<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>Naled
(CAS No: 300-76-5)
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/074, The Hague, 22 september 2003
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. Naled; Health-based Reassessment of Administrative
Occupational Exposure Limits. The Hague: Health Council of the Netherlands,
2003; 2000/15OSH/074.
all rights reserved
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of naled 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)*.
          In December 1999, literature was searched in the on-line databases Medline,
      Toxline, and Chemical Abstracts, covering the period of 1964-1966 until
      December 1999, and using the following key words: naled, dibrom, and 300-76-
      5. Reviews published in the ‘Handbook of pesticide toxicology’ (Gal91) and by
      the American Conference of Governmental Industrial Hygienists (ACG99) were
      also used. Data of unpublished studies were generally not taken into account.
      Exceptions were made for studies that were summarised and evaluated by
      international bodies such the Food and Agricultural Organization/World Health
      Organization (FAO/WHO) (WHO78) and the Health Effects Division (HED) of
      the US Environmental Protection Agency (EPA) (Hum99), as part of its hazard
      identification assessment review. The final search was carried out in Toxline and
      Medline in May 2002.
          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 literature search in Toxline and Medline in April 2003 did not
      result in information changing the committee’s conclusions.
2     Identity
      name                       :    naled
      synonyms                   :    phosphoric acid 1,2-dibromo-2,2-dichloroethyl dimethyl ester; dimethyl
                                      1,2-dibromo-2,2-dichloroethyl phosphate; bromchlophos; Dibrom; Bromex
      molecular formula          :    C4H7Br2Cl2O4P
*      Current address: Institute of Risk Assessment Sciences (IRAS), University of Utrecht, Utrecht, the Netherlands.
074-3 Naled
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<pre>       structural formula       :
       CAS number               :    300-76-5
3      Physical and chemical properties
       molecular weight          :    380.78
       boiling point             :    at 0.07 kPa: 120oC
       melting point             :    26.5-27.5oC (pure)
       flash point               :    -
       vapour pressure           :    at 20oC: 0.3 Pa
       solubility in water       :   poorly soluble (at 20oC: 0.2 g/100 mL)
       Log Poctanol/water        :    1.38
       conversion factors        :    not applicable
       Data from ACG99, Gal91, NLM02, Rob99.
       Pure naled is a white solid, while the technical form is 60% pure and is usually
       obtained as a liquid that has a slightly pungent odour. Naled is completely
       hydrolysed within 48 hours at room temperature in the presence of water. It is
       degraded by sunlight and should be stored in lightproof containers (ACG99).
4     Uses
       Naled is used to control mites, sucking pests, and some other insects in a wide
       variety of crops. It is also used for the control of public and animal health pests
       including mosquitoes. Naled is available as a 4% dust and 96% emulsifiable
       concentrate.
             According to the database of the Dutch Pesticide Authorisation Board
       (CTB)*, naled is at present not registered for its use as an active ingredient in
       pesticides in the Netherlands.
*       at: http://www.ctb-wageningen.nl/geel.html.
074-4  Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>5     Biotransformation and kinetics
      In cows and rats, oral doses of 32P-labelled naled were rapidly excreted in the
      urine and faeces (>90%). Metabolism of naled occurs via debromination to yield
      2,2-dichlorovinyl dimethyl phosphate (dichlorvos), hydrolysis to yield dimethyl
      phosphate and bromodichloroacetaldehyde, and demethylation to yield
      desmethyldichlorvos and monomethylphosphate (Cas62). In addition, the
      dichlorvos metabolite dichloroacetaldehyde might be formed (Hum99, Rob99).
6     Effects and mechanism of action
      Human data
      Naled was reported to have caused dermatitis in several publications. Contact
      sensitisation-type dermatitis was reported in women picking flowers sprayed
      with a mixture of naled (11%), captan (6%), and dicofol (2.4%). Results of patch
      tests gave strong evidence that naled had caused these effects (Edm67). In
      another case, contact dermatitis was reported in an aerial applicator who had
      used naled (Mic70). Technical-grade naled also was a skin irritant in adult white
      male volunteers (n=8-16) in a modified Draize skin irritancy test (5% w/v in
      ethanol), a 21-day continuous closed patch test (1% w/v), and a 21-day open
      patch test (at concentrations >10% w/v) (Phi72).
      Animal data
      Irritation and sensitisation
      Naled caused dermal irritation in a modified Draize test with New Zealand white
      rabbits and is also a severe eye irritant (Phi72, Hum99). The chemical was
      weakly positive in a guinea pig maximisation test after induction and challenge
      with a 0.2% solution in distilled water. However, a 2% solution was extremely
      allergenic (Mat85).
