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<pre>      Valeraldehyde
      (CAS No: 110-62-3)
      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/066, The Hague, 3 March 2003
066-1
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<pre>      Preferred citation:
      Health Council of the Netherlands: Committee on Updating of Occupational
      Exposure Limits. Valeraldehyde; Health-based Reassessment of Administrative
      Occupational Exposure Limits. The Hague: Health Council of the Netherlands,
      2003; 2000/15OSH/066.
      all rights reserved
066-2
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of
      valeraldehyde 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 MA Maclaine Pont, M.Sc. (Wageningen University
      and Research Centre, Wageningen, the Netherlands).
           Literature was retrieved from the databases Medline, Toxline, and Chemical
      Abstracts, covering the periods 1966 to May 1999, 1981 to April 1999, and
      1937 to April 1999, respectively, and using the following key words:
      valeraldehyde, pentanal, pentaldehyde, hexanal, caproaldehyde, butanal,
      butyraldehyde, butylaldehyde, 110-62-3, 66-25-1, and 123-72-8. Data
      considered to be critical were evaluated by reviewing the original publications.
      The final literature search was carried out in May 1999.
           In September 2001, the President of the Health Council released a draft of
      the document for public review. The committee received no comments.
           An additional literature search in May 2002 did not result in information
      changing the committee's conclusions.
2     Identity
       name                     :    valeraldehyde
       synonyms                 :    amyl aldehyde; butyl formal; pentanal; n-pentanal;
                                     valeric aldehyde; valeral; n-valeraldehyde; valerianic aldehyd;
                                     valeric acid aldehyde; n-valeric aldehyde;
                                     valeryl aldehyde
       molecular formula        :    C5H10O
       structural formula       :    O=CH-CH2-CH2-CH2-CH3
       CAS number               :    110-62-3
      Data from How92.
066-3 Valeraldehyde
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<pre>3     Physical and chemical properties
       molecular weight            :  86.13
       boiling point               :  103oC
       melting point               :  -91.5oC
       flash point                 :  open cup: 12.2o C; closed cup: 6oC
       vapour pressure             :  at 20oC: 3.46 kPa
       solubility in water         :  slightly soluble
       Log Poctanol/water          :  1.31 (estimated)
       conversion factors          :  1 mg/m3 = 0.28 ppm
       (20oC, 101.3 kPa)              1 ppm = 3.59 mg/m3
      Data from ACG99, Möl93, Rou86, http://esc.syrres.com.
      Valeraldehyde is a colourless liquid with a strong, pungent odour. Because of
      its low flash point, it is a dangerous fire hazard (ACG99). Its vapour mixes well
      with air, forming explosive mixtures. Valeraldehyde can polymerise violently
      under the influence of inorganic acids and bases, ammonia, and amines. It reacts
      vigorously with oxidants (Che99). Odour thresholds of 0.10 and 0.36 mg/m3
      (0.028, 0.10 ppm) were reported (Amo83, Joh73)
4     Uses
      Valeraldehyde is used in flavouring compounds, in resin chemistry, and as a
      rubber accelerator (ACG99).
           Valeraldehyde occurs naturally in a large number of food products (Bec96,
      Mar94, Opd79).
5     Biotransformation and kinetics
      The committee did not find data on the biotransformation and kinetics of
      valeraldehyde.
           Apart from inhalation of valeraldehyde in occupational settings, exposure
      can also take place by inhaling the volatile compounds of wood and by
      ingestion. It can also be generated by lipid peroxidation processes in the liver
      (Bec96, Mar94, Opd79).
066-4 Health-based Recommended Occupational Exposure Limits
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<pre>6     Effects and mechanism of action
      Human data
      Tested at a concentration of 2% in petrolatum, valeraldehyde did not cause
      irritation in a 48-hour closed-patch test in (an unknown number of) human
      subjects or sensitisation in a maximisation test carried out on 25 volunteers
      (Opd79).
           The committee did not find other data on the effects of valeraldehyde in
      humans.
      Animal data
      Following application of 0.01 mL of undiluted aldehyde to the uncovered
      clipped abdomen of 5 albino rabbits, valeraldehyde scored an injury grade of 2
      (i.e., giving rise to ‘an average reaction equivalent to a trace of a capillary
      injection’) on a scale from 1 to 10 (Smy69; see also Smy49). In another
      (unpublished) study, undiluted compound was found moderately irritating after
      24-hour covered application to the intact or abraded skin of rabbits (Opd79). In
      guinea pigs, it was reported to be severely skin irritating (Fas63).
