<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>Demeton
(CAS No: 8065-48-3)
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/068, The Hague, 22 september 2003
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. Demeton; Health-based Reassessment of Administrative
Occupational Exposure Limits. The Hague: Health Council of the Netherlands,
2003; 2000/15OSH/068.
all rights reserved
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of 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 L Portengen, M.Sc. (Wageningen University and Research Centre,
      Wageningen, the Netherlands)*.
          The evaluation of the toxicity of demeton has been based on reviews
      published by the American Conference of Governmental Hygienists (ACG99)
      and in the ‘Handbook of pesticide toxicology’ (Gal91). 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
      Medline, Toxline, and Chemical Abstracts, covering the period of 1965/1966
      until December 1999, and using the following key words: demeton, demeton-O,
      demeton-S, systox, isosystox, 8065-48-3, 298-03-3, and 126-75-0. The results of
      unpublished studies were not considered with the exception of studies that were
      summarised and evaluated by international bodies as the Food and Agricultural
      Organization/World Health Organization (FAO/WHO: Joint Meeting of the FAO
      Committee on Pesticides in Agriculture and the WHO Expert Committee on
      Pesticides Residues (JMPR)) (FAO65, WHO87).
          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 May 2003 did not result in
      information changing the committee’s conclusions.
*      Current address: Institute for Risk Assessment Sciences (IRAS), University of Utrecht, Utrecht.
068-3 Demeton
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<pre>2     Identity
      Demeton consists of a mixture of two isomers: demeton-O (thionate isomer) and
      demeton-S (thiolate isomer), in a ratio of approximately 2:1.
      name                     : demeton (mixture of demeton-O and demeton-S)
      synonyms                 : phosphorothioic acid, O,O-diethyl O-(ethylthio)ethyl ester (demeton-O); phos-
                                 phorothioic acid, O,O-diethyl S-(ethylthio)ethyl ester (demeton-S); O,O-diethyl
                                 O-(and S-)2-(ethylthio)ethyl phosphorothioate; systox; systemox; demox; mer-
                                 captofos
      molecular formula        : C8H19O3PS2
      structural formula       :
                                    C 2H 5O            S
                                                       P        O (C H 2 ) 2 S C 2 H 5
                                    C 2H 5O
                                                             +
                                    C 2H 5O            O
                                                       P        S (C H 2 ) 2 S C 2 H 5
                                    C 2H 5O
      CAS number               : 8065-48-3 (mixture), 298-03-3 (demeton-O), 126-75-0 (demeton-S)
3     Physical and chemical properties
      molecular weight         : 258.34
      boiling point            : at 0.2 kPa: 134oC
      melting point            : > -25oC
      flash point              : 45oC (closed cup)
      vapour pressure          : at 20oC : 0.03 Pa
      solubility in water      : at 20oC: 1.2 mg/100 mL
      Log Poctanol/water       : 4.02
      conversion factors       : not applicable
      Data from ACG99, Gal91, NLM02.
068-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      The mixture is an oily, colourless to yellow liquid with a characteristic sulphur
      odour. Contact with strong oxidisers may cause fire and explosions.
4     Uses
      Demeton is a systemic insecticide and acaricide effective against sap-feeding
      insects and mites. It is available as emulsifiable concentrates of varying active
      ingredient contents (Gal91). According to the database of the Dutch Pesticide
      Authorisation Board (CTB)*, demeton is at present not registered for its use as
      an active ingredient in pesticides in the Netherlands. In the USA, demeton as an
      active ingredient is no longer contained in any registered product, and, thus, the
      Office of Pesticide Programs of the US Environmental Protection Agency has
      characterised demeton as ‘cancelled’ in its Pesticide Registration Status (EPA98)
      implying that no toxicological review for a reregistration eligibility decision will
      be prepared.
5     Biotransformation and kinetics
      In the mouse, 50-70% of an orally administered dose of demeton was eliminated
      in the urine within 24 hours. Demeton-S is the same molecule as the oxon
      metabolite of disulfoton, an analogous insecticide/acaricide (EPA88).
