<b>Bijsluiter</b>. De hyperlink naar het originele document werkt niet meer. Daarom laat Woogle de tekst zien die in dat document stond. Deze tekst kan vreemde foutieve woorden of zinnen bevatten en de opmaak kan verdwenen of veranderd zijn. Dit komt door het zwartlakken van vertrouwelijke informatie of doordat de tekst niet digitaal beschikbaar was en dus ingescand en vervolgens via OCR weer ingelezen is. Voor het originele document, neem contact op met de Woo-contactpersoon van het bestuursorgaan.<br><br>====================================================================== Pagina 1 ======================================================================

<pre>Methyl-S-demeton
(CAS No: 919-86-8)
Health-based Reassessment of Administrative Occupational Exposure Limits
Committee on Updating of Occupational Exposure Limits,
a committee of the Health Council of the Netherlands
No. 2000/15OSH/072, The Hague, 22 september 2003
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. Methyl-S-demeton; Health-based Reassessment of
Administrative Occupational Exposure Limits. The Hague: Health Council of the
Netherlands, 2003; 2000/15OSH/072.
all rights reserved
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of methyl-S-
      demeton by the Committee on Updating of Occupational Exposure Limits, a
      committee of the Health Council of the Netherlands. The first draft of this
      document was prepared by JAGM van Raaij, Ph.D. and WK de Raat, Ph.D.
      (OpdenKamp Registration & Notification, Zeist, the Netherlands) and J Krüse,
      Ph.D. (Kinetox, Vleuten, the Netherlands).*
          The evaluation of the toxicity of methyl-S-demeton has been based on
      reviews published in the ‘Handbook of pesticide toxicology’ (Gal91) and by the
      American Conference of Governmental Industrial Hygienists (ACG99). Where
      relevant, the original publications were reviewed and evaluated as will be
      indicated in the text. In addition, in December 1999, literature was searched in
      the on-line databases Toxline, Medline, Chemical Abstracts, covering the period
      of 1964-1966 until December 1999, and using the following key words: methyl
      demeton and 919-68-8. Data from unpublished studies were generally not taken
      into account. Exceptions were made for studies that were summarised and
      evaluated by international bodies such as the Food and Agricultural
      Organization/World Health Organization (FAO/WHO: Joint Meeting of the FAO
      Panel of Experts on Pesticides Residues on Food and the Environment and the
      WHO Expert Group on Pesticides Residues - JMPR) (FAO90, WHO85) and the
      International Programme on Chemical Safety/World Health Organization (IPCS/
      WHO) (WHO97).
          The early commercial methyl demeton consisted of methyl-S-demeton and
      methyl-O-demeton in a ratio of 30:70. From 1957 onwards, this ‘methyl
      demeton’ was replaced by a product without methyl-O-demeton. The assessment
      was, therefore, focussed on methyl-S-demeton; studies with the older ‘methyl
      demeton’ were not taken into account; only studies carried out after 1957 were
      included in the assessment. No assessment is made of oxodemeton-methyl, a
      metabolite of methyl-S-demeton, which is used as an insecticide in itself.
          In October 2002, the President of the Health Council released a draft of the
      document for public review. Comments were received from the following
      individuals and organisations: J Soave (Health and Safety Executive, London,
      England).
          An additional search in Toxline and Medline in April 2003 did not result in
      information changing the committee’s conclusions.
*     Current address: Opdenkamp Registration and Notification, Zeist, the Netherlands.
072-3 Methyl-S-demeton
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<pre>2     Identity
      name                   :   methyl-S-demeton
      synonym                :    phosphorothioic acid O,O-dimethyl S-[2-(ethylthio)ethyl] ester; S-(2-ethylthioet-
                                 hyl) O,O-dimethyl phosphorothioate; O,O-dimethyl S-2-(ethylthio)ethyl phospho-
                                 rothioate; O,O-dimethyl-S-2-ethylmercaptoethyl phosphorothioate; demeton-S-
                                 methyl; metasystox; meta-isosystox; isomethylsystox; methyl-mercaptophos
      molecular formula      :   C6H15O3PS2
      structural formula     :
      CAS number             :   919-86-8
      No consistent nomenclature is used in the open literature. Studies on methyl-S-
      demeton should not be confused with studies on methyl demeton (30:70 mixture
      of S- and O-isomers) or studies on oxydemeton-methyl (a metabolite of methyl-
      S-demeton). The CAS registry numbers of methyl demeton, oxydemeton-methyl
      (metasystox R) or methyl-S-demeton are not always correctly cited in scientific
      publications.
