<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>      4-Ethylmorpholine
      (CAS reg no: 100-74-3)
      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/034, The Hague, 7 March 2002
034-1
</pre>

====================================================================== Einde pagina 1 =================================================================

<br><br>====================================================================== Pagina 2 ======================================================================

<pre>      Preferred citation:
      Health Council of the Netherlands: Committee on Updating of Occupational
      Exposure Limits. 4-Ethylmorpholine; Health-based Reassessment of
      Administrative Occupational Exposure Limits. The Hague: Health Council of the
      Netherlands, 2002; 2000/15OSH/034.
      all rights reserved
034-2
</pre>

====================================================================== Einde pagina 2 =================================================================

<br><br>====================================================================== Pagina 3 ======================================================================

<pre>1     Introduction
      The present document contains the assessment of the health hazard of
      4-ethylmorpholine 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 Center, Amsterdam, the Netherlands).
           Literature was retrieved from the data bases Medline, Toxline, Embase, and
      Chemical Abstracts starting from 1966, 1967, 1988, and 1970, respectively, and
      using the following key words: ethylmorpholine and 100-74-3. HSEline, Cisdoc,
      Mhidas, and NIOSHtic (covering the period 1985/87 until 1997), data bases
      available from CD-ROM, were consulted as well. Data considered to be critical
      were evaluated by reviewing the original publications. The final literature search
      was carried out in October 1997, followed by an additional search in June 2001.
           In July 2001, the President of the Health Council released a draft of the
      document for public review. The committee received no comments.
2     Identity
       name                          :  4-ethylmorpholine
       synonyms                      :  N-ethylmorpholine
       molecular formula             :  C6H13NO
       structural formula            :
       CAS no                        :  100-74-3
034-3 4-Ethylmorpholine
</pre>

====================================================================== Einde pagina 3 =================================================================

<br><br>====================================================================== Pagina 4 ======================================================================

<pre>3     Physical and chemical properties
       molecular weight           :     115.2
       boiling point              :     139 oC
       melting point              :     -62.8 oC
       flash point                :     32.2 oC (closed cup)
       vapour pressure            :     at 20 oC: 0.81 kPa
       solubility in water        :     soluble
       Log P octanol/water        :     0.14 (estimated)
       conversion factors         :     1 mg/m 3 = 0.21 ppm
       (20 oC; 101.3 kPa)               1 ppm = 4.79 mg/m 3
      Data from ACG99, http://esc.syres.com.
      4-Ethylmorpholine is a colourless liquid with an ammonia-like odour. It is
      flammable and a dangerous fire hazard (ACG99). An odour threshold of 6.7
      mg/m3 (1.4 ppm) has been reported (Amo83).
4     Uses
      4-Ethylmorpholine is used as a catalyst in the manufacture of urethane foam, as
      an intermediate for dyestuffs, pharmaceuticals, rubber accelerators and
      emulsifying agents, as a solvent for dyes, resins, and oils, and as a substrate for
      enzyme reactions (NLM01).
5     Biotransformation and kinetics
      There is no primary data available on the kinetics of this compound. Secondary
      information reported that the substance can be absorbed by inhalation and
      through skin contact (Hat91).
6     Effects and mechanism of action
      Human data
      In an unpublished study cited by ACGIH, irritation to the eyes, nose, and throat,
      and olfactory fatigue was reported in 10 volunteers when exposed to 479 mg/m3
034-4 Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

====================================================================== Einde pagina 4 =================================================================

<br><br>====================================================================== Pagina 5 ======================================================================

<pre>      (100 ppm) for 2.5 minutes. There were slight and no irritation at 2.5-minute
      exposures to 240 and 120 mg/m3 (50 and 25 ppm), respectively (ACG99).
          In polyurethane foam workers occupationally exposed to a variety of
      aliphatic amine catalysts among which 4-ethylmorpholine, (transient) corneal
      oedema and vision abnormalities have been reported (Der66, Mas65). However,
      the committee is of the opinion that no conclusions concerning dosis-effect
      relationships can be drawn. Exposure was to several amines and it was not clear
      at which levels these effects occurred. In one report (Der66), it was stated that
      incomplete studies showed that lesions occurrred at "substituted morpholine"
      levels of 40 ppm or higher, while in another paper (Mas65) it was said that vision
      distortion was experienced at (not specified) conentrations below those
      producing eye or respiratory irritation. Furthermore, in unpublished information
      cited by ACGIH workers exposed to 4-ethylmorpholine levels of generally 3-4
      ppm, but never higher than 11 ppm, were reported to complain of drowsiness and
      visual abnormalities (optical halos, foggy vision) may occur at (ACG99).
      Animal data
      Smyth et al. reported an injury grade of 7 on a scale from 1 to 10 following
      instillation of 4-ethylmorpholine into the eyes of rabbits (Smy54). Following
      instillation of one drop of pure 4-ethylmorpholine into the eye of an
      anaesthetised rabbit, Mellerio and Weale reported blinking reactions, and, after 5
      minutes, reddening of the inner surfaces of the lids and the nictating membrane,
      and further "haziness" of the cornea, irregularities and sloughing of the surface,
      and general appearance associated with violent desiccation (Mel66).
          When tested for its potential skin irritating properties, Smyth et al. reported
      an injury grade of 1 (i.e., giving rise to 'the least visible capillary injection') on a
      scale from 1 to 10 when 0.01 mL of undiluted 4-ethylmorpholine was applied to
      the clipped skin of 5 albino rabbits for 24 hours (Smy54).
          The committee did not find data on the sensitising potential of
      4-ethylmorpholine.
      Following exposure of rats to 9580 mg/m3 (2000 ppm) 4-ethylmorpholine for 4
      hours, 1 out of 6 animals died. When exposed to saturated vapour*, 2 hours was
      the maximum exposure duration which did not induce mortality (Smy54).
*     The (theoretic) concentration in saturated air can be calculated using the formula: (vapour pressure in Pa
      x 10 6 ppm)/10 5 Pa. Using a vapour pressure of 810 Pa, the committee estimates that these animals could
      have been exposed to, at most, 8,100 ppm or (roughly) 39,000 mg/m 3.
034-5 4-Ethylmorpholine
</pre>

