<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>Prop-2-yn-1-ol
(CAS No: 107-19-7)
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/137 The Hague, November 9, 2004
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. Prop-2-yn-1-ol; Health-based Reassessment of Administrative
Occupational Exposure Limits. The Hague: Health Council of the Netherlands,
2004; 2000/15OSH/137.
all rights reserved
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of prop-2-yn-
      1-ol, referred to as propynol in this document, 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.,
      S Bosman-Hoefakker, Ph.D., and H Stouten, M.Sc. (TNO Nutrition and Food
      Research, Zeist, the Netherlands).
           The evaluation of the toxicity of propynol 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, in April 1997, literature was searched in the on-
      line databases Medline, Toxline, and Chemical Abstracts covering the period
      1966 to May 1997, 1965 to March 1997, and 1972 to April 1997, respectively,
      and using the following key words: propargyl alcohol, propynyl alcohol, ethynyl
      carbinol, propynol, and 107-19-7.
           In February 1999, the President of the Health Council released a draft of the
      document for public review. Comments were received by the following
      individuals and organisations: A Aalto (Ministery of Social Affairs and Health,
      Tampere, Finland) and M Beth-Hübner, Ph.D. (BG-Chemie, Heidelberg, FRG).
      These comments were taken into account in deciding on the final version of the
      document.
           An additional literature search in Toxline and Medline in July 2004 did not
      result in information changing the committee’s conclusions.
2     Identity
      name                       :   prop-2-yn-1-ol
      synonyms                   :   propargyl alcohol, 2-propyn-1-ol, acetylene carbinol, ethenyl
                                     methanol, ethynyl carbinol, propyn-(2)-ol, 1-propyn-3-ol,
                                     propiolic alcohol
      molecular formula          :   C3H4O
      structural formula         :   HC≡C-CH2OH
      CAS number                 :   107-19-7
137-3 Prop-2-yn-1-ol
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<pre>3     Physical and chemical properties
      molecular weight           :   56.06
      boiling point              :   114-115oC
      melting point              :   -48 to –52oC
      flash point                :   36oC (open cup)
      vapour pressure            :   at 20ºC: 1.5 kPa
      solubility in water        :   soluble
      log Poctanol/water         :   -0.38 (experimental); -0.47 (estimated)
      conversion factors         :   (20oC, 101.3 kPa): 1 ppm = 2.3 mg/m3
                                                        1 mg/m3 = 0.43 ppm
      Data from BCG00, Lin94, NLM04, http://www.syrres.com/esc/est_kowdemo.htm.
      Propynol is a moderately volatile, clear to slightly straw-coloured liquid with a
      mild geranium-like odour (ACG91).
4     Uses
      Propynol has been used to prevent the hydrogen embrittlement of steel. It has
      also been employed as a corrosion inhibitor, a solvent for cellulose acetate, a
      stabiliser for chlorinated hydrocarbon formulations, a herbicide, a polishing
      agent in galvanotechnics, a soil fumigant, and as a chemical intermediate
      (ACG91, BGC00, Lin94).
5     Biotransformation and kinetics
      The committee did not find data on biotransformation and kinetics in humans or
      on absorption following inhalation or oral exposure. From dermal lethality data
      on rabbits (see Table 1), it can be seen that propynol is readily absorbed through
      the skin (Ols57).
      Banijamali et al. studied the metabolism of propynol in rats and mice by
      identifying urinary metabolites following oral administration of radiolabelled
      [1,2,3-13C, 2,3-14C]propynol. In male Sprague-Dawley rats, 56% of the
      radioactivity administered was excreted in the urine within 96 hours. The highest
      concentration was observed in the first 24-hour urine. The main metabolites were
      2-propynoic acid, 3,3-bis[(2-(acetylamino)-2-carboxyethyl)thio]-1-propanol,
      3-(carboxymethylthio)-2-propenoic acid, and 3-[[2-(acetylamino)-2-
137-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      carboxyethyl]sulphinyl]-3-[[2-(acetylamino)-2-carboxyethyl]thio]-1-propanol
      accounting for 27, 20, 20, and 15%, respectively, of the total radioactivity
      excreted in the urine during the first 24 hours post-administration (see Figure 1,
      Annex I). From the results, Banijamali et al. suggested that the metabolism of
      propynol in rats involves oxidation into 2-propynoic acid and multiple
      glutathione additions to the carbon-carbon triple bond yielding numerous
      metabolites (see Figure 2, Annex III for metabolism scheme) (Ban99). In mice,
      about 60% of the radiolabel administered was excreted in the urine by 96 hours.