3     Physical and chemical properties
                                   methyl-S-demeton                     methyl-O-demeton
      molecular weight         :   230.29                               230.29
                                                       o
      boiling point            :   at 0.052 mm Hg: 89 C                 at 0.15 mm Hg: 74oC
      melting point            :   -                                    -
      flash point              :   -                                    -
      vapour pressure          :   at 20oC: 0.04 Pa                     -
                                                 o
      solubility in water      :   soluble (at 20 C: 22 9/100 mL        insoluble (33 mg/100 mL)
      Log Poctanol/water       :   at 20oC: 1.32
      Conversion factors       :   not applicable
      Data from ACG99, Gal91, NLM02, Rob99, Tom97.
072-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      Technical-grade methyl demeton is a mixture of the O-isomer and the S-isomer
      in a ratio of approximately 70:30. The purified S-isomer was introduced in 1957
      and after some time, it replaced the mixture because it was found to be more
      toxic to insects than the O-isomer. The S-isomer is a pale yellow oily liquid with
      an unpleasant odour.
          Methyl-S-demeton rapidly hydrolyses after contact with alkaline substances.
      Under acidic and neutral circumstances methyl-S-demeton is more slowly
      hydrolysed (Tom97). Methyl-S-demeton is oxidised to the sulphoxide
      (oxydemeton-methyl) and eventually to the sulphone (demeton-S-methyl
      sulphone) before it finally decomposes. Furthermore, several sulphonium
      compounds of variable stability can be found, which are known to be strong
      inhibitors of ChE activity (ACG99, Hea57). The final toxicity of the methyl
      demeton formulations may depend on formation of these impurities during
      storage (Gal91, Mei90).
4     Uses
      Methyl-S-demeton is applied as insecticide and acaricide for control of aphids,
      mites, and whiteflies on fruit, vegetables, potatoes, beet and hops (Tom97).
          According to the database of the Dutch Pesticide Authorisation Board (CTB),
      methyl-S-demeton is at present not registered for its use as an active ingredient in
      pesticides in the Netherlands.
5     Biotransformation and kinetics
      Methyl-S-demeton absorbs into the human body through the intact skin (Red68),
      from the gastro-intestinal tract (Sch88), or by inhalation of spray mist (Heg65,
      Kli58). The committee did not find quantitative data on inhalation or dermal
      absorption of the compound in humans or experimental species.
          The kinetics of methyl-S-demeton were studied by administration of single
      oral doses of 14C-labelled compound of 0.1, 0.5, 5, or 10 mg/kg bw or single
      intravenous doses of 0.5 or 1.0 mg/kg bw to male and single oral doses of 0.5
      mg/kg bw to female Sprague-Dawley rats (n=5/sex/group). Total recovery of
      radioactivity was 99-100% in each animal. The authors reported that test results
      were largely independent of dose level, administration route, and sex of the
      animals, and presented, therefore, mainly data on male rats receiving a dose of 5
      mg/kg. The test material was very rapidly and almost completely absorbed. The
      blood concentration peaked at about one hour following administration, and
072-5 Methyl-S-demeton
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<pre>      decreased thereafter with half-lives of 2, about 6, and considerably longer than 6
      hours during the first 6 hours, the next 48 hours, and thereafter, respectively.
      Nearly all the radioactivity in blood after 24 hours was accounted for by a high
      retention in erythrocytes, serum radioactivity levels being low. More than 50%
      and approximately 90% of the radioactivity administered were eliminated within
      about 3 and 8 hours following administration, respectively. Forty-eight hours
      after dosing, radioactivity excreted in urine, faeces, and exhaled air accounted for
      98-99, 0.5-2.0, and 0.2% of the amount administered, respectively. The half-life
      of urinary elimination was 2-3 h during the first 24 hours and 1.5 days thereafter.
