<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>Phorate
(CAS No: 298-02-2)
Health-based Reassessment of Administrative Occupational Exposure Limits
Committee on Updating of Occupational Exposure Limits,
a committee of the Health Council of the Netherlands
No. 2000/15OSH/075, The Hague, 22 september 2003
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. Phorate; Health-based Reassessment of Administrative
Occupational Exposure Limits. The Hague: Health Council of the Netherlands,
2003; 2000/15OSH/075.
all rights reserved
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of phorate 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 JAGM van Raaij, Ph.D. and WK de Raat, Ph.D. (OpdenKamp
      Registration & Notification, The Hague, The Netherlands) and J Krüse, Ph.D.
      (Kinetox, Vleuten, The Netherlands)*.
          The evaluation of the toxicity of phorate has been based on reviews
      published by the American Conference of Governmental Industrial Hygienists
      (ACG99) and in ‘Handbook of pesticide toxicology’ (Gal91). Where relevant,
      the original publications were reviewed and evaluated as will be indicated in the
      text. In addition, in December 1999, literature was searched in the on-line
      databases Medline, Toxline, and Chemical Abstracts covering the period of
      1965/1966 until December 1999, and using the following key words: phorate and
      298-02-2. Data of unpublished studies were generally not taken into account.
      Exceptions were made for studies that were summarised and evaluated by
      international bodies such as the Food and Agricultural Organization/World
      Health Organization (FAO/WHO: Joint Meeting of the FAO Panel of Experts on
      Pesticides Residues on Food and the Environment and the WHO Expert Group
      on Pesticides Residues - JMPR) (FAO95, FAO97, WHO88), and the Health
      Effects Division (HED) of the US Environmental Protection Agency (EPA)
      (Oli99), as part of its hazard identification assessment review.
          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.
*     Current address: Opden Kamp Registration and Notification, Zeist, the Netherlands.
075-3 Phorate
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<pre>2     Identity
      name                   :   phorate
      synonym                :   phosphorodithioic acid O,O-diethyl S-[(ethylthio)methyl] ester; O,O-diethyl S-
                                 (ethylthio)methyl phosphorodithioate; O,O-diethyl S-ethylmercaptomethyl
                                 dithiophosphate; Thimet; Timet; Granatox; Rampart
      molecular formula      :   C7H17O2PS3
      structural formula     :
      CAS number             :   298-02-2
3     Physical and chemical properties
      molecular weight       :   260.38
      boiling point          :   at 0.1 kPa: 118-120oC
      melting point          :   -43.7oC
      vapour pressure        :   at 25oC: 0.09 Pa
      solubility in water    :   slightly soluble (at 25oC: 5 mg/100 mL)
      Log Poctanol/water     :   3.92
      conversion factors     :   not applicable
      Data from ACG99, Rob99, Tom97.
      Phorate is a clear, pale yellow mobile liquid. It is formulated in emulsifiable or
      granular concentrates (Gal91). Phorate is stable at room temperature and
      between pH 5 and pH 7 for at least 2 years. However, under very acidic (pH<2)
      or alkaline (pH>9) conditions, the compound hydrolyses (ACG99).
4     Uses
      Phorate is a systemic and contact insecticide and acaricide used to control
      sucking and chewing pests in a wide range of crops, among others corn, sugar
      beets, cotton, brassicas, and coffee. It is also used as a nematocide (ACG99,
      Gal91, Tom97).
075-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>           According to the database of the Dutch Pesticide Authorisation Board
      (CTB)*, phorate is at present not registered for its use as an active ingredient in
      pesticides in the Netherlands.
5     Biotransformation and kinetics
      Two studies have been reported on the kinetics of the compound following oral
      dosing, but the committee did not find information from dermal or inhalation
      studies.
           Male rats were given a single dose of 0.8 mg/kg bw of 14C-labelled phorate
      (label on methyl group in thioether moiety) in corn oil by gavage. Within the first
      24 hours after administration, 77% of the dose was excreted in the urine and 12%
      in the faeces. Through the 8th day, 83% of the dose was excreted in the urine and
      13% in the faeces. Less than 1% of the total radioactivity was found in tissues
      (highest level in blood) at 24 hours (Hus87).
           Similar results were obtained in female rats following a single oral dose of
      0.44 mg/kg bw (Mil90).
           Phorate is biotransformed by oxidation of the thioether moiety to the
      corresponding sulphoxide and sulphone and by desulphuration of the P=S moiety
      to P=O, producing a phosphorothiolate ester. By hydrolysis of these oxidative
      intermediates, 10 metabolites have been identified in the urine. The 2 major
      metabolites were the following non-phosphorylated metabolites:
      sulphoxide(ethylsulphonyl)methyl (43% of urinary metabolites) and
      methane(ethylsulphonyl)(methylsulphonyl) (24-28% of urinary metabolites).
      Phosphorylated metabolites accounted for <15% of urinary metabolites in males
      and no phosphorylated metabolites were identified in the urine of females. The
      main residues in liver, kidney, and muscle were dephosphorylated metabolites
      (Hus87, Mil90).
