at 200 ppm and slightly in males at 100
and 25 ppm and in females at all dose levels.
No enhanced tumour incidence was observed (Hellwig, 1986a).
Rats
Groups of 50 male and 50 female Wistar rats were fed diets
containing 0, 5, 25 and 100 ppm dimethoate (purity > 96.71%) for
24 months. Satellite groups of 15 male and 15 female rats received
diets containing dimethoate at the same dietary levels and were used,
together with a satellite group of 20 rats/sex receiving a diet
containing 1 ppm dimethoate, for hematological, clinico-chemical and
urinalysis examinations. All satellite groups received the diet for
24 months also. Observations included clinical signs, mortality, food
consumption, body weight, ophthalmoscopy, hematology, clinical
chemistry, cholinesterase activities in plasma, erythrocytes and brain
and urinalysis. Surviving animals were sacrificed after 24 months.
Organs were weighed and comprehensive histopathological examinations
were made.
Towards the end of the study mortality was increased in females
at 100 ppm. Body weight gain was decreased in males and females at the
highest dose group during the first 12 months. Hemoglobin and
hematocrit values were significantly decreased in males and females at
100 ppm (tendency in males at 25 ppm) and mean corpuscular hemoglobin
concentration was increased. The number of erythrocytes was
significantly decreased in males at 100 ppm (tendency at 25 ppm) and
the number of leucocytes was significantly increased in females at 100
and 25 ppm and in males at 100 ppm only. Plasma cholinesterase
activity was significantly decreased (about 50%) in male and female
rats at 100 and cholinesterase activity in erythrocytes and the brain
were significantly decreased at 5 (males only), 25 and 100 ppm in both
sexes (erythrocytes: max. 35%, 55% and 90%, respectively; brain: max.
23%, 40% and 60% respectively). In females, potassium values in blood
were significantly decreased at 100 and 25 ppm and alanine
amino-transferase activity was significantly increased at 100 ppm. In
males of the same dose group, total protein was significantly
increased and relative ovary weight in females was significantly
decreased.
No enhanced tumor incidence was observed. The NOAEL in this study
is 1 ppm, equivalent to 0.05 mg/kg bw (Hellwig, 1986b).
COMMENTS
Toxicology
The 1984 JMPR replaced the ADI of 0.02 mg/kg bw by a temporary
ADI of 0.002 mg/kg bw because the data on which the former ADI was
based were considered inadequate. The meeting was aware that new
toxicological studies were under way. These studies were reviewed by
the present meeting.
Maternal toxicity and fetotoxicity were observed in
teratogenicity studies in rats and rabbits, but no teratogenic
effects.
In 1984 the Joint Meeting concluded that dimethoate was mutagenic
in a limited number of in vitro and in vivo studies reported in
the literature. Since then, additional negative mutagenicity data have
become available. It was concluded that dimethoate is mutagenic in
bacterial tests, but not in mammalian cells or in in vivo tests.
In long-term toxicity/carcinogenicity studies with mice and rats
no indication of carcinogenicity was found. In the mouse study the
lowest dose of 25 ppm produced decreased body weight and decreased
cholinesterase activities in erythrocytes as well as slight
extramedullary hematopoiesis in the spleen.
Two years' administration of dimethoate to rats also revealed a
decrease in body weight, decreased cholinesterase activities
(in erythrocytes and brain) and slight anemia. No effects were
observed at 1 ppm (equivalent to 0.05 mg/kg bw/day).
The required dog study was not available.
The 1984 evaluation of human data was based on the understanding
that plasma CHE activity was measured. Re-examination of the data
showed that they were in fact based on erythrocyte CHE and that a
NOAEL was present. The present meeting therefore decided that an ADI
could be established on the basis of these data.
TOXICOLOGICAL EVALUATION
LEVEL CAUSING NO TOXICOLOGICAL EFFECT
Rat: 1 ppm in the diet, equivalent to 0.05 mg/kg bw/day
Man: 0.2 mg/kg bw/day
ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN
0-0.01 mg/kg bw.
STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE IN THE CONTINUED
EVALUATION OF THE COMPOUND
1. Observations in man.
2. A one-year dog study.
3. An up-to-date reproduction study in rats.
REFERENCES
Becker, H., 1985. Dominant lethal study with dimethoate technical in
the mouse. Unpublished report no.: 039003 d.d. September 12, 1985 from
RCC, Research & consulting Company AG, CH 4452 Itingen/Switzerland.
Submitted to WHO by Dimethoate Task Force, Milano, Italy.
Edwards, J.A., Leeming, N.M. & Clark, R., 1984. Effect of dimethoate
on pregnancy of the rat. Unpublished report no.: DTF 3/84245 d.d.
April 13, 1984 from Huntington Research Centre. Submitted to WHO by
Dimethoate Task Force, Milano, Italy.
Edwards, J.A., et al., 1984. Effect of dimethoate on pregnancy of
the New Zealand white rabbit. Unpublished report no.: DTF 4/84247 d.d.
April 19, 1984 from Huntington Research Centre. Submitted to WHO by
Dimethoate Task Force, Milano, Italy.
Johnson, E., Caterson, C.R. & Allen, J.S., 1985. Mutagenicity testing
of dimethoate in the in vitro CHO/HGPRT mutation assay. Unpublished
report No. 0423 d.d. January 30, 1985 from American Cyanamid Co.,
Princeton, New Jersey. Submitted to WHO by Dimethoate Task Force,
Milano, Italy.
Hellwig, J., 1986a. Report on the study of the toxicity of dimethoate
in mice after 78-week administration in the diet. Unpublished report
no.: 75CO326/8242 from BASF, Department of Toxicology, Ludwigshafen/
Rhein, FRG, Submitted to WHO by Dimethoate Task Force, Milano, Italy.
Hellwig, J., 1986b. Report on the study of the toxicity of dimethoate
in rats after 24-month administration in the diet. Unpublished report
no.: 70CO326/8241 d.d. October 9, 1986 from BASF, Department of
Toxicology, Ludwigshafen/Rhein, FRG, Submitted to WHO by Dimethoate
Task Force, Milano, Italy.
San Sebastian, J.R., 1985. In vivo bone marrow cytogenetics rat
metaphase analysis. PH 315-AC-00-84, Dimethoate CL 12880. Unpublished
report d.d. August 29, 1985 from Pharakon Research International,
Inc., Waverly, PA 18471. Submitted to WHO by Dimethoate Task Force,
Milano, Italy.
Sorg, R.M., 1985. Micronucleus Test (MNT). PM 309A-AC-004-84,
Dimethoate CL 12880. Unpublished report d.d. March 1, 1985 from
Pharakon Research International, Inc., Waverly, PA 18471. Submitted to
WHO by Dimethoate Task Force, Milano, Italy.
See Also:
Toxicological Abbreviations
Dimethoate (EHC 90, 1989)
Dimethoate (HSG 20, 1988)
Dimethoate (ICSC)
Dimethoate (FAO Meeting Report PL/1965/10/1)
Dimethoate (FAO/PL:CP/15)
Dimethoate (FAO/PL:1967/M/11/1)
Dimethoate (JMPR Evaluations 2003 Part II Toxicological)
Dimethoate (AGP:1970/M/12/1)
Dimethoate (Pesticide residues in food: 1983 evaluations)
Dimethoate (Pesticide residues in food: 1984 evaluations)
Dimethoate (Pesticide residues in food: 1984 evaluations)
Dimethoate (Pesticide residues in food: 1996 evaluations Part II Toxicological)