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
ACEPHATE
Explanation
Acephate was evaluated by the Joint Meeting of the FAO Panel of
Experts (JMPR) in 1976 (FAO/WHO, 1977) at which time an ADI was
established, based on no-effect levels taken exclusively from IBT
studies. Additional data were evaluated by the 1982 JMPR (FAO/WHO,
1983) that changed the ADI to a temporary status, as relevant studies
from IBT were found to be invalid. Studies required were a
multigeneration reproduction study, a delayed neurotoxicity study, and
individual animal data from the 28-month toxicity/carcinogenicity rat
study. Some of these data have been made available and are summarized
in the following monograph addendum.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOCHEMICAL ASPECTS
Absorption, Distribution and Excretion
Two male Sprague-Dawley rats received dermally a single treatment
with S-methyl-14C-Acephate at level of 10 mg/kg bw. Blood and urine
were collected at regular intervals and assayed for total 14C.
Acephate and its major metabolite (methamidophos) were also determined
in the urine. The 14C-dose was rapidly absorbed into the blood, with
the maximum concentration occurring at one to three hours. The 14C
content of the blood then decreased with time and a secondary peak was
observed at 48 h.
The excretion profile of acephate in the urine is similar to the
14C absorption profile into the blood. The maximum concentration of
acephate occurred at six and 24 h for the two rats. After three days,
approximately 35 percent of the 14C dose was excreted in the urine.
Approximately 30 percent of the dermal treatment was excreted as
unchanged acephate and 1 percent as methamidophos. The amount of the
dose left on the treated area of the rats was not determined (Tucker,
1974).
Effects on Enzymes and other Biochemical Parameters
The in vitro inhibitory activity (I50) of acephate technical
on brain and RBC acetylcholinesterase (AChE) and plasma cholinesterase
(ChE) was determined for the rat, monkey and human. The I50 for
acephate was between 1 × 10-3 M and 5 × 10-3 M for all enzyme
sources. Acephate was approximately 100 000 times less effective than
eserine (positive control) as an inhibitor of AChE and 10 000 times
less effective as an inhibitor of ChE. The inhibitory effect of
acephate was more effective against rat brain and RBC AChE than
against monkey and human brain. For plasma ChE, the I50 value was
lower for the monkey and human than for the rat. For humans, the
inhibitory activity (I50) was in the order: plasma > RBC > brain
(Bennett & Morimoto, 1982).
I50 VALUES
Brain RBC AChE Plasma
Rat 1.6 x 10-3 M 1.3 x 10-3 M 4.5 x 10-3 M
Monkey 3.4 x 10-3 M 2.7 x 10-3 M 2.3 x 10-3 M
Human 5.4 x 10-3 M 2.7 x 10-3 M 1.8 x 10-3 M
TOXICOLOGICAL STUDIES
Special Studies on Reproduction
Rat
Groups of six-week-old SPF-CD rats (12 males and 24 females per
group) were fed diets containing Acephate (technical, 92.8 percent
purity) at levels of 0, 50, 150, or 500 ppm until they were 21 weeks
old. At that time they were mated (one male to two females) to start a
two-generation (one litter per generation) reproduction study. Diets
were maintained during mating, gestation, and lactation.
F1 offspring were weaned at three weeks of age, at which time 12
males and 24 females per group were selected to form the basis of F1
generation. The remaining offspring and all F0 parents were
sacrificed. The selected animals were reared on their respective diets
and mated at 21 weeks of age to produce the F2 generation.
For parent animals, observations included regular inspection and
regular recording of body weight, food consumption, and food
conversion. Sample checks on water consumption were made, and breeding
performance was monitored. Litter values were recorded and at
termination all animals were subjected to macroscopic post-mortem
examination. More detailed macroscopic and microscopic examinations
were made on all F1 males; some F1 females failing to produce live
young; the majority of F1 females bearing live young; and a small
sample (five males and five females per group) of F1 and F2 weanlings.
The F1 adults selected for microscopic examinations were also
subjected to organ weight analysis.
Significantly reduced water consumption was recorded at 500 ppm
for both sexes of F0 and F1 generations and at 150 ppm for F0 females.
Food consumption and food conversion were unaffected by treatment.
