<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>3-Methylbutan-1-ol
(CAS No: 123-51-3)
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/085, The Hague, 22 October 2003
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. 3-Methylbutan-1-ol; Health-based Reassessment of
Administrative Occupational Exposure Limits. The Hague: Health Council of the
Netherlands, jaartal; 2000/15OSH/2003.
all rights reserved
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<pre>1      Introduction
      The present document contains the assessment of the health hazard of 3-
      methylbutan-1-ol 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 October 1997, literature was searched in the on-line databases Medline,
      Toxline, Embase, and Chemical Abstracts starting from 1966, 1967,1988, and
      1970, respectively. CD-ROM versions of the databases HSELINE, CISDOC,
      MHIDAS, and NIOSHTIC (covering the period 1985/87 until 1997) were also
      consulted. The following key words were used: isoamyl alcohol and 123-51-3.
      The final literature 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                          :  3-methylbutan-1-ol
      synonyms                      :  Isoamyl alcohol; isopentanol; isopentyl alcohol; isobutyl
                                       carbinol; primary isoamyl alcohol
      molecular formula             :  C5H12O
      structural formula
      CAS number                       123-51-3
085-3 3-Methylbutan-1-ol
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<pre>3     Physical and chemical properties
      molecular weight      :   88.2
      boiling point         :   131oC
      melting point         :   -117.2oC
      flash point           :   43oC (closed cup)
      vapour pressure       :   at 20oC : 0.37 kPa
      solubility in water   :   slightly soluble (at 14oC: 2.0 g/100mL)
      log Poctanol/water    :   1.16 (experimental); 1.26 (estimated)
      conversion factors    :   at 20oC, 101.3 KPa: 1 mg/m3 = 0.27 ppm
                                                      1 ppm = 3.67 mg/m3
      Data from ACG99, BGC90, NLM01, http://esc.syrres.com.
      3-Methylbutan-1-ol is an oily colourless liquid, with a characteristic odour and a
      pungent, repulsive taste (ACG99). An air odour threshold of 0.15 mg/m3 (0.042
      ppm) has been reported (Amo83).
4     Uses
      3-Methylbutan-1-ol is used in the manufacture of photographic chemicals and
      pharmaceutical products, as a solvent for oils, fats, resins, and waxes, as a
      component of paint stripper, and in the plastics industry in the spinning of
      polyacrylonitrile (ACG99, BGC90). 3-Methylbutan-1-ol is the primary
      constituent of fusel oil, a by-product of alcoholic carbohydrate fermentation
      (ACG99).
5     Biotransformation and kinetics
      The respiratory uptake defined as (Cinhaled air – Cmixed exhaled air/Cinhaled airx100% for
      3-methylbutan-1-ol was determined by exposing 4 healthy male volunteers to ca.
      92 mg/m3 (25 ppm) 3-methylbutan-1-ol at rest for 10 minutes. The percentage
      solvent in end-exhaled air and in mixed-exhaled air increased after the start of
      the exposure and reached a quasi-steady-state level within a few minutes. The
      mean respiratory uptake for the last 5 minutes of 3-methylbutan-1-ol respiration
      was 63% (Kum99). In rats, the nasal uptake for 3-methylbutan-1-ol was
      estimated to be 80%, using physiologically-based pharmacokinetic modelling
085-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      (PB-PK) in which nasal enzyme distribution as well as nasal airflow patterns
      were incorporated. Morris et al. concluded that gender differences in the upper
      respiratory tract deposition might not be widespread among vapours (Mor91,
      Mor93).
      Data on biotransformation and excretion of 3-methylbutan-1-ol were
      summarised by BG Chemie (BGC90) and Lington and Bevan (Lin94).
