<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>       n-Butylamine
      (CAS No: 109-73-9)
      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/060, The Hague, 3 March 2003
060-1
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<pre>      Preferred citation:
      Health Council of the Netherlands: Committee on Updating of Occupational
      Exposure Limits. n-Butylamine; Health-based Reassessment of Administrative
      Occupational Exposure Limits. The Hague: Health Council of the Netherlands,
      2003; 2000/15OSH/060.
      all rights reserved
060-2
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of
      n-butylamine 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. (Coronel Institute of the
      Academic Medical Centre, Amsterdam, the Netherlands).
          The evaluation of the toxicity of n-butylamine has been based on the review
      by the American Conference of Governmental Industrial Hygienists (ACG96).
      Where relevant, the original publications were reviewed and evaluated as will
      be indicated in the text. In addition, literature was retrieved from the databases
      Medline, Toxline, Chemical Abstracts, and Embase, (starting from 1966, 1967,
      1970, and 1988, respectively), and HSEline, Cisdoc, Mhidas, and NIOSHTIC
      (from 1997 backwards), and using the following key words: n-butylamine and
      109-73-9. The final literature search was 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 organisations: 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.
060-3 n-Butylamine
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<pre>2     Identity
       name                            :   n-butylamine
       synonyms                        :   1-butanamine; 1-aminobutane; mono-n-butylamine;
                                           monobutylamine; butylamine
       molecular formula               :   C4H11N
       molecular structure             :   CH3-CH2-CH2-CH2-NH2
       CAS number                      :   109-73-9
3     Physical and chemical properties
       molecular weight                :    73.14
       boiling point                   :    77.8oC
       melting point                   :    -50oC
       flash point                     :   -12oC (closed cup); -1oC (open cup)
       vapour pressure                 :    at 20oC: 10.9 kPa
       solubility in water             :    miscible
       log Poctanol/water              :    0.97 (experimental); 0.83 (estimated)
       conversion factors              :    1 mg/m3 = 0.33 ppm
       (20oC, 101.3 kPa)                    1 ppm = 3.0 mg/m3
      Data from ACG96, NLM02, http://esc.syrres.com.
      n-Butylamine is a clear colourless liquid with a pungent fish- or ammoniac-like
      odour. Air odour thresholds were reported to be between 0.24 and 2 mg/m3
      (0.08 and 1.8 ppm) (Amo83, Rut86). Referring to unpublished industrial
      information, it was stated that the odour was moderately strong at levels of 6-15
      mg/m3 (2-5 ppm), strong at 15-30 mg/m3 (5-10 ppm), and strong and irritating at
      higher levels (Bea81, Ben94).
060-4 Health-based Recommended Occupational Exposure Limits
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<pre>4     Uses
      n-Butylamine is used as an intermediate for the production of pharmaceuticals,
      dyestuffs, emulsifying agents, insecticides, synthetic tanning agents, and rubber
      chemicals (ACG96).
5     Biotransformation and kinetics
      The committee did not find quantitative data on the (toxico)kinetics of
      n-butylamine. However, based on its structure (a short-chain, non-substituted,
      primary amine), it will be metabolised readily by monoamine oxidase to its
      corresponding aldehyde, which would be oxidised further to the corresponding
      carboxylic acid, and ammonia, which would be eliminated as urea (Ben94).
          In vitro, in guinea pig liver slices, one of the metabolites found was
      acetoacetic acid (Ben94).
6     Effects and mechanism of action
      Human data
      Referring to unpublished industrial information, it was stated that direct skin
      contact with liquid n-butyl amine caused severe primary irritation and deep
      second-degree burns (blistering) in humans. Nose, throat, and eye irritation and
      headaches were said to have been experienced by workers with daily exposures
      to 15-30 mg/m3 (5-10 ppm). Higher levels (30-75 mg/m3 or 10-25 ppm) were
      unpleasant to intolerable for more than a few minutes. No complaints or
      symptoms were said to occur at levels below 15 mg/m3 (5 ppm) (mostly
      between 3 and 6 mg/m3 (1 and 2 ppm)) (Bea81, Ben94).