Overall body weight changes were variably affected but no consistent
dose-related effects. However, [illegible text] demonstrated decreased
body [illegible text] during lactation. Pregnancy rate for all F0
generation dose groups, including control, was low. Pregnancy rate for
F1 generation was decreased at 50 and 500 ppm, and only slightly at
150 ppm. Duration of gestation was unaffected by treatment.
There were no effects on organ weights, macroscopic or
microscopic changes related to treatment.
For both generations viable litter size of all test groups was
lower than that of controls, with initial differences at birth
maintained or enhanced during lactation. The difference was
statistically different only for the 150 and 500 ppm groups.
There were slightly lower litter weights in test groups at birth,
enhanced during lactation, such that by day 21 post partum a
significant dosage-related trend for reduced litter weight was evident
for both generations. Intergroup differences from controls was
statistically significant at 150 and 500 ppm in both generations.
Histopathological examination of weanlings was unremarkable.
Dietary concentrations of 150 and 500 ppm acephate adversely
affected reproductive performance and rearing of offspring during
lactation. As many effects were also observed at 50 ppm. A clear
no-effect level was not determined (Palmer, et al. 1983).
Special Studies on Mutagenicity
See Table 1.
Mouse
Groups of CD-1 mice (75 males and 75 females/group) were given
diets containing acephate (purity not reported) at levels of 0, 50,
250, or 1 000 ppm for 104 weeks. The mice were observed daily for
signs of toxicity, moribundity and mortality. Detailed observations
were recorded weekly. Individual body weights and food consumption
values were recorded weekly for the first eight weeks of study and
monthly thereafter. Haematology was conducted on ten mice/sex/group at
study termination. An interim sacrifice of ten mice/sex/group was
conducted at 12 months of study.
No compound- or dose-related changes in appearance, behaviour, or
mortality were noted. Group mean body weights and average food
consumptions were decreased for the 250 and 1 000 ppm mice when
compared to the controls. No changes were seen in the haematological
parameters. No compound-related gross necropsy lesions were observed
for mice that died during the first 12 months of study. However, lung
foci were observed grossly and alveolar macrophages identified
microscopically at the 12-month interim sacrifice in the high dose
group. At 12 months there were also microscopically visible
compound-related liver hypertrophy and pigmented macrophages present
among the high-dose males and females.
TABLE 1. Special Studies on Mutagenicity
Test Organism Test Substance Result Reference
GENE MUTATION STUDIES
Bacteria
S. thyphimurium Acephate techn. -TA100: 7 samples weakly Bullock,
(eight samples) mutagenic without metabolic Carver &
activation in the range Wong
2-50 mg/plate, one sample 1982a
negative without metabolic
activation in the range
0.01-50 mg/plate;
-TA98 and TA1537:4 samples
tested were not mutagenic
without metabolic activation
in the range 10-50 mg/plate.
Acephate techn. -TA100:5 samples weakly Bullock,
(six samples) mutagenic without metabolic Carver &
activation in the range 2-50 Wong
mg/plate; 1 sample inconclusive. 1982b
Acephate techn. -Very weakly mutagenic to Simmon
(93.5% purity) TA100 at doses above 2.5 1979
mg/plate, with and without
metabolic activation.
Acephate -Positive TA100 without Moriya,
metabolic activation at et al.
concentration of 5 mg/plate 1983
and higher; Negative TA1535,
TA1537, TA1538, TA98.
TABLE 1. (continued)
Test Organism Test Substance Result Reference
E.coli WP2 her Acephate -Positive Moriya, et al.
1983
E.coli WP2 Acephate techn. -No significant increase of Simmon
(93.5% purity) revertants, with and without 1979
activation, at doses up to
10 mg/plate.
Yeasts and Fungi
S. cerevisiae D3 Acephate techn. -Increased mitotic recombination Simmon
(93.5% purity) with and without metabolic 1979
activation, at concentrations
of 1 to 5%.
S. cerevisiae D7 Acephate techn. -Induction of mitotic crossing Mortelmans,
(93.5% purity) over and gene conversion in Riccio &
the 3 to 5% range, with and Shepherd
without metabolic activation. 1980
CHROMOSOMAL EFFECTS
Cytogenetics-In Vitro
Mouse Lymphoma Acephate -Dose-related increase in Kirby
L5178Y Cells (98.7% purity) mutation frequency both with 1982a
and without metabolic activation
at TK+/-locus, in the range
500-5000 ug/ml.