      Generally, both in humans and experimental animals, the compound is rapidly
      oxidised in the liver to its corresponding aldehyde and acid (3-methylbutanal or
      isovaleraldehyde and 3-methylbutanoic acid or isovaleric acid) following oral or
      parental administration. Shortly after administration, no or only very low levels
      of parent compound were found in the blood. As a minor pathway, the compound
      can be conjugated directly with glucuronic acid. In rabbits given a single oral
      dose of 2200 mg/animal, 9% of the dose was excreted in the urine within 24
      hours, as the glucuronide conjugate (identified as triacetyl-ß-isoamylglucuronide
      methyl ester) (BGC90, Lin94). Following intraperitoneal injections of 1000
      mg/kg bw to rats, small amounts of 3-methylbutan-1-ol were excreted in exhaled
      air and urine (0.97 and 0.27 of total dose, respectively). The maximum blood
      concentrations (measured at the first time point at t=1 h) were ca. 36 mg/100 mL,
      and the alcohol disappeared from the blood in less than 5 hours (Hag45). Similar
      findings were reported following oral doses of 3-methylbutan-1-ol of 2 g/kg bw.
      One hour after administration, a maximum blood level of parent compound of 17
      mg/100 mL was found, with only trace amounts detectable after 4 hours (ca. 1
      mg/mL); no parent compound was detected in the urine (BGC90, Lin94). From
      in vitro experiments studying the solubility of 3-methylbutan-1-ol in rabbit and
      human tissues, it was concluded that contrary to short-chain primary alcohols
      (methanol, ethanol), 3-methylbutan-1-ol was distributed in aqueous as well as
      anhydrous tissues and that there were no basic differences between human and
      rabbit tissues and between the various types of tissues (BGC90).
          In vivo experiments showed that concomitant exposure to ethanol retarded
      the metabolism of 3-methylbutan-1-ol (BGC90). From in vitro experiments, it
      can be seen that 3-methylbutan-1-ol can interfere with cytochrome-P450-
      mediated metabolic processes. Louis et al. reported the induction of cytochrome
      P450 2H1/2 in cultured chick hepatocytes. 3-Methylbutan-1-ol combined with
      ethanol caused a synergistic induction of P450 2B1/2 in cultured rat hepatocytes
      and an additive to synergistic induction of P450 2H1/2 in cultured chick
      hepatocytes (Lou93). Kostrubsky et al. reported that 3-methylbutan-1-ol was
      more potent in the induction of cytochrome P450 in human hepatocytes than was
      previously shown in rat hepatocytes (Kos95). Genetic factors (ethnic
085-5 3-Methylbutan-1-ol
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<pre>      predisposition) may retard metabolism as well: in Orientals having a deficiency
      in low Km aldehyde dehydrogenase isoenzyme oxidation of the aldehyde is
      delayed (Wil85a).
6     Effects
      Human data
      In a volunteer study, the majority of the male and female subjects (n=10) found
      exposure to calculated, nominal concentrations of 3-methylbutan-1-ol of 367 mg/
      m3 (100 ppm) and 551 mg/m3 (150 ppm), for 3 to 5 minutes, irritating to the
      throat and irritating to the eyes and nose, respectively. The extent of irritation
      was scored subjectively using 3 categories: no, slight, and very. Test vapours
      were generated by either continuously adding a known quantity of vapour-
      saturated air to a measured flow of air in case of volatile solvents or by dropping
      at a known rate on to a hot plate and introducing the resulting vapour into the air
      supply system in case of less volatile solvents (Nel43). Irritation of the throat
      was reported in a respiratory uptake study in which 4 healthy male volunteers
      were exposed through a mouthpiece to ca. 92 mg/m3 (25 ppm) 3-methylbutan-1-
      ol for 10 minutes (Kum99). The committee considers the results of these studies
      not suitable for assessing an irritation-concentration relationship because of
      methodological flaws (subjective criteria, lack of detailed information on
      generating vapours and controlling and measuring of concentrations in the
      Nelson study, and direct introduction into the throat by using a mouth piece in the
      Kumagai study).
          Applied at 8% in petrolatum in a 48-hour closed patch test, 3-methylbutan-1-
      ol did not cause skin irritation in human volunteers (unpublished report
      submitted to the Research Institute for Fragrance Materials - RIFM -, Inc,
      Englewood Cliffs NJ, USA, cited by Opd78). No skin sensitisation reactions
      were reported when a solution of 8% 3-methylbutan-1-ol in petrolatum was
      tested in 25 volunteers in a maximisation test (unpublished report submitted to
      RIFM, cited by Opd78). A positive reaction (i.e., the presence of erythema as
      well as filtration and/or papules-vesicles) to a 10% solution of 3-methylbutan-1-
      ol (as well as to some other alcohols) was found upon 48-hour epicutaneous
      testing of various concentrations of agents used for local treatment and routine
      test substances, among which 3-methylbutan-1-ol, in a 62-year-old housewife
      with a history of a post-thrombotic leg ulcer with periodic dermatitis for the
      previous 12 years (Fre63). In patch testing in low Km aldehyde dehydrogenase
085-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      isoenzyme-deficient Oriental subjects, 3-methylbutan-1-ol gave positive results
      (erythema) caused by its aldehyde metabolite (Wil85a, Wil85b).
