<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>      p-tert-Butyltoluene
      (CAS reg no: 98-51-1)
      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/030, The Hague, 7 March 2002
030-1
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<pre>      Preferred citation:
      Health Council of the Netherlands: Committee on Updating of Occupational
      Exposure Limits. p-tert-Butyltoluene; Health-based Reassessment of
      Administrative Occupational Exposure Limits. The Hague: Health Council of the
      Netherlands, 2002; 2000/15OSH/030.
      all rights reserved
030-2
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of
      p-tert-butyltoluene 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 A Wientjes, M.Sc. and H Stouten, M.Sc. (TNO
      Nutrition and Food Research, Zeist, the Netherlands).
           The evaluation of the toxicity of p-tert-butyl toluene has been based on the
      review by the American Conference of Governmental Industrial Hygienists
      (ACG99). Where relevant, the original publications were reviewed and evaluated
      as will be indicated in the text. In addition, literature was retrieved from the online
      data bases Medline, Toxline, and Chemical Abstracts covering the period 1966 to
      26 April 1999 (19990426/UP), 1965 to 29 January 1999 (19990129/ED), and 1967 to
      24 April 1999 (19990424/ED; vol 130, iss 18), respectively, and using the
      following key words: tert-butyltoluene, methyl-butylbenzene, and 98-51-1. HSDB
      and RTECS, data bases available from CD-ROM, were consulted as well (NIO99,
      NLM99). The final literature search has been carried out in April 1999.
           In July 2001, the President of the Health Council released a draft of the
      document for public review. Comments were received from the following
      individuals and organisations: A Aalto (Ministry of Social Affairs and Health,
      Tampere, Finland). These comments were taken into account in deciding on the
      final version of the document.
2     Identity
       name:p-tert-butyl toluene        :   p-tert-butyl toluene
       synonyms                         :   4-t-butyltoluene; 1-methyl-4-tert-butylbenzene;
                                            p-methyl-tert-butylbenzene; tertiary butyltoluene
       molecular formula                :   C11H16
       CAS reg no                       :   98-51-1
       structural formula               :
      Data from ACG99, Ric92
030-3 p-tert-Butyltoluene
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<pre>3     Physical and chemical properties
      molecular weight                :      148,18
      boiling point                   :      192.8 oC
      melting point                   :      -52.4 oC
      flash point                     :      68.3 oC (open cup)
      vapour pressure                 :      at 20 oC: 70 Pa; at 25oC: 86.7 Pa
      solubility in water             :      insoluble
      Log P octanol/water             :      4,35
      conversion factors              :      1 ppm     = 6.1 mg/m 3
      (20 oC, 101.3 kPa)              :      1 mg/m 3 = 0.16 ppm
      Data from ACG99, Ano86a.
      p-tert-Butyltoluene (p-TBT) is a clear flammable liquid with a distinct, aromatic,
      gasoline-like odour (ACG99). Odour thresholds of 0.067 and 0.011 mg/m3 (0.01
      and 0.002 ppm) have been reported (Ano83). Human volunteers exposed to
      several concentrations ranging between 30 and 975 mg/m3 (5-160 ppm), for 5
      minutes, immediately recognized the odour of the compound at concentrations
      as low as 5 ppm. Olfactory agnosia was experienced in a few subjects (Hin54).
           p-TBT can react with strong oxidisers to cause explosion and fire (ACG99).
4     Uses
      p-TBT is used primarily as an intermediate in the production of tert-butylbenzoic
      acid which is utilised in the manufacture of unsaturated polyesters and alkyd
      resins, and furthermore as a solvent, and as a perfume fixative (ACG99, NLM99).