      The highest concentration was observed in the first 24-hour urine. The main
      metabolites were (E + Z)-3-[(2-amino-2-carboxyethyl)thio]-2-propenoic acid,
      3-[[2-(acetylamino)-2-carboxyethyl]thio]-3-[[2-(amino)-2-carboxyethyl]thio]-1-
      propanol, 3,3-bis[(2-(amino)-2-carboxyethyl)thio]-1-propanol, and 3-[(2-
      formylamino-2-carboxyethyl)thio]-2-propenoic acid accounting for 41, 17, 15,
      and 13%, respectively, of the total radioactivity excreted in the urine during the
      first 24 hours post-administration (see Annex II). The data suggested that
      metabolism of propynol in mice involves glucuronide conjugation to form 2-
      propyn-1-ol glucuronide as well as oxidation into 2-propynal which undergoes
      either multiple glutathione additions or oxidation into 2-propynoic acid (only ca.
      2%) (see scheme in Annex III). Comparison of rat and mice data indicate
      quantitative and qualitative differences in formation of glucuronide conjugates
      and of 2-propynoic acid and metabolites derived from glutathione (see Annex
      III) (Ban00).
           DeMaster et al. stated that the oxidative metabolic conversion of propynol
      into its aldehyde is not likely to occur via alcohol dehydrogenase since propynol
      appeared to be a poor substrate for this enzyme. Based on in vitro experiments,
      they hypothesised that catalysis by liver catalase via a hydrogen peroxide-
      supported reaction could be an alternative oxidative pathway, but did not exclude
      other possible pathways such as oxidation by hydroxyl radicals and microsomal
      cytochrome P450 2E1 (DeM94). From in vitro experiments with rat hepatocytes,
      Moridani et al. concluded that propynol is preferentially oxidised by cytochrome
      P450 2E1 rather than by catalyse or alcohol dehydrogenase to form propynal that
      caused hepatocyte lysis as a result of glutathione depletion and lipid peroxidation
      (Mor01).
137-5 Prop-2-yn-1-ol
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<pre>6     Effects and mechanism of action
      Human data
      The committee did not find data on adverse effects in humans following
      exposure to propynol.
      Animal data
      Irritation and sensitisation
      When instilled into the conjunctival sac of the rabbit eye, undiluted material
      caused marked pain, irritation, and permanent corneal injury. A 10% solution
      caused slight pain and irritation that cleared up. A 1% solution was not irritating
      (BGC00, Tor64).
           Undiluted propynol caused hyperaemia, oedema, and superficial necrosis
      after topical application to rabbits. A 10% aqueous solution produced mild
      irritation, and a 1% aqueous solution had no effect (BGC00, Tor64).
           Propynol was not a skin sensitiser to guinea pigs (ACG91, BGC00, Lin94).
      Acute and subacute exposure
      Acute lethal toxicity data on propynol are summarised in Table 1.
      Table 1 Acute lethal toxicity data for propynol.
      species       route                    LC50/LD50       reference
      rat           inhalation (1 h)         2392-2760 mg/m3 Ver77
      rat           inhalation (2 h)         1955 mg/m3      Ken91
      rat           inhalation (2 h)         2000 mg/m3      BGC00
      mouse         inhalation (2 h)         2000 mg/m3      BGC00
      rabbit        dermal                   16-88 mg/kg bw  BCG00, Ols57, Ver77
      rat           oral                     20-110 mg/kg bw ACG91, BGC00, Ken91, Lin94, Ver77
      mouse         oral                     50 mg/kg bw     ACG91, BGC00, Lin94
      guinea pig    oral                     39-97 mg/kg bw  ACG91, BGC00, Lin94
      rabbit        oral                     19-39 mg/kg bw  BGC00
      cat           oral                     10-19 mg/kg bw  BGC00
      mouse         intraperitoneal          44 mg/kg bw     BGC00
137-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      After oral and intraperitoneal administration, animals displayed excitation,
      accelerated breathing, lying on the side, apathy, atonia, diarrhoea, tonic spasms,
      paresis, and/or proteinuria. At autopsy, liver and kidney damage and
      haemorrhages in several organs were observed, irrespective of the species
      examined and the route of administration (BGC00).
           Exposure to 790 to 4020 mg/m3 (340 to 1730 ppm), for 6 hours, killed all
      animals (species not indicated) during exposure or within 48 hours post-exposure
      (depending on exposure level), while concentrations of 380 mg/m3 (160 ppm)
      caused no deaths (Eas64).
           In a preliminary study, 10 mice, 10 rats, 4 guinea-pigs, 2 rabbits, and 1 cat, all
      exposed for 1 hour to approximately 1300 ppm (ca. 2290 mg/m3) propynol,
      showed slight irritation of the mucous membranes. Apathy, vomiting, and lying
      on the side were seen in the cat, which died 2 days after exposure. Clinical
      chemistry studies revealed functional disturbances in the liver and kidneys of the
      cat and the rabbits. In this study, 3/10 mice and 1/10 rats died after 1-3 days,
      whereas all guinea pigs and the rabbits survived (BGC00, review, original report
      unpublished). After exposure of 10 rats to 1490 ppm propynol vapour (ca. 3430
      mg/m3) for 1 hour, all animals died by day 2-3. The animals displayed languid
      behaviour, prostration, squinted eyes, and increased secretory responses during
      exposure. At necropsy, there were no lesions obviously related to the treatment
      (Ter89).