      Ingestion of 50 to 100 mL 3-methylbutan-1-ol was reported to have induced
      central nervous system depression, weakness pain, a burning sensation in the
      chest and stomach, nausea, headache, and sleep within 10 to 15 minutes, and
      terminal coma and death within 1 hour to 6 days. Asphyxiation was stated to be
      the cause of death; swollen tissues (brain and all other organs) and gastric
      mucosa and vascular effects were seen (Opd78).
      The committee did not find human data on effects of long-term exposure to 3-
      methylbutan-1-ol.
      Animal data
      Irritation and sensitisation
      When instilled into the eyes of rabbits, 3-methylbutan-1-ol scored an injury
      grade of 8 on a scale from 1 to 10, which was defined as producing a certain
      injury score, representative of ‘severe injury’, 18 to 24 hours after application of
      an ‘excess’ of a 5% solution (Smy69; see also Car46). Slowly diminishing
      reddening and swelling of the mucous membranes and a mist-like corneal
      opacity were seen when unknown amount of 3-methylbutan-1-ol was instilled
      into the eyes of rabbits (unpublished report cited in BGC90).
           Following uncovered application of 0.01 mL of undiluted material to the
      clipped skin (abdomen) of albino rabbits (n=5), 3-methylbutan-1-ol scored an
      injury grade of 2 on a scale from 1 to 10, which was defined as giving rise to ‘the
      least visible capillary injection from undiluted material’ (Smy69; see also
      Smy62). In 2 separate studies, 3-methylbutan-1-ol was rated as moderately
      irritant following 24-hour occlusive application to the intact and abraded or
      scarified skin of rabbits (unpublished study cited in BGC90; unpublished report
      submitted to RIFM, cited by Opd78).
           With respect to the respiratory tract, the sensory irritation in the upper part
      was studied by determining the concentration associated with a 50% decrease in
      the respiratory rate (RD50). Using different strains of mice and different
      protocols, RD50 values of 16,339 and 2624 mg/m3 (4452, 708 ppm), respectively,
      were reported for 3-methylbutan-1-ol (Kan80, Mul84; see also Bos92, Sch93).
085-7 3-Methylbutan-1-ol
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<pre>             Acute toxicity
             No mortality was found in rats (n=6; sex not indicated) following an 8-hour
             exposure to ‘concentrated vapour’ (concentration not reported; observation
             time: 14 days) (Smy69; see also Smy62) or in rats (n=12; sex not indicated)
             following a 7-hour exposure to an ‘enriched atmosphere’ (concentration not
             reported) (unpublished study cited in BGC90). In the latter study, panting and
             loss of pain reflex were reported (BCG90).
                  A dermal LD50 of 3.97 mL/kg bw (i.e., ca. 3200 mg/kg bw) has been reported
             for rabbits (24-hour covered application; observation time: 14 days) (Smy69; see
             also Smy62).
                  Oral LD50 values are presented in Table 1. In rabbits, the ND50 (narcotic dose;
             i.e., the dose producing stupor, loss of voluntary movements in half of the
             animals) was ca. 705 mg/kg bw (8 mMol/kg ) (Mun72).
