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
DEMETON-S-METHYL-SULPHOXIDE
(Oxydemeton-Methyl)
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOCHEMICAL ASPECTS
Absorption, Distribution and Excretion
Single 5 mg/kg doses of purified oxydemeton-methyl were orally
administered to fasted male Wistar rats. Levels of oxydemeton-methyl
and its sulfone, demeton-S-methyl sulfone, were determined in blood
and selected organs at intervals up to 24 hours. Zero to 24 hour urine
and faeces samples were also analyzed for the two compounds. Thin
layer chromatography was used to separate the two compounds in
extracts of blood and organs. All quantitative analyses were performed
by gas liquid chromatography. Oxydemeton-methyl was rapidly absorbed.
Distribution in the body organs peaked at 30 minutes and then
decreased to non-detectable levels within 24 hours. In assayed organs,
sulfone residues were generally 20-40 percent of oxydemeton-methyl
residues. Approximately 45 percent of the administered dose was
recovered in urine within 24 hours and was present almost entirely as
unchanged parent. Very little parent or its sulfone was recovered in
faeces. Blood levels of oxydemeton-methyl and its sulfone correlated
well with blood cholinesterase activity determinations which decreased
rapidly to a minimum at two hours and then gradually recovered (Oyama
Takase, 1977).
Absorption, distribution and excretion of radioactivity were
assayed in male Sprague-Dawley rats given single oral doses of 0.1,
0.5, 5 or 10 mg/kg or intravenous doses of 0.5 or 1 mg/kg of
14C-oxydemeton methyl. Additional female rats were given a single
oral dose of 0.5 mg/kg. The test material was very rapidly and nearly
completely absorbed following oral administration. Approximately 50
percent of the administered radioactivity was excreted within three
hours and 90 percent within nine hours following an oral dose of 0.5
or 5 mg/kg. Within 48 hours, radioactivity excreted in the urine
accounts for 98-99 percent of the administered dose. Faeces accounted
for 0.6-1.2 percent and expired air for less than 0.1 percent.
Radioactivity remaining in the body was about 60 percent of the
administered dose at two hours (about 40 percent having been already
excreted at that time), 1.3 percent at 24 hours, 0.4 percent at 48
hours and about 0.1 percent at 10 days. Total recovered radioactivity
in experiments averaged 91-101 percent. Recovery percentages in
excreta were largely independent of dose level, route of
administration and sex of the animal. Rates of elimination were dose
proportional. In a separate experiment in which 0.5 mg/kg of
14C-oxydemeton methyl was intraduodenally administered to male rats
with bile duct fistulas, only 3.5 percent of the administered
radioactivity was excreted in the bile within 24 hours.
Blood levels of radioactivity peaked about one hour following
oral administration of 5 mg/kg of the test material. From zero to six
hours following administration, the blood half-life was calculated to
be about 1.5 hours, from six to 214 hours to be about five hours and
after 24 hours to be considerably longer. Nearly all the radioactivity
in blood after 24 hours was accounted for by a high retention in
erythrocytes which had considerably higher levels of radioactivity
than other organs and tissues for up to ten days. Serum levels after
24 hours were quite low compared to erythrocytes and at ten days were
negligible. Distribution of radioactivity in various body organs and
tissues was relatively uniform at two hours. Radioactivity did not
concentrate in fat tissue or in the reticuloendothelial system (liver,
spleen, bone marrow). By days 2-3 post-administration, radioactivity
was nearly undetectable in the majority of organs and tissues except
for blood and erythrocytes. At day 10, very low levels of
radioactivity were still present in these two tissues and the adrenal
gland. In a separate experiment, whole body autoradiography confirmed
previous findings regarding distribution of radioactivity in body
tissues, but also indicated some localized accumulation of
radioactivity in the pineal gland, thyroid and in some glands of the
genital tract (Cowper's gland, seminal vescicle, accessory genital
gland) (Weber, Patzschke and Wegner, 1978).