      Acute toxicity
      Mice exposed to an air concentration of 1500 mg/m3 naled for 6 hours did not
      show adverse effects (Tom94). However, EPA reported 4-hour inhalation LD50s
074-5 Naled
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<pre>              of 200 and 190 mg/m3 for male and female rats, respectively (EPA99). No further
              details were provided in either of the studies.
                  Acute inhalation LC50 values and dermal and oral LD50 values in test animals
              are summarised in Table 1.
Table 1 Acute lethal toxicity data for naled.
exposure route     vehiculum                    species (strain)     sex           LC50 or LD50   reference
(duration)
inhalation (4 h)                                rat                  male          200 mg/m3      Hum99
                                                                                             3
           (4 h)                                rat                  female        190 mg/m       Hum99
           (6 h)                                mouse                not specified >1500 mg/m3    Tom94
dermal             xylene                       rat (Sherman)        male          800 mg/kg bw   Gai69
                                                mouse                not specified 600 mg/kg bw   NIO02
                                                rabbit               male          390 mg/kg bw   Hum99
                                                rabbit               female        360 mg/kg bw   Hum99
                                                rabbit               not specified 1100 mg/kg bw  Wei93
oral               peanut oil                   rat (Sherman)        male          250 mg/kg bw   Gai69
                   corn oil                     rat                  male          325 mg/kg bw   Hum99
                   carboxymethylcellulose       rat                  male          191 mg/kg bw   Hum99
                   carboxymethylcellulose       rat (Sprague-Dawley) male          85.1a mg/kg bw Hum99
                                                rat                  female        281 mg/kg bw   Brz69
                   soya bean oil                rat (Sprague-Dawley) female        160 mg/kg bw   Ber78
                   corn oil                     rat                  female        230 mg/kg bw   Hum99
                   carboxymethylcellulose       rat                  female        92 mg/kg bw    Hum99
                                                                                       a
                   carboxymethylcellulose       rat (Sprague-Dawley) female        81.2 mg/kg bw  Hum99
                                                rat                  not specified 430 mg/kg bw   Wei93
                   polysorbate 80               mouse (CD-1)         male          375 mg/kg bw   Hal75
                   polysorbate 80               mouse (CD-1)         female        360 mg/kg bw   Hal75
                   soya bean oil                mouse (NAMRU)        female        222 mg/kg bw   Ber78
a
     Preliminary study to an in vivo cytogenetics assay.
074-6         Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      In an acute neurotoxicity study, male and female rats (no numbers given) were
      given single oral (gavage) doses of naled of 0, 25, 100, or 400 mg/kg bw.
      Functional observational battery (FOB) and locomotor activity were assessed
      pre-treatment, and 30 minutes, 7, and 14 days after treatment. The high dose
      caused mortality, overt clinical signs of toxicity (e.g., orange/yellow material on
      body surfaces; red material around mouth/nose/eyes), and a transient decrease in
      body weight gain (days 0-7). Animals given 100 and 400 mg/kg bw showed
      marked effects in the FOB on the day of treatment. Convulsions, tremors,
      increased secretions, exophthalmus, respiratory changes, reduced muscle
      strength, slowed response to stimuli, and reduced total motor activity were
      observed. At 25 mg/kg on the day of treatment only, one female had tremors, 2
      displayed exophthalmus, and one had reduced hind limb grip strength. No effects
      were observed 7 or 14 days after treatment at any dose level. The NOAEL for
      acute neurotoxicity was 25 mg/kg bw in males. Although no NOAEL could be
      identified for females, based on the minimal neurological findings in the main
      study and the lack of toxicity at doses of 5 and 25 mg/kg bw in the preliminary
      range-finding study (no details given), the NOAEL for female rats was set at 5
      mg/kg bw (Hum99).
          Adult domestic hens (n=40) were given an acute LD50 dose of naled (42
      mg/kg), preceded by treatment with atropine sulphate and 2-PAM to protect from
      acute cholinergic effects. Animals were observed for neurotoxic signs for 21
      days, re-dosed, observed for another 21 days, and then sacrificed for histological
      examination of central and peripheral nervous system tissue. Four treated and
      2/10 control hens died during the study. All treated animals showed clinical signs
      of neurotoxicity (‘subdued’, unsteady), but did not display locomotor ataxia
      characteristic of delayed neurotoxicity. Axonal degeneration was increased in the
      spinal cord compared to controls, but it was less severe than that produced by the
      positive control. A second group of hens (number not presented) was treated with
      single doses of 8 and 42 mg/kg bw and sacrificed 24 hours later for
      determination of brain AchE and neurotoxic esterase activities. Brain AChE was
      markedly depressed (50% at 42 mg/kg bw), but neuropathy target esterase (NTE)
      activity was unaffected (no more data presented) (Hum99).