Table 1 Acute lethal oral toxicity data for 3-methylbutan-1-ol.
species                    LD50                  remarks                                                       reference
                           (mg/kg bw)
rat                        5720                  observation time: 14 days                                     Smy69; see also
(Carworth-Wistar; male;                                                                                        Smy62
n=5)
rat                        >5000                 doses administered: 2150, 5000 mg/kg; mortality in 1/5 BGC90
(Sprague-Dawley; n=5/                            females in each group; symptoms: dyspnoea, apathy,            (unpublished study)
sex)                                             staggering, atonia, pareses of rear extremities, poor general
                                                 condition; observation time: 14 days
rat                        male: 1300            degenerative changes in liver and kidneys; observation        BCG90
(male, female)             female: 4000          time: 10 days
rabbit                     3440                                                                                Mun72
(male, female)
             Following intravenous injection, an LD50 of about 230 mg/kg bw was determined
             in 7-8-week-old female mice (BGC90) while in rabbits, 1570 mg/kg bw was
             reported to be the minimal lethal dose (Opd78).
                  Intraperitoneal injections of doses of 3-methylbutan-1-ol of 700 mg/kg bw
             caused mortality in 3/5 male and 3/5 female mice. Toxic symptoms were similar
             to those found after oral administration (see Table 1) (unpublished study cited in
             BGC90).
085-8        Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      Repeated-dose toxicity including carcinogenicity
      In a range-finding study, rats (SPF-Wistar; n=3/sex/group) were given 3-
      methylbutan-1-ol (purity: >98%) in the drinking water at concentrations of about
      1360 mg/kg bw for 2 weeks and of 1160 mg/kg bw for the next 2 weeks (20,000
      and 16,000 ppm, respectively). Treatment did not affect body weight gain or food
      consumption. In the females, there was a reduction in water consumption during
      the first 2 weeks, but no difference among treated and control animals was found
      during the next 2 weeks when the dose was lowered. No treatment-related effects
      were seen upon gross post-mortem examination. Based on the palatability
      problems observed in females at 20,000 ppm, the authors concluded that the
      maximum drinking water concentration that could be tested would be 16,000
      ppm. In the subsequent 90-day study, performed according to OECD Guideline
      408 and OECD GLP principles, animals (n=10/sex/group) were given daily
      drinking water concentrations of 0, 1000, 4000, and 16,000 ppm (males: 0, 73,
      295, 1068 mg/kg bw/d; females: 91, 385, 1657 mg/kg bw/d). Treatment did not
      induce any effect on mortality, body weight, various clinical chemistry
      parameters, or organ weights or any abnormality at gross and microscopic
      examination. The only effects found were marginal increases in red blood cell
      counts in the male animals of the mid- and high-dose groups (8.18±0.37 and
      8.41±0.38x1012/L, respectively, vs. 7.76±0.20x1012/L in controls; p<0.05 and
      <0.01, respectively) and slight decreases in mean corpuscular volume (by 4.3%;
      p<0.05) and in mean corpuscular haemoglobin content (by 5.7%; p<0.01) in the
      male animals of the high-dose group (Sch97). The committee concludes that in
      this 13-week drinking water study in rats, 1068 and 1657 mg/kg bw/day, the
      highest levels tested, are the NOAELs for males and females, respectively.
      In a separate study, Ash/CSE rats were 3-methylbutan-1-ol by oral intubation at
      daily (7 days/week) doses of 0, 500, or 1000 mg/kg bw, for 3 or 6 weeks (n=5/
      sex/group), or to 0, 150, 500, or 1000 mg/kg bw, for 17 weeks (n=15/sex/group).
      Parameters/end points included clinical observations, body weights, food and
      water consumption, haematology, clinical chemistry, urinalysis, organ weights
      (brain, heart, liver, spleen, stomach, small intestine, caecum, adrenals, gonads,
      pituitary, and thyroid), and macroscopic and microscopic evaluation. Apart from
      2 high-dose rats dying from lung congestion, claimed to be caused by accidental
      introduction of the test substance into the lungs, no deaths or abnormalities in
      behaviour occurred during the experiment in any of the groups. In male rats
      dosed with 1000 mg/kg bw for 3 weeks, the absolute weights of most organs and
      the terminal body weights were significantly lower than those of controls. The
085-9 3-Methylbutan-1-ol
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<pre>       males dosed with 500 mg/kg bw for 3 weeks had significantly lower absolute
       brain, kidneys, stomach, small intestine, and testes weights. When expressed
       relative to body weight, only the relative testes weights were decreased. No
       effects were seen in females exposed for 3 weeks. After 6 weeks of treatment, the
       only effect observed was a decrease in absolute pituitary weight in male rats
       receiving 1000 mg/kg bw. Treatment for 17 weeks induced slight decreases in
       body weight (gain) in the high-dose male animals, being statistically significant
       from week 9 onwards, which were ascribed to a consistently 5-10% lower food
       intake (when compared to controls) during the first 6 weeks. No other consistent,
       compound-related effects were seen in any of the groups exposed for 17 weeks.