Biotransformation
Rat urine samples from the experiments performed by Weber,
Patzschke and Wegner in 1978, were collected and subjected to thin
layer chromatographic and radioactivity counting methods designed to
identify and quantitate the parent compound and metabolites. Zero to
eight hour and eight to 24 hour samples were collected from male rats
given a single oral dose of 10 mg/kg of 14C-oxydemeton methyl and
zero to 24 hour samples from male rats given a single oral dose of
5 mg/kg. About 92 percent of the administered radioactivity was
recovered in the urine within eight hours. The routes of metabolism of
oxydemeton-methyl (demeton-S-methyl sulfoxide) included oxidation of
the side chain sulfoxide group to form the corresponding sulfone and
to a slight extent in some, but not all, rats reduction of the same
sulfoxide group to form the corresponding sulfide. The reduction to
sulfide was only observed after eight hours post-administration and
may have been the result of anaerobic microbiological activity in
individual animals. Three corresponding O-demethylated metabolites for
the sulfoxide, sulfone and sulfide moieties were also identified in
the urine as were two additional metabolites, presumably resulting
from cleavage of the O-methyl-phosphoric ester group and subsequent
methylation and sulfoxidation steps. Approximately 97-99 percent of
the radioactivity in zero to 24 hour urine samples, equivalent to
about 95 percent of the administered oral dose of 5 mg/kg, was
identified and quantitated as follows: demeton-S-methyl sulfoxide
(unchanged parent compound), 65 percent; demeton-S-methyl sulfone,
6 percent; O-demethyl-demeton-S-methyl sulfoxide, 6 percent;
O-demethyl-demeton-S-methyl sulfone, 4 percent; O-demethyl-demeton-
S-methyl, <2 percent; methyl sulfinyl-2-ethyl sulfinyl ethane,
6 percent; and methyl sulfinyl-2-ethyl sulfonyl ethane, 10 percent.
Treatment of urine with glucuronidase or sulfatase did not indicate
the presence of any glucuronide or sulfate conjugates (Ecker, 1978;
Ecker and Colln, 1983).
TOXICOLOGICAL STUDIES
Special Study on Eye and Skin Irritation
R 2170 (oxydemeton-methyl, purity 94.7 percent) was applied in
standard tests for irritation to the skin or eyes of New Zealand White
rabbits. No erythema or edema was observed at intact or abraded skin
sites of six rabbits for up to 72 hours. The primary irritation score
was zero. Slight conjunctival reddening for up to 24 hours and slight
conjunctival swelling at 1 hour were observed in the eyes of five
rabbits exposed for five minutes to the test material. Nearly
identical readings were also made for the eyes of three rabbits
exposed for 24 hours. All other readings in all rabbits were zero for
up to seven days (Thyssen, 1981).
Short-Term Studies
Rabbit
New Zealand White rabbits were given dermal applications of
R 2170 (oxydemeton-methyl, purity 94.7 percent) five times per week
for three weeks. Each group consisted of six male and six female shorn
rabbits, three of each sex with intact skin sites and three with
abraded skin sites. Each exposure was six hours in duration. The
initial dosage levels of 0 (control), 2 and 20 mg/kg/day were reduced
to 0 (control), 0.5 and 5.0 mg/kg/day after two exposures because
signs of cholinergic poisoning, consisting of slight muscular tremors
lasting about 3.5 hours, were observed in treated animals. General
appearance and behaviour were recorded daily. Body weights were
determined weekly. Erythema and edema at sites of application were
scored after each exposure. Laboratory tests consisting of basic
haematology, clinical chemistries and urinalyses were performed at the
start and termination of the study. Plasma and erythrocyte
cholinesterase activity determinations were performed at the start of
the study, after the tenth exposure and at termination of the study.
Brain cholinesterase activity was also determined. Gross necropsies
were performed on all animals at 24 to 48 hours after the last
exposure. Organ weights for heart, lung, liver, spleen, kidney,
adrenals, testes, ovaries and thyroid were recorded. Histopathological
examination of the above organs and epididymis, uterus and treated and
untreated skin from all control and high-dosage level animals was
performed.
