<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>‘Iso-octyl’ alcohol (mixed isomers)
(CAS No: 26952-21-6)
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/082, The Hague, 22 October 2003
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. ‘Iso-octyl’ alcohol (mixed isomers); Health-based
Reassessment of Administrative Occupational Exposure Limits. The Hague:
Health Council of the Netherlands, jaartal; 2000/15OSH/082.
all rights reserved
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of isooctyl
      alcohol 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).
      In January 1998, literature was searched in the databases Medline, Embase, and
      Chemical Abstracts, starting from 1966, 1988, and 1970, respectively, and using
      the following key words: isooctyl alcohol, methylheptyl alcohol, and
      26952-21-6. NIOSHTIC, HSELINE, CISDOC, MHIDAS (from 1997
      backwards) and POLTOX (Toxline, Cambridge Scient Abstr and FSTA) (from
      1986-December 1994), databases available from CD-ROM, were consulted as
      well. The final search was carried out in Toxline and Medline in November 2002.
           In April 2003, the President of the Health Council released a draft of the
      document for public review. The committee received no comments.
2     Identity
      name                    :    ‘iso-octyl’ alcohol
      synonyms                :    isooctanol; isooctane-1-ol; 1-isooctanol; 6-methyl-1-heptanol
      molecular formula       :    C8H18O
      structural formula      :    (CH3)2CH2-CH2- CH2-CH2- CH2-CH2OH
      CAS number              :    26952-21-6.
082-3 ‘Iso-octyl’ alcohol (mixed isomers)
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<pre>3     Physical and chemical properties
      molecular weight        :   130.23
      boiling point           :   184-191oC
      melting point           :   -
      flash point             :   82oC (open cup)
      vapour pressure         :   at 25oC: 10 Pa (extrapolated value)
      solubility in water     :   insoluble
      log Poctanol/water      :   2.73 (estimated)
      conversion factors      :   at 20oC, 101.3kPa: 1 mg/m3 = 0.18 ppm
                                                      1 ppm = 5.41 mg/m3
      Data from ACG99, NLM01, http://esc.syres.com.
      ‘Iso-octyl’ alcohol is a mixture of closely related isomeric, primary alcohols with
      branched chains having the general formula R-CH2OH in which R- represents
      heptyl radicals; these are mostly methyl groups usually located in the 3-, 4-, or
      5-positions (ACG99). A typical ‘iso-octyl’ alcohol mixture was described to
      consist of 70-80% dimethyl-1-hexanols, 10-20% methyl-1-heptanols, and 5-10%
      other homologous primary alcohols (Sca73). ‘Iso-octyl’ alcohol is a colourless
      liquid with characteristic odour (ACG99). The odour threshold is not known.
4     Uses
      ‘Iso-octyl’ alcohol is used as a solvent and as a chemical intermediate in the
      production of plasticisers and other products, as an intermediate for non-ionic
      detergents and surfactants, in synthetic drying oils, cutting and lubricating oils,
      and hydraulic fluids, as a resin solvent, emulsifier, and antifoaming agent, and as
      a reagent for introducing the iso-octyl group into other compounds (ACG99).
5     Biotransformation and kinetics
      The committee did not find quantitative data on the biotransformation and
      kinetics of ‘iso-octyl’ alcohol.
           Based on systemic effects observed after occlusive applications of doses of
      0.10-3.16 mL/kg (i.e., ca. 83 to 2630 mg/kg bw) to the clipped, intact abdominal
      skin of rabbits, percutaneous absorption is evident (Sca73).
082-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>6     Effects and mechanism of action
      Human data
      In an irritation/sensitisation test in which unreported amounts of undiluted ‘iso-
      octyl’ alcohol were applied to the skin of volunteers using ‘standard patch testing
      procedures’ (no details given), mild primary irritation reactions consisting of
      very mild erythema in 8/32 and erythema in 5/32 while no reactions were seen in
      the remaining 19 volunteers. Retesting 2 weeks later showed an intensification of
      reactions in 8 volunteers all showing very mild erythema while irritation was
      absent following the first application. The others had a similar reaction (n=12; no
      or very mild) or a less severe reaction (n=12) (Nel51). Contrary to Nelson who
      concluded that there was no evidence of sensitisation, the committee considers
      this test as inconclusive because of a slight intensification of irritation reactions
      in a number of the volunteers and the lack of experimental data.