           Exposure to an atmosphere saturated with propynol (at 20oC) caused
      mortality in 6/12 and 6/6 rats after exposure for 3 and 10 minutes, respectively.
      Most of the animals died a few hours after the beginning of the study, although
      some survived for 1-2 days. Symptoms of acute toxicity included flight
      behaviour at the beginning of exposure, irritation of the mucous membranes,
      marked pallor of the ears and paws, and shortness of breath. Macroscopic
      examination revealed isolated bleeding in the gastro-intestinal region (BGC00,
      review, original report unpublished).
           Dermal application of doses of 1894 mg/kg bw for >3 minutes was lethal to
      all 5 rats while no animals died when exposed for 1 minute. Symptoms of
      toxicity included apathy and irregular breathing. In animals exposed for 10
      minutes, necrosis and bleeding were seen at the application site, as well as
      bleeding in the thymus and jejunum (BGC00, review, original report
      unpublished).
           Subcutaneous injections of propynol doses of 237 or 474 mg/kg bw caused
      the death of rabbits within 2.5 hours. Another rabbit survived a subcutaneous
      dose of 47 mg/kg bw but died within 6.5 hours following a dose of 94 mg/kg bw
      given the next day (BGC00).
137-7 Prop-2-yn-1-ol
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<pre>      In a subacute inhalation toxicity study, exposure to ca. 1300 ppm propynol (ca.
      2990 mg/m3), 1 hour/day, for 5 days caused mortality in 4/10 rats, 7/10 mice, 0/4
      guinea pigs, 1/2 rabbits, and 1/1 cats, mostly before the end of the experiment.
      Animals showed irritation of the mucous membranes. The deceased animals
      showed liver damage. In the surviving animals, body weight gain was normal,
      and examination of the blood, urine, liver, and kidneys revealed no adverse
      effects (BGC00, review, original report unpublished).
          After exposure to 88 ppm (ca. 200 mg/m3) propynol (purity: 99%) for periods
      of 4-14 days, mice displayed lesions of respiratory and olfactory epithelium.
      These lesions were of maximum severity after 4 days of exposure; severity after
      14 days of exposure was similar. Trachea and lungs were not affected. Exposure
      to 25 ppm (58 mg/m3) did not induce such respiratory tract effects. Systemic
      toxicity was not addressed in the study report (Zis95).
          In a 14-day dose range-finding study for a subsequent 90-day inhalation
      study, exposure of rats (n=5/sex/group) to propynol (purity: 99.4%)
      concentrations of 0, 10, 50, and 200 ppm (0, 23, 114, and 460 mg/m3),
      6 hours/day, 5 days/week, for 2 weeks, caused clinical signs including apathy,
      red-coloured nasal secretions, and irregular breathing at 200 ppm while no
      clinical signs were seen in the animals of the two lower concentrations groups.
      One female animal of the 200-ppm group died. Decreased body weight gain was
      found at 50 in males and at 200 ppm in males and females. Changes in blood
      chemistry parameters associated with liver lesions (increased alanine
      aminotransferase (ALAT) and alkaline phosphatase (ALP) serum activities,
      increased thromboplastin times, increased bilirubin serum levels, decreased total
      protein, triglyceride and cholesterol serum levels) were seen at 50 and 200 ppm.
      Relative liver and kidney organ weights were significantly increased at 200 ppm
      and at 50 and 200 ppm, respectively. In the liver, hepatocyte hypertrophy and
      single cell necrosis were seen at 200 ppm and, due to an irritating effect, changes
      of the respiratory epithelial cells of the nasal mucosa were observed in the form
      of inflammatory processes (at 200 ppm) as well as metaplastic changes (at 50
      and 200 ppm) (confidential study report cited in BGC00; the original study
      report was available to the committee). From these results, it can be concluded
      that the NOAEL in rats for 14-day inhalation exposure to propynol is 10 ppm (23
      mg/m3).
          Rats orally exposed to doses of propynol (purity: 97%) of 0.1-10 mg/kg
      bw/day for 14 days did not show effects on body weight gain, organ weights, and
      hepatic microsomal enzyme activities, as well as several histological and
      haematological parameters examined (Kom89).
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<pre>          Groups of 10 Bor:WISW (SPF:Cpb) rats/sex received daily oral (gavage)
      doses of propynol (purity: 99%) (vehicle: water) of 0, 5, 15, or 45 mg/kg bw for
      4 weeks. The study was performed in accordance with OECD guideline 407
      (‘Repeated dose 28-day oral toxicity study in rodents’). Significant and dose-
      dependent increases in relative liver and kidney weights were seen in all treated
      groups. At 15 and 45 mg/kg bw, significantly decreased red blood cell counts and
      haemoglobin and haematocrit levels were observed in both sexes. Reticulocyte
      counts were increased in males. At 45 mg/kg bw, mean corpuscular volume
      (MCV) and mean corpuscular haemoglobin (MCH) were decreased in males.
      The authors concluded these changes to be indicative of hypochromic anaemia.