One high-dosage female rabbit died during the study due to a
fractured spine. Other than signs of cholinergic poisoning on the
second day of exposure, appearance and behaviour of all rabbits was
normal. Mean body weights of treated male and female animals were
comparable to respective control weights and remained relatively
constant during the study. Transient slight erythema and regularly
observed slight edema were observed at application sites due to
abrading, but were not increased in animals treated with oxydemeton-
methyl. Haematology, clinical chemistry and urinalysis tests were
negative. Plasma cholinesterase activity was unaffected. Erythrocyte
cholinesterase activity was decreased in male and female, intact and
abraded, high-dosage level animals at termination of the study. Brain
cholinesterase activity was also decreased in intact and abraded
high-dosage female animals at termination of the study. No effects
related to the test material were observed at necropsy. Small
differences in organ weights and organ/body weight ratios were
probably not biologically meaningful. Histopathological examinations
did not indicate any alterations attributable to the test material.
The cholinesterase NOEL for this study is 0.5 mg/kg/day (Mihail and
Nash, 1982).
Dog
Oxydemeton-methyl (R 2170) was administered to four groups of
pure bred Beagle dogs at dosage levels of 0 (tap water control),
0.025, 0.25 and 2.5 mg/kg/day for 12 months. Each group consisted of
six male and six female dogs that were 21 to 25 weeks old at the
initiation of dosing. The test material, which was 51.1 percent pure,
was dissolved in tap water and administered by gavage. The
individually-housed dogs were fed one to three hours following
intubation. The test material was administered by stomach tube because
it was found to be unstable in feed but stable in tap water for at
least eight days. Daily observations were made for appearance,
behaviour and signs of toxicity. Food consumption and water intake
were estimated. Weekly body weights were recorded. Clinical
examinations for general state of health, including nutritional state,
body temperatures and pulse rates were performed at regular intervals
throughout the study as were neurological (i.e. reflexes) and
ophthalmoscopic examinations. Laboratory tests, consisting of
extensive haematological, clinical chemistry and urinalysis
examinations, were performed at -2, 3, 6, 13, 26, 39 and 52 weeks.
Cholinesterase activities were assayed in plasma and erythrocytes
at -2, -1, 3, 6, 13, 26, 39 and 52 weeks and in brain tissue (bulbus
olfactorius) as termination of the study. Gross necropsies were
performed on all dogs. Organ weights were determined for brain, heart,
testes, ovaries, liver, lung, spleen, adrenals, kidneys, pancreas,
prostate, thyroid and thymus (the last organ in male dogs only). A
full set of 37 organs and tissues was excised and fixed for each dog
but, with the exception of a very few tissues from the low- and
mid-dosage groups only the histopathological results for control and
high-dosage animals were presented in the study report.
One female dog in the mid-dosage level group was sacrificed in
week eight due to a severely declining state of health. Pathological
examination of this animal indicated suppurative bronchitis and/or
pneumonia caused its moribund condition and its death was not
attributed treatment with oxydemeton-methyl. Normal appearance and
behaviour were observed in all other dogs at all times. No signs of
toxicity, including typical signs of cholinergic poisoning, were
observed in any of the animals at any time. Food consumption and water
intake of treated dogs were comparable to that of control dogs.
Clinical, neurological and ophthalmoscopic examinations were uniformly
negative for pathological findings attributable to the test material.
Mean body weights for all male and female treatment groups were
comparable to the respective male and female control groups throughout
the entire study. Mean body weights at week -1 for male dogs were 8.5,
8.2, 8.5 and 8.2 kg and for female dogs were 7.3, 7.6, 7.8 and 7.7 kg
for the control, low-, mid- and high-dosage groups respectively. At 52
weeks, mean body weights for male dogs were 13.3, 13.4, 14.3 and
12.8 kg and for female dogs were 11.6, 11.7, 12.2 and 11.9 kg for the
control, low-, mid- and high-dosage levels respectively. Total mean
body weight gains during the entire study for male dogs were 4.8, 5.2,
5.8 and 4.6 kg and for female dogs were 4.3, 4.1, 4.4 and 4.2 kg for
control, low-, mid-and high-dosage groups respectively. Results of
haematological, clinical chemistry and urinalysis examinations
indicated no treatment-induced alterations in any of the male or
female treatment groups when compared to the respective male and
female control groups.
