<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>Temephos
(CAS No: 3383-96-8)
Health-based Reassessment of Administrative Occupational Exposure Limits
Committee on Updating of Occupational Exposure Limits,
a committee of the Health Council of the Netherlands
No. 2000/15OSH/076, The Hague, 22 september 2003
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. Temephos; Health-based Reassessment of Administrative
Occupational Exposure Limits. The Hague: Health Council of the Netherlands,
2003; 2000/15OSH/076.
all rights reserved
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of temephos
      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 AAE Wibowo, Ph.D. and MM Verberk, Ph.D. (Coronel Institute of
      the Academic Medical Centre, Amsterdam, the Netherlands).
           The evaluation of the toxicity of temephos was based on reviews published in
      the ‘The handbook of pesticide toxicology’ (Gal91) and by the American
      Conference of Industrial Hygienists (ACG99). Where relevant, the original
      publications were reviewed and evaluated as will be indicated in the text. In
      addition, in July 1998, literature was searched in the databases Medline, Embase,
      and Chemical Abstracts, starting from 1966, 1988 and 1970, respectively, as well
      as from the Hazardous Substances Data Bank (HSDB) (NLM02). CD-ROM
      versions of the databases Poltox (1990-1994) HSELINE, CISDOC, MHIDAS,
      and NIOSHTIC (from 1998 backwards) were also consulted. In May 2002, a
      literature search was carried out in Toxline and Medline. The following key
      words were used: temephos, temefos, abate, and 3383-96-8. 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) (FAO75)
      and the Health Effects Division (HED) of the US Environmental Protection
      Agency (EPA) as part of their hazard identification assessment review (Lie98,
      Paq99b).
           In October 2002, the President of the Health Council released a draft of the
      document for public review. Comments were received from the following
      individuals and organisations: J Soave (Health and Safety Executive, London,
      England).
           An additional search in Toxline and Medline in April 2003 did not result in
      information changing the committee’s conclusions.
076-3 Temephos
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<pre>2     Identity
      name                  : temephos
      synonyms              : phosphorothioic acid, O,O’-(thiodi-1,4-phenylene) O,O,O’,O’-tetramethyl ester;
                               O,O,O’,O'-tetramethyl O,O‘-thiodi-p-phenylene phosphorothionate; Abate;
                               Abathion; Amercan Cyanamid CL-52160
      molecular formula     : C16H20O6P2S3
      structural formula    :
      CAS number            : 3383-96-8
3     Physical and chemical properties
      molecular weight       :  466.48
      boiling point          :  decomposes at 120-125oC
      melting point          :  30.5oC
      vapour pressure        :  at 25oC: 1 x 10-5 Pa
      solubility in water    :  insoluble
      Log Poctanol/water     :  4.91
      conversion factors     :  not applicable
      Data from NLM02, Rob99.
      Pure temephos is a white crystalline solid, while the technical grade is a brown
      viscous liquid. Temephos is hydrolysed by strong acids and alkalis (ACG99).
4     Uses
      Temephos is used to control mosquito and black fly larvae in aqueous
      environments and as a human and veterinary ectoparasiticide. It is also used on
      crops for the control of cutworms, thrips on citrus, and lygus bugs. Temephos is
      formulated as emulsifiable concentrates, wettable powders, or granules (Gal91,
      NLM01). According to the database of the Dutch Pesticide Authorisation Board
076-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      (CTB)*, temephos is at present not registered for its use as an active ingredient in
      pesticides in the Netherlands.
5     Biotransformation and kinetics
      Human data
      Urine specimens were collected from people residing in an area sprayed by
      aircraft with naled and temephos. Increased concentrations of the temephos
      metabolite O,O-dimethylphosphorothioate (DMPT) were found in post-treatment
      samples, indicating absorption of temephos by inhalation of the aerosol or
      through skin contact (Kut77).
      Animal data
      In a biokinetic study, Sprague-Dawley rats, New Zealand white rabbits, and
      beagle dogs were given single intravenous doses of [14C-ring]-labelled Abate
      (dissolved in methanol) of 0.033 mg each. The amount of radiocarbon recovered
      in urine and faeces after 7 days was 24.6% of the administered dose for rats, 55%
      for rabbits, and 35% for dogs. Less than 0.5% of the dose was retained in the
      tissues. No explanation could be given of these relatively low recoveries. In rats
      and rabbits, the major portion of the label was excreted in the urine (17.7 and
      47% of the dose, respectively), but in dogs most of the radioactivity was excreted
      in the faeces (23% of the dose). Most of the radiocarbon excreted in the urine
      over 7 days was produced during the first 24-hour period following
      administration (69-79%). In dogs, the radioactivity in blood peaked between 5
      and 30 minutes after application and then decayed with an initial half-life of
      about 4 h. The dermal penetration of Abate was studied in the same species.
      Following topical application of 0.033 mg [14C-ring]-labelled Abate, 6.7% and
      24.6% of the applied dose was recovered in the urine and 11% and 9% in the
      faeces for rats and rabbits, respectively, over 7 days. However, dogs that received
      a dermal dose of 0.33 mg [14C-ring]-labelled Abate had only 0.5% of the applied
      dose recovered in the urine and 0.87% in the faeces within 7 days. Most of the
      radioactivity excreted in the urine over 7 days was produced during the first 2
      days following topical application (51-65%). In dogs, nearly all of the
      unabsorbed compound was recovered from a non-occlusive patch that protected
      the area and apparently trapped evaporation of the compound. Tissue specimens
*     at: http://www.ctb-wageningen.nl/geel.html.