       To investigate the changes in organ weights, the authors performed a 3-week
       pair-feeding study. Eight male rats received daily doses of 1000 mg/kg bw in
       corn oil and were fed ad libitum while 2 other groups of 8 male rats were both
       given corn oil and pair-fed to the exposed group and fed ad libitum, respectively.
       There were no differences in absolute or relative weights of any organ among
       these groups. Body weight gains of the treated group and pair-fed controls were
       similar but slightly less than those of controls given free access to food indicating
       that the body weight decreases in the 17-week experiment are most likely to be
       due to a reduced food intake rather than a toxic effect of 3-methylbutan-1-ol
       (Car73). In agreement with Carpanini et al., the committee concludes that oral
       exposure of rats to doses up to 1000 mg/kg bw/day, the highest level tested, for
       17 weeks, was not accompanied by adverse effects.
       Gibel et al. (Gib75) studied the potential carcinogenicity of 3-methybutan-1-ol
       (an analytical grade, double-distilled batch was tested; purity: unknown) in male
       and female Wistar rats. Doses of 0.1 and 0.04 mL/kg bw (i.e., ca. 81 and 32
       mg/kg bw) were given orally twice a week to a total of 15 or subcutaneously
       once a week to a total of 24 animals, respectively (mean total doses 27 and 38
       mL or 21,843 and 30,742 mg/kg, respectively, suggesting experimental dosing
       periods of 135 and 95 weeks, respectively). All animals were observed until they
       died naturally. The average survival times were 527 and 592 days for the oral and
       subcutaneous route, respectively, vs. 643 in oral and subcutaneous control male
       and female animals (n=25/dosing route). Oral administration induced 4
       malignant tumours: 2 liver cell carcinomas, 1 forestomach carcinoma, and one
       myeloid leukaemia. Following subcutaneous administration, a total of 10
       malignant tumours were reported: one liver carcinoma, one liver sarcoma, one
       spleen sarcoma, one glandular stomach carcinoma, and 2 myeloid leukaemias.
       No malignant tumours were found in the respective control groups. Benign
       tumours, mostly forestomach papillomas and papillomatosis and mammary
085-10 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       fibroadenomas, were found in 3/15 orally and in 5/24 subcutaneously treated
       animals vs. 3/25 and 2/25 in their respective controls. Furthermore, 'nearly all
       rats' showed liver damage including congestion, steatosis, necrosis, fibrosis,
       cirrhosis, and metaplasia, hyperplasia of the haematopoietic bone marrow
       parenchyma, and spleen metaplasia (Gib75).The committee noted the small
       numbers of animals used in the experiments, the unknown sex ratios in the
       experimental groups, the irregular pattern of administration, the lack of
       statistical analysis, the exceeding of the maximum tolerated dose as evidenced by
       the effects on the liver and the haematopoietic system, and the poorly detailed
       description of neoplastic and non-neoplastic effects. Despite the flaws in
       design, the committee recommends confirmation of this study
       Mutagenicity and genotoxicity
       Reporting on 29 chemicals including food additives in an abstract without
       presenting experimental details suggested that 3-methylbutan-1-ol was negative
       when tested in the presence and absence of a metabolic activation system in S.
       typhimurium strains TA98, TA100, TA1535, and TA1537 (spot test and plate
       incorporation assay) (Slo82). It did not induce mutations in the HPRT assay in
       the Chinese hamster lung fibroblast cell line V79 when tested with and without
       the addition of a metabolic activation system at an adequate dose range (Sei99).
       3-Methylbutan-1-ol did not induce DNA damage (strand breaks; alkali-labile
       sites) in blood cells obtained from healthy volunteers in the Comet assay (Sei99).