Mean plasma cholinesterase activities in male and female mid- and
high-dosage groups were decreased below respective concurrent control
group activities at every sampling time during the entire period of
administration of test material i.e. at weeks 3, 6, 13, 26, 39 and 52.
The decreased activities were dose-related. Mean percentage decreases
over the entire study, compared to concurrent control values of 100
percent, ranged from 15 to 22 percent, and from 6 to 20 percent for
male and female dogs respectively in the mid-dosage group. Similarly,
mean percentage decreases ranged from 37 t 48 percent and from 40 to
45 percent for male and female dogs respectively in the high-dosage
level group. The consistency and dose-relatedness of these
determinations indicate a depression of plasma cholinesterase activity
due to the test material at the mid-dosage level of 0.25 mg/kg/day and
at the high-dosage level of 2.5 mg/kg/day. At the low-dosage level of
0.025 mg/kg/day, there was very little or no depression of plasma
cholinesterase activity. Depression of erythrocyte cholinesterase
activity due to the test material was also observed at the high-dosage
level of 2.5 mg/kg/day. Mean erythrocyte cholinesterase activities in
the male and female high-dosage level groups were decreased below
concurrent control activities during the entire period of
administration of test material. Mean percentage decreases, compared
to concurrent control values of 100 percent, ranged from 33 to 45
percent for male dogs and from 41 to 53 percent for female dogs. At
the mid-dosage level of 0.25 mg/kg/day, there was no consistent or
apparently meaningful inhibition of erythrocyte cholinesterase
activity. At the low dosage level of 0.025 mg/kg/day, there was no
inhibition of erythrocyte cholinesterase activity. Brain
cholinesterase activity was also decreased in the high dosage level
group. Mean percentage decreases for brain cholinesterase activity,
compared to control values of 100 percent, were 45 percent for male
dogs and 47 percent for female dogs in the 2.5 mg/kg/day group.
Equivocal decreases of 10 percent and 13 percent were noted for male
and female dogs respectively in the 0.25 mg/kg/group. No decrease was
observed in the 0.025 mg/kg/day group.
Gross necropsies revealed random findings across control and
treated groups that were unrelated to the test material. Mean organ
weight determinations for male dogs suggested decreased absolute and
organ/body weight ratios for heart and thymus in high- and/or
mid-dosage level groups. Mean organ/body weight ratios for testes and
pancreas were slightly increased in high- and/or mid-dosage level male
groups. In female dogs, mean absolute liver and liver/body weight
ratios for high- and mid-dosage animals were slightly higher than
control values. Mean absolute pancreas weight and kidney/body weight
ratios were also slightly increased in high- and mid-dosage level
animals. None of these organ weight changes were supported by relevant
clinical, laboratory or histopathological findings. Organ weight
changes, therefore, could not be directly related to the test
material. Histopathological examination of organs/tissues did not
indicate any pathological alterations attributable to the test
material. The few lesions noted occurred randomly across control and
treated groups and were of types often observed in dogs of similar
ages. The plasma cholinesterase NOEL for this study is 0.025 mg/kg/day
and the erythrocyte and brain NOEL is 0.25 mg/kg/day. No somatic
changes due to oxydemeton-methyl were observed at dosage levels up to
2.5 mg/kg/day (Hoffman and Ruhl, 1984).