5     Biotransformation and kinetics
      Uptake, distribution, and elimination of p-TBT were studied by exposing outbred
      albino male NMRI-mice to 6100 mg/m3 (1000 ppm), for up to 8 hours. After 30
      minutes of exposure, concentrations of p-TBT in kidney, brain, and mesenteric
      fat were roughly 5 times those in blood. Thereafter, kidney:blood concentration
      ratios remained about the same, while the brain:blood concentration ratios
      declined to about 2-3 at 8 hours. At this latter time point, mesenteric fat
      concentrations increased to about 9 times those in blood. The ratio of the
030-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      liver:blood concentration was nearly constant: about 1.5 and about 3 at 30
      minutes and 8 hours, respectively. Elimination curves for p-TBT of blood, brain,
      liver, kidney, and mesenteric fat after a 4-hour exposure showed nonlinearity
      indicative of a kinetic model with at least 2 compartments. The data did not
      suggest accumulation of the compound in fat or nervous tissue. This was
      confirmed by the lack of detectable amounts of p-TBT in mesenteric fat 24 hours
      after a single 4-hour exposure to 6100 mg/m3 (1000 ppm). Barely detectable
      amounts were found after 5 subsequent daily 4-hour exposures to 6100 mg/m3
      (1000 ppm) (Ras80).
          The distribution of p-TBT was studied by exposing male Wistar rats to
      [methyl-14C]p-tert-butyltoluene, for 15 minutes. Results from whole-body
      autoradiography showed that radioactivity was rapidly distributed throughout
      the body with relatively high amounts in the brain and the spinal cord (white
      matter), the liver, lungs, kidneys, bone marrow, and Harderian gland. The
      radioactivity in the brain rapidly declined to trace levels at 4 hours. In lungs and
      kidneys, trace levels were found at 12 and 48 hours, respectively, while in the
      liver, radioactivity was still present at 96 hours. Radioactivity was detected in
      bile and intestinal contents from 1 to 96 hours, in adrenals from immediately after
      exposure up to 8 hours, and in blood, intestinal mucosa, and bone marrow up to
      12 hours. Radioactivity was present at all time points in the skin, adipose tissue,
      and the Harderian gland at levels increasing with time, and in subcutaneous and
      mesenteric fat at levels decreasing with time (Ing82).
          Metabolism was studied in male Wistar rats and male Dunkin Hartley guinea
      pigs by oral (gavage) administration of 100 mg radiolabelled p-TBT/kg bw or by
      inhalation of trace concentrations for 24 hours. There were no route-dependent
      differences in metabolism. The tert-butyl group was oxidised to alcohol and
      carboxylic acid derivates. The majority of the radioactivity was eliminated in
      urine and faeces (ratio: 3.5:1) over the first 3 days and a recovery of 83% was
      achieved (over 10 days). The major urinary metabolites in rats were
      p-tert-butylbenzoic acid and its alcohol derivate
      2-(p-carboxyphenyl)-2-methylpropan-1-ol, whereas p-tert-butylbenzoylglycine
      was the most prominent in the guinea pig urine. Based on these data, the authors
      proposed a metabolism scheme as presented in Annex II (Wal83).
030-5 p-tert-Butyltoluene
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<pre>6     Effects and mechanism of action
      Human data
      When human volunteers were exposed to 30, 61, 122, 244, 366, 488, and 975
      mg/m3 (10-160 ppm) (n=4-9/group), for 5 minutes, 1/9, 1/4, 1/6, 0/4, 3/5, 2/5, and
      2/4 volunteers complained of eye irritation. The degree of irritation was not
      classified, but irritation was generally mild except for 2 cases of moderate
      irritation at 488 mg/m3 (80 ppm). Occasionally, nose - 1 or 2 cases at levels of 61
      mg/m3 (10 ppm) and higher - and throat - 2 cases at 366 and 975 mg/m3 (60, 160
      ppm) each - irritation were noted. Other incidental complaints included metallic
      or menthol taste (at 122, 366, and 488 mg/m3), nausea, and giddiness and
      increased breathing (at 975 mg/m3). Except for the highest concentration of 975
      mg/m3 (160 ppm), these exposure levels were not experienced as objectionable
      (Hin54).
           Reviewing health records of 33 operators exposed to p-TBT over the past 3
      years revealed that 8 of them had volunteered specific complaints of symptoms
      such as nasal irritation, nausea, malaise, headache, and weakness. Objective
      findings were: a cardiovascular symptom characterised by decreased blood
      pressure, increased pulse rates, and failure to respond satisfactorily to the
      Master’s test in 8 persons, tremor and anxiety in 4, and evidence of a chemical
      irritation from contact with p-TBT in 2. Laboratory findings showed evidence of
      peripheral blood changes. These changes included decreased haemoglobin
      values (in 8 persons; lowest value obtained: 78%), decreased erythrocyte count
      (in 2), leucopenia (in 7), eosinophilia (in 13), prolonged clotting time (in 5), and an
      elevated icterus index (in 2). The changes were of a mild and transient nature.