      Animal data
      Irritation and sensitisation
      In Wistar rats, Swiss mice, and English Short Hair guinea pigs (n=10/group; sex:
      not reported) exposed to nearly saturated vapours of ‘iso-octyl’ alcohol
      calculated to be 200 ppm (1082 mg/m3), for 6 hours, slight to moderate irritation
      (on a 4-point grading scale of slight-moderate-marked-severe) of the mucous
      membranes of the eyes, nose, throat, and respiratory tract (blinking,
      lachrymation, preening, nasal discharge, salivation, gasping, chewing
      movements) were seen (Sca73) (see also ‘Acute toxicity’).
          When 0.1 mL of undiluted ‘iso-octyl’ alcohol was instilled into the left eye of
      rabbits (n=6), the compound was concluded to be severely irritating (on a 4-point
      grading scale of slight-moderate-marked-severe) observations at 1 and 4 hours,
      and 1, 2, 3, 4, and 7 days. Draize scores presented only for the observation points
      1, 3, and 7 days were 24, 18, and 0, respectively (maximum score possible: 110)
      (Sca73).
          ‘Iso-octyl’ alcohol was concluded to be moderately irritating (on a 4-point
      grading scale of slight-moderate-marked-severe) following 24-hour occlusive
      application of doses of 0.10 to 3.16 mL/kg (i.e., ca. 83 to 2630 mg/kg bw) to the
      clipped intact abdominal skin of rabbits (n=4/dose). Signs of irritation observed
      included slight to moderate or severe erythema, slight to moderate oedema, as
082-5 ‘Iso-octyl’ alcohol (mixed isomers)
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<pre>      well as atonia, blanching, desquamation, coriaceousness, necrosis, and eschar
      (Sca73). Application of unknown amounts of undiluted ‘iso-octyl’ alcohol to the
      skin of rabbits for 6 to 24 hours induced extensive erythema and oedema, and in
      several cases intracutaneous haemorrhages. The erythema disappeared within 2
      or 3 days, the skin appeared dry and wrinkled, assuming a tanned and leathery
      appearance, and becoming very tough and rigid within 7 to 10 days. Thereafter,
      the leathery skin was completely sloughed (Nel51).
      Acute toxicity
      Scala and Burtis performed an inhalation study in which groups of Wistar rats,
      Swiss mice, and English Short Hair guinea pigs (n=10/species; sex: not reported)
      were exposed to atmospheres nearly saturated with ‘iso-octyl’ alcohol vapours,
      for 6 hours. Atmospheres were generated by passing all air entering the chamber
      through fritted-disk glass bubblers containing a measured amount of alcohol. No
      attempts to impact entrained droplets and no analytical determinations of the
      chamber concentrations were made. The nominal concentration, calculated from
      the net loss of alcohol from the bubblers and the total chamber airflow, was
      stated to be 200 ppm (1082 mg/m3). Apart from slight to moderate irritation of
      the mucous membranes (see also ‘Irritation and sensitisation’), no effects were
      seen during the 24-hour observation period and at necropsy (Sca73).
          Twenty-four-hour occlusive application of doses of ‘iso-octyl’ alcohol of
      0.10 to 3.16 mL/kg (i.e., ca. 83 to 2630 mg/kg bw) to the clipped intact
      abdominal skin of rabbits (n=4/dose) resulted in the death of one animal in the
      highest dose group groups. Further, dermal irritation (see ‘Irritation and
      sensitisation’) and central nervous system depression (laboured respiration,
      ataxia, sprawled limbs), disappearing 4 to 48 hours after exposure began, were
      seen. No information on dose-effect relationship, severity, or incidences was
      given (observation time: 7 days) (Sca73). All 3 rabbits survived dermal treatment
      with unknown amounts of undiluted ‘iso-octyl’ alcohol for 6 hours. All animals
      showed incoordination and unsteadiness. Treatment for 8.7, 12, or 24 hours
      caused mortality in 2/4 (at the end of the experiment), 3/3 (within 1-2 days), and
      2/2 (within 1 day) animals, respectively. Systemic signs observed included
      incoordination, unsteadiness, very weak or absent corneal reflexes, and narcosis
      (observation period: 14 days) (Nel51).