       In vivo, a positive effect was found in bone marrow cells from rats (n=8)
       sacrificed 48 hours after a single intragastric dose of 1/5 LD50. Results of
       cytogenetic analyses (a total of 500 cells examined) showed increases in the
       number of cells with chromosomal aberrations (2.6±0.7% vs. 0% in controls)
       while no changes were found in the number of polyploid cells (0.6±0.3% vs.
       0.5±0.3%) and cells with chromosome gaps (0.4±0.2% vs. 0.3±0.2%) (Bar88).
       1-Methylbutan-1-ol inhibited metabolic cooperation between 6-thioguanine-
       sensitive and resistant Chinese hamster V79 cells (Che84), a phenomenon
       thought to reflect carcinogenic promotion ability and not to be indicative of
       genotoxic potential (WHO90).
085-11 3-Methylbutan-1-ol
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<pre>       Reproduction toxicity
       Klimisch and Hellwig studied the prenatal toxicity of 3-methylbutan-1-ol by
       exposing female rats (Wistar; n=25/group) and rabbits (Himalayan; n=15/group)
       to concentrations of 0, 500, 2500, and 10,000 mg/m3 (0, 135, 675, 2700 ppm), 6
       hours/day, on gestational days 6-15 and 7-19, respectively. All rats and rabbits
       were killed on study days 20 and 29, respectively. In both species, maternal
       toxicity manifested by slight retardation of body weight gain during the first days
       of the exposure period was observed in the animals of the high-concentration
       groups. The rabbits of this group had eye irritation (reddish, lid closure, or slight
       discharge) during exposure. There were no compound-related signs of embryo/
       fetotoxicity or teratogenicity in any of the treated rat groups. In rabbits, there was
       a statistically significantly increased incidence of total fetal soft tissue variations
       that was mainly caused by a significant increase in the incidence of 'separated
       origin of carotids'. Because figures were within the range of biological variation
       and unexpectedly low in control animals, Klimisch and Hellwig considered these
       findings to be incidental (Kli95). From this study, the committee concludes the
       NOAEL for maternal toxicity in both rats and rabbits to be 2500 mg/m3 (675
       ppm), and the NOAEL for developmental toxicity to be 10,000 mg/m3 (2700
       ppm).
7      Assessment of health hazard
       Following exposure by inhalation, respiratory uptake was found to be ca. 60% in
       human volunteers (at exposure to 92 mg/m3 for 10 minutes) and 80% in rats. Oral
       and parental human and animal data showed a rapid conversion into its
       corresponding alcohol and acid. This metabolism may be retarded by
       concomitant exposure to ethanol or by genetic factors, e.g., the low Km aldehyde
       dehydrogenase isoenzyme-deficiency in Orientals resulting in increased
       aldehyde blood levels.
            Unpublished information did not indicate an irritating or sensitising potential,
       but increased aldehyde levels as occurred in the aforementioned deficient
       Orientals caused skin irritation.
            Although irritation may be an important effect, the committee did not find
       adequate human data on local as well as systemic effects.
            Experimental animal data showed 3-methylbutan-1-ol to be severely
       irritating to the eyes and hardly or moderately irritating to the skin of rabbits. Eye
       irritation was observed in (pregnant) rabbits exposed to vapour concentrations of
085-12 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       10,000 mg/m3 (2700 ppm), 6 hours/day, but not at 2500 mg/m3 (675 ppm), while
       these levels were not irritating to rats.
           Inhalation exposure of rats to ‘concentrated vapours’ or ‘enriched
       atmospheres’ for 7-8 hours did not result in mortality. A dermal LD50 of ca. 3200
       mg/kg bw has been reported in rabbits. Oral LD50 values were 3440 and 5720
       mg/kg bw in rabbits and rats, respectively.
           No compound-related, toxicologically relevant effects were found in
       adequately performed studies in which male and female rats were exposed by
       oral intubation to doses up to 1000 mg/kg bw/day, 7 days/week, for 17 weeks
       (Car73), or in the drinking water to doses up to 1068 (males) or 1657 (females)
       mg/kg bw/day, 7 days week, for 13 weeks (Sch97). Oral administration of ca. 81
       mg/kg bw, twice a week, for (probably) 135 weeks or subcutaneous injection of
       ca. 32 mg/kg bw, once a week, for 95 weeks, induced an increase in the incidence
       of malignant tumours in rats (4 and 10, respectively). However, due to
       methodological shortcomings, the committee cannot assess the relevance of
       these results but verification is recommended. The committee did not find data
       from subchronic or chronic inhalation studies.
