<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>Disulfoton
(CAS No: 298-04-4)
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/071, The Hague, 22 september 2003
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. Disulfoton; Health-based Reassessment of Administrative
Occupational Exposure Limits. The Hague: Health Council of the Netherlands,
2003; 2000/15OSH/071.
all rights reserved
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of disulfoton
      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 disulfoton has been based on the review by
      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 databases Medline, Toxline, and Chemical Abstracts covering the period of
      1966 until December 1999, and using the following key words: disulfoton,
      disystox, di-syston, thiodemeton, and 298-04-4. Data of unpublished studies
      were generally not taken into account. Exceptions were made for 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 Panel of Experts on Pesticides Residues on Food and the
      Environment and the WHO Expert Group on Pesticides Residues (JMPR))
      (FAO92) and the Health Effects Division (HED) of the US Environmental
      Protection Agency (EPA) as part of its hazard identification assessment review
      (And00).
          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
071-3 Disulfoton
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<pre>2     Identity
      name                        :      disulfoton
      synonyms                    :     phosphorodithioic acid O,O-diethyl S-[2-(ethylthio)ethyl] ester; O,O-diethyl S-
                                         2-(ethylthio)ethyl) phosphorodithioate; O,O-diethyl-S-ethylmercaptoethyl
                                         dithiophosphate; di-syston
      molecular formula           :      C8H19O2PS3
      structural formula          :
      CAS number                  :      298-04-4
3     Physical and chemical properties
      molecular weight             :      274.41
      boiling point               :       at 0.2 kPa: 132-133°C
      melting point               :       -25°C
      vapour pressure              :      at 20°C: 0.007 Pa
      solubility in water         :       at 20°C: 12 mg/L
      log Poctanol/water           :      4.02
      conversion factors           :      not applicable
      Data from ACG99, Tom94.
      Technical-grade disulfoton is a brown liquid, while the pure substance is an oily,
      colourless liquid with a characteristic sulphur odour.
            Disulfoton is a selective, systemic insecticide and acaricide that is especially
      effective against sucking insects. Disulfoton is used on a variety of crops
      including cotton, coffee, tobacco, sugar beets, cole crops, rice, corn, peanuts,
      wheat, ornamentals, cereal grains, potatoes, and fruit and nut crops (Tom94).
      According to the database of the Dutch Pesticide Authorisation Board (CTB)*,
*      at: http://www.ctb-wageningen.nl/geel.html
071-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      disulfoton is at present not registered for its use as an active ingredient in
      pesticides in the Netherlands.
4     Biotransformation and kinetics
      Human data
      In the urine of workers, formulating disulfoton, diethyl phosphate (DEP),
      diethylphosphorothioate (DEPT), and diethylphosphorodithioate (DEPDT) were
      detected as principal metabolites (Bro81).
      Animal data
      In a dermal absorption study, labelled disulfoton was applied to the clipped backs
      (approximately 15cm2) of male rats (4/group) at 0.85, 8.5, and 85 µg/cm2
      (approximately 0.05, 0.5, and 5.1 mg/kg bw) for 1, 4, and 10 hours. At
      termination of exposure, skins were washed and animals were kept for an
      additional 158 hours to determine the kinetics of absorption and excretion of
      applied material. A total of about 31-37% of the administered dose was excreted
      in the urine and 2.7-3.3% in the faeces throughout the 168 hours following
      dermal application. Ten to 30% of the applied dose evaporated during the
      10-hour exposure periods. At the low dose, 5.9%, 13.7%, and 26% were
      absorbed at 1, 4, and 10 hours following dermal application, at the mid dose,
      percentages were 4.6, 15.9, and 32.7% and at high dose, 3.6, 12.5, and 25.6%,
      respectively (War94).
          Male and female Sprague-Dawley rats (n=3/sex/group) were given single
      oral doses of either 0.2 or 1.0 mg 1-ethylen-14C-disulfoton kg/bw. Another 3 rats/
      sex received 14 daily doses of 0.2 mg/kg unlabelled disulfoton followed by one
      dose of 0.2 mg/kg bw labelled disulfoton on day 15. The chemical was rapidly
      absorbed, metabolised, and eliminated under all dosing regimens.
      Approximately 90% of the radioactivity was recovered in the urine within 24
      hours after dosing and excretion was practically completed at 72 hours. Less than
      2% of radioactivity was excreted in the faeces, less than 1% exhaled as CO2 and
      less than 0.4% retained in tissues and carcasses (Lee85). Disulfoton is
      biotransformed by oxidation of the thioether moiety into the corresponding
      disulfoton sulphoxide and disulfoton sulphone and by desulphuration of the P=S
      moiety to P=O to its disulfoton oxon (demeton-S) analogues. By hydrolysis of
      these oxidative metabolites, metabolites were identified as sulphonyl [1-
071-5 Disulfoton
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<pre>      (ethylsulphonyl)-2-(methylsulphinyl)ethane] (43-60% of urine radioactivity) and
      sulphinyl [1-(ethylsulphinyl)-2-(methylsulphinyl)ethane] (6-20% of urine
      radioactivity). The committee considers that also the non-labelled metabolites
      DEPDT, DEPT and DEP are formed and excreted in the urine (Figure1; see
      Annex I).
          In mice, disulfoton was found to bind strongly to cytochrome P450. Since
      disulfoton also inhibited microsomal ethyl morphine demethylase activity, it was
      suggested that disulfoton may interfere with the action of mixed function
      oxidases (Ste74).
5     Effects and mechanism of action
      Human data
      Apart from a suicidal attempt by a 75-year-old woman, the committee did not
      find reports on cases of intoxication of human subjects using disulfoton. After
      ingestion of a large, not further specified, quantity of granular disulfoton, the
      woman had been admitted to the hospital having vomiting, complaints of nausea,
      and muscle fasciculations, and 90 minutes after admission, confusion, severe
      miosis, and cardiac arrhythmias (Fut95).
          Five human volunteers were given a daily oral dose of 0.75 mg of disulfoton
      for 30 days. Two persons served as controls. No changes were observed in levels
      of plasma ChE and red blood cell AChE. No further details were provided
      (Rid72).
      Animal data
      Irritation and sensitisation
      The committee did not find data from irritation or sensitisation studies on
      disulfoton. In a repeated dermal dose study using rabbits, neither skin irritation
      nor sensitisation were observed (Flu86).
      Acute toxicity
      Acute inhalation, dermal, and oral LC50 and LD50 values in test animals are
      summarised in Table 1.
