Concise International Chemical Assessment Document 18


    This report contains the collective views of an international group of
    experts and does not necessarily represent the decisions or the stated
    policy of the United Nations Environment Programme, the International
    Labour Organisation, or the World Health Organization.

    Concise International Chemical Assessment Document 18


    First draft prepared by Dr Gary Foureman, National Center for
    Environmental Assessment, US Environmental Protection Agency, Research
    Triangle Park, NC, USA

    Published under the joint sponsorship of the United Nations
    Environment Programme, the International Labour Organisation, and the
    World Health Organization, and produced within the framework of the
    Inter-Organization Programme for the Sound Management of Chemicals.

              World Health Organization
              Geneva, 1999

         The International Programme on Chemical Safety (IPCS),
    established in 1980, is a joint venture of the United Nations
    Environment Programme (UNEP), the International Labour Organisation
    (ILO), and the World Health Organization (WHO). The overall objectives
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    the risk to human health and the environment from exposure to
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    technical assistance in strengthening national capacities for the
    sound management of chemicals.

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    Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and
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    field of chemical safety. The purpose of the IOMC is to promote
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    sound management of chemicals in relation to human health and the

    WHO Library Cataloguing-in-Publication Data


         (Concise international chemical assessment document ; 18)

         1.Benzene derivatives - chemistry  2.No-observed-adverse-effect
         3.Risk assessment  4.Environmental exposure  I.International
         Programme on Chemical Safety  II.Series

         ISBN 92 4 153018 9            (NLM Classification: QV 633)
         ISSN 1020-6167

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              6.1. Environmental levels
              6.2. Human exposure



              8.1. Single exposure
              8.2. Irritation and sensitization
              8.3. Short-term exposure
              8.4. Long-term exposure
                   8.4.1. Subchronic exposure
                   8.4.2. Chronic exposure and carcinogenicity
              8.5. Genotoxicity and related end-points
              8.6. Reproductive and developmental toxicity
              8.7. Immunological and neurological effects




              11.1. Evaluation of health effects
                   11.1.1. Hazard identification and dose-response assessment
                   11.1.2. Criteria for setting guidance values for cumene
                   11.1.3. Sample risk characterization
              11.2. Evaluation of environmental effects



              13.1. Human health hazards
              13.2. Advice to physicians
              13.3. Health surveillance advice
              13.4. Spillage
              13.5. Storage










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    1  International Programme on Chemical Safety (1994)
        Assessing human health risks of chemicals: deriviation of
        guidance values for health-based exposure limits. Geneva, World
       Health Organization (Environmental Health Criteria 170).


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    FIGURE 1


         This CICAD on cumene was prepared by the US Environmental
    Protection Agency (EPA) and is based on the US EPA's  Health and
     environmental effects document for cumene (US EPA, 1987), the US
    EPA's Integrated Risk Information System (IRIS) file on cumene (US
    EPA, 1997), and the United Kingdom's  Environmental hazard assessment
     (EHA): Cumene (UK DOE, 1994), supplemented by a literature search on
    the ecology-based AQUIRE (Aquatic Toxicity Information Retrieval)
    database. The literature search for the IRIS file was through November
    1996 and for the AQUIRE database through April 1998. Information on
    the nature of the peer review and the availability of the source
    documents is presented in Appendix 1. Information on the peer review
    of this CICAD is presented in Appendix 2. This CICAD was approved as
    an international assessment at a meeting of the Final Review Board,
    held in Washington, DC, USA, on 8-11 December 1998. Participants at
    the Final Review Board meeting are listed in Appendix 3. The
    International Chemical Safety Card (ICSC 0170) for cumene, produced by
    the International Programme on Chemical Safety (IPCS, 1993), has also
    been reproduced in this document.

         Cumene (CAS no. 98-82-8) is a water-insoluble petrochemical used
    in the manufacture of several chemicals, including phenol and acetone.
    It readily volatilizes into the atmosphere from water and dry soil.
    Cumene is expected to adsorb moderately to strongly to soil/sediments
    and to undergo biodegradation in water and soil.

         Cumene is metabolized primarily to the secondary alcohol,
    2-phenyl-2-propanol, in both humans and animals. This alcohol and its
    conjugates are readily excreted by both rodents and humans.

         Increases in organ weights, primarily kidney weights, are the
    most prominent effects observed in rodents repeatedly exposed to
    cumene by either the oral or inhalation route. No adverse effects were
    observed in rat or rabbit fetuses whose mothers had been exposed to
    cumene during fetal development. Although no multigenerational
    reproductive studies have been performed using cumene, its rapid
    metabolism and excretion, coupled with lack of effects on sperm
    morphology in a subchronic study, suggest that it has a low potential
    for reproductive toxicity. A guidance value for oral exposure of 0.1
    mg/kg body weight per day has been derived, based on the
    no-observed-adverse-effect level (NOAEL) of 154 mg/kg body weight per
    day for increased kidney weight in female rats in a 6- to 7-month oral
    study; the NOAEL was adjusted for the dosing schedule, and a total
    uncertainty factor of 1000 was applied. Guidance values for the
    general population of 0.4 mg/m3 and 0.09 mg/m3 were derived for
    inhalation exposure, based on alternative NOAELs derived from the same
    subchronic inhalation study; again, the NOAELs were adjusted to a
    continuous exposure, and a total uncertainty factor of 1000 was

         No data are available with which to quantify human exposure to

         It is not possible to assess cumene's potential for
    carcinogenicity in humans, because long-term carcinogenicity studies
    with cumene have not been performed. Most genotoxicity test data with
    cumene are negative.

         Inadequate data, especially measured exposure information, exist
    to allow a quantitative evaluation of the risk to populations of
    aquatic or terrestrial organisms from exposure to cumene. Based on
    existing data, however, cumene is anticipated to be of relatively low
    risk. Values indicate a slight potential for bioconcentration of
    cumene in fish. There are no data on bioaccumulation through food
    chains (biomagnification).


         Cumene (CAS no. 98-82-8; C9H12; 2-phenyl-propane,
    isopropylbenzene, (1-methylethyl)-benzene) is a volatile, colourless
    liquid at room temperature with a characteristic sharp, penetrating,
    aromatic odour (Ward, 1979). It is nearly insoluble in water but is
    soluble in alcohol and many other organic solvents (Windholz, 1983).
    Structurally, cumene is a member of the alkyl aromatic family of
    hydrocarbons, which also includes toluene (methylbenzene) and
    ethylbenzene. Its structural diagram is given below.


         Some relevant physical and chemical properties of cumene are
    listed in Table 1. Additional physical/chemical properties are
    presented in the International Chemical Safety Card (ICSC 0170)
    reproduced in this document.

        Table 1: Physical/chemical properties of cumene.

    Property                           Value                    Reference

    Molecular weight                   120.2 g/mol

    Boiling point                      152.39 °C                Ward, 1979

    Vapour pressure,                   611 Pa                   Mackay & 
    25 °C                                                       Shiu, 1981

    Water solubility,                  50 mg/litre              Mackay &
    25 °C                                                       Shiu, 1981

    Log Kow                            3.66                     Hansch &
                                                                Leo, undated

    Density, 20 °C                     0.8619 g/cm3             Ward, 1979

    Flashpoint (tag closed-cup)        35 °C                    Ward, 1965

    Odour threshold limit              0.088 ppm (v/v)          Amoore & 
    value (TLV)                        0.43 mg/m3               Hautala, 1983

    Table 1 (continued)

    Conversion factor,                 1 ppm = 5.2 mg/m3
    20 °C, 101.3 kPa                   1 mg/m3 = 0.19 ppm

    Partition coefficients                                      Sato &
    Oil/air                            6215                     Nakajima, 1979
    Oil/water                          4316
    Water/air                          1.44
    Human blood/air                    37


         For sampling and measurement of cumene in air, Method 1501 of the
    US National Institute for Occupational Safety and Health (NIOSH, 1994)
    includes use of a solid sorbent tube (coconut shell charcoal) sampler
    with a gas chromatography/flame ionization detector measurement
    technique. The detection limit of this method is 1 mg/m3 (0.2 ppm).

         US EPA (1996) methods for detecting cumene in media other than
    air include the use of gas chromatography using photoionization Method
    8021B, which is applicable to nearly all types of samples, regardless
    of water content. The method detection limit for cumene is 0.05
    µg/litre, and the applicable concentration range for this method is
    approximately 0.1-200 µg/litre. The standard recovery using this
    method is 98%, with a standard deviation of 0.9%. Another commonly
    used gas chromatographic assay for volatiles including cumene is
    Method 8260B (US EPA, 1996), with a general estimated quantitation
    limit of approximately 5 µg/kg wet weight for soil/sediment samples,
    0.5 mg/kg wet weight for wastes, and 5 µg/litre for groundwater.


         Cumene is a naturally occurring constituent of crude oil and may
    be released to the environment from a number of anthropogenic sources,
    including processed hydrocarbon fuels. Crude oils typically contain
    approximately 0.1 wt% of cumene, but concentrations as high as 1.0 wt%
    have been reported.1 Measurements of various grades of petrol
    revealed that cumene concentrations range from 0.14 to 0.51 vol% and
    that the average cumene concentration was 0.3 vol%. Premium diesel
    fuel contains 0.86 wt% of cumene; furnace oil (no. 2) contains 0.60

         Primary sources of release of cumene include losses in wastewater
    and fugitive emissions from manufacturing and use facilities and
    petrochemical refineries, accidental spills of finished fuel products
    during transport or processing, and emissions from petrol stations and
    motor vehicles (US EPA, 1987). Cigarette tobacco also releases cumene
    (Johnstone et al., 1962). Cumene release from all these sources is
    estimated to be 9500 tonnes annually (US EPA, 1988). Other,
    unquantifiable anthropogenic cumene releases include the rubber
    vulcanization process (Cocheo et al., 1983), building materials
    (Moelhave, 1979), jet engine exhaust (Katzman & Libby, 1975), outboard
    motor operation (Montz et al., 1982), solvent uses (Levy, 1973),
    pharmaceutical production, and textile plants (Gordon & Gordon, 1981).
    Cumene is also released to the environment from leather tanning, iron
    and steel manufacturing, paving and roofing, paint and ink
    formulation, printing and publishing, ore mining, coal mining,
    organics and plastics manufacturing, pesticide manufacturing,
    electroplating, and pulp and paper production (Shackelford et al.,

         SRI International (1986) reported the 1985 Western European
    cumene production levels (in tonnes) for the following producer

              Federal Republic of Germany     438 000
              Finland                          70 000
              France                          370 000
              Italy                           335 000
              Netherlands                     240 000
              Spain                           120 000
              United Kingdom                  220 000

    This total 1985 production of 1 793 000 tonnes may be compared with
    production in the USA, which was reported as 2 775 000 tonnes in 1997
    (Anon., 1998).