      No changes were observed in leukocyte numbers, thrombocyte numbers, and
      differential counts. In addition to the haematological and organ weight effects, a
      dose of 45 mg/kg retarded body weight gain and increased ALAT, ALP, and
      glutamate dehydrogenase (GLDH) activities in male rats. Furthermore, plasma
      cholinesterase activity was significantly decreased (by 60%) in females and
      plasma creatinine levels were significantly decreased in both sexes. Histological
      changes in the liver were noted in a dose-dependent manner in animals treated
      with 15 and 45 mg/kg propynol. No changes were noted at microscopic
      examination of the kidneys and in urinalysis (Mih84). In a second study
      described in the same report, the suggested direct action of propynol on
      microsomal liver enzymes was addressed in a 4-week gavage study in
      Bor:WISW (SPF:Cpb) rats. Fifteen animals/sex were daily administered 60
      mg/kg bw propynol. Because of the occurrence of marked symptoms of toxicity
      (apathy, atonia, bloody salivation) and the death of one of the 15 treated male
      rats, the daily dose was lowered to 50 mg/kg bw from day 4 to 21. From day 22
      to 28, animals were given 60 mg/kg bw propynol again. After 28 days, the
      treated animals displayed decreased body weight, increased relative liver and
      kidney weights, and haematological changes comparable to the first experiment.
      No effects were noted in urinalysis. Clinical chemistry analysis indicated
      increased plasma activities of ALAT, GLDH, ALP, and γ-glutamyl transferase in
      both sexes and of aspartate aminotransferase in males. Plasma cholinesterase
      activity was decreased in females. Creatinine levels were decreased in both
      sexes, whereas urea nitrogen levels were increased in females. In liver tissue, the
      activities of N-demethylase (both sexes), O-demethylase (males), and
      cytochrome P450 (both sexes) were significantly decreased. Triglyceride levels
      were not affected in liver tissue. In addition, macroscopic changes were noted in
      the liver of males, whereas microscopic changes (e.g., focal necrosis, increased
      mitotic rates in liver parenchyma, and unusual mitotic figures) were noted in all
      treated animals (Mih84). Based on these results, Mihail et al. concluded that
137-9 Prop-2-yn-1-ol
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<pre>       propynol has a specific effect on liver mixed function oxidases and induces liver
       cell damage. Other effects were on red blood cells and the kidneys. Because the
       changes in relative liver and kidney weights at 5 mg/kg bw were not
       accompanied by clinical chemistry or histological changes, the authors
       considered this dose level to be a ‘limit dose’. However, the committee
       concludes that the effects noted at 5 mg/kg bw are toxicologically significant,
       since the organ weight effects were dose-dependent and statistically significantly
       increased. Moreover, at higher dose levels, they were accompanied by changes in
       clinical chemistry and histology. Therefore, the effects noted at the lowest dose
       level were judged to be a precursor stage of the effects noted at the higher dose
       levels. In conclusion, the committee considers 5 mg/kg bw dose level to be a
       LOAEL for 4-week oral exposure to propynol.
           In rabbits, no mortality occurred following administration of propynol of 9.7
       mg/kg bw/day, 5 days/week, for 4 weeks, while all animals died within 9-23 days
       at doses of 18.9 mg/kg bw. Examination of the dead animals showed dilation of
       the peripheral vessels, signs of lung congestion and oedema, haemorrhages in the
       gastrointestinal tract and heart, and slight histological changes in the liver and the
       kidneys (BCG00; unpublished study not available to the committee).
           Two cats given oral doses of 9.7 mg/kg bw, 5 days/week, died on treatment
       16 and 17, animals showing liver and kidney damage upon post-mortem
       examinations. Toxic signs and effects included vomiting, loss of appetite, weight
       loss, and considerably disturbed liver function (in one cat) (BGC00).
       Subchronic exposure
       Propynol vapour was tested for its inhalation toxicity in Wistar rats in a 90-day
       study performed in accordance with OECD guideline 413 (‘Subchronic
       inhalation toxicity; 90-day study’). Ten animals/sex/group were exposed to
       concentrations of propynol (purity: 99.4%) of 0, 1, 5, or 25 ppm (0, 2.3, 11.5, or
       57.5 mg/m3, respectively; 6 hours/day, 5 days/week, total 65 ‘whole body’
       exposures). Parameters examined included clinical signs, body weight,
       ophthalmology, blood chemistry, haematology, and macroscopic and
       microscopic evaluation. At 25 ppm, body weight gain was retarded in males
       (during the first 2 weeks of the exposure period), relative kidney and liver
       weights were increased in males and females, and serum cholinesterase activity
       was decreased in females. No other abnormalities were observed upon
       macroscopic and microscopic evaluations. At 1 and 5 ppm, no treatment-related
       effects were noted. The NOAEL for 90-day inhalation toxicity of propynol in
       rats was concluded to be 5 ppm (11.5 mg/m3) (BGC92, BGC00).