074-7 Naled
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<pre>      Short-term toxicity
      No toxic effects were observed in rats and guinea pigs exposed to naled at a
      concentration of 19 mg/m3, 6 hours/day, 5 days/week, for 5 weeks. At 42 mg/m3,
      discomfort and inactivity were evident and cholinesterase activity (not further
      specified) was depressed (ACG99, WHO78). Exposure of rats (numbers and
      strain not given) to an aerosol of technical-grade naled at concentrations of 3.4,
      7.2, or 12.1 mg/m3, 6 hours/day, 5 days/week, for 3 weeks, caused a dose-
      dependent inhibition of brain and red blood cell acetylcholinesterase (AChE) and
      of plasma cholinesterase (ChE). Inhibition of cholinesterases started already at
      the lowest air concentration in both male and female rats (no more data
      presented) (Rit85). In a 13-week inhalation study, male and female Fischer 344
      rats (no numbers given) were exposed to aerosols containing 0, 0.2, 1, or
      6 mg/m3 of naled, 6 hours/day, 5 days/week. Additional control and high-
      concentration groups recovered for 6 weeks. At 6 mg/m3, brain and red blood cell
      AChE and plasma ChE were all inhibited (% not specified), and clinical signs
      consistent with cholinergic effects (tremors, salivation, nasal discharge,
      abnormal respiration, and anogenital staining) were observed. Only plasma ChE
      continued to be inhibited (% not given) after the 6-week exposure-free period. At
      1 mg/m3, plasma ChE (25-30% throughout the study) and red blood cell AChE
      (50-60% early in the study, 25-30% at 13 weeks) were still inhibited, but brain
      AChE activity was not different from the control group. The 13-week NOAEL
      for brain AChE inhibition in this study is 1 mg/m3 and for plasma ChE and RBC
      AChE inhibition 0.2 mg/m3 (Hum99).
           In a 28-day dermal study, doses of 0, 1, 20, or 80 mg/kg bw/day of naled in
      carboxymethylcellulose were applied to the intact skin of male and female
      CD/Sprague-Dawley rats (no numbers given). The 2 highest doses produced
      severe skin irritation (erythema, oedema, necrosis, and exfoliation), reduced
      body weight gain, and inhibition of brain AChE, red blood cell AChE, and
      plasma ChE activities. At 20 mg/kg bw, these activities were decreased by 60%,
      25%, and 50%, respectively. At the top dose, blood urea nitrogen was increased
      but creatinine, total protein, and albumin concentrations were decreased. Gross
      pathology revealed increased liver and adrenal weights (not specified) of females
      but histopathology did not show abnormalities. The NOAEL for dermal
      irritation, systemic toxicity, brain and red blood cell AChE, and plasma ChE
      inhibition was 1 mg/kg bw/day (Hum99).
           Groups of male and female rats (species and numbers not given) were given
      technical naled in their diets at doses equivalent to 10, 20, and 40 mg/kg bw for
074-8 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      28 days and to 40, 80, and 160 mg/kg bw for 29-94 days. Significant growth
      depressions and reduced food intake were observed at the 2 top doses. At 160
      mg/kg bw, there were tremors in some animals but no mortality occurred. No
      abnormalities in haematology or clinical chemistry and no gross or microscopic
      changes were found. Cholinesterase activities were not reported (WHO78). In a
      28-day oral (gavage) study, rats (n=10/sex/group) were given doses of naled
      (purity: not presented) of 0, 0.25, 1, 10, or 100 mg/kg bw/day. Feeding 100
      mg/kg bw/day produced mortality and marked cholinergic signs of toxicity. At
      10 mg/kg bw/day, mild cholinergic signs and marked inhibition of plasma ChE
      and brain AChE (50%) were observed. Feeding of 1 mg/kg bw/day resulted in a
      small decrease (15%) in plasma ChE activity only. The NOAEL for brain AChE
      inhibition in this study is therefore 1 mg/kg bw/day (no more details presented)
      (Hum99). Rats tolerated a dose of 28 mg/kg bw/day for 9 weeks without visible
      signs of poisoning and with only moderate inhibition of plasma ChE and brain
      AChE. No further details were given (Brz69). Rats given approximately 5 mg/kg
      bw/day of technical naled in the diet for a period of 12 weeks did not show signs
      of toxicity. Further details were not available (Tom94, Wei93).
