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 SULFONE
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOCHEMICAL ASPECTS
Absorption, Distribution and Excretion
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-demeton-S-methyl sulfone. 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. More than
50 percent of the administered radioactivity was eliminated in about
three hours and approximately 90 percent within about 10 hours
following an oral dose of 0.5 or 5 mg/kg. Within 48 hours,
radioactivity excreted in the urine accounted for 97-99 percent of the
administered dose. Faeces accounted for 0.6-2.5 percent and expired
air for less than 0.1 percent. Radioactivity remaining in the body was
about 50 percent of the administered dose at two hours (about 50
percent having been already excreted at that time), about 1 percent at
24 hours, 0.7 percent at 48 hours and 0.27 percent at 10 days. Total
recovered radioactivity in experiments averaged 90-110 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-demeton-S-methyl sulfone was intraduodenally
administered to male rats with bile duct fistulas, about 4 percent of
the administered radioactivity was excreted in the bile within 24
hours.
Blood levels of radioactivity peaked at about 1 hour following
oral administration of 5 mg/kg of the test material. From 0 to 6
hours post-dosing, the blood half-life was calculated to be about two
hours, from 6 to 24 hours to be about 7 hours and after 24 hours to be
considerably longer. Nearly all the radioactivity in the 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 10 days were negligible. Distribution
of radioactivity in various body organs and tissues were relatively
uniform at two hours. Radioactivity did not concentrate in fat tissue
or in the reticuloendothelial system (liver, spleen, bone marrow). By
day two post-administration, radioactivity in most organs and tissues,
except blood and erythrocytes, had dropped 75 fold. At day 10,
radioactivity was nearly undetectable in the majority of organs and
tissues except for lungs, blood and erythrocytes. In a separate
experiment, whole-body autoradiography confirmed previous findings
regarding distribution of radioactivity in body tissues, but also
indicated some localized accumulation or radioactivity in the pineal
gland and in some glands of the genital tract (Cowper's gland, seminal
vescicle, accessory genital gland) (Weber, Patzschke and Wegner,
1978).
Biotransformation
Urine samples from male Sprague-Dawley rats given single oral
administrations of 10 mg/kg of 14C-demeton-S-methyl sulfone were
subjected to chemical analyses to identify and quantitate unchanged
parent and metabolites. Zero to 8 hour and 8 to 24 hour urine samples
used in this study were collected from four rats utilized in the study
by Weber, Patzschke and Wegner in 1978. Approximately 90 percent of
the administered radioactivity was recovered in the urine within eight
hours and an additional 5 percent by 24 hours. Compounds were
separated by thin layer chromatography and high-pressure liquid
chromatography. Radioactivity was assayed by several counting
techniques. Mass spectroscopy in conjunction with chemical synthesis
was used to identify the main metabolite. This metabolite was
determined to be methyl sulfinyl-2-ethyl sulfonyl ethane, which is
presumably formed after cleavage of the O-methyl-phosphoric ester
group, methylation and sulfoxidation of the methyl thioether group.
Identities and percentages of total radioactivity in the 0-8 hour
urine sample were as follows: demeton-S-methyl sulfone (unchanged
parent compound), 30 percent O-demethyl-demeton-S-methyl sulfone, 20
percent; and methyl sulfinyl-2-ethyl sulfonyl ethane, 40 percent. The
remaining unknown metabolites each accounted for less than 5 percent
of the total radioactivity. The 8-24 hour urine samples, from the same
rats as the 0-8 hour sample, showed the same distribution of parent
compound and metabolites, but with a considerably lower radioactivity
content (Ecker and Wunsche, 1980).
Effects on Enzymes and Other Biochemical Parameters
Aqueous solutions of technical grade demeton-S-methyl sulfone
were dermally applied on foam rubber pads to the shorn backs of giant
Chinchilla rabbits for single 24 hour exposures at dosage levels of
500 and 50 mg/kg/day. At 500 mg/kg, plasma and erythrocyte
cholinesterase activities were decreased for at least seven days. At
50 mg/kg, cholinesterase activities were unaffected. When dermally
applied for four consecutive exposures of 24 hours each at dosage
levels of 50 and 10 mg/kg/day, a decrease in plasma cholinesterase
activity persisted at least five days after the end of treatment. A
decrease in erythrocyte cholinesterase activity, present at the end of
treatment, was not as pronounced, and recovered to the control level
by five days after the end of treatment. When dermally applied to five
male and five female rabbits per group for 14 consecutive exposures of
24 hours each at dosage levels of 0 (control) and 2.5 mg/kg/day,
plasma and erythrocyte cholinesterase activities were unaffected by
the treatments. In addition, no differences were observed between
treated and control animals in appearance, behaviour or body weights.