      Except for erythrocytes, radioactivity was distributed rather uniformly in various
      body tissues and organs and did not concentrate in fat tissue or in the
      reticuloendothelial system (liver, spleen, bone marrow). The radioactivity
      remaining in the body was about 60%, 1%, and 0.5% of the administered dose at
      2, 24, and 48 hours after dosing, respectively. At 10 days, radioactivity was
      nearly undetectable in most organs and tissues except in the erythrocytes. In a
      separate experiment, whole-body autoradiography confirmed these findings
      regarding distribution of radioactivity but also indicated some localised
      accumulation in the pineal gland, thyroid, and some genital tract glands
      (Cowper’s gland, seminal vesicle, accessory genital gland). When a dose of 0.5
      mg/kg bw was administered into the duodenum of rats with cannulated bile
      ducts, about 3% of the radioactivity was excreted in the bile within 24 hours
      (Web78). Analysis of urine sampled from those rats 8 or 24 hours after
      administration of a single oral dose of 5 or 10 mg/kg bw of 14C-labelled methyl-
      S-demeton showed almost complete metabolism. The main route was oxidation
      of the side chain to the corresponding sulphoxide (58%), and further oxidation to
      the sulphone (6%). Another route involved O-demethylation resulting in the
      formation of O-demethyl-methyl-S-demeton (6%) and the corresponding
      sulphoxide (6%) and sulphone (4%). Finally, 2 other metabolites, probably the
      result of cleavage of the O-methylphosphoric ester group and subsequent
      methylation and sulphoxidation, were identified as methyl sulphinyl-2-ethyl
      sulphinyl ethane (8.4%) and methyl sulphinyl-2-ethyl sulphonyl ethane (10.4%).
      One other metabolite accounting for less than 1% of the radioactivity
      administered was not further investigated. There were no indications for the
      presence of glucuronide or sulphate conjugates (Eck78, Eck83).
          Hydrolysis leads to the formation of dimethyl phosphate. The analysis of the
      metabolite O,O-dimethylphosphorothioate (DMPT) has been shown to be a good
      indicator for the occupational exposure to demeton-S-methyl (Vas87).
072-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>6     Effects and mechanism of action
      Human data
      Ingestion of 50 to 500 mg methyl-S-demeton/kg bw resulted in acute
      cardiovascular collapse and death 83 hours after exposure (Gos84). Another case
      involved a 65-year-old man who died following ingestion of approximately 15
      mL of a mixture of methyl-S-demeton (25% w/w) and benzene methylchloride.
      The subject developed severe signs of poisoning such as perspiration, pulmonary
      discharge, and other characteristic symptoms of organophosphorus intoxication
      32 hours after exposure. Acute pulmonary embolism was responsible for his
      death. It is unclear from this study to which extent benzene methylchloride
      contributed to the toxic effects (Bar64). A farmer who drunk about 90 mL of an
      old type formulation in which 70% of the active ingredient was present as
      methyl-O-demeton, developed nervous excitation, salivation, coughing of
      mucus, and muscle fasciculations. Gastric lavage in hospital improved his
      condition (UKM69). Headaches, nausea, and dizziness were observed in a
      farmer 2 weeks after he started handling/spraying methyl-S-demeton
      (‘metasystox new formula’). He was exposed to the chemical on at least 23
      occasions for periods varying from 20 minutes to 6¾ hours, and was mostly
      engaged with flagging during aerial spraying but also in the preparation of the
      formulation. Clinical signs and symptoms of intoxication gradually increased,
      and he collapsed while using another organophosphorus pesticide. Serum ChE
      activity was depressed by 90%. Following treatment with atropine, he fully
      recovered. The author suggested that absorption through the skin contributed to
      the toxic effects of methyl-S-demeton and that the acute exacerbation of the
      symptoms were possibly the result of inhalation of the chemical (Red68). A
      2-year-old boy who ingested 10 mL methyl-S-demeton was admitted to the
      hospital and treated with atropine and obidoxime for 5 days. Clinical signs and
      symptoms were excessive salivation, vomiting, bronchial hypersecretion,
      muscarinic effects on pulse rate and pupil size, and slight bradycardia. Initial
      values of plasma-ChE concentrations were depressed by 90%, but returned to
      baseline levels 8 days after admission to the hospital (Rol98).
