DEMETON-S-METHYL AND RELATED COMPOUNDS
DEMETON-S-METHYL
EXPLANATION
Demeton-S-methyl was evaluated by JMPR in 1973, 1982 and 1984
(Annex 1, FAO/WHO 1974a, 1983a, 1985b). In 1984, no ADI was
established pending the submission of a teratology study on a
species other than rabbit, a reproductive study, a long-term study
in rodents, a 6-month or longer study in dogs and a delayed
neurotoxicity study in hens. These studies were submitted, together
with other studies for mutagenicity and skin-sensitizing effects,
for evaluation by the present JMPR and are summarized in this
monograph addendum.
TOXICOLOGICAL STUDIES
Short-term studies
Dogs
In a one-year study purebred beagle dogs (n=6
animals/sex/group) were given 0, 1, 10 or 100 (day 1-36) reduced to
50 on day 37-termination) ppm of demeton-S-methyl (52.2% in xylene)
in the diet. Animals were observed twice daily for mortality and
clinical signs and once for food consumption. Body weight was
determined weekly. Hematological, clinical chemistry and urinalysis
parameters were determined during pretest period and at months 1, 2,
3, 4, 5, 6, 8, 10, 12. Hearing tests and ophthlamoscopic
examinations were performed once in the pretest period and at months
3, 6 and 12 of treatment. At termination, animals were sacrificed
for pathology and determination of organ weights, brain ChE
activity, hepatic cytochrome P-450 and tryglyceride contents, and
N-demethylase activity.
All animals survived the study. Diarrhoea and vomiting were
observed in all animals, most frequently in the high-dose group:
these animals also showed reduced food consumption before dosage
reduction to 50 ppm. Body weight was similar in all groups. No
alteration of hearing test and ophthalmoscopic examination was
observed. Hematological, clinical chemistry (excluding ChE
activities) and urinalysis parameters and organ weights at
termination were not significantly altered by any of the treatments.
Hepatic biochemical parameters were not altered by any of the
treatments. No treatment-related gross pathology alterations were
found. However, multifocal atrophy/hypertrophy of proximal tubules
was demonstrated in 3 males and 3 females of the high-dose group.
Plasma ChE activity was reduced relative to controls by 20-30% and
5-20% in males and females, respectively, in the 10 ppm group, and
by 45-65% (males) and 50-70% (females) in the 50 ppm group. RBC ChE
activity was reduced by 25-35% and 30-45% in males and females,
respectively, of the 10 ppm group. A higher inhibition was found in
the 50 ppm group where inhibition was 80-90% and 55-65% in males and
females, respectively. Brain ChE activity was reduced by 25% in
males of the 10 ppm group and by 64% (males) and 15% (females) in
the 50 ppm group.
The NOAEL was 1 ppm in the diet, equal to 0.036 mg/kg bw/day
(Bathe, 1983).
Long-term/carcinogenicity studies
Mice
NMRI mice (70 animals/group/sex) were given demeton-S-methyl
(about 50% in xylene) in the diet at concentrations of 0, 1, 15 or
75 ppm, or xylene (75 ppm). Groups were subdivided in two subgroups:
one (n=20) was terminated at 12 months, the second one was
terminated at 21 months. Toxicity following chronic administration
and carcinogenic potential of demeton-S-methyl was evaluated. At
termination, animals were necropsied, histological examination was
performed and hematological and clinical chemical parameters
(including plasma and RBC ChE activities) were determined. Brain
ChE activity was measured in 10 animals/group at 21 months.
The animals in the high-dose group had a lower (significantly
during the first 4 weeks only) food consumption and a reduced (about
10% throughout the study in males, only, at the beginning in
females) body weight. Clinical signs of cholinesterase inhibition
were not observed. Hematological and clinical chemical parameters
were not affected by the treatment except plasma urea which was
lower than control in the high-dose males, and plasma and RBC ChE
activities. RBC ChE activity was only slightly reduced in high-dose
groups (in males by 70%, in females by 38%). Histological
examination did not reveal an increased incidence of neoplastic and
non-neoplastic lesions in treated groups.
The NOAEL for inhibition of brain ChE activity was 1 ppm in the
diet (equal to 0.24-0.29 mg/kg bw/day) (Schmidt & Bomhard, 1988).
Rats
Wistar rats (60 animals/group/sex) were given demeton-S-methyl
(about 50% in xylene) in the diet at concentrations of 0, 1, 7 or
50 ppm, or 50 ppm of xylene. Groups were subdivided in two
subgroups: one (n=10) was terminated at 12 months, the second one
was terminated at 24 months. Toxicity and carcinogenic potential of
demeton-S-methyl were evaluated. At termination, animals were
necropsied, histological examination was performed and brain ChE
activity was measured in 10 animals/group.
Hair loss (up to 50% of females) and diarrhea (up to 50% of
males) were observed significantly more frequently in the animals of
the high-dose group. Body weight was reduced in mid-dose males (by
5-10%) and in both males (by 10-20%) and females (by 5%) in the
high-dose group. Hematological and clinical chemical parameters,
measured at months 6, 12, 18 and 24, were not affected by the
treatments except plasma and RBC ChE activities. Plasma and RBC ChE
activities, measured at months 3, 6, 12 and 24, were significantly
decreased in mid- (RBC ChE by 12-31%) and high-dose (RBC ChE by
20-44%) groups. Brain ChE activity was reduced in the high-dose
groups (by 67-75%) and in the mid-dose group (by 15-47%).
Histological examination did not reveal an increased incidence of
neoplastic lesions in treated groups. Increased incidence of
retinal atrophy (78% of males, 92% of females as compared to 36-63%
and 61-70% in the other groups) and keratitis (44% of males, 22% of
females as compared to 4-12% and 0-2%, respectively, in the other
groups) was observed in the 50 ppm group.
The NOAEL for inhibition of brain ChE activity was 1 ppm in the
diet (equal to 0.05-0.06 mg/kg bw/day) (Schmidt & Western, 1988).
Reproduction study
SPF rats (10 males and 20 females) were given 0, 1, 5 or 25 ppm
of demeton-S-methyl in the diet. Compound was used as a premix in
xylene (about 50%). Rats of an extra control group were given 25 ppm
xylene. F0 generation parents were mated once at the age of about
120 days; after 28 days of lactation F1a generation was discarded
and after a further 14-day waiting period F0 parents were mated
again. Selected F1b pups were mated at the age of 100 days; F2a
generation was discarded after a 28-day lactation period. After a
waiting period of 14 days, F1b parents were mated again; F2b pups
were then discarded after 28 days of lactation. Compound was
administered to 42-49 day-old F0 generation rats and continued
uninterrupted throughout the successive generations.
F0 generation: None of the animals died. No
treatment-related signs were observed in any animal. Body weight
gain was reduced in males (by 10%) and in some females of the 25 ppm
group. Food intake was also reduced (by 7%) in high-dose males.
Fertility index was not affected by treatment. In the 25 ppm group,
the number of pups born (2nd mating) and their viability (1st and
2nd matings) were reduced. Lactation index was also reduced in the
high-dose group. Body weight at birth was comparable in all groups
while body weight gain was significantly reduced (by 8-10%) in the
25 ppm group pups.
F1b generation: One female was found dead in the 5 ppm group
and one in the 25 ppm group; one male and one female of one 25 ppm
litter also died. Autopsy did not reveal treatment-related
alterations. No treatment-related signs were observed in any
animal. Body weight gain was sporadically reduced in low-dose males
and consistently in mid- and high-dose and xylene treated males when
compared to untreated animals; when compared to xylene-treated
animals (which were 5-15% lighter than untreated animals), however,
only males of the 25 ppm group had a significantly reduced (by about
15%) body weight gain. Females of the 25 ppm and xylene groups had
a reduced body weight as compared to controls (by about 10%); the
former being at times lighter than the latter. Fertility index was
not significantly reduced. The number of pups at birth was reduced
in the 25 ppm group and pup viability was also reduced in the 5 and
25 ppm groups in a dose-related manner (82-88% and 47-67% of
controls, respectively).
No compound related malformation was found in animals of any of
the treatment groups.
The NOAEL was 1 ppm in the diet, equal to 0.07-0.08 mg/kg
bw/day (Eiben, 1984).
Special studies on mutagenicity
Results of additional mutagenicity studies are reported in
Table 1.
Special studies on delayed neurotoxicity
Adult hens (n=20) were given two doses of 100 (a.i.) mg/kg bw
(about the LD50) of demeton-S-methyl (51.2% in xylene) by gavage.
The second dose was given 21 days after the first one. Positive
control animals (n=5) received tri-ortho-cresylphosphate (TOCP)
mg/kg bw by gavage. Animals were pretreated with atropine 100 mg/kg
bw i.m. 10 min. before the dose of demeton-S-methyl and 50 mg/kg bw
s.c. 6 hours later. Surviving animals received atropine 30 mg/kg
s.c. 24, 30 and 48 hours later. At the second dose, atropine
treatment was suspended after 24 hours. Animals were observed daily
for toxic signs. Hens treated with demeton-S-methyl had signs of
cholinergic toxicity. The recovery started on day 3 and by day 8
all treated animals, except 1, were free of signs. After the second
dose, the recovery started on day 2 and by day 5 all treated animals
were free of signs. One animal died after the second treatment and
surviving animals did not develop neurological deficits.
