<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>Dioxathion
(CAS No: 78-34-2)
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/070, The Hague, 22 september 2003
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. Dioxathion; Health-based Reassessment of Administrative
Occupational Exposure Limits. The Hague: Health Council of the Netherlands,
2003; 2000/15OSH/070.
all rights reserved
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of dioxathion
      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 E Meijer, M.D. (Wageningen University and Research Centre,
      Wageningen, The Netherlands)*.
          The evaluation of the toxicity of dioxathion 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 February 2000, literature was searched in the on-line databases
      Medline, Toxline, and Chemical Abstracts, covering the period 1964-1966 until
      February 2000, and using the following key words: dioxathion and 78-34-2. Data
      of unpublished studies were generally not taken into account. Exceptions were
      made for studies that were summarised and evaluated by international bodies
      such as the Food and Agricultural Organization/World Health Organization
      (FAO/WHO: Joint Meeting of the FAO Working Party of Experts and the WHO
      Expert Committee on Pesticide Residues (JMPR) (FAO69).
          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.
2     Identity
      name                            :     dioxathion
      synonyms                        :     phosphorodithioic acid S,S’-1,4-dioxan-2,3-diyl O,O,O’,O’-tetraethyl ester;
                                            2,3-p-dioxanedithiol S,S-bis(O,O-diethyl phosphorodithioate); 1,4-dioxane-
                                            2,3-diyl O,O,O’,O’-tetraethyl di(phosphorodithioate); Delnav®; Hercules
                                            AC-528
      molecular formula               :     C12H26O6P2S4
*      Current address: Institute of Risk Assessment Sciences (IRAS), University of Utrecht, Utrecht.
070-3 Dioxathion
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<pre>       structural formula          :
       CAS number                  :   78-34-2
3     Physical and chemical properties
      molecular weight           :    456.54
      boiling point              :    decomposes above 135ºC
      melting point              :    -20ºC
      vapour pressure            :    at 25oC: non-volatile
      solubility in water        :    at 25oC: insoluble
      Log Poctanol/water         :    3.0
      conversion factors         :    not applicable
      Data from ACG99, Gal91.
      Dioxathion is a non-volatile, very stable, dark amber liquid. Dioxathion in its
      most common commercial technical grade form contains 68% cis- and
      trans-isomers (1:2 ratio) of 2,3-p-dioxanedithiol S,S-bis(O,O-diethyl
      phosphorodithioate) as the principal ingredient. The remaining 32% consists of
      insecticidally active related compounds (Cas59, Fra63). It is unstable on iron or
      tin surfaces, and decomposes on heating above 135oC.
4     Uses
      Dioxathion is an acaricide, insecticide, and miticide used on citrus, grapes,
      walnuts, and stone fruits. It is also used to control ticks, lice, and horn flies on
      cattle, goats, dogs, horses, and sheep. Dioxathion is available as a 25% wettable
      powder and a 48% emulsifiable concentrate (Gal91).
           According to the database of the Dutch Pesticide Authorisation Board
      (CTB)*, dioxathion is at present not registered for its use as an active ingredient
070-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      in pesticides in the Netherlands. In the USA, dioxathion 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
      dioxathion 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
      32
         P-labelled dioxathion, applied dermally to cattle, was absorbed into the blood
      rapidly and a peak level of radioactivity was reached within 3 hours. About 20%
      of the administered dose (20.4%) was recovered from the urine and traces from
      the faeces within 7 days after the application. Diethyl phosphate (DEP),
      diethylphosphorothioate (DEPT) and diethylphosphorodithioate (DEPDT) were
      detected in the urine. Traces of radioactivity, mainly non-metabolised
      dioxathion, were found in the fat of the cattle 7 days following dermal
      application (Cha60). Rats were treated orally with 32P-labelled dioxathion (trans/
      cis ratio 2:1) at levels of 1, 5, and 15 mg/kg bw/day for 10 days. Metabolites
      were primarily excreted in the urine and to a lesser extent in the faeces.
      Metabolic products excreted in the first 12 hours after treatment with 15 mg/kg
      were identified as DEP, DEPT, and DEPDT (Art59). In a later study, male albino
      Sprague-Dawley rats were given single oral doses of 1.6 or 2.05 mg/kg bw of
      trans-dioxathion and 3.0 or 3.2 mg/kg bw of cis-dioxathion. Both isomers were
      14
         C-labelled either in the ethoxy moiety or in the dioxane ring. Both cis- and
      trans-dioxathion were rapidly excreted: between 75 and 98% of the administered
      dose within 96 hours, of which 80-87% of both isomers was present in the urine.