          Lethal suicidal intoxication with methyl-S-demeton has been reported for a
      man who deliberately ingested an estimated amount of 5 g of the chemical.
      Chromatographic analysis of various body tissues revealed that the
      concentrations of methyl-S-demeton varied from 7 mg/kg in the liver to 165.3
072-7 Methyl-S-demeton
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<pre>      mg/kg in the upper intestinal tract. A remarkably high concentration of methyl-S-
      demeton was observed in the liquor (83.8 mg/L) when compared with heart
      blood (16.1 mg/L) (Sch88).
           One field study has been reported in which the health implications following
      application of methyl-S-demeton were assessed. The study dealt with a number
      of sprayers and bystanders who had been exposed occupationally or accidentally
      to the chemical during cotton spraying. Serum ChE activity was measured
      following the onset of toxic signs and symptoms. At day one after the signs of
      intoxication, serum ChE activity was inhibited in 25 sprayers by 64% when
      compared to the average activity in 53 control persons. Recovery to normal
      values occurred 21 days after the intoxication. ChE activity in bystanders was not
      changed. The main signs of toxicity in the accidentally exposed bystanders
      included drowsiness, vomiting, and abdominal pain. These symptoms were also
      observed in the occupationally exposed sprayers, who further showed diarrhoea,
      nausea, fatigue, headache, respiratory problems, salivation, and lachrymation. A
      correlation between serum ChE levels and symptomatology was found for
      sprayers but not for bystanders (Heg65). Two groups of 2 human volunteers
      applied metasystox (a 30:70 mixture of the S- and O-isomers) in greenhouses for
      5 consecutive days, 5 hours/day. No significant changes were found in serum
      ChE or red blood cell AChE activities. Two different types of spray equipment
      were used. The average airborne concentrations were 1.9 mg/m3 and 0.28 mg/m3.
      Haemoglobin, erythrocyte count, and lymphocyte count were not altered.
      However, a marked increase (400%) in mean reticulocyte count was observed
      (Kli58).
      Animal data
      Irritation and sensitisation
      Following instillation of 0.1 mL of a 0.5% aqueous solution of a commercial
      formulation of methyl-S-demeton (50% active ingredient) into the eyes of New
      Zealand white rabbits (n=3) for 24 hours, no signs of irritation were observed.
      Instillation of undiluted test substance caused severe lachrymation and miosis on
      application. Mild corneal opacity and discrete redness and oedema of
      conjunctivae were observed and recovered in about 7 days (Flu83). Testing a ca.
      50% solution in xylene showed slight eye irritation in rabbits but this was
      attributed to xylene (Thy81).
072-8 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      Occluded application of 0.5 mL of a similar formulation to the shaved skin of
      New Zealand white rabbits (n=3) for 4 hours caused mild erythema and oedema,
      which generally disappeared within 3 days (Flu83). Testing a ca. 50% solution in
      xylene showed slight skin irritation in rabbits but this was attributed to xylene
      (Thy81).
          In a Magnusson-Kligman maximisation test, 20/20 guinea pigs reacted
      positively to a the first challenge with a 10% solution of methyl-S-demeton
      (purity: 96.3%), after a intradermal induction with a 0.1% solution, and 16/20 to
      a second challenge with a 1% solution vs. 4/10 and 3/10 positive reactions in
      controls, respectively (Hei87a). When testing methyl-S-demeton (purity: 95.6%)
      in the Buehler epidermal patch test on 12 guinea pigs (topical induction with a
      10% solution, once a week, for 3 weeks; 1st challenge: 10% solution; 2nd
      challenge: 20% solution), there were no indications for a skin-sensitising
      potential of methyl-S-demeton (Hei87b).
      Acute toxicity
      Four-hour LC50 values for methyl-S-demeton in rats were 500 (sex not
      specified), 310 (male Wistar), and 210 mg/m3 (female Wistar) (Flu83, NIO02).