====================================================================== Einde pagina 5 =================================================================

<br><br>====================================================================== Pagina 6 ======================================================================

<pre>          An oral LD 50 of 1780 mg/kg bw (range: 1490 - 2120 mg/kg bw) has been
      reported in rats (observation period: 14 days) (Smy54).
      4-Ethylmorpholine was positive when tested in the presence of metabolic
      activation systems from induced rat or hamster livers in a preincubation assay
      using S. typhimurium strain TA1535 at concentrations of 100-10,000 µg/plate. A
      negative result was obtained when tested without adding such metabolic
      activation systems. When tested with and without metabolic activation in strains
      TA98, TA100, and TA1537, results were negative as well (Zei87). Hedenstedt
      found 4-ethylmorpholine to be mutagenic upon testing in S. typhimurium strains
      TA100 and TA1535 both in the absence and the presence of a microsomal
      system obtained from induced rat livers. No other strains were tested. Since the
      compound itself was not an alkylating agent, an alkylating impurity might have
      been responsible for the mutagenic effect. This possibility was investigated by
      testing 4-ethylmorpholine for alkylating properties by means of the reaction with
      4-(p-nitrobenzyl)pyridine. Since a positive response was obtained with
      4-ethylmorpholine in this latter test, an alkylating impurity, possibly
      ethyleneimine or some derivative of this highly potent mutagenic agent, might
      have been responsible for the positive response in the former test (no more
      details presented; only abstract available) (Hed76). Presented in an abstract
      without further details, 4-ethylmorpholine was stated to be negative when tested
      at 5 dose levels with and without metabolic activation in the L5178Y mouse
      lymphoma assay (Con82).
          In the same abstract, it was stated that 4-ethylmorpholine was negative as
      well in the BALB/3T3 transformation assay (Con82).
      The committee did not find data on the toxicity, including carcinogenicity and
      reproduction toxicity, of 4-ethylmorpholine following repeated exposure.
7     Existing guidelines
      The current administrative occupational exposure limit (MAC) for
      4-ethylmorpholine in the Netherlands is 25 mg/m3 (5 ppm), 8-hour TWA, with a
      skin notation.
          Existing occupational exposure limits for 4-ethylmorpholine in some
      European countries and in the USA are summarised in the annex.
034-6 Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

====================================================================== Einde pagina 6 =================================================================

<br><br>====================================================================== Pagina 7 ======================================================================

<pre>8      Assessment of health hazard
       The committee did not find adequate human data.
            From experimental animal data that are old and not from tests performed
       according to current guidelines, the committee concludes that 4-ethylmorpholine
       is severely irritating to the eyes, but not irritating to the skin.
            In acute inhalation studies, 4-ethylmorpholine caused lethality in 1 out of 6
       rats at a 4-hour exposure to 9580 mg/m3 (2000 ppm). The oral LD50 was 1780
       mg/kg bw in rats.
            4-Ethylmorpholine induced mutations in vitro in S. typhimurium but not in
       mouse lymphoma cells. 4-Ethylmorpholine was negative in the BALB/3T3
       transformation assay.
            The committee did not find data on the toxicity, including carcinogenicity
       and reproduction toxicity, of 4-ethylmorpholine following repeated exposure.
       The committee considers the toxicological data base on 4-ethylmorpholine too
       poor to justify recommendation of a health-based occupational exposure limit.
       The committee concludes that there is insufficient information to comment on the
       level of the present MAC value.
       References
ACG99  American Conference of Governmental Industrial Hygienists (ACGIH). N-Ethylmorpholine.
       In: ACGIH. TLVs ® and other occupational exposure values - 1999. [CD-ROM]. Cincinnati
       OH, USA: ACGIH® , Inc, 1999.
ACG00  American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
       exposure values - 2000. Cincinnati OH, USA: ACGIH® , Inc, 2000: 56.
ACG01  American Conference of Governmental Industrial Hygienists (ACGIH). 2001 TLVs ® and
       BEIs® . Threshold Limit Values for chemical substances and physical agents. Biological
       Exposure Indices. Cincinnati OH, USA: ACGIH® , Inc, 2001: 32.
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.
Arb00a Arbejdstilsynet. Grænseværdier for stoffer og materialer. Copenhagen, Denmark:
       Arbejdstilsynet, 2000; (At-vejledning C.0.1).
034-7  4-Ethylmorpholine
</pre>