      Most of the radiocarbon recovered within 96 hours was excreted during the first
      24-hour period following administration, i.e., 92-96% for urine, 72-91% for
      faeces, and 88-95% for 14CO2. The principal metabolic pathway for both the
      trans- and cis-isomer was hydrolytic cleavage of the phosphorodithioate
      grouping at the phosphorus-sulphur as well as the carbon-sulphur bonds, forming
      DEPT (46 and 47% of administered trans- and cis-isomers, respectively) and
      DEPDT (15 and 3% of administered trans- and cis-isomers, respectively). A
      secondary pathway involves oxidation of P=S to P=O, forming the
      corresponding oxons and dioxons, with subsequent degradation by hydrolysis to
      DEP (13 and 17% of administered trans- and cis-isomers, respectively). The
      compound also undergoes cleavage of the dioxane ring as demonstrated by
*      at: http://www.ctb-wageningen.nl/geel.html.
070-5 Dioxathion
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<pre>      formation of 14CO2 (approximately 6% of dose) from both isomers. Parent
      dioxathion appeared in the faeces, more with the cis- (4.7% of dose) than with
      the trans-isomer (2.1% of dose) (Har76).
6     Effects and mechanism of action
      Human data
      Acute toxicity
      One case of acute poisoning has been described in a 5-year-old boy. Within 30
      seconds after he had received 3/4 teaspoonful of a dioxathion formulation
      mistaken for cough medicine, he started vomiting. Within 2 hours after ingestion,
      the child was mentally dull and unable to stand; he had shallow rapid
      respirations, muscle fasciculation, tearing, and miosis. Serum cholinesterase
      (ChE) activity was less than 10% of normal. After 12 hours of appropriate
      treatment, most of the signs and symptoms cleared. The dose ingested was
      estimated to be 1100 mg of technical dioxathion, equivalent to 75 mg/kg bw. The
      absorbed dose was somewhat less; both the colour and odour of the formulation
      were detected in the vomitus (Gal91).
      Short-term toxicity
      In a study with human volunteers, 5 males and 5 females were given 0.075
      mg/kg bw/day of dioxathion (as Delnav), for 28 days. No changes were observed
      in plasma ChE or red blood cell AChE activity compared to pre-treatment levels.
      Treatment was continued for another 28 days at levels of 0.075 and 0.150 mg/kg
      bw/day in one male and one female per dose group. No inhibition of red blood
      cell AChE was observed at any of these levels, but plasma ChE was inhibited by
      10 to 20% in the 2 subjects who received 0.150 mg/kg/day. Two weeks after
      cessation of exposure, plasma ChE activity returned to pre-treatment level.
      Transient clinical symptoms, like nausea, vomiting, diarrhoea, headache,
      prolonged menstrual cycle, and hay fever were reported throughout the 3-4
      months observation period. In 4 control subjects, receiving placebos, identical
      symptoms were reported during the same period. The symptoms, therefore, were
      considered not related to Delnav administration (Fra63).
070-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>             Animal data
             Irritation and sensitisation
             Dioxathion produced mild, transient conjunctivitis but no transient or permanent
             corneal damage when 0.1 mL was instilled into the eyes of rabbits (Fra63).
                 The committee did not find data from studies on the possible sensitising
             properties of dioxathion.
             Acute toxicity
             Acute lethal toxicity values in test animals are summarised in Table 1.
Table 1 Summary of acute lethal toxicity studies for dioxathion in experimental animals.