071-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>Table 1 Summary of acute lethal toxicity studies for disulfoton in experimental animals.
exposure route (duration) vehiculum                  species (strain             sex           LC50/LD50   reference
                                                                                                         3
inhalation (1 h)                                     rat (Wistar)                male          290 mg/m    Thy78
            (4 h)                                    rat (Wistar)                male          60 mg/m3    Thy78
                                                                                                       3
            (1 h)                                    rat (Wistar)                female        63 mg/m     Thy78
            (4 h)                                    rat (Wistar)                female        15 mg/m3    Thy78
                                                                                                         3
                                                     rat                         not specified 200 mg/m    NIO02
dermal                    xylene                     rat (Sherman)               male          25          Gai69
                          xylene                     rat (Sherman)               female        6           Gai69
           (24 h)                                    rat (Wistar)                male          15.9        Mih78
           (24 h)                                    rat (Wistar)                female        3.6         Mih78
                                                     rat (Sprague-Dawley)        male          20          ATS95
                                                     rat                         male          22.6        Iya80
                                                     rat                         female        7.3         Iya80
                                                     mouse                       male+female   35          Iya80
                                                     mouse                       not specified 15.6        NIO02
oral                      propylene glycol:ethanol rat (Sprague-Dawley)          male          12.5        Bom58
                          propylene glycol:ethanol rat (Sprague-Dawley)          female        2.6         Bom58
                          peanut oil                 rat (Sherman)               male          6.8         Gai69
                          peanut oil                 rat (Sherman)               female        2.3         Gai69
                                                     rat (Hindustan antibiotics) male          7.2         Paw78
                                                     rat (Hindustan antibiotics) female        3.2         Paw78
                                                     rat (Wistar)                male          6.2         Mih78
                                                     rat (Wistar)                female        1.9         Mih78
                                                     rat                         male          9.6         Iya80
                                                     rat                         female        4.2         Iya80
                                                     rat                         not specified 10          Sch72
                                                     rat                         not specified 2.6         NIO02
                                                     mouse (Hindustan            male          5.8         Paw78
                                                     antibiotics)
                                                     mouse (Hindustan            female        2.7         Paw78
                                                     antibiotics)
                                                     mouse (NMRI)                male          7.0         Mih78
                                                     mouse (NMRI)                female        8.2         Mih78
                                                     mouse                       male+female   27          Iya80
071-7         Disulfoton
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<pre>                                           mouse (Swiss-Webster) male          19.3      Ste72
                                           mouse                 not specified 4.8       NIO02
                                           guinea pig            male          8.9       ATS95
                                           guinea pig            female        12.7      ATS95
                  propylene glycol:ethanol guinea pig            male          10.8      Bom58
                                           dog                   female        ca. 5     Tom94
      Induction of cytochrome P450 by pre-treatment with phenobarbital or
      3-methylcholanthrene reduced the acute oral toxicity of disulfoton in rats and
      mice, while pre-treatment with inhibitors of haem or protein synthesis resulted in
      an increased mortality (Paw78).
          In an acute neurotoxicity study, male Sprague-Dawley rats (n=10/group)
      were given oral doses of 0, 0.25, 1.5, or 5.0 mg/kg bw of disulfoton (purity:
      97.8%) and female rats (10/group) 0, 0.25, 0.75, or 1.5 mg/kg bw. All animals
      were assessed for reactions in a functional observational battery (FOB) and for
      motor activity measurements at 90 minutes and at days 7 and 14 after dosing.
      Plasma ChE and red blood cell AChE activity were determined 24 hours after
      dosing. Female and male rats had muscle fasciculations and decreased activity of
      plasma ChE (by 30% in females) and red blood cell AChE (by 53% in females)
      at 0.75 and 1.5 mg/kg bw, respectively. In addition, at the top doses, both sexes
      had tremors, ataxia, decreased motor and locomotor activity, and decreased
      activity of plasma ChE (by 52% in females and 25% in males) and red blood cell
      AChE (by 75% in females and 21% in males). The NOAEL for neurotoxicity and
      for inhibition of AChE activity is 0.25 mg/kg bw (And00).
          Three studies have been reported on the possible delayed neuropathy of
      disulfoton in hens. In the first study, chickens were tested for leg weakness
      following a single oral dose of disulfoton. All animals were given atropine to
      protect against the acute toxic effects of the pesticide and at the highest dose
      tested (50 mg/kg bw), no mortality was observed. Birds that received 32 mg/kg
      bw showed leg weakness within 24 hours for a period of up to 13 days. The
      NOAEL for neurotoxicity was 16 mg/kg bw (Gai69). Twenty adult White
      Leghorn hens were given oral doses of 30 mg/kg bw disulfoton (purity: 97.8%)
      on two separate occasions 22 days apart and observed for 42 days. Birds were
      protected from lethality with atropine and 2-PAM. Negative control birds were
      dosed either with atropine/2-PAM without disulfoton (n=5), or not treated (n=5),
      and positive controls (n=10) were given 500 mg/kg tri-o-cresol phosphate
      (TOCP). Cholinergic symptoms (loss of equilibrium, decreased activity,
      locomotor ataxia) were observed in 14/20 hens, starting soon after dosing but
071-8 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      disappearing within 5 days. Birds treated with TOCP (8/10) showed symptoms
      between days 12 and 24 which disappeared in 5 hens before termination of the
      study. Disulfoton-treated birds did not show histological changes suggestive of
      neuropathy in peripheral nerves or in spinal cord. TOCP-dosed hens showed
      axonal degeneration in brain and spinal cord. The authors concluded that
      disulfoton did not induce acute delayed neuropathy (Hix83). In a third study, 18
      LSL laying hens were given a single dose of 40 mg/kg bw of disulfoton. Fifteen
      hens were used as controls. Prior to disulfoton treatment, immediately after
      treatment, and at day 1 after treatment, the animals were given atropine/2-PAM.
      No typical signs of disulfoton-induced neuropathy were seen during the 3-week
      observation period. No hens died, but body weight was slightly decreased. Brain
      AChE was inhibited by 83% and 59% at 24 and 48 hours after treatment,
      respectively. The activity of neuropathy target esterase (NTE), a specific enzyme
      for delayed neurotoxicity, in spinal cord, sciatic nerves, and brain did not change,
      nor were microscopic abnormalities observed in these tissues (And00). The
      committee concludes that disulfoton does not cause acute delayed neuropathy in
      hens.
      Short-term toxicity
      Wistar rats (n=10/sex/group) were exposed (nose-only) to technical-grade
      disulfoton (purity: 94.4%) at aerosol concentrations of 0, 0.5, 1.8, or 9.8 mg/m3,
      4 hours/day, for 5 days, and kept under observation for an additional 14 days.
