<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>2-Pyridylamine
(CAS No: 504-29-0)
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/053, The Hague, 31 October 2002
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. 2-Pyridylamine; Health-based Reassessment of
Administrative Occupational Exposure Limits. The Hague: Health Council of
the Netherlands, 2002; 2000/15OSH/053.
all rights reserved
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of
      2-pyridylamine 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 C de Heer, Ph.D., and H Stouten, M.Sc. (TNO
      Nutrition and Food Research, Zeist, the Netherlands).
          The evaluation of the toxicity of 2-pyridylamine 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 databases Medline, Cancerlit, Toxline, and Chemical Abstracts
      covering the periods 1966 to 30 June 1997 (19970630/UP), 1963 to 18 June
      1997 (19970618/ED), 1965 to 21 March 1997 (970321/ED), and 1967 to 1 July
      1997 (970701/ED; vol 127, iss 1), respectively, and using the following key
      words: 2-aminopyridine, alpha-aminopyridine, 2-pyridinamine, 2-pyridylamine,
      and 504-29-0. HSDB and RTECS, databases available from CD-ROM, were
      consulted as well (NIO97, NLM97). The final literature search was carried out
      in July 1997.
          In December 1998, the President of the Health Council released a draft of
      the document for public review. Comments were received by the following
      individuals and organizations: A Aalto (Ministry of Social Affairs and Health,
      Tampere, Finland), P Wardenbach Ph.D. (Bundesanstalt für Arbeitsschutz und
      Arbeitsmedizin, Dortmund, Germany). These comments were taken into
      account in deciding on the final version of the document.
          An additional literature search in May 2002 did not result in information
      changing the committee’s conclusions.
053-3 2-Pyridylamine
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<pre>2     Identity
       name                       :     2-pyridylamine
       synonyms                   :     2-aminopyridine; α-aminopyridine; 2-pyridinamine;
                                        2-pyridylamine; o-aminopyridine; α -pyridinamine;
                                        α-pyridylamine; 1,2-dihydro-2-iminopyridine; 2-AP
       molecular formula          :     C5H6N2
       structural formula         :
       CAS number                 :     504-29-0
      Data from ACG91, NLM97, Ric92, Tro94 .
3     Physical and chemical properties
       molecular weight            :     94,11
       boiling point               :     210.6oC
       melting point               :     58.1oC
       flash point                 :     92oC (open cup); 67.78oC (closed cup)
       vapour pressure             :     at 20oC: very low
       solubility in water         :     highly soluble
       Log Poctanol/water          :     0.48 (experimental); 0.53 (estimated)
       conversion factors          :     1 ppm = 3.9 mg/m3
       (20oC, 101.3 kPa)                 1 mg/m3 = 0.26 ppm
      Data from ACG91, NLM97, Ric92, Tro94, http://esc.syrres.com.
      2-Pyridylamine is a colourless, crystalline solid with a characteristic and
      unpleasant odour.
4     Uses
      2-Pyridylamine is an organic synthetic intermediate used in the synthesis of
      antihistaminic drugs and other pharmaceuticals (ACG91).
053-4 Health-based Recommended Occupational Exposure Limits
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<pre>5     Biotransformation and kinetics
      The committee did not find information on absorption, distribution, metabolism,
      or excretion of 2-pyridylamine. Human case reports suggest that absorption can
      occur following inhalation of the dust or vapour, or possibly by dermal
      absorption following direct contact.
          Based on physico-chemical properties, a potential for dermal absorption has
      been assigned (Fis90).
          Because of the dermal LD50 in guinea pigs of approximately 500 mg/kg bw,
      it was concluded that dermal absorption in guinea pigs occurs readily (Tro94).
6     Effects and mechanism of action
      Human data
      Three cases of 2-pyridylamine intoxication in humans have been reported. A
      fatal case of accidental exposure to 2-pyridylamine was reported in a chemical
      plant worker. After spillage during distillation, skin absorption, as well as
      inhalation of vapour probably occurred. The worker continued on his job for 1.5
      hour, but 2 hours later he developed dizziness, headache, respiratory distress,
      and convulsions that progressed to respiratory failure and death (ACG91,
      Tro94).