137-10 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>           Rats (n=12/sex/group) that inhaled 80 ppm (184 mg/m3) propynol, 7
       hours/day, 5 days/week, for 3 months, initially appeared to have eye irritation
       and to be lethargic. Relative liver weights in males and relative liver and kidney
       weights in females were increased by 18%, 43%, and 17%, respectively. Other
       organ weights appeared normal. Histological examination showed hepatic and
       renal degeneration. There was a statistically significant elevation of white blood
       cell counts with no change in red blood cells (counts, haemoglobin, haematocrit).
       In females, lymphocyte counts were significantly increased, whereas differential
       counts in males were normal. Terminal serum alkaline phosphatase and urea
       nitrogen values were normal, but ALAT values were increased. Bone marrow
       smears were considered normal (Tor64, only limited data description).
           In a dermal study, propynol was applied to the abraded or intact skin of
       young adult rabbits at daily doses of 1 or 3 mg/kg bw/day over a 90-day period,
       or 10 mg/kg bw/day for day 1-62 and subsequently 20 mg/kg bw/day for day
       63-90. No systemic effects (including body weight gain, haematology, and
       histology) were noted (Git65).
           Male and female Crl:CD(SD)BR rats (n=30/sex/group) were dosed orally
       (gavage) with 0, 5, 15 or 50 mg/kg bw of propynol (purity: >99%) (at 10 mL/kg
       in deionised water) daily for 13 weeks. The first 10 rats of each group were
       sacrificed on days 28-29 after dosing and the remaining rats were sacrificed on
       days 91 or 92 after dosing. Parameters examined included clinical signs, body
       and organ weight changes, food consumption, ophthalmology, haematology,
       blood chemistry and histological evaluations. Treatment-related mortality was
       reported for 4/30 males in the high-dose group. The most prevalent clinical sign
       was salivation, occurring mainly at 50 mg/kg bw. Body weights were
       significantly lower in the high-dose animals. Haematological changes observed
       in the high-dose animals comprised decreased haemoglobin, MCV (also at 15
       mg/kg bw), MCH, and mean corpuscular haemoglobin concentration (MCHC)
       values. Enzyme changes characteristic of liver damage were seen in the mid- and
       high-dose animals. These changes included significantly increased ALAT,
       ASAT, LDH, and ALP serum activities. Moreover, decreased glucose, sodium,
       total cholesterol, total protein, albumin, globulin, and creatinine serum levels
       were seen, whereas inorganic phosphate and total bilirubin serum levels were
       significantly higher. The haematological and blood chemistry changes were
       considered to be treatment-related. Absolute and relative liver and kidney
       weights were significantly increased in males and/or females at 15 and 50 mg/kg
       bw/day. At 5 mg/kg bw, mean absolute and relative liver weights were higher
       compared to controls, but statistical significance was not reached. Macroscopic
       findings were confined to the liver (15 and 50 mg/kg bw) and the stomach (50
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<pre>       mg/kg bw). Hepatocytic megalocytosis with a less prominent proliferation of the
       bile ducts and cytoplasmic vacuolation of hepatocytes was observed in the
       majority of rats in the mid- and high-dose groups. In the low-dose group,
       megalocytosis was seen only in one rat treated for 3 months. Karyomegaly of
       renal tubular epithelial cells was reported to occur in a dose-response fashion in
       the mid- and high-dose groups, but not in the low-dose group. Treatment-related
       effects at 15 mg/kg bw included increased liver weights in both genders,
       increased kidney weights in females, and megalocytosis of the liver after 4 and
       13 weeks of dosing. The daily oral administration of 5 mg/kg bw/day of
       propynol produced no apparent treatment-related effects and hence this dose
       level was considered a NOAEL for subchronic oral exposure to propynol
       (Mar88).
       Chronic toxicity and carcinogenicity
       The committee did not find data from chronic toxicity, including carcinogenicity,
       studies on propynol.
       Mutagenicity and genotoxicity
       Propynol (tested at 4-2500 µg/plate) was negative in mutagenicity tests in S.
       typhimurium strains TA97, TA98, TA100, TA102, TA1535, TA1537, and
       TA1538 with and without metabolic activation. At high concentrations
       (>500 µg/plate), the product was cytotoxic. Propynol was weakly mutagenic to
       one unusual strain of S. typhimurium, D3052 (BGC00, Bla94, Lin94).
           Propynol induced chromosomal aberrations in CHO cells in vitro when tested
       with and without metabolic activation (Bla94).
           In vivo, propynol (purity: 97%) did not induce an increase in micronuclei in
       bone-marrow cells of male and female C57BL mice given oral (gavage) doses of
       24, 48, and 72 mg/kg bw for 2 days. The high dose caused mortality preventing
       evaluation of the bone marrow for micronuclei (Bla94). Similarly, negative
       results were obtained in male and female NMRI mice given single oral (gavage)
       doses of 70 mg/kg bw (purity: 99.4%). In preceding experiments, this dose was
       found to be the maximum dose tolerated (BCG00).