TOCP-treated animals showed locomotor impairment beginning on day
10. Histological examination showed moderate axonal degeneration in
peripheral nerves and medulla in TOCP-treated animals but not in
demeton-S-methyl treated animals.
Demeton-S-methyl did not cause delayed polyneuropathy in hens
at a dose about the LD 50 level (Flucke & Kaliner, 1988).
In another study, neuropathy target esterase (NTE) was not
found to be inhibited in hen brain and spinal cord 1, 2 and 7 days
after treatment with demeton-S-methyl 80 mg (a.i.)/kg bw by gavage.
Positive controls (TOCP 100 mg/kg bw) showed NTE inhibition (higher
than 90%) in both brain and spinal cord (Flucke & Eben, 1988).
TABLE 1. RESULTS OF MUTAGENICITY ASSAYS ON DEMETON-S-METHYL
CONCENTRATION OF
TEST SYSTEM TEST OBJECT DEMETON-S-METHYL PURITY RESULTS REFERENCE
DNA damage (pol E. coli 0.65-10 mg/plate 93% Negative Herbold, 1983a
test; with and (1)
without activation)
Forward mutation Mouse lymphoma 50-500 ug/ml 94% Positive Cifone, 1984
(with and without (2)
activation)
Sister chromatid Chinese hamster 5-20 mg/kg 94% Negative Herbold, 1983b
exchange bone marrow (3)
(1) Positive controls (methylmethanesulfonate) yielded expected positive results.
(2) Positive controls (ethylmethanesulfonate, dimethylnitrosamine and methylcholanthrene) yielded
positive results.
(3) Positive controls (endoxan) yielded expected positive results.
Special study on teratogenicity
Rats
Groups (n=25) of fertilized female rats (BAY:FB 30 strain) were
daily given 0, 0.3, 1 or 3 mg/kg bw p.o. of demeton-S-methyl (52.6%
in xylene) dissolved in corn oil from day 6 through 15 of gestation.
The day when sperm was found in vaginal smear was considered day 0
of gestation. Animals were observed routinely for physical
appearance, behaviour and body weight gain. At day 20 of gestation
pups were delivered by cesarean section. Fetuses were weighed,
sexed, examined for external abnormalities and visceral and bone
malformations.
No alteration of physical appearance and behaviour was observed
in any group. All animals survived until the cesarean section.
Body weight gain was reduced (by 13%) in the high-dose group. The
number of live fetuses, resorptions, fetal weight, number of fetuses
with malformations and number of implants was comparable in all
groups. No treatment-related visceral or skeletal abnormalities
were observed.
There was no evidence of embryotoxicity or teratogenicity at
any of the doses used. The dose of 3 mg/kg bw was maternally toxic.
The NOAEL was 1 mg/kg bw/day (Renhof, 1985).
Special studies on sensitization
The skin-sensitizing potential of demeton-S-methyl was assessed
by the Magnusson and Kligman's maximization test on guinea pigs
(n=20). The concentrations of demeton-S-methyl (96.3%, average of 3
determination) used were: 0.1% for the intra-dermal induction, 10%
for the topical induction and the first challenge and 1% for the
second challenge. Twenty animals reacted positively to the first
(controls 4/10) and 16 reacted to the second challenge (controls
3/10). The results indicate that demeton-S-methyl has a
skin-sensitizing potential (Heimann, 1987a).
In another study, Buehler epidermal patch test was used on
guinea pigs (n=12). The concentrations of demeton-S-methyl (95.6%
purity, average of 3 determinations) used were 10% for topical
induction (once a week for 3 weeks) and the first challenge, and 20%
for the second challenge. The results indicate that
demeton-S-methyl does not have a skin-sensitizing potential under
these conditions (Heimann, 1987b).
DEMETON-S-METHYL SULFONE
EXPLANATION
Demeton-S-methyl sulfone was evaluated by JMPR in 1973, 1982
and 1984 (Annex 1, FAO/WHO 1974a, 1983a, 1985b). In 1984, no ADI
was established pending the submission of a long-term study in
rodents, a reproduction study and a 6-month or longer feeding study
in dogs. The studies were submitted, together with two additional
mutagenicity studies and a study for skin-sensitizing effects, for
evaluation and are summarized in this monograph addendum.
TOXICOLOGICAL STUDIES
Short-term studies
Dogs
In a one-year study, purebred beagle dogs (n=4 animals/
sex/group) were given 0, 1, 10 or 100 ppm of demeton-S-methyl
sulfone (97.7% purity) in the diet. Animals were observed twice
daily for mortality and clinical signs and once for food
consumption. Body weight was determined weekly. Hematological,
blood biochemical and urinalysis parameters were determined during
pretest period and at months 1, 2, 3, 4, 5, 6, 8, 10, 12. Hearing
tests and ophthalmoscopic examinations were performed once in the
pretest period and at months 3, 6 and 12 of treatment. At
termination, animals were sacrificed for pathology determination of
organ weights, of brain ChE activity, hepatic cytochrome P-450 and
tryglyceride contents and N-demethylase activity.
One control female died from rupture of the diaphragm.
Episodes of diarrhea and vomiting were observed in all animals, most
frequently in the high-dose group when the symptoms were also more
severe. Some animals of the 100 ppm group displayed at times
typical symptoms of AChE inhibition (tremors, tonic spasm, motility
disturbances). No alteration of hearing test and ophthalmoscopic
examination were observed. Body weight was similar in all groups.
Hematological, blood chemistry (excluding ChE activities) and
urinalysis parameters and organ weights at termination were not
significantly altered by any of the treatments as well as hepatic
biochemical parameters. No treatment-related gross pathology
alterations were found. RBC ChE activity was reduced by 50-80% and
60-85% in males and females, respectively, of the 100 ppm group.
Brain ChE activity was reduced by 50% in males and only slightly in
3 females of the 100 ppm group. Brain ChE activity was also found
reduced in 2 males of the 10 ppm group. This reduction was not
correlated with inhibition of plasma and RBC ChE activities.
The NOAEL for inhibition of brain ChE activity was found 10 ppm
in the diet, equal to 0.36 mg/kg bw/day for 12 months (Bathe, 1983).
Long-term/carcinogenicity studies
Mice
SPF-bred CFW1 mice (50 animals/group/sex) were given
demeton-S-methyl sulfone (99.3% purity) in drinking water at
concentrations of 0, 1, 5 or 25 ppm for 24 months. An additional 5
animals/group were terminated at 3 months for determination of brain
ChE activity and 10 animals/group were terminated at 12 months for
autopsy; the brain of 5 of these animals were used for determination
of brain ChE activity. Toxicity following chronic administration
and carcinogenic potential of demeton-S-methyl were evaluated. At
termination, animals were necropsied, histological examinations were
performed and brain ChE activity was measured in 10 animals/group.
No treatment-related signs were observed in any group. Body
weight gain was delayed in the high-dose group; but no significant
difference was evident from week 4 onward. Food intake was also
reduced (by 9-13%) in the high-dose group during the first 26
(males) or 52 (females) weeks. Hematological and clinical chemical
parameters, measured in 10 animals/group at months 6, 12, 18 and 24,
were not affected by the treatments except plasma aspartate amino
transferase and plasma and RBC ChE activities. A dose-dependent
increase (up to 80% in the 25 ppm group) of plasma aspartate amino
transferase was evident during the final part of the study; values
remained, however, within normal range. RBC ChE activity was
significantly decreased (by 15-26%) in the high-dose groups. Brain
ChE activity was reduced in the high-dose groups (by 41-61%) and in
the mid-dose group at 12 and 24 months by 10-44%. Histological
examination did not reveal an increased incidence of non-neoplastic
or neoplastic lesions in treated groups.
The NOAEL for inhibition of brain ChE activity was 1 ppm in
drinking water (equal to 0.25-0.32 mg/kg bw/day) (Suberg, 1988).
Rats
SPF-bred Wistar rats (60 animals/group/sex) were given
demeton-S-methyl sulfone (99.3% purity) in drinking water at
concentrations of 0, 1, 5 or 25 ppm. Groups were subdivided in two
subgroups: one (n=10) was terminated at 12 months, the second one
was terminated at 24 months. Toxicity following chronic
administration and carcinogenic potential of demeton-S-methyl
sulfone were evaluated. At termination, animals were necropsied,
histological examination was performed and brain ChE activity was
measured in 10 animals/group. Diarrhea was observed significantly
more frequently in the animals of the high-dose group, tremors were
observed in 2 females of the high-dose group. Body weight gain was
delayed in the high-dose group but no significant different was
evident at termination. Hematological and clinical chemical
parameters, measured in 10 animals/group at months 6, 12, 18 and 24,
were not affected by the treatments except plasma urea and plasma
and RBC ChE activities. Plasma urea was increased at 18 and 24
months by 7-27% in both males and females of the high-dose group;
the values were, however, within historical control data. RBC ChE
activity, measured at months 3, 6, 12 and 24, was significantly
decreased in mid- (13-31%) and high-dose (by 33-48%) groups. Brain
ChE activity was reduced in the high-dose groups (by 67-71%) and in
the mid-dose group (by 29-33%). Histological examination did not
reveal an increased incidence of neoplastic lesions in treated
groups. Progressive senile nephropathy was observed in all males
(controls 40/50) and in 34/47 females (controls 20/50) of the 25 ppm
group.
