<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>Gezondheidsraad                               Voorzitter
Health Council of the Netherlands
Aan de Staatssecretaris van Sociale Zaken en Werkgelegenheid
Onderwerp            : Aanbieding adviezen herevaluatie bestuurlijke MAC-waarden
Uw kenmerk           : ARBO/AMIL/97/00648
Ons kenmerk          : U 2706/CB/MP/563-O3
Bijlagen             : 18
Datum                : 14 december 2000
Mijnheer de staatssecretaris,
Op verzoek van uw ambtsvoorganger bied ik u hierbij de eerste adviezen aan van een
reeks over de gezondheidskundige basis van uit het buitenland overgenomen
grenswaarden voor beroepsmatige blootstelling aan stoffen. Het verzoek om deze
adviezen is in algemene zin vervat in brief nr ARBO/AMIL/97/00648 en in latere stadia
door uw departement toegespitst op afzonderlijke stoffen. De adviezen zijn opgesteld
door een daartoe door mij geformeerde internationale commissie van de Gezondheidsraad
en beoordeeld door de Beraadsgroep Gezondheid en Omgeving.
     De beoogde reeks van in het Engels gestelde adviezen zal losbladig worden
gepubliceerd onder ons publicatienummer 2000/15OSH en, conform de aan de
Gezondheidsraad voorgelegde toespitsingen van de adviesaanvraag, betrekking hebben
op 168 stoffen. Het u thans aangeboden eerste pakket bestaat uit een Algemene Inleiding
(publicatienummer 2000/15OSH/000) en uit de adviezen genummerd 2000/15OSH/001
tot en met 2000/15OSH/017, respectievelijk betrekking hebbend op:
cesiumhydroxide, cyclopentaan, diboraan, dimethoxymethaan, dipropylketon,
fenylfosfine, germaniumtetrahydride, hexachloornaftaleen, methaanthiol,
methylcyclohexanol, methylisopropylketon, mica, natriumhydroxide,
octachloornaftaleen, silaan, tetrachloornaftaleen, en yttrium en yttriumverbindingen.
     Bij afronding van de werkzaamheden van de hierboven bedoelde commissie ontvangt
u een Nederlandstalige samenvatting van de in de gehele reeks van adviezen neergelegde
bevindingen.
Bezoekadres                                                                  Postadres
Parnassusplein 5                                                             Postbus 16052
2511 VX Den Haag                                                             2500 BB Den Haag
Telefoon (070) 340 75 20                                                     Telefax (070) 340 75 23
email: GR@gr.nl
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<pre>Gezondheidsraad
Health Council of the Netherlands
Onderwerp            : Herevaluatie uit het buitenland overgenomen grenswaarden
Ons kenmerk          :U
Pagina               :2
Datum                : 14 december 2000
    De u thans aangeboden adviezen heb ik vandaag ter informatie doen toekomen aan
de Minister van Volksgezondheid, Welzijn en Sport en aan de Minister van
Volkshuisvesting, Ruimtelijke Ordening en Milieubeheer.
Hoogachtend,
prof. dr JJ Sixma
Bezoekadres                                                                   Postadres
Parnassusplein 5                                                              Postbus 16052
2511 VX Den Haag                                                              2500 BB Den Haag
Telefoon (070) 340 75 20                                                      Telefax (070) 340 75 23
email: GR@gr.nl
</pre>

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<pre>      Phenylphosphine
      (CAS reg no: 638-21-1)
      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/013, The Hague, 14 December 2000
013-1
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<pre>      Preferred citation:
      Health Council of the Netherlands: Committee on Updating of Occupational
      Exposure Limits. Phenylphosphine; Health-based Reassessment of
      Administrative Occupational Exposure Limits. The Hague: Health Council of
      the Netherlands, 2000; 2000/15OSH/013.
      all rights reserved
013-2
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of
      phenylphosphine 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 RN Hooftman, M.Sc. and H Stouten, M.Sc.
      (TNO Nutrition and Food Research Institute, Zeist, the Netherlands).
           The evaluation of the toxicity of phenylphosphine has been based on the
      review by the American Conference of Governmental Industrial Hygienists
      (ACG91). Where relevant, the original publications were reviewed and
      evaluated as will be indicated in the text. In addition, literature was retrieved
      from the online data bases Medline, Toxline, and Chemical Abstracts covering
      the period 1966 to 24 October, 1997 (19971024/UP), 1965 to 20 October 1997
      (19971020/ED), and 1967 to 28 October, 1997 (971028/ED); vol 127 iss 18),
      respectively. Medline was searched with the CAS Registry Number 638-21-1
      and the name (mono)phenylphosphine. HSDB (no record) and RTECS, data
      bases available from CD-ROM, were consulted as well (NIO97). The final
      literature search has been carried out in October 1997.