           In an older study, male albino rats received a single oral dose of 2 mg/kg
      bw of 32P-labelled phorate. Only 35% of the administered dose was detected in
      the urine and 3.5% in the faeces within the first 6 days. Six daily oral doses of
      1 mg/kg bw of phorate resulted in an excretion of 12% of the administered dose
      in the urine and 6% in the faeces within 7 days. The major metabolites identified
      were O,O-diethylphosphorothioate (DEPT; 80% of urinary metabolites) and
      diethylphosphoric acid (DEP; 17% of urinary metabolites). The brain, liver, and
      kidney tissues of the repeatedly dosed animals contained unidentified and largely
      unextractable residues. The authors did not discuss the difference in excretion
*     at: http://www.ctb-wageningen.nl/geel.html.
075-5 Phorate
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<pre>      pattern of single and repeated dosing (Bow58). The aforementioned metabolites
      were also identified in operator exposure studies (PSD94).
           Based on the results of the more recent studies (Hus87, Mil90), the
      committee concludes that phorate and its metabolites are rapidly excreted and
      that accumulation of a toxic metabolite is not a concern.
6     Effects on mechanism of action
      Human data
      Several cases of poisoning associated with the use of phorate have been reported.
      A 16-year-old boy became ill after he had worked for several days with phorate-
      treated cottonseed. Clinical symptoms of intoxication were lowered blood
      pressure, pinpoint pupils, convulsions, and unconsciousness. After several
      treatments with atropine, he recovered. One day after the onset, red blood cell
      acetylcholinesterase (AChE) and plasma cholinesterase (ChE) activities were
      21% and 49% of normal values, respectively, and 15 days later plasma ChE, but
      not red blood cell AChE, had recovered completely (Gal91, WHO88).
           In a pesticide formulation plant, cases of poisoning have been reported for 2
      workers who were engaged in Thimet formulation. Symptoms of intoxication
      were dizziness, nausea, vomiting, constricted pupils, cardiac tachycardia,
      excessive salivation, respiratory distress, muscle fasciculations, and pinpoint
      pupils. After treatment with atropine and/or 2-PAM (2-pyridine-aldoxime
      methiodide), both men recovered. Phorate air concentrations in the plant ranged
      from 0.07 to 14.6 mg/m3. No cholinesterase measurements were reported
      (You79, WHO88). In another incident, a formulator experienced neurological
      symptoms (not specified) following exposure to phorate while cleaning a mixing
      tank. Plasma ChE and red blood cell AChE activities were reduced by 50% of
      base level values and increased concentrations of diethyl phosphate in urine, a
      metabolite of phorate, were observed (WHO88). Forty male workers who were
      engaged in formulation of phorate for 2 weeks developed toxic symptoms,
      including gastro-intestinal effects, bradycardia, and neurological effects
      (headache, giddiness, fatigue). Skin and eye irritation also occurred. In 60% of
      the subjects, mean plasma ChE activity was decreased by 55% at the end of the
      first week and by 71% at the end of the second week compared to pre-exposure
      activity. Within 10 days after cessation of exposure, ChE activity had recovered
      to 79% of pre-exposure value (Kas84).
075-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>            Animal data
            Irritation and sensitisation
            No data have been reported on irritation and sensitisation in experimental
            animals, as the high acute toxicity of phorate prohibited administration of
            appropriate dose levels (Oli99).
            Acute toxicity
            Results of acute lethal toxicity tests are summarised in Table 1.
Table 1 Summary of acute lethal toxicity studies for phorate in mammals.
exposure route   vehiculum               species (strain)             sex           LC50/LD50     reference
                                                                                    (duration)
inhalationa                              rat (Sprague-Dawley)         male          60 mg/m3 (1h) New78
                                                                                             3
                                         rat (Sprague-Dawley)         female        11 mg/m (1h)  New78
dermal           xylene                  rat (Sherman)                male          6.2 mg/kg bw  Gai69
                 xylene                  rat (Sherman)                female        2.5 mg/kg bw  Gai69
                 propylene glycol        rat (Sprague-Dawley)         male          9.3 mg/kg bw  New78
                 propylene glycol        rat (Sprague-Dawley)         female        3.9 mg/kg bw  New78
                                         rat                          male          5.7 mg/kg bw  FAO95
                                         rabbit                       male          5.2 mg/kg bw  FAO95
                                         rabbit                       not specified 99 mg/kg bw   NIO02
oral             peanut oil              rat (Sherman)                male          2.3 mg/kg bw  Gai69
                 peanut oil              rat (Sherman)                female        1.1 mg/kg bw  Gai69
                                         rat                          male          2.8 mg/kg bw  FAO95
                                         rat                          female        1.6 mg/kg bw  FAO95
                 propylene glycol        rat (Sprague-Dawley)         male          3.7 mg/kg bw  New78
                 propylene glycol        rat (Sprague-Dawley)         female        1.4 mg/kg bw  New78
                                         rat                          not specified 1 mg/kg bw    NIO02
                                         mouse                        male          2.25 mg/kg bw Gal91
075-7       Phorate
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<pre>intravenous        propylene glycol      rat (Sprague-Dawley)   male               2.2 mg/kg bw New78
                   propylene glycol      rat (Sprague-Dawley)   female             1.2 mg/kg bw New78
 a
   As an aerosol generated from a 1% solution in xylene.