The NOAEL for inhibition of RBC and brain ChE activities was
1 ppm, equal to 0.06-0.10 mg/kg bw/day in drinking water (Suberg &
Janda, 1988).
Reproduction study
SPF rats (10 males and 20 females) were given 0, 1, 5 or 25 ppm
of demeton-S-methyl sulfone technical (97.7% purity) in drinking
water. F0 generation parents were mated once at the age of about
120 days; after 28 days of lactation. The F1a generation was
discarded and after a further 14-day waiting period F0 parents were
mated again. Selected F1b pups were mated at the age of 100 days;
F2a generation was discarded after a 28-day lactation period.
After a waiting period of 14 days, F1b parents were mated again; F2b
pups were then discarded after 28 days of lactation. Compound was
administered to 42-49 day-old F0 generation rats and continued
uninterrupted throughout the successive generations.
F0 generation: One pregnant control animal was sacrificed
moribund and one pregnant animal in the 1 ppm group and two females
in the 25 ppm group were found dead. Autopsy did not reveal
treatment-related alterations. Tremors were occasionally observed
during the first week of treatment in the animals of the high-dose
group. Body weight gain was reduced in the males of the 5 ppm group
and in both males and females of the 25 ppm group as compared to
controls (about 10% decrease). After the second mating, the
fertility index was reduced (87%) and gestation period slightly
lengthened in the 25 ppm group. The number of pups born and their
viability (76-92%) were also reduced in both matings of the 25 ppm
group. Body weight at birth was comparable in all groups while body
weight gain was significantly reduced in the 25 ppm group.
F1b generation: In the 25 ppm group two female rats were
found dead and one was sacrificed moribund (pneumonia) and F1b dams
with pups exhibited spasms at times. Autopsy in the 25 ppm group
did not reveal treatment-related alterations. Females of the 5 ppm
group and both males and females of the 25 ppm group had a reduced
body weight. The fertility index (67-78%) was reduced and gestation
period slightly lengthened in the 25 ppm group. The number of pups
born was reduced in the 5 and 25 ppm groups (9.1 and 5.6
pups/litter, respectively, controls 11.2) and their viability was
reduced in the 25 ppm group only.
The NOAEL was 1 ppm in drinking water, equal to 0.11 mg/kg
bw/day (Eiben & Janda, 1985).
Special studies on mutagenicity
Results of additional mutagenicity tests are reported in Table
1.
Special study on skin sensitization
The skin-sensitizing potential of demeton-S-methyl sulfone was
assessed by the Buehler epidermal patch test on guinea pigs (n=12).
The concentrations of demeton-S-methyl sulfone (97.5%-96.9% purity
in two different determinations) used were 5% for topical induction
(once a week for 3 weeks) and first challenge, and 0.5% for the
second challenge. The vehicle was sterile physiological saline
solution. Six and 7 animals were positive after the first and
second challenge, respectively (vehicle controls 0/12 and 2/12,
respectively). The results indicate that demeton-S-methyl sulfone
has a skin-sensitizing potential under these conditions (Heimann,
1987).
TABLE 1. RESULTS OF IN VITRO MUTAGENICITY ASSAYS ON DEMETON-S-METHYLSULFONE
TEST SYSTEM TEST OBJECT CONCENTRATION PURITY RESULTS REFERENCE
Forward mutation Mouse lymphoma 25-500 ug/ml 97.2% Positive Witterland, 1984
(with and without cells (L5178Y) (1)
metabolic activation)
Unscheduled DNA Rat hepatocytes 1.01-251.25 ug/ml 97.2% Negative Cifone, 1984
synthesis (2)
(1) Positive controls (ethylmethanesulfonate, methylcholanthrene) yielded expected responses.
(2) Positive control (2-acetylaminofluorene) yielded expected positive response.
OXYDEMETON-METHYL
EXPLANATION
Oxydemeton-methyl was evaluated by JMPR in 1973, 1982 and 1984
(Annex 1, FAO/WHO 1974a, 1983a, 1985b). In 1984, the Meeting
expressed concern with respect to liver toxicity observed in some
short-term rat studies. The Meeting also noted an increased
incidence of stunted fetuses and hypoplasia of the telencephalon at
the level of 3.0 mg/kg bw/day in a rat teratology study. The 1984
Meeting did not allocate an ADI pending the submission of the final
report on a chronic rodent feeding study. This was submitted,
together with teratology studies in rats and rabbits and some other
additional studies, for evaluation by and are summarized in this
monograph addendum.
Biochemical aspects
Absorption excretion, metabolism
14C-oxydemeton-methyl was given (2.5 mg/kg bw) intravenously
or dermally to Sprague-Dawley rats (3 animals/sex/group). Animals
were sacrificed after 2, 4, 8, 12, 24, 48, 72 hours, and when
urinary radioactivity was less than twice the background. The final
sacrifice was at 264 hours and 653 hours for i.v. treated males and
females. After i.v. injection, some signs of AChE inhibition were
evident. Plasma t1/2 was 2 hours after i.v. and 3-4 hours after
dermal application. Urinary t1/2 after i.v. injection was 5-14 h
in males and 4-9 h in females. Skin t1/2 was 150-200 h. Urinary
recovery measured on the day of the final sacrifice was 67% (males)
- 81% (females) after i.v. injection and 33% (males) - 41% (females)
after dermal application. Dermal absorption was estimated to be
50-52% of the applied dose. The calculated dermal absorption rates
were 0.15 and 0.17 µg/cm2/hour for males and females, respectively
(Bond, 1986).
Hens (n=5) were treated daily with 6.9 mg/kg bw of
14C-oxydemeton-methyl (8 mCi/mMole, 99.3% purity) p.o. for 3 days.
Animals were sacrificed 4 hours after the third dose. Radioactivity
content in eggs was 0.086 ppm on day 1, 0.198 ppm on day 2 and
0.365 ppm on day 3. Radioactivity content was between 0.392 and
0.596 ppm in most tested organs (liver, heart, gizzard, skin, breast
and thigh muscle) except fat (0.026 ppm) and kidney (1.4 ppm).
Des-methyl sulfone was the major or only metabolite in all organ
except kidney and gizzard where 2-ethylsulfinyl ethane sulfonic acid
and 2-ethyl sulfonyl ethane sulfonic acid were found. Kidney and
thigh contained unidentified residues which accounted for about 10%
of total radioactivity (Marsh, 1987).
A goat was given 7 mg/kg bw of 14C-oxydemeton-methyl (98.3%
purity) p.o. for 3 days. The animal was sacrificed 2 hours after
the last dose. Radioactivity content in milk was 3.03-3.83 ppm in
the afternoon and 0.75-0.99 ppm in the morning. The highest
concentration was found in the kidney (13.02 ppm) and the lowest in
fat (0.62 ppm). The milk of the morning contained more than 90% of
unchanged oxydemeton-methyl, while in the afternoon, sulfone and two
other metabolites were found. Other organs, including muscle, fat,
liver and kidney, contained the unchanged compound, the sulfone and
4 other metabolites (unidentified) at variable percentages
(Merricks, 1987).
Female Rhesus monkeys (Macaca mulatta) (n=4, 4-11 kg. bw)
were given 14C-oxydemeton-methyl (98.3% purity, 19.3 mCi/mM)
topically at the dose of 23.5, 127.6 or 604.3 µg for 24 hours, or
610.8 µg for 9 hours or intravenously at the dose of 4.87 µg.
Percutaneous absorption was about 22% for the low and mid-doses; for
the high-dose it was 33% when applied for 24 hours or 18% when
applied for 9 hours; the interindividual variability was high. The
total recovery of radioactivity was similar after i.v. or dermal
application.
Effects on enzymes and other biochemical parameters
Rats
Sprague-Dawley rats (5 animals/sex/group) were given
oxydemeton-methyl in the diet (0, 3, 9 or 50 ppm from a 54.8%
concentrate) for 14 days. Animals were observed daily for toxic
signs, mortality, body weight and food consumption. Gross pathology
was performed at termination and plasma, RBC and brain ChE
activities determined. All animals survived the study without toxic
signs. A reduced body weight gain was observed in males of the 9
and 50 ppm groups. Gross pathology did not reveal any
treatment-related effect. ChE activity was inhibited 6-18%, 18-50%
and 70-87% in plasma, 4-16%, 22-36% and 47-51% in RBC, 12-20%,
36-57% and 79-82% in brain of the 3, 9 and 50 ppm groups,
respectively. The NOAEL was 3 ppm, equal to 0.22 in males and 0.21
in females mg/kg bw (Hayes, 1987a).
Oxydemeton-methyl was applied for 6 h/day to shorn backs of
Sprague-Dawley rats (5 animals/sex/group) at 0, 0.3, 1 or 5 mg/kg bw
(94.6% purity) for 14 days. Animals were observed daily for toxic
signs, mortality, body weight and food consumption. Gross pathology
was performed at termination and plasma, RBC and brain ChE
activities determined. All animals survived the study without toxic
signs. Treatment did not affect body weight or food consumption.