Acephate -Dose-related increase in Kirby
mutation frequency both with 1982b
and without metabolic activation
at TK+/-locus, in the range
500-5000 ug/ml.
TABLE 1. (continued)
Test Organism Test Substance Result Reference
-Dose-related increase in Jotz &
mutation frequency both with Mitchell
and without metabolic activation 1980
at TK+/-locus, in the range
1000-5000 ug/ml.
Chinese Hamster Acephate -Dose-related increase of Evans &
ovary cells Sister Chromatid Exchange, Mitchell
in vitro with and without metabolic 1980
activation at concentrations
of 125-2000 ug/ml.
Cytogenetics-In Vivo
Mouse Bone Acephate -Negative for Chromosomal Esber
Marrow (98.7% purity) aberrations at doses of 1982
11.2-112 mg/kg bw.
Acephate -Negative for Sister Chromatid Cimino &
(98.7% purity) Exchange (some cell cycle Brusick
delay) at doses of 29-96 mg/ 1983
kg bw.
Monkey Acephate -Negative for Chromosomal Cummins
Lymphocytes (98.7% purity) aberrations and Sister 1983
Chromatid Exchange at dose
of 2.5 mg/kg bw/day.
Micronucleus Test
Mouse Acephate -No increase of incidence of Kirkhart
micronucleated polychromatic 1980
erythrocytes at doses of 75-300
mg/kg bw.
TABLE 1. (continued)
Test Organism Test Substance Result Reference
Dominant Lethal
Mouse Acephate -Negative at dose of 50-500 Eisenlord
(99%) mg/kg in the diet. 1982
DNA damaqe and repair
Unscheduled DNA Acephate -Increase without metabolic
synthesis (93.5% purity) activation at doses of 1 mg/kg
WI - 38 cells and higher. Doubtful result
with metabolic activation.
Differential toxicity
S. typhimurium Acephate -Negative Mortelmans
SL4525(rec+)- (93.5% purity) & Riccio
SL4700(rec-) 1981
S. typhimurium Acephate -Negative Mortelmans
TA1978(UVrB+)- (93.5% purity) & Riccio
TA1538(UVrB-) 1981
Special Studies on Carcinogenicity
(See also under long-term studies)
At terminal autopsy a dose-related increase of lung foci was
macroscopically observed in males at 250 and 1 000 ppm, and in females
of all the treated groups (6, 24, 53 and 73 percent for control, 50,
250 and 1 000 ppm groups, respectively). Liver masses or hyperplastic
nodules were present in 64.7 percent of the high-dose females, but
were not significantly different from controls in the other two
groups. In males, the incidence of liver masses or nodules were
comparable in all groups. At terminal sacrifice there was a
statistically significant increase in the mean relative weight of
liver, ovaries and brain of high-dose females, and testes and brain of
high-dose males.
At the terminal sacrifice, an increased incidence of hyperplastic
nodules and hepatocellular carcinoma was microscopically observed only
in the livers of the high-dose females when compared to controls.
Hepatocyte hypertrophy, nuclear enlargement (karyomegaly) and
intranuclear inclusion bodies were increased only in the two
highest-dose groups (both males and females) in a dose-related manner.
Mononuclear inflammatory cell foci were increased in treated groups of
males in a dose-related manner.
Lung lesions included alveolar hyalinosis and dark-pigmented
alveolar macrophages which were increased in all treated groups in a
dose-related manner, while eosinophilic foreign bodies were increased
only in the highest-dose groups (both males and females). Increased
incidence of acute rhinitis was also observed in all treated groups in
a dose-related manner.
Dark pigment in the reticuloendothelial cells of mediastinal
lymph nodes was observed to be increased and dose-related in all male
treated groups and in the females at the two highest doses. Incidence
of neoplastic lesions was comparable with respect to type and site
among all groups, except for the increase of hepatocellular carcinomas
in high-dose females (Geil & Richtter, 1981).
Special Studies on Skin Sensitization
Twenty male Hartley albino guinea-pigs received dermal
applications of Acephate at the concentration of 35 percent w/w in
saline solution which was previously determined to be the maximum
non-irritant concentration. The positive control material,
1-chloro-2,4-dinitrotoluene 0.1% w/w in saline solution, and the
saline vehicle were similarly each tested in ten male guinea-pigs. The
induction phase of the study consisted of ten repeated topical
applications, 0.4 ml of the test solution, on alternate days over a
22-day period. Fourteen days following the tenth induction
application, the test animals were challenged by applying the
respective test material.