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<pre>       Reproduction toxicity
       The committee did not find data from reproduction or developmental toxicity
       studies on propynol.
7      Existing guidelines
       The current administrative occupational exposure limit (MAC) for propynol in
       the Netherlands is 2 mg/m3 (1 ppm), 8-hour TWA, with a skin notation.
           Existing occupational exposure limits for propynol in some European
       countries and in the USA are summarised in Annex IV.
8      Assessment of health hazard
       The committee did not find data on the biotransformation and kinetics of
       propynol following inhalation or dermal exposure. Following oral administration
       of radiolabelled compound to rats and mice, 56-60% of the radiolabel
       administered was excreted in the urine within 96 hours. Analysis of the urinary
       metabolites indicated quantitative and qualitative differences in their formation
       between rats and mice. In rats, metabolism might involve oxidation into 2-
       propynoic acid and multiple glutathione additions to the carbon-carbon triple
       bond yielding numerous metabolites. In mice, glucuronide conjugation to form
       2-propyn-1-ol glucuronide as well as oxidation into 2-propynal which undergoes
       either multiple glutathione additions or oxidation into 2-propynoic acid (only ca.
       2%) might occur. In vitro experiments suggested metabolic activation by
       cytochrome P450 2E1 rather than catalase or alcohol dehydrogenase.
           Propynol has a dose-dependent irritant to corrosive effect on the skin, eyes,
       and respiratory tract of animals. It has no skin-sensitising properties. Based on
       lethal toxicity data, the committee considers propynol as toxic following
       inhalation, dermal, and oral exposure.
           Subchronic (13-week) exposure of animals to propynol by inhalation to 25
       ppm (57.5 mg/m3) and 80 ppm (184 mg/m3) or by gavage to 15-50 mg/kg bw/day
       caused haemotological changes and liver and kidney damage. Irritation was
       observed after inhalation exposure but was not addressed in oral studies.
       Haemorrhages occurred in several organs, irrespective of the route of
       administration. Considerable mortality was observed in several species after
       intermittent exposure to 100 ppm (230 mg/m3) for 75 days. Dermal application
       of propynol to the abraded or intact skin of young adult rabbits at daily doses of 1
137-13 Prop-2-yn-1-ol
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<pre>       or 3 mg/kg bw/day over a 90-day period, or 10 mg/kg bw/day on day 1 to 62 and
       subsequently 20 mg/kg bw/day on day 63 to 90, did not induce systemic toxicity.
           An NOAEL of 5 ppm (11.5 mg/m3) was derived from a 90-day inhalation
       study in rats, based on the occurrence of liver and kidney effects at the next
       higher dose level (25 ppm). No respiratory irritation was observed in rats and
       mice after 14-day exposures to 10 (23 mg/m3) and 25 ppm (57.5 mg/m3),
       respectively, while an oral NOAEL for systemic effects was set at 5 mg/kg bw in
       rats after a 13-week exposure.
           In mutagenicity tests with S. typhimurium strains TA98, TA100, TA1535,
       TA1537, and TA1538, propynol was negative. In the unusual strain D3052, a
       weakly positive effect was noted. Propynol induced chromosomal aberrations in
       CHO cells in vitro when tested with and without metabolic activation. In vivo, it
       did not induce an increase in micronuclei in bone-marrow cells in two strains of
       mice at oral (gavage) doses up to 72 mg/kg bw.
           The committee did not find data on the long-term, including carcinogenicity,
       or reproduction toxicity of propynol.
           The committee takes the NOAEL of 11.5 mg/m3 from the 90-day inhalation
       study in rats (BGC92, BGC00) as a starting point for deriving a health-based
       recommended occupational exposure limit (HBROEL). For the extrapolation to a
       HBROEL, the committee establishes an overall assessment factor of 18. This
       factor covers the following aspects: inter- and intraspecies variation and the
       duration of exposure. Comparison of the results of the 14-day and 90-day
       inhalation studies and the 4-week and 13-week oral studies in rats indicate that
       the nature and severity of effects are not significantly affected by prolonged
       exposure which justifies a small factor for the duration of exposure. Thus,
       applying this factor and the preferred-value approach, a health-based
       occupational exposure limit of results in a HBROEL of 0.5 mg/m3 (0.2 ppm) is
       recommended for propynol.
       The committee recommends a health-based occupational exposure limit
       (HBROEL) for prop-2-yn-1-ol of 0.5 mg/m3 (0.2 ppm), as an 8-hour time-
       weighted average (TWA).
            Because dermal lethality data in rabbits indicate that prop-2-yn-1-ol is
       readily absorbed through the skin, a skin notation is recommended.
137-14 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       References
ACG91  American Conference of Governmental Industrial Hygienists (ACGIH). Propargyl alcohol. In:
       Documentation of the threshold limit values and biological exposure indices. 6th ed. Cincinnati OH,
       USA: ACGIH®, 1991; 1290-1.
ACG04a American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
       exposure values - 2004. Cincinnati OH, USA: ACGIH®, 2004: 121.