exposure route    vehiculum                   species (strain)           sex             LC50/LD50        reference
                                                                                                   3
inhalation                                    rat (Wistar)               male, female    1398 mg/m (1 h)  Fra63
                                              mouse                      male, female    340 mg/m3 ( 1 h) Fra63
dermal            xylene                      rat (Sherman)              male            235 mg/kg bw     Gai60
                  xylene                      rat (Sherman)              female          63 mg/kg bw      Gai60
                  xylene                      rabbit                     male, female    100 mg/kg bw     Fra63
                  none                        rabbit                     male, female    106 mg/kg bw     Fra63
                                              rabbit                     not specified   85 mg/kg bw      NIO02
oral              corn oil                    rat (Osborne-Mendel)       male            118 mg/kg bw     Hag61
                  peanut oil                  rat (Sherman)              male            43 mg/kg bw      Gai60
                  peanut oil                  rat (Sherman)              female          23 mg/kg bw      Gai60
                  corn oil                    rat (Holtzman)             male            50 mg/kg bw      Fra63
                  ethanol-propylene glycol    rat (Sprague-Dawley)       male            45 mg/kg bw      Fra63
                  corn oil                    rat (Sprague-Dawley)       male            64 mg/kg bw      Fra63
                                              rat                        not specified   20 mg/kg bw      NIO02
                  corn oil                    mouse                      male            176 mg/kg bw     Fra63
                  none                        dog (mongrel)              male, female    10-40 mg/kg bw   Fra63
                                              chicken (Rhode Island      female          316 mg/kg bw     Fra63
                                              Red)
intraperitoneal   ethanol-propylene glycol    rat (Sprague-Dawley)       female          30 mg/kg bw      Fra63
                                              mouse                      not specified   33 mg/kg bw      NIO02
070-7        Dioxathion
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<pre>      The cis-isomer is more toxic than the trans-isomer (subcutaneous rat LD50: cis:
      66-86 mg/kg bw; trans: 230-290 mg/kg bw). Hypersalivation, diarrhoea,
      lachrymation, rapid breathing, and tremors were typical symptoms of toxicity.
      Death was usually preceded by clonic seizures. Following intraperitoneal
      administration of 13 mg/kg bw of Delnav to rats, red blood cell and brain AChE
      activities were inhibited by 60-80% and plasma ChE by 100%. Recovery to
      normal activities required 3 weeks for plasma ChE and over 3 weeks for red
      blood cell and brain AChE (Fra63).
          Delnav did not produce acute delayed neurotoxicity in hens following single
      oral doses of 10-1000 mg/kg bw or subcutaneous doses of 25-200 mg/kg bw
      (Fra63).
      Short-term toxicity
      Weanling albino Charles River rats (n=25/sex/group) were given dietary levels
      equivalent to 0, 0.077, 0.22, 0.78, 7.5, and 37 mg/kg bw of Delnav, for 90 days.
      Five animals per sex per group were sacrificed after 3, 6, 9, and 13 weeks of
      treatment while the remaining 5 animals per sex were placed on a control diet for
      3 weeks before being sacrificed. Animals fed 37 mg/kg bw/day were sacrificed
      after one week because of marked food refusal and body weight loss. Clinical
      signs observed were limited to hyperexcitability and slight tremors in female rats
      fed 7.5 mg/kg bw/day. Neither increase in mortality, nor any gross or
      microscopic pathology related to the compound were observed in any of the
      groups. Throughout the treatment period, plasma ChE and red blood cell AChE
      were inhibited by about 95% and brain AChE by about 80% in rats fed 7.5 mg/kg
      bw/day. After cessation of administration of Delnav, plasma ChE returned to
      almost normal activity while brain and red blood cell AChE recovered more
      slowly remaining statistically significant below control levels. At 0.78 mg/kg bw,
      treatment did not affect brain AChE activity. Plasma ChE and red blood cell
      AChE activities were statistically significantly lower than those in control
      animals throughout treatment but returned to normal values during the recovery
      period. At 0.22 and 0.077 mg/kg bw, no statistically significant alterations in
      brain or red blood cell AChE or plasma ChE were observed (Fra63). According
      to the committee, the NOAELs in this study are 0.22 mg/kg bw for plasma ChE
      and red blood cell AChE activities and 0.78 mg/kg bw for brain AChE activity.
          In another 13-week study, 30 male and 30 female rats (strain: Holzman) were
      given levels equivalent to 0.01, 0.05, 0.25, and 1.25 mg/kg bw/day of dioxathion
      in the diet. Fifteen animals of each sex were used for determination of
070-8 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      cholinesterase activities in brain, liver, and serum and 15 of each sex for
      determination of carboxylesterase (aliesterase) activity. The latter enzyme was
      measured to investigate possible potentiation by Delnav of the toxicity of
      organophosporus pesticides containing carboxyester linkages, e.g., malathion. At
      1.25 mg/kg bw/day, the chemical produced inhibition of brain AChE (by
      2-30%), serum ChE (by 45-71%), and liver ChE (by 47-58%) activities. Feeding
      of 0.25 mg/kg bw did not inhibit brain AChE activity, but serum and liver ChE
      activities were depressed by 0-27% and 10-34%, respectively. At 0.05 mg/kg bw/
      day and below, no significant inhibition of the enzyme activity was found in any
      of the tissues. The NOAEL for inhibition of brain AChE activity was 0.25 mg/kg
      bw and for inhibition of serum or liver ChE activity 0.05 mg/kg bw.