      There were no indications of abnormal kidney functioning. Generally, exposure
      concentrations were 60 mg/m3 (10 ppm) or less, but at specific operations,
      exposure could amount to 2135 mg/m3 (350 ppm) (Hin54).
      Animal data
      Irritation and sensitisation
      When p-TBT was applied to the clipped intact and scarified skin of rabbits, the
      Draize irritation score was less than 0.5 (maximum possible score: 8.0). Further, it
      was reported that erythema was more pronounced in the intact than in the
030-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      scarified skin and that oedema at the application site was found in 1/6 animals. A
      subcutaneous injection of 1 mL/kg caused extensive skin ulcerations in 2/3
      rabbits (Hin54).
          In the Magnusson-Kligman maximisation test performed according to OECD
      guidelines, intracutaneous administration at a concentration of 20% and
      subsequent epidermal administrations at concentrations of 100 and 50%,
      respectively, did not induce sensitisation in female guinea pigs (Hül87).
          When installed into the eyes of rabbits, average total Draize’s scores were
      9.3, 6.6, and 4.0 at 1, 24, and 72 hours, respectively (maximum possible score:
      110). The most consistent sign of irritation was a moderate to heavy discharge.
      At 24 hours, slight chemosis was seen but this had disappeared before the next
      reading at 48 hours (Hin54).
          Some eye and respiratory tract irritation was seen in rats exposed for 8 hours
      to 363 mg/m3 (60 ppm), the lowest concentration tested in a study on the acute
      toxicity of p-TBT (Hin54).
          Sensory irritation of the upper respiratory tract was evaluated in mice (male
      Swiss-Webster) during a 30-minute oronasal exposure to increasing
      concentrations of p-TBT. The airborne concentration resulting in a 50% decrease
      in the respiratory rate (RD50) was 2200 mg/m3 (360 ppm). No pulmonary irritation
      was found in cannulated mice exposed to a concentration eliciting a 50%
      decrease in the respiratory rate due to sensory irritation in normal mice (i.e., 2000
      mg/m3 or 330 ppm)(Nie82).
      Acute toxicity
      In female rats (Long-Evans), an 8-hour LC50 of 1000 mg/m3 (165 ppm) has been
      estimated while 1-, 2-, and 4-hour LC50s were 5660, 4448, and 1503 mg/m3 (934,
      734, 248 ppm), respectively. In male mice, the 4-hour LC50 was 1503 mg/m3 (248
      ppm). The principle effects were impairment of the nervous system and the
      respiratory tract (among others, spastic and flaccid paralysis, clonic and tonic
      convulsions, epileptoid seizures, extreme respiratory difficulty, nasal discharge,
      salivation). Apart from slight dyspnea at the higher concentration, no effects
      were seen in rabbits exposed to 2727 or 6060 mg/m3 (450, 1000 ppm) for 4 hours.
      No systemic effects were seen in rats exposed to 363 mg/m3 (60 ppm), for 8 hours.
      At postmortem examinations, pulmonary tract irritation, enlargement and
      yellowish discolouration of the liver, and engorgement of the abdominal viscera
      were generally observed. Microscopic lesions were described in a general way
      and not clearly in relation to exposure levels and exposure routes. They included
030-7 p-tert-Butyltoluene
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<pre>      amongst others centrolobular or diffuse fatty infiltration in the liver, fine granular
      changes in renal tubular epithelium, pulmonar emphysema, diffuse pulmonary
      oedema and severe haemorrhage. Lesions in the brain obviously found in
      animals exposed to levels of1210 mg/m3 (200 ppm) were summarily characterised
      by oedema of the meninges and white matter, myelin degeneration, and reactive
      gliosis (Hin54; see also Ung55). Exposure to ca. 24,000 mg/m3 (4000 ppm), for 30
      and 50 minutes, or to ca. 6100 mg/m3 (1000 ppm), for 60 minutes, caused mortality
      in 8/8 and 4/7 male rats (Long-Evans), respectively. One of the survivors showed
      residual neurologic signs after 24 hours (Fur58).