      The dermal LD50 value for undiluted methyl-S-demeton in male rats was 250
      mg/kg bw (Dub62) while values ranging from about 10 (25% formulation) to
      100-200 (‘technical’) mg/kg bw were listed as well for rats (WHO97). Oral LD50
      values in rats were between 33 and 129 mg/kg bw (WHO97).
          Hens, given 2 oral doses of 100 mg/kg bw methyl-S-demeton (about the LD50
      value) with a 21-day interval, and atropinised to survive, did not show nerve
      injury. No organophosphate-induced delayed polyneuropathy (OPIDN) was
      observed in the animals (Flu88a). In another study, neuropathy target esterase
      (NTE), an enzyme which may be predictive for delayed polyneuropathy, was not
      inhibited in hen brain and spinal cord 1, 2, and 7 days after treatment with an oral
      dose of 80 mg/kg bw (Flu88b).
      Subchronic toxicity
      In a one-year study, dogs (n=6/sex/group) were fed diets containing 52.2%
      methyl-S-demeton in xylene at dose levels equivalent to 0, 0.036, 0.36, or 3.6
      mg/kg bw/day. From week 37 onwards, the concentration in the high-dose group
      was reduced to 1.8 mg/kg bw/day. No mortality was reported. Clinical signs
      (vomiting, diarrhoea) were most frequently seen in the high-dose group.
072-9 Methyl-S-demeton
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<pre>       Reduced food intake occurred in the high-dose group before dosage reduction.
       Body weights were not affected in any of the groups. Abnormalities were neither
       detected in haematological and clinical chemical parameters, nor in organ
       weights and gross examination at termination. Hepatic cytochrome P450 and N-
       demethylase activity were not altered by the treatment. However, hypertrophy of
       the proximal tubules was observed in 3 males and 3 females of the high-dose
       group. Brain AChE activity was suppressed by 64% in the males and by 15% in
       the females of the high-dose group when compared to their control counterparts;
       red blood cell AChE by 80-90% and 55-65% in males and females, respectively,
       and plasma ChE by 45-65% (males) and 50-70% (females). In the mid-dose
       group, brain AChE activity was suppressed when compared to controls by 25%
       in males. Red blood cell AChE activity was also reduced by 25-35% in males
       and by 30-45% in females, and plasma ChE by 20-30% in males and by 5-20%
       in females. The one-year dog NOAEL for brain and red blood cell AChE
       inhibition was 0.036 mg/kg bw (Bat83).
       Chronic toxicity and carcinogenicity
       In a 2-year study with Wistar rats (n=60/sex/group), the animals were given
       methyl-S-demeton (50% in xylene) in dietary concentrations equivalent to 0,
       0.05, 0.35, or 2.5 mg/kg bw/day. Rats in the control group were given xylene at a
       concentration of 2.5 mg/kg bw. Clinical signs (hair loss, diarrhoea) were
       observed in the high-dose group. Clinical chemical and haematological
       parameters were not affected by the treatment. Histological examination did not
       reveal an increased incidence of neoplastic lesions in treated groups. Retinal
       atrophy and keratitis were observed in animals of both sexes given 2.5 mg/kg bw.
       Red blood cell AChE activity was reduced at 0.35 mg/kg bw (by 12-31%) and
       2.5 mg/kg bw (by 20-44%) from the third month onwards. AChE activity in the
       brain was reduced by 67-75% in the high-dose group and by 15-47% in the mid-
       dose group. The 2-year rat NOAEL for inhibition of brain and red blood cell
       AChE activity was 0.05 mg/kg bw/day (Sch88b).