Gross pathology did not reveal any treatment-related effect. At day
14, ChE activity was inhibited 11-24% and 30-55% in plasma, 7-11%
and 37-46% in RBC and 4-11%, 12-16% and 48-60% in brain of the 0.3,
1.0 and 5.0 mg/kg bw groups, respectively. The NOAEL was 0.3 mg/kg
bw (Hayes, 1987b).
Oxydemeton-methyl was given by gavage to Sprague-Dawley rats (5
animals/sex/group) at 0, 0.15, 0.45 or 2.5 mg/kg bw (94.6% purity)
for 14 days. Animals were observed daily for toxic signs,
mortality, body weight and food consumption. Gross pathology was
performed at termination and plasma, RBC and brain ChE activities
determined. All animals survived the study without toxic signs.
Treatment did not affect body weights and food consumption. Gross
pathology did not reveal any treatment-related effect. ChE activity
was inhibited 0-16%, 19-31% and 45-60% in plasma, 6-9%, 15-28% and
48-49% in RBC, 11%, 23-29% and 66-68% in brain of the 0.15, 0.45 and
2.5 mg/kg bw groups, respectively. The NOAEL was 0.15 mg/kg bw
(Hayes, 1987c).
Acute toxicity
LD50 and LC50 values are reported in Table 1. The symptoms
observed in treated animals were of cholinergic type. Death usually
occurred within 2 days after treatment. Necropsy, when performed,
did not show specific alterations.
Short-term studies
Rats
SPF rats (30 animals/sex/group) were given 0, 1, 10 or 100 ppm
of oxydemeton-methyl (52.6-54.5% in isopropylacetone) in the diet
for 3 months. Animals were observed for clinical signs, body weight
and food consumption. Plasma and RBC ChE activities were determined
on days 1 and 3 and weeks 1, 4 and 13. Hematological and clinical
chemical tests were performed on week 4 and 12/13. Brain ChE
activity, liver mixed-function oxidase, cytochrome P-450 and
triglyceride contents were determined in 10 animals on weeks 1 and
13. Histological examination of selected tissues was performed on
10 animals at termination.
TABLE 1. ACUTE TOXICITY OF OXYDEMETON-METHYL
SPECIES SEX ROUTE LD50 LC50 REFERENCE
(mg/kg bw) (mg/l)
Rat M oral 61 (1) - Sheets, 1988c
M 32 (2) - Mihail, 1984b
F 48 (1) - Sheets, 1988c
M 119 (3) - Sheets, 1988d
F 96 (3) - Sheets, 1988d
M dermal 152 (4) - Mihail, 1984b
F (24h exp.) 112 (4) - Mihail, 1984b
M&F inhal.(4h exp.) (5) 0.471 Pauluhn, 1988
M (4h exp.) (3) 0.443 Shiotsuka, 1988
F (4h exp.) (3) 0.427
Rabbit M dermal 844 (3) - Sheets, 1988e
F (24h exp.) 918 (3) - Sheets, 1988e
(1) 93.3% purity
(2) purity not reported
(3) 53% in methyl-iso-buthylketone
(4) 91.5% purity
(5) 51.3% in monochlorobenzene.
Dynamic aerosol spraying (ethanol/polyethylenglycol) was conducted
in inhalation studies.
In the 100 ppm group, food consumption in males and body weight
gain in both sexes were reduced (by 20% and 15-30%, respectively).
ChE activities were reduced in the 10 ppm group by 27-45% (plasma),
about 25% (RBC) and up to 67% (brain) and in the 100 ppm group by
43-90% (plasma), about 35% (RBC) and 41-78% (brain). Cholinergic
symptoms were observed in this group. One month after beginning of
treatment, increased alkaline phosphatase, GOT, and GPT, were found
in both sexes in the 100 ppm group, males had also increased urea
concentration. At termination, males of the 100 ppm group had
increased alkaline phosphatase, GOT and glutamate dehydrogenase.
Females did not show any difference from controls. In the 100 ppm
group liver mixed-function oxidase and triglyceride contents were
reduced at weeks 1 and 13. All biochemical indices of liver
toxicity were, however, within historical control values. In the
100 ppm group a reduced urine volume and an increased urine density
were observed; two rats had increased proteinuria. Reduced weight
of most organs was observed in the 100 ppm group as a consequence of
reduced body weight (relative weights were normal or higher than
normal). A delay of the bony growth zone in the 100 ppm group was
observed. No treatment-related histological alterations were round.
The NOAEL was 1 ppm, equal to 0.98-0.09 mg/kg bw/day
(Krötlinger & Janda, 1984).
Rabbits
Oxydemeton-methyl was applied for 6 h/day to shorn backs of New
Zealand White rabbits (5 animals/sex/group) at 0, 0.3, 1.8 or
10.8 mg/kg bw (93.3% purity) for 15 times in 19 days. Animals were
sacrificed on the day of the last application. Additional groups (5
animals/sex) of controls and high-dose animals were used as recovery
groups and were sacrificed after a 14-day post-treatment period.
Animals were observed daily for toxic signs, mortality, body weight
and food consumption. At termination, gross pathology was performed
and brain ChE activity determined. Plasma and RBC ChE activities,
hematological and the common chemical plasma parameters were
measured. All animals survived the study without toxic signs.
Treatment did not affect body weights, food consumption,
hematological and chemical clinical parameters including plasma, RBC
and brain ChE activities. Gross pathology did not reveal any
treatment-related effect. The NOAEL was 20.8 mg/kg bw/day (Sheets,
1988f).
Dogs
Complete histopathological report of all animals of the oral
one-year study in dogs (Hoffman & Rühl, 1984) already evaluated by
the 1984 Meeting was submitted. No treatment-related histological
alterations were found.
The NOAEL for inhibition of brain ChE activity was 0.125 mg
(a.i.)/kg bw daily for 12 months (Hoffman & Rühl, 1984; Hoffman &
Rühl-Fehlert, 1988).
Long-term/carcinogenicity studies
Rats
Fisher 344 rats (50 animals/group/sex) were given
oxydemeton-S-methyl (51.5% in methyl isobutyl ketone) in the diet at
a.i. concentrations of 0, 1, 10 or 100 ppm for 27 months. Toxicity
following chronic administration and carcinogenic potention of
demeton-S-methyl were evaluated. At termination animals were
necropsied, histological examination was performed and brain ChE
activity was measured. Brain ChE activity was also measured in a
satellite group at month 1. Body weight was reduced (by 5-15%) in
both males and females of the high-dose group. Increased incidence
of rough coat, urine stain, loose stool, sore feet, tail rush, nasal
discharge and skin lesions was observed in the high-dose group from
month 6 onward. Mortality at 27 months was (males-females) 44-66,
48-64, 60-68 and 56-66 in the control, low-, mid- and high-dose
groups, respectively. Hematological and clinical chemical
parameters, measured in 10 animals/group at months 6, 12, 18, 24 and
27, were not affected by the treatments except plasma and RBC ChE
activities. Plasma and RBC ChE activities measured at months 3, 6,
12 and 24, were significantly decreased in mid- and high-dose
groups. Brain ChE activity was reduced in the high-dose groups and
in the mid-dose group (by 49-53%). Minimal inhibition of ChE
activities was found at times in the low dose-group. Histological
examination did not reveal an increased incidence of neoplastic
lesions in treated groups. An increased number of animals with
enlarged and/or reddened cervical lymph nodes, laryngeal
inflammation and bronchopneumonia was observed in the 100 ppm group.
The NOAEL for inhibition of brain ChE activity was 1
(analytical 0.57) ppm in the diet (equal to 0.03-0.04 mg/kg bw/day)
(Hayes, 1984).
Reproduction study
Rats
SPF rats (10 males and 20 females) were given 0, 1, 10 or
50 ppm of oxydemeton-methyl (52.5% in methyl-iso-butylketone) in the
diet. F0 generation parents were mated once at the age of about
120 days; after 28 days of lactation F1a generation was discarded
and after a further 14-day waiting period F0 parents were mated
again. Selected Flb pups were mated at the age of 100 days; F2a
generation was discarded after a 28-day lactation period. After a
waiting period of 14 days, F1b parents were mated again; F2b pups
were then discarded after 28 days of lactation. Compound was
administered to 42-49 day-old F0 generation rats and continued
uninterrupted throughout the successive generations.
F0 generation: one pregnant control in the 1 ppm group was
sacrificed moribund and one in the 50 ppm group died. Autopsy did
not reveal treatment-related alterations. Tremors were observed
until the 14th week of treatment in the animals of the high-dose
group. Food consumption was reduced by 10% in the 50 ppm group.
Body weight gain was reduced in animals of the 50 ppm group
throughout the study and in the 10 ppm group during the second half
of the study only. Fertility index was reduced and reduced number
and viability of pups born were found in both matings of the 50 ppm
group. Lactation index was reduced in all treatment groups in the
F1a generation as compared to control; however, only in the 50 ppm
group was the index lower than historical control values. Body
weight at birth was comparable in all groups.