Very slight to well-defined irritation was observed after the
last induction application. No sensitization responses were observed
either for the animals challenged with Acephate or for the vehicle
control animals (Silveira, 1982).
Toxicity
See Table 2.
TABLE 2. Acute Toxicity of Acephate
Animal Sex Route Compound LD50 Reference
Purity
Rat M+F oral 98.7% 1.3-0.93 Duke,1982
g/kg bw
Mouse M oral 98.7% 403 Esber,
F oral 98.7% 323 1982
g/kg bw
Special Studies on Antidotes
The LD50 values for groups of male and female Sprague-Dawley rats
treated with atropine sulphate (10 mg/kg bw) 15 minutes following oral
dosing with technical Acephate, were 4.2 and 6.6 times higher,
respectively, than the LD50 of groups receiving no antidote.
Similarly, the LD50 of groups of male and female Sprague-Dawley rats
treated with pralidoxime chloride (2-PAM) (50 mg/kg bw/i.m.) 15
minutes following oral dosing with Acephate technical, were each 2.9
times higher than the LD50 of groups receiving no antidote (Duke,
1982).
Short-Term Studies
Monkey - oral
Two male and two female cynomolgus monkeys (Macaca
fascicularis) received technical Acephate (98.7 percent pure) by
oral gavage at doses of 0 or 2.5 mg/kg bw/day for up to 34 consecutive
days (33 days for males, 34 days for females).
No noteworthy differences between groups were observed with
respect to clinical signs, food and water consumption, body weight
changes, physical examination, haematology, blood chemistry (except
cholinesterase activity), urinalysis, organ weights or macroscopic
pathology at terminal autopsy.
Cholinesterase activities were assayed in red blood cells and
plasma every two days and in brain at sacrifice. Erythrocyte acetyl-
and plasma acetyl- and butyrylcholinesterase activities were depressed
in all treated monkeys compared to control animals. Maximum inhibition
was observed after approximately six days for plasma cholinesterases
and 14 days for erythrocyte cholinesterase.
Mean inhibition (relative to mean pre-treatment values) of 42
percent (males) and 43 percent (females) was recorded for plasma
acetylcholinesterase activity and 37 percent (males) and 40 percent
(females) for plasma butyrylcholinesterase activity during days 6 to
34. Mean inhibition of 53 percent (males) and 47 percent (females) for
erythrocyte acetylcholinesterase activity was recorded during days 14
to 34. No erythrocyte butyrylcholinesterase activity was detected in
treated or control animals. There was no relevant difference in the
pattern of inhibition between plasma acetyl and butyryl activity or
between sexes for each cholinesterase parameter.
Brain cholinesterase activity after four weeks of treatment was
lower in all treated animals compared to controls. Compared to
contemporaneous control values treated animals showed mean
inhibition of 16 percent (males) and 32 percent (females) for
butyrylcholinesterase activity and 50 percent (males) and 43 percent
(females) for acetylcholinesterase activity. Thus, brain
cholinesterase inhibition was similar to (acetylcholinesterase) or
less marked than (butyrylcholinesterase) that recorded for blood.
These levels of cholinesterase inhibition were without any visible
cholinergic signs (Cummins, 1983).
Long-Term Studies
(see also under Special Studies on Carcinogenicity)
Rat
Groups of Sprague-Dawley CD rats (75 males and 75 females per
group) received Acephate technical (92.4 percent purity) in the diet
at dose levels of 0, 5, 50, and 700 ppm for 28 months. Interim
sacrifices were performed on ten animals/sex/group at four and 12
months and on four or five sex/group at 22 months. Physical
observations for signs of toxic or pharmacological effects and
palpations for tissue masses were performed weekly throughout the
study. Body weights and food consumption were monitored and clinical
laboratory evaluations (haematology, clinical chemistry,
cholinesterase activity, and urinalysis) were performed periodically
on ten animals/sex/group. Ophthalmoscopic examinations were performed
periodically on all animals. Complete gross post-mortem examinations
were conducted on all animals and microscopic examinations were
performed on all tissues from control and high-dose animals and on
gross lesions, tissue masses, eyes and adrenals from low- and mid-dose
animals. Organ weights were recorded at interim and terminal
necropsies, and organ/body weight ratios were calculated.