    1  Letter and attachment from W.F. O'Keefe, American Petroleum
       Institute, to M. Greif, Toxic Substances Control Act (TSCA)
       Interagency Testing Committee, US Environmental Protection
       Agency, Washington, DC (TS-792).

         The use pattern for cumene in the early 1970s in the USA was as
    follows (Anon., 1984): oxidation for phenol/acetone production, 98%;
    polymerization of alpha-methylstyrene, 1.8%; and exports, 0.2%. Cumene
    is also used captively for the production of phenol and
    alpha-methyl-styrene (SRI International, 1986).


         In the atmosphere, cumene is expected to exist almost entirely in
    the vapour phase (Eisenreich et al., 1981). Cumene does not absorb
    ultraviolet light at wavelengths greater than 290 nm (US EPA, 1987),
    which suggests that cumene would not be susceptible to direct
    photolysis. In one study, the estimated half-life of cumene in the
    atmosphere from photolysis alone was approximately 1500 years (Parlar
    et al., 1983). Cumene is not susceptible to oxidation by ozone in the
    atmosphere (US EPA, 1987). Thus, reaction with ozone and direct
    photolysis are not expected to be important removal processes. Rather,
    reaction with photochemically generated hydroxyl radicals appears to
    be the primary degradation pathway (t´ 1-2 days) (Lloyd et al.,
    1976; Ravishankara et al., 1978). Small amounts of cumene may be
    removed from the atmosphere during precipitation. Cumene has been
    assigned a Photochemical Ozone Creation Potential (POCP) value of 35
    relative to ethylene at 100 (Derwent & Jenkin, 1990). POCP values
    represent the ability of a substance to form ground-level ozone as a
    result of its atmospheric degradation reactions.

         In water, important fate and transport processes are expected to
    be volatilization (t´ 4 h from a typical river) and aerobic
    biodegradation (Kappeler & Wuhrmann, 1978; Sasaki, 1978; Van der
    Linden, 1978). Chemical hydrolysis, oxidation, photolysis, and
    reaction with hydroxyl radicals are not expected to be important fate
    processes in water (Mill et al., 1978, 1979, 1980). Using an aerobic
    freshwater sediment/water test system, Williams et al. (1993)
    demonstrated that 10 days after addition of radiolabelled cumene (2.5
    mg/litre) to the system, 46.9% was trapped as radiolabelled carbon
    dioxide and another 21.8% was recovered as radiolabelled organics, the
    overall recovery of cumene ranging from 56.8% to 88.3%. The
    disappearance half-life based on these results was 2.5 days. During a
    20-day incubation of cumene at 10 mg/litre under aerobic conditions in
    either fresh water or salt water, Price et al. (1974) observed 70%
    degradation in fresh water but only about 2% degradation in seawater.
    Cumene was, however, observed to be degraded to a significant extent
    by microorganisms isolated from ocean sediment samples incubated in
    seawater, as Walker et al. (1976) noted decreases in cumene (gas
    chromatographic analysis) ranging from 37% to 60% of initial amounts
    over a period of 21 days in three separate incubations with seawater
    and microorganisms isolated from Atlantic Ocean sediments. On the
    other hand, cumene was found to be essentially non-biodegradable under
    anaerobic conditions by Battersby & Wilson (1989), who noted that
    cumene produced only about 2% of theoretical gas production when
    incubated at 50 mg carbon/litre sludge for 60 days at 35°C under
    anaerobic conditions; compounds at 80% of theoretical gas production
    under these conditions were assumed to represent complete degradation,
    whereas compounds at less than 30% production were considered

         In soil, it appears that cumene might biodegrade fairly rapidly
    under aerobic conditions, because a number of microorganisms capable
    of degrading cumene have been isolated (Yamada et al., 1965; Jamison
    et al., 1970; Omori et al., 1975). Regression equations based on the
    limit of cumene water solubility (50 mg/litre) predicted  Koc (soil
    sorption coefficient standardized to organic carbon) values ranging
    from 513 to 1622. For equations based instead on log octanol/water
    partition coefficients (log  Kow) for cumene, predicted  Koc
    values were in a similar range, from 589 to 3890 (Lyman et al., 1982).
    Other estimates of  Koc values at 884 (Jeng et al., 1992) and 2800
    (US EPA, 1987) were also in this range. These  Koc values indicate
    that cumene is expected to adsorb moderately to strongly to soil and
    have only slight mobility. The relatively high vapour pressure of
    cumene suggests that volatilization of this compound from dry soil
    surfaces would be significant.

         Measured and estimated bioconcentration factors (BCFs) suggest a
    slight potential for cumene to bioconcentrate in fish species. A BCF
    of 36 for cumene in goldfish ( Carassius auratus) has been measured
    (Ogata et al., 1984), and a BCF of 356 was estimated from the log
     Kow and a linear regression correlation equation (log BCF = 0.76
    log  Kow - 0.23) by the US EPA (1987). This value was concordant
    with the BCF of 316 calculated for fish species in general exposed to
    cumene (Sabljic, 1987). Cumene was detected at levels of 0.5-1.4 ng/g
    wet weight (detection limit 0.5 ng/g wet weight by gas chromatography/
    mass spectrometry) in 12 of 138 sampled fish (various species) from
    several locations near a potential emission source (Japan Environment
    Agency, 1987). Cumene has been detected in "oakmoss" ( Evernia
     prunastri (L.) Ach.) (Gavin et al., 1978) and marsh grass (Mody et
    al., 1974a,b).


    6.1  Environmental levels

         Cumene has been found as a contaminant in various industrial
    effluents and in groundwaters. Significant levels of cumene have been
    recorded in groundwater near chemical plants (1581 µg/litre, Botta et
    al., 1984; 360 µg/litre, Teply & Dressler, 1980; 11 µg/litre,
    Pellizzari et al., 1979), around outboard motor operations (700
    µg/litre, Montz et al., 1982), near coal gasification facilities (up
    to 54 µg/litre, Steurmer et al., 1982), and around petroleum plants
    and petroleum refineries (5 µg/litre, quantification method not clear;
    Snider & Manning, 1982). Cumene was detected in 8 of 135 samples of
    surface water (detection limit 0.03 µg/litre with gas
    chromatography/mass spectrometry) at concentrations ranging from 0.09
    to 0.44 µg/litre in several locations near a potential emission source
    in the 1986 monitoring of the general environment in Japan (Japan
    Environment Agency, 1987). Cumene levels in sediments and biota in
    Puget Sound, Washington, USA, ranged from 0.02 to 19 µg/g, with a mean
    concentration of 2.3 µg/g (Brown et al., 1979). A cumene level of
    140 µg/litre was found in seawater near an offshore drilling platform
    in the Gulf of Mexico (Sauer, 1981). Cumene was detected in 6 of 111
    sediment samples at concentrations ranging from 0.58 to 11 ng/g dry
    weight (detection limit 0.5 ng/g with gas chromatography/mass
    spectrometry) in several locations near a potential emission source
    (Japan Environment Agency, 1987).

         Reports of air sampling in the USA indicate the mean
    concentration of cumene to be about 14.7 µg/m3 (3 ppb) in urban
    settings and as high as 2.5 µg/m3 (0.5 ppb) in rural settings.
    Samples taken in Los Angeles, California, in 1966 averaged 14.7 µg/m3
    (3 ppb) (Lonneman et al., 1968), and samples taken in Houston, Texas,
    in 1973-1974 averaged 12.15 µg/m3 (2.48 ppb) (Lonneman et al., 1979).
    The US EPA (1987) reported a mean concentration of 16.7 µg cumene/m3
    (3.4 ppb) in undated samples from Los Angeles. In samples taken in the
    fall of 1981 in Los Angeles, Grosjean & Fung (1984) did not detect
    cumene, although a minimum detection level of 9.8 µg/m3 (2 ppb) was
    reported. Although a number of sampling attempts in rural and remote
    areas reported no detectable levels of cumene in air (detection limit
    <0.05 µg/m3 [<0.01 ppb]), two attempts were positive: Seila (1979)
    reported mean levels of 2.5 µg/m3 (0.5 ppb) in samples taken in a
    rural area near Houston, Texas, in 1978, and Arnts & Meeks (1980,
    1981) reported 0.25 µg/m3 (0.05 ppb) in samples taken near campfires
    in the Great Smokey Mountains, USA, in 1978.

         Average atmospheric concentrations of cumene in Europe are
    reported to be somewhat less than those in the USA, although
    concentrations in urban areas are also consistently much higher than
    those in rural areas. Isodorov et al. (1983) recorded an average
    cumene level of 8.3 µg/m3 (1.7 ppb) in the urban atmosphere of

    Leningrad, USSR, in 1977-1979, with a maximum of 11.8 µg/m3 (2.4
    ppb). Ambient air concentrations for the Netherlands in 1980 were
    reported to average 0.5-1.0 µg/m3 (0.1-0.2 ppb), with maxima ranging
    up to 34.8 µg/m3 (7.1 ppb) (Guicherit & Schulting, 1985). An annual
    average of 1.6 µg/m3 (0.3 ppb) (maximum 3.9 µg/m3 [0.8 ppb]) was
    reported from the Grenoble area in France in 1987 (Foster et al.,

    6.2  Human exposure

         Humans can be exposed to cumene via industrial emissions, petrol
    station or motor vehicle emissions, accidental releases, food,
    cigarette smoke, and drinking-water (US EPA, 1987).

         In condensates of cigarette smoke, Johnstone et al. (1962)
    recorded yields of cumene ranging from 7 to 14 µg/cigarette. Holzer et
    al. (1976) detected cumene at 10 µg/m3 (2 ppb) in air samples taken
    from a room immediately after a single cigarette had been smoked. No
    further specifics, such as indication of a median value or minimum
    detection level, are given.

         Brugnone et al. (1989) reported cumene as measurable in all
    alveolar air samples collected (single breath; range 1-81 µg/m3
    [0.2-17 ppb], method detection limit not given) from among two groups
    of workers ( n = 86, gender not specified) exposed to <0.1 mg
    cumene/m3 (<0.02 ppm) through the work shift. These authors analysed
    for but were unable to detect any significant differences in cumene
    concentrations between smokers and non-smokers in either alveolar air
    or blood samples. In another study, gases collected from 60 min of
    normal continuous respiration from each of eight male volunteers
    (three smokers) were analysed for trace organic constituents (Conkle
    et al., 1975). Cumene was listed as detected in one of the three
    smokers (expressed as 21 µg/h) and in one of the five non-smokers
    (expressed as 0.13 µg/h). Krotoszynski & O'Neill (1982) also
    identified cumene in expired air from non-smokers.