             Phorate metabolites, including the sulphoxide and sulphone derivatives of
             phorate and phorate oxygen analogues, are even more acutely toxic and have
             greater anticholinesterase activity than phorate (FAO95, Oli99).
                  The potential of phorate to induce delayed neuropathy was investigated in
             Leghorn hens (n=50) that were given an oral dose of phorate (purity: 89.5%) of
             14.2 mg/kg bw. Before dosing, atropine was administered for protection. At day
             21 after dosing, all surviving hens were given a second dose of atropine and 14.2
             mg/kg bw phorate. Fifteen hens were used as negative controls and were given
             atropine but no phorate, and 15 hens, used as positive controls, were given 2
             doses of 500 mg/kg bw tri-ortho-tolyl phosphate at days 1 and 21. Of the 50
             phorate-treated hens, 23 died within 24 hours of the first dose and 13 more
             within 24 hours of the second dose, 10 hens surviving until the termination of the
             study at day 42. Vehicle controls and phorate-treated hens had slight generalised
             limb weakness (lasting for about 2 hours) shortly after each atropine treatment,
             phorate-treated hens showing slightly more severe reactions as well as slight to
             moderate ataxia for up to 2 hours after phorate treatment. No clinical signs of
             delayed neuropathy were observed in any vehicle-control or phorate-treated
             hens. At necropsy, no effects were seen in any of the 50 phorate-treated animals.
             Histological examination of the 10 surviving phorate-treated hens revealed
             minimal to mild focal axonal degeneration of the sciatic nerves, which was not
             observed in the negative controls. This degeneration was associated with
             interstitial infiltration of lymphoid cells, which was also seen in other test and
             vehicle-control hens. This syndrome, which was distinctly different from that
             observed in the positive-control animals, was ascribed to lesions of a naturally
             occurring disease, and was considered not to be related to phorate treatment
             (Fle84).
                   Recently, an acute neurotoxicity study has been conducted in 7-week-old
             Sprague-Dawley CD rats. The rats (n=20/sex/group) were given a single oral
             dose of phorate (purity: 91.8%) by gavage at levels 0, 0.25, 0.50, or 1.0 mg/kg
             bw. The Functional Observational Battery (FOB) revealed miosis in 2/10 males
             and 2/10 females of the mid-dose group and in 2/10 males and 5/10 females of
             the high-dose group, approximately 4-5 hours after dosing. Other effects were
             tremors, fasciculations, slightly impaired locomotion, and splayed hind limbs in
075-8        Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      one high-dose female and moderate tremors in another high-dose female. These
      symptoms disappeared within the first week and were no longer present during
      the 8th day of observation. In the male and female rats of the high-dose group,
      there was significant inhibition of plasma ChE, red blood cell AChE, and brain
      AChE (not quantified). In the mid-dose group, a small but statistically significant
      decrease in brain AChE activity (6%) was observed in male rats at 0.5 mg/kg bw.
      The NOAEL in this acute neurotoxicity rat study was 0.25 mg/kg bw, based on
      the evidence of miosis and inhibition of brain AChE in males (Oli99).
      Short-term toxicity
      In a dermal toxicity study, 3 groups of Sprague-Dawley CD rats (n=10/sex/
      group) received topical applications of granular phorate (20.3%) at 0, 0.41, 0.81,
      or 3.1 (females) or 4.1 (males) mg active ingredient/kg bw/day, 6 hours/day, 5
      days/week, for 4 weeks. High mortality (5 out of 10 animals) was seen in the
      high-dose female group during the first 3 weeks of the study. In this group, signs
      of toxicity were lachrymation, lethargy, tremors, and irregular gait. However,
      male rats were not affected. At the top dose, plasma ChE activity was inhibited
      up to 61% in males and 91% in females. Inhibition of red blood cell AChE was
      up to 76% in males and 97% in females, while brain AChE was inhibited by 41%
      in males and 68% in females. A small but statistically significant decrease in red
      blood cell AChE and brain AChE was observed in females at 0.81 mg/kg
      bw/day. The NOAEL in this 4-week dermal rat study was established at 0.41 mg
      active ingredient/kg bw/day (Oli99).
