PESTICIDE RESIDUES IN FOOD - 1980
Sponsored jointly by FAO and WHO
Joint meeting of the
FAO Panel of Experts on Pesticide Residues
in Food and the Environment
WHO Expert Group on Pesticide Residues
Rome, 6-15 October 1980
Parathion-methyl was evaluated by the Joint Meeting in 1968, 1972,
1975, and in 1979 (FAO/WHO 1969, 1973, and 1976; FAO, 1980). In
1979, based on the consideration that parathion-methyl was neither
teratogenic nor embryotoxic in rats and that previously requested
long-term studies were in progress, the Meeting extended the
temporary Acceptable Daily Intake.
Further information on the toxicological hazards associated with
the use of parathion-methyl under actual field conditions in India
and short-term studies were made available to the Meeting. These
data are reviewed in this monograph addendum.
DATA CONSIDERED FOR DERIVATION OF ACCEPTABLE DAILY INTAKE
Special studies on potentiation
In an effort to evaluate the possible acute interaction of
parathion-methyl and other toxic insecticides, acute studies with
DDT and parathion-methyl in rats were performed. Male rate were
orally administered fractions of the LD50 of each material. The
ratio of LD50 value calculated to that observed in the study
suggested a less than additive effect when the two insecticides are
administered simultaneously (i.e., the acute toxicity was less than
anticipated based on preliminary toxicity data with each material
alone) (Kimmerle, 1975 ). An additional trial in male rats
administered parathion-methyl and parathion-ethyl (parathion)
showed the combined toxic effects to be additive (Flucke and
Special studies an carcinogenicity
In a dose range-finding study, groups of mice (5 male and 5 female,
B6C3F1, mice/group) were fed parathion-methyl at dosage levels of
0, 20, 40, 60, 80, 100, 125, 250 or 500 mg/kg for 7 weeks. After
1 week of control diet (following parathion-methyl dosing) the
animals were sacrificed and tissues of some of the upper dosage
groups were examined microscopically. The criterion of 10% weight
loss was chosen to develop the dosage levels of the chronic study
(the data were not reported in detail enough to determine whether
the 10% weight loss would be the criterion for the high or low
dosage groups in the chronic study).
Mortality was noted in the study; the high dose group had no
survivors and the 250 mg/kg group had only 1 female of 10 mice
surviving the 7-week trial. Mean body weights were not
substantially reduced (maximum was 6% at week 7). From these data
the initial dosage levels for the chronic study were chosen as 0,
62.5 or 125 mg/kg.
Groups of mice, 50 male and 50 female (20 of each sex were used as
controls) B6C3F1 mice/group, were fed parathion methyl for 102
weeks. All animals were 6 weeks of age at the inception of the
study and were fed parathion-methyl diets 7 days per week. Animals
were housed in groups of five under clean, but not SPF conditions,
and were in rooms where other chemicals were administered to mice
in chronic studies. The animals were weighed every two weeks during
the initial phase of the study and monthly for the remainder of the
study. At the conclusion of the study all animals were sacrificed
and necropsied. Histopathologic evaluations were made on all major
tissues and organs and on all lesions, noted on gross examination.
There was a substantial decrease in growth of male mice, such that
the dosage levels had to be reduced at 38 weeks from 125 and 62.5
mg/kg to 50 and 20 mg/kg respectively. Thereafter, the males grew
normally. The 125 mg/kg dose in females was responsible for a
slight weight loss over the entire course of the study. There were
no differences in mortality with respect to control groups.
Sufficient survivors were available for an adequate study on the
development of neoplastic and non-neoplastic lesions.
On pathologic examination, a variety of lesions were observed in
both treated and control animals. The incidence and type of each
neoplasm was not attributable to the presence of parathion-methyl
in the diet. All lesions encountered were attributed to the common
ageing process in this strain of mice. Statistical evaluation of
the data concurred with the gross and pathological findings. It
was concluded that under the conditions of this bioassay,
parathion-methyl was not carcinogenic to the B6C3F1 mouse. These
conclusions were confirmed by a Data Evaluation/Risk Assessment
Subgroup of the Clearinghouse on Environmental Carcinogens (NCI,
In a dose range-finding study, groups of rats ( 5 female and 5
male, F344 (Fischer) rats), were fed parathion-methyl in the diet
at dosage levels of 0, 10, 20, 30, 40, or 50 mg/kg for 7 weeks. At
the conclusion of the dietary trial, all animals were maintained on
control diets for one week and sacrificed. Growth had been
measured twice a week for the 8-week trial. Abnormalities noted on
gross and microscopic analyses of tissues and organs and a 10%
growth reduction were chosen as requisites for the dosage levels to
be used in the chronic study.
There was no mortality in the male rats and survival of the females
mixed. There were no serious lesions noted on sacrifice and based
on growth the dosage levels of 0, 20 or 40 mg/kg were chosen for the
Groups of rats (50 male and 50 female (20 of each sex were used as
controls, F344 (Fischer) rats per group) were fed parathion-methyl
in the diet, 7 days per week for 105 weeks at dosage levels of 0,
20 or 40 mg/kg. Groups of rats were housed together (4 of each sex
per cage) in a clean room where several other chemicals were being
studied. The animals were not maintained under SPF conditions.