          In a 90-day neurotoxicity study, male and female Sprague-Dawley rats
      (number not presented) were given naled (purity: 94.4%) at doses of 0, 0.4, 2.0,
      or 10.0 mg/kg/day by gavage. Neurological parameters were measured by both
      the FOB and locomotor activity. Minimal neurological effects (tremors of
      forelimb, hind limb, whole body) were recorded in 3 out of 10 females at the
      high dose, but no other clinical effects were observed. The 90-day neurotoxic
      NOAEL was 2.0 mg/kg bw (Hum99).
          Dogs were given dietary levels of 0.25, 0.75, 2.5, and 7.5 mg/kg bw/day for
      89 days. No mortality or clinical symptoms of intoxication were observed.
      Haematology, urinalysis, liver and kidney function tests, and gross and
      microscopic examination did not reveal adverse effects. At 2.5 and 7.5 mg/kg
      bw/day, red blood cell AChE and plasma ChE activities were reduced in all
      animals. Plasma ChE was slightly inhibited at 0.25 and 0.75 mg/kg bw. The 13-
      week NOAEL for inhibition of red blood cell AchE was 0.75 mg/kg/day (no
      more details presented) (WHO78). In another study, naled in aqueous
      carboxymethylcellulose (0.5% w/w) was administered by gavage to male and
      female beagle dogs for one year at doses of 0, 0.2, 2, or 20 mg/kg bw/day. The 2
      highest doses produced clinical signs of emesis, diarrhoea, and increases in
      mineralisation of the lumbar spinal cord in both sexes. Red blood cell count,
      haemoglobin levels, and haematocrit were decreased at these doses. At the high
      dose only, liver and kidney weights were increased but no histological changes
074-9 Naled
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<pre>             were found. At 2 mg/kg bw, brain AChE was inhibited by 5-17% (females only),
             red blood cell AChE by 43-58%, and plasma ChE by 24-48%. The 1-year
             NOAEL was 0.2 mg/kg bw for inhibition of brain and red blood cell AChE and
             for systemic toxicity (Hum99).
                 Laying hens given oral doses of 0, 0.4, 2.0, or 4.0 mg/kg bw/day of technical
             naled for 28 days did not display any treatment-related signs of clinical or
             delayed neuropathy. Brain AChE was inhibited at both 2.0 and 4.0 mg/kg bw/day
             (Hum99).
                 The results of the short-term toxicity studies in mammals are summarised in
             Table 2.
Table 2 Summary of short-term toxicity studies for naled in mammals.
exposure   species             dose levels                           exposure critical effecta NOAELb reference
route                                                                duration
inhalation rat                 19, 42 mg/m3                          5w        BAChE           19     ACG99,
                                                                               RAChE           19     Gal91,
                                                                                                      WHO78
           rat                 3.4, 7.2, 12.1 mg/m3                  3w        BAChE           <3.4   Rit85
                                                                               RAChE           <3.4
           rat                 0, 0.2, 1, 6 mg/m3                    13 w      BAChE           1      Hum99
           (Fischer 344)                                                       RAChE           0.2
dermal     rat                 0, 1, 20, 80 mg/kg bw/d               28 d      BAChE           1      Hum99
           (Sprague-Dawley                                                     RAChE           1
           CD)
oral       rat                 10, 20, 40 mg/kg bw/d                 28 d                             WHO78
           rat                 40, 80, 160 mg/kg bw/d                29-94 d  clinical signs   40
           rat                 0, 0.25, 1, 10, 100 mg/kg bw/d        28 d     BAChE            1      Hum99
           rat                 28 mg/kg bw/d                         9w       BAChE            <28    Brz69
           rat                 5 mg/kg bw/d                          12 w     clinical signs   5      Tom94,
                                                                                                      Wei93
           rat                 0, 0.4, 2, 10 mg/kg bw/d              90 d     neurological     2      Hum99
           (Sprague-Dawley)
           dog                 0, 0.25, 0.75, 2.5, 7.5 mg/kg bw/d    89 d     RAChE            0.75   WHO78
           dog                 0, 0.2, 2, 20 mg/kg bw/d              1y       BAChE            0.2    Hum99
           (beagle)                                                           RAChE            0.2
a
     BAChE=brain AChE; RAChE=red blood cell AchE.
b
     mg/m3 or mg/kg bw/day.