          Rats (n=50/sex/group; strain not specified) were given phorate (purity: 92%)
      in the diet at levels equivalent to 0, 0.01, 0.03, 0.1, 0.3, 0.6, and 0.9 mg/kg
      bw/day for 13 weeks. At the 2 highest levels, 25 male and 25 female rats were
      used. In the 2 highest dose groups, there were severe excitability, intermittent
      tremors, ataxia, reduced body weight gain and food consumption, and mortality
      (100% and 50% at 0.9 and 0.6 mg/kg bw/day, respectively). Plasma, red blood
      cell, and brain cholinesterase activity was significantly depressed (not
      quantified). At 0.3 mg/kg bw, cholinergic signs of intoxication (excitability,
      intermittent tremors) were observed occasionally in females only. Plasma ChE,
      red blood cell AChE, and brain AChE activities were significantly reduced (not
      quantified). At 0.1 mg/kg bw, red blood cell AChE was reduced (not quantified)
      in females only. Animals dosed with 0.3 mg/kg bw or less did not show changes
      in survival, growth, and food intake, or abnormalities at gross necropsy and
      histological examination (performed on 3/10/sex only). The 13-week oral rat
075-9 Phorate
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<pre>       NOAELs were 0.03 mg/kg bw/day for inhibition of plasma ChE activity and 0.1
       mg/kg bw/day for inhibition of red blood cell and brain AChE (Tus56a).
           Swiss mice (Crl:CD-1 (ICR) BR; n=20/sex/group) were given phorate
       (purity: 92.1%) via the diet in concentrations equivalent to 0, 0.18, 0.55, or 1.10
       mg/kg bw/day in males, and 0, 0.23, 0.67, or 1.38 mg/kg bw/day in females for
       13 weeks. No significant changes in survival rates, food intake, or body weight
       gain, or remarkable clinical signs were observed in any of the treated groups.
       Histological examinations were not performed; cholinesterase activities were
       measured before terminal sacrifice. Plasma ChE activity was reduced by 15% at
       0.23 mg/kg bw/day in females and in both sexes at the 2 highest dose levels (not
       specified). Red blood cell AChE was decreased by 17% at 0.67 mg/kg/day in
       females and by 50% in males and 61% in females at the top dose. Brain AChE
       was significantly decreased in both sexes by approximately 10% and 50% at the
       mid and high dose, respectively. The NOAEL in the 13-week oral mouse study
       was 0.18 mg/kg bw/day based on inhibition of brain AChE (Tru90).
           To study the effect of phorate on AChE and butyrylcholinesterase (ChE) in
       the olfactory bulb of the mouse brain, adult albino mice (n=10/sex/group; strain
       not specified) received 1.0 and 1.5 mg phorate/kg bw/day via the diet for 32
       weeks. Histoenzymological examination showed that AChE activity in the
       different layers of the olfactory bulb was reduced only at 1.5 mg/kg bw, whereas
       reduced ChE activity was found at both dose levels (Van97).
           Several short-term studies were carried out with dogs. In a range-finding
       study, dogs (n=2/sex/group) received oral (capsules) doses of phorate (purity:
       92%) of 0.01, 0.05, 0.10, 0.25, or 0.50 mg/kg bw/day for 2 weeks. Controls
       (n=3/sex) received capsules with corn oil only. At the highest dose, one female
       dog showed cholinergic effects (excessive salivation and tremors) while
       decreased body weight gain and decreased total serum protein levels were seen
       in animals of both sexes. Treatment did not affect survival, food intake,
       haematological parameters, organ weights, or gross pathology. Histological
       examinations were not performed. At 0.05 mg/kg bw/day, plasma ChE activity
       alone was significantly decreased (not specified) in males only. At 0.10 mg/kg
       bw/day and higher, both plasma ChE and brain AChE activities were
       significantly reduced in both sexes. Red blood cell AChE activity was
       significantly reduced at 0.50 mg/kg bw/day only. The 2-week oral dog NOAEL
       was 0.05 mg/kg bw/day, based on inhibition of brain AChE (Pic87).
           In a study conducted in 1961, beagle dogs (n=3/sex/group) that were fed
       phorate (purity: not given) at dose levels equivalent to 0, 0.012, or 0.025 mg/kg
       bw/day for 6 weeks, did not show changes in plasma ChE or red blood cell
075-10 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       AChE activity (Kay61). Another study dealt with mongrel dogs (one female and
       2 males per group) that received oral (capsules) doses of phorate (purity: 92%) of
       0. 0.01, 0.05, 0.25, 1.25, or 2.5 mg/kg bw/day, 6 days/week, for 13-15 weeks. All
       dogs at the 2 top doses showed typical cholinergic signs and subsequently died.
       Plasma ChE activity was inhibited at 0.05 mg/kg bw or above and red blood cell
       AChE at 0.25 mg/kg bw/day or above (not specified). The NOAEL in this 15-
       week oral dog study was 0.05 mg/kg bw/day, based on inhibition of red blood
       cell AChE (Tus56b).
           A one-year feeding study was carried out in beagle dogs (n=6/sex/group) that
       were given oral (capsules) doses of phorate (purity: 92%) of 0, 0.005, 0.01, 0.05,
       or 0.25 mg/kg bw/day. Eight control animals of each sex were used. At the
       highest dose, clinical signs (tremors) were occasionally observed in both sexes
       and mean body weights were decreased in males. Treatment did not affect food
       consumption or haematological parameters for any group. However, serum total
       protein levels were significantly reduced in males treated at 0.25 mg/kg bw/day.