076-5 Temephos
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<pre>      collected from each species showed only trace amounts or complete absence of
      radioactivity 7 days after application. The percentage of dermal absorption was
      calculated by dividing the percent of the dose excreted in the urine following
      dermal application by the percent of the dose excreted in the urine following
      intravenous dosing and then multiplying by 100. The percent dermal absorption
      was 38% in rats, 52% in rabbits, and approximately 5% in dogs. By comparison
      of the dermal penetration potential of organophosphorus pesticides between
      species, the authors concluded that topically applied Abate should not present a
      dermatotoxic hazard to man following a single application, and that absorption
      would be expected to be less than 3% of the applied dose (Paq99a, Sno80).
          In another paper, it is reported that following administration of either a single
      oral dose of 300 mg/kg bw of temephos or repeated oral doses of 300 mg/kg
      bw/day, for 5 days, the elimination of temephos in plasma of Sprague-Dawley
      rats followed monoexponential kinetics. The half-life of temephos after acute
      exposure was 7 h and after subchronic exposures 24 h (Fer85).
          When Sprague-Dawley rats were given a single oral dose of radiolabelled
      [3H-phenylene]temephos, 95-98% of the radioactivity was eliminated within 72
      hours, the faeces (52-65%) being the principle route of excretion. Parent
      compound accounted for ca. 60% of the radioactivity in the faeces, while urine
      contained only trace amounts of unchanged temephos. The concentration of
      radioactivity in the blood peaked between 5 and 8 hours and then dissipated with
      a half-life of about 10 h. Appreciable radioactivity was found in the
      gastrointestinal tract and the fat. The main mechanism of biotransformation of
      temephos is hydrolysis of the P-O linkages, to give O,O-
      dimethylphosphorothioate (DMPT) and 4,4’-thiodiphenol, which is subsequently
      biotransformed by oxidation of the thioether moiety into its sulphoxide (4,4’-
      sulphinyldiphenol) and its disulphoxide (4,4’-sulphonyldiphenol). These
      metabolites are excreted in the urine as water-soluble sulphate ester conjugates,
      which together comprised some 80% of total urinary radioactivity (Blin69,
      Rob99).
6     Effects and mechanism of action
      Human data
      Two studies were conducted in which human volunteers were given oral doses of
      technical Abate (purity: not given) to investigate the toxicity of the compound.
      The aim of first study was to discover the acute dose of Abate necessary to
076-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      produce inhibition of red blood cell acetylcholinesterase (AChE) or plasma
      cholinesterase (ChE) in humans. Two groups of 10 healthy male volunteers were
      involved, one to receive Abate and one control group. Each subject in the
      experimental group started with an oral dose of 2 mg Abate and the dose was
      then doubled every 3 to 4 days to reach a level of 256 mg at day 25. Subjects in
      the control group were not given Abate. The study was terminated on day 28.
      Cholinesterase (ChE) activities were examined 3 times a week. Urine samples
      for the determination of Abate were also collected. The aim of the second study
      was to determine a NOAEL for inhibition of cholinesterases following repeated
      oral intake of Abate. One experimental group and one control group of 9
      volunteers each were involved. Each subject in the experimental group was given
      a daily dose of 64 mg Abate, for 4 weeks. Subjects in the control group did not
      receive Abate. ChE activities were determined twice a week and an additional
      blood sample was taken 5 days after the last dose. Urine samples for the
      determination of Abate were collected during dosing of Abate and for 3 weeks
      following the last dose. At no time in either study, there was a significant
      difference between the red blood cell AChE or plasma ChE activities of the
      volunteers receiving Abate and the control groups. No clinical symptoms or
      other reactions related to Abate were observed. The concentration of Abate in
      urine was proportional to doses and was still detectable 3 weeks after dosing
      stopped (Law67). From these studies, the committee concludes that the NOAEL
      of a 4-week oral study with temephos in man is at least 64 mg/person/day
      (average of 0.91 mg/kg bw/day).
      Animal data
      Irritation and sensitisation
      Temephos is slightly irritating to eyes but not irritating to skin of rabbits (EPA99,
      Lev70). The compound is not a dermal sensitiser (Paq99b). No further details
      were given.
      Acute toxicity
      Rats survived an 8-hour inhalation exposure to air almost saturated with
      temephos (LC50>1300 mg/m3 )(Lev70, Lie98).
          Acute inhalation LC50 and dermal and oral LD50 values in test animals are
      summarised in Table 1.