Minimal haematology, clinical chemistry and urinalysis laboratory
determinations also indicated no differences between treated and
control animals (Kimmerle and Solmecke, 1972).
TOXICOLOGICAL STUDIES
Acute Toxicity
Acute oral LD50s were determined for seven production batches of
demeton-S-methyl sulfone (E 158, M 3/158, purity approximately 97.7
percent). In studies on non-fasted male rats, LD50s ranged from 37 to
44 mg/kg. In another study on fasted male rats, the LD50 was 23 mg/kg
(Mihail, 1980; Mihail, 1981).
Short-term studies
Dog
Demeton-S-methyl sulfone (e 158, M 3/158, assayed purity 100.3
percent) was incorporated in feed at concentrations of 0 (control), 1,
5 and 25 ppm and presented to 17-21 week old thoroughbred Beagle dogs
for 13 weeks. Based on diet analyses, food consumption and body
weights determined during the study, the mean dosage levels were
calculated to be 0 (control), 0.3, 1.5 and 7.4 mg/kg/day. Each group
consisted of four male and four female dogs. Appearance and behaviour
were checked several times per day. Body weights were recorded weekly.
Examinations for reflexes and ophthalmoscopic effects were conducted
before and during the study at 6 and 12 weeks. Standard haematology,
clinical chemistry and urinalysis examinations were performed on the
same days. Plasma and erythrocyte cholinesterase activities were
performed before and during the study at weeks 2, 4, 7, 10 and 13.
Brain cholinesterase activity was determined at termination of the
study. Gross necropsies were performed on all dogs. Organ weights were
recorded for brain, heart, lung, liver, spleen, kidneys, thymus,
pancreas, testes, prostate, ovaries, pituitary, thyroid and adrenals.
Histopathological examination was performed on 13 major organs and
tissues of all dogs. Thirteen additional organs and tissues were
microscopically examined only from dogs in the control and 25 ppm
groups.
One 25 ppm female dog was sacrificed in week 11 of the study due
to a severe acute infection which developed in its right chin during
week 10 and which increased rapidly in size to "child's fist size".
The large abscess prevented the dog from eating. This animal's death
was not attributed to the test material. There were no other
mortalities during the study. Appearance and behaviour were normal in
all dogs at all times during the study. Reflex and ophthalmoscopic
examinations were negative. Food and water consumptions were
equivalent in treated and control male and female groups respectively.
Mean body weights were comparable at all times during the study
between treated and control male and female groups respectively.
Haematology, clinical chemistry and urinalysis examinations indicated
no alterations attributable to the test material. Plasma
cholinesterase activity levels were significantly decreased in 25 ppm
male dogs from week two to termination of the study and in 25 ppm
female dogs from week 7 to termination of the study. Decreases in
erythrocyte cholinesterase activity were more pronounced than in
plasma. Statistically significant decreases were reported in both male
and female 25 ppm groups from week 4 to termination of the study and
also in 5 ppm male dogs from week 9 to termination of the study. Brain
cholinesterase activity was unaffected in male dogs, but was
significantly decreased in 25 ppm female dogs. Gross necropsies
revealed a few minor alterations commonly seen in dogs of comparable
ages. Organ weights and organ/body weight ratios suggested possibly
increased thyroid weights in 25 ppm male dogs, possibly increased
heart weights in 25 ppm female dogs. None of the organ weight changes,
however, were likely to be biologically meaningful since no supporting
histopathological lesions were observed. Microscopic examination of
organs and tissues indicated no lesions attributable to the test
material. Observed lesions were of types often seen in dogs of
comparable ages and were randomly observed in all groups. The
cholinesterase NOEL for this study is 1.0 ppm (equal to
0.3 mg/kg/day). The NOEL for somatic effects is 25 ppm (equal to
7.4 mg/kg/day) (Hoffman, Luckhaus and Dycka, 1975).
Special Studies on Teratogenicity
Rat
Previously inseminated BAY:FB 30 strain rats were given orally by
stomach tube on days 6 to 15 of gestation E 158 (demeton-S-methyl
sulfone, purity 97.7 percent) at dosage levels of 0 (control), 0.3,
1.0 and 3.0 mg/kg/day. Each group contained 25 rats. Dams were
observed daily for appearance and behaviour and were weighed several
times during gestation. Following caesarean section on gestation day
20, numbers of implantations, implantation losses and live and dead
foetuses were determined. Placentas were weighed. Foetuses were
weighed, sexed and examined for external malformations. Approximately
30 percent of the foetuses were examined for visceral malformations by
a modification of Wilson's technique and the remainder for skeletal
alterations by the Alizarin Red S technique.