ACG04b American Conference of Governmental Industrial Hygienists (ACGIH). 2004 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®, 2004: 47.
Arb02  Arbejdstilsynet. Grænseværdier for stoffer og materialer. Copenhagen, Denmark: Arbejdstilsynet,
       2002: 49 (At-vejledning C.0.1).
Ban99  Banijamali AR, Xu Y, Strunk RJ, et al. Identification of metabolites of [1,2,3-13C]propargyl alcohol in
       rat urine by 13C NMR and mass spectrometry. J Agric Food Chem 1999; 47: 1717-29.
Ban00  Banijamali AR, Xu Y, DeMatteo V, et al. Identification of metabolites of [1,2,3-13C]propargyl alcohol
       in mouse urine by 13C NMR and mass spectrometry and comparison to rat. J Agric Food Chem 2000;
       48: 4693-710.
BGC92  Berufsgenossenschaft der Chemischen Industrie (BG Chemie). Study on the inhalation toxicity of
       propargylalkohol as a vapour in rats, 90-day test. Heidelberg, FRG: BG Chemie, 1992 (study
       performed by BASF AG, Department of Toxicology, Ludwigshafen, FRG by order of BG Chemie ;
       project no: 501969/88100; confidential report submitted to the committee by BG Chemie).
BGC00  Berufsgenossenschaft der Chemischen Industrie (BG Chemie). Propargylalkohol. CAS-Nr 107-19-7.
       Heidelberg, FRG: BG Chemie, 2000; Toxikologische Bewertung Nr. 116.
Bla94  Blakey DH, Maus KL, Bell R, et al. Mutagenic activity of 3 industrial chemicals in a battery of in
       vitro and in vivo tests. Mutat Res 1994; 320: 273-83.
DeM94  DeMaster EG, Dahlseid T, Redfern B. Comparative oxidation of 2-propyn-1-ol with other low
       molecular weight unsaturated and saturated primary alcohols by bovine liver catalase in vitro. Chem
       Res Toxicol 1994; 7: 414-9.
DFG04  Deutsche Forschungsgemeinschaft (DFG): Commission for the Investigation of Health Hazards of
       Chemical Compounds in the Work Area. List of MAK and BAT values 2004. Maximum
       concentrations and biological tolerance values at the workplace. Weinheim, FRG: Wiley-VCH Verlag
       GmbH & Co. KGaA, 2004: 99 (rep no 40).
Eas64  Eastman Kodak Co: Lab Ind Med. Toxicity and health hazard summary for 2-propyn-1-ol with cover
       letter dated 042886. Rochester NY, USA: Eastman Kodak Co, 1964, (report submitted to US EPA;
       availabe from NTIS, Springfield VA, USA: order no OTS0510348).
EC04   European Commission: Directorate General of Employment and Social Affairs. Occupational
       exposure limits (OELs). http://europe.eu.int/comm/employment_social/health_safety/areas/
       oels_en.htm.
137-15 Prop-2-yn-1-ol
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<pre>Git65  Gittes HR, Shelanski MV. 90-Day chronic skin absorption study with propargyl alcohol with cover
       letter dated 041086. Midland MI, USA: Dow Chem Co, Ind Bio Labs Inc, 1965 (report submitted to
       US EPA; availabe from NTIS, Springfield VA, USA; order no OTS0510181).
HSE02  Health and Safety Executive (HSE). EH40/2002. Occupational Exposure Limits 2002. Sudbury
       (Suffolk), UK: HSE Books, 2002: 24.
Ken91  Kennedy GL, Graepel GJ. Acute toxicity in the rat following either oral or inhalation exposure.
       Toxicol Lett 1991; 56: 317-26.
Kom89  Komsta E, Secours VE, Chu I, et al. Short-term toxicity of nine industrial chemicals. Bull Environ
       Contam Toxicol 1989; 43: 87-94.
Lin94  Lington AW, Bevan C. Propargyl alcohol. In: Clayton GD, Clayton FE, eds. Toxicology 4th ed. New
       York, USA: J. Wiley & Sons, 1994: 2727-9 (Patty's industrial hygiene and toxicology; Vol II, Pt D).
Mar88  Markiewicz VR, Payne BJ. Rat oral subchronic toxicity study with propargyl alcohol. Muskegon MI,
       USA: Toxicity Research Laboratories Ltd, 1988.
Mih84  Mihail F, Luckhaus G, Nash G. Propargylalkohol. Subakute orale Toxizitätsversuche an Ratten.
       Wuppertal-Elberfeld, Germany: Bayer AG, Institut für Toxikologie, 1994; report no 12653.
Mor01  Moridani MY, Khan S, Chan T, et al. Cytochrome P450 2E1 metabolically activates propargyl
       alcohol: propiolaldehyde-induced hepatocyte toxicity. Chem Biol Interact 130-132: 931-42.