      Symptoms typical for cholinergic toxicity were observed in all animals of both
      sexes at 1.8 mg/m3 and above. There was no mortality except for 9/10 females
      exposed to 9.8 mg/m3 (dying between 1-8 days from the beginning of the study).
      Body weight and gross pathology were not different among groups. After 3-5
      exposures to 1.8 mg/m3 and above, plasma ChE and red blood cell AChE
      activities were reduced in males by more than 40% and 16 %, respectively. In
      females, plasma ChE activity was reduced by more than 31% at 0.5 mg/m3 and
      above and red blood cell AChE activity by more than 17% at 1.8 mg/m3 and
      above. In this 5-day inhalation rat study, the NOAEL for inhibition of red blood
      cell AChE activity was 0.5 mg/m3 (Thy78).
          A 3-week inhalation study was conducted on Wister rats (n=10/sex/group)
      exposed to aerosol concentrations of technical disulfoton (purity: 94.4%) of 0,
      0.02, 0.1, 0.5, and 3.7 mg/m3 (6 hours/day, 5 days/week). At the highest dose
      level, all rats showed cholinergic symptoms and 5 female rats died. Body weight
      and clinical chemistry and haematology test data remained within normal limits
071-9 Disulfoton
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<pre>       at all exposure concentrations. Plasma ChE activity was significantly decreased
       (>30%) at 0.1 mg/m3 and above in females but in males only at the highest dose
       level. Red blood cell AChE and brain AChE activities were significantly
       inhibited (>20%) at 3.7 mg/m3 in both sexes. Microscopic examination showed
       inflammation of the respiratory tract and concurrent bone marrow changes at 0.5
       mg/m3 and higher. The 3-week inhalation rat NOAEL was 0.1 mg/m3 (Thy80).
            In another 3-week inhalation study, Fischer 344 rats were exposed (nose-
       only) to 0, 0.006, 0.07, and 0.7 mg/m3 of disulfoton aerosol (purity: 97.8%), 6
       hours/day, 5 days/week. No deaths, signs of toxicity, or reduction of brain AChE
       activity were observed at the termination of the study. The 3-week inhalation rat
       NOAEL was 0.7 mg/m3, the highest concentration tested (no more data
       presented, e.g., whether other cholinesterase activities were measured) (Shi88).
            In a 13-week inhalation study, Fisher 344 rats (n=12/sex/group) were
       exposed (nose-only) to aerosol concentrations of disulfoton (purity: 97.8%) of 0,
       0.018, 0.16, or 1.4 mg/m3, 6 hours/day, 5 days/week. No mortality or cholinergic
       symptoms of toxicity were observed. At 1.4 mg/m3, significant inhibition of
       brain AChE (by 29% and 28% in males and females, respectively), red blood cell
       AChE (not specified), and plasma ChE activity (by 14% and 31% in males and
       females, respectively) was measured at termination of the study. At 0.16 mg/m3,
       at termination, red blood cell AChE and plasma ChE activities were not
       significantly changed from pre-exposure levels, but brain AChE activity was
       statistically significantly depressed by 10%. This inhibition was not considered
       biologically relevant due to the variation noted in this parameter. Upon
       microscopic examination of terminally derived tissues, only an increased
       incidence of inflammation of nasal turbinates in male animals exposed to 1.4
       mg/m3 was observed. In this 3-week inhalation rat study, the NOAEL was 0.16
       mg/m3 based on biological significant inhibition of brain AChE at higher
       exposures (Shi89).
       In a dermal study, disulfoton (technical grade; purity: 97.8%) was applied in a
       Cremophor EL emulsion to the shaven skin of New Zealand White rabbits (n=5/
       sex/group) at levels of 0, 0.4, 1.6, or 6.5 mg/kg bw/day (uncovered after
       application; test substance washed off at the end of each exposure period), 6
       hours/day, 5 days/week, for 3 weeks. No dermal reaction to repeated dermal
       application was seen. Cholinergic signs (muscle spasm, dyspnoea, salivation)
       were observed in both sexes at the highest dose level and all animals died within
       the first 10 experimental days. At 1.6 mg/kg bw and lower, no mortality, signs of
       toxicity, or abnormalities in clinical chemistry and haematology tests, gross or
071-10 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       microscopic examination were seen. At 1.6 mg/kg bw/day, plasma ChE, red
       blood cell AChE, and brain AChE activities were depressed at termination in
       both females (by 31-44%, 7-33%, and 7-8%, respectively) and males (by 17-
       24%, 15-19%, and 7-8%, respectively) compared to controls. In this 3-week
       dermal rabbit study, the NOAEL was 0.4 mg/kg bw, based on inhibition of red
       blood cell AChE (Flu86).
       Oral (gavage) administration of disulfoton (technical grade; purity: 97%) at 2
       mg/kg bw/day for 2 weeks caused a 81% decrease in AChE activity in the
       cerebral cortex of adult male Sprague-Dawley rats (Yag96).
            Long Evans rats (n=4) given disulfoton by gavage at 2 mg/kg/day for 2
       weeks showed a significant decrease (16-36%) in the density of muscarinic
       receptors in the cerebral cortex, hippocampus, and striatum, and depression of
       brain AChE activity (16-32%). Recovery of brain AChE activity was relatively
       slow when compared to that of muscarinic receptors and ChE activity in
       peripheral blood lymphocytes (Fit93). Decreases in muscarinic receptor density
       following disulfoton administration have been associated with the development
       of tolerance and with impairment in spatial memory (Cos82).
            Disulfoton (technical grade; purity: >98.7%) was fed to Fischer 344 rats
       (n=18/sex/group) for 13 weeks at dose levels equivalent to 0, 0.063, 0.27, or 1.08
       mg/kg bw/day for males and 0, 0.071, 0.315, or 1.3 mg/kg/day for females. At
       the highest dose, increased CNS activity, tremors, muscle fasciculations, perianal
       staining, increased defecation, decreased forelimb grip strength, decreased motor
       and locomotor activity, decreased body weight gain, and corneal opacities were
       observed. At 0.315 mg/kg bw/day, muscle fasciculations and urine staining were
       observed in females only. Cholinergic signs of toxicity were evident within 2-3
       weeks and persisted till the end of the study. Brain AChE, red blood cell AChE,
       and plasma ChE activities were inhibited at all dose levels in females (by 14-
       87%, 15-100%, and 13-96%, respectively) and at the mid and top doses in males
       (by 35-73%, 67-95%, and 31-74%, respectively). In the males of the low-dose
       group, red blood cell AChE activity was statistically significantly inhibited by
       15% in males but brain AChE and plasma ChE activities remained within normal
       limits. All ophthalmological findings were considered incidental and not related
       to treatment and no treatment-related differences in gross or microscopic
       pathology were observed. In this 13-week oral rat study, no NOAEL for
       inhibition of brain or red blood cell AChE activity could be determined since
       these activities were affected at the lowest doses tested (She97).