           In March 2000, the President of the Health Council released a draft of the
      document for public review. Comments were received by the following
      individuals and organizations: L Whitford (Health & Safety Executive,
      London, United Kingdom), dr P Wardenbach (Bundesanstalt für Arbeitsschutz
      und Arbeitsmedizin, Dortmund, Germany). These comments were taken into
      account in deciding on the final version of the document.
2     Identity
       name                              :     (mono)phenylphosphine
       synonyms                          :     phosphine, phenyl-
       molecular formula                 :     C6H7P
       structural formula                :
       CAS reg nr                        :     638-21-1
      Data from ACG91 and Ric93.
013-3 Phenylphosphine
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<pre>3     Physical and chemical properties
       molecular weight                 :     110.1
       boiling point                    :     160-161°C
       flash point                      :     73°C
       solubility                       :     insoluble in water
                                              soluble in alkali organic solvents
                                              (very soluble in alcohol and ether)
       density                          :     1.001 at 15°C
       reactivity                       :     spontaneously combustible in air at high
                                              concentrations
       conversion factors                     1 ppm = 4.6 mg/m3
       (20°C, 101.3 kPa)                      1 mg/m3 = 0.22 ppm
      Data from ACG91, IUC96 and Ric93.
      Phenylphosphine is a clear, colourless, foul smelling liquid.
           There were no data on odour threshold, but in a report on a 90-day
      inhalation study using rats and dogs, it was stated that a concentration of 0.6
      ppm (2.8 mg/m3) (the lowest concentration tested in this experiment) was
      detected by odour (duP92).
4     Uses
      The compound may be used as an intermediate or as a chemical reagent
      (ACG91).
5     Biotransformation and kinetics
      No data on biotransformation or kinetics of phenylphosphine were found.
6     Effects and mechanism of action
      Human data
      Potential exposure may occur in industry when phenylphosphinates, which are
      polyamidation catalysts and antioxidants, are heated above 200°C.
      Concentrations of 0.57 ppm (2.6 mg/m3) were readily detected by an odour
013-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      panel; the odour was experienced as obnoxious. As lower concentrations were
      not evaluated, an odour threshold was not established (War75).
           There are no human data on workers occupationally exposed to
      phenylphosphine.
      Animal data
      Adult male rats (n=6 per group) were exposed for 4 hours by inhalation. The
      4-h LC50 was 38 ppm (175 mg/m3) (95% C.I.: 31-47 ppm). Mild irritation such
      as red ears, excessive salivation, lacrimation, face-pawing, and dyspnea were
      observed. There were no gross or histopathological effects that could be
      attributed to phosphine exposure in any of the tissues (War75).
           When rats (n=6) were exposed to 7.6 ppm (35 mg/m3), 4 hours/day, 5
      days/week, for 2 weeks, mild irritation similar to that in the acute study was
      observed together with weight loss during exposure, but the weight gain
      returned in the subsequent 14-day recovery period. A transient dermatitis
      around mouth and feet appeared after the last exposure. Increased
      haematopoiesis in the spleen occurred, not returning to normal during the
      recovery period (War75). Furthermore, oligospermia was reported to have
      occurred in this study (duP92).
           In a 90-day inhalation study, male and female rats (Charles-River CD:
      n=20 per sex per group) and male dogs (beagle; n=4 per group) were exposed
      to phenylphosphine for 6 hours/day, 5 days/week, to approximate average
      concentrations of 0, 0.6, or 2.2 ppm (0, 2.8, and 10 mg/m3, respectively).
      Thirty rats (n=5 per sex per group) and 6 dogs (n=2 per group) at a time were
      sacrificed after 30 and 90 days and after a 28-day recovery period, while the
      remaining rats were killed after a 65-day recovery period. Parameters studied
      included clinical observations (schedule not reported) and clinical chemistry
      analysis (rats: once prior to the start, 4 times during the test, twice during the
      recovery period; dogs: twice, 4 times, and once, resp; parameters: erythrocyte
      counts, haemoglobin concentration, haematocrit, total leukocyte count), and all
      animals sacrificed were examined grossly and histologically. Treatment did not
      result in mortality in any of the rat and dog exposure groups. In rats of the low
      exposure group (2.8 mg/m3), hypersensitivity to sound and touch and mild
      hyperaemia were observed from the first month onwards both during and after
      the daily exposures (no data on incidence or severity were given). At the end of
      the exposure period, mild dermatitis and decreased body weight (concluded
      from a graph; no data or statistical analysis presented) occurred. Only slight
013-5 Phenylphosphine
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<pre>      changes in erythrocyte counts, haemoglobin concentrations, and haematocrit
      were observed. Apart from a mild increase in red blood cell formation in the
      spleen in 5 out of 5 (5/5) female and 2/5 male rats and an increased spleen
      weight at the 30-day time point*, no changes were found upon any of the
      postmortem examinations. The committee noticed that high dose group severe
      testicular damage similar to that observed in the group 1/5 animals at day 90
      showed; this was not seen in the animals examined after the recovery periods.
