<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>2-Phenylpropene
(CAS No: 98-83-9)
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/088, The Hague, 22 October 2003
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. 2-Phenylpropene; Health-based Reassessment of
Administrative Occupational Exposure Limits. The Hague: Health Council of the
Netherlands, 2003; 2000/15OSH/088.
all rights reserved
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of
      2-phenylpropene 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 JJC Paulussen, Ph.D., Ir M Busschers, and H
      Stouten, M.Sc. (TNO Nutrition and Food Research, Zeist, The Netherlands).
          The evaluation of the toxicity of 2-phenylpropene 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, in April 1999, literature was searched
      in the on-line databases Medline, Toxline, CA, and NIOSHTIC covering the
      period 1966 to May 1999, 1965 to February 1999, 1967 to May 1999, and 1973
      to August 1998, respectively, and using the following key words:
      phenylpropylene, 2-phenyl-2-propene, 2-phenylpropene, isopropenylbenzene, 1-
      methyl-1-phenylbenzene, 1-methyl-1-phenylethylene, 1-methylethenylbenzene,
      1-methylvinylbenzene, 1-phenyl-1-methylethylene, 2-phenyl-1-propene,
      methylstyrene, methylstyrol, and 98-83-9. HSDB and RTECS, databases
      available from CD-ROM, were consulted as well (NIO99, NLM99). The final
      search was carried out in Toxline and Medline in December 2002.
          In April 2003, the President of the Health Council released a draft of the
      document for public review. The committee received no comments.
088-3  2-Phenylpropene
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<pre>2     Identit
       name                    :  2-phenylpropene
       synonyms                :  α-methylstyrene; isopropenylbenzene; 1-methyl-1-phenylethylene;
                                  β-phenylpropene; β-phenylpropylene; 1-methylethenylbenzene;
                                  1-methylethylenebenzene; 1-phenyl-1-methylethylene; 2-phenyl-1-propene;
                                  2-phenylpropylene
       molecular formula       :  C9H10
       structural formula      :
       CAS number              :  98-83-9
      Data from ACG99, NLM99.
3     Physical and chemical properties
       molecular weight        :  118.18
       boiling point           :  165.4oC
       melting point           :  -23oC
       flash point             :  83.9oC (closed cup); 57.8oC (open cup)
       vapour pressure         :  at 20oC: 0.25 kPa
       solubility in water     :  insoluble
       log Poctanol/water      :  3.48
       conversion factors      :  at 20oC, 101.3 kPa: 1 ppm = 4.9 mg/m3
                                                       1 mg/m3 = 0.20 ppm
      Data from ACG99, Lid94, NLM99.
      2-Phenylpropene is a colourless liquid, with a sweet, aromatic, penetrating
      odour. The odour threshold is about 0.3 ppm (1.4 mg/m3) (Amo83).
           During storage, 2-phenylpropene will polymerise, and is, therefore, usually
      stabilised with tert-butyl catechol as an inhibitor (ACG99, HSE96).
088-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>4     Uses
      2-Phenylpropene is used mainly as a monomer in plastic and resin manufacture
      (ACG99, Cav94, HSE96, NLM99).
5     Biotransformation and kinetics
      Dermal absorption may be limited since application of (an unknown amount of)
      undiluted 2-phenylpropene to the rabbit skin (5 days/week, for 2-4 weeks) did
      not result in signs of systemic toxicity (Wol56). Referring to an abstract, it was
      stated that absorption rates of 9.5 and 0.048-0.256 mg/cm2 were found for pure
      2-phenylpropene and for various aqueous dilutions, respectively. These figures
      were calculated based on spectophotometrical analysis of the amount remaining
      and washed off with ethanol after 0.1 mL of the test material was put in contact
      with human skin for 10 minutes (no more details available) (EPA87, NLM99).
          Urinary excretion data from inhalation experiments in human volunteers,
      rats, and guinea pigs and from oral experiments in rats and dogs indicate that 2-
      phenylpropene can be metabolised into 2-hydroxy-2-phenylpropionic acid
      (atrolactic acid or a-methylmandelic acid) while in human urine an additional
      metabolite, 2-hydroxy-2-phenylpropanol glucuronide, was identified (Bar70,
      EPA87). According to an abstract cited by EPA, the amount of 2-hydroxy-2-
      phenylpropionic acid excreted as percentage of inhaled 2-phenylpropene was 21,
      15.7, and 26.2% in guinea pigs, rats, and in humans, respectively, after exposure
      to 20-4000 mg/m3. In humans, the excretion kinetics of 2-phenylpropene
      metabolites were stated to be a first-order process being monophasic for
      2-hydroxy-2-phenylpropanol glucuronide and biphasic for 2-hydroxy-2-
      phenylpropionic acid (no more data presented) (EPA87). In rats treated orally
      with 2000 mg/kg, 2-phenylpropene was detected in the blood, liver, and placenta
      (abstract cited in EPA87; no further details given).