074-10       Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       Long-term toxicity and carcinogenicity
       In a 2-year oral (gavage) toxicity/carcinogenicity study, male and female
       Sprague-Dawley CD rats (no numbers given) were given (purity: not specified)
       in aqueous carboxymethylcellulose (0.5% w/w) at doses of 0, 0.2, 2, or 10 mg/kg
       bw/day. There was a dose-related reduction of cholinesterase activities. At 2 mg/
       kg/day, brain AChE was depressed by 24%, red blood cell AChE by 4-33%, and
       plasma ChE by 54-60%. No other treatment-related findings were observed. The
       incidence of neoplastic lesions in the treated animals was similar to that of the
       controls. No further details were provided. The NOAEL for inhibition of brain
       and red blood cell AChE was 0.2 mg/kg bw/day and for systemic toxicity 10 mg/
       kg bw/day (Bat84). Rats were daily given 100 mg/kg bw of technical naled
       (purity: 91%) in their diets for a period of 2 years. No adverse effects were
       observed. No further details were given (Tom94, Wei93).
           In an 89-week carcinogenicity study naled in aqueous
       carboxymethylcellulose (0.5% w/w) was administered to male and female CD-1
       mice by gavage at doses of 0, 3, 15, or 75 mg/kg bw/day. The high dose was
       reduced to 50 mg/kg bw after 26 weeks due to high mortality (10-13% after 26
       weeks; 2% in controls). Body weight gain was reduced in male mice at the levels
       of 15 and 50/75 mg/kg bw/day. Cholinesterase activities were not determined.
       No treatment-related neoplastic findings were observed (Hum99).
       Mutagenicity and genotoxicity
       Mutagenicity and genotoxicity assays comprised tests for the detection of gene
       mutations in bacteria and in vitro and in vivo cytogenicity and other in vitro
       genotoxicity assays.
       •   In vitro tests:
           • Gene mutation assays. Naled was tested positive for reverse mutations in
              the TA100 strain of S. typhimurium at concentrations of 0.5, 1, and 2 µM
              with and without metabolic activation. Supplementation of the S9 mix
              with reduced glutathion reduced the mutagenic activity of naled (Brau83).
              At concentrations up to 300 µg/plate, naled increased the frequency of
              reverse gene mutations in S. typhimurium strains TA98, TA100, TA1535,
              TA1536, TA1537, and TA1538 and in B. subtilis strains TKJ5211 and
              TKJ6321. This activity was reduced when an induced rat liver S9 mix was
              added (Shi81). In a similar bacterial reversion-assay with S. typhimurium
074-11 Naled
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<pre>              strains TA98, TA100, TA1535, TA1537, and TA1538 and E. coli strain
              WP2 hcr, no mutagenic activity was noted when tested with and without
              metabolic activation at doses up to 5000 µg/plate (Mor83). In assays
              performed without metabolic activation only, naled was positive only in
              S. typhimurium strain TA1535 after an overnight incubation of a saturated
              aqueous solution at 45oC in a water bath before spot testing, and produced
              negative results in a set of other S. typhimurium LT-2 strains as well as in a
              set of isogenic E. coli WP2 strains (Han75). Naled at concentrations of
              0.1, 1.0, 10, or 100 µg/plate did not induce reverse gene mutations in the
              β-lactamase gen in a recently developed assay with S. typhimurium
              (Hou98).
           • Cytogenicity assays. Naled induced chromosome aberrations and
              micronuclei in an in vitro mouse culture. No further details were given
              (Sha88).
           • Other genotoxicity assays. Naled was tested for DNA damage in a rec-
              type repair test with P. mirabilis strains. The chemical was negative at
              inhibitory concentrations of 10 and 40 µM/plate (Bra83).
       • In vivo tests:
       Male and female Swiss mice that were given naled as a single oral dose of 0, 55,
       110, 220 (males), or 290 (females) mg/kg bw did not show an increased
       incidence of micronuclei in polychromatic bone marrow erythrocytes. Naled had
       no cytotoxic effect on bone marrow cells at these dose levels (Hum99). In
       another study, male and female Sprague-Dawley rats were given single oral
       doses of 0, 6.2, 21, or 62 mg/kg bw for males and of 0, 3.9, 13, or 39 mg/kg bw
       for females. Naled did not show clastogenic effects in bone marrow cells. No
       cytotoxicity was found at any dose level. No further details were given (Hum99).
       Reproduction toxicity
       In an oral (gavage) 2-generation reproduction study, Sprague-Dawley CD rats
       were given naled at doses of 0, 2, 6, or 18 mg/kg bw/day. Body weight gain was
       depressed at 18 mg/kg bw for F0 males and at all dose levels for F1 males.