          An oral LD50 of 1480 mg/kg bw has been calculated for rats (Sprague-
      Dawley; n=5/dose) given doses of 0.032 to 10.0 mL/kg bw (i.e., ca. 27-8320
      mg/kg bw). The principal effects included signs of central nervous system
      depression (such as inactivity, ataxia, limb sprawling, depressed righting and
082-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      placement reflexes, prostration, coma) and laboured respiration. At gross
      necropsy, there were no remarkable findings (Sca73). Nelson did not observe
      mortality or signs of toxicity in rats (n=2/dose) given single oral doses up to 3160
      mg/kg bw or in rabbits (n=2) given 320 mg/kg bw. In rats, doses of 4220, 5620,
      and 10,000 mg/kg bw caused mortality (generally within 1 day) in 1/10, 10/10,
      and 2/2 animals, respectively. In rabbits, mortality (generally within 6 hours)
      incidences were 3/4, 3/4, and 2/2 at doses of 560, 1000, and 1780 mg/kg bw,
      respectively. Signs of toxicity such as incoordination, unsteadiness, weakened or
      absent corneal reflexes, and narcosis were observed. Upon histological
      examination, there were no remarkable findings (Nel51).
      Repeated-dose toxicity
      Male rats (Crl:CD®(SD)BR; n=10/group) were exposed nose-only to 0, 110, 600,
      or 3100 mg/m3 of ‘isooctanol’ consisting of C8 isomers, predominantly primary
      dimethylhexanols and methylheptanols, 6 hours/day, 5 days/week, for 2 weeks.
      Half of the animals were killed after the 10th exposure, the remaining animals
      after a 14-day recovery period. Clinical observations and body weight recordings
      were made regularly. Post-mortem examinations included analysis of urine and
      blood samples, organ and body weights, gross and microscopic evaluations of
      amongst others nasal cavity and trachea. There was no treatment-related
      mortality. Clinical signs observed included lung noise in 3/20 rats of the 2 lower
      exposure groups and frequent instances of lung noise, eye and nose irritation,
      red-stained perineum, inactivity, impaired balance, ruffled fur, and alopecia in
      the animals exposed to 3100 mg/m3. None of these signs were seen during the
      recovery period in any of the groups. There were no effects on the body weights
      of the animals of the 2 lower exposure groups, but those of the animals of the
      high-exposure group were significantly lower from day 2 onwards when
      compared to controls. Statistically significant organ weight changes observed in
      the animals sacrificed after the 10th exposure included increased absolute kidney
      weights in the low- and mid-concentration group, increased relative kidney
      weights in the mid- and high-concentration group, decreased absolute and
      relative spleen weights, decreased absolute lung and thymus weights, and
      increased relative liver weights in the high-concentration group. After the 14-day
      recovery period, there were statistically significant decreases in absolute and
      relative spleen weights in all treated groups and increases in relative kidney
      weights in the high-concentration group. Upon macroscopic and microscopic
      examination only nasal effects were found. In the animals sacrificed after the
      10th exposure, dermatitis of the nasal area and acute rhinitis with respiratory
082-7 ‘Iso-octyl’ alcohol (mixed isomers)
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<pre>      nasal epithelial necrosis and squamous metaplasia were seen in 5/5 animals of
      the high-concentration group (all with severity degree ‘moderate’) and
      respiratory nasal epithelial squamous metaplasia in 4/4 animals of the mid-
      concentration group (severity: ‘moderate’ in 3, ‘slight’ in 1; no tissue present on
      slide of remaining animal). After a 14-day exposure-free period, there were still
      ‘slight’ rhinitis and ‘slight’ squamous metaplasia in 2/5 animals of the high-
      concentration group and ‘slight’ squamous metaplasia in 1/5 animals of the mid-
      concentration group. No lesions were observed in the animals exposed to 110
      mg/m3. Upon urine and blood analysis, the only effects considered to be test
      substance-related were significant increases in red blood cell parameters
      indicative of polycythaemia found in animals immediately sacrificed after the
      final exposure to 600 or 3100 mg/m3 (DuP85). From this study, the committee
      could not establish a no-observed-adverse-effect level, since decreased absolute
      and relative spleen weights were found in animals sacrificed 14 days after
      receiving a final exposure to 110 mg/m3, the lowest concentration tested. [the
      committee notes the relatively wide ranges in concentrations at the exposure
      levels (18-180, 230-900, and 1600-4600 mg/m3) and further that it could not be
      assessed whether the aerosols were adequately generated since the appendix
      presenting the results of these measurements was not present in the copy made
      available to the committee although particle size was determined at 2
      occasions].