      Animal data
      Direct contact of a solution of n-butylamine may induce extensive irritation to
      the eyes. Guthrie and Seitz determined that the weakest solution causing
      microscopic epithelial damage would be a 0.5% (v/v) n-butylamine solution
      (Gut75). When instilled into the eyes of rabbits, n-butylamine scored an injury
      grade of 8 on a scale from 1 to 10, which was defined as producing a certain
      injury score, representative of ‘severe injury’, 18 to 24 hours after application of
060-5 n-Butylamine
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<pre>      an ‘excess’ of a 5% solution (Smy44; see also Car46). n-Butylamine was stated
      to be irritating to the eyes of rabbits in an unpublished study (no details)
      (EC00)*.
           Following uncovered application of 0.01 mL of undiluted material to the
      clipped skin (abdomen) of albino rabbits (n=5), n-butylamine scored an injury
      grade of 6 on a scale from 1 to 10, which was defined as giving rise to ‘necrosis
      from undiluted material’ (Smy44; see also Smy51 and Smy62). n-Butylamine
      was stated to be corrosive to the skin of rabbits in an unpublished study (no
      details) (EC00).
           In an unpublished guinea pig maximisation test conducted according to
      OECD Guide-line 406, n-butylamine was stated to be not sensitising (no details
      available) (EC00).
      Nielsen and Vinggaard studied the sensory irritation of n-butylamine in CF-1
      male mice by determining the decrease in respiratory rate during a 30-minute
      oronasal exposure to increasing concentrations of the test compound. The
      concentration resulting in a 50% decrease in the respiratory rate (RD50) was
      estimated to be 362 mg/m3 (121 ppm; range: 302-431 mg/m3). The pulmonary
      irritation was determined from the decrease in respiratory rate in tracheally
      cannulated mice (RD50TC). The plateau-level was reached slowly. The RD50TC
      for n-butylamine was found to be 900 mg/m3 (300 ppm) (Nie88). In male NMRI
      mice and using the same methods, Vinggaard et al. (Vin89) found RD50 and
      RD50TC values of 738 and 1086 mg/m3 (246 and 362 ppm), respectively
      (Vin89). In another study using male OF1 mice, an RD50 value of 336 mg/m3
      (112 ppm) was determined (exposure time: 15 minutes) (Gag89).
      Rats could tolerate exposure to a concentrated, probably saturated level** of
      n-butylamine without mortality occurring for a maximum of 2 minutes
      (Smy44). When exposed for 4 hours, rats survived exposure to 6000 mg/m3
      (2000 ppm) (Smy56), while exposure to 12,000 mg/m3 (4000 ppm) caused
      mortality in 2-4/6 rats (observation time: 14 days) (Car49). In an unpublished
      study, a 4-hour LC50 of 4200 mg/m3 (1386 ppm) was found in rats (EC00). In
      mice, a 2-hour LC50 of 800 mg/m3 (264 ppm) has been reported (Izm82).
           Following dermal application, an LD50 of 0.5 mL/kg bw (370 mg/kg bw) has
      been found in guinea pigs (Smy44). In a separate study, LD50 values for guinea
      pigs were 0.58 mL/kg bw (425 mg/kg bw) when applied to intact abdomen and
*     See remark in ‘References’.
**    Theoretically, the concentration in saturated vapour can amount to 327,000 mg/m3 (109,000 ppm; calculated
      from: (vapour pressure in Pa/105 Pa) x 106 ppm).
060-6 Health-based Recommended Occupational Exposure Limits
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<pre>      >1.5 mL/kg bw (>1110 mg/kg bw) when applied to abraded back. This was
      thought to be due to the fact that extensive and severe necrosis of the skin of the
      abdomen was more likely to lead to complications and death than necrosis over
      a larger area involving primarily the back (Rou65). For rabbits, dermal LD50
      values of 0.85 mL/kg bw (630 mg/kg bw) (NIO02) and >1.5 mL/kg bw (>1110
      mg/kg bw) (abraded back skin) (Rou65) were listed.
          Oral LD50 values were 366 and 382 mg/kg bw in male and female
      Sprague-Dawley CD rats, respectively (Che82), 500 mg/kg bw in male Wistar
      rats (Smy44), and 720 mg/kg bw in not further specified rats (EC00). Further,
      LD50 values of 430-450 mg/kg bw were listed for rats, mice, and guinea pigs (no
      details) (Izm82). In their oral rat studies administering doses of 100, 200, 300,
      400, 500, and 600 mg/kg bw, Cheever et al. observed signs of toxicity such as
      sedation, ataxia, nasal discharge, gasping, salivation, and, at higher doses,
      convulsions and death, which generally occurred within 1 to 3 hours after
      administration. Gross post-mortem examination of animals that died following
      treatment showed pulmonary oedema while animals surviving the 14-day
      observation period appeared normal. The authors did not present data on
      dose-effect/response relationships (Che82).