         The presence of cumene in foods can be biogenic or due to
    environmental contamination (US EPA, 1987). Although the detection
    limit of cumene in various foods was not specified, the US EPA (1987)
    noted that cumene has been detected but not quantified in foods as
    diverse as tomatoes, Concord grapes, cooked rice, fried chicken,
    bacon, Beaufort cheese, and dried legumes.

         Only two reports of cumene quantification in drinking-water were
    found in the available literature. Coleman et al. (1984) detected
    cumene in Cincinnati, Ohio, USA, drinking-water at a level of 0.014
    µg/litre (quantification method not clear). Keith et al. (1976)
    reported 0.01 µg cumene/litre drinking-water in Terrebonne-Parish,
    Louisiana, USA, but found none in the drinking-water of nine other
    cities across the USA. These concentrations are considerably below the
    0.5 µg/litre detection limit reported by Westrick et al. (1984), who

    found no cumene in 945 US drinking-water systems, 479 of which were
    selected because of known contamination problems. Burmaster (1982) and
    Burnham et al. (1972) reported unquantified levels of cumene/
    alkylbenzenes in drinking-water obtained from groundwater. Based on
    the results of these studies, it may be concluded that cumene
    contamination above 0.5 µg/litre is uncommon in drinking-water in the

         One industrial hygiene survey (US EPA, 1988) reported that
    approximately 739 US workers were occupationally exposed to cumene.
    Personal exposure data in this report consisted of 1487 air samples
    taken over the course of 12 years (1973-1984), of which 6 were in the
    range of 20-150 mg/m3 (4-30 ppm), 4 in the range of 15-20 mg/m3 (3-4
    ppm), and 25 in the range of 5-10 mg/m3 (1-2 ppm), with the remaining
    samples below 5 mg/m3 (1 ppm) (US EPA, 1988).

         Based on available monitoring data, it appears that the general
    population would be exposed to cumene primarily by inhalation,
    although occupational populations may be reasonably anticipated to be
    exposed by the dermal route. Minor exposure may result from contact
    with refined petroleum products and ingestion of contaminated foods
    and possibly drinking-water.


         Cumene has been shown to be absorbed after inhalation exposure in
    humans and after inhalation, oral, and dermal exposure in animals
    (Senczuk & Litewka, 1976; Research Triangle Institute, 1989). Tests
    conducted in humans indicate that cumene is absorbed readily via the
    inhalation route, that it is metabolized efficiently to water-soluble
    metabolites within the body, and that these metabolites are excreted
    efficiently into the urine with no evidence of long-term retention
    within the body; these results concur with the results of animal

         Senczuk & Litewka (1976) exposed human volunteers (five men and
    five women) head only to one of three different concentrations of
    cumene vapours (240, 480, or 720 mg/m3 [49, 98, or 147 ppm]) for 8 h
    every 10 days. Exhaled breath samples (10 cm3) were collected near
    the beginning and at the end of the exposure from a tube placed in the
    breathing zone. The total amount of cumene absorbed during exposure,
    calculated from retention, ventilation, and exposure duration, was
    nearly twice as high at all exposure levels in the males (466-1400 mg)
    as in the females (270-789 mg). The respiratory tract absorption
    ranged from 45% to 64% depending on the time of exposure, with the
    overall mean retention estimated at 50%. In rats, inhalation studies
    (nose only for 6 h at 510, 2420, or 5850 mg/m3 [104, 494, or 1194
    ppm]) indicate rapid absorption, with detectable levels of cumene
    appearing in the blood within 5 min of the beginning of exposure at
    all three exposure levels (Research Triangle Institute, 1989). Gavage
    studies in rats showed that cumene was absorbed readily via this
    route, with maximum levels in blood occurring at the earliest time
    point sampled (4 h) for a lower dose (33 mg/kg body weight) and at 
    8-16 h for a higher dose (1350 mg/kg body weight) (Research Triangle
    Institute, 1989). Dermal absorption of cumene was demonstrated in rats
    and rabbits (Monsanto Co., 1984).

         The human data reported by Brugnone et al. (1989) regarding
    cumene distribution suggest that the cumene concentration was about 40
    times higher in blood than in alveolar air, a figure concordant with
    the reported human blood/air partition coefficient of 37 (Sato &
    Nakajima, 1979; Table 1). Cumene was widely distributed in rats, and
    distribution, presumably determined immediately after exposure, was
    independent of administration route (inhalation, oral, or
    intraperitoneal in 10% aqueous Emulphor). Adipose, liver, and kidney
    were all shown to have elevated tissue/blood ratios of cumene
    following all doses and routes of exposure (Research Triangle
    Institute, 1989). Fabre et al. (1955) demonstrated that after rats
    inhaled cumene vapour for up to 150 days, cumene was distributed to
    the endocrine organs, central nervous system, bone marrow, spleen, and

         The patterns of cumene disappearance (as total radioactivity)
    from the blood in the nose-only inhalation studies were fitted with a
    monoexponential model, with the half-lives increasing with dose, from
    3.9 h at 490 mg/m3 (100 ppm) to 6.6 h at 5880 mg/m3 (1200 ppm). The
    half-life of cumene in the blood in gavage studies with rats was
    calculated to be between 9 and 16 h.

         Metabolism of cumene by cytochrome P-450 is extensive and takes
    place within hepatic and extrahepatic tissues, including lung (Sato &
    Nakajima, 1987), with the secondary alcohol 2-phenyl-2-propanol being
    a principal metabolite. Metabolites excreted in urine of rats and
    rabbits include 2-phenyl-2-propanol and its glucuronide or sulfate
    conjugates, conjugates of 2-phenyl-1,2-propanediol, and an unknown
    metabolite, possibly the dicarboxylic acid that would result from
    complete oxidation of the 1- and 3-alkyl carbons of phenylmalonic acid
    (Research Triangle Institute, 1989; Ishida & Matsumoto, 1992; MAK,

         Senczuk & Litewka (1976) also conducted excretion studies with
    human volunteers exposed to cumene vapours (240, 480, or 720 mg/m3
    [49, 98, or 147 ppm]) for 8 h every 10 days. These authors reported
    excretion of the metabolite 2-phenyl-2-propanol in the urine as
    biphasic, with a rapid early phase (t´ 2 h) and a slower later phase
    (t´ 10 h); excretion of this metabolite in the urine (about 35% of
    the calculated absorbed dose) was maximal after 6-8 h of exposure and
    approached zero at 40 h post-exposure. With rats, the extent of
    elimination across routes of administration (inhalation, oral, or
    intraperitoneal) and exposure concentrations was very similar, with
    urine being the major route of elimination, about 70% in all cases
    (Research Triangle Institute, 1989). Total body clearance in the rats
    was rapid and complete, with less than 1% of the absorbed fraction
    being present in the body 72 h after the highest exposure regime
    examined (5880 mg/m3 [1200 ppm] for 6 h). Following oral
    administration of cumene in rabbits, 90% was recovered as metabolites
    in the urine within 24 h (Robinson et al., 1955).


    8.1  Single exposure

         Cumene is not highly toxic to laboratory animals by inhalation,
    oral, or dermal routes of exposure. An LC50 of 9800 mg cumene/m3
    (2000 ppm) in mice has been reported (MAK, 1996). A 4-h inhalation
    LC50 of 39 200 mg/m3 (8000 ppm) in rats was reported by several
    investigators (Smyth et al., 1951; Koch Refining Co., 1984; Union
    Carbide Corp., 1985). Acute oral LD50 values for rats range from 1400
    to 2900 mg/kg body weight (Smyth et al., 1951; Koch Refining Co.,
    1984; Monsanto Co., 1984; Ciba-Geigy Co., 1985; Union Carbide Corp.,
    1985). Tanii et al. (1995) reported an intraperitoneal LD50 in male
    mice in the same range, 2000 mg/kg body weight (16.9 mmol/kg).
    Clinical signs of toxicity reported in rats in acute oral studies
    include weakness, ocular discharge, collapse, and death; pathological
    findings in animals that died were haemorrhagic lungs, liver
    discolorations, and acute gastrointestinal inflammation (Monsanto Co.,
    1984). The character of the dose-response for these effects is,
    however, unclear.

         Acute dermal LD50s for cumene applied undiluted to rabbit skin
    range from >3160 mg/kg body weight (Monsanto Co., 1984) to >10 000
    mg/kg body weight (Ciba-Geigy Co., 1985). Pathological findings in
    animals that died were similar to those in animals that died after a
    single oral exposure (Monsanto Co., 1984).

    8.2  Irritation and sensitization

         Undiluted cumene applied to the skin of New Zealand albino
    rabbits (0.5 ml) according to standardized guidelines caused slight
    defatting with skin flaking, a symptom not generally classified as
    relating to primary skin irritancy (Monsanto Co., 1984). A study
    conducted by Ciba-Geigy Co. (1985) reported a similar low level of

         Cumene is an ocular irritant. Ocular irritation, including
    immediate discomfort followed by "erythema" (redness of the
    conjunctiva) and copious discharge, was observed after the
    instillation of undiluted cumene to rabbit, with these effects being
    reversible within 120 h (Monsanto Co., 1984). Ciba-Geigy Co. (1985)
    judged eye irritation as slight when cumene was applied to rabbit
    eyes. However, a study by Union Carbide Corp. (1985) reported that
    cumene was harmless to rabbit eyes when applied undiluted.
    Observations of lacrimation (Tegeris & Balster, 1994) and periocular
    swelling and blepharospasm (Cushman et al., 1995) also indicate that
    cumene may exhibit ocular irritancy at high airborne concentrations.

         The concentration of cumene causing a 50% reduction in the
    respiratory rate in mice after 30 min of exposure was determined to be
    10 084 mg/m3 (2058 ppm) (Kristiansen et al., 1986). This

    concentration is quite high and in the range where repeated exposure
    caused death and morbidity in rats (Gulf Oil Corp., 1985; Chemical
    Manufacturers Association, 1989) and rabbits (Darmer et al., 1997).

         No skin sensitization reactions were noted among a group of 20
    female guinea-pigs treated with cumene in a Magnusson-Kligman
    maximization test conducted in accordance with Organisation for
    Economic Co-operation and Development (OECD) Guideline 406 (Hüls,
    1988). No data were available on respiratory sensitization to cumene.

    8.3  Short-term exposure

         In a study by Monsanto Co. (1986), male and female Sprague-Dawley
    rats (10 per sex per group) were exposed whole body to cumene vapour
    concentrations of 0, 515, 1470, or 2935 mg/m3 (0, 105, 300, or
    599 ppm) for 6 h/day, 5 days/week, for approximately 4 weeks (minimum
    exposure, 20 days). Cage-side observations included
    concentration-related increases in side-to-side head movements in both
    males and females in all dose groups, head tilt in all dose groups,
    and arched back in one female in the high-dose group. Increases in
    mean absolute left and right kidney weights were observed in high-dose
    males, as were increases in mean absolute left kidney weight in
    low- and mid-dose males. In high-dose females, the mean absolute
    weight of left kidneys was greater than in controls. This study
    confirms that renal weight changes occur in females and corroborates
    similar effects reported by Cushman et al. (1995). It should be noted
    that the effects associated with central nervous system perturbation
    (i.e., head movements) were not noted in several other longer-term
    studies, including that of Cushman et al. (1995), in which
    neurotoxicity was specifically assessed. If it is assumed that the
    renal changes among the males were associated with male rat-specific
    nephropathy (see section 8.4.1), the cage-side observations of head
    tilt and head movements become the critical effects for this
    short-term study.