There were no mortalities or abnormalities in appearance or
behaviour noted in the control, 0.3 or 1.0 mg/kg/day dosage level
groups. In the 3.0 mg/kg/day group, all dams showed toxic effects
consisting of tremor, high respiration rate, protusio bulbi, passing
of hard stools and/or hollow flanks. Mean body weights were
significantly (p < 0.01) decreased in 1.0 mg/kg/day dams during
gestation days 6 to 15 and in 3.0 mg/kg/day dams during gestation days
6 to 15 and also during the entire gestation period. The numbers of
dams delivering litters were 21, 22, 19 and 22 for the control, low-,
mid- and high-dosage groups respectively. No significant differences
between control and treated groups were noted for numbers of
implantations, implantation losses or live and dead foetuses. Placenta
weights, foetal weights and foetal sex ratios in treated groups were
comparable to those of the control group. Numbers of stunted foetuses
(less than 3 grams) were 0/248, 0/279, 1/234 and 6/262 for the
control, low-, mid- and high-dosage groups respectively. In units of
mean numbers of stunted foetuses per litter, the respective incidences
were 0.00, 0.00, 0.05 and 0.27. This malformation was observed in 1/19
litters in the 1.0 mg/kg/day group and in 3/22 litters in the
3.0 mg/kg/day group. Historical control data presented in the study
report expressed as numbers of dams with stunted foetuses in each of
30 control groups, indicated the incidence in this study (up to 3/22)
to be within the normal range of variation. No historical control data
was presented, however, in which numbers of affected foetuses were
indicated. [Note - in view of the causative relationship between
oxydemeton-methyl and this same malformation in the study by Machemer,
1979, the increased incidence of stunted foetuses in this study should
be considered as possibly related to the test material]. Other
visceral and skeletal malformations in foetuses in this study were few
and not related to the test material. In particular, there were no
hypoplasias of the cerebral hemisphere noted for any of the foetuses
in this study. [Note - there was a causative relationship established
between oxydemeton-methyl and this malformation in the study by
Machemer, 1979]. The numbers of foetuses with skeletal variations in
treated groups were comparable to control levels (Roetz, 1982).
Rabbit
E 158 (demeton-S-methyl sulfone, purity 97.7 percent) was
administered by gavage to mated Chinchilla Hybrid rabbits on
gestation days 6 to 18 at dosage levels of 0 (control), 0.5, 1.0 and
2.0 mg/kg/day. Dosage levels were selected after a preliminary study
in which animals similarly treated with 3.0 and 6.0 mg/kg/day
displayed diarrhoea, decreased body weights, decreased food
consumption and mortalities. Each group consisted of 16 rabbits. The
dams were observed two times daily for mortality, appearance and
behaviour. Body weights were recorded daily and food consumption was
determined six times during the study. Caesarean sections were
performed on gestation day 28. Dams were necropsied for gross changes
and special attention was given to ovaries and particularly to uterine
contents. All foetuses were counted, weighed, sexed, inspected
externally and then subjected to thorough and comprehensive visceral
and skeletal examinations.
There were no mortalities. Appearance and behaviour were normal
in all animals in all groups at all times. There were no meaningful
differences in body weights or food consumption between treated groups
and the control group throughout the entire study. The numbers of
litters examined were 15, 15, 16 and 16 in the control, low-, mid- and
high-dosage groups respectively. One animal in the control group and
one in the 0.5 mg/kg/day group had no implantations. There were no
abortions. Regarding reproductive parameters, there were no relevant
differences between test and control groups in the numbers of
implantations per dam, pre-implantation losses, post-implantation
losses, resorptions, living and dead foetuses or sex ratios. The
numbers of foetuses examined were 134, 120, 140 and 143 in the
control, low-, mid- and high-dosage groups respectively. There were no
relevant differences in foetal body weights. External and visceral
examinations revealed no findings in any group. Similarly, skeletal
examinations revealed no relevant findings in any group. Isolated
instances of irregular ossified sternebrae and other minor skeletal
variations occurred randomly across all groups. No embryotoxic or
teratogenic potential was observed in the rabbits in this study at
dosage levels up to 2.0 mg/kg/day (Becker, 1983).
Special Studies on Mutagenicity
For the results of mutagenicity studies see Table 1.
Comments
Demeton-S-methyl sulfone was rapidly and nearly completely
absorbed in rats following oral administration. More than 50 percent
of single doses was excreted within three hours and 90 percent within
about ten hours. By 48 hours, only 0.7 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 (30 percent), O-demethylated parent
compound (20 percent) and methyl sulfinyl-2-ethyl sulfanyl ethane
(40 percent). Two unknown metabolites each accounted for less than
5 percent.
In a 13-week dietary feeding study in dogs, the NOEL for
erythrocyte cholinesterase depression was 1 ppm (equal to
0.3 mg/kg/day), and for plasma and brain was 5 ppm (equal to
1.5 mg/kg/day). No other effects attributable to demeton-S-methyl
sulfone were observed at dosage levels up to 25 ppm (equal to
7.4 mg/kg/day).