071-11 Disulfoton
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<pre>           In a special 6-month study designed to establish a NOAEL and LOAEL for
       ChE inhibition, 35 male and female Fischer 344 rats were given technical-grade
       disulfoton (purity: 98-99%) at levels equivalent to 0, 0.02 and 0.03 mg/kg
       bw/day for both sexes and 0.06 and 0.07 mg/kg bw/day, for males and females,
       respectively. After 2, 4, and 6 months, 10 rats/sex/group were taken for
       measurement of red blood cell and brain AChE and plasma ChE assays. No
       changes occurred in body weight and food consumption, and no clinical signs of
       toxicity were observed. In females, red blood cell AChE activity was
       significantly inhibited at all dose levels in a dose-related way (3-14%, 11-17%,
       and 23-29%, respectively), but in males, inhibition (by 10-16%) was measured at
       0.06 mg/kg bw/day only. In females, plasma ChE (8-17%) and brain AChE (7-
       13%) were inhibited at 0.07 mg/kg bw/day only, but no biologically significant
       inhibition of brain AChE, red blood cell AChE, or plasma ChE was observed in
       males at any dose level (Chr93). According to EPA, the NOAEL was 0.03
       mg/kg/day, based on biological meaningful cholinesterase inhibition (And00).
       The committee feels, however, that the 3-14% inhibition of red blood cell AChE
       activity in females at 0.02 mg/kg/day, the lowest level tested, has to be
       considered as significant. Therefore, the committee could not establish a
       NOAEL for AChE inhibition in this 6-month oral rat study.
           In a one-year study addressing potential ocular and neurological effects,
       disulfoton (technical grade in corn oil; purity: 97%) was fed to beagle dogs
       (n=4/sex/group) at dose levels equivalent to 0, 0.015, 0.12, and 0.32 mg/kg bw/
       day for males and 0, 0.013, 0.094, and 0.28 mg/kg bw/day for females.
       Cholinesterase activity was measured in plasma, red blood cell, brain, ocular
       tissues (retina, cornea, ciliary body), and extraocular muscles (lateral and dorsal
       recti) of the left eye. An ophthalmological and neurological examination and
       electroretinography were performed pre-treatment, at 6 months, and just prior to
       termination. No treatment-related effects on neurovisual performance, clinical
       neurology (task performance), and clinical chemistry and haematology test data
       or gross or microscopic post-mortem changes were observed. In the high-dose
       groups, plasma ChE and red blood cell AChE activities were inhibited by 56-
       63% and 30-91%. In the mid-dose groups, inhibition of plasma ChE and red
       blood cell AChE activities was 38-46% and 38-40%, respectively. In the low-
       dose groups, only plasma ChE activity was slightly inhibited (10%) in males
       after 6 months. Brain AChE activity was depressed in the high-dose group in
       male and female animals by 32-33% and in the mid-dose group only in females
       by 22%. ChE activities in the cornea, the retina, and in the ciliary body were also
       depressed at the mid and top doses. The depression in ChE activity at the lowest
071-12 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       dose in plasma (10%, temporarily), cornea (33%, males only), and ciliary body
       (15%, males only) was considered equivocal and not related to treatment. In this
       one-year oral dog study, the NOAEL was 0.013 mg/kg bw, based on inhibition of
       brain and red blood cell AChE (Jon99).
           In a 2-year oral (diet) study, beagle dogs (n=4/sex/group) were given
       disulfoton (technical grade; purity: 95.7%) at levels equivalent to 0, 0.0125,
       0.025, or 0.05 mg/kg bw/day. After 69 weeks, the top dose was subsequently
       increased to 0.125 mg/kg bw/day during weeks 70-72, and to 0.2 mg/kg bw/day
       from week 73 to termination. No treatment-related signs of intoxication or
       changes in general appearance and behaviour, ophthalmoscopy parameters, food
       consumption, body weight, haematology, clinical chemistry, or organ weights, or
       upon microscopic examination were observed. A single dog dosed with 0.0125
       mg/kg bw of disulfoton developed interstitial nephritis and died at week 93. No
       inhibition of plasma ChE or red blood cell or brain AChE activity was observed
       at dose levels ≤0.025 mg/kg/day. At 0.05 mg/kg bw/day, plasma ChE and red
       blood cell AChE activity were depressed by 50 and 33% in males and 22 and
       36% in females, respectively, at week 40. At termination of exposure, at 0.2 mg/
       kg bw/day, plasma ChE and red blood cell and brain AChE activities were
       depressed by 65, 58, and 34% in males and 49, 48, and 18% in females,
       respectively. The NOAEL for red blood cell and brain AChE inhibition in this 2-
       year oral dog study was 0.025 mg/kg/day (Hof76).
       One-week-old White Leghorn chicks (Gallus domesticus) were fed doses of
       disulfoton (purity: 90%) of 0.29 mg/kg bw for 71 days. No adverse effect on
       growth was noted. After termination, tissues were pooled for analysis of lipid
       concentrations. Total lipid content in all organs, except liver and sciatic nerves,
       was decreased. Also, the ratio of phospholipids to total cholesterol was decreased
       in all nervous tissues except the spinal cord. However, this ratio was increased in
       liver and kidney (due to a decrease in total cholesterol in these organs). These
       results were interpreted as an indication of degenerative changes in the brain
       (Gop79).
           The results of these short-term toxicity studies are summarised in Table 2.