          In order to obtain a definitive characterisation of the metabolism of
      2-phenylpropene, the 14C-labelled compound was orally and intravenously
      administered to 1 and 4 male rats (F344), respectively, and tissue distribution,
      metabolism, and excretion (intravenous injection of 11 mg/kg bw) were
      investigated and metabolites characterised (oral dose of 1000 mg/kg bw).
      Following intravenous injection, ca. 34, 53, and 86% of the dose administered
      were excreted (cumulatively) in the urine within 6, 12, and 72 hours,
      respectively. About 2% each were excreted in the faeces and as breath volatiles
      within 72 hours while elimination as carbon dioxide was negligible. At sacrifice
088-5  2-Phenylpropene
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<pre>      (at 72 hours), only 0.3% of the radioactivity administered was found in the
      tissues sampled with the highest concentrations in the spleen (blood/tissue ratio:
      17), kidney (blood/tissue ratio: 12), bladder (blood/tissue/ratio: 7), and lung
      (blood/tissue ratio: 6). After oral administration, the percentage radioactivity
      excreted in urine and the urinary metabolite profile were similar to those after
      intravenous injection. The following 5 metabolites were isolated from the urine:
      2-phenyl-1,2-propanediol (3% of urinary radioactivity) and its glucuronide
      (50%), 2-hydroxy-2-phenylpropionic acid (atrolactic acid; 27%), S-(2-hydroxy-
      2-phenylpropyl)-N-acetylcysteine (13%), and 2-phenylpropionic acid (1%); the
      glucuronides and mercapturates were each conjugated on the methylene carbon
      beta to the ring. The presence of both of the diastereomeric forms of those
      conjugates suggested that the initial epoxidation of 2-phenylpropene was not
      selective and proceeded with addition of active oxygen to yield enantiomeric
      epoxide. Incubation of 2-phenylpropene with human liver slices for 5 hours,
      resulted in the formation of the same as found in vivo in rats, with 2-phenyl-1,
      2-propanediol accounting for 25% of the radioactivity, 2-hydroxy-2-
      phenylpropionic acid (atrolactic acid) and 2-phenylpropionic acid each for about
      1%, and the remainder for less than 0.3%. Based on these data, a metabolism
      scheme as presented in Figure 1 (see Annex I) has been proposed (Cos01).
          An in vitro study in rat liver mitochondria revealed that 2-phenylpropene
      uncouples the oxidative phosphorylation, stimulates the Mg2+-dependent ATPase
      activity, and thereby stimulates the passive entry of protons into mitochondria
      (Mic88).
6     Effects and mechanism of action
      Human data
      In letters sent to the Document Control Officer at US EPA, two cases of urticaria
      were reported, for which there was reasonable medical indication that these
      allergic reactions were probably related to occupational exposure to
      2-phenylpropene. The first, more severe case, was described in more detail: since
      the allergy occurred, the symptoms like itching and hives with pressure or skin
      scratching (dermatographism) had progressed without known 2-phenylpropene
      exposure (Ano86, Ano88). In an attachment, abstracts of two papers (the results
      of a literature search on dermal sensitisation of 2-phenylpropene) were
      presented. In one of these, 2-phenylpropene was stated to be one of the chemicals
      used in the production of divinylstyrene rubber causing skin sensitisation. In the
      other paper, exposure was to ‘methylstyrene’ (not ‘α-methylstyrene’) and,
088-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      therefore, no definitive statement to the sensitisation potential of 2-
      phenylpropene was said to be possible (Ano88).
      Human subjects quickly entering a room in which 2-phenylpropene was present
      in the atmosphere reported no detectable odour at concentrations less than 48
      mg/m3 (10 ppm) while 241 mg/m3 (50 ppm) was detectable but not irritating. A
      level of 483 mg/m3 (100 ppm) resulted in a strong odour but was tolerable
      without excessive discomfort and 970 mg/m3 (200 ppm) caused an objectionable,
      strong odour and slight eye irritation. Concentrations of 2900 mg/m3 (600 ppm)
      and higher had a very strong odour and induced strong eye and nasal irritation
      (Wol56).
          EPA has summarised data - all from abstracts - on occupationally exposed
      workers. Findings included effects on the nervous system, the respiratory tract,
      and the haematopoietic system. However, mostly, exposure was to mixtures of
      chemicals and no information on exposure levels was available (EPA87).