      Exposure to 2.2 ppm (10 mg/m3) induced similar effects, but to a more severe
      extent (no details presented). In addition, dermatitis around eyes, mouth, and
      feet were seen. At the end of exposure, there were hair loss, red swollen areas
      around the extremities, and, in male animals, a marked decreased body weight
      (see remark 0.6 ppm group). Throughout the experiment, decreased erythrocyte
      counts, haemoglobin concentrations, and haematocrit and increased leukocyte
      counts were seen, reaching statistical significance in the male animals for all
      measurements at every examination. Postmortem examinations at the 30-day
      time point showed a greater increase in red blood cell formation in all male and
      female animals and increased spleen weights. Severe testicular degeneration,
      characterized by the loss of germinal cells, severe stromal oedema, proliferation
      of interstitial cells, and aspermia in semiferous tubules as well as the
      epididymis, and mild haemolytic anaemia were found in males sacrificed at the
      end of the exposure period. Average testis weights were more that 50% lower
      than those of control animals (1.62 g vs 3.46 g). Most of the changes returned
      to normal following the 28- or 65-day recovery period, but the testicular
      degeneration was still present after the 65-day recovery period. Finally, various
      degrees of chronic murine pneumonia and tracheitis were found in the test
      groups at different sacrifices. Since this was found to a similar incidence and
      severity in the control animals as well, they could not be attributed to exposure
      to phenylphosphine. In dogs, exposure did not affect body weight (gain). In the
      animals of the low exposure group (2.8 mg/m3), intermittent loss of appetite
      (in 1/4), nausea (in 1/4), diarrhoea (in 4/4 at the first time point only), and
      lacrimation (no incidences given) were observed during but not after the daily
      exposure periods. There were no effects on the clinical chemistry parameters.
      Apart from a moderate haemopoietic activity in the bone marrow at the 90-day
      sacrifice, no changes were seen in any of the postmortem examinations.
      Exposure to 2.2 ppm (10 mg/m3) induced similar signs, but to a more severe
      extent, as well as hind leg tremors (in 2/4) and intermittent increased water
      consumption (in 4/4). Erythrocyte counts, haemoglobin concentrations, and
*      At this time point, only the spleen was examined in animals of the low exposure group.
013-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      haematocrit were decreased at every time point during the exposure period.
      Upon postmortem examinations, a mild haemolytic anaemia and testicular
      degeneration were observed. The testicular degeneration was mild compared to
      that seen in rats. It was stated that these testicular lesions were reversible.
      However, the committee could not verify this from the copy of the report that
      was made available (duP92).
          No no observed adverse effect levels (NOAELs) could be derived from this
      study, since exposure to 0.6 ppm (2.8 mg/m3), the lowest level tested, for 6
      hours/day, 5 days/week, for 90 days, induced dermatitis and some slight
      clinical signs in rats (observed both during and after the daily exposures) and
      some slight clinical signs in dogs (during exposure). Furthermore, the severe
      testicular damage observed in one out of 5 male rats exposed to 2.8 mg/m3 and
      sacrificed immediately after the end of exposure was considered to be treatment
      related as well.
7     Existing guidelines
      The current administrative occupational exposure limit (MAC) for
      phenylphosphine in the Netherlands is 0.05 ppm (0.25 mg/m3), as a ceiling
      limit.
          Existing occupational limits for phenylphosphine in some European
      countries and the USA are summarized in the annex.
8     Assessment of health hazard
      No data on occupationally exposed workers, biotransformation, kinetics,
      mutagenicity, genotoxicity or carcinogenicity of phenylphosphine have been
      found.
          From the 4-h LC50 of 38 ppm (175 mg/m3) in rats, phenylphosphine should
      be considered as very toxic by inhalation (War75).
          From repeated inhalation exposure experiments, it can be seen that
      phenylphosphine induced haematological effects and effects on the testes in
      both rats and dogs, and that rats were the more sensitive species (duP92). In
      the subchronic inhalation study in rats, exposure to 2.2 ppm (10 mg/m3), 6
      hours/day, 5 days/week, for 90 days, caused severe testicular damage, which
      was persistent even after a 65-day recovery period, and a mild haemolytic
      anaemia. The haematological effects were not seen at 0.6 ppm (2.8 mg/m3), the
013-7 Phenylphosphine
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<pre>      lowest level tested, but dermatitis, some slight clinical signs and severe
      testicular damage (in one out of 5 animals sacrificed at day 90) were found.