In a teratology study on rats, the incidence of stunted foetuses
was increased at the highest dosage level of 3.0 mg/kg/day. Although
historical control data presented in the study report indicated the
observed incidence to be within the normal range of variation, in view
of the causative relationship between oxydemeton-methyl and this same
malformation also in rats (Machemer, 1979), the increased incidence of
stunted foetuses in this study should be considered as possibly
related to the test material. At the same dosage level, maternal
toxicity, including cholinergic signs of poisoning and decreased mean
body weights, was also observed. A teratology study in rabbits at
dosage levels up to 2.0 mg/kg/day did not demonstrate embryotoxic,
foetotoxic or teratogenic effects.
Mutagenicity studies on demeton-S-methyl sulfone were equivocal
in a number of in vitro tests, but were negative in in vivo tests.
FURTHER WORK OR INFORMATION NEEDED BEFORE AN ADI CAN BE ESTABLISHED
Required:
Reproduction study.
Long-term feeding study in rodents.
6-month or longer feeding study in dogs.
Desirable:
Observations in humans.
REFERENCES
Becker, H. Embryotoxicity and teratogenicity study on E 158
1983 (Demeton-S-methyl-sulphon) in rabbits. Research and
Consulting Company Ltd. Itingen, Switzerland. Report No. R.
2444. Submitted by Bayer AG to WHO.
DeGraff, W.G. Mutagenicity evaluation of E 158 batch 808 108 117,
1983 Content 98.5% (Demeton-S-methylsulphon) in the reverse
mutation induction assay with Saccharomyces cerevisiae
strains S 138 and S 211 (Revised Final Report). Kensinton,
MD. Litton Bionetics, Inc. LBI Project No. 20998, Report No.
R 2417. Submitted by Bayer AG to WHO.
Ecker, W. and Wunsche, C. Biotransformation of [ethylene-1-14C]
1980 Demeton-S-methyl sulphone (Metaisosystox-sulphone active
ingredient) in rats. Bayer AG, Institute for
Pharmacokinetics. PF Report No. 1485, Pharma Report No.
9604. Submitted by Bayer AG to WHO.
Herbold, B. M 3/158 (E 158; Demeton-S-methylsulfon)/Dominant-Lethal
1980a Test an der männlichen Maus zur Prüfung auf mutagene
Wirkung. Bayer AG, Institute for Toxicology. Report No.
9612. Submitted by Bayer AG to WHO (in German).
Herbold, B. M 3/158 (E 158; Demeton-S-methylsulfon):
1980b Salmonella/Mikrosomen-Test zur Untersuchung auf
punktmutagene Wirkung. Bayer AG, Institute for Toxicology.
Report No. 9169. Submitted by Bayer AG to WHO (in German).
Herbold, B. M 3/158 (eE 158; Demeton-S-methylsulfon): Mikronucleus-
1981 Test an der Maus zur Prüfung auf mutagene Wirkung. Bayer AG,
Institute for Toxicology. No. 10261. Submitted by Bayer AG
to WHO (in German).
Hoffman, K., Luckhaus, G. and Dycka, J. M 3/158 (Metaisosystoxy-
1975 sulphone): subchronic toxicity study on dogs with
administration in the feed (13 week study). Bayer AG,
Institute for Toxicology. Report No. 5355. Submitted by
Bayer AG to WHO.
Kimmerle, G. and Solmecke, B. Metaisosystox-sulphone sub-acute dermal
1972 application to rabbits. Bayer AG, Institute for Toxicology.
Report No. 3351. Submitted by Bayer AG to WHO.
Machemer, L. R. 2170 (Oxydemeton-methyl; active ingredient of
1979 metasystox R): evaluation for embryotoxic and teratogenic
effects in orally dosed rats. Bayer AG, Institute for
Toxicology. Report No. 8436. Submitted by Bayer AG to WHO.
Mihail, F. Determination of acute toxicity (LD50). Bayer AG, Institute
1980 for Toxicology. Submitted by Bayer AG to WHO
Mihail, F. Determination of Acute Toxicity (LD50). Bayer AG, Institute
1981 for Toxicology. Submitted by Bayer AG to-WHO.
Roetz, R. E 158 (Demeton-S-methylsulphon, Metaisosystox-sulphon):
1982 study for embryotoxic effects on the rat after oral
administration. Bayer AG, Institute for Toxicology. Report
No. 11234. Submitted by Bayer AG to WHO.
Weber, H., Patzschke, K. and Wegner, L.A. [14C] Demeton-S-methyl-
1978 sulphone: Biokinetic studies on rats. Bayer AG, Institute
for Pharmacokinetics. Report No. 7558. Submitted by Bayer AG
to WHO.
See Also:
Toxicological Abbreviations