           3-Methylbutan-1-ol did not induce mutations in S. typhimurium or in Chinese
       hamster V79 cells or DNA damage (strand breaks; alkali-labile sites) in human
       blood cells. Single intragastric dosing of rats caused an increase in the number of
       bone marrow cells with chromosomal aberrations, but not in the number of
       polyploid cells or cells with chromosomal gaps. 3-Methylbutan-1-ol inhibited
       metabolic cooperation in Chinese hamster V79 cells, a phenomenon thought to
       reflect carcinogenic promotion ability and not to be indicative of genotoxic
       potential.
           3-Methylbutan-1-ol did not induce developmental toxicity in rats and rabbits
       exposed to concentrations up to 10,000 mg/m3 (2700 ppm) during organogenesis.
           From the repeated oral studies by Carpanini et al. (Car73) and Schilling et al.
       (Sch97), the committee takes 1000 mg/kg bw/day - the highest dose tested - as
       NOAEL as a starting point in deriving a health-based recommended
       occupational exposure limit (HBROEL). Since workers are exposed for 5 days a
       week, this NOAEL from continuous (i.e., 7 days/week) exposure studies is
       adjusted by multiplying with a factor of 7/5, resulting in a NAEL of 1400 mg/kg
       bw/day. For the extrapolation to a HBROEL, a factor of 4 for the allometric
       scaling from rat to man, based on basal metabolic rate, and an overall factor of
       18, covering inter- and intraspecies variation and differences between the
       experimental conditions and the exposure pattern of the worker, are applied
       resulting in an NAEL for humans of 19.4 mg/kg bw/d. Assuming a 70-kg worker
       inhales 10 m3 of air during an 8-hour working day and a retention of 100%, and
085-13 3-Methylbutan-1-ol
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<pre>       applying the preferred-value approach, a health-based occupational limit of 100
       mg/m3 (27 ppm) is recommended for 3-methylbutan-1-ol. In view of the -
       inadequate - human data on irritation (see first paragraph of Chapter 6), the
       committee expects (nevertheless) that this limit will protect workers from eye
       and respiratory tract irritation.
       The committee recommends a health-based occupational exposure limit for 3-
       methylbutan-1-ol of 100 mg/m3 (27 ppm), as an 8-hour time-weighted average
       (TWA).
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085-16 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>              Annex
Occupational exposure limits for 3-methylbutan-1-ol 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      100          360            8h                 administrative                 SZW03
Employment
Germany
                                                                                                          c
- AGS                                 100          360            8h                                                TRG00
                                      400          1440           15 min
                                                                                                          c
- DFG MAK-Kommission                  100          370            8h                                                DFG02
                                      200          740            15 mind
Great-Britain
- HSE                                 100          366            8h                 OES                            HSE02
                                      125          458            15 min
Sweden                                -            -                                                                Swe00
                                                                                                          e
Denmark                               100          360            8h                                                Arb02
USA
- ACGIH                               100          -              8h                 TLV                            ACG03b
                                      125          -              15 min             STEL
- OSHA                                100          360            8h                 PEL                            ACG03a
- NIOSH                               100          360            10 h               REL                            ACG03a
                                      125          450            15 min             STEL
European Union -SCOEL
                                      -            -                                                                EC03
a
     S = skin notation; which mean that skin absorption may contribute considerably to body burden; sens = substance can cause
     sensitisation.
b
     Reference to the most recent official publication of occupational exposure limits.
c
     Classified in pregnancy risk group C, i.e., among substances for which there is no reason to fear a risk of damage to the
     embryo or fetus when MAK and BAT (Biological Tolerance Value for Working Materials) values are observed.
d
     Maximum number per shift: 4, with a minimum interval between peaks of 1 hour.
e
     For all pentanol isomers.
085-17        3-Methylbutan-1-ol
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<pre>085-18 Health-based Reassessment of Administrative Occupational Exposure Limits</pre>

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<br><br>