          In a non-fatal-case report, the chief symptoms described were mainly severe
      headache, increased blood pressure, flushing of extremities, and nausea. Air
      samples taken subsequently indicated a concentration of approximately 20
      mg/m3 (5.2 ppm). The exposure resulting in the incident was about 5 hours of
      duration. Recovery was complete within 24 hours (Wat50).
          Finally, a more serious non-fatal case involved severe headache and
      weakness followed by convulsions and a stuporous state that lasted several days
      (exposure levels and duration not indicated) (Tro94).
      Animal data
      2-Pyridylamine was shown to cause a slight, transient eye injury when applied
      as a 0.02 M aqueous solution (pH>9.4) on the rabbit cornea. No other dermal or
      eye irritation studies were available.
053-5 2-Pyridylamine
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<pre>      The approximate LD50 values for 2-pyridylamine are 200 and 50 mg/kg bw for
      rats and mice, respectively. In guinea pigs, where death followed convulsions, a
      dermal LD50 of 500 mg/kg bw was reported (Tro94)*.
            In cats, intravenous injection of 1 mg/kg bw of 2-pyridylamine caused an
      increase in blood pressure and respiratory rate with symptoms of central
      nervous system stimulation and muscle twitching (NLM97), whereas exposure
      to approximately 2 mg/kg bw resulted in convulsions (Wat50).
      The committee did not find data from repeated-dose toxicity studies, including
      carcinogenicity and reproduction toxicity, of 2-pyridylamine.
      In in vitro experiments, 2-pyridylamine and other aminopyridines have been
      found to act on the cholinergic system, by increasing the release of
      acetylcholine at the neuromuscular junction. The primary site of action of
      aminopyridines involves the voltage-sensitive K+ channels of motor nerve
      terminals (Mol85). In another study, the effect of aminopyridine analogs on
      ionic conductance of the squid giant axon membrane was examined using
      voltage clamp and internal perfusion techniques. Reduced K+ currents, but no
      effect upon transient Na+ currents, were noted in a voltage-, time-, and
      frequency-dependent way. The effects on K+ channels were independent of the
      direction of K+ ion movement. The potencies of the different aminopyridine
      analogs tested were apparently unrelated to their pKa values (Yeh76). Blocking
      of the voltage-sensitive K+ channels leads to an enhanced calcium influx and
      consequently to an increase in acetylcholine release (Mol85). In addition, the
      voltage-sensitive K+ channels may be involved in the regulation of smooth
      muscle membrane potential. In in vitro experiments using patch-clamp
      techniques in smooth muscle cells isolated from rabbit cerebral (basilar)
      arteries, 2-pyridylamine (5 mM) inhibited voltage-dependent K+ currents. These
      voltage-dependent K+ channels may be involved in the regulation of arterial
      diameter through control of smooth muscle membrane potential in vivo
      (Rob94).
      2-Pyridylamine (up to 2 mg/plate) was negative in mutagenicity tests in S.
      typhimurium strains TA98, TA100, TA1535, and TA1537 when tested with and
      without metabolic activation or with metabolic activation and norharman
      (Kam86, Ric92, Wak82).
*     It is noticed that ACGIH cites other acute lethal toxicity data from former citations of Patty’s Industrial Hygiene
      and Toxicology, but that these are not included in the most recent (4th) edition of Patty’s. The concerning data
      were also not included in this document.
053-6 Health-based Recommended Occupational Exposure Limits
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<pre>      The committee did not find data from other genotoxicity or mutagenicity
      studies.
7     Existing guidelines
      The current administrative occupational exposure limit (MAC) in the
      Netherlands is 2 mg/m3 (0.5 ppm), 8-hour TWA.
          Existing occupational exposure limits for 2-pyridylamine in some European
      countries and in the USA are summarised in the annex.