076-7 Temephos
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<pre>Table 1 Summary of acute toxicity studies for temephos in mammals.
exposureoute vehiculum           species (strain)           sex         LC50 or LD50        reference
                                                                                    3
inhalation                       rat                        not given   >1300 mg/m (8 h)    Lev70, Lie98
dermal        none               rat (Sherman)              male        >4000 mg/kg bw      Gai67, Gai69
              none               rat (Sherman)              female      >4000 mg/kg bw      Gai67, Gai69
                                 rat                        not given   1200 mg/kg bw       Gon75
                                 rabbit                     male        1850 mg/kg bw       Lie98
                                 rabbit                     female      970 mg/kg bw        Lie98
                                 rabbit                     not given   2000 mg/kg bw       Lev70
oral          none               rat (Sherman)              male        8600 mg/kg bw       Gai67, Gai69
              none               rat (Sherman)              female      13000 mg/kg bw      Gai67, Gai69
                                 rat                        not given   1226 mg/kg bw       Ito72
                                 rat                        not given   2000 mg/kg bw       Lev70
                                 rat                        not given   1650 mg/kg bw       Gon75
                                 rat                        not given   444 mg/kg bw        Lie98
              none               mouse (‘white’)            male        4700 mg/kg bw       Gai67
                                 mouse                      unknown     460 mg/kg bw        Gon75
            In their studies, Gaines et al. found that some manufacturing batches of technical
            Abate (purity: not given) had an approximately 3-fold lower acute oral LD50 in
            female rats than the value of 13,000 mg/kg bw reported in Table 1 (Gai67,
            Gai69). The acute dermal or oral LD50s of temephos reported by other authors
            (Gon75, Ito72, Lev70, Lie98) were appreciably lower than that reported by
            Gaines et al. It is not known whether this difference in acute toxicity was
            associated with a difference of Abate manufacture or with some unidentified
            factor (Gal91).
                Sprague-Dawley rats (n=32) given a single oral dose of 300 mg/kg bw of
            temephos (purity: 93.1%) did not show mortality or clinical signs of intoxication.
            However, red blood cell AChE activity was depressed by 67% and 47% at 4 and
            48 hours after treatment, respectively (Fer85). The same authors studied the
            influence of temephos on the mixed function oxidase (MFO) system by
            measuring the hexobarbital sleeping time (HST) 4 hours after oral administration
            of doses of temephos of 0, 30, and 300 mg/kg bw. Animals in the high-dose
            group showed a significant increase in duration of HST compared to the control
            group. The HSTs were significantly correlated with plasma temephos
            concentrations. This study indicates that at high acute doses, temephos has an
076-8       Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      inhibitory effect on the activity of the MFO system (Fer85). In a study to
      compare the susceptibility to inhibition by temephos of cholinesterase and
      carboxylesterase enzymes, male Holzman rats (n=3/group) were given single
      oral (gavage) doses of Abate (purity: 86.2%) of 2.5, 5, 10, 25, 50, 100, or 250
      mg/kg bw. Using the 50%-inhibition point, the susceptibility to inhibition by
      Abate was in the order: liver carboxylesterase > red blood cell AChE > plasma
      ChE > red blood cell AChE. Carboxylesterase was 3-18 times more sensitive
      than red blood cell AChE and 8-45 times more sensitive than brain AChE. No
      signs of intoxication were observed (Mur72). To investigate the effects on
      behaviour, Sprague-Dawley rats received intraperitoneal injections of Abate
      (purity: 90%) of 316, 562, or 1000 mg/kg bw and were tested for 16 days. At the
      top dose, animals showed signs of intoxication and an impaired avoidance
      performance 6 days after injection, but not 2, 8, 10, or 16 days after treatment.
      No behavioural changes were observed in the other groups (Kur79).
          White Leghorn chicken hens were tested for leg weakness following a single
      subcutaneous dose of temephos. All animals were given atropine to protect
      against the acute toxic effects of the chemical. The lowest dose that caused
      mortality was 1000 mg/kg bw. Birds that received 125 mg/kg bw showed leg
      weakness within 24 hours for a period of 6-31 days (Gai69). According to EPA,
      no evidence of temephos-induced delayed neurotoxicity or neuropathology was
      observed in 3 acute delayed neurotoxicity studies in hens. However, these studies
      were judged inadequate for various technical deficiencies, but no details were
      provided (Paq99b).
      Short-term toxicity
      Albino rats (n=10/sex/group) received dermal doses of 12 or 60 mg/kg bw of
      temephos (purity: not given) applied as an aqueous emulsion, 5 days/week, for
      3 weeks. No mortality or clinical signs of systemic toxicity were observed, but
      animals receiving the high dose had lower food intake and lower body weight
      gain. Gross and microscopic examination revealed increased liver weights in
      females but no other treatment-related lesions. Cholinesterase activities were not
      reported (FAO75, Lev70).
          Rabbits (strain, sex, and number not given) that received dermal doses of 178
      mg/kg bw/day of temephos (purity: not given) for 5 consecutive days showed no
      mortality, but diarrhoea occurred in 7 treated animals. Cholinesterase activity
      was reduced, but no further details were given (FAO75).
076-9 Temephos
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<pre>           Sprague-Dawley rats (n=32) receiving temephos at oral (gavage) doses of
       300 mg/kg bw/day, for 5 days, did not show mortality. Cholinergic signs such as
       muscle fasciculations and salivation appeared on day 4 of the treatment. Red
       blood cell AChE activity was depressed by 100% for all animals at 2 and 48
       hours after treatment. Treated animals showed a significant increase in
       hexobarbital sleeping time compared to the control group (Fer85).
           Male rats (Sherman) were given technical-grade Abate (purity not given) by
       gavage or in the diet. Besides monitoring of symptoms of intoxication and
       terminal gross and microscopic examinations, only plasma ChE and red blood
       cell AChE activities were measured. However, since red blood cell AChE
       activity was always affected more rapidly and to a greater extent than plasma
       ChE activity, almost only effects on red blood cell AChE activity were presented.