           In a 21-month study, groups of NMRI mice (n=70/sex/group) were fed
       methyl-S-demeton (50% in xylene) at levels equivalent to 0, 0.25, 3.75, or 18.75
       mg/kg bw/day. The control group was fed xylene at a dose of 18.75 mg/kg bw in
       the diet. No clinical signs of cholinesterase inhibition were observed. Food
       intake and body weight were reduced in the high-dose group. Clinical chemical
       and haematological parameters were not affected by the treatment, except plasma
       urea that was lower in the high-dose males. Histopathology did not reveal an
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<pre>       increased incidence of tumours and of non-neoplastic lesions. At the 2 highest
       dose levels, red blood cell AChE activity was reduced up to 70% in males and
       38% in females. The 21-month mouse NOAEL for inhibition of brain and red
       blood cell AChE activity was 0.25 mg/kg bw/day (Sch88a).
       Mutagenicity and genotoxicity
       In vitro, methyl-S-demeton (purity: not known) induced reverse gene mutations
       in S. typhimurium strains TA1530 and TA1535, but not in several other strains,
       such as TA1531, TA1532, TA1534, hisC117, and hisG46 (tests without
       metabolic activation only) (Han75). Tested both with and without metabolic
       activation, methyl-S-demeton (purity: >98%) was positive in S. typhimurium
       strains TA100 and TA1535 and negative in strains TA98 and TA100 (Her80a)
       while an overall positive result was reported for a 50.2% formulation using the
       same 4 strains (Her79). Testing in several E.coli strains without metabolic
       activation resulted in positive results in strain WP2 uvrA only (not tested with
       metabolic activation) (Han75). Methyl-S-demeton as a 53% formulation in
       xylene did not induce mutations in S. cerevisiae strains S138 and S211a when
       tested in the presence or absence of an S9 mix (Hoo83). The chemical induced
       recessive-lethal mutations in D. melanogaster (Han75). A test for forward gene
       mutations in cultured mouse lymphoma L5178Y cells was positive at doses of
       50-500 µg/mL in the presence and absence of metabolic activation (Cif84).
           Methyl-S-demeton (purity: 93%) was negative when tested with and without
       metabolic activation the E. coli polA (W3110/p3478) assay, a test indicative for
       DNA damage (Her83a).
       In vivo, in NMRI mice, methyl-S-demeton (purity: >98%) was negative in a
       dominant lethal assay (route: oral; highest dose tested: 5 mg/kg bw; no more data
       available) (Her80b) as well as in a bone marrow micronucleus test (route: oral;
       highest dose tested: 2 x 5 mg/kg bw; no more data available) (Her80c).
       Methyl-S-demeton (purity: 94%) did not cause a significant increase in the
       frequency of sister chromatid exchanges in bone marrow cells of Chinese
       hamsters at oral doses of 5-20 mg/kg bw (Her83).
       Reproduction toxicity
       In a 2-generation study, SPF rats (10 males and 20 females) were given 0, 0.07,
       0.35, or 1.75 mg/kg bw of methyl-S-demeton in the diet. Controls received 1.25
072-11 Methyl-S-demeton
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<pre>       mg/kg bw of xylene. The chemicals were administered to 42-49-day-old F0
       generation rats and continued uninterrupted throughout the successive
       generations. No mortality occurred in the F0 generation groups, but in the F1
       generation, one animal died at 0.35 mg/kg bw and one at 1.75 mg/kg bw.
       Reduced body weight gain and food intake were observed at the highest dose in
       both F0 and F1 generations compared to the xylene-treated animals. Animals in
       the control group also showed a reduced body weight. Fertility index was not
       affected by the treatment. The number of pups at birth was reduced in the high-
       dose group and pup viability was decreased at 0.35 and 1.75 mg/kg bw in a dose-
       related manner. Body weight at birth was comparable among groups while body
       weight gain was reduced by 8-10% in pups in the high-dose group. Lactation
       index was also reduced in the high-dose group. No compound-related
       malformations were found in any of the treatment groups. The NOAEL for
       maternal and reproduction toxicity was 0.07 mg/kg bw/day (Eib84).
           Oral treatment of fertilised female rats (BAY:FB 30; n=25/group) with 0, 0.3,
       1, or 3 mg methyl-S-demeton/kg bw/day (52.6% in xylene), during days
       6-15 of pregnancy did not result in clinical signs of intoxication. Body weight
       gain was reduced in the high-dose group. Pups were delivered at day 20. The
       number of resorptions, implants and live fetuses, fetal body weight, and fetuses
       with malformations were comparable among groups. No treatment-related
       external, visceral, or skeletal abnormalities in fetuses were observed. There was
       no evidence of embryotoxicity or teratogenicity at any of the doses tested. The
       NOAEL for maternal toxicity was 1 mg/kg bw/day and for developmental
       toxicity 3 mg/kg bw/day, the highest dose tested (Ren85).