      Carboxylesterase was found to be more susceptible to inhibition by Delnav than
      cholinesterase activities. The NOEL for inhibition of carboxylesterase activity in
      liver was 0.01 mg/kg bw and in serum 0.05 mg/kg bw (Dub68).
          In a range-finding dog study (mongrel; n=2/sex/group), Delnav was
      administered at doses equivalent to 0.25 and 0.80 mg/kg bw, for 12 days (5
      days/week), 2.5 mg/kg bw, for 10 days, and 8.0 mg/kg bw, for 5 days. At the top
      dose only, dogs developed symptoms of intoxication (diarrhoea, hypersalivation,
      tremors). Concomitant red blood cell AChE and plasma ChE activities were
      inhibited by 79% and 75%, respectively. Administration of 2.5 mg/kg bw for 10
      days produced inhibitions of 63% for red blood cell AChE and of 87% for
      plasma ChE activity. No significant inhibition of red blood cell AChE activity
      was observed at the lowest dose. However, plasma ChE activity was inhibited by
      25%. The NOAEL for inhibition of red blood cell AChE activity was 0.25 mg/kg
      bw (Fra63). In the subsequent study, groups of dogs (mongrel; n=2/sex/group)
      fed levels equivalent to 0.013, 0.025, or 0.075 mg/kg bw, 5 days/week, for 90
      days, did not show statistically significant inhibition of either red blood cell
      AChE or plasma ChE, measured throughout the study and during a 4-week
      exposure-free period, when compared to 3 pre-treatment cholinesterase values
      (Fra63). The NOAEL in dogs for plasma ChE and red blood cell AChE in this
      study was 0.075 mg/kg bw/d, the highest dose tested.
      A summary of the above studies is presented in Table 2.
070-9 Dioxathion
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<pre>Table 2 Summary of short-term oral toxicity studies for dioxathion.
species                                dose levels                exposure duration critical effecta NOAEL        reference
(strain; number; sex)                  (mg/kg bw/d)                                                  (mg/kg bw/d)
rat                                    0.077, 0.22, 0.78, 7.5, 37 13 weeks          BAChE            0.78         Fra63
(Charles River ; n=25/sex/group)                                                    RAChE            0.22
rat                                    0.01, 0.05, 0.25, 1.25     13 weeks          BAChE            0.25         Dub68
(Holzman; n=30/sex/group)
dog                                    0.25, 0.80 (12 d);         5, 10, 12 days    RAChE            0.25         Fra63
(mongrel; n=2/sex/group))              2.5 (10 d); 8.0 (5 d)
dog                                    0.013, 0.025, 0.075        13 weeks          RAChE            0.075        Fra63
(mongrel; n=2/sex/group))
a
     BAChE = brain AChE; RAChE = red blood cell AChE.
             Long-term toxicity and carcinogenicity
             Osborne-Mendel rats (n=50/sex/group) were given technical-grade dioxathion
             (purity: 68-75%) in the feed for 33 weeks, at concentrations equivalent to 0, 2.6,
             or 5.2 mg/kg bw/day for males and 0, 1.3, or 2.6 mg/kg bw/day for females.
             Then, dioxathion concentrations were increased to 3.5 or 7.0 mg/kg bw/day for
             males, and to 1.75 or 3.5 mg/kg bw/day for females, during the following 45
             weeks. After the 78-week dosing period, observation of the rats continued for an
             additional 33 weeks. Clinical signs of toxicity in all treated groups included
             tremors, hyperactivity, and apparent hind-limb paralysis. No dose-related
             changes in mortality or in mean body weights were seen. A variety of neoplasms
             was observed in treated and control animals of both sexes. However, the
             incidence of neoplasms in treated groups was not statistically significantly
             different from controls. Gross and microscopic examination did not reveal any
             dose-related non-carcinogenic effects. Cholinesterase activities were not
             determined (NCI78).