       Gross and microscopic examination did not reveal treatment-related
       abnormalities. With regard to effects on cholinesterase activities, red blood cell
       AChE (>20%) and brain AChE (43-54%) were significantly reduced at the top
       dose, but were within normal levels at 0.05 mg/kg bw/day. Plasma ChE activity
       was decreased at the 2 highest dose levels. The NOAEL in this one-year oral dog
       study was 0.05 mg/kg bw/day based on decreased body weights, inhibition of red
       blood cell and brain AChE activities, and clinical signs observed at the next
       higher dose of 0.25 mg/kg bw (She87).
           The potential of phorate to induce neuropathy following repeated exposure
       was investigated in a study in which hens received 5 mg phorate/kg bw/day via
       the diet for 4 weeks. No treatment-related structural nerve damage, such as
       myelin loss was found. In contrast, the positive control tri-ortho-tolyl phosphate
       induced myelin loss in each treated hen (Lev65).
           The results of these studies are summarised in Table 2. In nearly all studies,
       inhibition of brain or red blood cell AChE is the critical effect.
075-11 Phorate
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<pre>       Long-term toxicity and carcinogenicity
       Five-week-old rats (Crl:COBS CD BR; n=50/sex/group) were fed doses of
       technical-grade phorate (purity: 84.5%) equivalent to 0, 0.05, 0.16, or 0.32
       mg/kg bw/day in males and 0, 0.07, 0.19, or 0.43 mg/kg bw/day in females for 2
       years. The mortality rate was increased in females at the highest dose. However,
       more than 60% of animals in all groups lived more than 90 weeks. Treatment-
       related effects were growth retardation in females during the first half year and
       again between weeks 74 and 102, and a decreased red blood cell count,
       haemoglobin, and haematocrit level in females at month 12. Red blood cell
       AChE activity was not significantly changed (<20%) at any dose level at any
       time. After 24 months, plasma ChE was decreased by more than 20% at all dose
       levels in males and at 0.19 and 0.43 mg/kg bw/day in females. Brain AChE
       activity was reduced by more than 20% in males at 0.32 mg/kg bw and in
       females at 0.19 and 0.43 mg/kg bw/day. At sacrifice, females given the highest
       dose had increased relative adrenal, brain, heart, liver, and spleen weights. Gross
       and histological examination revealed a significant treatment-related increase of
       inflammation and hyperplasia of the forestomach in both sexes at the highest
       dose level. Incidence, type, or time of appearance of tumours were not
       significantly different between treated and control groups. The 2-year oral rat
       NOAEL was 0.07 mg/kg bw/day, based on inhibition of brain AChE at 0.19
       mg/kg bw/day in female rats (Man81a).
           CD-1 outbred Swiss albino mice (n=50/sex/group) were fed technical-grade
       phorate (purity: 85.5%) at doses equivalent to 0, 0.15, 0.45 or 0.9 mg/kg bw/day
       for 18 months. Compared with controls, a higher incidence of tremor,
       hyperactivity, excessive salivation, and growth retardation (in females only) was
       observed at 0.9 mg/kg bw/day, but survival was not adversely affected. Gross
       and histological examination did not show alterations related to treatment. There
       was no significant dose-related increase in the incidence of any particular type of
       tumour or of animals with malignant or benign tumours. Cholinesterase activities
       were not measured in this study. The 18-month oral mouse NOAEL was 0.45
       mg/kg bw/day, based on growth retardation in female mice at 0.9 mg/kg bw
       (Man81b).
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<pre>       Mutagenicity and genotoxicity
       A battery of assays was performed to test the genotoxicity of phorate. Assays
       comprised tests for gene mutation, cytogenicity, and other genotoxic effects in
       vitro and in vivo.
       •   In vitro tests
           • Gene mutation assays. Phorate was negative in tests for reverse mutation
              in S. typhimurium strains TA100, TA1535, TA 1537, and TA 1538 and in
              E. coli p3478 at doses up to 1000 µg/plate in the presence or absence of an
              S9 metabolic activation system (Pan86, Sim87, Wat80,). Phorate did not
              induce gene mutations at the hprt locus in cultured Chinese hamster ovary
              (CHO) cells (Thi85).
           • Cytogenicity assays. No statistically significant changes were found in the
              frequency of sister chromatid exchanges (SCE) in either cultured human
              lymphocytes (up to 20 µg phorate/mL), cultured CHO cells (up to 40
              µg/mL), or cultured rat tracheal epithelial cells (up to 50 µg/mL), in the
              presence or absence of S9 (Pan84, Wan87). However, a statistically
              significant increase in the frequency of SCEs was reported in cultured
              human lymphoid cells treated with 2 and 20 µg phorate/mL without
              metabolic activation of S9 (Sob82). The frequency of chromosomal
              aberrations in cultured CHO cells was increased at 40 µg/mL without S9,
              but no change occurred in the presence of S9 (Lin87).
           • Other genotoxicity assays. Phorate did not induce mitotic recombination
              in S. cerevisae D3 at a concentration of 5% with and without metabolic
              activation (Sim77). No unscheduled DNA synthesis (UDS) was seen in
              cultured human fibroblasts (WI-38 cells) at concentrations up to 1 mM
              (Sim77).