Special studies on Teratogenicity
Rat
Oxydemeton-methyl was administered orally by gavage to four
groups of pregnant rats from gestation day 6 to gestation day 15 at
dosage levels of 0 (control), 0.3, 1.0 and 3.0 mg/kg/day. Dosage
levels were selected after a range finding study on non-pregnant
female rats demonstrated tremors and severely affected body weight
gains at a dosage level of 5.0 mg/kg/day, but no apparent toxicity at
2.5 mg/kg/day when administered daily for ten days. Each group
consisted of 20 to 23 FB 30 (Long Evans) strain female rats that were
2.5 to 3.5 months old at initiation of the study. The test material,
R 2170 (93.5 percent oxydemeton-methyl), was administered in a 0.5
percent aqueous Cremophor EL emulsion at a constant volume of
10 mg/kg/day to all groups. All rats were housed singly and permitted
feed and water ad libitum. Dams were examined daily for mortality,
appearance and behaviour. Body weights were recorded on gestation days
0, 20, and on all days of administration of the test material. On
gestation day 20, foetuses were removed by caesarean section. Numbers
of implantations, viable and dead foetuses, stunted foetuses (less
than 3 grams) and foetal sex ratios were recorded. Litter weights,
mean foetus weights and mean placenta weights were determined. All
foetuses were grossly examined for external anomalies. Approximately
30 percent of the foetuses were examined for visceral malformations by
a modification of Wilson's technique. The remaining 70 percent were
eviscerated and following examination of abdominal and thoracic
organs, were cleared, stained with Alizarin Red and examined for
skeletal malformations. In a second experiment, oxydemeton-methyl was
administered two additional groups of 25 pregnant rats, one group at a
dosage level of 0 (control) and the other group at a dosage level of
3.0 mg/kg/day. The rats in this second experiment were treated exactly
as in the first experiment.
One control and one mid-dosage level rat in the first experiment
died of causes unrelated to the test material. In the first experiment
three, one and five rats exhibited transient diarrhoea during
gestation days 6 to 15 in the low-, mid-and high-dosage groups
respectively. In the second experiment, four control and eight treated
rats also exhibited transient diarrhoea during the same period.
Although this condition was reported as frequently occurring
spontaneously, the incidences observed in both experiments at the
dosage level of 3.0 mg/kg/day may possibly be related to the test
material. In the first experiment, a significantly decreased weight
gain (p < 0.05) of about 16 percent was observed in high-, but not in
low- or in mid-dosage level rats during gestation days 6 to 15
compared to weight gains in the control rats. In the second
experiment, a similar decrease in weight gain was not observed in the
treated rats. In neither experiment was a significantly lower weight
gain for any treated group observed when determined for the entire
gestation period (days 0 to 20). Non-significant slight decreases in
weight gain, however, were observed in the high dosage level rats in
the first experiment and in the treated rats in the second experiment
for gestation days 0 to 20.
In the first experiment, 20 litters were examined in each control
and oxydemeton-methyl-treated group. In the second experiment, 24 and
23 litters were examined in the control and treated groups
respectively. In neither experiment did the test material have any
biologically meaningful effect on the number of pregnancies, mean
number of implantations, mean number of viable and dead foetuses, mean
number of resorbed embryos, sex ratios of foetuses, mean placent
weights or mean foetal body weights. Although gross external
examinations did not suggest any localized abnormalities due to the
test material, statistically significant ( p < 0.05) increased
incidences of stunted foetuses (less than 3 grams) were observed at
the dosage level of 3.0 mg/kg/day in both experiments. In the first
experiment, the number of stunted foetuses/number of foetuses examined
was 2/242, 6/257. 2/237 and 10/243 for the control, low-, mid- and
high-dosage levels respectively. In units of mean number of stunted
foetuses/litter, the calculated values respectively were 0.10, 0.30,
0.10 and 0.50. In the second experiment the number of stunted
foetuses/number of foetuses examined was 1/288 and 9/257 for the
control and treated groups respectively. In units of mean number of
stunted foetuses/litter, the respective values were 0.08 and 0.39. At
a dosage level of 3.0 mg/kg/day, an increased incidence of stunted
foetuses was causatively related to the test material.
[Note - Historical control data for stunted foetuses was
presented in Roetz, 1982 for the same strain of rat and from the same
testing laboratory. The number of dams with stunted foetuses in each
of 30 control groups (1978-1981) with an average of 23 litters per
group was as follows: in seven studies, zero dams with stunted
foetuses; in ten studies, one dam; in seven studies, two dams; in five
studies, three dams; and in one study four dams. In the first
experiment of this study, 4/20 dams had stunted foetuses at
3 mg/kg/day and in the second experiment, 6/23 dams had stunted
foetuses at 3 mg/kg/day. The incidence in the first experiment is at
the extreme upper limit and the incidence in the second experiment
exceeds the historical control range for this effect].