           When instilled into the eyes of rabbits, valeraldehyde scored an injury grade
      of 5 on a scale of 1 to 10, which was defined as producing an injury of up to 5.0
      points (out of a maximum of 20) 18 to 24 hours after instillation of 0.005 mL of
      undiluted test substance (0.02 mL gives over 5.0 points) (Smy69; see also
      Car46)*. According to unpublished information, it was severely irritating to the
      skin of rabbits (Fas63).
           The sensory irritation potential of inhaled valeraldehyde was investigated in
      B6C3F1 and Swiss-Webster mice. Groups of 3 or 4 mice were exposed in a
      head-only exposure chamber for 10 minutes. Sensory irritation was quantified
      by measuring respiratory rate depression during these exposures. Five
      concentrations of valeraldehyde were used to construct a
      concentration-response curve from which the RD50 value was determined. These
      RD50 values (the concentrations eliciting a 50 % decrease in respiratory rate)
      were 4284 and 4036 mg/m3 for B6C3F1 and Swiss-Webster mice, respectively
      (Ste84).
*     Grade 5 was also characterised as a ‘severe burn from 0.005 mL’ (Smy54).
066-5 Valeraldehyde
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<pre>      Rats could tolerate exposure to a concentrated, probably saturated* level of
      valeraldehyde without mortality occurring for a maximum of 15 minutes while a
      4-hour exposure to 14,400 mg/m3 (4000 ppm) caused mortality in 3/6 rats
      (Smy69). In other, unpublished studies, 3 rats exposed to approximately
      172,000 mg/m3 (48,000 ppm) all died within 1.2 hours while 6/6 rats survived a
      6-hour exposure to approximately 5000 mg/m3 (1400 ppm (Fas63). In a study
      on the inhalation toxicity of a series of aldehydes, groups of 50 mice, 20 guinea
      pigs, and 5 rabbits were exposed to a concentration of 2359 mg/m3
      valeraldehyde aerosol. The animals were exposed for periods up to 10 hours, or
      until death intervened. Exposure to the aldehydes caused an initial increase in
      activity in all of the animals used. The animals blinked, closed their eyes, and
      rubbed their faces with their paws. After the initial irritation, the animals settled
      down and respiration became slow and deep. This was observed until the
      animals convulsed just prior to death. Of the animals exposed to valeraldehyde
      aerosol, 2 mice died during the period of exposure, and 5 guinea pigs and 2
      mice died on subsequent days. No rabbits died during or after exposure. At
      autopsy, all animals were observed to have expanded, oedematous, and
      haemorrhagic lungs. Fluid was observed in the pleural cavity. The animals
      showed consolidated lungs, distended alveoli, and ruptured alveolar septa. The
      livers appeared enlarged and fluid was observed in the peritoneal cavity. Most
      of the lung sections showed dilated and engorged blood vessels (Sal60).
          The dermal LD50 for male rabbits (albino New Zealand; n=4/group) was
      4857 mg/kg bw (exposure time: 24 hours; observation time: 14 days) (Smy69;
      see also Smy62). For guinea pigs, a dermal LD50 of >20,000 mg/kg bw has been
      reported (Fas63).
          The oral LD50 determined in non-fasted male rats (Carworth-Wistar;
      n=5/group) was 4580 mg/kg bw (observation time: 14 days) (Smy69; see also
      Smy62). Oral LD50 values for rats and mice of 3200-6400 and 6400-12,800
      mg/kg bw, respectively, were reported (Fas63).
      No data on repeated-dose toxicity, potential carcinogenicity, or reproduction
      toxicity of valeraldehyde were found.
*     Theoretically, the concentration in saturated vapour (at 20oC) can amount to 35,000 ppm; calculated from:
      (vapour pressure in Pa/105 Pa) x 106 ppm.