Evaluation of mortality, physical observations, haematology,
clinical chemistry (except cholinesterase activity), and urinalysis
revealed no significant differences between control and treated
animals, which were considered compound-related. A slight, transient
increase in the incidence of aggressive behaviour and/or increased
activity occurred in high-dose animals during the first six months.
Body weights of high-dose males were significantly lower
(4-18 percent) than those of control males throughout the study. Also,
the feed efficiency in high-dose males was significantly lower than in
control males.
Although the ophthalmoscopic examinations revealed a variety of
abnormalities more frequently in treated than in control animals, they
were not considered compound-related, due to the infectious or
traumatic origin and the unilateral nature of many of the
observations.
Plasma and erythrocyte cholinesterase activities were
significantly lower than control activities at most intervals for
high-dose males and females. Mean plasma and erythrocyte
cholinesterase activity ranged from 28 to 90 percent and 31 to 79
percent of control activity, respectively, for high-dose animals and
62 to 106 percent and 58 to 111 percent of control activity for
mid-dose animals. No statistically significant decreases in plasma and
erythrocyte cholinesterase activity occurred in low-dose animals. Mean
brain cholinesterase activity of mid- and high-dose (but not low-dose)
animals was significantly lower than control activity at all intervals
(17 to 34 percent of control in high-dose animals and 55 to 67 percent
in mid-dose animals). Statistically significant differences in organ
weights and organ/body weight ratios occurred sporadically in mid- and
high-dose animals with no consistent dose-related pattern.
Grossly observable abnormalities were most common in the lung,
liver, kidneys, pituitary glands and subcutaneous tissue, but there
was no significant difference in the incidence between control and
treated groups. Microscopically various non-neoplastic lesions were
observed in most of the organs, lungs and kidney being most frequently
affected. The incidence of these lesions does not indicate a
treatment-related effect. Various neoplasms were observed in different
organs and tissues examined microscopically. Based on these
examinations, the number of neoplasm-free animals, the number of
animals with benign neoplasms only and the number of animals with
malignant neoplasms were similar among groups. Neoplasms most commonly
observed were those of the pituitary gland. They were more frequent in
female rats of all groups compared to males. There was no significant
difference in the number of pituitary neoplasms between treated and
control groups. Mammary gland neoplasm represented the second largest
group; the incidence was 33/75 in control females compared to 43/73 in
the high-dose group. The incidence of neoplasm of adrenal medulla was
increased in all males of the treated group; however, historical
control data demonstrate the relatively low control value for the
present study and the great variability in the incidence of this
neoplasm. Statistical analysis of these data was inconclusive. The
incidence of thyroid gland neoplasm, though slightly increased in the
high-dose group of both male and female rats when compared to
controls, was below the mean value of the laboratory's historical
control groups.
The 5 ppm dose-level (equal to 0.2-0.6 mg/kg bw/day) may be
considered the no-effect level for the parameters investigated
(Auletta & Hogan, 1981).
COMMENTS
Acephate was first evaluated by the JMPR in 1976 and most
recently re-evaluated in 1982, when invalid IBT studies and
consideration of additional data caused the ADI to be changed to a
temporary ADI with requirements for a multigeneration reproduction
study, a delayed neurotoxicity study and data for individual animals
in the 28-month rat toxicity/carcinogenicity study.
A two-generation, one-litter-per-generation study showed that
Acephate adversely affected reproduction and neonatal weight gain
during lactation, but it was considered to be an inadequate study
(JMPR report, 1982). The 28-month rat toxicity study showed no
consistent biologically significant increased incidences of neoplasia,
and mutagenicity tests were mostly negative. The previously requested
delayed neurotoxicity study was not presented. In view of the
inadequate multigeneration study and the lack of a delayed
neurotoxicity study, only a temporary ADI, with a high safety factor,
was allocated.
Level Causing no Toxicological Effect
Rat: 5 ppm in the diet, equivalent to 0.25 mg/kg bw.
Dog: 30 ppm in the diet, equivalent to 0.75 mg/kg bw.
Estimate of Temporary Acceptable Daily Intake for Humans
0 - 0.0005 mg/kg bw
FURTHER WORK OR INFORMATION
Required (by 1987):
1. An adequate multigeneration study, with two litters per
generation.
2. An appropriate delayed neurotoxicity study.
Desirable:
Observations in humans.
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