      Animal data
      Irritation and sensitisation
      Moderate to marked irritation and slight necrosis were observed when undiluted
      2-phenylpropene was applied to the ear and onto the shaved abdomen of white
      rabbits, 10-20 times, over a period of 2-4 weeks (Wol56). Uncovered application
      of 0.01 mL of undiluted 2-phenylpropene to the belly of 5 rabbits resulted in
      marked capillary injection in all rabbits within 24 hours (Mye75). Irritation
      scores of 0.0 (maximum: 8.0) were found when 0.5 mL of undiluted ‘crude’
      2-phenylpropene (purity unknown) or 0.5 mL undiluted cumene-containing
      material (purity: 95%, amount of cumene unknown) were applied to the clipped
      skin of rabbits (1 female and 2 males per compound), under occlusion for 24
      hours (observation period: 7 days). Testing 0.5 mL of another lot of undiluted
      ‘crude’ material (purity unknown), under occlusion for 4 hours, caused very
      slight to slight erythema and very slight to clear oedema at 4, 24, 48, and 72
      hours while readings were zero at 1, 120, and 168 hours (Bir72). Referring to an
      abstract, it was stated that 20 daily applications of 30% 2-phenylpropene, caused
      inflammation, hyperaemia, oedema, hyperkeratosis, changes in the thickness of
      the epithelial layer, and desquamation of the skin of the treated rabbits (EPA87).
          Two drops of 2-phenylpropene applied to the eyes of rabbits resulted in slight
      conjunctival irritation and no corneal injury (Wol56). No corneal injury was
      observed, 24 hours after instillation of 0.5 mL of undiluted 2-phenylpropene into
088-7  2-Phenylpropene
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<pre>      the eyes of 5 rabbits (Mye75). When 0.1 mL undiluted ‘crude’ 2-phenylpropene
      was instilled into the right eye of one male and 2 female rabbits, the average
      maximum score was 14.0 (maximum: 110) found at 1 hour declining to 2.0 at 72
      hours. Readings were zero at 120 and 168 hours. During the observation period,
      slight to severe erythema, very slight to slight oedema, and slight to copious
      discharge were observed. Similar results were obtained with the aforementioned
      cumene-containing test substance (Bir72).
          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 (probably 10 Swiss OF1) mice, the RD50 for
      2-phenylpropene was approximately 1320 mg/m3 (264 ppm) (Mul84; see also
      Bos92).
          No data were available on the potential sensitising properties of
      2-phenylpropene.
      Acute toxicity
      Three out of 6 male rats died within 48 hours following a 6-hour exposure to
      22,850 mg/m3 (4570 ppm) of ‘crude’ 2-phenylpropene of unknown purity.
      During exposure, shallow and rapid respiration and roughened fur were observed
      while all animals collapsed in the second part of the exposure period. At autopsy,
      slight lung congestion was seen in the survivors sacrificed at the end of the 10-
      day observation period while haemorrhagic lungs, slight liver discolouration, and
      gastrointestinal inflammation were observed in the treatment-related deaths.
      Following exposure to 10,000 mg/m3 cumene-containing 2-phenylpropene (see
      section on irritation), no mortality was observed. No toxic signs were seen during
      exposure and the 10-day post-exposure observation period. There were no
      changes at macroscopic examinations (Bir72). In another report, an 8-hour
      exposure to ‘substantially saturated vapour’ caused mortality in 2/6 rats. Clinical
      signs included closed eyes, poor coordination, prostration, followed by complete
      anaesthesia within 5 hours and eventually death within 7 hours. There were no
      remarkable changes at post-mortem gross examinations (Mye75). Exposure to
      14,500 mg/m3 (3000 ppm) has been reported to cause mortality in rats and guinea
      pigs (no details) (Cav94, NLM99). Further, it was summarised that exposure to
      2920 ppm (14 g/m3), for 5 hours, caused respiratory irritation and central nervous
      system depression in rats, mice, and guinea pigs within 15 to 60 minutes, and
      mortality in mice after about 4 hours while rats and guinea pigs survived the
      5-hour exposure (Her87). In a subacute experiment, mortality - of which the
      cause could not be established - was found in 1/18, 10/18, and 5/24 mice after the
088-8 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      first 6-hour exposure to mean actual concentrations of 596, 799, and 1056 ppm
      (2920, 3915, 5174 mg/m3), respectively (Mor99).
           Following dermal application of ‘crude’ compound (purity: unknown), no
      mortality was observed in rabbits (n=1/dose) at doses of 501 to 7940 mg/kg bw
      (observation time: 10 days). Toxic signs included reduced appetite, reduced
      activity, and weight loss in female animals. No changes were seen upon post-
      mortem examinations. When cumene-containing material (see section on
      irritation) was applied at doses of 2000 (1 male), 3160 (1 female), 5010 (1 male),
      and 7940 (1 male, 1 female) mg/kg bw, the high-dose male rabbit died, autopsy
      revealing haemorrhagic areas of the lungs and slight liver discolouration. In the
      surviving animals, reduced appetite and activity, lethargy, collapse, and some
      weight loss were seen. Viscera were normal at macroscopic examination (Bir72).