          No mortality or any other effects were reported in rats (n=5) exposed to air
      saturated with ‘iso-octyl’ alcohol vapour at 20oC for 150 hours (no further data
      available) (Nel51).
          In a study to examine whether and to what extent ‘plasticiser alcohols’ had
      similar effects as industrial plasticisers, such as di-(2-ethylhexyl) phthalate and
      adipate, daily oral (gavage) administration of 130 mg/kg bw of ‘iso-octyl’
      alcohol to male rats (Alderley Park Wistar derived ; n=5), for 14 subsequent
      days, did not induce testicular atrophy, hepatomegaly, peroxisome proliferation,
      or hypolipidaemia (Rho84).
      The committee did not find data on the potential long-term toxicity,
      carcinogenicity, mutagenicity/genotoxicity, or reproduction toxicity of ‘iso-
      octyl’ alcohol.
082-8 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>7     Existing guidelines
      The current administrative occupational exposure limit (MAC) for ‘iso-octyl’
      alcohol in the Netherlands is 270 mg/m3 (50 ppm), 8-hour TWA.
          Existing occupational exposure limits for ‘iso-octyl’ alcohol in some
      European countries and in the USA are summarised in the annex.
8     Assessment of health hazard
      The committee did not find data on the toxicokinetics of ‘iso-octyl’ alcohol, but
      from acute dermal toxicity data in experimental animals, percutaneous
      absorption was evident.
      Upon testing in human volunteers, mild skin irritation was found while results
      were negative or inconclusive regarding sensitisation. In experimental animals,
      ‘iso-octyl’ alcohol was irritating to eyes and skin.
          Exposure to nearly saturated vapours (probably 1082 mg/m3 or 200 ppm), for
      6 hours, caused eye, nose, throat, and respiratory tract irritation but no other
      effects in several animal species. Dermal occlusive application of unknown
      amounts to rabbits induced effects on the nervous system (laboured respiration,
      ataxia, incoordination, unsteadiness, narcosis) and mortality. Following oral
      administration, a LD50 of 1480 mg/kg bw was found in rats. Effects observed
      were similar to those seen after dermal exposure.
          In a 14-day inhalation study using male rats (DuP85), exposure to aerosol
      concentrations of 110, 600, and 3100 mg/m3 caused, amongst others, clinical
      signs, decreased body weight, relative organ weight changes (increase: kidney,
      liver; decrease: spleen), changes indicative of polycythaemia, and acute rhinitis
      with respiratory epithelial necrosis and squamous metaplasia in animals
      sacrificed immediately after the last exposure to 3100 mg/m3 and increased
      relative kidney weights, changes indicative of polycythaemia, and respiratory
      nasal epithelial squamous metaplasia in animals sacrificed after the last exposure
      to 600 mg/m3. After a 14-day recovery period, the only effects observed were,
      amongst others, decreased absolute and relative spleen weights in all groups and
      nasal lesions in 2/5 and 1/5 animals of the high- and mid-concentration group,
      respectively. Because of the effects on spleen weights found in the recovery
      group at all concentration levels, the committee could not set a NOAEL in this
      study. In view of the limited number of animals (n=5/group/sacrifice), the short
      duration, and the lack of data on particle size and particle size distribution, the
082-9 ‘Iso-octyl’ alcohol (mixed isomers)
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<pre>       committee is of the opinion that this study cannot be used to derive a health-
       based occupational exposure limit.
            The committee did not find data on the potential long-term toxicity,
       carcinogenicty, mutagenicity/genotoxicity, or reproduction toxicity of ‘iso-octyl’
       alcohol.
       The committee considers the toxicological database on ‘iso-octyl’ alcohol too
       poor to recommend a health-based occupational exposure limit.