         Although not statistically significant, leukocytosis was noted in
    a group of rats ( n = 15, mixed sex) exposed to cumene at 1200 mg/m3
    (245 ppm) for 8 h/day, 5 days/week, for 30 exposures (Jenkins et al.,

         Other short-term toxicity studies are described in section 8.7.

    8.4  Long-term exposure

    8.4.1  Subchronic exposure

         In an inhalation exposure study by Jenkins et al. (1970), groups
    of squirrel monkeys ( n = 2), beagle dogs ( n = 2),
    Princeton-derived guinea-pigs ( n = 15), and Sprague-Dawley and
    Long-Evans rats ( n = 15) were exposed whole body to cumene at
    concentrations of 0, 18, or 147 mg/m3 (0, 4, or 30 ppm) continuously
    for 90 days. Initial and terminal body weights, haematological and

    clinical chemistry parameters, and histopathological data were
    collected. No toxicologically significant effects were noted in the
    monkeys, dogs, or guinea-pigs. The only effect noted in the rats was a
    slight degree of leukocytosis at both concentrations.

         Cushman et al. (1995; also reported as Bushy Run Research Center,
    1989a) conducted two successive subchronic whole-body inhalation
    toxicity studies with cumene vapours (>99.9% pure) on Fischer-344
    rats. In the first study, groups (21 per sex) were exposed to cumene
    vapour at 0, 490, 2430, or 5890 mg/m3 (0, 100, 496, or 1202 ppm) 6
    h/day, 5 days/week, for 13 weeks. The second study was a repeat of the
    first, except that the group size was decreased to 15 per sex and an
    additional group (at 245 mg/m3 [50 ppm]) and a 4-week post-exposure
    period were added. Parameters monitored included clinical signs of
    toxicity, auditory brain stem responses, ophthalmology, sperm count
    and morphology, and histopathological examination of all respiratory
    tract tissues (lungs and nasal turbinates) and the perfused nervous
    system. Evaluations of neurological function (functional observation
    battery and motor activity) were conducted in both studies. Light
    microscopic evaluation of the perfused-fixed nervous system tissues
    (six rats per sex per group) was conducted in the first study only.

         In the first study, transient, reversible cage-side observations
    during exposure periods included hypoactivity, blepharospasm, and a
    delayed or absent startle reflex at the highest concentration. Rats
    exposed to 2430 mg/m3 were reported as being hypoactive during
    exposure, although no further specifics were given. Statistically
    significant ( P < 0.05) exposure-related decreases in motor activity
    (total) were observed in male rats exposed to the two highest
    concentrations of cumene, but these results were not observed in the
    second study in either sex. There were no exposure-related changes
    noted in the functional observation battery in this or the subsequent
    study. No effects were observed in the neurohistopathological
    examinations. Cataracts were reported in males at all exposure
    concentrations in this study. However, these results were not observed
    in the second study in which a more comprehensive protocol for eye
    examination was employed. Evaluation of the auditory brain stem
    responses revealed no meaningful changes in the auditory function of
    the exposed animals. The only gross histopathology noted was
    periocular swelling, which occurred in animals at the two highest
    concentrations (and for which neither incidence nor severity was
    reported). Both absolute and relative weights were increased
    significantly (>10%) in the kidneys, adrenal glands, and livers of
    both sexes at the highest concentration. These changes were also noted
    in the liver at the next lower concentration (2430 mg/m3) for both
    females and males. Kidney lesions described in male rats at the two
    highest exposure concentrations were considered to be closely related
    to male rat-specific nephropathy (i.e., lesions were limited to males,
    and tubular proteinosis, hypertrophy, and hyperplasia as well as
    hyaline droplet formation were noted, although the identity of the
    protein in the droplets was not confirmed) and are of questionable

    relevance to human toxicity, principally because renal lesions
    characteristic of this type of nephropathy have not been observed in
    humans (US EPA, 1991a; Hard et al., 1993). Chronic progressive
    nephropathy, a common spontaneous renal disease of Fischer-344 male
    rats that occurs as early as 5 months of age (Montgomery & Seely,
    1990), may also contribute to these renal lesions. Water consumption
    was significantly increased (about 40%) in male rats above control
    values at both 2430 and 5890 mg/m3. Several haematological and serum
    measures were also changed in a statistically significant dose-related
    manner at both 2430 and 5890 mg/m3: leukocytes (both sexes),
    platelets (both sexes), lymphocytes (males only), glucose (females
    only), and calcium/phosphorus (males only).

         The results of the second study, with a 4-week post-exposure
    period, indicated limited reversibility of the organ weight
    alterations, because significant mean weight increases were still
    present in female liver and female adrenals of the highest exposure
    group. In males, only relative kidney weights (significant at 6%) and
    absolute liver weights remained increased significantly. Blood and
    serum parameters were not reported in this study. Morphological
    evaluation of epididymal and testicular sperm showed no cumene-related
    differences in count, morphology, or stages of spermatogenesis,
    although one high-dose rat did have diffuse testicular atrophy.

         The weight alterations in the male and female adrenals and female
    kidney are considered potentially adverse, as the persistence noted
    indicates limited reversibility and engenders uncertainty about the
    progression and fate of these alterations under chronic exposure. The
    increased water consumption noted may also indicate potential for
    renal effects, although this effect was present at the next to highest
    dose level at which renal weights were not altered. Although the
    progression of these weight alterations from continued exposure cannot
    be ascertained from this subchronic study, data from the second
    (post-exposure) study indicate limited reversibility of effects on the
    adrenals, at least in females. The liver weight alterations are not
    viewed as adverse, because increase in liver weight without
    accompanying pathology is a trait of common microsomal enzyme inducing
    agents, although it should be noted that induction of hepatic
    microsomal enzymes may influence the metabolism of other substances
    and may either increase or decrease their toxicity (Sipes & Gandolfi,
    1991). The altered haematological and serum parameters noted at the
    two highest concentrations may be considered as significant, although
    all are within normal ranges (Mitruka & Rawnsley, 1981). Based on the
    lowest dose at which both relative and absolute weight alterations in
    adrenal tissues of both sexes and in the kidneys of females are
    statistically ( P < 0.05) and biologically (>10%) significant, 5890
    mg/m3 may be considered as a lowest-observed-adverse-effect level
    (LOAEL), and 2430 mg/m3 the corresponding NOAEL. Based on
    consideration of the various measures in the first study (motor
    effects, increased water consumption in males, haematological and
    serum parameters, sporadic weight increases in male adrenals and
    female kidneys) as significant, 2430 mg/m3 may be considered as a

    LOAEL and 490 mg/m3 as the corresponding NOAEL. It should be noted
    here that a LOAEL of 2391 mg/m3 (488 ppm) and a NOAEL of 485 mg/m3
    (99 ppm) were noted for maternal toxicity in the short-term
    developmental study in rats by Darmer et al. (1997), discussed in
    section 8.6.

    8.4.2  Chronic exposure and carcinogenicity

         There are no long-term  in vivo bioassays addressing the issue
    of cancer. No data exist to support any quantitative cancer

         Wolf et al. (1956) conducted a study involving groups of 10
    female Wistar rats administered cumene by gavage in olive oil at 154,
    462, or 769 mg/kg body weight per day, 5 days/week, over a 194-day
    (6- to 7-month) period, equivalent to 110, 331, or 551 mg/kg body
    weight per day, adjusted for daily exposure. Rats given olive oil
    served as controls ( n = 20). A pronounced increase in average kidney
    weight, noted as a "moderate effect," occurred at 769 mg/kg body
    weight per day, although no quantitative data are presented. An
    increase in average kidney weight was noted as a "slight effect" at
    462 mg/kg body weight per day. It is stated in the report that at 154
    mg/kg body weight per day, no evidence of ill effects, as determined
    by gross appearance, growth, periodic blood counts, analysis for blood
    urea nitrogen, average final body and organ weights, and bone marrow
    counts, was noted. The LOAEL is 462 mg/kg body weight per day, and the
    NOAEL is 154 mg/kg body weight per day. These results are consistent
    with those observed in more recent, better-reported studies described
    elsewhere in this document.

         In an inhalation study by Fabre et al. (1955), Wistar rats were
    exposed (whole body) to cumene vapour at 2500 mg/m3 (510 ppm), and
    rabbits were exposed to 6500 mg/m3 (1327 ppm), for 8 h/day, 6
    days/week, for up to 180 days. Histological effects reported were
    "passive congestion" in the lungs, liver, spleen, kidney, and adrenals
    and the presence of haemorrhagic zones in the lung, haemosiderosis in
    the spleen, and lesions from epithelial nephritis "in some cases." It
    was not clear from the study if these effects occurred in rats or
    rabbits, or both.

    8.5  Genotoxicity and related end-points

         In general, negative results have been obtained in a relatively
    complete battery of  in vivo and  in vitro mutagenicity tests,
    including gene mutation, chromosomal aberration, and primary DNA
    damage (US EPA, 1997). Cumene was tested at concentrations up to
    2000 µg/plate in a  Salmonella typhimurium reverse mutation assay
    (modified Ames test); negative results were observed with and without
    metabolic activation (Lawlor & Wagner, 1987). Cumene was negative in
    an Ames assay at concentrations up to 3606 µg/plate with
     S. typhimurium strains TA98, TA100, TA1535, and TA1537 (Florin et
    al., 1980). Cumene also tested negative, with and without metabolic

    activation, in a set of HGPRT assays (using Chinese hamster ovary
    cells) at cumene concentrations of 100-125 µg/ml, at which the
    relative cloning efficiencies (a measure of cytotoxicity) ranged from
    29% to 110% (Gulf Life Sciences Center, 1985a; Yang, 1987). A
    micronucleus assay performed in mice given up to 1 g cumene/kg body
    weight by gavage was negative (Gulf Life Sciences Center, 1985b).
    Micronucleus assays done in Fischer-344 rats, however, gave values
    that were weakly positive, although little dose-response was seen, and
    deaths occurred at the highest dose (5 of 10 animals at 2.5 g/kg body
    weight intraperitoneally; NTP, 1996). The positive control used in the
    micronucleus tests, cyclophosphamide, produced strong positive
    responses in all assays.