          Widy-Tyszkiewicz and Czlonkowski studied the effect of single
      intraperitoneally injected doses of aliphatic monoamines on motor activity of
      male Swiss mice, using electronic activity cages. No effects were found after a
      dose of 3 mg/kg bw butylamine. A dose of 100 mg/kg bw caused a transient
      inhibition of the locomotor activity, and did not produce autonomic symptoms
      (e.g., tremor, salivation, piloerection, urination, exophthalmus, and Straub tail).
      More severe effects were seen when the animals were given pentylamine or
      hexylamine at the same doses (Wid63).
      In an in vitro experiment using cultured mouse peritoneal macrophages, Riches
      and Stanworth demonstrated that n-butylamine at millimolar concentrations
      released substantial amounts of lysosomal ß-glucuronidase and ß-galactosidase
      activities. It has been known that these cells perpetuate inflammatory lesions by
      secreting a wide repertoire of biologically active materials in response to
      appropriate stimuli (Ric80). In another in vitro experiment using rabbit
      reticulocytes to study the influence of n-butylamine on iron uptake, Glass and
      Nunez reported that the compound (1) retards the internalisation of transferrin
      bound to transferrin receptors on the plasma membrane of reticulocytes, (2)
      retards the externalisation of internalised transferrin, and (3) blocks transport of
      iron released from transferrin into the cytosol (Gla86).
060-7 n-Butylamine
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<pre>      The committee did not find data from repeated-dose toxicity studies, including
      carcinogenicity and reproduction toxicity.
      n-Butylamine was negative when tested both with and without adding a
      metabolic activating system from induced rat and hamster livers in S.
      typhimurium strains TA98, TA100, TA1535, and TA1537 at concentrations of
      3.3-3333 µg/plate (Zei87).
          In vivo, in an unpublished micronucleus assay conducted according to
      OECD Guideline 474, n-butylamine (hydrochloride) was stated to be negative
      following intraperitoneal injections of doses of 200, 400, and 800 mg/kg bw
      into NMRI mice (no details available) (EC00).
7     Existing guidelines
      The current administrative occupational exposure limit (MAC) of n-butylamine
      in the Netherlands is 15 mg/m3 (5 ppm), as a ceiling limit.
          Existing occupational exposure limits for n-butylamine in some European
      countries and in the USA are summarised in the annex.
8     Assessment of health hazard
      Unpublished human data suggest that n-butylamine is an eye and skin irritating
      compound and that daily exposure to concentrations of 15-30 mg/m3 (5-10 ppm)
      and higher can cause irritation of eyes, nose, and throat and headaches with
      severity increasing with concentration. Exposure to levels below 15 mg/m3 (5
      ppm) (mostly between 3 and 6 mg/m3 (1 and 2 ppm)) were said to induce no
      complaints or symptoms.
          In experimental animal studies, n-butyl amine was found to be a severely
      eye- and skin-irritating compound. Rats survived a 4-hour exposure to 6000
      mg/m3 (2000 ppm), while exposure to 12,000 mg/m3 (4000 ppm) caused
      mortality in 2-4/6 rats. The dermal (in guinea pigs) and oral (in rats) LD50 values
      were 3700 and ca. 375-500 mg/kg bw, respectively.
          The committee did not find data on repeated-dose toxicity, including
      carcinogenicity and reproduction toxicity. n-Butylamine was negative in an in
      vitro mutation assay in bacteria and an in vivo micronucleus test in mice.
      The committee considers the toxicological database on n-butylamine too poor to
      justify recommendation of a health-based occupational exposure limit.
060-8 Health-based Recommended Occupational Exposure Limits
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<pre>       The committee concludes that there is insufficient information to comment on
       the level of the present MAC-value.