F1b generation: one female rat was found dead in the 1 ppm group;
autopsy did not reveal treatment-related alterations. Males of the
10 ppm group and both males and females of the 50 ppm group had a
reduced body weight. Fertility index was reduced in the second
mating of the 50 ppm group. The number of pups born was reduced in
the 50 ppm group (7.9-8.3 pups/litter, controls 10.8-11.1).
Lactation index and body weight at birth were not affected by any
treatment. Body weight in the F2a generation of the 50 ppm group
was, however, slightly reduced.
Histopathological examinations showed spongy alteration in
apical and basal cytoplasm of the epithelia of the cranial section
of the corpus epididymis of male rats of the 50 ppm group. Large
vacuoles were present in the medial corpus section. Similar
alterations were found in one animal of the 10 ppm group.
The NOAEL was 1 ppm in the diet, equivalent to 0.050 mg/kg
bw/day (Krötlinger & Kaliner, 1985).
To better characterize the epididymal lesion, Sprague-Dawley
male rats (40-50 animals/group) were dosed with 0, 3, 9 or 50 ppm of
oxydemeton-methyl (65.8% concentrate in methyl isobutyl ketone) or
50 ppm of methyl isobutyl ketone in the diet. Nine/ten animals per
group were sacrificed after 2, 4, 6 or 8 months of treatment.
Nine/ten animals from a second 50 ppm group were taken off treatment
diet after 3.5, 4, 6 or 8 months and maintained on control diet as
recovery groups from 18 days to 4 months. At termination, all
animals were examined for ChE activities and reproductive toxicity.
One control animal was found dead, one animal from the mid-dose and
two from the high-dose groups were sacrificed moribund for teeth
problems and dehydration. No treatment-related signs were found.
Food consumption and body weight were not significantly altered by
any treatment. ChE activities (in plasma, RBC and brain) were
inhibited in a dose-related manner. There were no significant
differences in testicular weights and sperm count, morphology or
motility. Vacuolation of the epithelium of the body of the
epididymis occurred in a dose-related manner for time-of-onset and
severity. The vacuoles were first observed at 2 months in the
50 ppm group and at 4 months in the 9 ppm group; at 8 months all
high-dose rats had severe vacuolation, while minimal vacuolation was
present in some rats of the 9 ppm group. The vacuolation did not
cause cell death and underwent regression after removal from
treatment diet. The time to regression was dose and time-dependent.
No effect was seen in animals treated with methyl isobutyl ketone.
No vacuolation was demonstrated in animals treated with 3 ppm,
equivalent to 0.15 mg/kg bw/day (Eigenberg, 1987).
Special study on delayed neurotoxicity
Hens
Adult hens (n=23) were given two doses of 200 mg/kg bw (about
the LD50) oxydemeton-methyl (54% concentrate) by gavage. The
second dose was given 21 days after the first one. Positive control
animals (n=8) received tri-ortho-tolylphosphate (TOTP) 556 mg/kg bw.
Animals were treated with atropine 50 mg/kg bw i.m. and 2-PAM
31 mg/kg bw i.m. 30 and 45 min, respectively, after the dose of
oxydemeton-methyl. Animals were observed twice weekly for the perch
test. Hens treated with oxydemeton-methyl had signs of toxicity
which lasted for an average of 1.56 days. Eight hens died after
oxydemeton-methyl treatment, surviving animals did not develop
neurological deficits. TOTP-treated animals showed locomotor
impairment beginning on days 15-17. Histological examination showed
moderate axonal degeneration in lumbosacral spinal cord and sciatic
and tibial nerves in TOTP-treated animals but not in
oxydemeton-methyl treated animals.
Oxydemeton-methyl did not cause delayed polyneuropathy in hens
at the LD50 level (Hathaway, 1984).
Special studies on teratogenicity
Rats
Groups (n=45) of mated female rats (Charles River COBS CD) were
given oral daily doses (0, 0.5, 1.5 or 4.5 mg/kg bw) of
oxydemeton-methyl (90.6% purity) dissolved in distilled water from
day 6 through 15 of gestation (the day sperm was identified in
vaginal smear was considered day 0 of gestation). Doses were chosen
on the basis of the results of a range-finding experiment where 6/8
animals treated with 6 mg/kg bw showed tremors and 7/8 animals
treated with 15 mg/kg bw died. Five females were sacrificed on day
16 of gestation, 28 on day 20 (whose pups were delivered by cesarean
section) and 12 females were sacrificed on day 21 post-partum.
Blood and brain tissues were collected for ChE determination at days
16 and 20 of gestation. Fetal brain ChE activity was measured from
representative fetuses (n=20) in each group. Animals were observed
routinely for physical appearance, behaviour and body weight gain.
Fetuses were weighed, sexed, inspected for external abnormalities
and examined for visceral and bone malformations.
Tremors were observed in 98% of the high-dose group animals
during treatment. One low-dose animal died, possibly from
non-treatment related renal problems. Body weight gains during
gestation and food consumption during treatment were significantly
reduced in the high-dose group. Plasma, RBC and brain ChE
activities were reduced at day 16 in a dose-related manner (up to
72%, 56% and 68% reduction, respectively). At day 20, RBC ChE
activity was significantly reduced in the high-dose animals only (by
40%); brain ChE activity was still reduced in a dose-related manner
(up to 56%). The number of live fetuses, resorptions, fetuses with
malformations and implants and fetal weights were comparable in all
groups. Fetal brain ChE activity was not significantly inhibited by
any treatment. No treatment-related visceral or skeletal
abnormalities were observed. Part of the F1 generation was
observed for 44 days after delivery; no alterations of survival
rate, body weight gain, developmental indices or reflexes were
found.
There was no evidence of embryotoxicity or teratogenicity at
any of the doses used. The dose of 4.5 mg/kg bw caused signs of
maternal toxicity, while all doses inhibited ChE activities
(Clemens, 1985).
A study was performed with American Dutch rabbits following the
same dosing schedule of a previous teratology study (Clemens &
Hartnagel, Jr, 1984, reviewed by JMPR in 1984) to measure the effect
on ChE activities. The doses used were 0, 0.1, 0.4 or 1.6 mg/kg bw
p.o. Oxydemeton-methyl (53.5% a.i. in methyl isobutyl ketone) was
administered daily to pregnant rabbits by gavage from day 7 to 19 of
gestation. Animals (n=8 group/time-point) were sacrificed on days
20 and 29. No effect was seen on bw gain and plasma ChE activity.
RBC ChE activity was inhibited by 43% on day 20, brain ChE activity
was inhibited by 21% on day 20 and by 22% on day 29 in the high-dose
group. Oxydemeton-methyl is not embryotoxic or teratogenic at doses
which significantly inhibit brain ChE activity (Bare, 1985).
Special studies on eye and skin irritation and sensitization
Guinea pigs
The skin-sensitizing potential of oxydemeton-methyl was
assessed by the Magnusson and Kligman's maximization test on
guinea-pigs (n=20). The concentrations of oxydemeton-methyl (52.3%
purity in monochlorobenzene) used were: 0.25% for the intra-dermal
induction, 25% for the topical induction and the first challenge and
12.5% for the second challenge. A third challenge was done with 6%
monochlorobenzene. Sixteen animals reacted positively to the first
and second challenge (controls 0/10). The challenge with
monochlorobenzene gave positive results in 8/16 oxydemeton-methyl
treated animals and in 1/10 controls. The results indicate that
oxydemeton-methyl has a skin-sensitizing potential (Mihail, 1985).
The Klecak's test was performed on male guinea pigs (8
animals/group). For induction (4 weeks, 5 days/week) 0, 3, 10 or 30%
concentration was used. The 30% group was stopped after 4 days of
treatment because of the appearance of signs of toxicity (including
two deaths). The first (4 weeks after start of induction) and
second (6 weeks after induction) challenges were done with 3, 10, 30
and 100% concentrations in four different areas of each animal.
Induction: Skin reactions were observed in 4/8 and 6/8 animals of
the 3% and 10% group, respectively (control 0/8).
First challenge: Positive reactions were observed in 4/8 controls
and in all treated animals in the areas exposed to 100%
concentration.
Second challenge: 2/8 controls reacted. All treated animals showed
positive reactions with at least 6/8 animals/group reacting to
10-100% challenge concentrations. Moreover, in treated groups, skin
reactions were more pronounced and long-lasting.
Oxydemeton-methyl is to be considered a skin sensitizer under these
conditions (Mihail, 1986).
The skin sensitizing potential of oxydemeton-methyl was
assessed by the Buehler patch test on guinea pigs (n=12). The
concentrations of oxydemeton-methyl (51.7% in monochlorobenzene)
used were 25% for induction (once a week for 3 weeks) and first
challenge, and 5% for the second challenge. Ten and 3 animals were
positive after the first and second challenge, respectively (control
0/12 and 3/12, respectively). The results indicate that
oxydemeton-methyl has a skin-sensitizing potential under these
conditions (Heimann, 1987).