      Metabolism studies conducted in the 1950’s showed that the principal metabolic
      pathway for both demeton-S and demeton-O is oxidation of the thioether moiety
      into the corresponding sulphoxides and sulphones. For demeton-O, a secondary
      pathway involves oxidation of P=S to P=O with subsequent oxidation into its
      sulphoxide and sulphone. Both isomers and their metabolites are degraded by
      hydrolysis to form O,O-diethylphosphorothiolate (DEPTH) and O,O-
      diethylphosphorothionate (DETP), respectively. By isomerisation, DETP is
      transformed into DEPTH (Fuk55, Fuk71, Mar55, Men69, WHO87).
            When pregnant mice were given a single intraperitoneal injection of 5 mg/kg
      bw of 32P-labelled demeton at day 14 of gestation, placental tissue, fetal muscle,
      and osteogenic mesenchyma were highly radioactive within 20 minutes. Fetal
      tissue showed only a trace of activity after 3 hours, suggesting rapid metabolism
      and elimination (Bud73a).
*      at: http://www.ctb-wageningen.nl/geel.html.
068-5 Demeton
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<pre>6     Effects and mechanism of action
       Human data
       Acute toxicity
       A number of cases of serious poisoning and a few deaths caused by intentional or
       occupational use of demeton have been reported in humans (ACG99, Gal91,
       WHO87). Death was attributed to demeton in the case of a worker cleaning a
       plane used in application of the pesticide. Severely depressed plasma ChE and
       red blood cell AChE activities were measured (Gal91). A case of intoxication has
       been reported following occupational spraying with demeton by a 16-year-old
       boy. He suffered general weakness, difficulty in breathing, unconsciousness, and
       lack of coordination in walking. After 3 months, he still had disturbances of the
       autonomic nervous system (Gal91).
       Short-term toxicity
       No clinical symptoms of intoxication were reported in agricultural workers who
       inhaled demeton at estimated air concentrations between 1 and 6 mg/m3 during
       field application of demeton. Most workers had a depressed plasma
       cholinesterase (ChE) activity (Kag56, Kag58). In a series of controlled human
       studies over a number of years, test subjects were given daily oral doses of
       technical grade demeton (‘systox’) in capsules for 25 days, followed by a
       recovery period of 32 days. Eighteen different dose levels were given. Beginning
       at 0.750 mg/person/day, the amount was then increased stepwise with 0.375
       mg/person/day until the highest dose of 7.125 mg/person/day was reached. At
       each dose level, 2 groups were composed: 5 test subjects who were given systox
       and 2 control subjects who received capsules containing only corn oil. No
       clinical signs of intoxication were observed at any dose level. At a dose of 4.125
       mg/day (0.06 mg/kg bw/day), one out of 5 test subjects showed a marked
       decrease in plasma ChE and red blood cell AChE activity (59% and 29%,
       respectively). At dose levels ranging from 4.5 to 6.75 mg/person/day, the average
       plasma ChE activity was depressed up to 21%, but the average red blood cell
       AChE activity was not significantly inhibited at any level. However, at the top
       dose, the average red blood cell AChE activity was inhibited by 16% at the end
       of administration, while the average plasma ChE activity was decreased by 40%
068-6  Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>            compared to pre-test levels. Neither inhibition of plasma ChE nor of red blood
            cell AChE reached a plateau after 25 days of systox administration. Plasma ChE
            returned to pre-test level within 30 days, but red blood cell AChE was still
            considerably inhibited. The short-term NOAEL was 3.75 mg/day (i.e., ca. 0.05
            mg/kg bw/day), based on inhibition of red blood cell AChE in one out of 5
            persons (Rid69).
            Animal data
            Irritation and sensitisation
            The committee did not find data on irritation and sensitisation of demeton using
            standard methods.
            Acute toxicity
            Inhalation exposure of 6 Sprague-Dawley rats to commercial systox (60%
            demeton-O, 40% demeton-S) at an air concentration of 18 mg/m3 was fatal to all
            rats within 50-90 minutes after exposure. Following exposure to 3 mg/m3 for 2
            hours, no death or clinical signs of intoxication were reported (Dei55).
            Acute oral and dermal LD50 values in test animals are summarised in Table 1.