In the first experiment, a statistically significant (p < 0.01)
increased incidence of hypoplasia of the telencephalon was also
observed in the high-dosage group. The number of foetuses with brain
hypoplasia/number of foetuses examined, was 2/242, 8/257, 2/237 and
17/243 for the control, low-, mid- and high-dosage levels
respectively. In units of mean numbers of foetuses with brain
hypoplasia/litter, the calculated values respectively were 0.10, 0.40.
0.10 and 0.85. In the second experiment, the number of foetuses with
hypoplasia of the telencephalon in the control group was 0/288 and in
the treated group was 3/257. At a dosage level of 3.0 mg/kg/day, an
increased incidence of hypoplasia of the telencephalon was causatively
related to the test material. Other visceral and skeletal
malformations, including delayed ossification of bones and minor
skeletal variations, occurred sporadically across all treatment and
control groups and were not related to treatment with oxydemeton-
methyl.
Since increased incidences of stunted foetuses and hypoplasia of
the telencephalon were observed only at the dosage level of
3.0 mg/kg/day, the possibility that these effects may be related to
maternal toxicity, also observed only at 3.0 mg/kg/day, must be
considered. Maternal toxicity reported at this dosage level consisted
of slightly increased incidences of transient diarrhoea during
gestation days 6 to 15 in both experiments and a significantly
decreased body weight gain of about 16 percent during the same period
in the first experiment, but not in the second experiment.
Significantly decreased weight gains were not observed in the first
experiment however, when determined for gestation days 0 to 20.
Whether or not these rather minor maternal toxic effects, together
with probably decreased cholinesterase activities, were solely
responsible for the observed malformations is equivocal (Machemer,
1979).
Rabbit
Oxydemeton-methyl was administered by gavage to four groups of
17 HCG primed and artificially inseminated female American Dutch
rabbits at dosage levels of 0 (distilled water control), 0.1, 0.4 and
1.6 mg/kg/day. Deaths, severe body weight losses and/or poor
reproductive performances were observed in a preceding range-finding
study at dosage levels of 3 mg/kg/day and higher. The dosage, from a
0.05 percent solution of 50 percent Metasystox-R in distilled water,
was administered on gestation days 7 through 19. Body weights,
pregnancy rates and daily observations of does were recorded. On
gestation day 28, the does were sacrificed, necropsied and the uterine
contents were examined. Numbers of corpora lutea, implantations,
resorption and pre- and post-implantation losses were determined.
Litter sizes, foetal body weights, viability of foetuses and foetal
sex ratios were also determined. All foetuses were examined for gross
external, visceral and skeletal anomalies.
Three does died during the study due to intercurrent respiratory
infections, one each in the control, low- and mid-dosage groups.
Maternal body weights of oxydemeton-methyl treated does were
comparable to control body weights throughout the study. Maternal
toxicity, consisting of transient, dose-related loose stools were
observed in 8/17 high-dose and 5/17 mid-dose does. At necropsy,
several does had pitted kidneys suggestive of nosematosis. Pregnancy
rates were 17/17, 15/17, 16/17 and 14/17 for the control, low-, mid-
and high-dosage level groups respectively. Four control animals
aborted during the study and one high-dose doe was observed to have
only resorption sites at necropsy. The number of litters available for
examination at termination of the study were 12, 15, 16 and 13 for the
control, low-, mid- and high-dosage levels respectively.
The mean numbers of resorptions per doe were 0.8, 0.6, 0.8 and
1.6 and the mean percentage post-implantation losses were 18.1
percent, 10.0 percent and 24.4 percent for the control, low-, mid- and
high-dosage levels respectively. Although numbers of resorptions and
post-implantation losses were slightly increased for the high-dose
animals, neither was significantly different from control values. In
addition, increased resorptions were not observed in the preceding
range-finding study at dosage levels up to 12 mg/kg/day. Numbers of
corpora lutea, implantations, pre-implantation losses and litter
sizes, late foetal mortality, foetal body weights, foetal viability
and foetal sex ratios in the treated groups were comparable to the
control group.