      Dermal application of 16 mL/kg (ca. 14,400 mg/kg), for 24 hours, killed 3 out of
      7 rabbits. Erythema and leathery or scaly skin, and hiccup-like spasms were
      noted. Spleens and kidneys were congested in the animals that died during the
      study while no remarkable changes were seen in the animals sacrificed at the end
      of the observation period (Mye75).
           Following the administration of single oral doses in male rats, an LD50 of
      4900 mg/kg was reported. At autopsy, slight liver changes were observed
      (Wol56). Using both male and female rats, an LD50 of 2840 mg/kg bw has been
      estimated for ‘crude’ 2-phenylpropene (purity unknown). Most animals died
      within 3 days. Signs observed included reduced appetite and activity, increased
      weakness, ocular discharge, and collapse. At autopsy, hyperaemia of lungs and
      liver and gastrointestinal inflammation were seen in the treatment-related deaths
      while there were no changes in the other animals. For the aforementioned
      cumene-containing lot, an LD50 of 4470 mg/kg bw was estimated (Bir72). In a
      separate study performed in young (3-4 weeks) male rats, mortality rates of 0/5,
      4/5, and 5/5 were found after single oral doses of 4.0, 8.0, and 16.0 mL/kg
      respectively, resulting in a LD50 of 6.50 mL/kg (ca. 5900 mg/kg). Clinical signs
      included rubbing mouth on bottom of cage immediately after dosing,
      sluggishness, prostration, and unsteady gait. Necropsy of the treatment-related
      deaths revealed slight petechial haemorrhages in the lungs, mottled livers and
      spleens, distended stomachs filled with liquid or gas, white pylorus, yellow,
      liquid- or gas-filled transparent intestines, slightly congested kidneys, and full
      bladders. In the animals sacrificed at the end of the observation period, mottled
      livers were observed (Mye75).
088-9  2-Phenylpropene
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<pre>       Repeated-dose toxicity
       When rats (F344; n=5/sex/group) were exposed to target concentrations of 0,
       600, or 1000 ppm (2940, 4900 mg/m3), 6 hours/day, 5 days/week, for a total of
       12 exposures, no mortality, sedation, or effects on body weight or clinical
       chemistry values were observed. Post-mortem examinations of lungs, liver,
       kidneys, spleen, nasal cavity, brain, stomach, heart, thymus, and adrenal glands
       showed significant increases in relative weights of the livers of the animals of
       both exposure groups, of the lungs of the male animals of the high-concentration
       group, and of the kidneys of the males of the low-concentration group.
       Microscopically, no significant lesions other than increased accumulation of
       hyaline droplets in the renal tubules of the male animals exposed to 600 and 1000
       ppm were found. In order to better characterise this latter effect, male and female
       F344 rats and male NBR rats (an α2u-globulin-deficient strain) (n=4/strain/sex/
       group) were exposed to target concentrations of 0, 125, 250, and 500 ppm (0,
       612, 1225, 2450 mg/m3), 6 hours/day, 5 days/week. After a total of 9 exposures,
       animals were sacrificed and (only) the kidneys were collected for histological
       evaluation. There was no effect on body or kidney weight in any of the treated
       groups. The only renal lesion observed was hyaline droplet accumulation. This
       was seen only in male F344 rats exposed to 250 and 500 ppm and not in female
       F344 rats, male NBR rats, or male F344 rats exposed to 125 ppm (Mor99). When
       mice (B6C3F1; n=30 males, 18 females/group) were exposed to actual mean
       levels of 0, 133, 245, and 489 ppm (652, 1200, 2396 mg/m3), 6 hours/day, 5 days/
       week, for 12 days, no compound-related effects were found on body or organ
       weights, haematology, clinical chemistry, or histology in any of the treated
       groups. In a follow-up study, mice (n=18/sex/group, plus an additional 6/sex in
       the high-concentration group) were exposed to mean actual concentrations of
       596, 799, and 1056 ppm (2920, 3915, 5174 mg/m3), 6 hours/day, 5 days/week,
       for 12 days (target concentrations: 600, 800, 1000 ppm). Interim sacrifices (n=6/
       sex/group) were performed after 1 (only for liver weighing and glutathione
       analysis) and 5 exposures. Treatment induced mortality in female animals only:
       after the first exposure, 5/24, 10/18, 1/18 animals were found dead in the high-,
       mid- and low-concentration group, respectively. The cause of death could not be
       established. Immediately after the first 6-hour exposure, all mice of all groups
       were sedated. During exposure and for about 1-hour post-exposure, the animals
       were hypoactive and did not respond to noise. By the second week, there was
       adaptation, and animals were no longer sedated during exposure. Significant
       decreases in body weights were found in the male animals of all exposure groups
       while those of female animals were comparable to those of controls throughout
088-10 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       the study. Significant relative organ weight changes found included decreases in
       spleen weights in all exposure groups and increases in liver weights in male
       animals exposed to 799 and 1056 ppm for 1, 5, or 12 days and to 596 ppm for 5
       days and in female animals of all exposure groups at all these time points (except
       those exposed to the low concentration for 1 day). There were no changes in
       clinical chemistry. Liver glutathione levels measured after 1 and 5 exposures
       were decreased. No lesions were found at microscopic examinations of lungs,
       kidneys, nasal cavity, brain, stomach, heart, thymus, or adrenal glands (Mor99).