Table 1 Acute lethal oral and dermal toxicity data for demeton.
exposure route       vehiculum                 species (strain)     sex           LD50 (mg/kg bw) reference
dermal               xylene                    rat (Sherman)        male          14.0            Gai60
                     xylene                    rat (Sherman)        female        8.2             Gai60
                                               rabbit               not specified 24              Tom94
oral                 alcoholic solution        rat (‘albino’)       male          10a             Bar54
                     alcoholic solution        rat (‘albino’)       female        4a              Bar54
                     corn oil                  rat (Sprague-Dawley) male          5-6             Dei55
                     corn oil                  rat (Sprague-Dawley) female        3-5             Dei55
                     peanut oil                rat                  male          6.2             Gai60
                     peanut oil                rat                  male          2.5             Gai60
                                               rat                  male          3.8             Bro63
068-7       Demeton
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<pre>                                        mouse                      not specified 7.85        Tom94
                    peanut oil          mouse (Charles River CF-1) female        14b         Bud73b
intravenous                             mouse                      not specified 1.75        Tom94
                                        cat                        not specified 3.9         Tom94
a
     ‘Approximate’ LD50.
b
     Observation time: 24 hours.
            The composition of the material and formulation used should be taken into
            account when evaluating the results of different studies. When orally
            administered in corn oil, purified demeton-S is appreciably more toxic in rats
            than purified demeton-O based on LD50 values of 1.5 and 117 mg/kg bw,
            respectively (Dei55). The composition of formulation has great impact on the
            dermal toxicity of demeton. Addition of extra emulsifier reduced the LD50 from
            <24 mg/kg to approximately 620 mg/kg, whereas dilution to spray-strength
            greatly enhanced the toxicity (LD50: ca. 5 mg/kg) (Dei52).
                  Demeton (probably the demeton-S isomer) was found not to be neurotoxic in
            atropinised Rhode Island Red hens (n=2-10/dose level) observed for 30 days
            after single subcutaneous doses of 5-80 mg/kg bw. The estimated LD50 in this
            study was 20 mg/kg bw and signs of cholinergic poisoning were already obvious
            at 10 mg/kg bw (Dur56).
            Short-term toxicity
            Rats (Sprague-Dawley; n=20; sex not indicated) were exposed by inhalation to 3
            mg/m3 commercial systox, 1 hour/day for up to 12 days. No signs of intoxication
            were observed following 2 days of exposure. Brain AChE, red blood cell AChE,
            and plasma ChE activities, measured in 2 rats immediately after the second
            exposure, were inhibited by about 25%, 30%, and 15%, respectively. Mild
            tremors were observed after 4 days of exposure, marked tremors and
            lachrymation after 6 days of exposure. Eight out of 20 rats died during exposure
            days 6 to 12. Immediately following 6 or 12 days of exposure, cholinesterase
            activities (measured in 2 rats after each exposure) were reduced to a similar
            extent; brain AChE activity was inhibited by about 55%, red blood cell AChE by
            about 52%, and plasma ChE by about 39% (Dei55). Daily 2-hour inhalation of 3
            mg/m3 systox for 2 to 3 days caused tremors and lachrymation; death of 10 out of
            17 Sprague-Dawley rats was observed after 4 days of exposure (no more data
            presented) (Dei55).
068-8       Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>           Female albino rats (n=12/group) were fed levels equivalent to 0, 0.5, 1.0, and
      2.5 mg/kg bw/day of systox (approximately 52% demeton-O and 48% demeton-
      S) for 16 weeks. Animals at the high dose showed cholinergic signs of toxicity
      (tremors, salivation, fasciculations, weakness). During the first 4 weeks, food
      intake and body weight gain were decreased, and after 4 weeks, 3 out of 12 rats
      were killed because of the severity of their illness. Thereafter, the remaining rats
      gradually recovered despite continued ingestion of the high-dose diet. However,
      body weights of the high-dose rats remained below those of control animals
      throughout the study in spite of a high food intake. Terminal whole blood
      cholinesterase (combined activity of plasma ChE and red blood cell AChE) and
      brain AChE activities were inhibited by 92 and 93%, respectively. At 1 and 0.5
      mg/kg bw/day, no overt signs of toxicity were observed. However, terminal
      whole blood cholinesterase activity was inhibited by 85 and 72% and brain
      AChE by 87 and 73%, respectively (Bar54). In a subsequent experiment by the
      same authors, female rats (n=18/group) were given systox at dietary levels
      equivalent to 0, 0.05, 0.15, and 0.5 mg/kg bw/day for 11 weeks. In the mid- and
      high-dose groups significant decreases in terminal plasma ChE (30 and 72%),
      red blood cell AChE (20 and 84%) and brain AChE (34 and 80%) activities
      (measured in 7 or 8 animals) were recorded. At 0.05 mg/kg bw/day, a slight
      decrease in terminal cholinesterase activities (measured in 7 animals) was still
      detectable (plasma ChE: 4.5%, red blood cell: AChE 17%, brain: AChE 7%)
      (Bar54). The committee considers inhibition of red blood cell and brain AChE
      activity at the lowest dose level tested (0.05 mg/kg/day) not biologically
      significant, and, therefore, the NOAEL for red blood cell and brain AChE
      inhibition in this study was 0.05 mg/kg/day.