         Cumene failed to induce significant rates of transformation in
    BALB/3T3 cells (without activation) at concentrations up to 500 µg/ml
    (Putnam, 1987) but tested positive in an earlier cell transformation
    test also using BALB/3T3 cells, in which an increase in
    transformations was observed at 60 µg/ml (Gulf Oil Corp., 1984a).
    Results from an unscheduled DNA synthesis assay in rat hepatocytes
    conducted by Gulf Oil Corp. (1984b) indicated positive results at
    doses of 16 and 32 µg cumene/ml (with 128 µg/ml noted as toxic to the
    hepatocytes). However, apparent technical difficulties with this test
    (US EPA, 1988) prompted a repeat of the unscheduled DNA synthesis
    assay in rat hepatocytes, the results of which showed cumene to be
    clearly negative at doses up to 24 µg/ml, with doses above 24 µg/ml
    noted as being too toxic for evaluation of unscheduled DNA synthesis
    (Curren, 1987; US EPA, 1988).

    8.6  Reproductive and developmental toxicity

         No multigeneration reproductive study exists for this compound by
    either the oral or inhalation route. There are no data concerning
    cumene exposure of females prior to mating, from conception to
    implantation, or during late gestation, parturition, or lactation.

         The first subchronic inhalation study of Cushman et al. (1995),
    however, conducted morphological evaluation of epididymal and
    testicular sperm in rats exposed for 13 weeks to cumene vapours (see
    section 8.4.1). No cumene-related differences in count, morphology, or
    stages of spermatogenesis were noted, although one high-dose rat did
    have diffuse testicular atrophy. No alterations (weight changes,
    histopathology) were noted in the female reproductive organs that were
    examined at the termination of this same study.

         In an inhalation study (Darmer et al., 1997; also reported as
    Bushy Run Research Center, 1989b), Sprague-Dawley rats (25 per group)
    were exposed whole body to 0, 485, 2391, or 5934 mg cumene/m3 (0, 99,
    488, or 1211 ppm) for 6 h/day on days 6 through 15 of gestation.
    Perioral wetness and encrustation, a significant ( P < 0.01)
    decrease in body weight gain on gestation days 6 through 9
    (accompanied by a significant decrease in food consumption), and a

    slight increase (7.7%) in relative liver weight were observed in dams
    at the high dose only. Hypoactivity, blepharospasm, and significantly
    ( P < 0.05) decreased food consumption were observed in the dams at
    the next highest concentration. There were no statistically
    significant adverse effects on reproductive parameters or fetal
    development. For this study, 5934 mg/m3 is a developmental NOAEL, and
    485 mg/m3 is a maternal NOAEL.

         In another inhalation study (Darmer et al., 1997; also reported
    as Bushy Run Research Centre, 1989c), New Zealand white rabbits (15
    per group) were exposed whole body to 0, 2411, 5909, or 11 255 mg
    cumene/m3 (0, 492, 1206, or 2297 ppm) for 6 h/day on days 6 through
    18 of gestation. Two does died and one aborted at the highest exposure
    concentration. There were significant ( P < 0.01) reductions in body
    weight gain (178 g lost compared with 31 g gained in the control
    group) and food consumption at the highest exposure level during the
    treatment period. Significantly reduced food consumption was also
    observed in the 2411 and 5909 mg/m3 exposure groups, but it was not
    accompanied by any decrease in weight gain. Clinical signs of toxicity
    observed in the does included significant ( P < 0.01) increases in
    perioral and perinasal wetness and blepharospasm at the highest
    concentration. At necropsy, there were colour changes in the lungs of
    33% of the does exposed to 11 255 mg/m3. Relative liver weight was
    significantly ( P < 0.01) elevated (16.8% over control weight) at
    the highest exposure level. There were no statistically significant
    effects on gestation parameters; however, there were non-significant
    increases in non-viable implants and early resorptions and a
    non-significant decrease in the percentage of live fetuses concurrent
    with maternal toxicity at 11 255 mg/m3. Apparent increases in
    ecchymosis (haemorrhagic areas of the skin) of the head were shown to
    be within the ranges observed for the historical controls of this test
    facility (US EPA, 1991b). The highest exposure level resulted in
    maternal mortality. The next lower dose of 5909 mg/m3, at which the
    only effect noted was reduced food consumption without accompanying
    weight loss, is considered the NOAEL of the study.

    8.7  Immunological and neurological effects

         No studies were located that examined immunotoxicity in animals
    after exposure to cumene by any route.

         Cumene appears to be similar to many solvents, such as alcohol,
    that are known central nervous system depressants. The occurrence of
    neurological effects from inhalation exposure to cumene has been
    confirmed in several studies. These studies are acute exposures that
    show neurotoxicological effects only at quite high concentrations
    (>2450 mg/m3 [>500 ppm]). Neurotoxicological effects were not
    observed in the longer-term inhalation study by Cushman et al. (1995),
    which included complete batteries of functional and motor activity
    tests and neurohistopathology and in which the highest exposure
    concentration was 5890 mg/m3 (1202 ppm).

         Cumene was tested at 0, 9800, 19 600, or 39 200 mg/m3 (0, 2000,
    4000, or 8000 ppm) and produced a short-lived profile of
    neurobehavioural effects in mice that indicated central nervous system
    depressant activity (Tegeris & Balster, 1994). Effects noted from
    brief (20-min) whole-body exposures to cumene included those on
    central nervous system activity (decreased arousal and rearing at 9800
    mg/m3), muscle tone/equilibrium (changes in grip strength and
    mobility at 19 600 mg/m3), and sensorimotor activity (including
    decreased tail pinch and touch response at 19 600 mg/m3).

         In an acute experiment accompanying the subchronic exposures (see
    section 8.4.1), Cushman et al. (1995) exposed Fischer-344 rats (whole
    body) once to 0, 490, 2430, or 5890 mg/m3 (0, 100, 496, or 1202 ppm)
    for 6 h and conducted functional observations 1 h post-exposure. Gait
    abnormalities and decreased rectal temperatures were noted for both
    sexes at the highest exposure level only. Decreased activity levels
    were noted for both sexes at the highest level and for females only at
    the next highest level (2430 mg/m3) of exposure. Males, but not
    females, from the highest exposure group had decreased response to toe
    pinch at 6 h post-exposure.

         In a 5-day inhalation study, Fischer-344 rats exposed whole body
    to 9800 or 24 500 mg cumene vapour/m3 (2000 or 5000 ppm) for 6 h/day
    showed toxic effects from exposure (Gulf Oil Corp., 1985). All rats in
    the high-exposure group died after 2 days. At the lower dose, females
    demonstrated central nervous system effects (hypothermia and
    staggering). Similar, but more severe, symptoms were observed in the
    high-exposure animals before they died.

         Fischer-344 rats (10 per sex per group) were exposed whole body
    to cumene at 0, 1230, 2680, 5130, or 6321 mg/m3 (0, 251, 547, 1047,
    or 1290 ppm) for 6 h/day, 5 days/week, for 2 weeks (Chemical
    Manufacturers Association, 1989). Initial exposures to 9800 mg/m3
    (2000 ppm) for 1-2 days resulted in such severe neurological and
    respiratory effects that the concentration levels were reduced to
    those given above. During the remainder of the 2-week exposure period,
    clinical observations (ocular discharge, decreased motor activity or
    hyperactivity, and ataxia) were noted sporadically at all levels
    except 1230 mg/m3. For females in the two highest dose groups, the
    average relative kidney weight and relative and absolute adrenal
    weights were increased significantly over control values. These data
    provide corroboration for these same effects reported in the study of
    Cushman et al. (1995).


         No information was located regarding the toxicity of cumene in
    humans following acute, subchronic, or chronic exposure (US EPA,
    1997). The minimum lethal human exposure to this agent has not been
    delineated. No epidemiology, case reports, or clinical controls of
    humans were located for this compound. There are no epidemiological or
    occupational studies examining the carcinogenicity of cumene in humans
    (US EPA, 1997).

         No information was located regarding dermal irritation and
    sensitization in humans following exposure to cumene.


         The available environmental effects studies are inadequate to
    allow a quantitative assessment of the acute toxicity of cumene to
    environmental organisms owing to the variability of the data and
    flawed experimental designs. For example, 24-h toxicity values for
    water fleas ranged from an EC50 of 91 mg/litre (Bringmann & Kuhn,
    1982) down to an IC50 of 0.6 mg/litre (Abernathy et al., 1986).
    Further, many of the reported toxicity values for aquatic
    invertebrates exceed the water solubility of cumene at 50 mg/litre,
    with Glickman et al. (1995) noting that actual measured concentrations
    of cumene were only about 10% of nominal concentrations. The lowest
    reported toxic concentration was 0.012 mg/litre, the toxicity
    threshold for the protozoan  Colpidium colpoda (Rogerson et al.,
    1983). Concentrations of up to 50 mg/litre did not affect the growth
    of the larvae of the mussel  Mytilis edulis during a 27-day exposure
    (Le Roux, 1977). Selected data demonstrating effect concentrations are
    shown in Table 2. It should be noted that the high volatility and
    biodegradability of cumene may further reduce the hazard to the
    aquatic environment, especially for chronic exposure conditions.

        Table 2: Acute toxicity of cumene to organisms other than laboratory mammals.

    Species                                End-point               Concentration
                                           (effect)                (mg/litre)                      Reference


    Green alga                             3-h EC50                21                             Hutchinson et al.,
    (Chlorella vulgaris)                   (photosynthetic                                        1980

    Green alga                             3-h EC50                9                              Hutchinson et al.,
    (Chlamydomonas angulosa)               (photosynthetic                                        1980

    Green alga                             72-h EC50               2.6                            Galassi et al.,
    (Selenastrum capricornutum)            (growth                                                1988

    Green algae                            72-h static EC50        2.0                            Hüls, 1998a
    (Scenedesmus subspicatus)              (growth


    Water flea (Daphnia magna)             24-h EC50               91                             Bringmann & Kuhn,
                                           (immobilization)                                       1982

    Water flea (Daphnia magna)             24-h LC50               4.8                            Glickman et al.,

    Water flea (Daphnia magna)             21-day static EC50      1.5                            Hüls, 1998b

    Water flea (Daphnia magna)             24-h IC50a              1.4                            Galassi et al.,

    Table 2 (continued)

    Water flea (Daphnia magna)             24-h IC50               0.6                            Abernathy et al.,

    Mysid shrimp (Mysidopsis bahia)        96-h flow LC50          1.3                            Glickman et al.,

    Mysid shrimp (Mysidopsis bahia)        96-h flow LC50          1.2                            Chemical Manufacturers
                                                                                                  Association, 1990

    Ciliate protozoan                      "toxicity threshold"    0.012                          Rogerson et al., 
    (Colpidium colpoda)                    (NR)b                                                  1983


    Rainbow trout                          96-h LC50               4.8                            Glickman et al.,
    (Oncorhynchus mykiss)                                                                         1995

    Rainbow trout                          no observed effect      1.9                            Glickman et al.,
    (Oncorhynchus mykiss)                                                                         1995

    Sheepshead minnow                      96-h flow LC50          4.7                            Glickman et al.,
    (Cyprinodon variegatus)                                                                       1995

    Sheepshead minnow                      no observed effect      <2.9                           Glickman et al.,
    (Cyprinodon variegatus)                                                                       1995

    a IC50 = immobilization concentration for 50% of the organisms.
    b NR = not reported.