       Reproduction indices were unaffected in both generations. Survival of pups was
       reduced at 18 mg/kg/day in F1 and F2b generations. A decrease in pup weight
       was also noted during lactation in both generations. No further details were
       provided. The NOAELs for parental and reproduction toxicity were 6 mg/kg
       bw/day (Hum99).
074-12 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>           In an oral (gavage) teratology study, Sprague-Dawley rats were given naled
       at doses of 0, 2, 10, or 40 mg/kg/day on days 6-19 of gestation. Dams were
       sacrificed at day 20. At 40 mg/kg bw/day, maternal toxicity (clinical signs and
       reduced weight gain) was observed. Apart from a marginal increase in litters
       with 2 or more resorptions, no treatment-related developmental effects were
       found. This increase in resorptions occurred at a dose that was maternally toxic
       (40 mg/kg bw). No further details were provided. The NOAEL for maternal
       toxicity was 10 mg/kg bw and for developmental toxicity 40 mg/kg bw
       (Hum99). In another teratology study, naled was orally (gavage) administered to
       female rats (n=20/group) at doses of 25, 50, and 100 mg/kg (36% w/v
       formulation) on days 6-15 of gestation. A slightly higher number of fetuses with
       delayed ossification of the sternebrae were found in the high-dose group.
       However, these effects were not statistically significant and according to the
       authors, they were probably not related to treatment (Khe79). Artificially
       inseminated New Zealand rabbits were given oral (gavage) doses of naled of 0,
       0.2, 2, or 8 mg/kg/day on days 7-19 of gestation. Does were sacrificed on day 29.
       No treatment-related maternal or developmental toxicity was reported. No
       further details were provided (Hum99).
           In an in vivo/vitro teratology study, naled was administered to pregnant
       Wistar rats either 4 or 24 hours prior to the delivery of embryos at day 10 of
       gestation. The rate of development of these embryos was monitored in an in vitro
       culture of Waymouth's medium and fetal calf serum and was found to be
       inhibited. No details were provided about the dose levels of naled used (Bea81).
7      Existing guidelines
       The current administrative occupational exposure limit (MAC) for naled in the
       Netherlands is 3 mg/m3, 8-hour TWA.
           Existing occupational exposure limits in some European countries and the
       USA are summarised in the annex.
8      Assessment of health hazard
       The health hazard assessment of naled is mainly based on toxicology reviews
       issued by the Health Effect Division of the US EPA (Hum99) and by the FAO/
       WHO (WHO78). 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.
074-13 Naled
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<pre>           Absorption of naled into the body may occur via inhalation, skin contact, or
       oral ingestion. In the only experimental animal study reported, it is stated that
       following oral dosing, naled is rapidly metabolised into breakdown products,
       which are mainly excreted in the urine.
           In humans, skin contact with naled may lead to severe irritation or to allergic
       dermatitis. No cases of mortality or systemic effects have been reported in
       humans manufacturing or using the chemical or its formulations.
           In test animals, naled is irritating to the eyes and the skin, and a dermal
       sensitiser. Based on results of acute lethal toxicity studies in test animals, the
       committee considers the compound as very toxic via the respiratory route and
       toxic via the dermal and oral routes. The compound did not cause neurological
       changes indicative of acute delayed neurotoxicity. In some of the short-term
       toxicity studies in rats and dogs, liver or kidney damage or anaemia was reported
       at high dose levels. Most short-term toxicity studies in rats and dogs and the
       long-term/carcinogenicity study in rats showed inhibition of plasma ChE and of
       red blood cell and brain AChE. Plasma ChE and red blood cell AChE appeared
       to be somewhat more sensitive for inhibition by naled than brain AChE in these
       species. The inhalation NOAELs were 1 and 0.2 mg/m3 for brain and red blood
       cell AChE inhibition, respectively, in rats (13-week study). The dermal NOAEL
       for both brain and red blood cell AChE inhibition was 1 mg/kg bw (28-day
       dermal study) in rats while 0.2 mg/kg bw was the oral NOAEL in both rats
       (2-year study) and dogs (one-year oral study).
           Results of in vitro gene mutation tests with naled were conflicting and seem
       to be dependent on the test system used. Naled induced chromosome aberrations
       in vitro, but 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 naled were thus not reflected in carcinogenicity. Effects on
       reproduction toxicity with rats were observed at doses that caused toxicity in
       parental animals, and were considered to be due to maternal toxicity by the
       committee.
           Based on the above data, the committee concludes that the mechanism of
       toxicity of naled 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 naled 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
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<pre>       brain AChE, is used as a surrogate for brain AChE in assessing the human health
       risk of exposure to naled (Jey94).