           In a 90-day oral study, Sprague-Dawley rats (n=5/group; sex not indicated)
      were given systox (approximately 60% demeton-O and 40% demeton-S) in corn
      oil at levels equivalent to 0, 0.4, 0.66, 0.9, or 1.89 mg/kg bw (0, 4, 7, 10, and 20%
      of previously determined oral LD50) by stomach tube, for 5 days/week. No signs
      of intoxication were observed at the 2 lower doses, but at 0.9 mg/kg bw, animals
      displayed hyperexcitability and tremors, and at 1.89 mg/kg bw, 1 out of 5
      animals died after 17 days. Gross and microscopic examination of the major
      organs of the treated animals revealed no significant differences when compared
      to controls. Cholinesterase activities were not reported. The NOAEL for signs
      and symptoms was 0.66 mg/kg/day (Dei55).
           New Zealand rabbits (n=6/group; sex not indicated) were fed systox-
      contaminated greens at levels equivalent to 0.07, 0.15, 0.5, 1.5, and 2.3 mg/kg
      bw/day for 94, 98, 100, 30, and 40 days respectively. At 2.3 mg/kg bw/day, 3 out
068-9 Demeton
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<pre>       of 6 animals died during treatment days 14-30. Plasma ChE activity was reduced
       immediately after dosing levelling off after 15 days of treatment at 70% of
       normal. Treatment was discontinued after 40 days. Ingestion of 1.5 mg/kg/day
       caused mortality in 4 out of 6 animals during days 15-30, after which treatment
       was discontinued. Plasma ChE activity was promptly reduced levelling off after
       about 12 days at about 45%. Determination of plasma ChE activity in the 2
       surviving animals 3 weeks after ending treatment showed values within the
       normal range. Feeding 0.5 mg/kg bw for 100 days caused mortality in one out of
       6 animals (at day 64). Treatment gradually decreased plasma ChE activity, which
       levelled off after 30 days at 85% of normal. At 0.15 and 0.07 mg/kg bw/day, fed
       for 98 and 94 days, respectively, neither fatalities nor reduced plasma ChE levels
       occurred. Generally, no animal showed any obvious signs of toxicity at a time
       when marked reductions in plasma ChE activities were observed. In animals that
       died, symptoms observed 3 to 5 days preceding death included respiratory
       distress, frothing at nose and mouth, marked diarrhoea, muscular paralysis,
       coma, and mild asphyxial convulsions. The NOAEL for plasma ChE inhibition
       was 0.15 mg/kg/day (Dei55).
           Groups of young adult dogs (mixed breed; n=1/sex/group) were given dietary
       levels of systox equivalent to 0, 0.025, 0.047, and 0.149 mg/kg bw/day for 24
       weeks. Only effects on plasma and red blood cell cholinesterase activity were
       studied. Blood samples were regularly drawn during a 3-week pre-treatment
       period (5 times), during treatment (at weekly intervals for the first month, at
       biweekly intervals for the next 5 months), and during the exposure-free recovery
       period (weekly for the first month, 2- or 3-weekly thereafter) until normal
       activity was restored. Dogs receiving 0.149 mg/kg bw/day showed decreases in
       plasma ChE and red blood cell AChE activities reaching maximum inhibition by
       approximately 70% and 30%, when compared to pre-treatment levels, after about
       12 weeks of feeding. Recovery of plasma activity to ‘ normal’ levels was
       complete within 4 weeks after ending treatment. Recovery of red blood cell
       activity was much slower. Although levels were comparable to those of control
       animals after an 11-week exposure-free period, they were still only about 80-
       85% of the pre-treatment activities. At 0.047 mg/kg bw/day, significant plasma
       ChE inhibition (ca. 25%) was found only after 16 weeks of feeding, returning to
       ‘normal’ levels within 2-4 weeks post-exposure. Red blood cell AChE activity
       was not affected. At 0.025 mg/kg bw/day, no significant inhibition of plasma
       ChE or red blood cell AChE was found. The NOAEL for ChE inhibition in this
       study was 0.025 mg/kg/day, based on inhibition of plasma ChE and 0.047 mg/kg
       bw for inhibition of red blood cell AChE (Fra57).