071-13 Disulfoton
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<pre>Table 2 Summary of short-term toxicity studies for disulfoton.
exposure    species (strain; sex;   dose levels                    exposure critical effecta     NOAEL         reference
route       number)                                                duration
inhalation  rat (Wistar; n=10/sex/  0, 0.5, 1.8, 9.8 mg/m3         5 days   RAChEb               0.5 mg/m3     Thy78
            group)
            rat (Wistar; n=10/sex/  0, 0.02, 0.1, 0.5, 3.7 mg/m3   3 weeks  BAChEc RAChE 0.1 mg/m3             Thy80
            group)
            rat (F344; ?)           0, 0.006, 0.07, 0.7 mg/m3      3 weeks  BAChE                0.7 mg/m3     Shi88
            rat (F344; n=12/sex/    0, 0.018, 0.16, 1.4 mg/m3      13 weeks BAChE RAChE          0.16 mg/m3    Shi89
            group)
dermal      rabbit (New Zealand     0, 0.4, 1.6, 6.5 mg/kg bw/d    3 weeks  BAChE RAChE          0.4 mg/kg bw Flu86
            White; n=5/sex/group)
oral        rat (Sprague-Dawley;    2.0 mg/kg bw/d                 2 weeks  BAChE                LOAEL:        Yag96
            male; ?)                                                                             2.0 mg/kg bw
            rat (Long-Evans; ?;     2.0 mg/kg bw/d                 2 weeks  BAChE                LOAEL:        Fit93
            n=4)                                                                                 2.0 mg/kg bw
            rat (F344; n=18/sex/    0, 0.06, 0.27, 1.1 mg/kg bw/d 13 weeks  BAChE RAChE          LOAEL:        She97
            group)                                                                               0.06 mg/kg bw
            rat (F344; n=35/sex/    0, 0.02, 0.03, 0.07 mg/kg bw/d 6 months BAChE RAChE          LOAEL:        Chr93
            group)                                                                               0.02 mg/kg bw
            dog (beagle; n=4/sex/   0, 0.015, 0.12, 0.32 mg/kg bw/ 1 year   BAChE RAChE          0.015 mg/kg   Jon97,
            group)                  d                                                            bw            Jon99
            dog (beagle; n=4/sex/   0, 0.0125, 0.025, 0.05/0.125/  2 years  BAChE RAChE          0.025 mg/kg   Hof76
            group)                  0.2 mg/kg bw/d                                               bw
            chicken (White Leg-     0.29 mg/kg bw/d                71days   lipids in nerve tis- LOAEL:        Gop79
            horn; female; ?)                                                sue                  0.29 mg/kg bw
a
     RAChE = red blood cell AChE, BAChE = brain AChE.
           Long-term toxicity and carcinogenicity
           In a 104-wk feeding study, Fisher 344 rats (n=60/sex/group) were given
           technical-grade disulfoton (purity: 98.1%) at doses equivalent to 0, 0.04, 0.165,
           or 0.650 mg/kg bw/day. No effect on mortality or on clinical chemistry and
           haematology test results were seen at any dose. However, at the highest dose,
           mean body weights and body weight gains were depressed in both males and
           females. Gross examination showed an increase in relative organ weight of heart,
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<pre>       liver, kidneys, and lung in female rats and brain in both sexes at 0.650 mg/kg
       bw/day. Corneal vascularity was increased in males and females at this dose,
       while corneal epithelial hyperplasia and optic nerve degradation were elevated in
       females only. No microscopic changes in the eyes could be detected at the lower
       doses. An increased incidence of cystic degeneration of the Harderian gland was
       seen at the highest dose in males and at 0.165 and 0.650 mg/kg bw/day in
       females. Since there is no Harderian gland in humans, the significance of these
       pathological changes is uncertain. Other non-neoplastic changes in females
       included skin inflammation, ulceration and hyperkeratosis, skeletal muscle
       atrophy, and granulomatous inflammation of the lungs at the top dose. There was
       no statistically significant difference in the incidence and in the type or time of
       onset of neoplasms between controls and disulfoton-treated animals. At
       termination of the study, a dose-related inhibition in plasma ChE and red blood
       cell and brain AChE was observed at all doses in both sexes. Plasma ChE and red
       blood cell AChE activities were inhibited by 11-94% and 19-80%, respectively,
       in males and by 25-95% and 12-76%, respectively, in females. Brain AChE
       activities were inhibited by 15%, 53%, and 79% in males and 21%, 53%, and
       82% in females at 0.04, 0.165, and 0.650 mg/kg bw, respectively. Consequently,
       a NOAEL for inhibition of brain and red blood cell AChE activities could not be
       established in this 2-year oral rat study (Hay85).
           In a 108-week feeding study, Crl:CD-1 mice (n=50/sex/group) were given
       disulfoton (purity: 98.2%) at levels equivalent to 0, 0.15, 0.6, or 2.4 mg/kg
       bw/day. No treatment-related effects were observed on body weight, food
       consumption, haematology, or mortality. At termination of the study, gross
       examination showed enlarged spleen, liver, and lymph nodes in the high-dose
       group, with greater frequency in females than in males. There was no statistically
       significant difference in the incidence of malignant lymphomas or any other
       tumours between disulfoton-treated groups and the control group. At the end of
       the study, plasma ChE, red blood cell AchE, and brain AChE activities in the
       high-dose group were inhibited by 79%, 56%, and 44% in males and by 82%,
       50%, and 46% in females, respectively. In this 108-week oral mouse study, the
       NOAEL for inhibition of red blood cell and brain AChE activities was 0.6
       mg/kg bw (Hay83).
           Based on these results, the committee does not consider disulfoton to be a
       carcinogenic compound.
071-15 Disulfoton
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<pre>       Mutagenicity and genotoxicity
       Mutagenicity and genotoxicity assays comprised tests for the detection of gene
       mutations in bacteria, yeast, and mammalian cells in vitro and in vitro and in vivo
       cytogenicity and other in vitro genotoxicity assays.
       •   In vitro tests
           • Gene mutation assays. Tests for reverse mutations in several strains of S.
              typhimurium and in E. coli WP2 were positive at concentrations up to
              20,000 µg/plate both with and without metabolic activation (Han75,
              Mor83, Shi79), but negative when tested by EPA up to 5000 µg/plate
              (And00). Negative results were also found in S. typhimurium strains up to
              1000 µg/plate and S. cerevisae up to 200 µl/well in the presence or
              absence of metabolic activation (Inu76, Jag81, Kie86, Wat80). Disulfoton
              induced gene mutations in cultured mouse lymphoma L5178Y cells at
              concentrations of 40-90 µg/mL in the absence of S9 activation, but no
              mutagenic activity was seen in the presence of S9 activation up to a
              cytotoxic dose (And00). Equivocal results were obtained in an hprt
              forward gene mutation assay in cultured Chinese hamster ovary cells
              (CHO) when tested at concentrations of 0.03-10 µg/mL with and without
              S9 activation (Yan88). Disulfoton did not induce sex-linked recessive
              lethal mutations in D. melanogaster (Lee83).
           • Cytogenicity assays. In cultured Chinese hamster V79 cells, the chemical
              did not induce sister-chromatid exchanges (SCE) at doses up to 80 µg/mL
              in the presence or absence of a metabolic activation system (Che82).