       References
ACG96  American Conference of Governmental Industrial Hygienists (ACGIH). n-Butyl amine. In: TLVs
       and other occupational exposure values - 1996. [CD ROM], version 1.7 - s4 02/01/95. Cincinnati
       OH, USA: ACGIH, 1996.
ACG02a American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
       exposure values -2002. Cincinnati OH, USA: ACGIH®, Inc, 2002: 17.
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: 19.
Amo83  Amoore JE, Hautala E. Odor as an aid to chemical safety: odor thresholds compared with threshold
       limit values and volatilities for 214 industrial chemicals in air and water dilution. J Appl Toxicol
       1983; 3: 272-90.
Arb02  Arbejdstilsynet. Grænseværdier for stoffer og materialer. Copenhagen, Denmark: Arbejdstilsynet,
       2002: 19 (At-vejledning C.0.1).
Bea81  Beard RR, Noe JT. Aliphatic and alicyclic amines. In: Clayton GD, Clayton FE, eds. Toxicology.
       3rd rev ed. New York: John Willey & Sons, 1981: 3155 (Patty’s industrial hygiene and toxicology;
       Vol 2B).
Ben94  Benya TJ, Harbison RD. Aliphatic and alicyclic amines. In: Clayton GD, Clayton FE, eds.
       Toxicology. 4th ed. New York: John Willey & Sons, 1994: 1087-175 (Patty’s industrial hygiene and
       toxicology; Vol II, Pt B, Ch 17).
Car46  Carpenter CP, Smyth HF Jr. Chemical burns of the rabbit cornea. Am J Ophthalmol 1946; 29:
       1363-72.
Car49  Carpenter CP, Smyth HF Jr, Pozzani UC. The assay of acute vapor toxicity, and the grading and
       interpretation of results of 96 chemical compounds. J Ind Hyg toxicol 1949; 31: 343-6.
Che82  Cheever KL, Richards DE, Plotnick HB. The acute oral toxicity of isomeric monobutylamines in the
       adult male and female rats. Toxicol Appl Pharmacol 1982; 63: 150-2.
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: 20 (rep no 38).
060-9  n-Butylamine
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<pre>EC00   European Commission (EC) - European Chemicals Bureau (ECB). IUCLID Dataset - butylamine.
       In: Public data on high volume chemicals. IUCLID CD-ROM. Year 2000 ed. Ispra, Italy: European
       Commission, Joint Research Centre, Institute for Health and Consumer Protection, European
       Chemicals Bureau, 2000.*
EC02   European Commission (EC): Directorate General for Employment and Social Affairs. Occupational
       exposure limits (OELs). http://europe.eu.int/comm/employment_social/h&s/areas/oels_en.htm.
Gag89  Gagnaire F, Azim S, Bonnet P, et al. Nasal irritation and pulmonary toxicity of aliphatic amines in
       mice. J Appl Toxicol 1989; 9: 301-4.
Gla86  Glass J, Nunez MT. Amines as inhibitors of iron transport in rabbit reticulocytes. J Biol Chem 1986;
       261: 8298-302.
Gut75  Guthrie JW, Seitz GF. An investigation of the chemical contact lens problem. J Occup Med 1975;
       17: 163-6.
HSE02  Health and Safety Executive (HSE). EH40/2002. Occupational exposure limits 2002. Sudbury
       (Suffolk), England: HSE Books, 2002: 13.
Izm82  Izmerov NF, Sanotsky IV, Sidorov KK. Butylamine. In: Toxicometric parameters of industrial toxic
       chemicals under single exposure. Moscow, Russia: Centre of International Projects/United Nations
       Environment Programme (UNEP)-International Register of Potentially Toxic Chemicals (IRPTC),
       1982: 28.
Nie88  Nielsen GD, Vinggaard AM. Sensory irritation and pulmonary irritation of C3-C7 n-alkylamines:
       mechanisms of receptor activation. Pharmacol Toxicol 1988; 63: 293-304.
NIO02  US National Institute for Occupational Safety and Health (NIOSH), ed. Butylamine. In: Registry of
       Toxic Effects of Chemical Substances (RTECS) (last update n-butylamine file: July 2000);
       http://www.cdc.gov/niosh.
NLM02  US National Library of Medicine (NLM), ed. n-Butylamine. In: Hazardous Substances Data Bank
       (HSDB) (last revision date n-butylamine file: 31 January 1999); http://toxnet.nlm.nih.gov.