          In male rats (Wistar) exposed to 0, 305, and 915 mg/m3 (50, 150 ppm), for 6
      hours, statistically significant differences were found lasting for 5 days in
      animals exposed to 305 mg/m3 and for at least 12 days in animals exposed to 915
      mg/m3 (Lun93).
          A dermal LD 50 of 19.6 mL/kg (ca. 17,000 mg/kg) has been estimated in rabbits.
      In the treatment-related deaths, mainly effects on the nervous system were seen.
      No effects were seen at a dose of 10.7 mL/kg (ca. 9,200 mg/kg) (Hin54).
          Oral LD 50s of 1500, 800, and 1800 mg/kg bw have been reported for male rats
      (Long-Evans), male mice (Webster), and male albino rabbits, respectively. As
      with inhalation and dermal exposure, signs of impairment of the nervous system
      were predominant (Hin54).
      Repeated dose toxicity
      When rats (Long-Evans) were exposed to air saturated with vapours of p-TBT
      (ca. 5185 mg/m3 or 850 ppm) for 1 hour/day, 5 days/week, for 5 (n=5/sex), 7
      (n=10/sex), or 10 (n=5/sex) days, clonic convulsions and tremors were induced in
      30% of the animals followed by dyspnea and paralysis after the second and third
      exposure. After 10 exposures, mortality amounted to 80%. In most animals, death
      was caused by pulmonary oedema and pneumonia (Hin54).
          When male rats (Long-Evans; n=10) were exposed to 6100 mg/m3 (1000 ppm)
      gradually increasing from 12 minutes/day (on day 1) to 2 hours/day (on days
      10-17) over a 17-day period, mean body weight gain was decreased when
      compared to controls, but no mortality occurred. At day 17, the rats were so
      weak, lethargic, and poorly coordinated that the exposures were terminated. At
      autopsy, no changes were found in the nervous system tissues of exposed
      animals (Fur58).
          In male Wistar rats (n=9) exposed to 132 mg/m3 (20 ppm), 6 hours/day, for 14
      days, significant changes were found in the amplitudes of flash evoked
030-8 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      potentials on day 2, 19, and 26 after cessation of the exposure, but not on days 5
      and 12. The authors considered these effects as adverse since they were thought
      to be indicative of impairment of an important function of the brain, namely
      selective control and reduction of the stream of information from the sensory
      organs. There were no significant differences in body weight gain during and
      after exposure between the exposed and control group (Lun95).
           Female rats (Long-Evans; n=10/group) were exposed to ca. 175 and 350
      mg/m3 (25-30 and 50-60 ppm) of p-TBT for 1, 2, 4, or 7 hours/day, 5 days/week.
      Half of the animals of the 50-60-ppm and 25-30-ppm group were killed after 5 and
      10 weeks, respectively, while the remaining animals were exposed for 26 weeks.
      In the animals exposed for 5 or 10 weeks, no mortality, statistical significant body
      weight gain changes, or unusual behaviour were observed. During exposure, eye
      irritation (blinking, closing lids, encrustation) and slightly lowered respiration
      rate occurred. Relative organ weight changes which were determined for liver,
      kidneys, lungs, spleen, and heart included increases in liver weights in animals
      exposed to 175 mg/m3 for 2, 4, or 7 hours and in animals exposed to 350 mg/m3 for
      7 hours, in kidney weights in animals exposed to 350 mg/m3 for 2 hours, and in
      spleen weights in animals exposed to 175 mg/m3 for 1 hour. There were no effects
      on mean haemoglobin, erythrocyte, and leucocyte values. Apart from moderate
      brown-mottled discolouration of the liver of the animals exposed for 7 hours, no
      gross or histological changes were found in the low-concentration group. In the
      high-concentration group, there were effects on the liver (brown-mottled
      discolouration; mild peripheral fatty changes), the lungs (patchy emphysema;
      oedema of tracheal mucosa with partial desquamation of the surface epithelium),
      kidneys (fat deposits in renal tubular epithelium), and the heart (focal necrosis in
      the myocardium). As to the nervous system, no lesions were found at exposures
      for 1 or 2 hours while those in animals exposed for 4 or 7 hours were not
      concentration related and of identical severity. They were stated to be