068-10 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>              The above studies are summarised in Table 2.
Table 2 Summary of short-term toxicity studies for demeton.
exposure species                          dose levels                  exposure     critical effecta     NOAEL     reference
route      (strain; number; sex)                                       duration
inhalation rat                            0, 3 mg/m3                   1 h/d, up to BAChE                <3 mg/m3 Dei55
           (Sprague-Dawley; n=20; ?)                                   12 d
           rat                            0, 3 mg/m3                   2 h/d, up to cholinergic symptoms <3 mg/m3 Dei55
           (Sprague-Dawley; n=17; ?)                                   4d
oral       rat                            0, 0.5, 1.0, 2.0 mg/kg bw/d 16 w          BAChE                <0.5 mg/ Bar54
           (‘albino’; n=12/group; female)                                                                kg bw/d
           rat                            0, 0.05, 0.15, 0.5 mg/kg bw/11 w          BAChE and RAChE 0.05 mg/ Bar54
           (‘albino’; n=18/group; female) d                                                              kg bw/d
           rat                            0, 0.04, 0.66, 0.9, 1.89 mg/ 90 d         cholinergic symptoms 0.66 mg/ Dei55
           (Sprague-Dawley; n=5/group; ?) kg bw/d                                                        kg bw/d
           rabbit                         0, 0.07, 0.15, 0.5, 1.5, 2.3 94-30 d      cholinergic symp-    0.15 mg/ Dei55
           (New Zealand; n=6/group; ?)    mg/kg bw/d                                toms or plasma ChE kg bw/d
           dog                            0, 0.025, 0.047, 0.149 mg/ 24 w           RAChE                0.047 mg/ Fra57
           (mixed breed; n=1/sex/group)   kg bw/d                                                        kg bw/d
c
     BAChE= brain AChE; RAChE= red blood cell AchE
              Long-term toxicity and carcinogenicity
              The committee did not find data from long-term or carcinogenicity studies.
                   No carcinogenicity was observed for disulfoton, of which demeton-S is a
              metabolite (HCN03).
              Mutagenicity and genotoxicity
              Mutagenicity and genotoxicity assays comprised in vitro tests for the detection of
              gene mutations in bacteria and in vitro cytogenicity and other genotoxicity
              assays.
              • Gene mutation assays. In vitro tests for reverse mutations in several strains
                   of S. typhimurium (TA98, TA100, TA 1535, TA 1537, TA 1538) and in E.
                   coli WP2 were positive both with and without metabolic activation (Bru80,
                   Kie86, Sim79, Wat80). Demeton was negative in a sex-linked recessive
                   lethal test with D. melanogaster (Lee83).
068-11        Demeton
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<pre>       •    Cytogenicity assays. In cultured Chinese hamster V79 cells, the chemical
            induced sister-chromatid exchanges (SCE) in the presence of a metabolic
            activation system (Che82). An increase in the frequency of SCE was also
            observed in cultured lymphocytes (source not specified) (Dzw89).
       •    Other genotoxicity assays. Demeton induced mitotic recombination in S.
            cerevisiae D3 both with and without metabolic activation (Zim84). The
            chemical was positive in DNA-repair-deficient B. subtilus but negative in
            DNA-repair-deficient E. coli polA (Lei81).
       In summary, demeton is an in vitro mutagen, but the committee did not find data
       from genotoxicity studies in test animals.