       Considering the effects found in a 14-day (male) rat inhalation study (organ
       weight changes at 110 mg/m3 and the nasal lesions at 600 mg/m3), the committee
       concludes that the present MAC value for ‘iso-octyl’ alcohol of 270 mg/m3 (50
       ppm), 8-hour TWA, may be too high.
       References
ACG99  American Conference of Governmental Industrial Hygienists (ACGIH). Isooctyl alcohol. In: TLVs®
       and other occupational exposure values - 1999. [CD-ROM]. Cincinnati OH, USA: ACGIH®, Inc,
       1999.
ACG03a American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
       exposure values - 2003. Cincinnati OH, USA: ACGIH®, Inc, 2003: 74.
ACG03b American Conference of Governmental Industrial Hygienists (ACGIH). 2003 TLVs® and BEIs®
       based on the documentation of the Threshold Limit Values for chemical substances and physical
       agents & Biological Exposure Indices. Cincinnati OH, USA: ACGIH®, Inc, 2003: 36.
Arb02  Arbejdstilsynet. Grænseværdier for stoffer og materialer. Copenhagen, Denmark: Arbejdstilsynet,
       2002: 28 (At-vejledning C.0.1).
DFG02  Deutsche Forschungsgemeinschaft (DFG): Commission for the Investigation of Health Hazards of
       Chemical Compounds in the Work Area. List of MAK and BAT values 2002. Maximum
       concentrations and biological tolerance values at the workplace. Weinheim, FRG: Wiley-VCH, 2002;
       rep no 38.
DuP85  EI du Pont de Nemour and Company. Subchronic inhalation toxicity of isooctanol. Newark DE,
       USA: EI du Pont de Nemour and Company, Haskell Lab Toxicol Ind Med, 1985; Haskell Lab rep no
       378-84 (available from NTIS, Springfield VA, USA; order no: NTIS/OTS0570889).
EC03   European Commission: Directorate General of Employment and Social Affairs. Occupational
       exposure limits (OELs). http://europe.eu.int/comm/employment_social/h&s/areas/oels_en.htm.
HSE02  Health and Safety Executive (HSE). EH40/2002. Occupational Exposure Limits 2002. Sudbury
       (Suffolk), England: HSE Books, 2002: 20.
Nel51  Nelson N. Solvent toxicity with particular reference to certain octyl alcohols and dioxanes. Med Bull
       1951; 11: 226-39.
082-10 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>NLM01  US National Library of Medicine (NLM), ed. Isooctyl alcohol. In: Hazardous Substances Data Bank
       (HSDB) (last review date file: 7 August 1991; last revision date: 29 September 2000); http://
       toxnet.nlm.nih.gov.
Rho84  Rhodes C, Soames T, Stonard MD, et al. The absence of testicular atrophy and in vivo and in vitro
       effects on hepatocyte morphology and peroxisomal enzyme activities in male rats following the
       adminstration of several alkanols. Toxicol Lett 1984; 21: 103-9.
Sca73  Scala RA, Burtis EG. Acute toxicity of a homologous series of branched-chain primary alcohols. Am
       Ind Hyg Ass J 1973; 34: 493-9.
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; Ordinance AFS 2000:3.
SZW03  Ministerie van Sociale Zaken en Werkgelegenheid (SZW). Nationale MAC-lijst 2003. The Hague,
       The Netherlands: Sdu, Servicecentrum Uitgevers, 2003: 31.
TRG00  TRGS 900. Grenzwerte in der Luft am Arbeitsplatz; Technische Regeln für Gefahrstoffe. BArbBl
       2000; 2.
082-11 ‘Iso-octyl’ alcohol (mixed isomers)
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<pre>              Annex
Occupational exposure limits for ‘iso-octyl’ alcohol 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     50        270           8h                administrative                   SZW03
Employment
Germany
- AGS                                -         270                                                 S            TRG00
- DFG MAK-Kommission                 -         -                                                                DFG02
Great Britain
- HSE                                50        271           8h                OES                              HSE02
Sweden                               -         -                                                                Swe00
Denmark                              50        270           8h                                    S            Arb02
USA
- ACGIH                              50        -             8h                TLV                 S            ACG03b
- OSHA                               -         -                                                                ACG03a
- NIOSH                              50        270           10 h              REL                 S            ACG03a
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.
082-12        Health-based Reassessment of Administrative Occupational Exposure Limits
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