      essentially those of chronic encephalomeningitis characterised by accumulation
      of neuroglial cells around the damaged neurons of the deep cortical areas,
      striatum, and medulla oblongata. Diffuse demyelination of the corpus callosum
      and pedunculi cerebri were observed as well. In the animals exposed for 26
      weeks, no signs of toxicity were observed except for 3 rats exposed to 350 mg/m3,
      7 hours/day. One of these animals died in week 9, while the other animals
      showed transient effects on fore- or hindlegs. Although growth curves indicated
      a concentration- and exposure-duration-related increased growth retardation,
      these changes did not attain statistical significance, probably because of the
      original within-group weight variation. Relative organ weight changes included
030-9 p-tert-Butyltoluene
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<pre>       increases in liver weights in animals exposed to 175 mg/m3 for 4 and 7 hours and
       in all animals exposed to 350 mg/m3, and in kidney weights in animals exposed to
       350 mg/m3 for 2, 4, or 7 hours. Except for a decreased leucocyte count in animals
       exposed to 350 mg/m3 for 2, 4, or 7 hours, there were no statistically significant
       changes in haemoglobin, erythrocyte, and leucocyte values. At necropsy, there
       were no remarkable consistent changes in the animals exposed to 175 mg/m3. In
       the high-concentration group, only occasional gross findings were reported
       including 2 cases of bronchiectasis, 2 cases of friable liver, 1 case of discoloured
       kidneys and abnormally pale liver. Microscopic examinations only showed
       infrequent mild peripheral fatty changes in the liver, and there was no evidence
       of cirrhosis or renal tubular changes. Nervous system lesions were similar to
       those found at 5- and 10-week exposures (Hin 54; see also Ung55).
           Following oral (gavage) administration, no mortality was seen in male rats
       (SPF; n=8/group; controls: n=4) given 0, 12.5, 25, 50, or 100 mg/kg bw (vehicle:
       rape oil), once a day, for 5 days. Clinical signs were seen in the animals of the 2
       highest dose groups and included loss of hair, shaggy fur, hunched posture,
       lethargy, and diarrhoea. In these groups, body weight gain was severely
       affected. At autopsy, only the liver, kidneys, and testes were examined. No
       changes were seen in the animals given 12.5 or 25 mg/kg. In the other 2 groups,
       delineation of hepatic lobules and structural changes of germinal epithelium
       (degenerated spermatids and spermatocytes, reduced spermatozoa, sporadic
       occurrence of giant cells) were observed. In the animals of the 100 mg/kg group,
       testes weight were decreased (ca. 23%) when compared to controls. In a similar
       experiment in male mice (SPF; n=6) given 100 mg/kg bw, minor damage of
       germinal epithelium was found, while in guinea pigs (Himalayan spotted SPF;
       n=5) and dogs (Beagle; n=2), administration of 100 mg/kg bw caused moderate
       germinal epithelial damage and very slight seminiferous tubular atrophy in one
       guinea pig and one dog, respectively (Ano86b).
       Mutagenicity and genotoxicity
       p-TBT was found negative when adequately tested with and without metabolic
       activation in S. typhimurium strains TA1535, TA1537, TA1538, TA98, and
       TA100 (Bro81, Dea85, Hül87, Zei87) and E. coli strain WP2 and WP2 uvrA
       (Bro81, Dea85). In liquid cultures of the yeast S. cerevisiae JD1, p-TBT did not
       induce gene conversions (Bro81, Dea85). As to mammalian cell systems, the
       compound did not cause chromosome damage (chromatid gaps, breaks) when
       tested in cultured rat liver (RL1) cells (Bro81, Dea85).
030-10 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       Reproduction toxicity
       In rats, 5 daily doses of 50 or 100 mg/kg bw of p-TBT caused structural changes
       of the germinal epithelium while testes weights were decreased by 23% at the
       high dose. No such effects were seen at doses of 12.5 and 25 mg/kg bw. When
       mice, guinea pigs, and dogs were given 100 mg/kg bw (the only dose tested),
       minor germinal epithelial damage was found in mice, while there was moderate
       damage in 1/5 guinea pigs and very slight atrophy in 1/2 dogs (see also section
       on repeated dose toxicity) (Ano86b).