       Groups of 7 rats received doses of temephos of 0, 1, 10, or 100 mg/kg bw/day by
       gavage for 44 days (dosing regimen not indicated). After 11 days, administration
       of the test compound to ‘some’ of the animals of the high-dose group was
       stopped. No mortality was reported in any of the groups. Rats given the highest
       dose developed typical symptoms of organic phosphorus intoxication (not
       specified) after 3 doses when their red blood cell AChE activity was inhibited by
       64%. Gradual recovery from symptoms occurred while dosing progressed, even
       though the red blood cell AChE activity continued to fall to 87% inhibition after
       11 days of dosing. In the animals that were allowed to recover after 11 days, red
       blood cell AChE activity was inhibited by 27% at the end of the experiment (44
       days). The rats receiving 10 mg/kg bw showed no symptoms of intoxication, but
       red blood cell AChE was inhibited by 31% and 47% after 14 and 44 days,
       respectively. The NOAEL for inhibition of red blood cell AChE was 1 mg/kg
       bw/day. Other groups of 11-14 rats received temephos in their diets at levels
       equivalent to 0, 0.18, 1.8, 18, or 150 mg temephos/kg bw/day, for 99 days
       (dosing regimen not indicated). In the 150-mg/kg bw group, the red blood cell
       AChE activity was depressed by 100%, and only 2 animals survived the 99-day
       treatment period, both showing 100% and 80% inhibition of red blood cell AChE
       and plasma ChE activity, respectively. Animals in the 18 mg/kg bw group
       showed no grossly observable signs of toxicity in spite of 71% inhibition of red
       blood cell AChE at the end of the 99 days. Gross or microscopic examination did
       not reveal abnormalities in any of the treatment groups. The NOAEL for
       inhibition of red blood cell AChE was 1.8 mg/kg bw/day (Gai67).
           Male Holtzman rats were given oral (drinking water) doses of technical-
       grade Abate (purity: 86.2%) of 0, 0.3, 0.5, 1, 3, or 5 mg/kg bw for 7 days
       (n=5/group) or of 0, 0.1, 0.3, or 0.5 mg/kg bw/day, 7 days/week, for 8 weeks
076-10 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       (number: not given). At the end of the 7-day study, liver carboxylesterase activity
       was inhibited by 20% in the lowest dose group, while red blood cell AChE
       activity was inhibited (20%) at 5 mg/kg bw only. Brain AChE and plasma ChE
       levels remained unaffected. In the 8-week study, groups of 4-5 rats from each
       dose group were sacrificed at intervals of 14, 22, 28, and 56 days for
       cholinesterase and liver carboxylesterase determinations. No inhibition of brain
       or red blood cell AChE or plasma ChE activity was observed for any dose at any
       time. However, liver carboxylesterase activity was depressed in a dose-
       dependent way. The NOAEL for inhibition of cholinesterase activities in the
       8-week study was 0.5 mg/kg bw/day, the highest dose tested. No NOAEL could
       be established for liver carboxylesterase since its activity was depressed at 0.1
       mg/kg bw, the lowest level tested (Mur72).
           In a 13-week feeding study, groups of rats (strain: not given; n=45/sex/group;
       controls: n=65/sex) were given temephos (purity: 96.4%) at levels equivalent to
       0, 0.1, 0.3, 0.9, or 17.5 mg/kg bw/day. At the top dose, the female body weight
       gain was significantly depressed. No treatment-related mortality, cholinergic
       signs of intoxication, ophthalmological abnormalities, changes in food
       consumption, or changes in clinical chemistry and haematological data were
       observed. No gross and microscopic treatment-related changes were noted in any
       of the groups. However, the relative liver weight of males in the highest dose
       group was significantly decreased. Significantly decreased activities of brain
       AChE (77%, males and females), red blood cell AChE (89% for males and 91%
       for females), and plasma ChE (48% for males and 61% for females) were
       measured in the highest dose group at the end of the 13-week treatment period.
       At 0.9-mg/kg bw, brain AChE activity was decreased by 17% in males and 14%
       in females in the first 5 weeks of the study, but these effects disappeared at the
       end of the 13 weeks with red blood cell AChE activities decreased by 25% for
       males and 23% for females, but no significant changes found for plasma ChE for
       either sex. At 0.18 mg/kg bw, the red blood cell AChE activity was inhibited in
       males only by 16% at week 13 with no changes noted in either brain AChE or
       plasma ChE. Since inhibition of red blood cell AChE at 0.3 mg/kg bw and brain
       AChE at 0.9 mg/kg bw were considered equivocal, the study was repeated at
       dietary levels equivalent to 0, 0.3, 0.9, and 2.7 mg/kg bw/day, for 90 days.
       Statistically significant decreases were only seen in red blood cell AChE activity
       in both sexes at 0.9 and 2.7 mg/kg bw. In this 90-day oral rat study, the NOAEL
       for inhibition of red blood cell AChE activity is, therefore, 0.3 mg/kg bw/day
       (Lev70, Lie98).