           Methyl-S-demeton (52.2% in xylene) was orally (gavage) given to mated
       female rabbits (Chinchilla Hybrid; n=16/group) at doses of 0, 3, 6, and 12 mg/kg
       bw/day during gestation days 6 to 18. Caesarean sections were performed on
       gestation day 28. There was no mortality. Maternal toxicity was limited to the
       high-dose group and included diarrhoea - after 4 to 10 days of treatment;
       beginning 1-2 hours after dosing and persisting for 6-24 hours – and decreased
       food consumption and body weight gain. Apart from a decrease in mean fetal
       body weight of 6.6% in the high-dose group when compared to mean control
       weight, no treatment-related effects were seen on reproductive parameters or on
       incidences of external, visceral, or skeletal malformations in fetuses in any of the
       treated groups. In this oral developmental toxicity in rabbits, the NOAEL for
       both maternal and developmental toxicity was 6 mg/kg bw (Bec83).
072-12 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>7      Existing exposure limits
       The current administrative exposure occupational limit (MAC) for methyl-S-
       demeton in the Netherlands is 0.5 mg/m3, 8-hour TWA.
           Existing occupational exposure limits for methyl-S-demeton in some
       European countries and in the USA are summarised in the annex.
8      Assessment of health hazard
       The health hazard assessment of methyl-S-demeton is based mainly on a
       toxicology review issued by the FAO/WHO Joint Meeting on Pesticide Residues
       for recommendation of an acceptable daily intake (FAO90). The toxicity profile
       in this review is obtained mainly from unpublished reports of toxicology studies
       conducted for registration purposes by the chemical companies manufacturing or
       marketing the compound.
           Methyl-S-demeton is absorbed into the body through the intact skin, by
       inhalation of the spray mist, and from the gastro-intestinal tract. The committee
       did not find quantitative data on kinetics and metabolism. Case studies in
       humans show a high acute toxicity of methyl-S-demeton following accidental
       and occupational exposures. Effects observed in these studies were typical
       clinical symptoms of cholinergic toxicity, such as drowsiness, vomiting,
       salivation, nervous excitation. Inhibition of serum ChE activity has been
       observed during occupational exposure. In a human volunteer study, exposure to
       a 30:70 mixture of S- and O-isomers, 5 hours/day, for 5 days, did not produce
       effects on red blood cell AChE and plasma ChE at 5-hour TWA airborne levels
       up to 1.9 mg/m3.
           Skin sensitisation tests in test animals, using the ‘guinea-pig maximisation
       test’ and the ‘occluded-patch test’ produced conflicting results. Based on results
       of acute lethal toxicity studies, the committee considers the compound as toxic
       after respiratory, dermal, and oral exposure. No significant systemic effects have
       been reported in short-term and long-term toxicity studies in test animals.
       Inhibition of serum ChE and of red blood cell and brain AChE was found in
       dogs, rats, and mice following short-term and long-term exposure. NOAELs for
       brain and red blood cell AChE inhibition were 0.036 mg/kg bw for dogs (one-
       year study), 0.05 mg/kg bw for rats (2-year study), and 0.25 mg/kg bw for mice
       (21-month study). Methyl-S-demeton produced gene mutations in in vitro tests in
       bacteria and mouse lymphoma cells. However, the only test performed in
072-13 Methyl-S-demeton
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<pre>       mammals (Chinese hamster) did not show an increased frequency of sister
       chromatid exchanges. Carcinogenic effects were not observed following long-
       term oral exposure of rats and mice to methyl-S-demeton. The committee
       concludes that the positive genotoxic effects of methyl-S-demeton were thus not
       reflected in carcinogenicity. Methyl-S-demeton was not embryotoxic or
       teratogenic. However, the compound showed a dose-dependent reduction in
       number of live pups and pup viability in a 2-generation study in rats, probably
       due to maternal toxicity. The overall NOAEL associated with reproduction
       toxicity was 0.07 mg/kg bw/day.