    11.1  Evaluation of health effects

    11.1.1  Hazard identification and dose-response assessment

         Kinetic analysis shows that there is rapid and complete clearance
    of cumene and its metabolites from the body, indicating little
    potential for accumulation. No human toxicity data are available from
    exposure to cumene. Short-term exposures of animals to high
    concentrations (>2450 mg/m3 [>500 ppm]) demonstrate that cumene,
    like other solvents, may be considered harmful, inducing transient
    reversible central nervous system effects. However, neurotoxicity,
    portal-of-entry effects, developmental effects, and markedly adverse
    systemic toxicity were not observed after long-term repeated-dose
    studies conducted in animals at lower concentrations (<2450 mg/m3
    [<500 ppm]). Cumene has caused dermal and ocular irritation in
    animals in one study, but it had no such effects in others. A single
    study indicates that cumene does not elicit dermal sensitization in

         Increases in organ weights (most notably kidney) are the most
    prominent and consistent effects observed in rodents exposed for 6-7
    months by the oral route (Wolf et al., 1956) or for 3 months by the
    inhalation route (Cushman et al., 1995). No adverse effects were
    observed in rat or rabbit fetuses whose mothers had been exposed to
    airborne cumene during fetal development.

         The sparsity of long-term repeated-dose toxicity data and the
    absence of any human toxicity data both constitute areas of scientific
    uncertainty. The only repeated-dose toxicity studies of any
    appreciable duration are the oral study of Wolf et al. (1956), at
    about 7 months, and the 3-month subchronic inhalation study of Cushman
    et al. (1995). Both of these studies are concurrent in indicating
    kidneys of female rats as the target organ, regardless of exposure
    route. Although neither of these studies is sufficient in duration to
    reveal the fate of the observed alterations in organ weights from
    lifetime chronic exposure, the subchronic study of Cushman et al.
    (1995) is more scientifically comprehensive in its analyses than the
    study of Wolf et al. (1956) and offers much more extensive data
    reporting on more animals (both genders). The study of Cushman et al.
    (1995) is therefore chosen as the pivotal study.

         No multigeneration reproductive studies have been performed for
    cumene. The rapid metabolism and excretion of cumene, coupled with the
    lack of effects on sperm morphology reported by Cushman et al. (1995),
    indicate that cumene has low potential for reproductive toxicity.
    However, this lack of concern must be weighed against the fact that
    kinetic studies indicate extensive and wide distribution of cumene,
    including to reproductive organs, and the fact that the consequences
    of long-term repeated/continuous exposure on either organs or
    reproductive function have not been evaluated.

         There are no data in humans or animals concerning the development
    of cancer following exposure to cumene. The potential hazard for
    carcinogenicity of cumene to humans has not been determined, although
    the predominant evidence suggests that this compound is not likely to
    produce a carcinogenic response (i.e., numerous genotoxic tests,
    including gene mutation, chromosomal aberration, and primary DNA
    damage tests, were conducted, all but one of which were negative or
    not reproducible). No highly reactive chemical species are known to be
    generated during the metabolism of cumene.

    11.1.2  Criteria for setting guidance values for cumene

         For oral exposures, the NOAEL for increased average kidney weight
    in female rats following subchronic (139/194 days) oral (gavage)
    exposure is 154 mg/kg body weight per day, which was adjusted, based
    on the dosing schedule, to 110 mg/kg body weight per day (Wolf et al.,
    1956). These data were not amenable to benchmark dose analysis. For
    purposes of quantitative assessment, the quality of the principal oral
    study is marginal, because the group sizes were minimal, the groups
    comprised females only, and little quantitative information was
    presented. Full uncertainty factors of 10 each are applied for
    interindividual and interspecies variations. A partial uncertainty
    factor (100.5) for extrapolation from subchronic to chronic duration
    is applied, as the study was intermediate between chronic and
    subchronic duration. Another partial uncertainty factor (100.5) is
    also used owing to lack of a full-scale multigeneration reproductive
    study. The total uncertainty factor applied was 1000 (10 × 10 × 100.5
    × 100.5). This yields a guidance value for oral exposure of 0.1 mg/kg
    body weight per day. This guidance value is meant to provide
    information for risk managers to enable them in making decisions
    concerning the protection of human health.

         Interpretation of the effects reported in the subchronic
    inhalation study of Cushman et al. (1995) allows for consideration of
    either the 490 mg/m3 (100 ppm) (MAK, 1996) or the 2430 mg/m3 (496
    ppm) (US EPA, 1997) exposure level as a defensible NOAEL. Whereas the
    motor effects, organ weight changes, and clinical effects reported at
    2430 mg/m3 (496 ppm) may be regarded as non-adverse indicators of
    exposure (in other words, as a NOAEL), these same effects may be
    regarded alternatively as potentially adverse indicators of
    toxicologically significant effects apparent at the next highest
    exposure level (in other words, a LOAEL). Consideration of both these
    interpretations may be justified in derivation of an inhalation
    guidance value for cumene. The experimental exposure scenario of the
    NOAEL (either 490 or 2430 mg/m3 [100 or 496 ppm]) is first adjusted
    to a continuous exposure scenario for the general population by
    factoring the NOAEL by the hours exposed as a fraction of the day
    (6/24 hours) and the number of days exposed as a fraction of the week
    (5/7), resulting in the figure of 436 mg/m3 (89 ppm) for the 2430
    mg/m3 (496 ppm) experimental exposure level and 88 mg/m3 (18 ppm)
    for the 490 mg/m3 (100 ppm) experimental exposure level. Full
    uncertainty factors of 10 each were applied for subchronic to chronic

    extrapolation and for interindividual variations. A partial
    uncertainty factor (100.5) is applied to account for the toxicodynamic
    component of the interspecies extrapolation. In long-term inhalation
    exposures, the blood/air partition coefficient ( Hb/a) is a principal
    factor determining the amount of compound reaching a systemic tissue
    (such as kidney). For a given external concentration and similar
    exposure conditions, the smaller the  Hb/a values, the less compound
    in the blood and at the tissue. The blood/air partition coefficient
    has been determined with human blood (Sato & Nakajima, 1979, 1987),
    but not for rats. Information available on compounds structurally
    related to cumene (xylenes and benzene; Gargas et al., 1989) indicates
    that human  Hb/a values are nearly always smaller than rat  Hb/a
    values, such that, for a given external concentration, human tissues
    would receive less compound than would rat tissues. Thus, use of the
    rat in a long-term repeated-dose study with cumene obviates the need
    for the toxicokinetic component of the animal to human extrapolation.
    An additional partial uncertainty factor (100.5) is used for database
    deficiencies, owing principally to lack of a full-scale
    multigeneration reproductive study, as discussed above. The total
    uncertainty factor would be 1000 (10 × 10 × 100.5 × 100.5).
    Application of this factor would result in guidance values of 0.4
    mg/m3 (0.08 ppm) for the NOAEL of 436 mg/m3 (89 ppm), adjusted for
    continuous exposure from 2430 mg/m3 (496 ppm), and 0.09 mg/m3
    (0.02 ppm) for the NOAEL of 88 mg/m3 (18 ppm), adjusted for
    continuous exposure from 490 mg/m3 (100 ppm).

         The carcinogenic potential of cumene cannot be determined because
    no adequate data, such as well-conducted long-term animal studies or
    reliable human epidemiological studies, are available with which to
    perform an assessment.

    11.1.3  Sample risk characterization

         The scenario chosen as an example is continuous lifetime exposure
    for the general population.

         No human data are available with which to characterize the
    toxicity of cumene directly. The reported ambient cumene concentration
    of 0.0147 mg/m3 (0.003 ppm) is appreciably below either of the
    guidance values of 0.4 mg/m3 (0.08 ppm) (27-fold) or 0.09 mg/m3
    (0.02 ppm) (6-fold). The upper limit of ambient cumene concentrations
    reported in rural air, 2.5 µg/m3 (0.5 ppb), is even further below the
    guidance values (36- to 160-fold). Other data presented in this
    report, such as estimates from cigarette smoke, suggest that humans
    would primarily be exposed through inhalation, although ingestion
    through food may occur. Exposure via drinking-water is probably

         The critical effect in the principal study for the oral
    assessment is increased kidney weight in female rats and, although
    poorly reported, is corroborated by inhalation studies with cumene.
    Increased organ weights have been found in other toxicity studies with

    cumene and have been observed across routes of exposure. Insufficient
    data on oral exposure exist to apply the guidance value of 0.1 mg/kg
    body weight per day derived above.

         Following inhalation exposure, the effects observed included
    increased kidney and adrenal weights and central nervous system,
    haematological, and clinical biochemical alterations, which were
    observed in rats. The critical effect was observed across species and
    was observed in several studies. These results partially corroborate
    and reinforce the significance of similar results seen in the
    long-term oral study of cumene.

         The potential hazard for carcinogenicity of cumene in humans
    cannot be determined. Studies have indicated that cumene has low, if
    any, genotoxicity.

         Neither chronic nor multigeneration reproductive studies are
    available for this substance.

         Data are not available to determine whether young or aged animals
    are more susceptible than adult animals (e.g., 2-year-old rats) to the
    effects of cumene, and there is no evidence to suggest that this would
    be so in young or aged humans. There is also no convincing evidence to
    suggest that gender differences in susceptibility to cumene toxicity
    would exist in humans.

    11.2  Evaluation of environmental effects

         Cumene is a volatile liquid and exists mainly in the vapour phase
    in the atmosphere. It degrades in the atmosphere via reaction with
    hydroxyl radicals. Although small amounts of cumene may be removed
    from the atmosphere by precipitation, cumene is not expected to react
    with ozone or directly with light. In water, cumene can be
    volatilized, undergo biodegradation, or adsorb to sediments. In soil,
    it is expected to biodegrade rapidly under aerobic conditions; as in
    water, it can readily adsorb to soil or volatilize.

         BCFs suggest a slight potential for cumene to bioconcentrate in
    fish species. No data were available on the bioconcentration of cumene
    in terrestrial organisms. Although the existing toxicological database
    and limited exposure data do not permit a quantitative risk
    assessment, the available information suggests that cumene will not
    adversely affect populations or communities of terrestrial or aquatic
    organisms based on its low availability (volatility, rapid


         No previous evaluations by international bodies were identified.