076-11 Temephos
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<pre>            Male rabbits were administered technical-grade Abate (purity: not given) at
       oral (gavage) doses of 0.1, 1, or 10 mg/kg/day for 35 days (n=4/group) (dosing
       regimen not indicated) or 100 mg/kg bw/day for 5 days (n=8). Three out of the
       animals given 100 mg/kg bw died. Out of the 7 animals of this 100-mg/kg bw
       group autopsied, 4 showed focal or diffuse liver necrosis. Effects on
       cholinesterase activities were not discussed. None of the animals exposed for 35
       days developed any sign of toxicity. At 10 mg/kg bw, red blood cell ACE activity
       was inhibited by 47% at the end of the 35 days. No significant inhibition of red
       blood cell AChE activity occurred in the other groups. At autopsy, there were
       neither liver lesions, such as seen in the 100-mg/kg bw group, nor any other
       pathological changes in any of the groups treated for 35 days. Brain AChE and
       plasma ChE activities were not determined in this study (Gai67).
            Dogs (n=2/sex/group) were given technical-grade Abate (purity: not given)
       in drinking water at doses of 0, 0.7, or 3.5 mg/kg bw/day, for 18 weeks (dosing
       regimen not indicated). No clinical signs of toxicity were observed. At 3.5 mg/kg
       bw/day, red blood cell AChE was inhibited by 78% in males and 50% in females
       at the end of the 18 weeks. No effect was found on red blood cell AChE nor on
       plasma ChE activity of either of the dogs given 0.7 mg/kg bw (Gai67).
            In a 13-week dog study, Abate caused severe cholinergic signs of
       intoxication at a dietary level equivalent to about 17.5 mg/kg bow/day.
       Reduction of the dose level of Abate to about 12.5 mg/kg bw/day during the rest
       of the study markedly decreased cholinergic signs. However, brain and red blood
       cell AChE and plasma ChE activities were severely inhibited. No gross or
       microscopic treatment-related lesions were noted. No effects on cholinesterase
       activities were found at about 0.45 mg/kg bw/day. No further details were
       provided (Lev70, Lie98, Paq99b).
            Male guinea pigs (n=5) given a daily dose of 100 mg/kg bw/day by stomach
       tube for 5 days showed no signs of intoxication. No pathological changes were
       observed. Cholinesterase activities were not investigated (Gai67).
            Hens (n=2/group) were given dietary levels of technical-grade Abate (purity:
       not given) of 0, 7.4, or 15.3 mg/kg bw, for 108 days. Hens in the high-dose group
       developed leg weakness after 30 days of treatment. The hens given 7.4 mg/kg
       bw/day did not show symptoms of leg weakness during the 108 days of treatment
       (Gai67).
            To investigate the effects of repeated administration of technical-grade Abate
       (purity: 90%) on behaviour, Sprague-Dawley rats (n=10/group) received daily
       intraperitoneal injections of 167 mg/kg bw/day, for 6 days. Groups were tested
       one day and 6 days after treatment. At either day, no changes in avoidance
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<pre>       performance were noted. However, motor activity was depressed by 56% and
       78%, red blood cell AChE by 100%, brain AChE by 85% and 78%, and plasma
       ChE by 39% and 8% at post-treatment day 1 and day 6, respectively (Kur79).
       CFHB-remote Wistar rats were given Abate (purity: not given) daily by intrap-
       eritoneal injection at doses between 10 and 300 mg/kg bw (not further specified)
       for 4, 7, or 10 days. A dose-related decrease in whole blood cholinesterase and
       brain AChE was noted. No effects were observed on liver enzymes alanine ami-
       notransferase (ALAT) or aspartate aminotransferase (ASAT) or on acid phos-
       hatase. However, significant reductions were found of glutamate dehydrogenase
       (GLDH) and aminopyrine demethylase levels after all dose periods (doses not
       specified). Cytochrome P450 activity was reduced after 7 and 10 days treatment,
       but the activity was increased at the higher doses (doses not specified) after 4
       days of treatment (Enn79).
           Short-term toxicity studies are summarised in Table 2 (see page 14).
       Long-term toxicity and carcinogenicity
       In a 2-year study, rats (n=60/sex/group) were fed levels of temephos (purity:
       95.5%) equivalent to 0, 0.5, 5.0, or 15 mg/kg bw/day. Rats used for the treated
       groups were derived from the offspring of 140 pregnant Sprague-Dawley CD
       rats that were given temephos via the diet at a level of 5 mg/kg bw (length of
       treatment not given). The controls were derived from offspring of untreated
       female rats. Neither signs of toxicity nor treatment-related effects on survival,
       body weight gain, food consumptions, or haematology and clinical chemistry
       data were observed in any of the treatment groups. Gross post-mortem
       examination revealed an increase in both absolute and relative liver weight in the
       high-dose group. According to EPA, these increases were not related to
       treatment. Histological examination showed tumour incidences evenly
       distributed among the treated groups and the control group, and no statistically
       significant differences among groups were found. According to EPA, the
       NOAEL for long-term toxicity in this study was 15 mg/kg bw/day (Lie98).
       Mutagenicity and genotoxicity
       The committee did not find any data on the mutagenic and genotoxic potential of
       temephos.