            When pregnant rats (Mol:WIST; number not reported) were exposed to 132
       mg/m3 (20 ppm) p-TBT, 6 hours/day, on gestational days 7-20, no maternal
       toxicity was induced. In the offspring, viability was not decreased, but lower pup
       body weight until day 10 and delayed ontogeny of reflexes, also after correction
       for body weight, was observed. Learning and memory abilities were investigated
       at the age of 3, 17, and 22 months using the Morris water maze. In this test, rats
       have to spatially navigate using distal extramaze cues to locate a small platform
       under the water surface in a large pool. At 3 months, latencies and swim length
       were increased in the learning period in the female offspring of the exposed
       group (p=0.6%). When tested 3 weeks later, there were some indications of
       impaired memory, but increases in latency and swim length did not reach
       statistical significance (p=8.7%). At 17 months, no impairment was seen. At 22
       months, memory impairment of the female offspring of the exposed animals was
       observed, but it was not clear whether this was the consequence of prenatal
       exposure to the test substance or to an interaction of prenatal exposure and
       aging (only an abstract available) (Has96).
            In an abstract on screening a number of compounds - selected as
       representatives of chemical classes - for possible teratogenic effects, it was
       reported that p-TBT was teratogenic - defined as producing either a gross
       abnormality or a significant change in body weight and certain bone lenghts -
       when tested in the rat fetus and the chick embryo (no details given) ( Roc68).
7      Existing guidelines
       The current administrative occupational exposure limit (MAC) for p-TBT in the
       Netherlands is 6.1 mg/m3 (1 ppm), 8-hour TWA.
            Existing occupational exposure limits for p-TBT in some European countries
       and in the USA are summarised in Annex I.
030-11 p-tert-Butyltoluene
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<pre>8      Assessment of health hazard
       p-TBT is readily absorbed from the respiratory and gastrointestinal tract, rapidly
       distributed throughout the body, and after being metabolised excreted in urine
       and faeces within a few days.
            Following exposure to 30 mg/m3 (5 ppm) of p-TBT, for 2 minutes, one out of 9
       volunteers complained of eye irritation. At higher levels, eye, nose, and throat
       irritation, metallic/menthol taste, nausea, and giddiness were occasionally
       complained of, and a concentration of 975 mg/m3 (160 ppm) was experienced as
       objectionable. Reviewing health records of operators considered to be exposed
       to average levels of p-TBT of 60 mg/m3 (10 ppm) with peak levels of 2135 mg/m3
       (350 ppm) revealed subjective symptoms (nasal irritation, nausea, malaise,
       headache, weakness) and objective findings (cardiovascular effects, tremor and
       anxiety, chemical irritation, and changes in peripheral blood), generally of mild
       and transient nature.
            Based on experimental animal data, the committee concludes that liquid
       p-TBT is at most slightly irritating to eyes and skin. The compound did not show
       sensitising properties when tested in the maximisation test in guinea pigs. In rats,
       concentrations of ca. 360 mg/m3 (60 ppm) were found to be irritating to the eyes
       and respiratory tract.
            From acute lethality data (4-hour LC50 rat: 1500 mg/m3; oral LD 50 rat: 1500
       mg/kg bw), the committtee considered p-TBT as toxic by inhalation and as
       harmful if swallowed, while no such qualification is warranted as to dermal
       exposure (LD 50 rabbit: ca. 17,000 mg/kg bw).
            Acute and repeated inhalation experiments in rats and rabbits showed that
       irritation of eyes and respiratory tract and effects on the nervous system are
       predominant and that chronic exposure may induce slight effects on the liver. In
       a generally poorly reported and limitedly designed 26-week study in which rats
       were exposed to concentrations of ca. 175 or 350 mg/m3 (25-30, 50-60 ppm, resp),
       no NOAEL could be established since at the lower concentration increased
       relative liver weights and lesions in nervous system tissues were found. In a
       14-day study with only one concentration, namely 132 mg/m3 (20 ppm),
       sensory-evoked potentials were affected suggesting impairment of controlling
       information from sensory organs by the brain.
            p-TBT did not induce mutations in bacteria (S. typhimurium, E. coli), gene
       conversions in yeast (S. cerevisiae), or chromosome damage in mammalian cells
030-12 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       (rat liver RL1 cells). The committee did not find data on in vivo genotoxicity
       testing.