           In a subchronic study, rats (F344; n=10/sex/group) were exposed by whole-
       body inhalation to 2-phenylpropene vapour concentrations of 0, 75, 150, 300,
       600, or 1000 ppm (i.e., 0, 367.5, 735, 1470, 2940, 4900 mg/m3), 6 hours/day, 5
       days/week, for 13 weeks. No mortality or clinical signs of toxicity were seen in
       any of the groups. In the animals of the high-concentration group, there was a
       small - not statistically significant - decrease in mean final body weight (4.4 and
       5.1% in females and males, respectively). Exposure did not induce remarkable
       changes in haematology parameters in any of the treated groups. The most
       notable changes in clinical chemistry and urinalysis parameters included
       increased total bile acid concentrations in both sexes on day 3 and 23 at
       concentrations >600 ppm (on day 23 also in males at concentrations of 150 and
       300 ppm), increased blood urea nitrogen on day 3 in males and females and day
       23 (in males) at concentrations >600 ppm, and elevated urinary protein and
       enzymes in males and females at concentrations >300 and >600 ppm,
       respectively. Post-mortem examinations showed increases in absolute kidney
       weights in males and females at 1000 ppm, in relative kidney weights in males at
       >150 ppm and in females at >600 ppm, in absolute liver weights in males and
       females at >600 ppm, and in relative liver weights in males at >150 ppm and in
       females at >600 ppm. No gross lesions were seen in any of the treated groups.
       Histological changes included increased incidences in hepatocellular necrosis in
       females animals exposed to 600 (4/10) and 1000 ppm (9/10) when compared
       with controls (2/10). In males, incidences in hyaline droplets and tubular
       regeneration in the renal cortex were increased at >150 ppm. In male rats, the
       amount of α2u-globuline in the kidneys was dose dependently increased at
       >75 ppm while renal cortical cell turnover rates using proliferating cell nuclear
       antigen immunohistochemistry were elevated at 300 and 1000 ppm. No effects
       on the respiratory tract were observed (data, i.e., abstract and summary tables
       only, submitted to, but not peer reviewed by NTP) (NTP01). The committee
       considers the kidney lesions found in the male rats as an α2u-globuline-induced,
       typical male rat event and, therefore, not for human risk assessment. Based on
088-11  2-Phenylpropene
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<pre>       the increased relative liver weights in male rats exposed to 150 ppm and higher,
       the committee sets the NOAEL in this study at 75 ppm (367.5 mg/m3).
           In a similar study, mice (B6C3F1; n=10/sex/group) were whole-body
       exposed to 0, 75, 150, 300, 600, or 1000 ppm (i.e., 0, 367.5, 735, 1470, 2940,
       4900 mg/m3), 6 hours/day, 5 days/week, for 13 weeks. Except for 2 females in
       the 1000-ppm group dying after 2 exposures following sedation and coma, no
       mortality was observed. Clinical signs of toxicity were limited to moderate to
       severe sedation and ataxia in almost all male and female animals after exposure
       to 1000 ppm on day 1 and 2 (ataxia only) and in female animals on day 9 after 3
       days off exposure. Decreases in mean final body weights were observed in male
       animals exposed to 300 (-5.1%), 600 (-13.0%; p<0.01), and 1000 ppm (-16.6%;
       p<0.01) and in females exposed to 75 (-8.7%; p<0.01), 300 (-8.8%; p<0.01), 600
       (-4.2%), and 1000 ppm (-10.8%; p<0.01). Apart from a very mild, non-
       regenerative anaemia in females exposed to 1000 ppm, no haematological effects
       were found in any of the other treated groups. Post-mortem examinations did not
       reveal remarkable gross lesions. Organ weight changes included increases in
       absolute liver weights in females at >600 ppm, in relative liver weights in males
       and females at >300 ppm, and in increased relative lung weights in males at >300
       ppm (and in both sexes at 75 ppm), and in decreases in absolute thymus weights
       in males at >600 ppm and in females at 75 and 1000 ppm. Histologically, there
       were centrilobular hypertrophy in the livers of male and female mice exposed to
       600 and 1000 ppm and nasal lesions (olfactory epithelial necrosis, atrophy, and
       metaplasia; glandular atrophy and hyperplasia; respiratory epithelial hyaline
       degeneration) at concentrations of >75 ppm (data, i.e., abstract and summary
       tables only, submitted to but not peer reviewed by NTP) (NTP01). The
       committee could not establish a NOAEL in this study since nasal lesions were
       induced at 75 ppm (367.5 mg/m3), the lowest level tested.