Rabbits
The skin irritating potential of oxydemeton-methyl was assessed
in 3 male and 3 female New Zealand White rabbits by applying 0.5 ml
of a 53% solution in methyl isobutyl ketone with an occlusive patch
for 4 hours. Grade 1 erythema, which resolved by 72 hours, was
observed in 3/6 animals. Under these conditions oxydemeton-methyl
is to be considered a mild skin irritant (Sheets, 1988a).
The eye irritating potential of oxydemeton-methyl was assessed
in 3 male and 3 female New Zealand White rabbits by applying 0.1 ml
of a 53% solution in methyl isobutyl ketone into one eye. Corneal
opacity was observed in all rabbits by 24 hours. Conjunctival
redness and ocular discharge were observed within 1 hour. All signs
were resolved by day 21, except in 1 animal which had conjunctival
redness and corneal opacity at termination (35 days).
Oxydemeton-methyl is to be considered a primary eye irritant
(Sheets, 1988b).
Special studies on mutagenicity
Table 2 reports the results of additional mutagenicity studies.
TABLE 2. RESULTS OF MUTAGENICITY ASSAYS ON OXYDEMETON-METHYL
TEST SYSTEM TEST OBJECT CONCENTRATION PURITY RESULTS REFERENCE
In vitro:
Unscheduled DNA Rat hepatocytes 0.01-1.0 ul/ml 94.6% Negative Curren, 1988
synthesis (1)
Sister chromatid Chinese hamster without activation: 94.6% Positive Putman, 1988
exchange ovary cells 0.08-9.6 ul/ml (2)
with activation:
0.6-5 ul/ml
Chromosome Chinese hamster without activation: 95.2% Positive Taalman, 1987
aberration ovary cells 1-2.5 mg/ml (3)
with activation:
2-5 mg/ml
Chromosome Chinese hamster without activation: 94.6% Positive Putman, 1988b
aberration ovary cells 0.13-2 ul/ml (nonactivated)
with activation: Suspect
0.6-5 ul/ml (activated)
(2)
TABLE 2 (CONTD).
TEST SYSTEM TEST OBJECT CONCENTRATION PURITY RESULTS REFERENCE
In vivo assays:
Cytogenic study Chinese hamster 40 mg/kg bw 95.5% Negative Herbold, 1989
(i.p.) (4)
Dominant lethal test Male CD-1 mice 0.9-1.75 or 3.5 92.2% Negative Putman, 1988c
mg/kg bw (i.p.) (5)
Dominant lethal Male CD-1 mice 4.25 mg/kg bw 92.2% Negative Putman, 1987
i.p. (5)
(1) Positive control (7,12-dimethylbenzanthracene (DMBA)) yielded expected positive results.
(2) Positive controls (triethylenemelamine, cyclophosphamide) yielded expected positive.
(3) Positive controls (mitomycin c, cyclophosphamide) yielded expected positive.
(4) Positive control (cyclophosphamide) yielded expected positive results.
(5) Positive control (triethylenemelamine) yielded expected positive results.
COMMENTS
Demeton-S-methyl
In a one-year study in dogs, 100 ppm, later reduced to 50 ppm,
in the diet caused clinical signs of ChE inhibition and multifocal
atrophy/hypertrophy of renal proximal tubules in 6/12 animals, but
no alteration in urine. Plasma RBC and brain (in males only) ChE
activities were inhibited at 10 ppm. The NOAEL for inhibition of
brain ChE activity was found to be 1 ppm in the diet (equal to
0.936 mg/kg bw/day.
In a 21-month study in mice 75 ppm in the diet caused transient
decreases in body weight gain and food consumption. Plasma and
brain ChE activities were reduced in the 15 and 75 ppm groups.
Clinical signs and mortality were unaffected by treatment and no
neoplastic lesions were observed. The NOAEL for inhibition of brain
ChE activity was found to be 1 ppm in the diet (equal to 0.24 mg/kg
bw/day).
In a 24-month study in rats, 50 ppm in the diet caused toxic
signs and reduced body weight. Dose-related inhibitions of plasma,
RBC and brain ChE activities were demonstrated at 7 and 50 ppm.
Marked increased incidences of retinal atrophy and of keratitis were
observed in the 50 ppm group only. However, incidence of retinal
atrophy was high in all groups, including controls. No
treatment-related neoplastic lesions were observed. The NOAEL for
inhibition of brain ChE activity was found to be 1 ppm in the diet
(equal to 0.95 mg/kg bw/day).
Demeton-S-methyl neither caused delayed neurotoxicity nor
inhibited neuropathy target esterase in hens at doses about LD50.
In a two-generation two litters per generation reproduction
study in rats, reductions in body weight gain and food intake were
found in the 25 ppm group. The number of live pups and pup
viability were reduced in the 5 and 25 ppm groups. The NOAEL was
1 ppm in the diet (equal to 0.07 mg/kg bw/day).
In a teratogenicity study in rats, 3 mg/kg bw/day caused
reduced body weight gain in dams. No indication of embryotoxicity
or teratogenicity was evident at doses up to and including 3 mg/kg
bw/day (highest dose). The NOAEL was 1 mg/kg bw/day based on
maternal toxicity.
After reviewing all available in vitro and in vivo
short-term tests, the Meeting concluded that there was no evidence
of genotoxicity.
Demeton-S-methylsulfone
In a one-year feeding study in dogs, animals treated with
100 ppm displayed typical symptoms of ChE inhibition, and inhibition
of plasma, RBC and brain ChE activity. The NOAEL for inhibition of
brain ChE activity was found to be 10 ppm in the diet (equal to
0.36 mg/kg/bw/day).
In a two-year study, mice that received 25 ppm in drinking
water showed delayed body weight gain during the first 4 weeks of
the study, reduced food intake during the first 26 (male) and 52
(female) weeks of the study, reduced activity of plasma, RBC and
brain ChE, and increased plasma aspartate aminotransferase. The
activities of brain and plasma ChE were also reduced in the 5 ppm
group. No treatment-related neoplastic or non-neoplastic lesions
were found in any group. The NOAEL for inhibition of brain ChE
activity was found to be 1 ppm in drinking water (equal to
9.25 mg/kg bw/day).
In a two-year study in rats, 25 ppm in drinking water caused
signs of ChE inhibition, delayed body weight gain, increased
mortality, increased plasma urea levels, inhibition of plasma, RBC
and brain ChE activities and a higher incidence and severity of
senile nephropathy. Plasma and brain ChE activities were also
reduced in the 5 ppm group. Increased neoplastic lesions were not
observed. The NOAEL for inhibition of brain ChE activity was found
to be 1 ppm in drinking water (equal to 0.06 mg/kg bw/day).
In a 2-generation, 2 litters per generation reproduction study
in rats, reduced body-weight gain was observed at levels of 5 and
25 ppm in drinking water. At the 25 ppm level, tremors were also
occasionally observed. A reduced number of live pups was seen in
the 25 ppm group (both generations) and in the 5 ppm (group F1
generation only). Pup viability was also reduced in the 25 ppm
group. No teratogenic effects were observed at levels up to and
including 25 ppm in drinking water (equal to 3.06 mg/kg bw/day).
The NOAEL was 2 ppm in drinking water (equal to 0.11 mg/kg bw/day).
After reviewing all available in vitro and in vivo
short-term tests, the Meeting concluded that there was no evidence
of genotoxicity.
Oxydemeton-methyl
In a 14-day study in rats, neither toxic signs nor inhibition
of brain ChE activities were observed with 3 ppm in the diet (equal
to 0.21 mg/kg bw/day), with 0.3 mg/kg bw/day applied dermally, or
with 0.15 mg/kg bw/day given by gavage.
In a 3-month feeding study in rats, treatment with 100 ppm
resulted in biochemical indices of liver toxicity different from
concurrent controls, but within historical control values. The
NOAEL was 1 ppm in the diet, equal to 0.08 mg/kg bw/day.
Histological examination of all animals in the 1-year dog study
which had been reviewed by the 1984 JMPR did now show any
treatment-related alterations. The NOAEL for inhibition of brain
ChE activity was found to be 0.125 mg/kg bw/day.
In a 27-month study in rats, neither increased mortality nor
altered hematological or clinical chemical parameters (excluding ChE
inhibition) were found with doses up to and including 100 ppm of an
oxydemeton-methyl formulation in the diet. The dose of 100 ppm
caused signs of ChE inhibition while in the 10 ppm group, reduced
ChE (plasma, RBC and brain) activities were not accompanied by
symptoms. The NOAEL for inhibition of brain ChE activity was found
to be 1 ppm (0.57 ppm a.i.) in the diet for 27 months, equal to
9.03 mg/kg bw/day.
Oxydemeton-methyl given to hens at the LD50 level did not
produce delayed neurotoxicity.
In a 2-generation, 2 litters per generation reproduction study
in rats, 50 ppm in the diet caused reduction of the fertility index
and pup viability as well as vacuolation of the epithelium of the
body of the epididymis of male rats. Dose levels of 10 or 50 ppm
caused a reduction in body weight gain. The NOAEL was 1 ppm in the
diet, equivalent to 0.05 mg/kg bw/day. A feeding study in male rats
with doses up to 50 ppm was performed to better characterize the
epididymal lesion. The severity, time of onset and time of recovery
of the vacuolation after suspension of the treatment were
dose-dependent. Sperm count and motility were not affected. The
NOAEL based on absence of vacuolation was 3 ppm in the diet for 8
months, equivalent to 0.15 mg/kg bw/day.