076-13 Temephos
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<pre>Table 2 Summary of short-term toxicity studies for temephos in experimental animals.
exposure    species                             dose level             exposure    critical effecta NOAEL      reference
route       (strain; number, sex))              (in mg/kg bw/d)        duration                     (mg/kg bw)
dermal      rat                                 12 or 60               21 days     systemic         12         Lev70,
            (‘albino’; n=10/sex/group)                                             toxicity                    Lie98
dermal      rabbit                              178                    5 days      systemic         LOAEL: 178 FAO75
                                                                                   toxicity
oral        rat                                 0, 1, 10, 100          44 days     RAChE            1          Gai67
(gavage)    (Sherman; n=10 males/group)
oral        rat                                 0, 0.18, 1.8, 18, 150  99 days     RAChE            1.8        Gai67
(diet)      (Sherman; n=11-14 males/group)
oral        rat                                 0, 0.1, 0.3, 0.9, 17.5 92 days     RAChE            0.3        Lev70,
(diet)      (n=45/sex/group)                                                       BAChE                       Lie98
oral        rat                                 300                    5 days      RAChE            LOAEL: 300 Fer85
(gavage)    (Spague-Dawley; n=32 females)
oral        rat                                 0, 0.3, 0.5, 1, 3, 5   7 days      RAChE            3          Mur72
(drinking   (Holtzman; n=5 males/group)                                            liver carboxyl LOEL:0.3
water)                                                                             esterase
oral        rat                                 0, 0.1, 0.3, 0.5       8 weeks     RAChE            0.5        Mur72
(drinking   (Holtzman; n=16-20 males/group)                                        liver carboxyl LOEL:0.1
water)                                                                             esterase
oral        rabbit                              0.1, 1, 10             35 days     RAChE            1          Gai67
(gavage)    (n=4 males/group)
oral        dog                                 0, 0.7, 3.4            129 days    RAChE            0.7        Gai67
(drinking    (n=2/sex/group)
water)
oral        dog                                 0, 0.45, 12.5/17.5     13 weeks    RAChE            0.45       Lev70,
(diet)                                                                                                         Lie98, P
                                                                                                               aq99b
oral        guinea pig (n=5 males)              100                    5 days      systemic         100        Gai67
(gavage)                                                                           toxicity
a
     RAChE=red blood cell AChE; BAChE= brain ACHE.
           Reproduction toxicity
           In a one-generation reproduction study, groups of male and female Sherman rats
           (numbers not given) were fed dietary levels of technical-grade Abate (purity: not
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<pre>       given), equivalent to 0 or 25 mg/kg bw/day at the time they were placed together
       for breeding. This dose was sufficiently high to cause (not specified) symptoms
       of toxicity in some animals and was maintained during mating, gestation,
       parturition, and lactation. After 48 days of treatment, red blood cell AChE
       activity of females was inhibited by 90% while that of their 21-day-old young
       was inhibited by 30%. No significant differences in the fertility or gestation
       indices, number of litters produced, litter size, viability or lactation indices, or
       incidence of teratological defects were observed between the treated and the
       control group (Gai67).
            In a 3-generation study, albino rats were fed levels of temephos (purity:
       87%), equivalent to 0, 1.25, or 6.25 mg/kg bw/day, from weaning through
       reproductive age. The number of rats that were mated was 24/dose for the P
       generation and 16/dose for either the F1 or F2 generations. No treatment-related
       parental toxicity was observed at any dose level in any of the generations.
       Cholinesterase levels were not measured. The fertility, gestation, viability, and
       lactation indices for the temephos-fed animals were comparable to those of the
       controls. The combined (of all matings) mean pup weight at weaning was
       slightly higher in the low-dose groups and slightly lower in the high-dose groups
       when compared to the controls. The P generation fed 1.25 and 6.25 mg/kg bw
       and the F1 generation fed 6.25 mg/kg bw produced pups with a slight reduction
       in mean body weights at weaning for both males and females. No gross
       abnormalities were observed for all P and F1 pups and no gross and microscopic
       abnormalities for F2 pups of the control and high-dose groups. The NOAEL in
       this study for both the parental and reproduction toxicity was 6.25 mg/kg bw, the
       highest level tested (Lev70, Lie98).
            Pregnant New Zealand rabbits (no numbers given) were given oral doses of
       temephos (purity: 90.4%) at levels 0, 3, 10, or 30 mg/kg bw/day, during days 6
       through 18 of gestation. No maternal or reproduction toxicity was observed
       (Lie98).
            In a prenatal dermal developmental toxicity study, pregnant New Zealand
       rabbits (no numbers given) received repeated dermal applications of Abate
       formulations (purity/composition: not given) at 0, 12.5, 25, or 50 mg/kg bw/day,
       during days 6 through 18 of gestation. Decreased maternal body weights were
       observed in the high-dose group. Maternal plasma ChE activity was inhibited at
       all dose levels (brain or red blood cell AChE not evaluated). No reproductive
       abnormalities were noted. Further details were not provided. In this study, the
       maternal NOAEL could not be determined (LOAEL for inhibition of plasma
076-15 Temephos
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<pre>       ChE activity: 12.5 mg/kg bw/day), the NOAEL for reproduction toxicity was 50
       mg/kg bw/day, the highest level tested (Lie98).
7      Existing guidelines
       The current administrative occupational exposure limit (MAC) for temephos in
       the Netherlands is 10 mg/m3, 8-hour TWA.
           Existing occupational exposure limits for temephos in some European
       countries and the USA are summarised in the annex.
8      Assessment of health hazard
       The health hazard assessment of temephos is based to a great extent on a
       toxicology review issued by the EPA for the reregistration eligibility decision
       (Lie98, Paq99b). The toxicity profile in this review is obtained mainly from
       unpublished reports of toxicology studies conducted for registration purposes by
       chemical companies manufacturing or marketing the compound.