         Information on international hazard classification and labelling
    is included in the International Chemical Safety Card reproduced in
    this document.


         Human health hazards, together with preventive and protective
    measures and first aid recommendations, are presented in the
    International Chemical Safety Card (ICSC 0170) reproduced in this

    13.1  Human health hazards

         Cumene is flammable. Exposure could cause central nervous system
    effects and at high concentrations could result in unconsciousness.

    13.2  Advice to physicians

         In the event of poisoning, treatment is supportive.

    13.3  Health surveillance advice

         For workers exposed to cumene, a health surveillance programme
    should include surveillance of kidney function.

    13.4  Spillage

         In the event of spillage, measures should be taken to prevent
    cumene from reaching drains and watercourses, owing to the potential
    for hazardous effects on aquatic organisms.

    13.5  Storage

         Cumene should be stored away from acids and strong oxidants.
    Long-term storage could result in the formation of explosive
    peroxides. Proper safety and handling procedures must be used.


         Information on national regulations, guidelines, and standards
    may be obtained from UNEP Chemicals (IRPTC), Geneva.

         The reader should be aware that regulatory decisions about
    chemicals taken in a certain country can be fully understood only in
    the framework of the legislation of that country. The regulations and
    guidelines of all countries are subject to change and should always be
    verified with appropriate regulatory authorities before application.


    ISOPROPYLBENZENE                                              ICSC:0170
                                                                  October 1994

    CAS #        98-82-8                     Cumene
    RTECS#       GR8575000           (1-Methylethyl)benzene
    UN #         1918                    2-Phenylpropane
    EC #         601-024-00-X          C9H12/C6H5CH(CH3)2

                                         Molecular Mass


    TYPES OF HAZARD/    ACUTE HAZARDS/             PREVENTION               FIRST AID/
    EXPOSURE            SYMPTOMS                                            FIRE FIGHTING

    FIRE                Flammable                  NO open flames,          Powder, AFFF,
                                                   NO sparks, and           foam, carbon dioxide
                                                   NO smoking.

    EXPLOSION           Above 31°C explosive       Above 31°C use a         In case of fire: keep
                        vapour/air mixtures        closed system,           drums, etc., cool by 
                        may be formed.             ventilation, and         spraying with water.
                                                   electrical equipment.
                                                   Prevent build-up of
                                                   electrostatic charges
                                                   (e.g., by grounding).

    EXPOSURE                                       PREVENT GENERATION
                                                   OF MISTS!

    Inhalation          Ataxia. Cough.             Ventilation, local       Fresh air, rest.
                        Dizziness. Drowsiness.     exhaust, or breathing    Half-upright position.
                        Headache. Sore throat.     protection.              Refer for medical 
                        Unconsciousness.                                    attention.

    Skin                Dry skin.                  Protective gloves.       Remove contaminated
                                                   Protective clothing.     clothes. Rinse and
                                                                            then wash skin with
                                                                            water and soap.

    Eyes                Redness. Pain.             Safety spectacles.       First rinse with
                                                                            plenty of water for
                                                                            several minutes
                                                                            (remove contact lenses
                                                                            if easily possible),
                                                                            then take to a doctor.

    Ingestion           (further see inhalation).  Do not eat, drink, or    Rinse mouth. Do NOT
                                                   smoke during work.       induce vomiting. Refer
                                                                            for medical attention.


    SPILLAGE DISPOSAL                              PACKAGING & LABELLING
    Collect leaking and spilled liquid in           Marine Pollutant
    sealable containers as far as possible.        EU Classification
    Absorb remaining liquid in sand or inert       Symbol: Xi
    absorbent and remove to safe place.            R: 10-37
    Do NOT let this chemical enter the             S: (2-)
    environment (extra personal protection:        Note: C
    A/P2 filter respirator for organic vapour      UN Classification
    and harmful dust.)                             UN Hazard Class: 3
                                                   UN Pack Group: III

    EMERGENCY RESPONSE                             STORAGE
    Transport Emergency Card: TEC (R)-594 NFPA     Fireproof. Separated from strong oxidants,
    Code: H2; F3; R0                               acids. Cool. Keep in the dark. Store only
                                                   if stabilized.

                                      IMPORTANT DATA
    COLOURLESS LIQUID, WITH CHARACTERISTIC         The substance can be absorbed into the
    ODOUR.                                         the body by inhalation and through the

    PHYSICAL DANGERS:                              INHALATION RISK:
    As a result of flow, agitation, etc.,          A harmful contamination of the air will be
    electrostatic charges can be generated.        reached rather slowly on evaporation of this
                                                   substance at 20°C.

    CHEMICAL DANGERS:                              EFFECTS OF SHORT TERM EXPOSURE:
    The substance can form explosive peroxides.    The substance irritates the eyes and the
    Reacts violently with acids and strong         respiratory tract. Swallowing the liquid may
    oxidants causing fire and explosion hazards.   cause aspiration into the lungs with the risk
                                                   of chemical pneumonitis. The substance may 
                                                   cause effects on the central nervous system.
                                                   Exposure far above the OEL may result in

    TLV: 50 ppm; 246 mg/m3 (skin)                  Repeated or prolonged contact with skin
    (ACGIH 1996).                                  may cause dermatitis.

                                      PHYSICAL PROPERTIES
    Boiling point: 152 °C                          Flash point: 31°C
    Melting point: -96 °C                          Auto-ignition temperature: 420°C
    Relative density (water = 1): 0.90             Explosive limits, vol% in air: 0.9-6.5
    Solubility in water: none                      Octanol/water partition coefficient as 
    Vapour Pressure, Pa at 20°C: 427               log Pow: 3.66
    Relative Vapour density (air = 1): 4.2
    Relative density of the vapour/air-mixture
    at 20°C (air = 1): 1.01

                                      ENVIRONMENTAL DATA

    This substance may be hazardous to the environment; special attention should be given to
    water organisms, and birds.

    An added stabilizer or inhibitor can influence the toxicological properties of this
    substance, consult an expert. Check for peroxides prior to distillation; eliminate if

                                      ADDITIONAL INFORMATION


    LEGAL NOTICE       Neither the CEC nor the IPCS nor any person acting on behalf of
                       the CEC or the IPCS is responsible for the use which might be
                       made of this information.


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    Agency, Washington, DC

         The peer review process that this and other recent (post-1996)
    IRIS assessments undergo includes internal (i.e., US Environmental
    Protection Agency) and external review rounds. Comments of and
    responses to the external reviewers are a matter of record in the
     Toxicological review. Other aspects of the IRIS review process are
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         The US EPA (1987) report is used as an expanded reference source
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         The  Environmental hazard assessment (EHA): Cumene document was
    drafted by the Building Research Establishment (United Kingdom
    Department of the Environment) and the Institute of Terrestrial
    Ecology (United Kingdom Natural Environment Research Council), with
    I.R. Nielsen, J. Diment, and S. Dobson as the authors. The draft
    document was peer reviewed both within the United Kingdom and
    internationally. Comments and additional material were received from
    A.L. Barton (US Environmental Protection Agency), C.B. Buckley (South
    Western Water Services, United Kingdom), J.H. Duffus (Heriot-Watt
    University, Edinburgh, United Kingdom), D. Keating (Health & Safety
    Executive, United Kingdom), S. Killeen (National Rivers Authority,
    United Kingdom), J.S. Lawson (ICI Chemicals, United Kingdom), P.
    Matthiessen (Ministry of Agriculture, Fisheries and Food, United
    Kingdom), H.A. Painter (Freshfield Analysis Ltd.), N. Passant
    (Department of Trade and Industry, United Kingdom), T. Sheils
    (Department of the Environment, United Kingdom), and G. Thom (US
    Environmental Protection Agency) and were incorporated into the final
    document. The document was published in 1994 and covers published and
    unpublished material up to 1993.


         The draft CICAD on cumene was sent for review to institutions and
    organizations identified by IPCS after contact with IPCS national
    Contact Points and Participating Institutions, as well as to
    identified experts. Comments were received from:

         Commission of the European Communities, Directorate-General,

         Federal Institute for Health Protection of Consumers & Veterinary
         Medicine (BgVV), Berlin, Germany

         GSF-Forschungszentrum für Umwelt und Gesundheit GmbH, Institut
         für Toxikologie, Oberscheissheim, Germany

         Health & Safety Executive, Merseyside, United Kingdom

         Institut de Recherches en Santé et Sécurité du Travail du Québec,
         Montreal, Canada

         Institute of Occupational Medicine, Chinese Academy of Preventive
         Medicine, Ministry of Health, Beijing, People's Republic of China

         Institute of Terrestrial Ecology, Cambridgeshire, United Kingdom

         Joint Food Safety and Standards Group, London, United Kingdom

         National Chemicals Inspectorate, Solna, Sweden

         National Industrial Chemicals Notification and Assessment Scheme,
         Sydney, Australia

         National Institute of Health Sciences, Tokyo, Japan

         National Institute of Occupational Health, Budapest, Hungary

         National Institute of Public Health, Czech Republic

         United States Department of Health and Human Services (National
         Institute of Environmental Health Sciences)

         United States Environmental Protection Agency (National Center
         for Environmental Assessment; Region VIII)


    Washington, DC, USA, 8-11 December 1998


    Dr T. Berzins, National Chemicals Inspectorate (KEMI), Solna, Sweden
    ( Vice-Chairperson)

    Mr R. Cary, Toxicology Unit, Health Directorate, Health and Safety
    Executive, Bootle, Merseyside, United Kingdom ( Rapporteur)

    Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood, Abbots
    Ripton, Huntingdon, Cambridgeshire, United Kingdom

    Dr O. Faroon, Agency for Toxic Substances and Disease Registry,
    Centers for Disease Control and Prevention, Atlanta, GA, USA

    Dr G. Foureman, National Center for Environmental Assessment, US
    Environmental Protection Agency, Research Triangle Park, NC, USA

    Dr H. Gibb, National Center for Environmental Assessment, US
    Environmental Protection Agency, Washington, DC, USA ( Chairperson)

    Dr R.F. Hertel, Federal Institute for Health Protection of Consumers &
    Veterinary Medicine, Berlin, Germany

    Dr I. Mangelsdorf, Documentation and Assessment of Chemicals,
    Fraunhofer Institute for Toxicology and Aerosol Research, Hanover,

    Dr A. Nishikawa, Division of Pathology, National Institute of Health
    Sciences, Tokyo, Japan

    Dr E.V. Ohanian, Office of Water/Office of Science and Technology,
    Health and Ecological Criteria Division, US Environmental Protection
    Agency, Washington, DC, USA

    Dr J. Sekizawa, Division of Chem-Bio Informatics, National Institute
    of Health Sciences, Tokyo, Japan