           The lowest observed adverse effect level (LOAEL) of 2.8 mg/m3 in the
      aforementioned subchronic inhalation study in rats is taken as a starting point
      in deriving a health-based occupational exposure limit (HBROEL). For the
      assessment of a HBROEL, the following considerations were taken into
      account: intra- and interspecies variation, differences between experimental
      conditions and the exposure pattern of the worker, and the absence of an
      NOAEL. The committee considered an overall assessment factor of 54 to be
      appropriate for the extrapolation from the subchronic LOAEL in rats to a
      working lifetime exposed worker. Applying this factor and assuming that the
      dose inhaled by rats is equivalent to the dose inhaled by humans, a preferred
      value of 0.05 mg/m3 (0.01 ppm) is recommended as a HBROEL for
      phenylphosphine. This level is considered to prevent workers from
      haematological effects and effects on the male reproductive system.
      The committee recommends a health-based occupational exposure limit for
      phenylphosphine of 0.05 mg/m3 (0.01 ppm), as an 8 h time weighted average
      (TWA).
      References
ACG91 American Conference of Governmental Industrial Hygienists (ACGIH). Phenylphosphine. In:
      Documentation of the threshold limit values and biological exposure indices. 6th ed. Cincinnati OH,
      USA: ACGIH, 1991: 1241-2.
ACG00 American Conference of Governmental Industrial Hygienists (ACGIH). 2000 TLVs® and BEIs®.
      Threshold Limit Values for chemical substances and physical agents. Biological Exposure Indices.
      Cincinnati OH, USA: ACGIH, 2000.
Arb96 Arbejdstilsynet. Grænseværdier for stoffer og materialer. Copenhagen, Danmark: Arbejdstilsynet, 1996
      (At-anvisning nr 3.1.0.2).
DFG99 Deutsche Forschungsgemeinschaft (DFG): Senatskommission zur Prüfung gesundheitsschädlicher
      Arbeitsstoffe. MAK- und BAT-Werte-Liste 1999. Maximale Arbeitsplatzkonzentrationen und
      biologischeArbeitsstofftoleranzwerte. Weinheim, FRG: VCH Verlagsgesellschaft mbH, 1999;
      Mitteilung 35.
duP92 EI duPont et de Nemours & Co, Inc. Initial submission: 90-day inhalation toxicity study of
      phenylphosphine in rats and dogs with cover letter dated 101592. Springfield VA, USA: National
      Technical Information Services (NTIS), 1992; order no NTIS/OTS0571394.
013-8 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>HSE99 Health and Safety Executive (HSE). EH40/99 Occupational Exposure limits 1999 Sudbury (Suffolk),
      England: HSE Books, 1999
NBO96 National Board of Occupational Safety and Health. Occupational exposure limit values. Solna,
      Sweden: NBOSH, 1996; Ordinance AFS1996/2.
NIO97 US National Institute of Occupational Safety and Health (NIOSH). Registry of Toxic Effects of
      Chemical Substances (RTECS) [CD-ROM], issue October 1997. SilverPlatter International, 1997 (last
      update phenylphosphine file: October 1997).
Ric94 Richardson, Ml, Gangioli S, eds. P119 Phenylphosphine. In : The Dictionary of Substances and their
      Effects. Cambridge, UK: Royal society of Chemistry, 1994: 588 (Vol 6).
SZW00 Ministerie van Sociale Zaken en Werkgelegenheid (SZW). De nationale MAC-lijst 2000 The Hague,
      The Netherlands: Servicecentrum Sdu Uitgevers, 2000.
TRG00 TRGS 900: Grenzwerte in der Luft am Arbeitsplatz; Technische Regeln für Gefahrstoffe; B Arb Bl
      2000; 2.
War75 Waritz RS, Brown RM. Acute and subacute inhalation toxicities of phosphine, phenylphosphine and
      triphenylphosphine. Am Ind Hyg Assoc J 1975; 6: 452-8.
013-9 Phenylphosphine
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<pre>             Annex
Occupational exposure standards for phenylphosphine in various countries.
country                       occupational                         time-weighted     type of exposure   notea      lit refb
-organisation                 exposure limit                       average           limit
                              ppm              mg/m3
The Netherlands
-Ministry                     0.05             0.25                ceiling           administrative                SZW00
Germany
-AGS                          -                0.25                ceiling                                         TRG00
-DFG MAK-Kom.                 -                -                                                                   DFG99
Great-Britain
-HSE                          -                -                                                                   HSE99
Sweden                        -                -                                                                   NBO96
Denmark                       0.05             0.25                ceiling                                         Arb96
USA
-ACGIH                        0.05             0.23                ceiling           TLV                           ACG00
-OSHA                         -                -                   ceiling           PEL
-NIOSH                        0.05             0.25                ceiling           REL
European Union
-SCOEL                        -                -
a
     S = skin notation; this 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.
013-10       Health-based Reassessment of Administrative Occupational Exposure Limits
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