            The committee did not find adequate studies on the potential reproduction
       toxicity of p-TBT, but the available data indicate that exposure to p-TBT may
       induce developmental toxicity. In rats, germinal epithelial damage was seen after
       5 daily oral doses of 50 and 100 mg/kg bw, but not at 25 mg/kg bw. Similar
       damage was observed in mice and to a lesser degree in guinea pigs and dogs at
       doses of 100 mg/kg bw (no other doses were tested).
            The committee did not find data on the potential carcinogenicity of p-TBT.
       The committee considers the toxicological data base on p-tert-butyltoluene too
       poor to justify recommendation of a health-based occupational exposure limit.
       The committee concludes that the limited information from 14-day and 26-week
       rat inhalation studies in which effects were found at levels of 132 and ca. 175
       mg/m3 (20 and 25-30 ppm, resp.) suggests that the present MAC-value of 6.1
       mg/m3 (1 ppm), 8-hour TWA, may be too high.
       References
ACG99  American Conference of Governmental Industrial Hygienists (ACGIH). p-tert-Butyl toluene.
       In: TLVs ® and other occupational exposure values -1999. [CD-ROM]. Cincinnati OH, USA:
       ACGIH® , Inc, 1999.
ACG00  American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
       exposure values - 2000. Cincinnati OH, USA: ACGIH® , Inc, 2000: 18.
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Ano83  Anonymus. Odor threshold of TBT and TBB. Letter and report submitted to US EPA by
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       VA, USA; order no OTS0510305).
Ano86a Anonymus. Saturation concentrations of TBT and TBB. Letter and report submitted to US
       EPA by unknown (sanitized) company. Report dated February 1986 (available from NTIS,
       Springfield VA, USA; order no OTS0510309).
030-13 p-tert-Butyltoluene
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<pre>Ano86b Anonymus. Acute oral toxicity studies performed with p-tert-butylbenzaldehyde,
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DFG01  Deutsche Forschungsgemeinschaft (DFG): Commission for the Investigation of Health
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030-14 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>Hül88  Hüls AG. Test of the skin sensitising effect of p-tert-butyltoluene for guinea pigs. Marl, FRG:
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Ras80  Rasmussen A, Holmberg B, Jakobson I. Uptake, ditribution and elimination of
       p-tert-butyltoluene (TBT) in mice by inhalation. Acta Pharmacol Toxicol 1980; 47: 236-8.
Ric92  Richardson ML, Gangolli S, eds. B295 4-tert-butyltoluene. In: The dictionary of substances
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       Hague, the Netherlands: Sdu, Servicecentrum Uitgevers, 2001: 20.
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       p-tertiary-butyltolyeen. AMA Arch Pathol 1955; 60: 139-49.
Wal83  Walde A, Scheline RR. Metatabolsm of p-tert-butyltoluene in the rat and guinea pig. Acta
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030-15 p-tert -Butyltoluene
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<pre>            Annex I
Occupational exposure limits for p-tert-butyltoluene in various countries.
country                             occupational             time -weighted  type of           notea     lit refb
-organisation                       exposure limit           average         exposure limit
                                    ppm        mg/m 3
the Netherlands
-Ministry of Social Affairs and     1          6.1           8h              administrative              SZW01
Employment
Germany
-AGS                                10         60            8h                                          TRG00
                                    10         60            15 min
-DFG MAK-Kommission                 -c         -c                                                        DFG01
Great-Britain
-HSE                                -          -                                                         HSE01
Sweden                              -          -                                                         Arb00b
Denmark                             1          6,1           8h                                          Arb00a
USA
-ACGIH                              1          6.1           8h              TLV                         ACG01
-OSHA                               10         60            8h              PEL                         ACG00
-NIOSH                              10         60            10 h            REL                         ACG00
                                    20         120           15 min
European Union
-SCOEL                              -          -                                                         CEC00
a
     S = skin notation; which means that skin absorption may contribute considerably to the body burden; sens =
     substance can cause sensitisation
b
     Reference to the most recent official publication of occupational exposure limits
c
     Listed among substances for which studies of the effects in man or in experimental animals have yielded
     insufficient information for the establishment of MAK values
030-16      Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>          Annex II
Proposed metabolism of p-tert-butyltoluene (p-TBT) in rats and guinea pigs (from Wal83).
030-17    p-tert-Butyltoluene
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