Oxydemeton-methyl was neither embryotoxic not teratogenic in
rats or in rabbits at oral doses up to 4.5 mg/kg bw/day and
1.6 mg/kg bw/day, respectively. These doses inhibited brain ChE
activity and caused clinical signs (in rats only).
After reviewing all available in vitro and in vivo
short-term tests, the Meeting concluded that there was no evidence
of genotoxicity.
TOXICOLOGICAL EVALUATION
The Meeting allocated a group ADI to these three compounds
because residues following application of demeton-S-methyl,
demeton-S-methylsulfone and oxydemeton-methyl are determined after
oxidation and are expressed as demeton-methyl.
Level causing no toxicological effect
Demeton-S-methyl
Mouse: 1 ppm in the diet, equal to 0.24 mg/kg bw/day
Rat: 1 ppm in the diet, equal to 0.05 mg/kg bw/day
Dog: 1 ppm in the diet, equal to 0.036 mg/kg bw/day.
Demeton-S-methylsulfone
Mouse: 1 ppm in drinking water, equal to 0.25 mg/kg bw/day
Rat: 1 ppm in drinking water, equal to 0.06 mg/kg bw/day
Dog: 10 ppm in the diet, equal to 0.36 mg/kg bw/day.
Oxydemeton-methyl
Mouse: 30 ppm in the diet, equal to 4 mg/kg bw/day (ChE not
measured)
Rat: 0.57 ppm in the diet, equal to 0.03 mg/kg bw/day
Dog: 0.125 mg/kg bw/day.
Estimate of acceptable daily intake for humans
Demeton-S-methyl, oxydemeton-methyl and demeton-S-methylsulfone
0-0.0003 mg/kg bw (Group ADI, alone or in combination).
Studies which will provide information valuable to the continued
evaluation of the compounds
Further observations in humans.
REFERENCES
DEMETON-S-METHYL
Bathe, R. (1983) Twelve-month oral (feeding) toxicity study with E
154 in beagle dogs. Research & Consulting Company AG, Switzerland.
Unpublished Report No. R. 2542. Submitted to WHO by Bayer AG,
Wuppertal-Elberfeld, FRG.
Cifone, M.A. (1984) Mutagenicity evaluation of E 154 in the mouse
lymphoma forward mutation assay. Litton Bionetics, Inc., Maryland,
USA. Unpublished Report No. R 2789. Submitted to WHO by Bayer AG,
Wuppertal-Elberfeld, FRG.
Eiben R. (1984) E 154 - Generation study with rats (two
generation). Institute of Toxicology, Bayer AG. Unpublished Report
No. 13135. Submitted to WHO by Bayer AG, Wuppertal-Elberfeld, FRG.
Flucke, W. & Eben A. (1988) E 154 50 VL 00094/0487. Study for
acute delayed neurotoxicity after oral administration to the hen.
Institute of Toxicology, Bayer AG. Unpublished Report No. 17264.
Submitted to WHO by Bayer AG, Wuppertal-Elberfeld, FRG.
Flucke, W. & Kaliner, G 1988) E 154 50 VL 00094/0487. Study of
effect on neuropathy target esterase (NTE) after oral administration
to the hen. Institute of Toxicology, Bayer AG. Unpublished Report
No. 16920. Submitted to WHO by Bayer AG, Wuppertal-Elberfeld, FRG.
Heimann, K.G. (1987a) E 154 techn. Study for skin sensitizing
effect on guinea pigs. Institute of Toxicology, Bayer AG.
Unpublished Report No. 15896. Submitted to WHO by Bayer AG,
Wuppertal-Elberfeld, FRG.
Heimann, K.G. (1987b) E 154 techn. Study for skin sensitizing
effect on guinea pigs in the epicutaneous test. Institute of
Toxicology, Bayer AG. Unpublished Report No. 16106. Submitted to
WHO by Bayer AG, Wuppertal-Elberfeld, FRG.
Herbold, B. (1983a) E 154 - Metasytox (i) active ingredient Pol
test on E. coli to evaluate for DNA damage. Institute of
Toxicology, Bayer AG. Unpublished Report No. 12152. Submitted to
WHO by Bayer AG, Wuppertal-Elberfeld, FRG.
Herbold, B. (1983b) E 154 - Metasytox (i) active ingredient sister
chromatid exchange in the bone marrow of the Chinese hamster
in vivo to evaluate for harmful effect on DNA. Institute of
Toxicology, Bayer AG. Unpublished Report No. 12323. Submitted to
WHO by Bayer AG, Wuppertal-Elberfeld, FRG.
Renhof, M. (1985) E154 - Study for embryotoxic effects on rats
after oral administration. Institute of Toxicology, Bayer AG.
Unpublished Report No. 13237. Submitted to WHO by Bayer AG,
Wuppertal-Elberfeld, FRG.
Schmidt, W.M. & Bomhard, E. (1988) E 154 - Study for
carcinogenicity in NMRI-mice (administration in diet for up to 21
months). Institute of Toxicology, Bayer AG. Unpublished Report No.
16812. Submitted to WHO by Bayer AG, Wuppertal-Elberfeld, FRG.
Schmidt, W.M. & Westen, H. (1988) E 154 - Study for chronic
toxicity and carcinogenicity in Wistar rats (administration in diet
for up to 2 years). Institute of Toxicology, Bayer AG. Unpublished
Report No. 16888. Submitted to WHO by Bayer AG,
Wuppertal-Elberfeld, FRG.
DEMETON-S-METHYL SULFONE
Bathe, R. (1983) Twelve-month oral toxicity (feeding) study with E
158 techn. in beagle dogs. Research & Consulting Company AG,
Switzerland. Unpublished Report No. R 2530. Submitted to WHO by
Bayer AG, Wuppertal-Elberfeld, FRG.
Cifone, M.A. (1984) Evaluation of E 158 in the rat primary
hepatocyte unscheduled DNA synthesis assay. Litton Bionetics, Inc.,
Maryland, USA. Unpublished Report No. R 2874. Submitted to WHO by
Bayer AG, Wuppertal-Elberfeld, FRG.
Eiben, R. & Janda, B. (1985) E 158 two-generation study with rats
(administration in drinking water). Institute of Toxicology, Bayer
AG. Unpublished Report No. 13191. Submitted to WHO by Bayer AG,
Wuppertal-Elberfeld, FRG.
Heimann, K.G (1987) E 158 techn. - Study for skin sensitizing
effect in the epicutaneous test on guinea pigs. Fachbereich
Toxikologie, Bayer AG. Unpublished Report No. 16186. Submitted to
WHO by Bayer AG, Wuppertal-Elberfeld, FRG.
Suberg, H. (1988) E 158 - Carcinogenicity study in CFW1 mice
(administration in drinking water for up to 24 months). Institute
of Toxicology Industrial Chemicals, Bayer AG. Unpublished Report
No. 17182. Submitted to WHO by Bayer AG, Wuppertal-Elberfeld, FRG.
Suberg, H. & Janda, B. (1988) E 158 - Chronic toxicity and
carcinogenicity study in the rat (administration in drinking water
for up to 24 months). Institute of Toxicology Industrial Chemicals,
Bayer AG. Unpublished Report No. 17073. Submitted to WHO by Bayer
AG, Wuppertal-Elberfeld, FRG.
Witterland, W.F. (1984) Mutagenicity evaluation of E 158 in the
mouse lymphoma forward mutation assay. Litton Bionetics, The
Netherlands. Unpublished Report No. R 2906. Submitted to WHO by
Bayer AG, Wuppertal-Elberfeld, FRG.
OXYDEMETON-METHYL
Bare, J.J. et al. (1985) Addendum to Unpublished Report No. 470:
Evaluation of cholinesterase levels in rabbits treated with
Metasystox R. Mobay Chemical Corporation, Kansas, USA. Submitted
to WHO by Bayer AG, Wuppertal-Elberfeld, FRG.
Bond, G.P. (1986) Dermal absorption of 14C-Metasystox R in rats.
Mobay Chemical Corporation, Kansas, USA. Unpublished Report No.
706. Submitted to WHO by Bayer AG, Wuppertal-Elberfeld, FRG.
Clemens, G.R. (1985) A teratology study in the rat with Metasystox
R. Mobay Chemical Corporation, Kansas, USA. Unpublished Report
No. 594. Submitted to WHO by Bayer AG, Wuppertal-Elberfeld, FRG.
Curren, R.D (1988) Unscheduled DNA synthesis in rat primary
hepatocytes - Metasystox R. Microbiological Associates Inc.,
Maryland, USA. Unpublished Report No. 1006. Submitted to WHO by
Bayer AG, Wuppertal-Elberfeld, FRG.
Eigenberg, D.A. (1987) Male reproductive toxicity study in rats
with oxydemeton methyl (Metasystox R) in the diet. Mobay Chemical
Corporation, Kansas, USA. Unpublished Report No. 974. Submitted to
WHO by Bayer AG, Wuppertal-Elberfeld, FRG.