Among 87 control, 120 low-, 91 mid- and 97 high-dosage level
foetuses examined, no grossly visible, visceral or skeletal terata
were observed. A few dysmorphogenic variations and anomalies were
observed in control and oxydemeton-methyl-treated groups, but these
were of types frequently seen in teratology studies, were not
dose-related and were not considered to be related to treatment.
Abnormal skeletal development, delayed ossification and increased
frequency of spontaneously occurring variations were not promoted by
the test material. Oxydemeton-methyl, when administered to pregnant
rabbits at dosage levels up to 1.6 mg/kg/day did not induce visceral
or skeletal terata. In addition, neither embryotoxicity nor
foetotoxicity was observed (Clemens and Hartnagel Jr., 1984).
Special Study for Carcinogenicity
Mice
Oxydemeton-methyl was incorporated in feed at concentrations of
0 (control), 10, 30 and 100 ppm and presented ad libitum to groups
of SPF CF-1 mice for two years. The test material was R 2170
(Metosystox R) and had a purity of 91.4 to 93.7 percent. Each control
and treatment group consisted of 70 male and 70 female singly-housed
mice which were about six to eight weeks old at the initiation of
dosing. At twelve months, ten male and ten female mice from each group
were sacrificed and examined and at 24 months, all surviving mice were
similarly sacrificed and examined. General observations for
appearance, behaviour, activity, conditions of hair coat, appetite and
thirst were made daily. Body weights were recorded weekly for 14 weeks
and at three week intervals thereafter. Food consumption was
determined for seven-day intervals. Clinical laboratory tests
consisting of standard haematological examinations and clinical
chemistry determinations were performed on ten male and ten female
mice from each group at 12 and 24 months. Urinalyses and
cholinesterase activity determinations were not performed. Gross
necropsies were performed on all mice that died or were sacrificed due
to a moribund condition during the entire study, and on all mice
sacrificed at 12 and 24 months. Organ weights for heart, lung,
liver, spleen, kidneys and testes were determined. The
following organs/tissues from all mice were excised, fixed and
histopathologically examined: heart, lung, liver, pancreas, stomach,
kidneys, urinary bladder, testes or ovaries, uterus (females),
pituitary, thyroid (also parathyroid, if present in section), adrenal,
spleen, bone, skeletal muscle, brain and all gross lesions suspected
of being tumours. General observations of oxydemeton-methyl-treated
mice were comparable to those of control mice. Determinations of mean
feed consumption in units of grams of feed/mouse/day, indicated
slightly decreased feed intake by mid- and high-dose male mice and by
high-dosage level female mice. Calculations of mean intake of test
material, in units of mg/kg/day, yielded 2 and 2, 4 and 6, and 16
and 18 mg/kg/day for male and female mice for the low-, mid- and
high-dosage levels respectively. Mean body weights for high-dosage
level male and female mice decreased about 10 percent during the first
week of feeding of test material. Thereafter, high-dosage level male
mice had consistently lower body weights throughout the entire study,
and particularly after 26 weeks. High-dosage level female mice quickly
regained the lost weight and were generally comparable to the female
controls for the remainder of the study. Mean body weights of low- and
mid-dosage level male and female mice were similar at all times to
mean body weights of their respective control groups. The depressed
body weights of the high-dosage level male mice were attributed to the
test material. Mortalities during the study were equivalent in all test
and control groups. The numbers of mice surviving to termination of
the study, out of 60 per groups, were 17, 24, 24 and 22 for the male
mice and 17, 20, 27 and 24 for the female mice in the control, low-,
mid- and high-dosage levels respectively. Haematological examinations
did not reveal consistent alterations due to the test material.
Similarly, clinical chemistry determinations did not indicate
biologically meaningful changes due to the test material.
Significantly decreased urea and creatinine levels in treated male and
female mice at 24 months were noted, but could not be attributed to
toxic effects of the test material.