           In a - limitedly reported - inhalation study, rats (10-25), guinea pigs (5-10),
       rabbits (1-2), and monkeys (1-2) were exposed 7-8 hours/day, 5 days/week, for
       up to 7 months. Male and female rats and guinea pigs were exposed to 970, 2900,
       3860, and 14,490 mg/m3 (200, 600, 800, 3000 ppm), for 197, 212, 38, and 3-4
       days, respectively. Exposure to 14,490 mg/m3 (3000 ppm) for 3-4 days resulted
       in severe mortality (not specified) in both species. At 3860 mg/m3 (800 ppm),
       both in rats and guinea pigs, slight growth depression and slight liver and kidney
       weight changes (direction not indicated) were observed, while the 212-day
       exposure to 2900 mg/m3 (600 ppm) resulted in liver weight changes in rats and
       guinea pigs and in kidney weight changes in rats. There were no effects on
       growth, mortality, behaviour, appearance, organ weights, and gross and
       microscopic examinations (of lungs, heart, liver, kidneys, spleen, testes,
088-12 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       adrenals, pancreas, femoral bone marrow) following exposure to 970 mg/m3 (200
       ppm) for 197 days. In male and female rabbits exposed to 2900 mg/m3 (600 ppm)
       and 970 mg/m3 (200 ppm) for 212 and 197 days, respectively, no effects were
       observed at the lower concentration level while a slight increase in mortality and
       slight growth depression were seen at 2900 mg/m3 (600 ppm). Female monkeys
       exposed to 2900 mg/m3 (600 ppm) and female and male monkeys exposed to 970
       mg/m3 (200 ppm) for 212 and 197 days, respectively, showed no effects at all
       (Wol56). The committee notices that the results of this study were only limitedly
       reported in a table in a qualitative way without presenting incidences.
           Short-term exposure of male mice (Swiss; n=10/group) to 2-phenylpropene
       vapours increased the threshold for the onset of clonic convulsions induced by
       pentetrazole. For 2-phenylpropene, the concentration in air causing a 50%
       increase in this seizure threshold was 3589 mg/m3 (743 ppm) (Cea81).
           Citing abstracts, US EPA reported changes in neurotransmitter levels, amino
       acid content, and enzyme activities in various organs of rats exposed to
       concentrations of 2-phenylpropene of 3000-5000 mg/m3, for 1-6 days, and
       biochemical changes in the brain of rats exposed to 40-70 mg/m3, 4-6 hours/day
       or continuously, for 1-6 months (EPA87).
       Mutagenicity and genotoxicity
       In an Ames test with S. typhimurium strains TA97, TA98, TA100, and TA1535,
       2-phenylpropene (maximum dose: 3333 µg/plate) was negative when tested with
       and without metabolic activation (S9 fraction derived from both induced rat and
       hamster liver) (Zei92). In a separate study, negative results were reported as well
       when tested with and without an S-9 mix from induced rat livers in strains TA98,
       TA100, TA1535, TA1537, and TA1538 (maximum dose: 1000 µg/plate) (San91).
           In vitro SCE-tests in human whole blood lymphocytes showed a significant
       increase (but no doubling compared to control) in the number of SCEs. A similar
       slight increase was noted in isolated human lymphocytes. This indicated that the
       induction of SCEs by 2-phenylpropene is independent of erythrocytes, in
       contrast to styrene and several other styrene derivatives (Nor83a, Nor83b,
       Nor84).
           Negative results were obtained in a chromosomal aberration test using
       Chinese hamster ovary (CHO) cells tested with and without metabolic activation
       (S9 activation system) at dose levels up to 0.15 µL/mL. Cytotoxicity was
       observed at the two highest concentration levels of 0.10 and 0.15 µL/mL (Put91).
       Reproduction toxicity
088-13  2-Phenylpropene
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<pre>       In an abstract of a 4-month inhalation study, it was stated that exposure of female
       rats to maximum permissible concentrations (not further specified; possibly 5
       mg/m3: see EPA87) of 2-phenylpropene induced increases in embryolethality
       (from 7.5 to 33%) and teratogenic effects (not specified; from 3.0 to 21.0%) in
       their offspring (Ser78).
           In a preliminary study, young pregnant rats received intraperitoneal
       injections of 250 mg/kg bw of methylstyrene (not further specified) in corn oil on
       days 1-15 of gestation. No teratogenic effects (i.e., grossly visible external or
       internal - visceral or skeletal - malformations) nor maternal toxicity (i.e., reduced
       body weight gain or altered weights - absolute or relative - of two or more
       organs) were observed, but fetal toxicity was indicated by a statistically
       significant increase in the incidence of resorptions and a statistically significant
       change in fetal sex ratio (decrease in female fetuses) (Har81).