Body weight data were recorded periodically over the course of the
study as were chemical analyses of the dietary content. At the
conclusion of the study, all animals were sacrificed for gross and
microscopic analyses of tissues and organs.
There was no substantial effect of parathion-methyl on growth,
although the 40 mg/kg dosage level decreased female growth and
increased the mortality rate of females. Survival of females was
significantly reduced at 40 mg/kg.
A variety of neoplastic and non-neoplastic lesions were noted in
rats over the course of the study. Each type of neoplasm had been
noted previously in this strain of rat. The incidence by type and
site and by test group and sex was reported to be unaffected by
parathion-methyl in the diet. Based on the chronic bioassay data,
there was no evidence that parathion-methyl was carcinogenic to
this strain of rat. The conclusion was confirmed by the Data
Evaluation/Risk Assessment Subgroup of the Clearinghouse on
Environmental Carcinogens (NCI, 1979).
OBSERVATIONS IN MAN
In three supervised trials in India, groups of agricultural
workers, either wearing protective clothing or clothing normal to
the area, were examined before, during and after exposure to three
different formulations of parathion-methyl applied by hand in
different agricultural situations indigenous to India. Two
concentrations of parathion-methyl as an emulsifiable concentrate
in water and one trial with parathion-methyl as a 2% dust were used
in these trials. The duration of exposure for the individuals
participating was four hours per day for four successive days.
Pre-exposure, exposure, and post-exposure examinations with respect
to physical determinations, cholinesterase measurements and
haematological parameters ware performed on the individuals.
As might be expected from this type of experiment, the most
significant data reported were cholinesterase depression levels
reflective of exposure. In the trial with the high concentration
parathion-methyl emulsifiable concentrate, there was no substantial
difference with respect to cholinesterase depression in the
individuals wearing protective clothing from those wearing normal
clothing. Cholinesterase depression data suggested that exposure
had, indeed, occurred although cholinesterase depression levels
rarely exceeded the 25% level that would be indicative of excessive
In the trial where a lower concentration of the parathion-methyl
emulsifiable concentrate was used, none of the workers showed any
substantial inhibition of cholinesterase activity during the course
of the experiments. Differences in the two trials with
emulsifiable concentrates were probably reflective of the
differences in concentration of the technical material and in the
crop upon which the technical material was sprayed (in the higher
concentration the crop was a high span of cotton that presumably
increased the exposure from drift).
In the third trial, a 2% dust formulation of parathion-methyl did
not induce cholinesterase activity in any of the exposed workers
regardless of whether protective clothing was used.
In none of the above trials were there any of the variations in
haematological parameters or significant side effects noted with
some other insecticides (Anonymous, 1976).
Parathion-methyl was previously evaluated by the Joint Meeting in
1968, 1972, 1975 and 1979 (FAO/WHO, 1969b, 1973b, 1976b, 1980b) and
a temporary ADI of 0-0.001 mg/kg bw/day was allocated. Some data
were submitted to the meeting and reviewed. An extensive study of
agricultural field workers exposed to different formulations of
parathion-methyl under agricultural conditions in India showed
that, following good agricultural practices, occupational exposure
would not result in significant adverse short-term effects. While
these data were sufficient to relieve concerns about the short-term
hazards associated with short-term occupational exposure, the
meeting decided to extend the temporary ADI and request that
reproduction and long-term studies be made available.
Level causing no toxicological effect
Man: 0.3 mg/kg bw/day.
Estimate of temporary acceptable daily intake for man
0-0.001 mg/kg bw/day.
FURTHER WORK OR INFORMATION
Required (by 1982)
1. Reproduction study in species appropriate to such a test.
2. Results of adequate long-term study reported to be in progress.
Anonymous. Studies on the Toxic Hazards of Methyl-Parathion
Preparations to Human Workers When Engaged in Agricultural Pest
Control Operations Under Indian Field Conditions. (1976)
Unpublished report from the Haffkine Institute for Training
Research and Testing (Bombay) submitted by Bayer (India) Limited to
the World Health Organization.
Flucke, W. and Kimmerle, G. Studies on Acute Toxicity of
Simultaneously Administered Parathion-Methyl (Parathion-M) and
Parathion-ethyl (Parathion-A). (1977) Unpublished report from Bayer
AG Institut für Toxicologie submitted to the World Health
Organization by Bayer, AG.
Kimmerle, G. Acute Toxicity of DDT in Combination with
Parathion-Methyl and Penithrothion to Rats. (1975) Unpublished
report from Bayer AG Institut für Toxicologie submitted to the
World Health Organization by Bayer, AG.
NCI. Bioassay of Methyl Parathion for Possible Carcinogenicity.
National Cancer Institute, Carcinogenesis Technical Report Series
#157. D.H.E.W. Publication No. (NIH 79-1713). Report of a study
performed at the Fredrick Cancer Research Center, Fredrick, MD, and
prepared by Tracor Jitco, Inc. for the National Cancer Institute.