              Positive SCE results were seen in cultured Chinese hamster ovary (CHO)
              cells at concentrations up to 100 µg/mL disulfoton in the absence of
              metabolic activation, but no increased SCE frequency was observed with
              S9 activation (Put87). In contrast, in another study, a slightly increased
              incidence of SCEs was found with metabolic activation only (And00).
           • Other genotoxicity assays. Disulfoton did not induce mitotic
              recombination in S. cerevisiae D3 both with and without metabolic
              activation (Zim84). It increased unscheduled DNA synthesis in cultured
              WI-38 human lung fibroblasts at doses up to 4000 µg/mL, but failed to do
              so in the presence of a metabolic activation system (Mit83).
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<pre>       • In vivo tests
       NMRI mice given 2 oral doses of disulfoton of 6 and 12 mg/kg bw each, did not
       show an increased incidence of micronuclei in polychromatic erythrocytes
       (Her81). This test was also negative in Swiss-Webster mice up to a lethal dose (8
       mg/kg bw) administered once daily for 2 consecutive days by intraperitoneal
       injection (And00). Dominant lethal effects were not induced following a single
       oral dose of 5 mg/kg bw of disulfoton in male NMRI mice (Her80).
       Based on these results, the committee concludes that disulfoton has some
       mutagenic potential in vitro, but this is highly dependent on the type of test-
       system used. In test animals, no genotoxic activity was detected.
       Reproduction toxicity
       In a 2-generation reproduction toxicity study in Sprague-Dawley rats (n=30/sex/
       group), both the F0 generation and the F1 offspring (one litter/animal/group)
       were given technical-grade disulfoton (purity: 99%) at dose levels equivalent to
       0, 0.025, 0.10, or 0.45 mg/kg bw/day. Cholinesterase activities were measured in
       adults during pre-mating (at 8 weeks) and at termination of the study and in pups
       at postnatal days 4 and 21 in the 2 generations. In the F0 parents, muscle
       fasciculations, tremors, salivation, body weight reduction, dams with no milk,
       and decreased maternal care were observed at the high-dose level. In F0 males,
       plasma ChE, red blood cell, and brain AChE activities were significantly
       inhibited (both at pre-mating and at termination) at 0.10 mg/kg bw/day and
       above, and in females at all dose levels. In F1 parents, tremors, decrease in body
       weight, and dams with no milk were noted at 0.45 mg/kg bw/day. At 0.10 mg/kg
       bw/day and above, brain AChE activity was significantly inhibited in both sexes.
       No treatment-related organ weight or histological changes were observed in
       either F0 or F1 males or females at any dose level. Effects in F1 and F2 pups were
       inhibition of red blood cell and brain AChE at days 4 and 21 of lactation,
       treatment-related deaths, and decrease in body weights at 0.45 mg/kg bw/day.
       Pup deaths were considered to be due to failure of maternal care. Based on brain
       AChE inhibition, a parental NOAEL could not be established (LOAEL: 0.025
       mg/kg bw/day). The NOAEL for reproduction toxicity in this 2-generation oral
       rat study was 0.10 mg/kg bw/day (AST97).
            In an earlier 2-generation study, Sprague-Dawley rats (n=26/sex/group) were
       fed technical disulfoton (purity: 97.8%) at dose levels equivalent to 0, 0.04, 0.12,
       or 0.36 mg/kg bw/day. F0 and F1a rats were given the diet for 15 and 13 weeks,
071-17 Disulfoton
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<pre>       respectively, prior to mating, and the F1b rats were maintained on the diet
       continuously throughout production of F2 generations. Parental effects included
       cholinergic signs (tremors during gestation), reduced body weight gain during
       gestation and lactation, and reduced fertility index at 0.36 mg/kg bw/day.
       Cholinesterase activities were not determined. The gestation index and length
       were not different from the controls at any dose level. Effects in pups included
       reduced growth and survival, reduced litter count, litter weight, and viability and
       lactation indices, and inhibition of brain AChE activity (by 50-59%) in both
       generations at 0.36 mg/kg bw. At 0.12 mg/kg bw, embryotoxicity was noted in
       F2b animals only, and brain AChE activity was depressed in F1a pups by 24-
       32%. The parental NOAEL was 0.12 mg/kg bw/day, based on signs of toxicity.
       Based on reduced viability and lactation indices, and reduced brain AChE
       activity in F2b and F1a pups, respectively, the NOAEL for reproductive effects in
       this 2-generation oral rat study was 0.04 mg/kg bw/day (Hix86).
           In a developmental toxicity study, pregnant New Zealand White rabbits
       (n=14-22/group, artificially inseminated) were administered technical grade
       disulfoton in corn oil by gavage at 0, 0.25, 0.86, or 2.7 mg/kg bw/day during
       days 6-18 of gestation. Since the highest dose level caused mortality and clinical
       signs of toxicity in the dams, this level was reduced to 2.0 mg/kg bw/day and
       later to 1.5 mg/kg/day. On day 29 of gestation, the animals were sacrificed. Nine
       out of 22 animals survived at the top dose, but in the 2 lower dose groups, no
       treatment-related deaths were observed. Body weight gain during treatment was
       reduced in animals dosed with 0.86 mg/kg bw and above. The number of
       implantations, extent of pre- and post-implantation losses, pup weight at birth,
       and viability of pups were similar to controls for all treated groups. At the top
       dose, fetal toxicity was observed but survival, development, and growth were
       unaffected. No treatment-related soft tissue or skeletal anomalies were noted at
       any dose level. The NOAEL for maternal and developmental toxicity in this oral
       rabbit study were 0.25 mg/kg and >3 mg/kg bw/day, respectively (Tes82). In
       another teratology study, technical-grade disulfoton (purity: 98.2%; in
       polyethylene glycol 400) was fed by gavage to pregnant Sprague-Dawley rats
       (25/dose level) at dose levels of 0, 0.1, 0.3, or 1.0 mg/kg bw/day during days
       6-15 of gestation. On day 21, the animals were sacrificed. No mortality, signs of
       toxicity, or changes in body weight gain or feed consumption were observed in
       treated or control groups. On day 15, plasma ChE and red blood cell AChE
       activities were significantly reduced at 0.3 mg/kg bw/day. Gross examination did
       not show treatment-related lesions. There were no significant differences in the
       number of implantations per litter, live, dead, or resorbed fetuses, and the
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<pre>       incidence of soft tissue abnormalities between treated groups and control
       animals. At 1.0 mg/kg bw/day, fetuses showed incomplete ossification of the
       intraparietals and sternebrae. In this oral rat study, the NOAEL for maternal
       toxicity was 0.1 mg/kg bw/day, based on red blood cell AChE inhibition and the
       developmental NOAEL was 0.3 mg/kg bw/day (Lam83).