       • In vivo tests
       There was no increase in the incidence of chromosomal aberrations in bone
       marrow cells of male and female Sprague-Dawley rats (number not specified)
       receiving phorate capsules at doses varying from 0 to 2.5 mg/kg/day (duration of
       study not specified) (Ive86). No increased incidence of micronucleated bone
       marrow cells of Swiss albino mice (3/sex/group) was reported following 2
       intraperitoneal doses of 1.5 mg/kg bw of phorate at 24-hour intervals (Pan86). In
       contrast, a statistically significant increase was found in the frequency of
       micronuclei in bone marrow cells of male Wistar rats (n=5/group) after a single
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<pre>       intraperitoneal dose of 0.75 mg/kg bw. No changes were observed at 0.25 and
       0.50 mg/kg bw. The frequency of chromosomal aberrations in bone marrow cells
       of Wistar rats (n=5/group) was increased following daily intraperitoneal
       injections of 0.15 and 0.30 mg phorate/kg bw/day for 5 days (Gro85, Mah87).
       These effects were confirmed in another study with Wistar rats following
       administration of 2 intraperitoneal doses of phorate at 24-hour intervals.
       Increased chromosome aberrations and micronuclei were observed in bone
       marrow cells of rats that received of 0.09-0.37 and 7.5-15 mg/kg bw, respectively
       (Dhi90). Dominant lethal mutations were not found in male mice given dietary
       phorate levels varying from 0 to 20 mg/kg bw for 7 weeks (Sim77).
       Based on these results, the committee concludes that phorate does not induce
       gene mutations in vitro, but conflicting results have been reported for
       cytogenicity effects, both in vitro and in vivo.
       Reproduction toxicity
       A 2-generation study was conducted in groups of Sprague-Dawley rats (COBS
       CD (SD); n=25/sex/group) that were fed phorate (purity: 92%) at dose levels
       equivalent to 0, 0.09, 0.17, 0.35, or 0.52 mg/kg bw/day for males and 0, 0.10,
       0.20, 0.40, or 0.62 mg/kg bw/day for females for a minimum of 60 days before
       mating. The second-generation parental animals (n=25-30/sex/group) were
       treated for a minimum of 100 days before mating. Animals were exposed
       continuously to phorate before mating and throughout weaning of the offspring
       in both generations. Treatment-related effects in parental animals were tremors
       and decrease in body weight at 0.35 and 0.40 mg/kg bw/day in males and
       females, respectively. At the top dose, clinical signs, mortality, and ocular effects
       were observed. In F1 males, plasma ChE, red blood cell AchE, and brain AChE
       activities were inhibited at 0.52 mg/kg bw/day by >30, 11, and 40%,
       respectively. In F1 females, brain AChE was reduced by 59 and 83% and plasma
       ChE by more than 30% at 0.40 and 0.62 mg/kg bw/day, respectively. Red blood
       cell AChE was reduced at the top dose only. Mating or fertility indices,
       pregnancy rate, length of gestation, gestation index, sex distribution ratios, and
       reproductive organ morphology did not show treatment-related changes. Pup
       survival during the lactation period and mean pup weights were reduced at the 2
       highest doses and litter size at the highest dose. The NOAEL in this 2-generation
       oral rat study was 0.17 mg/kg bw/day for both parental and offspring toxicity
       (Sch91).
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<pre>            In an older reproduction study in mice (8 males and 16 females/group),
       carried out in 1965, phorate (purity: unknown) was given at dietary levels
       equivalent to 0, 0.09, 0.23, or 0.45 mg/kg bw/day. Compound administration was
       initiated 7 weeks before the first mating. The study involved 3 generations with 2
       litters per generation. No effects on fertility, gestation length, or on gross and
       microscopic alterations of tissues were observed. The lactation and viability
       indices were only slightly decreased at the highest dose. The NOAEL in this
       3-generation mouse study for parental and reproduction toxicity was 0.23 mg/kg
       bw/day (FAO95, Oli99).
            Several developmental toxicity studies have been reported for phorate.
       Groups of pregnant Sprague-Dawley rats (n=10/group) were exposed to aerosols
       of phorate (purity: 78-90%), generated from a 1% solution in xylene, 1 hour/day,
       on days 7-14 of gestation, at concentrations 0.15, 0.4, or, 1.94 mg/m3. Controls
       received xylene or air only. Signs of toxicity in the dams that received the highest
       dose were death (5/10), tremors, lachrymation, and exophthalmus. No treatment-
       related effects on body weight, food consumption, or pregnancy rate were
       observed. However, the average percentage of fetal mortality was significantly
       increased at the top dose. Average number of implants, average fetal weight,
       average number of ossification centres, or the incidence of supernumerary ribs
       were not affected by phorate. The NOAEL for maternal and offspring toxicity
       was 0.4 mg/m3 (New78). The committee considers this study to have a limited
       value due to the possible role of xylene as a solvent on these results.
