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    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