6      Existing guidelines
       The current administrative occupational exposure limit (MAC) for disulfoton 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 Annex II.
7      Health hazard assessment
       The health hazard assessment of disulfoton is based mainly on toxicology
       reviews issued by the Health Effect Division of the United States EPA for
       reregistration eligibility (And00) and by the FAO/WHO Joint Meeting on
       Pesticide Residues for recommendation of an acceptable daily intake (FAO92).
       The toxicity profile in these reviews is obtained mainly from unpublished reports
       of toxicology studies conducted for registration purposes by the chemical
       companies manufacturing or marketing the compound.
           Workers can be exposed to disulfoton through inhalation of vapour or
       aerosols or by direct skin contact with a formulation of the compound. No data is
       available of the percentage uptake of the compound following inhalation. In rats,
       the dermal absorption of disulfoton ranged from 25-33% of the dose, 10 hours
       after application. The extent of absorption following oral intake is greater than
       90% in the rat. Following oral or dermal absorption, the compound is rapidly
       metabolised into breakdown products that, in the rat, are excreted for more than
       90% of the dose in the urine. No cases of acute intoxications in humans have
       been reported. In a human volunteer study, oral intake of 0.75 mg/day for 30 days
       did not produce inhibition of plasma ChE or red blood cell AChE. Since only one
       dose was tested and no details were given, the committee considered the study
       inadequate for establishment of a health-based occupational exposure limit.
           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. The compound did not cause neurological changes indicative of acute
       delayed neurotoxicity. No significant systemic effects have been reported in
071-19 Disulfoton
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<pre>       short- or long-term toxicity studies in test animals. However, these studies
       showed inhibition of plasma ChE and of red blood cell and brain AChE in dogs,
       rabbits, and rats. These cholinesterases have approximately the same sensitivity
       for inhibition by disulfoton in these species. NOAELs for brain and for red blood
       cell AChE inhibition were 0.025 mg/kg bw for dogs (2-year oral study), 0.4 mg/
       kg bw for rabbits (3-week dermal study), 0.16 mg/m3 for rats (13-week
       inhalation study) and <0.04 mg/kg bw for rats (2-year oral study), respectively.
           Results of in vitro mutagenicity tests with disulfoton are conflicting and seem
       to be dependent on the test system. However, in vivo tests (cytogenicity assays in
       mice) did not show an increased incidence of abnormalities. Carcinogenicity
       studies in rats and mice did not show a treatment-related increase in tumour
       incidence. The committee concludes that the positive genotoxic effects of
       disulfoton were thus not reflected in carcinogenicity. With regard to reproduction
       toxicity, the committee concludes that there is no evidence of enhanced
       susceptibility of offspring as compared to adults in two 2-generation
       reproduction toxicity studies. In a developmental toxicity study in rats,
       incomplete ossification was only observed at higher doses as compared to those
       that cause maternal effects.
           Based on the above data, the committee concludes that the mechanism of
       toxicity of disulfoton 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 disulfoton 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 for brain AChE in assessing the
       human health risk of exposure to disulfoton (Jey94).
       The committee did not consider the disulfoton human volunteer study in deriving
       a health-based recommended occupational exposure limit (HBROEL).
       Therefore, studies in test animals are used. The committee takes the 13-week
       inhalation study in rats, with a NOAEL of 0.16 mg/m3, as a starting point. For
       extrapolation from rat to man, an overall assessment factor of 9, covering intra-
       and interspecies variation, is established. Thus, applying this factor of 9 and the
       preferred value approach, a health-based occupational exposure limit of 0.02
       mg/m3 is recommended for disulfoton.
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<pre>       The committee recommends a health-based occupational exposure limit for
       disulfoton of 0.02 mg/m3, as an 8-hour time-weighted average (TWA).
             Disulfoton 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 disulfoton*, the committee recommends a skin notation.
       References
ACG99  American Conference of Governmental Industrial Hygienists (ACGIH). Disulfoton. In: TLVs® and
       other occupational exposure values - 1999. [CD-ROM]. Cincinnati OH, USA; ACGIH®, Inc, 1999.
ACG03a American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
       exposure values - 2003. Cincinnati OH, USA: ACGIH®, Inc, 2003: 55.
ACG03b American Conference of Governmental Industrial Hygienists (ACGIH). 2003 TLVs® and BEIs®
       based on the documentation of the Threshold Limit Values for chemical substances and physical
       agents & Biological Exposure Indices. Cincinnati OH, USA: ACGIH®, Inc, 2003: 29.
And00  Anderson DG. Health Effects Division toxicity chapter for disulfoton for reregistration eligibility
       decision (RED) (Revised). Washington DC, USA: US Environmental Protection Agency, Office of
       Pesticide Programs, Health Effects Division, 2000; http://www.epa.gov/pesticides/op/disulfoton.htm.
Arb02  Arbejdstilsynet. Grænseværdier for stoffer og materialer. Copenhagen, Denmark: Arbejdstilsynet,
       2002; At-vejledning C.0.1.
Ast97  Astroff AB. A two generation reproductive toxicity study with disulfoton technical (disyston®) in the
       Sprague Dawley rat. Stilwell KA, USA: Bayer Corporation, 1997; lab rep no 95-672-FZ;
       unpublished report, cited in And00.
ATS95  Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for disulfoton.
       Atlanta GA, USA: US Department of Health and Human Services, Public Health Service, ATSDR,
       1995; http://www.atsdr.cdc.gov/toxpro2.html.
Bom58  Bombinski TJ, DuBois KP. Toxicity and mechanism of action of Di-Syston. AMA Arch Ind Health
       1958; 17: 192-9.
Bro81  Brokopp CD, Wyatt JL, Gabica J. Dialkyl phosphates in urine samples from pesticide formulators
       exposed to disulfoton. Bull Environ Contam Toxicol 1981; 26: 524-9.
Che82  Chen HH, Sirianni SR, Huang CC. Sister chromatid exchanges in Chinese hamster cells treated with
       seventeen organophosphorus compounds in the presence of metabolic activation system. Environ
       Mutagen 1982; 4: 621-4.
*      The dermal LD50 in male (Wistar) rats is 15.9 mg/kg bw; the inhalation LD50 calculated from the 4-hour LC50 of 60
       mg/m3 in male (Wistar) rats (assuming a retention of 1.0 and a minute volume of 125 mL/min for a 200-g weighing
       rat) is 9 mg/kg bw.