            During the gestational period (days 6-15), 25 Sprague-Dawley rats
       (Crl:COBS CD (SD) BR) received phorate (purity: 92%) at doses of 0, 0.125,
       0.25, or 0.5 mg/kg bw/day by gavage. Maternal toxicity resulting in death
       occurred in 7/23 of the high-dose dams. No effects on food intake, body weight,
       or general health condition were observed in the surviving dams. The incidence
       of cardiac hypertrophy was increased among the fetuses at the highest dose. The
       number of implantation sites, resorptions and dead fetuses, the mean live litter
       size, average fetal weight, and sex ratio were not significantly affected compared
       with controls. The NOAEL was 0.25 mg/kg bw/day for maternal and fetal
       toxicity (Bel79). In another study, Sprague-Dawley rats (CrL:CDBRVAF/Plus
       SD, n=24-25/group) received phorate (purity: 92%) at doses of 0, 0.1, 0.2, 0.3, or
       0.4 mg/kg bw/day by gavage on pregnancy days 6-15. Maternal toxicity at the
       highest dose was evident from death (6/25 animals), clinical signs (tremors,
       excessive salivation, stained fur, laboured breath, decreased motor activity,
       impaired righting reflex), and significantly decreased body weights, body weight
       gain, and food intake. Fetotoxicity at the highest dose was demonstrated by
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<pre>       decreased fetal body weight and delayed ossification of the sternum and pelvis
       when compared with controls. The NOAEL for fetal and maternal toxicity was
       0.3 mg/kg bw/day (Loc90). In a range-finding study, pregnant New Zealand
       white (NZW) rabbits (n=5/group) were given phorate (purity: 92%) in corn oil
       by gavage at dose levels 0, 0.3, 0.6, 0.9, 1.2, or 1.5 mg/kg bw/day on days 6-18
       of gestation. Death occurred in all exposed groups in a dose-dependent way.
       Mean body weight loss was seen at 1.2 mg/kg bw/day. Increased numbers of
       resorptions and post-implantation losses were reported at 0.6 mg/kg bw and
       higher. Decreased mean fetal body weights and shorter crown-rump lengths were
       found at 1.2 mg/kg bw/day. Gross examination of the fetuses did not show
       treatment-related malformations. The LOAEL for maternal toxicity and NOAEL
       for developmental toxicity were 0.3 mg/kg bw/day (Sch86). The same authors
       carried out a more extensive study in NZW rabbits (n=20/group) that were
       treated by gavage with phorate (purity: 92%) dissolved in corn oil, during days
       6-18 of gestation at doses of 0, 0.15, 0.5, 0.9, or 1.2 mg/kg bw/day. Maternal
       death occurred at the highest dose (8/20), 0.9 mg/kg bw/day (2/20), and at 0.5
       mg/kg bw/day (1/20). Reduced body weight gain, and decreased food
       consumption were observed at 0.5 mg/kg bw/day and above. Treatment had no
       effect on pre-implantation loss, number of resorptions, number of live fetuses,
       fetal body weight, or sex ratio. At the top dose, 3 remaining fetuses in a single
       litter (5/8 implantation sites showed early resorptions) showed open eyelids,
       curved scapulae, an absent supraorbital process, an irregular margin of the
       frontals, and a displaced anterior fontanel. Ocular and scapular defects were not
       seen in other fetuses from dams treated at this dose and the incidence of open
       eyes was within that of historical controls. The authors, therefore, considered
       this findings spurious and not phorate-treatment related. The maternal NOAEL,
       based on mortality and body weight loss was 0.15 mg/kg, and the developmental
       NOAEL 1.2 mg/kg/day (Sch87).
            The committee concludes that phorate showed effects on reproduction only
       at dose levels, which produce parental/maternal toxicity.
7      Existing exposure limits
       The current administrative occupational exposure limit (MAC) for phorate in the
       Netherlands is 0.05 mg/m3, 8-hour TWA, with a skin notation.
            Existing occupational exposure limits in some European countries and the
       USA are summarised in the annex.
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<pre>8      Assessment of health hazard
       The health hazard assessment of phorate is based mainly on toxicology reviews
       issued by the Health Effect Division of the United States EPA for reregistration
       eligibility (Oli99) and by the FAO/WHO Joint Meeting on Pesticide Residues for
       recommendation of an acceptable daily intake (FAO95, FAO97). 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. It should be realised that
       some of these studies were conducted in the 1960s and 1970s and do not meet
       current requirements.
           Workers can be exposed to phorate through inhalation of aerosols or by direct
       skin contact with a formulation of the compound, but the committee did not find
       quantitative data on dermal or inhalation absorption. In view of the high acute
       dermal toxicity in rats (LD50: 2.5-9.3 mg/kg bw), it is expected that a substantial
       percentage of a dermal dose will be absorbed through the skin. The extent of
       absorption following oral intake is essentially 100% in the rat. Following
       absorption, the compound is rapidly metabolised into breakdown products (e.g.,
       DEPT, DEP), which are mainly excreted in the urine. There is no evidence of
       accumulation of the compound in any of the tissues.