066-6 Health-based Recommended Occupational Exposure Limits
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<pre>      Mutagenicity and genotoxicity
      Valeraldehyde was negative in:
         a bacterial mutation assay using S. typhimurium strains TA98, TA100,
         TA1535, and TA1537, with and without rat liver metabolic activation
         (Flo80)
         a sister chromatid exchange (SCE) assay in human lymphocytes without
         metabolic activation (Obe79)
         a DNA repair test in B. subtilis (rec-assay), with and without metabolic
         activation (Mat89)
         a DNA-repair test (the umu-test) using S. typhimurium strain TA1535, with
         and without rat liver metabolic activation (Ono91)
         a test on the induction of DNA double and single strand breaks in
         bacteriophage PM2 DNA (Bec96)
         an unscheduled DNA synthesis (UDS) assay in human hepatocytes (Mar94).
      Valeraldehyde was positive in:
         a forward mutation assay using V79 Chinese hamster lung cells in the
         absence of a metabolic system (Bra89).
         a test on the induction of DNA double and single strand breaks in
         bacteriophage PM2 DNA in the presence of CuCl2 (Bec96)
         a test on the induction of DNA single strand breaks in Chinese hamster
         ovary (CHO) cells (Mar84)
         an unscheduled DNA synthesis (UDS) assay in rat hepatocytes (Mar94).
7     Existing guidelines
      The current administrative occupational exposure limit (MAC) in the
      Netherlands for valeraldehyde is 175 mg/m3, 8-hour TWA.
         Existing occupational exposure limits for valeraldehyde in some European
      countries and in the USA are summarised in the annex.
8     Assessment of health hazard
      The committee did not find human data on the toxicity of valeraldehyde.
         Valeraldehyde was irritating to eyes of rabbits and to the skin of rabbits and
      guinea pigs (Fas63, Opd79, Smy69). Inhalation exposure for 10 minutes
      induced sensory irritation and a decrease of the respiratory rate in mice. The
066-7 Valeraldehyde
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<pre>       RD50 was approximately 4150 mg/m3 (Ste84). The acute toxicity after oral or
       dermal administration was found to be low in all tested species (Fas63, Smy69).
       The acute inhalation toxicity of a series of aldehydes were studied by Salem and
       Cullumbine (Sal60). Valeraldehyde and iso-valeraldehyde were by far the least
       toxic substances: only a few of the experimental animals died after being
       exposed for 10 hours to a concentration of 2359 mg/m3. At autopsy, the animals
       were observed to have severe lung damage.
            No data on repeated-dose toxicity, carcinogenicity, or reproduction toxicity
       of valeraldehyde have been found.
       The committee considers the toxicological database on valeraldehyde 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-level.
       References
ACG99  American Conference of Governmental Industrial Hygienists (ACGIH). n-Valeraldehyde. In: TLVs®
       and other occupational exposure values - 1999. [CD-ROM]. Cincinnati OH, USA: ACGIH, 1999.
ACG02a American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
       exposure values - 2002. Cincinnati OH, USA: ACGIH®, Inc, 2002: 134.
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: 59.
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: 51 (At-vejledning C.0.1).
Bec96  Becker TW, Krieger G, Witte I. DNA single and double strand breaks induced by aliphatic and
       aromatic aldehydes in combination with copper(II). Free Rad Res 1996; 24: 325-32.
Bra89  Brambilla G, Cajelli E, Canonero R. Mutagenicity in V79 Chinese hamster cells of n-alkanals
       produced by lipid peroxidation. Mutagenesis 1989; 4: 277-9
Car46  Carpenter CP, Smyth HF Jr. Chemical burns of the rabbit cornea. Am J Ophthalmol 1946; 29:
       1363-72.
066-8  Health-based Recommended Occupational Exposure Limits
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<pre>Che99 Chemiekaarten: Gegevens voor het veilig werken met chemicaliën/ [ed. by]
      Samenwerkingsverband-Chemiekaarten (TNO Arbeid, VNCI) - 15e ed. 2000. - The Hague, the
      Netherlands: Ten Hagen & Stam, 1999.
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; rep no 38.
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.
Fas63 Fassett DW. Aldehydes and acetals. In: Fassett DW, Irish DD, eds. Toxicology. 2nd ed. New York,
      USA: Interscience Publishers, 1963: 1959-89 (Patty FA, ed. Industrial hygiene and toxicology; Vol
      II).
Flo80 Florin I, Rutberg L, Curvall M, et al. Screening of tobacco smoke constituents for mutagenicity
      using the Ames test. Toxicology 1980; 15: 219-32.
How92 Howard PH, Neil M, ed. Dictionary of chemical names and synonyms. Chelsea MA, USA: Lewis
      Publishers, 1992.