           Based on the above data, the committee concludes that the mechanism of
       toxicity of methyl-S-demeton in mammals is through inhibition of AChE activity
       in nerve tissue. The committee identifies inhibition of AChE in brain tissue as
       the most sensitive adverse toxic effect of methyl-S-demeton in animal studies,
       occurring at dose levels that are lower than those that cause other toxic effects. In
       human beings, for obvious reasons, brain AChE cannot be measured. Instead, red
       blood cell AChE, being the same molecular target for inhibition by
       organophosporus pesticide as brain AChE, is used as a surrogate in assessing the
       human health risk of exposure to methyl-S-demeton (Jey94). However, no data is
       available in the literature of effects of the compound on red blood cell AChE in
       human beings and, therefore, studies in test animals have to be used for the
       assessment of a health based recommended occupational exposure limit
       (HBROEL).
       Because no short- or long-term inhalation toxicity studies are available, the
       committee decided to select the 2-year feeding study in rats as a starting point. In
       this study, the NOAEL was 0.05 mg/kg bw/day, based on inhibition of brain and
       red blood cell AChE activity. Since workers are exposed for 5 days a week, this
       NOAEL from a continuous feeding study (i.e., 7 days a week) is adjusted by
       multiplying with a factor of 7/5 resulting in a no-adverse-effect level (NAEL) of
       0.07 mg/kg bw/day. For the extrapolation to a HBROEL, a factor of 4 for
       allometric scaling from rats to humans, based on caloric demand, and an overall
       factor of 9, covering inter- and intraspecies variation, are applied, resulting in a
       NAEL for humans of 0.002 mg/kg bw/day. Assuming a 70-kg worker inhales 10
       m3 of air during an 8-hour working day and a retention of 100%, and applying
       the preferred-value approach, a health-based occupational exposure limit of 0.01
       mg/m3 is recommended for methyl-S-demeton.
072-14 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       The committee recommends a health-based occupational exposure limit for
       methyl-S-demeton of 0.01 mg/m3, as an 8-hour time-weighted average (TWA).
            Methyl-S-demeton showed a high acute lethal dermal toxicity in rats. A ratio
       of the dermal LD50 and the calculated inhalation LD50 of less than 10 is proposed
       as one of the criteria for assigning a skin notation (ECE98). Since this criterion is
       met for methyl-S-demeton, the committee recommends a skin notation.
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072-18 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>              Annex
Occupational exposure limits for methyl demeton (CAS number: 8022-00-2) in various countries.
country                            occupational                 time-weighted       type of          notea      referenceb
- organisation                     exposure limit               average             exposure limit
                                   ppm          mg/m3
the Netherlands
- Ministry of Social Affairs and   -            0.5             8h                  administrative   S          SZW03
Employment
Germany
- AGS                              0.5          5               8h                                   S          TRG00
                                   2            20              15 min
- DFG MAK-Kommission               0.5          4.8             8h                                   S          DFG02
                                   1.0          9.6             15 minc
Great Britain
- HSE                              -            -                                                               HSE02
Sweden                             -            -                                                               Swe00
Denmark                            0.05d        0.5             8h                                   S          Arb02
USA
- ACGIH                            -            0.5             8h                  TLV              S          ACG03b
- OSHA                             -            -               -                                               ACG03a
- NIOSH                            -            0.5             10 h                REL              S          ACG03a
European Union
- SCOEL                            -            -                                                               EC03
a
     S = skin notation, which means that skin absorption may contribute considerably to body burden; sens = substance can
     cause sensitilisation.
b
     Reference to the most recent official publication of occupational exposure limits.
c
     Maximum number per shift: 4, with a minimum interval between peaks of 1 hour.
d
     Holds also for individual isomers (CAS numbers: 867-27-6, 919-86-8).
072-19        Methyl-S-demeton
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<pre>072-20 Health-based Reassessment of Administrative Occupational Exposure Limits</pre>

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<br><br>