                  Dioxathion was also administered in the feed of B6C3F1 mice (n=50/sex/
             group) at initial concentrations equivalent to 0, 23, or 47 mg/kg bw/day for males
             and 0, 37, or 74 mg/kg bw/day for females. Twenty animals of each sex were
             used as controls. In week 18, concentrations were increased to 31 or 62 mg/kg
             bw/day for males, and to 52 or 105 mg/kg bw/day for females. At the end of the
             78-week dosing period, the mice were observed for an additional 12 to 13 weeks.
             No clinical signs of intoxication were reported. Survival and mean body weight
             gain were not affected. There was no evidence of carcinogenicity in either male
070-10       Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       or female mice. However, a dose-related increase in the incidence of nodular
       hyperplasia of the liver was observed in male mice. Cholinesterase activities
       were not determined (NCI78).
       Mutagenicity and genotoxicity
       Dioxanthion was tested for reverse mutations in several strains of S. typhimurium
       (TA97, TA98, TA100, TA1535, TA1537) at concentrations of 0.10, 0.33, 1.0, 3.3,
       6.6, and 10 mg/plate in the presence and absence of rat or hamster liver S9. The
       compound was positive in all strains at 1.0 mg/plate and above (Mor86).
           The committee did not find results from other mutagenicity/genotoxicity
       studies on dioxathion.
       Reproduction toxicity
       A 3-generation reproduction study was conducted in groups of weanling
       Sprague-Dawley albino rats, each consisting of 8 males and 16 females. The
       animals were fed dietary levels equivalent to 0, 0.15, and 0.5 mg/kg bw of
       Delnav, for 39-42 weeks, starting at 28 days of age. No treatment-related
       increased mortality and no changes in body weight gain, behaviour,
       haematological and biochemical data, and gross and microscopic histology were
       found in any of the parental generations after 39-42 weeks of treatment. The
       incidence of tumours in the treated groups was not different from control
       animals. No effect on mating, fertility, and pregnancy indices, and on gestation
       time was observed in test animals compared to the control group. No effect on
       parturition, number of litters and live births, pup viability at birth and at various
       intervals in the lactation period, and on weanling body weight gain was noted at
       either level. Brain AChE, red blood cell AchE, and plasma ChE activities were
       not different between test and control groups of F2 parental animals. In summary,
       findings among all test animals, 3 parental generations and 6 litters of progeny
       were comparable to control animals for all parameters. The NOAEL for parental
       and reproductive effects in this study was 0.5 mg/kg bw, the highest dose tested
       (Ken73).
7      Existing occupational exposure limits
       The current administrative occupational exposure limit (MAC) for dioxathion in
       the Netherlands is 0.2 mg/m3, 8-hour TWA, with a skin notation.
070-11 Dioxathion
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<pre>           Existing occupational exposure limits in some European countries and the
       USA are summarised in the annex.
8      Health hazard assessment
       Workers can be exposed to dioxathion through inhalation of aerosols or by direct
       skin contact. No quantitative data is available of the percentage absorption of
       dioxathion through the lungs. The dermal absorption is about 20% of the applied
       dose in cattle, but no data is available of skin absorption in humans. The extent of
       absorption following oral intake is between 75% and 98% of the dose in rats.
       Following absorption, dioxathion is rapidly metabolised into breakdown
       products, e.g., DEPT, DEP and DEPDT, which are mainly excreted in the urine.
           No cases of intoxication have been reported in humans involved in
       manufacture or use of the compound. One case of intoxication following
       ingestion of dioxathion by a child showed that it takes 2-3 hours for symptoms
       and signs to become manifest, such as, inhibition of plasma ChE, respiratory
       difficulties, and muscle fasciculations. In a human volunteer study, oral intake of
       0.075 for 28 days, did not produce inhibition of plasma ChE or red blood cell
       AChE activity in 5 males and 5 females while treatment for another 28 days at
       levels of 0.075 and 0.15 mg/kg bw (n=1/sex/group) caused a decrease of plasma
       ChE activity by 10 to 20% in the high-dose group. Red blood cell AChE activity
       was not affected. A LOAEL for red blood cell AChE inhibition could not be
       established. The NOAEL was, therefore, equal to or greater than 0.150 mg/kg
       bw/day.