HSE02 Health and Safety Executive (HSE). EH40/2002. Occupational exposure limits 2002. Sudbury
      (Suffolk), England: HSE Books, 2002.
Joh73 Johansson B, Drake B, Berggren B, et al. Detection thresholds: effect of stimulus presentation order
      and addition of blanks. I. Odor of pentanal and hexanol. Lebensm-Wiss Technol 1973; 6: 115-22.
Mar84 Marinari UM, Ferro M, Sciaba L, et al. DNA-damaging activity of biotic and xenobiotic aldehydes
      in Chinese Hamster Ovary cells. Cell Biochem Function 1984; 2: 243-8.
Mar94 Martelli A, Canonero R, Cavanna M, et al. Cytotoxic and genotoxic effects of five n-alkanals in
      primary cultures of rat and human hepatocytes. Mutat Res 1994; 323: 121-6.
Mat89 Matsui S, Yamamoto R, Yamada H. The Bacillus subtilis/microsome rec-assay for the detection of
      DNA damaging substances which may occur in chlorinated and ozonated waters. Water Sci Technol
      1989; 21: 875-87.
Möl93 Möller W, Schulz P, Redeker T. Verfahren zur Abschätzung des Flammpunkts und der unteren
      Explosionsgrenze. Phys Tech Bundesamst 1993; PTB-Ber W-55.
Obe79 Obe G, Beek B. Mutagenic activity of aldehydes. Drug Alcohol Depend 1979; 4: 91-4.
Ono91 Ono Y, Somiya I, Kawamura M. The evaluation of genotoxicity using DNA repairing test for
      chemicals produced in chlorination and ozonation processes. Water Sci Technol 1991; 23: 329-38.
Opd79 Opdyke DLJ. Monographs of fragrance raw materials. n-Valeraldehyde. Food Cosmet Toxicol 1979;
      17 (suppl): 919-21.
Rou86 Rousselin X, Falcy M. Le nez, les produits chimiques et la sécurité. Cah Notes Doc 1986; 124:
      331-44.
Sal60 Salem H, Cullumbine H. Inhalation toxicities of some aldehydes. Toxicol Appl Pharmacol 1960; 2:
      183-7.
066-9 Valeraldehyde
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<pre>Smy49  Smyth HF Jr, Carpenter CP, Weil CS, et al. Range-finding toxicity data, List III. J Ind Hyg Toxicol
       1949; 31: 60-2.
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.
Smy62  Smyth HF Jr, Carpenter CP, Weil CS, et al. Range-finding toxicity data: List VI. Am Ind Hyg Assoc
       J 1962; 23: 95-107.
Smy69  Smyth HF Jr, Carpenter CP, Weil CS, et al. Range-finding toxicity data: List VII. Am Ind Hyg
       Assoc J 1969; 30: 470-6.
Ste84  Steinhagen WH, Barrow CS. Sensory irritation structure-activity study of inhaled aldehydes in
       B6C3F1 and Swiss-Webster mice. Toxicol Appl Pharmacol 1984; 72: 495-503.
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.
SZW02  Ministerie van Sociale Zaken en Werkgelegenheid (SZW). Nationale MAC-lijst 2002. The Hague,
       the Netherlands: Sdu, Servicecentrum Uitgevers, 2002: 43.
TRG00  TRGS 900. Grenzwerte in der Luft am Arbeitsplatz; Technisch Regeln für Gefahrstoffe. BArbBl
       2000; 2.
066-10 Health-based Recommended Occupational Exposure Limits
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<pre>             Annex
Occupational exposure limits for valeraldehyde 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          175             8h                administrative            SZW02
Employment
Germany
- AGS                                   -           175             8h                                          TRG00
- DFG MAK-Kommission                    -           -                                                           DFG02
Great Britain
- HSE                                   -           -                                                           HSE02
Sweden                                  -           -                                                           Swe00
Denmark                                  50         175             8h                                          Arb02
USA
- ACGIH                                 50          -               8h                TLV                       ACG02b
- OSHA                                  -           -                                                           ACG02a
- NIOSH                                 50          175             10 h              REL                       ACG02a
European Union
- SCOEL                                 -           -                                                           EC02
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.
066-11       Valeraldehyde
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<pre>066-12 Health-based Recommended Occupational Exposure Limits</pre>

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