    Professor P. Yao, Institute of Occupational Medicine, Chinese Academy
    of Preventive Medicine, Ministry of Health, Beijing, People's Republic
    of China


    Dr K. Austin, National Center for Environmental Assessment, US
    Environmental Protection Agency, Washington, DC, USA

    Dr I. Daly (ICCA representative), Regulatory and Technical Associates,
    Lebanon, NJ, USA

    Ms K.L. Lang (CEFIC, European Chemical Industry Council,
    representative), Shell International, London, United Kingdom

    Ms K. Roberts (ICCA representative), Chemical Self-funded Technical
    Advocacy and Research (CHEMSTAR), Chemical Manufacturers Association,
    Arlington, VA, USA

    Dr W. Snellings (ICCA representative), Union Carbide Corporation,
    Danbury, CN, USA

    Dr M. Sweeney, Document Development Branch, National Institute for
    Occupational Safety and Health, Cincinnati, OH, USA 

    Dr K. Ziegler-Skylakakis, GSF-Forschungszentrum für Umwelt und
    Gesundheit GmbH, Institut für Toxikologie, Oberschleissheim, Germany


    Dr M. Baril, Institut de Recherches en Santé et Sécurité du Travail du
    Québec (IRSST), Montreal, Quebec, Canada

    Dr H. Galal-Gorchev, Chevy Chase, MD, USA

    Ms M. Godden, Health and Safety Executive, Bootle, Merseyside, United

    Dr R.G. Liteplo, Environmental Health Directorate, Health Canada,
    Ottawa, Ontario, Canada

    Ms L. Regis, Programme for the Promotion of Chemical Safety, World
    Health Organization, Geneva, Switzerland

    Mr A. Strawson, Health and Safety Executive, London, United Kingdom

    Dr P. Toft, Programme for the Promotion of Chemical Safety, World
    Health Organization, Geneva, Switzerland


         Ce CICAD relatif au cumène a été préparé par l'Environmental
    Protection Agency (EPA) des Etats-Unis sur la base d'une de ses
    publications intitulée  Health and  environmental effects document
     for cumene (US EPA, 1987), du dossier cumène provenant de son
    système intégré d'information sur les risques (IRIS) (US EPA, 1997) et
    d'un document du Royaume Uni paru sous le titre de  Environmental
     hazard assessment (EHA): Cumene (UK DOE, 1994), complétés par une
    étude bibliographique à partir de la base de données écologiques
    AQUIRE (Aquatic Toxicity Information Retrieval). Les recherches
    bibliographiques effectuée pour l'établissement du dossier IRIS vont
    jusqu'à novembre 1996 et celles qui ont été effectuées à partir de la
    base de données AQUIRE, jusqu'à avril 1998. On trouvera à l'appendice
    1 des indications sur le mode d'examen par des pairs ainsi que sur les
    sources documentaires utilisées. Les renseignements concernant
    l'examen du CICAD par les pairs font l'objet de l'appendice 2. Ce
    CICAD a été approuvé en tant qu'évaluation internationale lors de la
    réunion du Comité d'évaluation finale qui s'est tenue à Washington du
    8 au 11 décembre 1998. La liste des participants à cette réunion
    figure à l'appendice 3. La fiche d'information internationale sur la
    sécurité chimique (ICSC 0170) relative au cumène, établie par le
    Programme internationale sur la sécurité chimique (IPCS, 1993) est
    également reproduite dans ce document.

         Le cumène (CAS No 98-82-8) est un produit pétrochimique insoluble
    dans l'eau utilisé dans la préparation d'un certain nombre d'autres
    substances chimiques, notamment le phénol et l'acétone. Il se
    volatilise facilement dans l'atmosphère à partir de l'eau et des sols
    secs. Il devrait en principe n'être que modérément adsorbé au
    particules du sol et aux sédiments et subir une décomposition dans
    l'eau et le sol.

         Le métabolisme du cumène donne principalement naissance, chez
    l'Homme comme chez l'animal, à un alcool secondaire le
    2-phényl-2-propanol. Cet alcool et ses conjugués sont rapidement
    excrétés chez les rongeurs comme chez l'Homme.

         Les effets les plus marqués observés chez des rongeurs exposés de
    façon répétée au cumène par la voie orale ou respiratoire, consistent
    en une augmentation du poids de certains organes, mais plus
    particulièrement du rein. Aucun effet indésirable n'a été relevé chez
    des foetus de rats et de lapins dont la mère avait été exposée à ce
    produit au cours du développement foetal. Il n'y a pas eu d'étude de
    reproduction portant sur plusieurs générations, mais la métabolisation
    et l'excrétion rapides du composé et le fait qu'une étude subchronique
    n'ait pas mis en évidence d'effets sur les spermatozoïdes, semblent
    indiquer que le cumène est dépourvu de toxicité génésique. On a établi
    une valeur-guide de 0,1 mg/kg par jour en se basant sur la dose sans
    effet nocif observable (NOAEL) de 154 mg/kg p.c. obtenue après avoir
    fait ingérer du cumène à des rats pendant 6 à 7 mois, le critère

    retenu étant l'hypertrophie rénale chez les femelles. Cette valeur de
    la dose a été corrigée pour tenir compte du programme d'administration
    et on a appliqué un facteur d'incertitude de 1000. D'autres valeurs de
    la NOAEL tirées d'une même étude d'inhalation en mode subchronique ont
    abouti à des valeurs-guides respectivement égales à 0,4 mg/m3 et 0,09
    mg/m3 pour la population générale; dans ce cas également, on a
    corrigé la valeur de la NOAEL pour tenir compte d'une exposition en
    mode continu et on a appliqué un facteur global d'incertitude égal à

         On ne possède pas de données qui permettent d'évaluer
    quantitativement l'exposition humaine au cumène.

         Il n'est pas possible d'évaluer le pouvoir cancérogène du cumène
    chez l'Homme en raison de l'absence d'études de cancérogénicité à long
    terme. La plupart des études de génotoxicité ont donné des résultats

         Les données qui permettraient une évaluation du risque encouru
    par les organismes aquatiques et terrestres sont insuffisantes,
    notamment en ce qui concerne la mesure de l'exposition à ce composé.
    Toutefois, si l'on se base sur les données existantes, on peut penser
    que ce risque est relativement faible. Les valeurs disponibles
    indiquent une légère tendance à la bioconcentration chez les poissons.
    On dispose d'aucune donnée sur la bioaccumulation du cumène le long
    des diverses chaînes alimentaires (bioamplification).


         Este CICAD sobre el cumeno, preparado por la Agencia para la
    Protección del Medio Ambiente de los Estados Unidos (EPA), se basa en
    un documento de la EPA sobre los efectos sanitarios y medioambientales
    del cumeno (US EPA, 1987), en un archivo sobre el cumeno del sistema
    integrado de información sobre riesgos (IRIS) de la EPA de los Estados
    Unidos (US EPA, 1997) y en un documento del Reino Unido sobre la
    evaluación de los riesgos medioambientales del cumeno (UK DOE, 1994),
    con el complemento de una búsqueda bibliográfica en la base de datos
    AQUIRE (Aquatic Toxicity Information Retrieval), especializada en
    ecología. La búsqueda bibliográfica en el archivo del IRIS se realizó
    hasta noviembre de 1996 y en la base de datos AQUIRE hasta abril de
    1998. La información relativa al carácter del examen colegiado y a la
    disponibilidad de los documentos originales figura en el apéndice 1.
    La información sobre el examen colegiado de este CICAD aparece en el
    apéndice 2. Este CICAD se aprobó como evaluación internacional en una
    reunión de la Junta de Evaluación Final celebrada en Washington, DC,
    Estados Unidos, los días 8-11 de diciembre de 1998. La lista de
    participantes en esta reunión figura en el apéndice 3. La ficha
    internacional de seguridad química (ICSC 0170) para el cumeno,
    preparada por el Programa Internacional de Seguridad de las Sustancias
    Químicas (IPCS, 1993), también se reproduce en el presente documento.

         El cumeno (CAS No 98-82-8) es un producto petroquímico insoluble
    en agua que se utiliza en la fabricación de varias sustancias
    químicas, entre ellas el fenol y la acetona. Se volatiliza fácilmente
    a la atmósfera a partir del agua y del suelo seco. Se supone que se
    adsorbe al suelo/sedimentos con una intensidad entre moderada y fuerte
    y que se biodegrada en el agua y en el suelo.

         El cumeno se metaboliza fundamentalmente al alcohol secundario
    2-fenil-2-propanol, tanto en el ser humano como en los animales. Los
    roedores y las personas excretan con facilidad este alcohol y sus

         Los efectos más notables observados en los roedores expuestos a
    dosis repetidas de cumeno por vía oral o por inhalación son un aumento
    del peso de los órganos, en particular de los riñones. No se
    detectaron efectos adversos en los fetos de rata o de conejo cuyas
    madres habían estado expuestas al cumeno durante el desarrollo fetal.
    Si bien no se han realizado estudios de reproducción multigeneracional
    con exposición al cumeno, la rapidez de su metabolismo y su excreción,
    junto con la falta de efectos en la morfología del esperma en un
    estudio subcrónico, parecen indicar un potencial bajo de toxicidad
    reproductiva. Se ha obtenido un valor guía para la exposición oral de
    0,1 mg/kg de peso corporal al día, basado en una concentración sin
    efectos adversos observados (NOAEL) de 154 mg/kg de peso corporal al
    día para el aumento del peso del riñón en ratas hembras en un estudio
    de administración oral de 6 a 7 meses de duración; la NOAEL se ajustó
    para un calendario de dosificación y se aplicó un factor de

    incertidumbre de 1 000. Con respecto a la exposición por inhalación,
    se obtuvieron valores guía para la población general de 0,4 mg/m3 y
    0,09 mg/m3, basados en otras NOAEL derivadas del mismo estudio de
    inhalación subcrónica; en este caso también se ajustaron las NOAEL
    para una exposición continua y se aplicó un factor de incertidumbre
    total de 1 000.

         No hay datos disponibles para cuantificar la exposición humana al

         No es posible evaluar el potencial de carcinogenicidad del cumeno
    en el ser humano, debido a que no se han realizado estudios de larga
    duración con esta sustancia. La mayor parte de los datos obtenidos en
    pruebas genotóxicas son negativos.

         Son insuficientes los datos, especialmente de información de la
    exposición medida, para poder realizar una evaluación cuantitativa del
    riesgo de la exposición al cumeno para las poblaciones de organismos
    acuáticos o terrestres. Sin embargo, teniendo en cuenta los datos
    existentes, se prevé para el cumeno un riesgo relativamente bajo. Los
    valores indican un ligero potencial de bioconcentración del cumeno en
    los peces. No hay datos acerca de la bioacumulación a través de la
    cadena alimentaria (bioamplificación).

    See Also:
       Toxicological Abbreviations
       Cumene (ICSC)