       Reproduction toxicity
       The teratogenic and embryotoxic potential of demeton was studied in Charles
       River CF-1 mice that were given demeton as single or as 3 consecutive
       intraperitoneal doses on specific days of gestation. Single doses of 7 or 10 mg/kg
       bw were administered to groups of mice (number not specified) on either day 7,
       8, 9, or 10 of gestation, single doses of 7, 10, or 14 mg/kg bw on day 11 of
       gestation, and a single dose of 10 mg/kg bw on day 12 of gestation. Consecutive
       doses of 10 mg/kg bw/day were administered on days 7-9, 8-10, or 9-11 of
       gestation. In some groups of pregnant mice, fetuses were removed by caesarean
       section on days 16 and 18 of gestation; other groups were allowed to deliver
       pups. A dose-related decrease in 16-day fetal weights was observed if demeton
       was given as single doses on or after day 9 of gestation. These effects were not
       seen in 18-day fetuses. The percentage of resorptions was not affected by
       demeton treatment; however, the percentage of dead fetuses was increased, the
       increase being statistically significant with treatment on day 12. A dose-related
       increase was found in the number of anomalies of the digestive and skeletal
       systems in 16-day fetuses compared to control animals. However, no such effects
       were observed in 18-day fetuses, indicating that the majority of the abnormalities
       in 16-day fetuses may have been due to growth retardation. Single treatment of
       10 mg/kg bw on days 8, 9, or 10 of gestation had no effect on litter size and
       stillbirths at delivery or on 28-day pup survival. However, at birth, pup weights
       were lower than that of the controls. Growth rate of pups was comparable to
       controls, but was lower if treatment was given on day 10 of gestation.
       Administration of 3 consecutive doses of 5 mg/kg bw each did cause some minor
       skeleton abnormalities. The frequency of dead fetuses was not increased, but 16-
068-12 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       day fetal weight was significantly lower than that of the controls. The author’s
       conclusion was that embryotoxic and teratogenic effects, observed at high doses
       (10 mg/kg bw) of demeton, were probably the result of maternal toxicity
       (Bud73b, WHO87).
           Ducklings hatched from eggs inoculated with 10 or 100 µg demeton on day
       13 via the yolk were hyperexcitable and in some cases had leg paralysis and body
       tremors with intermittent convulsions. Average body weight and growth rate
       during the 2-week observation period were lower than in controls (Khe65).
           The committee considers these studies not adequate for the assessment of
       reproduction toxicity.
7      Existing guidelines
       The current administrative occupational exposure limit (MAC) for demeton in
       the Netherlands is 0.1 mg/m3, 8-hour TWA, with a skin notation.
           Existing occupational exposure limits in some European countries and the
       USA are summarised in the annex.
8      Assessment of health hazard
       Workers can be exposed to demeton through inhalation or by direct skin contact
       with a formulation of the compound. However, the committee did not find
       quantitative data on absorption of demeton through the lungs or the skin. The
       extent of absorption following oral intake is at least 50-70% in mice, but the
       committee did not find data for other species. Demeton-S is a metabolite of
       disulfoton. Based on the rapid excretion of repeated oral doses of disulfoton
       (approximately 90% of the doses are excreted in the urine within 24 hours), the
       committee expects that, following absorption, demeton is rapidly metabolised
       and excreted and does not accumulate in tissues.
           Case studies in humans show a high acute toxicity of demeton following
       accidental exposures. Demeton-S was considerably more toxic than the O-
       isomer. Effects observed in these studies were typical cholinergic symptoms such
       as weakness, respiratory difficulty, and lack of coordination in walking. In a
       human volunteer study, oral intake of approximately 0.10 mg/kg bw/day for 25
       days produced inhibition of average red blood cell AChE (16%) and plasma ChE
       (40%) without cholinergic symptoms. The NOAEL for red blood cell AChE or
       plasma ChE inhibition in humans was 0.05 mg/kg bw/day.
068-13 Demeton
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<pre>           The committee did not find data from studies on eye or skin irritation or on
       skin sensitisation of the compound. Based on results of acute lethal toxicity
       studies in test animals, the committee considers the compound as very toxic after
       respiratory, dermal, and oral exposure. In a limited acute neurotoxicity study in
       hens, the compound did not cause acute delayed neurotoxicity. No significant
       systemic effects have been reported in short-term studies in test animals.
       However, these studies showed inhibition of red blood cell and brain AChE in
       rats and of red blood cell AChE in dogs (brain AChE not measured). For the rat,
       the NOAEL for inhibition of brain and red blood cell AChE was 0.05 mg/kg
       bw/day (11-week oral study). For the dog, the NOAEL for inhibition of red blood
       cell AChE was 0.047 mg/kg bw/day (24-week oral study).