071-21 Disulfoton
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<pre>Chr93  Christenson W R, Wahle BS. Technical grade disulfoton (Di-Syston®): a special 6-month feeding
       study to determine a cholinesterase no-observed-effect level in the rat. Stilwell KA, USA: Miles, Inc,
       Agricultural Division, Toxicology, 1993; study no 91-972-IR; unpublished report, cited in And00.
Cos82  Costa LG, Murphy SD. Passive avoidance retention in mice tolerant to the organophosphorus
       insecticide disulfoton. Toxicol Appl Pharmacol 1982; 65: 451-8.
DFG02  Deutsche Forschungsgemeinschaft (DFG): Commission for the Investigation of Health Hazards of
       Chemical Compounds in the Work Area. List of MAK and BAT values 2002. Maximum
       concentrations and biological tolerance values at the workplace. Weinheim, FRG: Wiley-VCH, 2002;
       rep no 38.
EC03   European Commission: Directorate General of Employment and Social Affairs. Occupational
       exposure limits (OELs). http://europe.eu.int/comm/employment_social/h&s/areas/oels_en.htm.
ECE98  European Centre for Ecotoxicolgy and Toxicology of Chemicals (ECETOC). Examination of a
       proposed skin notation strategy. Brussels, Belgium: ECETOC, 1998; Special Report No. 15.
FAO92  Food and Agricultural Organization/World Health Organization (FAO/WHO): Joint Meeting of the
       FAO Panel on Experts on Pesticide Residues in Food and the Environment and the WHO Expert
       Group on Pesticide Residues (JMPR). Disulfoton. In: Pesticides residues in food – 1991 evaluations.
       Part II. Toxicology. Geneva, Switzerland: WHO, 1992; rep no WHO/PCS92.52; http://
       www.inchem.org/documents/jmpr/jmpmono/v91pr10.htm.
Fit93  Fitzgerald BB, Costa LG. Modulation of muscarinic receptors and acetylcholinesterase activity in
       lymphocytes and in brain areas following repeated organophosphate exposure in rats. Fundam Appl
       Toxicol 1993; 20: 210-6.
Flu86  Flucke, W. Study of subacute dermal toxicity to rabbits. Wuppertal-Elberfeld, FRG: Bayer AG,
       Institute of Toxicology, 1986; study no 14747; unpublished report, cited in And00 and FAO92.
Fut95  Futagami K, Otsubo K, Nakao Y, et al. Acute organophosphate poisoning after disulfoton ingestion.
       Clin Toxicol 1995; 33: 151-5.
Gai69  Gaines TB. Acute toxicity of pesticides. Toxicol Appl Pharmacol 1969; 14: 515-34.
Gop79  Gopal PK, Ahuja SP. Lipid & growth changes in organs of chicks (Gallus domesticus) during acute &
       chronic toxicty with disyston & folithon. Indian J Exp Biol 1979; 17: 1153-4.
Han75  Hanna PJ, Dyer KF. Mutagenicity of organophosphorus compounds in bacteria and Drosophila.
       Mutat Res 1975; 28: 405-20.
Hay83  Hayes RH. Oncogenicity study of disulfoton technical on mice. Stilwell KA, USA: Mobay Chemical
       Corporation, Corporate Toxicology Department, 1983; study no 80-271-04; unpublished report, cited
       in And00 and FAO92.
Hay85  Hayes RH. Chronic feeding/oncogenicity study of technical disulfoton (Di-Syston) with rats. Stilwell
       KA, USA: Mobay Chemical Corporation, Corporate Toxicology Department, 1985; study no 82-271-
       01; unpublished report, cited in And00 and FAO92.
Her80  Herbold B. S276, Disulfoton, Disyston active ingredient. Dominant lethal test on male mouse to
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       Toxicology, 1980; rep no 9440; unpublished report, cited in FAO92.
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<pre>Her81  Herbold B. S276, Disulfoton, Disyston active ingredient. Micronucleus test on the mouse to evaluate
       S276 for mutagenic effect. Wuppertal-Elberfeld, FRG: Bayer AG, Institute of Toxicology, 1981; rep
       no 10451; unpublished report, cited in FAO92.
Hix83  Hixson EJ. Acute delayed neurotoxicity study on disulfoton. Stilwell KA, USA: Mobile Chemical
       Corporation, Environmental Health Research Institute, 1983; study no 82-418-01, toxicol rep no 365;
       unpublished report, cited in FAO92
Hix86  Hixson EJ, Hathaway TR. Effect of disulfoton (Di-Syston®) on reproduction in the rat. Stilwell KA,
       USA: Mobay Chemical Corporation, Corporate Toxicology Department, 1986; stud no 82-671-02;
       rep no 90965; unpublished report, cited in And00 and FAO92.
Hof76  Hoffman K, Weischer CH, Luckhaus, et al. S 276 (disulfoton) chronic toxicity study in dogs (two-
       year feeding experiment). Wuppertal-Elberfeld, FRG: Bayer AG, Institute of Toxicology, 1976; rep
       no 45287; unpublished study, cited in And00 and FAO92.
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071-25 Disulfoton
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<pre>       Annex I
       Figure 1 Metabolism scheme for disulfoton (from ATS95).
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<pre>              Annex II
Occupational exposure limits for disulfoton in various countries.
country                              occupational             time-weighted type of exposure limit         notea       referenceb
- organisation                       exposure limit           average
                                     ppm      mg/m3
the Netherlands
- Ministry of Social Affairs and     -        0.1             8h               administrative              S           SZW03
Employment
Germany
- AGS                                -        0.1                                                          S           TRG00
- DFG MAK-Kommission                 -        -                                                                        DFG02
Great Britain
- HSE                                -        0.1             8h               OES                                     HSE02
                                     -        0.3             15 min
Sweden                               -        -                                                                        Arb02
Denmark                              -        0.1             8h                                           S           Swe00
USA
- ACGIH                              -        0.05c           8h               TLV                         S, A4d      ACG03b
- OSHA                               -        -                                                                        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
     Measured as inhalable fraction of vapour and aerosol.
d
     Classified in carcinogenicity category A4, i.e., not classifiable as a human carcinogen: agents which cause concern that
     they could be carcinogenic for humans but which cannot be assessed conclusively because of lack of data. In vitro or
     animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other
     categories.
071-27        Disulfoton
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<pre>071-28 Health-based Reassessment of Administrative Occupational Exposure Limits</pre>

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