Hathaway, T.R. (1984) Acute delayed neurotoxicity of Metasystox R
50% concentrate. Mobay Chemical Corporation, Kansas, USA.
Unpublished Report No. 510. Submitted to WHO by Bayer AG,
Wuppertal-Elberfeld, FRG.
Hayes, R.H. (1984) Chronic feeding/oncogenicity study of oxydemeton
methyl (Metasystox R) in rats. Mobay Chemical Corporation, Kansas,
USA. Unpublished Report No. 543. Submitted to WHO by Bayer AG,
Wuppertal-Elberfeld, FRG.
Hayes, R.H. (1987a) Fourteen-day cholinesterase activity study of
oxydemeton methyl (Metasystox R 50% concentrate) in ration with
rats. Mobay Chemical Corporation, Kansas, USA. Unpublished Report
No. 968. Submitted to WHO by Bayer AG, Wuppertal-Elberfeld, FRG.
Hayes, R.H. (1987b) Fourteen-day cholinesterase activity study of
oxydemeton methyl (Metasystox R 50% concentrate) with rats by dermal
application. Mobay Chemical Corporation, Kansas, USA. Unpublished
Report No. 967. Submitted to WHO by Bayer AG, Wuppertal-Elberfeld,
FRG.
Hayes, R.H. (1987c) Fourteen-day cholinesterase activity study of
oxydemeton methyl technical (Metasystox R) with rats by oral gavage.
Mobay Chemical Corporation, Kansas, USA. Unpublished Report
No. 966. Submitted to WHO by Bayer AG, Wuppertal-Elberfeld, FRG.
Heimann, K.G. (1987) R 2170 - Study for skin sensitizing effect.
Epicutaneous test on guinea pigs. Institute of Toxicology, Bayer
AG. Unpublished Report No. 16174. Submitted to WHO by Bayer AG,
Wuppertal-Elberfeld, FRG.
Herbold, B. (1989) R 2170 - Cytogenetic testing of the bone marrow
of the Chinese hamster in vivo to check for chromosome damage.
Fachbereich Toxikologie, Bayer AG. Unpublished Report No. 17575.
Submitted to WHO by Bayer AG, Wuppertal-Elberfeld, FRG.
Hoffmann , K. & Rühl, C. (1984) Chronic toxicity to dogs on oral
administration (12-month stomach tube study). Institute of
Toxicology, Bayer AG. Unpublished Report No. 12734. Submitted to
WHO by Bayer AG, Wuppertal-Elberfeld, FRG.
Hoffmann , K. & Rühl-Fehlert, C. (1988) Chronic toxicity to dogs on
oral administration (12-month study by gavage). Institute of
Toxicology, Bayer AG. Unpublished Report No. 12734A addendum to
Report No. 12734). Submitted to WHO by Bayer AG,
Wuppertal-Elberfeld, FRG.
Krötlinger, F. & Janda, B. (1984) R 2170 - Subchronic toxicity
study on rats (3-month feeding experiment). Institute of
Toxicology, Bayer AG. Unpublished Report No. 12797. Submitted to
WHO by Bayer AG, Wuppertal-Elberfeld, FRG.
Krötlinger, F. & Kaliner, G. (1985) R 2170 - Two generation study
with rats Institute of Toxicology, Bayer AG. Unpublished Report
No. 13837. Submitted to WHO by Bayer AG, Wuppertal-Elberfeld, FRG.
Maibach, H.I. (1987) Percutaneous absorption of Metasystox R in the
Rhesus monkey. Mobay Chemical Corporation, Kansas, USA.
Unpublished Report No. 936. Submitted to WHO by Bayer AG,
Wuppertal-Elberfeld, FRG.
Marsh, J.D. (1987) Quantitative characterization of residues in
tissues and eggs of laying hens treated orally for three consecutive
days with Metasystox R. Mobay Chemical Corporation, Kansas, USA.
Unpublished Report No. 94955 (M-5183). Submitted to WHO by Bayer AG,
Wuppertal-Elberfeld, FRG.
Merricks, D.L (1987) 14C-Metasystox R goat metabolism study.
Mobay Chemical Corporation, Kansas, USA. Unpublished Report
No. 94956 (M-5181). Submitted to WHO by Bayer AG,
Wuppertal-Elberfeld, FRG.
Mihail, F. (1984a) Determination of acute toxicity (LD50).
Institute of Toxicology, Bayer AG. Letter of September 25.
Submitted to WHO by Bayer AG, Wuppertal-Elberfeld, FRG.
Mihail, F. (1984b) R 2170 - Determination of acute toxicity to the
rat. Institute of Toxicology, Bayer AG. Unpublished Report
No. 12828. Submitted to WHO by Bayer AG, Wuppertal-Elberfeld, FRG.
Mihail, F. (1985) R 2170 50 VL - Study for skin-sensitizing effect
on guinea pigs. Institute of Toxicology, Bayer AG. Unpublished
Report No. 13194. Submitted to WHO by Bayer AG,
Wuppertal-Elberfeld, FRG.
Mihail, F. (1986) R 2170 50 VL - Study for skin-sensitizing effect
on guinea pigs in the open epicutaneous test. Institute of
Toxicology, Bayer AG. Unpublished Report No. 14402. Submitted to
WHO by Bayer AG, Wuppertal-Elberfeld, FRG.
Pauluhn, J. (1988) R 2170 50 VL 00135/0548 A. Study for acute
inhalation toxicity in the rat in accordance with OECD guideline
No. 403. Bayer AG, Institute of Toxicology. Unpublished Report
No. 16604. Submitted to WHO by Bayer AG, Wuppertal-Elberfeld, FRG.
Putman, D.L. (1987) Dominant lethal mutations in mice. Metasystox
R Technical. Microbiological Associates, Inc., Maryland, USA.
Unpublished Report No. 965. Submitted to WHO by Bayer AG,
Wuppertal-Elberfeld, FRG.
Putman, D.L. (1988a) Sister chromatid exchange assay in Chinese
hamster Ovary (CHO) cells. Microbiological Associates, Inc.,
Maryland, USA. Unpublished Report No. 1004. Submitted to WHO by
Bayer AG, Wuppertal-Elberfeld, FRG.
Putman, D.L. (1988b) Chromosome aberrations in Chinese hamster
Ovary (CHO) cells - Metasystox R. Microbiological Associates, Inc.,
Maryland, USA. Unpublished Report No. 1005. Submitted to WHO by
Bayer AG, Wuppertal-Elberfeld, FRG.
Putman, D.L. (1988c) Dominant lethal mutations in mice. Metasystox
R Technical. Microbiological Associates, Inc., Maryland, USA.
Unpublished Report No. 993. Submitted to WHO by Bayer AG,
Wuppertal-Elberfeld, FRG.
Sheets, L.P. (1988a) Primary dermal irritation of Metasystox R 50%
concentrate in rabbits. Mobay Corporation, Kansas, USA.
Unpublished Report No. 1033. Submitted to WHO by Bayer AG,
Wuppertal-Elberfeld, FRG.
Sheets, L.P. (1988b) Primary eye irritation of Metasystox R 50%
concentrate in rabbits. Mobay Corporation, Kansas, USA.
Unpublished Report No. 1034. Submitted to WHO by Bayer AG,
Wuppertal-Elberfeld, FRG.
Sheets, L.P. (1988c) Acute oral toxicity of Metasystox R Technical
in rats. Mobay Corporation, Kansas, USA. Unpublished Report
No. 1035. Submitted to WHO by Bayer AG, Wuppertal-Elberfeld, FRG.
Sheets, L.P. (1988d) Acute oral toxicity of Metasystox R 50%
concentrate in rats. Mobay Corporation, Kansas, USA. Unpublished
Report No. 1036. Submitted to WHO by Bayer AG, Wuppertal-Elberfeld,
FRG.
Sheets, L.P. (1988e) Acute oral toxicity of Metasystox R 50%
concentrate in rabbits. Mobay Corporation, Kansas, USA.
Unpublished Report No. 1037. Submitted to WHO by Bayer AG,
Wuppertal-Elberfeld, FRG.
Sheets, L.P. (1988f) 21-day dermal toxicity of technical grade
Oxidemeton methyl in rabbits. Mobay Corporation, Kansas, USA.
Unpublished Report No. 1076. Submitted to WHO by Bayer AG,
Wuppertal-Elberfeld, FRG.
Shiotsuka, R.N. (1988) Acute four-hour inhalation toxicity study
with Metasystox R 50% concentrate in rats. Mobay Corporation,
Kansas, USA. Unpublished Report No. 1041. Submitted to WHO by
Bayer AG, Wuppertal-Elberfeld, FRG.
Taalman, R.D.F.M. (1987) Clastogenic evaluation of R 2170 in an in
vitro cytogenetic assay measuring chromosome aberration
frequencies in Chinese hamster ovary (CHO cells. Hazleton
Biotechnologies, The Netherlands. Unpublished Report No. R 4182.
Submitted to WHO by Bayer AG, Wuppertal-Elberfeld, FRG.
See Also:
Toxicological Abbreviations
Demeton-S-methyl and related compounds (WHO Pesticide Residues Series 3)
Demeton-S-methyl and related compounds (Pesticide residues in food: 1984 evaluations)