Ric80  Riches DW, Stanworth DR. Primary amines induced selective release of lysosomal enzymes from
       mouse macrophages. Biochem J 1980; 188: 933-6.
Rou65  Roudabush RL, Terhaar CJ, Fassett DW, et al. Comparative acute effects of some chemicals on the
       skin of rabbits and guinea pigs. Toxicol Appl Pharmacol 1965; 7: 559-65.
Rut86  Ruth JH. Odor thresholds and irritation levels of several chemical substances: a review. Am Ind Hyg
       Assoc J 1986: 47: A-142-A-151.
Smy44  Smyth HF Jr, Carpenter CP. The place of the range finding test in the industrial toxicology
       laboratory. J Ind Hyg Toxicol 1944; 26: 269-73.
Smy51  Smyth HF Jr, Carpenter CP, Weil CS. Range-finding toxicity data: List IV. Arch Ind Hyg Occup
       Med 1951; 4: 119-22.
*      This dossier is a compilation based on data reported by the European Chemicals Industry following ‘Council
       Regulation (EEC) No 793/93 on the Evaluation and Control of the Risks of Existing Substances’ to allow a risk
       assessment by member states of the EC. However, the data in this dossier have not undergone any evaluation by
       any EC member state yet.
060-10 Health-based Recommended Occupational Exposure Limits
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<pre>Smy56  Smyth HF Jr. Improved communication - hygienic standards for daily inhalation. Am Ind Hyg Assoc
       Q 1956; 17: 148.
Smy62  Smyth HF Jr, Carpenter CP, Weil CS, et al. Range-finding toxicity data: List VI. Am Ind Hyg Ass J
       1962; 23: 95-107.
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: 24 (Ordinance AFS 2000:3).
SZW02  Ministerie van Sociale Zaken en Werkgelegenheid (SZW). Nationale MAC-lijst 2002. The Hague,
       the Netherlands: Sdu, Servicecentrum Uitgevers, 2002: 19.
TRG00  TRGS 900. Grenzwerte in der Luft am Arbeitsplatz; Technische Regeln für Gefahrstoffe. BArbBl
       2000; 2.
Vin89  Vinggaard AM, Nielsen GD, Fries AS. Sensory and pulmonary irritation of inhaled n-butylamine in
       CF-1 and NMRI mice. Lab Anim 1989; 23: 1-6.
Wid63  Widy-Tyszkiewicz E, Czlonkowski A. Effect of aliphatic monoamines on motor activity of mice: no
       direct interaction with dopaminergic D2 receptor. Pol J Pharmacol Pharm 1963; 35: 467-72.
Zei87  Zeiger E, Anderson B, Haworth S, et al. Salmonella mutagenicity tests: III. Results from the testing
       of 255 chemicals. Environ Mutagen 1987; 9 (suppl 9): 1-110.
060-11 n-Butylamine
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<pre>               Annex
Occupational exposure limits for n-butylamine in various countries.
country                          occupational exposure         time-weighted       type of exposure   notea    referenceb
-organisation                    limit                         average             limit
                                 ppm           mg/m3
the Netherlands
-Ministry of Social Affairs      5             15              ceiling             administrative     S        SZW02
and Employment
Germany
-AGS                             5             15              8h                                     S        TRG00
                                 20            60              15 min
-DFG MAK-Kommission              5             15              8h                                     S,d      DFG02
                                 10            30              15 min,
                                                               momentary valuec
Great-Britain
-HSE                             5             15              15 min              OES                S        HSE02
Sweden                           5             15              ceiling                                S        Swe00
Denmark                          5             15              ceiling                                S,e      Arb02
USA
-ACGIH                           5             -               ceiling             TLV                S        ACG02b
-OSHA                            5             15              ceiling             PEL                S        ACG02a
-NIOSH                           5             15              ceiling             REL                S        ACG02a
European Union
-SCOEL                           -             -                                                               EC02
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
     I.e., a concentration that should not be exceeded at any time; maximim number per shift: 4, with a minimum interval
     between peaks of 1 hour.
d
     Listed among compounds for which no information regarding possible damage to the embryo or fetus was found for
     pregnancy risk group classification.
e
     Holds for all isomers of butyl amine.
060-12         Health-based Recommended Occupational Exposure Limits
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