====================================================================== Einde pagina 7 =================================================================

<br><br>====================================================================== Pagina 8 ======================================================================

<pre>Arb00b Arbetarskyddstyrelsen. Hygieniska gränsvärden och åtgärder mot luftföroreningar. Solna,
       Sweden: National Board of Occupational Safety and Health, 2000: 36; (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 ofCouncil 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.
Con82  Conaway CC, Myhr BC, Rundell JO, et al. Evaluation of morpholine, piperazine and
       analogues in the L5178Y mouse lymphoma assay and BALB/3T3 transformation assay.
       Environ Mutagen 1982; 4: 390.
Der66  Dernehl CU. Health hazards associated with polyurethane foam. J Occup Med 1966; 8:
       59-62.
DFG01  Deutsche Forschungsgemeinschaft (DFG): Commission for the Investigation of Health
       Hazards of Chemical Compounds in the Work Area. List of MAK and BAT values 2001.
       Maximum concentrations and biological tolerance values at the workplace. Weinheim, FRG:
       Wiley-VCH, 2001: 60; (rep no 37).
Hat91  Hathaway GJ, Proctor NH, Hughes JP, et al., eds. In: Proctor and Hughes's chemical hazards
       of the workplace. 3rd ed. New York, USA: Van Nostrand Reinhold, 1991: 299-300.
Hed76  Hedenstedt A. Mutagenicity screening of industrial chemicals: seven aliphatic amines and one
       amide tested in the Salmonella/microsomal assay. Mutat Res 1976; 53: 198-9.
HSE01  Health and Safety Executive (HSE). EH40/2001. Occupational Exposure Limits 2001.
       Sudbury (Suffolk), England: HSE Books, 2001: 18.
Mas65  Mastromatteo E. Recent occupational health experiences in Ontario. J Occup Med 1965; 7:
       502-11
Mel66  Mellerio J, Weale RA. Hazy vision in amine plant operatives. Br J Ind Med 1966; 23: 153-4.
NLM01  US National Library of Medicine (NLM). N-Ethylmorpholine. In: Hazardous Substances Data
       Bank (HSDB) (last revision date N-ethylmorpholine file: 2 February 2000);
       http://toxnet.nlm.nih.gov.
Smy54  Smyth HF Jr, Carpenter CP, Weil CS, et al. Range finding toxicity data. List V. AMA Arch
       Ind Hyg Occup Med 1954; 10: 61-8.
SZW01  Ministerie van Sociale Zaken en Werkgelegenheid (SZW). Nationale MAC-lijst 2001. The
       Hague, the Netherlands: Sdu, Servicecentrum Uitgevers, 2001: 27.
TRG00  TRGS 900. Grenzwerte in der Luft am Arbeitsplatz; Technische Regeln für Gefahrstoffe.
       BArbBl 2000; 2.
Zei87  Zeiger E, Anderson B, Haworth S, et al. Salmonella mutagenicity tests: III. Results from
       testing of 255 chemicals. Environ Mol Mutagen 1987; 9 (suppl 9): 1-110.
034-8  Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

====================================================================== Einde pagina 8 =================================================================

<br><br>====================================================================== Pagina 9 ======================================================================

<pre>            Annex
Occupational exposure limits for 4-ethylmorpholine in various countries.
country                           occupational               time-weighted type of               notea    lit refb
-organisation                     exposure limit             average         exposure limit
                                  ppm          mg/m 3
the Netherlands
-Ministry of Social Affairs and   5            23            8h              administrative      S        SZW01
Employment
Germany
-AGS                              -            23                                                S        TRG00
-DFG MAK-Kommission               -c           -c                                                         DFG01
Great-Britain
-HSE                              5            24            8h              OES                 S        HSE01
                                  20           96            15 min
Sweden                            5            25            8 h                                 S        Arb00b
                                  10           50            15 min
Denmark                           5            23.5          8h                                  S        Arb00a
USA
-ACGIH                            5            24            8h              TLV                 S        ACG01
-OSHA                             20           94            8h              PEL                 S        ACG00
-NIOSH                            5            23            10 h            REL                 S        ACG00
European Union
-SCOEL                            -            -                                                          CEC00
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
c
     Listed among substances for which studies of the effects in man or in experimental animals have yielded
     insufficient information for the establishment of MAK values
034-9       4-Ethylmorpholine
</pre>

====================================================================== Einde pagina 9 =================================================================

<br><br>