           Results of in vitro mutagenicity tests indicate that demeton has significant
       genotoxic potential. However, no data are available on the genotoxicity in test
       animals. No data on long-term or carcinogenicity studies are available for
       demeton. Since disulfoton, of which demeton-S is a metabolite, was not
       carcinogenic in experimental animal studies (see HCN03), the committee
       expects that demeton is not carcinogenic. The committee considered a
       developmental toxicity study of demeton in mice not to be adequate for the
       assessment of reproduction toxicity.
       Based on the above data, the committee concludes that the mechanism of toxicity
       of 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 demeton in animal studies, occurring at dose levels, which
       are lower than those causing 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 for brain AChE in assessing the human health risk
       of exposure to demeton (Jey94).
           The committee takes the NOAEL of 0.05 mg/kg bw/day derived from the 25-
       day human volunteer study as a starting point in deriving a health-based
       recommended occupational exposure limit (HBROEL). Since workers are
       exposed for 5 days a week, this NOAEL from a continuous 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. For extrapolation to a HBROEL, an
       overall assessment factor of 6 is used, covering the following aspects:
       intraindividual variation and confidence in the database. This results in a NAEL
       for humans of 0.01 mg/kg bw/day. Assuming a 70-kg worker inhales 10 m3 of air
068-14 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       during an 8-hour working day and a retention of 100%, and applying the
       preferred-value approach, a health-based occupational exposure limit of 0.1
       mg/m3 is recommended for demeton.
       The committee recommends a health-based occupational exposure limit for
       demeton of 0.1 mg/m3, as an 8-hour time-weighted average (TWA).
           In view of the high acute lethal dermal toxicity in rats, the committee
       recommends a skin notation.
       References
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       exposure values - 2003. Cincinnati OH, USA: ACGIH®, Inc, 2003: 38.
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       based on the documentation of the Threshold Limit Values for chemical substances and physical
       agents & Biological Exposure Indices. Cincinnati OH, USA: ACGIH®, Inc, 2003: 24.
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       reverse mutation assay. Mutat Res 1980; 76: 169-90.
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068-15 Demeton
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Eri92  Erickson-Lamy K, Grant MW. Ophthalmic toxicology of anticholinesterases. In: Ballantyne B, Marrs
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       (Suffolk), England: HSE Books, 2002.
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<pre>Kag56  Kagan YS. [Problems of industrial health in connection with the use of the new organic phosphorus
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       Environmental Protection Agency Gene-Tox program. Mutat Res 1983; 123: 363-410.
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       (last revision date demeton file: 14 January 2002; last review date: 29 September 1994); http://
       www.toxnet.nlm.nih.giv
Rid69  Rider JA, Moeller HC, Puletti EJ, et al. Toxicity of parathion, systox, octamethyl
       pyrophosphoramide, and methyl parathion in man. Toxicol Appl Pharmacol 1969; 14: 603-11.
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068-17 Demeton
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<pre>Wat80  Waters MD, Simmon VF, Mitchell AD, et al. An overview of short term tests for the mutagenic and
       carcinogenic potential of pesticides. J Environ Sci Health 1980; 15: 867-906.
WHO87  World Health Organization (WHO)/Food and Agriculture Organization (FAO). Demeton. Geneva,
       Switzerland: WHO, 1987; Data sheets on pesticides No 60; WHO/VBC/DS/87.60 rev 1; http://
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068-18 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>              Annex
Occupational exposure limits for demeton 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
Employment                           0.01       0.1          8h                 administrative     S              SZW03
Germany
- AGS                                0.01       0.1          8h                                    S              TRG00
                                     0.04       0.4          15 min
- DFG MAK-Kommission                 -c         -                                                  d
                                                                                                                  DFG02
Great Britain
- HSE                                -          -                                                                 HSE02
Sweden                               -          -                                                                 Arb02
Denmark                              0.01       0.1          8h                                    S              Swe00
USA
- ACGIH                              -          0.05 e       8h                 TLV                S              ACG03b
- OSHA                               -          0.1          8h                 PEL                S              ACG03a
- NIOSH                              -          0.1          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 sensitisation.
b
     Reference to the most recent official publication of occupational exposure limits.
c
     Listed among substances for which studies of the effects in man or in experimental animals have yielded insufficient
     information for the establishment of MAC values.
d
     Compound is not registered as a pesticide.
e
     Measured as inhalable fraction of vapour and aerosol.
068-19        Demeton
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<pre>068-20 Health-based Reassessment of Administrative Occupational Exposure Limits</pre>

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