NLM04  US National Library of Medicine (NLM), ed. Propargyl alcohol. In: The Hazardous Substances Data
       Bank (HSDB) (last revision date propynol file: March 2003; last review date: June 1992); http://
       toxnet.nlm.nih.gov.
Ols57  Olson KJ. Range finding skin absorption tests on propargyl alcohol with cover letter dated 060986.
       Midland MI, USA: Dow Chem Co, Dow Biochem Res Lab, 1957 (report submitted to US EPA;
       availabe from NTIS, Springfield VA, USA; order no OTS0510183).
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.
SZW04  Ministerie van Sociale Zaken en Werkgelegenheid (SZW). Nationale MAC-lijst 2004. The Hague,
       the Netherlands: Sdu Uitgevers, 2004: 39.
Ter89  Terrill JB. Acute inhalation study with propargyl alcohol in the rat with cover letter dated 040489.
       Rockville MD, USA: Hazleton Lab, 1989 (report submitted to US EPA by GAF Chemicals Corp,
       Wayne NJ, USA; availabe from NTIS, Springfield VA, USA; order no OTS0516716).
Tor64  Torkelson TR. Results of repeated exposure of male and female rats to 80 ppm of propargyl alcohol
       in air with cover letter dated 041086. Midland MI, USA: Dow Chem Co, Dow Biochem Res Lab,
       1964 (report submitted to US EPA; availabe from NTIS, Springfield VA, USA; order no
       OTS0510182).
TRG04  TRGS 900. Technische Regeln für Gefahrstoffe. Grenzwerte in der Luft am Arbeitsplatz. BArbBl
       2004; (7/8).
Ver77  Vernot EH, MacEwen JD, Haun CC, et al. Acute toxicity and skin corrosion data for some organic
       and inorganic compounds and aqueous solutions. Toxicol Appl Pharmacol 1977; 42: 417-23.
137-16 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>Zis95  Zissu D. Histopathological changes in the respiratory tract of mice exposed to ten families of airborne
       chemicals. J Appl Toxicol 1995; 15: 207-13.
137-17 Prop-2-yn-1-ol
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<pre>       Annex I
       Figure 1 Metabolism scheme of propynol in rats (Ban00)
       (Roman numericals refer to names in Annex III).
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<pre>        Annex II
       Figure 2 Metabolism scheme of propynol in mice (Ban99).
       (Roman numericals refer to names in Annex III)
137-19 Prop-2-yn-1-ol
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<pre>              Annex III
Metabolites of propynol in rats and mice as % of total urinary radioactivity in first 24-h urine (Ban99, Ban00).
metabolite                                                                                                       rat mouse
2-propynoic acid                                                                                          I      27  ca. 2
3,3-bis[(2-(acetylamino)-2-carboxyethyl)thio]-1-propanol                                                  II     20  6
3-[[2-(acetylamino)-2-carboxyethyl]sulphinyl]-3-[[2-(acetylamino)-2-carboxyethyl]thio]-1-propanol         III    15  0
3-[[2-(acetylamino)-2-carboxyethyl]thio]-3-[[2-(amino)-2-carboxyethyl]thio]-1-propanol                    IV     8   17
3,3-bis[(2-(amino)-2-carboxyethyl)thio]-1-propanol                                                        V      0   15
2-(methylsulfinyl)-3-(methylthio)-2-propenoic acid                                                        VI     7   0
propynol glucuronide                                                                                      VII    0   6
3-(carboxymethylthio)-2-propenoic acid                                                                    VIII   20  0
(E + Z)-3-[(2-amino-2-carboxyethyl)thio]-2-propenoic acid                                                 IX     0   41
3-[(2-formylamino-2-carboxyethyl)thio]-2-propenoic acid                                                   X      0   13
137-20        Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>              Annex IV
Occupational exposure limits for propynol in various countries.
country                               occupational                 time-weighted type of exposure      notea      referenceb
- organisation                        exposure limit               average         limit
                                      ppm          mg/m3
the Netherlands
- Ministry of Social Affairs and      1            2               8h              administrative      S          SZW04
Employment
Germany
- AGS                                 2            4.7             8h                                             TRG04
                                      4            9.4             15 min
- DFG MAK-Kommission                  2            4.7             8h                                  S,d        DFG04
                                      4            9.4             15 minc
Great-Britain
- HSE                                 1            2.3             8h              OES                 S          HSE02
                                      3            7.0             15 min
Sweden                                -            -                                                              Swe00
Denmark                               1            -               8h                                  S          Arb02
USA
- ACGIH                               1            -               8h              TLV                 S          ACG04b
- OSHA                                -            -               8h              PEL                 S          ACG04a
- NIOSH                               1            2               10 h            REL                 S          ACG04a
European Union
- SCOEL                               -            -                                                              EC04
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.
c
     Maximum number per shift:: 4, with a minimum interval between peaks of 1 hour.
d
     Listed among substances with MAK values but no pregnancy risk group classification.
137-21        Prop-2-yn-1-ol
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<pre>137-22 Health-based Reassessment of Administrative Occupational Exposure Limits</pre>

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<br><br>