           Workers can be exposed to temephos through inhalation of the dust or by
       direct skin contact with a formulation of the compound. No data is available of
       the percentage uptake of the compound through the lungs. The dermal absorption
       of temephos is of little significance and expected to be less than 3% of the
       applied dose in humans. Following oral administration to rats, the compound is
       metabolised into several breakdown products. Elimination half-lives from the
       blood ranged from ca. 10 to 24 hours following single and repeated exposure,
       respectively. After a single oral dose, the faeces were the major route of
       excretion accounting for 52-65% of the dose, 60% of which was parent
       compound; excretion was complete within 72 hours.
           In a human volunteer study, an oral dose of temephos of 0.9 mg/kg bw/day
       for 4 weeks did not inhibit the cholinesterase activities in red blood cells and in
       plasma. There were no clinical symptoms or other adverse effects found in the
       volunteers.
           In experimental animals, the compound is slightly irritating to the eyes, but is
       not irritating to skin or a skin sensitiser. Based on the results of acute lethal
       toxicity studies in test animals, the committee considers the compound of low
       toxicity by inhalation and of moderate toxicity by the dermal and oral route.
       Temephos did not cause neurological changes indicative of acute delayed
       neurotoxicity. With the exception of mild pathological changes in the liver in a
       short-term study with rabbits, no significant systemic effects have been reported
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<pre>       in test animals. However, acute and short-term oral studies showed inhibition of
       red blood cell AChE, brain AChE, and plasma ChE in rats, rabbits, and dogs.
       Red blood cell AChE was more sensitive for inhibition by temephos than brain
       AChE or plasma ChE in these species. In one study, it was demonstrated that
       liver carboxylestererase is even more sensitive for inhibition by temephos than
       red blood cell AChE. The 13-week oral NOAELs for red blood cell AChE
       inhibition were 0.3 and 0.45 mg/kg bw/day for rats and dogs, respectively. The
       LOEL for carboxylesterase was 0.1 mg/kg bw/day for the rat (8-week study).
       However, carboxylesterase does not appear to be critical for normal
       physiological function and inhibition of its activity is not considered as an
       adverse effect (WHO90). Therefore, the committee will not consider the data on
       carboxylesterase inhibition in the risk assessment. A carcinogenicity study in rats
       did not show a treatment-related increase in tumour incidence. There were no
       data available of the mutagenic and genotoxic potential of the compound. At
       doses below those causing parental toxicity, reproductive performance is not
       affected. The overall NOAEL associated with reproduction toxicity in rats was
       ≥6.25 mg/kg bw/day.
            Based on the above data, the committee concludes that the mechanism of
       toxicity of temephos in mammals is through inhibition of AChE activity in nerve
       tissue, occurring at dose levels that are lower than those that cause other toxic
       effects. Therefore, the committee identifies inhibition of brain AChE as the
       critical effect. In human beings, for obvious reasons, brain AChE cannot be
       measured. Instead, red blood cell AChE, being the same molecular target for
       inhibition by organophosphorus pesticides as brain AChE, is used as a surrogate
       for brain AChE in assessing the human health risk of exposure to temephos
       (Jey94). Studies in rats, rabbits, and dogs showed that red blood cell AChE is
       more sensitive for inhibition by temephos than brain AChE, and it may be
       assumed that this also is the case in humans.
       The committee prefers to use the human data as a basis in deriving a health-based
       recommended occupational exposure limit (HBROEL). The NOAEL of 0.91
       mg/kg bw/day, derived from the 4-week human volunteer study, is taken as a
       starting point. For extrapolation to a HBROEL, an overall assessment factor of 3,
       covering for intraindividual variation, is used. This results in a NAEL for
       humans of 0.30 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 2 mg/m3
       is recommended for temephos.
076-17 Temephos
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<pre>       The committee recommends a health-based occupational exposure limit for
       temephos of 2 mg/m3, as an 8-hour time-weighted average (TWA).
            In view of the relatively low (estimated) skin absorption in humans and the
       relatively low acute lethal toxicity in experimental animals, the committee does
       not recommend a skin notation*.
       References
ACG99  American Conference of Governmental Industrial Hygienists (ACGIH). Temephos. 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; 126.
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; 54.
Arb02  Arbejdstilsynet. Grænseværdier for stoffer og materialer. Copenhagen, Denmark: Arbejdstilsynet,
       2002; At-vejledning C.0.1.
Bli69  Blinn RC. Metabolic fate of Abate insecticide in the rat. J Agric Food Chem 1969; 17: 118-22; cited
       from Gal91 and Rob99.
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 Ecotoxicology and Toxicology of Chemicals (ECETOC). Examination of a
       proposed skin notation strategy. Brussels, Belgium: ECETOC, 1998; special report no 15.
Enn79  Ennin MA, Franklin CS. Some subcellar effects of an organophosphorous insecticide, Abate. Br J
       Pharmacol 1979; 66: 72P-73P.
FAO75  Food and Agricultural Organization/World Health Organization (FAO/WHO). Temephos. Geneva,
       Switzerland: FAO/WHO, 1975; Data sheets on pesticides no 8, rev 1; VBC/DS/75.8 (rev 1); http://
       www.inchem.org/documents/pds/pds/pest8_e.htm.
Fer85  Ferguson PW, Medon PJ, Nasri E. Temephos (Abate) metabolism and toxicity in rats. Arch Environ
       Contam Toxicol 1985; 14: 143-7.