           Dioxathion is slightly irritating to eyes of rabbits. The committee did not find
       data on skin irritation or sensitisation of the compound. Based on results of acute
       lethal toxicity studies in test animals, the committee considers the compound as
       toxic after respiratory, dermal, and oral exposure. The compound did not cause
       acute delayed neurotoxicity in hens when tested at single oral or subcutaneous
       doses up to 1000 and 200 mg/kg bw, respectively. No significant systemic effects
       have been reported in short-term studies in rats and dogs, apart from inhibition of
       plasma ChE, red blood cell AChE, or brain AChE. Brain and red blood cell
       AChE were found to be less sensitive to inhibition by dioxanthion compared to
       plasma ChE. In two 13-week studies in rats, the NOAELs for brain AChE
       inhibition were 0.78 and 0.25 mg/kg bw, respectively, and for red blood cell
       AChE inhibition were 0.22 or 0.25 mg/kg bw; in a 13-week dog study, the
       NOAEL for red blood cell AChE inhibition was equal to or greater than 0.075
       mg/kg bw (higher doses not tested).
070-12 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>            Dioxathion was positive in one bacterial mutagenicity test. The committee
       did not find data from other in vitro or in vivo mutagenicity/genotoxicity tests.
       Carcinogenicity studies in rats and mice did not show a treatment-related
       increase in tumour incidence. The committee concludes that the positive result of
       the bacterial mutagenicity test was not reflected in carcinogenicity. The
       compound did not induce maternal or reproduction toxicity in rats at a dietary
       concentrations up to 0.5 mg/kg bw. No teratology studies have been reported.
            Based on the above data, the committee concludes that the mechanism of
       toxicity of dioxathion 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 dioxathion in animal studies, occurring at
       dose levels that 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
       health risk of exposure to dioxathion (Jey94).
       The committee takes the dose of 0.075 mg/kg bw that did not affect plasma ChE
       and red blood cell AChE activity in 10 volunteers exposed for 28 days and in 2
       exposed for an additional, subsequent 28 days 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 0.105 mg/kg bw. For extrapolation to a
       HBROEL, an overall assessment factor of 3, covering intraindividual variation,
       is applied, resulting in a NAEL for humans of 0.035 mg/kg bw/day. Assuming a
       70-kg worker inhales 10 m3 of air during an 8-hour working day and a retention
       of 100%, and applying the preferred value approach, a health-based occupational
       exposure limit of 0.2 mg/m3 is recommended for dioxathion.
       The committee recommends a health-based occupational exposure limit for
       dioxathion of 0.2 mg/m3, as an 8-hour time-weighted average (TWA).
            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 dioxathion*, the committee recommends a skin notation.
*      The dermal LD50 in rats is 235 or 63 mg/kg bw, for males or females, respectively; the inhalation LD50 calculated
       from the 1-hour LC50 of 1398 mg/m3 in rats (assuming a retention of 1.0 and a minute volume of 125 mL/min for a
       200-g weighing rat) is ca. 50 mg/kg bw.
070-13 Dioxathion
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<pre>       References
ACG99  American Conference of Governmental Industrial Hygienists (ACGIH). Dioxathion. 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: 53.
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: 28.
Arb02  Arbejdstilsynet. Grænseværdier for stoffer og materialer. Copenhagen, Denmark: Arbejdstilsynet,
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Art59  Arthur BW, Casida JE. Biological activity and metabolism of Hercules AC-528 components in rats
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DFG02  Deutsche Forschungsgemeinschaft (DFG): Commission for the Investigation of Health Hazards of
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       acylamidase, and cholinesterase by EPN and Delnav®. Toxicol Appl Pharmacol 1968;12: 273-84.
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.
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070-14 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>Gal91  Gallo MA, Lawryk NJ. Dioxathion. In: Hayes WJ Jr, Laws ER Jr. Classes of pesticides. San Diego
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070-15 Dioxathion
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<pre>              Annex
Occupational exposure limits for dioxathion in various countries.
country                             occupational                   time-weighted      type of exposure      notea     referenceb
- organisation                      exposure limit                 average            limit
                                    ppm           mg/m3
the Netherlands
- Ministry of Social Affairs and    -             0.2              8h                 administrative        S         SZW03
Employment
Germany
- AGS                               -             0.2                                                       S         TRG00
- DFG MAK-Kommission                -             -                                                                   DFG02
Great Britain
- HSE                               -             0.2              8h                 OES                   S         HSE02
Sweden                              -             -                                                                   Arb02
Denmark                             -             0.2              8h                                       S         Swe00
USA
- ACGIH                             -             0.1c             8h                 TLV                   S, A4d    ACG03b
- OSHA                              -             -                                                                   ACG03a
- NIOSH                             -             0.2              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 carcinogen 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.
070-16        Health-based Reassessment of Administrative Occupational Exposure Limits
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