           Case studies in humans showed a high acute toxicity of phorate following
       accidental exposure. Effects observed in these studies were typical clinical
       symptoms of cholinergic toxicity such as salivation, constricted pupils, and
       muscle fasciculations.
           Based on results of acute lethal toxicity studies in test animals, the committee
       considers the compound as very toxic after dermal, inhalation, and oral exposure.
       Phorate did not cause neurological changes indicative of delayed neurotoxicity.
           Inhibition of serum ChE and of red blood cell and brain AChE were the main
       effects found in dogs, rats, and mice following short-term and chronic exposure,
       and, generally, no other systemic effects have been reported. The oral NOAELs
       for brain and red blood cell AChE inhibition were 0.05 mg/kg bw for dogs (one-
       year study), 0.07 mg/kg bw (brain AChE only) for rats (2-year study), and 0.18
       mg/kg bw for mice (13-week study).
           Phorate did not induce gene mutations in in vitro tests, but conflicting results
       were reported for cytogenicity effects, both in vitro and in vivo. In the latter,
       abnormalities were found if phorate was given by intraperitoneal injections, but
       not following oral administration. Carcinogenicity studies in rats and mice did
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<pre>       not show a treatment-related increase in tumour incidence. The committee
       concludes that the positive genotoxic effects of phorate were thus not reflected in
       carcinogenicity. The committee did not consider phorate as a reproduction
       toxicant, as effects occurred at doses above those causing parental or maternal
       toxicity. The NOAEL for reproduction toxicity in the rat was 0.17 mg/kg
       bw/day. The NOAELs for developmental toxicity were 0.25 and 1.2 mg/kg
       bw/day in rats and rabbits, respectively.
           Based on the above data, the committee concludes that the mechanism of
       toxicity of phorate in mammals is through inhibition of AChE activity in nerve
       tissue. The committee identifies inhibition of AChE activity in brain tissue as the
       most sensitive adverse toxic effect of phorate in animal studies, occurring at dose
       levels that are lower than those that cause other toxic effects. In human beings,
       for obvious reasons, brain AChE cannot be measured. Instead, red blood cell
       AChE, being the same molecular target for inhibition by organophosporus
       pesticide as brain AChE, is used as a surrogate for brain AChE in assessing the
       human health risk of exposure to phorate (Jey94). However, no data is available
       in the literature of effects of the compound on red blood cell AChE in human
       beings and, therefore, studies in test animals have to be used for the assessment
       of a health-based recommended occupational exposure limit (HBROEL).
       Because no short- or long-term inhalation toxicity studies are available, the
       committee takes the 2-year oral toxicity study in rats as a starting point in
       deriving a HBROEL. In this study, the NOAEL was 0.07 mg/kg bw/day. Since
       workers are exposed for 5 days a week, this NOAEL from a continuous feeding
       study (i.e., 7 days a week) is adjusted by multiplying with a factor of 7/5
       resulting in a no-adverse-effect level (NAEL) of 0.098 mg/kg bw/day. For the
       extrapolation to a HBROEL, a factor of 4 for allometric scaling from rats to
       humans, based on caloric demand, and an overall factor of 9 for inter- and
       intraspecies variation are applied, resulting in a NAEL for humans of 0.003
       mg/kg bw/day. Assuming a 70-kg worker inhales 10 m3 of air during an 8-hour
       working day, and a retention of 100%, and applying the preferred value
       approach, a health-based occupational exposure limit of 0.02 mg/m3 is
       recommended for phorate.
       The committee recommends a health-based occupational exposure limit for
       phorate of 0.02 mg/m3, as an 8-hour time-weighted average (TWA).
           Phorate showed a high acute lethal dermal toxicity in rats. A ratio of the
       dermal LD50 and the calculated inhalation LD50 of less than 10 is proposed as one
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<pre>       of the criteria for assigning a skin notation (ECE98). Since this criterion is met
       for phorate*, the committee recommends a skin notation.
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       m3 in male rats (assuming a retention of 1.0 and a minute volume of 125 mL/min for a 200-g weighing rat) is ca.
       2.3 mg/kg bw.
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<pre>               Annex
 Occupational exposure limits for phorate 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   -              0.05            8h                administrative S              SZW03
 Employment
 Germany
 - AGS                               -              0.05                                             S             TRG00
 - DFG MAK-Kommission                -              -                                                              DFG02
 Great Britain
 - HSE                               -              0.05            8h                OES            S             HSE02
                                     -              0.2             15 min
 Sweden                              -              -                                                              Swe00
 Denmark                             -              0.05            8h                               S             Arb02
 USA
 - ACGIH                             -              0.05            8h                TLV            S             ACG03b
                                     -              0.2             15 min            STEL
 - OSHA                              -              -                                                              ACG03a
 - NIOSH                             -              0.05            10 h              REL            S             ACG03a
                                     -              0.2             15 min            STEL
 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.
075-23         Phorate
</pre>

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<pre>075-24 Health-based Reassessment of Administrative Occupational Exposure Limits</pre>

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