Gai67  Gaines TB, Kimbrough R, Laws ER Jr. Toxicology of Abate in laboratory animals. Arch Environ
       Health 1967; 14: 283-8.
Gai69  Gaines TB. Acute toxicity of pesticides. Toxicol Appl Pharmacol 1969; 14: 515-34.
*      See ECE98 for criteria to assess the need to assign a skin notation.
076-18 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>Gal91  Gallo MA, Lawryk NJ. Temephos. In: Hayes WJ Jr, Laws ER Jr, eds. Classes of pesticides. San
       Diego CA, USA: Academic Press, Inc, 1991; 1036-8 (Handbook of pesticide toxicology; Vol 2: Sect
       16.6.24).
Gon75  Goncharenko NG. Toxicity of Abate during inhalation entrance into the organism. Vrach Delo 1975;
       9: 130-3; cited from Gal91.
HSE02  Health and Safety Executive (HSE). EH40/2002. Occupational Exposure Limits 2002. Sudbury
       (Suffolk), UK: HSE Books, 2002.
Ito72  Ito R, Kawamura H, Chang HS, et al. Acute, subchronic and chronic toxicity of O,O,O’O’-
       tetramethyl-O,O’-thio-di-para-phenylene phosphorothioate. J Med Soc Toho Univ 1972; 19: 363-7;
       cited from Gal91.
Kur79  Kurtz PJ, Weeks MH. Effects of single and repeated exposures to Abate on rat behavior and
       cholinesterase activity. Toxicology 1979; 13: 35-43.
Kut77  Kutz FW, Stassman SC. Human urinary metabolites of organophosphate insecticides following
       mosquito adulticiding. Mosq News 1977; 37: 211-8; cited from Gal91 and NLM02.
Law67  Laws ER Jr, Morales FR, Hayes WJ Jr, et al. Toxicology of Abate in volunteers. Arch Environ Health
       1967; 14: 289-91.
Lev70  Levinskas GJ, Shaffer CB. Toxicity of Abate, a mosquito larvicide, and its sulfoxide. Toxicol Appl
       Pharmacol 1970; 17: 301-2.
Lie98  Liem DS, Rowland J. Temephos - report of the hazard identification assessment review. Washington
       DC, USA: US Environmental Protection Agency, Office of Pesticide Programs, Health Effects
       Division (7509C), 1998; http:// www.epa.gov/pesticides/op/temephos.htm.
Mur72  Murphy SD, Cheever KL. Carboxylesterase and cholinesterase inhibition in rats. Abate and
       interaction with malathion. Arch Environ Health 1972; 24: 107-14.
NLM02  US National Library of Medicine (NLM), ed. Temephos. In: Hazardous Substances Data Bank
       (HSDB). http://toxnet.nlm.nih.gov.
Paq99a Paquette NC. Dermal penetration of radio-labeled temephos. Washington DC, USA: US
       Environmental Protection Agency, Office of Pesticide Programs, Health Effects Division (7509C),
       1999; http://www.epa.gov/pesticides/op/temephos.htm.
Paq99b Paquette NC, Becker J. Temephos: revised HED chapter for the reregistration eligibility decision
       (RED) document. Washington DC, USA: US Environmental Protection Agency, Office of Pesticide
       Programs, Health Effects Division (7509C), 1999; http:// www.epa.gov/pesticides/op/temephos.htm.
Rob99  Roberts TR, Hutson DH, eds. Temephos. In: Insecticides and fungicides. Cambridge, UK: the Royal
       Society of Chemistry, 1999: 490-3 (Metabolic pathways of agrochemicals; Pt 2).
Sno80  Snodgrass HL Jr. Toxicological assessment of abate. Dermal penetration of radio-labeled abate.
       Aberdeen Proving Ground MD, USA: US Army Environmental Hygiene Agency, 1980; study no 75-
       51-1302-80.
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.
076-19 Temephos
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<pre>SZW03  Ministerie van Sociale Zaken en Werkgelegenheid (SZW). Nationale MAC-lijst 2003. The Hague,
       the Netherlands: Sdu, Servicecentrum Uitgevers, 2003: 40.
TRG00  TRGS 900. Grenzwerte in der Luft am Arbeitsplatz; Technische Regeln für Gefahrstoffe. BArbBl
       2000; 2.
WHO90  World Health Organisation(WHO): International Program on Chemical Safety (IPCS). Principles for
       toxicological assessment of pesticide residues in food. Geneva, Switzerland: WHO, 1990;
       Environmental Health Criteria 104.
076-20 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>              Annex
Occupational exposure limits for temephos 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        -         10           8h              administrative                    SZW03
Employment
Germany
-AGS                                   -         -                                                              TRG00
-DFG MAK-Kommission                    -         -                                                              DFG02
Great-Britain
-HSE                                   -         -                                                              HSE02
Sweden                                 -         -                                                              Swe00
Denmark                                -         -                                                              Arb02
USA
-ACGIH                                 -         10           8h              TLV                               ACG03b
-OSHA                                  -         15c          8h              PEL                               ACG03a
                                       -         5d           8h
-NIOSH                                 -         10c          10 h            REL                               ACG03a
                                       -         5c           10 h
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
     Total dust.
d
     Respirabe fraction.
076-21        Temephos
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<pre>076-22 Health-based Reassessment of Administrative Occupational Exposure Limits</pre>

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<br><br>