       The committee did not find studies on the carcinogenicity and reproduction
       toxicity of 2-phenylpropene, but noticed that the compound was selected by the
       National Toxicology Program* for 2-year toxicity/carcinogenicity inhalation
       studies in rats and mice (n=50/sex/group) at concentrations of 0, 100, 300, 1000
       ppm, and 0, 100, 300, and 600 ppm, respectively, which were started in July
       2001.
7      Existing guidelines
       The current administrative occupational exposure limit (MAC) for 2-
       phenylpropene in the Netherlands is 240 mg/m3 (50 ppm), 8-hour TWA.
           Existing occupational exposure limits for 2-phenylpropene in some European
       countries and in the USA are summarised in Annex II.
8      Assessment of health hazard
       Limited information on the kinetics suggests that 2-phenylpropene is
       metabolised via an epoxide intermediate into 2-hydroxy-2-phenylpropanol
       glucuronide and 2-hydroxy-2-phenylpropionic acid.
           Information on effects on humans is limited as well. The compound may
       cause allergic reactions and effects on the nervous system, the respiratory tract,
       and the haematopoietic system. Exposure to levels as high as 483 mg/m3 (100
       ppm) for an unknown, short period was found not irritating although odour was
*      see: http://ntp-server.niehs.nih.gov/htdocs/Results_Status/Resstatm/98839.html.
088-14 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       strong. Levels of 970 mg/m3 (200 ppm) produced a strong, objectionable odour
       and slight eye irritation.
            Experimental animal testing did not show 2-phenylpropene to be a skin
       irritant following single applications but repeated applications caused moderate
       to marked irritation. Transient signs of irritation were found when the compound
       was instilled into the eyes of rabbits. The committee did not find experimental
       animal data on the sensitising properties of 2-phenylpropene.
            From lethal toxicity data, the committee concluded that 2-phenylpropene is
       of low toxicity following single or acute inhalation, dermal, or oral exposure.
            In a 2-week inhalation study with F344 rats (Mor99), increased relative liver
       weights (without accompanying histological lesions) in male and female animals
       and hyaline droplet formation in the kidneys of males were found after 12
       exposures (6 hours/day, 5 days/week) to ca. 2900 mg/m3 (600 ppm). No other
       organs including - among others - lungs, nasal cavity, and brain were affected. In
       a follow-up study addressing the kidney lesions only (Mor99), similar hyaline
       droplet formation was found in male F344 rats at concentrations of 1225 and
       2450 mg/m3 (250, 500 ppm), but not at 612 mg/m3 (125 ppm), while none of
       these concentrations induced such effects in female F344 rats or in male rats of
       an α2u-globulin-deficient strain (NBR). In mice (Mor99), no compound-related
       effects were seen at similar exposures up to ca. 2400 mg/m3 (489 ppm). At the
       next higher level of 2920 mg/m3 (596 ppm), nervous system depression (during
       the first week only), decreased body weights, decreased relative spleen weights,
       and increased relative liver weights were noted; there were no clinical chemistry
       or histology changes. In a 13-week study in rats and mice with exposure levels
       ranging from 367.5 to 4900 mg/m3 (75-1000 ppm) (NTP01), effects on the
       kidneys (increased relative weights, hyaline droplet formation and tubular
       regeneration in renal cortex) were seen in male rats exposed to levels of 735
       mg/m3 (150 ppm) and higher. However, since these effects were not seen in
       female rats and were accompanied by, amongst others, dose-dependent increases
       in the amount of α2u-globuline, the committee considers these effects as male-
       rat specific and not relevant for human risk assessment. Further, there were
       increased relative liver weights in male rats, not accompanied by histological
       lesions, at exposure levels >735 mg/m3 (150 ppm) and in female rats,
       accompanied by hepatocellular necrosis at levels >2940 mg/m3 (600 ppm). There
       were no effects on respiratory tract tissues. In mice, nasal lesions consisting of
       olfactory epithelial necrosis, atrophy, and metaplasia, glandular atrophy and
       hyperplasia, and respiratory epithelial hyaline degeneration were found at all
       concentration levels. Effects on organ weights were found at concentrations
       >1470 mg/m3 (300 ppm). Based on the relative liver weight changes found at 735
088-15  2-Phenylpropene
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<pre>       mg/m3 (150 ppm) in males, the committee considers the next lower dose of 367.5
       mg/m3 (75 ppm) as the NOAEL for rats. For mice, the committee could not
       establish a NOAEL since nasal lesions were found at 367.5 mg/m3 (75 ppm), the
       lowest concentration tested.