       The committee has chosen the 13-week inhalation study in rats, producing a
       NOAEL of 0.2 mg/m3 for inhibition of red blood cell AChE, as a starting point in
       deriving a health-based recommended occupational exposure limit (HBROEL).
       For the extrapolation to a HBROEL, an overall factor of 9 is established, cover-
       ing the following aspects: intra-and interspecies variation. Thus, applying this
       factor and the preferred-value approach, a health-based occupational exposure
       limit of 0.02 mg/m3 is recommended for naled.
       The committee recommends a health-based occupational exposure limit for
       naled of 0.02 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 not met for naled*, the committee does not recommend a skin
       notation.
       References
ACG99  American Conference of Governmental Industrial Hygienists (ACGIH). Naled. 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: 92.
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: 42.
Arb02  Arbejdstilsynet. Grænseværdier for stoffer og materialer. Copenhagen, Denmark: Arbejdstilsynet,
       2002; At-vejledning C.0.1.
Bat84  Batham P, Osborne BE, Bier C, et al. Dibrom oral toxicity/carcinogenicity study in rats. Montreal,
       Canada: Bio-Research Laboratories Ltd, 1984; proj no 9394; unpublished study, cited in ACG99 and
       Hum99.
Bea81  Beaudoin AR, Fisher DL. An in vivo/in vitro evaluation of teratogenic action. Teratology 1981; 23:
       57-61.
Ber78  Berteau PE, Deen WA. A comparison of oral and inhalation toxicities of four insecticides to mice and
       rats. Bull Environ Contam Toxicol 1978; 19: 113-20.
*      The dermal LD50 in rats is 800 mg/kg bw; the inhalation LD50 calculated from the 4-hour LC50 of 200 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. 60 mg/kg bw.
074-15 Naled
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<pre>Bra83  Braun R, Schoeneich J, Weissflog L, et al. Activity of organophosphorus insecticides in bacterial
       tests for mutagenicity and DNA repair per-se alkylation vs. metabolic activation. Chem Biol Interact
       1983; 43: 361-70.
Brz69  Brzezicka-Bak M, Bojanowska A. [The subacute toxicity of the organophosphorus insecticides:
       naled, ethoate-methyl and Supracide]. Polish. Rocz Panstw Zakl Hig 1969; 20: 463-9.
Cas62  Casida JE, McBride L, Niedermeier RP. Metabolism of 2,2-dichlorovinyl dimethyl phosphate in
       relation to residues in milk and mammalian tissues. J Agric Food Chem 1962; 10:370-7.
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:
       81 (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.
Edm67  Edmundson WF, Davies JE. Occupational dermatitis from naled. A clinical report. Arch Environ
       Health 1967; 15: 89-91.
Gai69  Gaines TB. Acute toxicity of pesticides. Toxicol Appl Pharmacol 1969; 14: 515-34.
Gal91  Gallo MA, Lawryk NJ. Naled. In: Hayes WJ Jr, Laws ER Jr, eds. Classes of pesticides. San Diego
       CA, USA: Academic Press, Inc, 1991: 1030-1 (Handbook of pesticide toxicology; Vol 2, Sect
       16.6.20).
Hal75  Haley TJ, Farmer JH, Harmon JR, et al. Estimation of LD1 and extrapolation of the LD0.1 for five
       organophosphates. Arch Toxicol 1975; 34: 103-9.
Han75  Hanna PJ, Dyer KF. Mutagenicity of organophosphorus compounds in bacteria and Drosophila.
       Mutat Res 1975; 28: 405-20.
Hou98  Hour TC, Chen L, Lin JK. Comparative investigations of the mutagenicities of organophosphate,
       phtalimide, pyrethroid and carbamate insecticides by the Ames and Lactam tests. Mutagenesis 1998;
       13: 157-66.
HSE02  Health and Safety Executive (HSE). EH40/2002. Occupational exposure limits 2002. Sudbury
       (Suffolk), UK: HSE Books, 2002: 22.
Hum99  Hummel S. Human health risk assessment, naled. Washington DC, USA: US Environmental
       Protection Agency, Office of Pesticide Programs, Health Effects Division (7509C), 1999; http://
       www.epa.gov/pesticides/op/naled.htm
Jey94  Jeyaratnam J, Maroni M. Health surveillance of pesticide workers. A manual for occupational health
       professionals. Organophosphorus pesticides. Toxicology 1994; 91: 15-27.
Khe79  Khera KS, Whalen C, Trivett G, et al. Teratologic assessment of maleic hydrazide and daminozide,
       and formulations of ethoxyquin, thiabendazole, and naled in rats. J Environ Sci Health B 1979; 14:
       563-77.