8     Assessment of health hazard
      There are no human data from which an concentration-effect relation after
      inhalation exposure can be estimated.
          After accidental exposure of a worker to 20 mg/m3 2-pyridylamine for 5
      hours, the occurrence of a headache, increased blood pressure, flushing of
      extremities, and nausea was reported. Convulsions have been reported in 2 other
      cases of accidental intoxication with 2-pyridylamine. Results of in vitro
      experiments indicate that 2-pyridylamine inhibits the voltage-sensitive K+
      channels of the neuromuscular junction and might be related to the neurotoxic
      effects reported in cases of intoxication. These data suggest that the nervous
      system is the target organ.
      In experimental animals, 2-pyridylamine was shown to cause a slight, transient
      eye injury when applied as a 0.02 M aqueous solution (pH>9.4) to the rabbit
      cornea. No other dermal or eye irritation studies were available.
          Based on LD50 data in rodents, the committee considers 2-pyridylamine to
      be ‘toxic when swallowed’ and ‘harmful in contact with skin’.
          2-Pyridylamine was negative in mutagenicity tests in S. typhimurium strains
      TA98, TA100, TA1535, and TA1537 with and without metabolic activation.
          The committee did not find data from other genotoxicity or mutagenicity
      studies or on repeated-dose toxicity, including carcinogenicity and reproduction
      toxicity.
      The committee considers the toxicological database on 2-pyridylamine too poor
      to justify recommendation of a health-based occupational exposure limit.
053-7 2-Pyridylamine
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<pre>       The committee concludes that there is insufficient information to comment on
       the level of the present MAC-value.
       References
ACG91  American Conference of Governmental Industrial Hygienists (ACGIH). Documentation of the
       threshold limit values and biological exposure indices. 6th ed. Cincinnati OH, USA; ACGIH, 1991:
       52-3.
ACG02a American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
       exposure values -2002. Cincinnati OH, USA: ACGIH®, Inc, 2002: 6.
ACG02b American Conference of Governmental Industrial Hygienists (ACGIH). 2002 TLVs® and BEIs®.
       Threshold Limit Values for chemical substances and fysical agents. Biological Exposure Indices.
       Cincinnati OH, USA: ACGIH®, Inc, 2002: 14.
Arb00a Arbejdstilsynet. Grænseværdier for stoffer og materialer. Copenhagen, Denmark: Arbejdstilsynet,
       2000; At-vejledning C.0.1.
Arb00b Arbetarskyddsstyrelsen. Hygieniska gränsvärden och åtgärder mot luftföroreningar. Solna, Sweden:
       Arbetarskyddsstyrelsen, 2000; Ordinance AFS 2000:3.
CEC00  Commission of the European Communities (CEC). Commission Directive 2000/39/EC of 8 June
       2000 establishing a first list of indicative occupational exposure limit values in implementation of
       Council Directive 98/24/EC on the protection of the health and safety of workers from the risks
       related to chemical agents at work. Official Journal of the European Communities 2000; L142
       (16/06/2000): 47-50.
DFG02  Deutsche Forschungsgemeinschaft (DFG): Senatskommission zur Prüfung gesundheitsschädlicher
       Arbeitsstoffe. MAK- und BAT-Werte-Liste 2002. Maximale Arbeitsplatzkonzentrationen und
       Biologische Arbeitsstofftoleranzwerte. Weinheim, FRG: Wiley-VCH, 2002: 22 (rep no 38).
Fis90  Fiserova-Bergerova V, Pierce JT, Droz PO. Dermal absorption potential of industrial chemicals:
       criteria for skin notation. Am J Ind Med 1990; 17: 617-35.
HSE02  Health and Safety Executive (HSE). EH40/2002. Occupational exposure limits 2002. Sudbury
       (Suffolk), England: HSE Books, 2002: 25.