Gross necropsies did not indicate any pathological findings
attributed to oxydemeton-methyl. Masses and nodes were oberved in
lungs and livers but appeared to be randomly distributed across
control and test groups. Organ weights and organ/body weight ratios
suggested possibly increased lung weights in high-dosage level male
mice and possibly decreased spleen weights in high-dosage level female
mice. Histopathologic examination revealed senile nephropathy in the
kidneys of most mice and cystic alterations in the ovaries and cystic
dilatations of endometrial glands in the uteri of most female mice.
Other non-tumorigenic findings were those commonly observed in mice of
comparable ages. The most frequently occurring neoplasms were lung and
liver tumours, malignant lymphomas in numerous organs and uterine
tumours in female mice. These tumour types occurred in control and
test groups with about equal incidences. The degree of malignancy,
latency period or incidence of any tumour type was not affected by the
test material. The somatic NOEL for this study was 30 ppm (Krotlinger,
Loser and Kaliner, 1981).
Human Exposure
A 41 year-old woman, five months pregnant, ingested approximately
12 grams of oxydemeton-methyl. Upon hospital admission 3.5 hours
later, characteristic signs of cholinesterase poisoning were observed
and blood cholinesterase activity decreased to 10 of normal. Following
14 days of vigorous treatment, the patient was discharged. The last
four months of pregnancy were uneventful and a normal child was
delivered. Follow-up examinations of the child revealed no
abnormalities of any kind (Carrington da Cost, et al, 1982).
Special Studies on Mutagenicity
For the results of mutagenicity studies on oxydemeton-methyl, see
Table 1.
Comments
Oxydemeton-methyl was rapidly and nearly completely absorbed in
rats following oral administration. About 50 percent single doses up
to 5 mg/kg was excreted within three hours and 90 percent within nine
hours. By 48 hours, only 0.4 percent remained in the body. Some
binding to erythrocytes occurred for at least ten days. Excretion was
almost entirely via the urine. Compounds identified in the urine were
unchanged parent: compound (65 percent), the corresponding sulfone
(6 percent), three O-demethylated metabolites (12 percent) and two
additional metabolites (16 percent).
In a one-year gavage study on dogs, the NOEL for plasma
cholinesterase depression was 0.025 mg/kg/day and for erythrocyte and
brain was 0.25 mg/kg/day. No other effects attributable to oxydemeton-
methyl were observed at dosage levels up to 2.5 mg/kg/day.
In a teratology study on rats, significantly increased incidences
of stunted foetuses and of hypoplasia of the telencephalon at the
highest dosage level of 3.0 mg/kg/day were attributed to treatment
with oxydemeton-methyl. Whether or not these effects might be related
to rather minor maternal toxic effects also observed at the same
dosage level is uncertain. A teratology study in rabbits at dosage
levels up to 1.6 mg/kg/day did not demonstrate embryotoxic, foetotoxic
or teratogenic effects.
A two-year oncogenicity study in mice demonstrated no tumours
attributable to treatment with oxydemeton-methyl.
In a series of mutagenicity studies, oxydemeton-methyl presented:
mixed results in both in vitro and in vivo tests.
Toxicity studies using oxydemeton-methyl as the test material
have demonstrated in a one-year gavage study on dogs, a NOEL of
0.025 mg/kg b.w. based on depression of plasma cholinesterase
activity, in 90-day dietary studies on rats, a NOEL of 1 ppm
(equivalent to 0.05 mg/kg b.w.) based on depression of erythrocyte
cholinesterase activity, and in a 60-day study on humans, a NOEL of
0.05 mg/kg b.w. based on depression of serum and erythrocyte
cholinesterase activity.
Considerable concern continues to exist, however,, with respect
to liver toxicity observed at low dosage levels in several short-term
rat studies on oxydemeton-methyl. Following submission of the final
report for a rat chronic feeding study presently in progress,
establishment of an ADI will be reconsidered.
FURTHER WORK OR INFORMATION BEFORE AN ADI CAN BE ESTABLISHED
Required:
Submission of the final report for the rat chronic feeding study
on oxydemeton-methyl.
Desirable:
Further observations in humans.
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