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<pre>Mat85  Matsushita T, Aoyama K, Yoshimi K, et al. Allergic contact dermatitis from organophosphorus
       insecticides. Ind Health 1985; 23: 145-54.
Mic70  Mick DL, Gartin TD, Long KR. A case report: Occupational exposure to the insecticide naled. J Iowa
       Med Soc 1970; 6: 395-6.
Mor83  Moriya M, Ohta T, Watanabe K, et al. Further mutagenicity studies on pesticides in bacterial
       reversion assay systems. Mutat Res 1983; 116: 185-216.
NIO02  US National Institute for Occupational Safety and Health (NIOSH), ed. Phosphoric acid, 1,2-
       dibromo-2,2-dichloroethyl dimethyl ester. In: Registry of Toxic Effects of Chemical Substances
       (RTECS) (last update: July 2000); http://www.cdc.gov/niosh/rtecs/tb903210.html.
NLM02  US National Library of Medicine (NLM), ed. Naled. In: Hazardous Substances Data Bank (HSDB)
       (last revision date naled file: 14 January 2002; last review date: 14 September 1995); http://
       www.toxnet.nlm.nih.gov.
Phi72  Phillips L II, Steinberg M, Maibach HI, et al. A comparison of rabbit and human skin response to
       certain irritants. Toxicol Appl Pharmacol 1972; 21: 369-82.
Rit85  Rittenhouse JR. Three-week aerosol inhalation toxicity study of Chevron naled technical in rats -
       preliminary data release. S-2334. Richmond CA, USA: Chevron Environmental Health Center, 1985;
       unpublished study cited in ACG99.
Rob99  Roberts TR, Hutson DH, eds. Naled. In: Insecticides and fungicides. Cambridge, UK: Royal Society
       of Chemistry, 1999: 394-6 (Metabolic pathways of agrochemicals; Pt 2).
Sha88  Sharma GP, Sobti RC. Cytotoxic, cytokinetic and cytogenetic effects of agricultural chemical in vitro
       and in vivo. J Agric Food Chem 1981; 29: 268-71.
Shi81  Shiau SY, Huff RA, Felkner IC. Pesticide mutagenicity in Bacillus subtilis and Salmonella
       typhimurium detectors. J Agric Food Chem 1981; 29: 268-71.
Swe00  Swedish National Board of Occupational Safety and Health. Occupational exposure limit values and
       measures against air contaminants. Solna, Sweden: National Board of Occupational Safety and
       Health, 2000; Ordinance AFS 2000:3.
SZW03  Ministerie van Sociale Zaken en Werkgelegenheid (SZW). Nationale MAC-lijst 2002. The Hague,
       the Netherlands: Sdu, Servicecentrum Uitgevers, 2002: 23.
Tom94  Tomlin CDS, ed. In: The pesticide manual; incorporating the agrochemical handbook. A world
       compendium. 10th ed. Farnham (Surrey), UK: British Crop Protection Council, 1994.
TRG00  TRGS 900. Grenzwerte in der Luft am Arbeitsplatz; Technische Regeln für Gefahrstoffe. BArbBl
       2000; 2.
Wei93  Weir RJ. Organic phosphates. In: Clayton GD, Clayton FE, eds. Toxicology. 4th ed. New York, USA:
       J Wiley & Sons, Inc, 1993: 711-50 (Patty's industrial hygiene and toxicology; Vol 2, Pt A)
074-17 Naled
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<pre>              Annex
Occupational exposure limits for naled in various countries.
country                               occupational             time-weighted type of                    notea           referenceb
- organisation                        exposure limit           average        exposure limit
                                      ppm        mg/m3
the Netherlands
- Ministry of Social Affairs and      -          3             8h             administrative            S               SZW03
Employment
Germany
- AGS                                 -          3c            8h                                       S               TRG00
                                      -          12            15 min
- DFG MAK-Kommission                  -          3c            8h                                                       DFG02
                                      -          6             15 mind
Great Britain
- HSE                                 -          3             8h             OES                                       HSE02
                                      -          6             15 min
Sweden                                -          -                                                                      Swe00
Denmark                               -          3             8h                                                       Arb02
USA
- ACGIH                               -          0.1c          8h             TLV                       S, sens, A4e    ACG03b
- OSHA                                -          3             8h             PEL                                       ACG03a
- NIOSH                               -          3             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 the inhalable fraction.
d
     Maximum frequency per shift: 4, with a minimum interval between peaks of 1 hour.
e
     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.
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