            In a condensedly reported, 6-7-month inhalation study (Wol56), a NOAEL of
       970 mg/m3 (200 ppm) was found in rats, guinea-pigs, and rabbits, based on slight
       liver (rat, guinea pig) and kidney (rat) weight changes, and slightly increased
       mortality and growth depression (both in rabbits), observed at the next higher
       dose level of 2900 mg/m3 (600 ppm).
            Negative results were obtained in several Ames tests and an in vitro
       chromosomal aberration test. In human lymphocytes, 2-phenylpropene induced a
       small (less than twice the control value), but significant increase in the number of
       SCEs.
            The committee did not find data on the carcinogenicity of 2-phenylpropene
       but noticed that the compound was selected by the National Toxicology Program
       for 2-year toxicity/carcinogenicity inhalation studies in rats and mice, which
       were started in July 2001.
            The committee takes the LOAEL of 367.5 mg/m3 found in the 13-week
       inhalation study in mice in which nasal lesions were observed (NTP01) as a
       basis for deriving a health-based recommended occupational exposure limit
       (HBROEL). For the extrapolation to a HBROEL, an overall assessment factor of
       16 is established. This factor covers the following aspects: the absence of a
       NOAEL, intra- and interspecies variation, differences between experimental
       conditions and the exposure pattern of the worker, and the type of critical effect.
       Thus, applying this factor of 16 and the fixed/preferred value approach, a health-
       based occupational exposure limit of 20 mg/m3 is recommended for
       2-phenylpropene.
       The committee recommends a health-based occupational exposure limit for
       2-phenylpropene of 20 mg/m3, as an 8-hour time-weighted average (TWA).
       References
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ACG03a American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
       exposure values - 2003. Cincinnati OH, USA: ACGIH®, Inc, 2003: 89.
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<pre>ACG03b American Conference of Governmental Industrial Hygienists (ACGIH). 2003 TLVs® and BEIs®
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       79 (rep no 38).
088-17  2-Phenylpropene
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<pre>EC03   European Commission: Directorate General of Employment and Social Affairs. OELs agreed to be
       included in next Commission Directive. http://europe.eu.int/comm/employment_social/h&s/areas/
       oels5_en.htm.
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       arbeitsmedizinische Begründungen von MAK-Werte (Maximale Arbeitsplatz-Konzentrationen). 1st-
       27th ed. Weinheim, FRG: VCH Verlagsgesellschaft mbH, 1998.
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       potential. Scand J Work Environ Health 1981; 7, suppl 4: 66-75.
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       Bulletin ORC-204A (available from NTIS, Springfield VA, USA; order no OTS0515743).
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       exposure limits. Sudbury (Suffolk), England: HSE Books, 1996: D52.
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       (Suffolk), England: HSE Books, 2002: 23.
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       1994: 3-55.
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       FAD- and NAD-linked substrates in rat liver mitochondria. Biochem Pharmacol 1988; 37: 4439-44.
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<pre>Nor83b Norppa H, Vainio H. Genetic toxicity of styrene and some of its derivates. Scand J Work Environ
       Health 1983; 9: 108-14.
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       29B: 547-59.
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       methylstyrene (CAS No. 98-83-8; C88006B) in rats and mice. Research Triangle Park NC, USA:
       Dept Health and Human Services, 2001; data (abstract and summary table) provided by NTP Central
       Data Management.
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       the Netherlands: Sdu, Servicecentrum Uitgevers, 2003: 35.
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       2000; 2.
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088-19  2-Phenylpropene
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<pre>           Annex I
Figure 1 Metabolism scheme for 2-phenylpropene (Cos01).
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<pre>              Annex II
 Occupational exposure limits for 2-phenylpropene 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     50          240            8h                   administrative            SZW03
 and Employment
 Germany
 - AGS                            100         480            8h                                             TRG00
                                  100         480            15 min
 - DFG MAK-Kommission             100         490            8h                                             DFG02
                                  100         490            15 minc
 Great-Britain
 - HSE                            50          246            8h                   OES                       HSE02
                                  100         491            15 min
 Sweden                           -           -                                                             Swe00
 Denmark                          50          240            8h                                             Arb02
 USA
 - ACGIH                          50          -              8h                   TLV                       ACG03b
                                  100         -              15 min               STEL
 - OSHA                           100         480            15 min, ceiling      PEL                       ACG03a
 - NIOSH                          50          240            10 h                 REL                       ACG03a
                                  100         485            15 min               STEL
 European Union
 -SCOEL                           50          246            8h                   ILVd                      EC03
                                  100         492            15 min
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 frequency per shift: 4, with a mininum time interval between peaks of 1 hour.
d
     Listed among compounds for which OELs are agreed to be included in next Commission Directive.
088-21         2-Phenylpropene
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<pre>088-22 Health-based Reassessment of Administrative Occupational Exposure Limits</pre>

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<br><br>