Kam86  Kammerer RC, Froines JR, Price T. Mutagenicity studies of selected antihistamines, their
       metabolites and products of nitrosation. Food Chem Toxicol 1986; 24: 981-5.
Mol85  Molgó J, Lemeigan M, Peradejordi F, et al. Effets présynaptiques des aminopyridines à la jonction
       neuromusculaire de vertébrés. J Pharmacol 1985;16 (Suppl 2):109-44.
NIO97  US National Institute of Occupational Safety and Health (NIOSH), ed. Registry of Toxic Effects of
       Chemical Substances (RTECS). [CD-ROM], issue February 1997. SilverPlatter International, 1997
       (last update ferric oxide file: January 1997).
053-8  Health-based Recommended Occupational Exposure Limits
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<pre>NLM97 US National Library of Medicine (NLM), ed. Hazardous Substances Data Bank (HSDB).
      [CD-ROM], issue February 1997. SilverPlatter International, 1997 (last update 2-aminopyridine file:
      February 1997).
Rob94 Robertson BE, Nelson MT. Aminopyridine inhibition and voltage dependence of K+ currents in
      smooth muscle cells from cerebral arteries. Am J Physiol 1994; 267: C1589-97.
Ric92 Richardson ML, Gangolli S, eds. A169 2-Aminopyridine. In: The dictionary of substances and their
      effects. Cambridge, UK: Royal Society of Chemistry 1992: 262-3 (Vol 1).
SZW02 Ministerie van Sociale Zaken en Werkgelegenheid (SZW). Nationale MAC-lijst 2002. The Hague,
      the Netherlands: Sdu, Servicecentrum Uitgevers, 2002: 39.
TRG00 TRGS 900. Grenzwerte in der Luft am Arbeitsplatz; Technische Regeln für Gefahrstoffe. BArbBl
      2000; 2.
Tro94 Trochimowicz HJ, Kennedy GL Jr, Krivanek ND. Heterocyclic and miscellaneous nitrogen
      compounds. In: Clayton GD, Clayton FE, eds. Toxicology. 4th ed. New York: John Wiley & Sons,
      1994: 3364-7 (Patty’s industrial hygiene and toxicology; Vol II, Pt E).
Wak82 Wakabayashi K, Yahagi T, Nagao M, et al. Comutagenic effect of norharman with aminopyridine
      derivatives. Mutat Res 1982; 105: 205-10.
Wat50 Watrous RM, Schulz HN. Cyclohexamine, p-chlonitrobenzene, 2-aminopyridine: toxic effects in
      industrial use. Ind Med Surg 1950; 19: 317-20.
Yeh76 Yeh JZ, Oxford GS, Wu CH, et al. Interactions of aminopyridines with potassium channels of squid
      axon membranes. Biophys J 1976; 16: 77-81.
053-9 2-Pyridylamine
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<pre>             Annex
Occupational exposure limits for 2-pyridylamine in various countries.
country                            occupational                    time-weighted      type of exposure notea    reference b
-organisation                      exposure limit                  average            limit
                                   ppm           mg/m3
the Netherlands
-Ministry of Social Affairs        0.5           2                 8h                 administrative            SZW02
and Employment
Germany
-AGS                               0.5           2                 8h                                           TRG00
-DFG MAK-Kommission                -c            -                                                              DFG02
Great-Britain
-HSE                               0.5           2                 8h                 OES                       HSE02
                                   2             7.8               15 min
Sweden                             -             -                                                              Arb00b
Denmark                            0,5           2                 8h                                           Arb00a
USA
-ACGIH                             0.5           -                 8h                 TLV                       ACG02b
-OSHA                              0.5           2                 8h                 PEL                       ACG02a
-NIOSH                             0.5           2                 10 h               REL                       ACG02a
European Union
-SCOEL                             -             -                                                              CEC00
a
     S = skin notation; which mean 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
     Listed among compounds for which studies of the effects in man or experimental animals have yielded insufficient
     information for the establishment of MAK values.
053-10       Health-based Recommended Occupational Exposure Limits
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