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    Concise International Chemical Assessment Document 17








    BUTYL BENZYL PHTHALATE









    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 17



    BUTYL BENZYL PHTHALATE



    First draft prepared by Ms M.E. Meek, Environmental Health
    Directorate, Health Canada



    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
    of the IPCS are to establish the scientific basis for assessment of
    the risk to human health and the environment from exposure to
    chemicals, through international peer review processes, as a
    prerequisite for the promotion of chemical safety, and to provide
    technical assistance in strengthening national capacities for the
    sound management of chemicals.

         The Inter-Organization Programme for the Sound Management of
    Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and
    Agriculture Organization of the United Nations, WHO, the United
    Nations Industrial Development Organization, the United Nations
    Institute for Training and Research, and the Organisation for Economic
    Co-operation and Development (Participating Organizations), following
    recommendations made by the 1992 UN Conference on Environment and
    Development to strengthen cooperation and increase coordination in the
    field of chemical safety. The purpose of the IOMC is to promote
    coordination of the policies and activities pursued by the
    Participating Organizations, jointly or separately, to achieve the
    sound management of chemicals in relation to human health and the
    environment.

    WHO Library Cataloguing-in-Publication Data

    Butyl benzyl phthalate.

         (Concise international chemical assessment document ; 17)

         1.Phthalic acids  2.Environmental exposure  3.Risk assessment
         I.International Programme on Chemical Safety  II.Series

         ISBN 92 4 153017 0  (NLM classification: QV 612)
         ISSN 1020-6167

         The World Health Organization welcomes requests for permission to
    reproduce or translate its publications, in part or in full.
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    (c) World Health Organization 1999

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    TABLE OF CONTENTS

    FOREWORD

    1. EXECUTIVE SUMMARY

    2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES

    3. ANALYTICAL METHODS

    4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         6.1. Environmental levels
         6.2. Human exposure

    7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS

    8. EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

         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. Peroxisomal proliferation
         8.8. Immunological and neurological effects

    9. EFFECTS ON HUMANS

    10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         10.1. Aquatic environment
              10.1.1. Pelagic organisms
              10.1.2. Benthic organisms
         10.2. Terrestrial environment

    11. EFFECTS EVALUATION

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

    12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    13. HUMAN HEALTH PROTECTION AND EMERGENCY ACTION

         13.1. Human health hazards
         13.2. Advice to physicians
         13.3. Spillage

    14. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS

    INTERNATIONAL CHEMICAL SAFETY CARD

    REFERENCES

    APPENDIX 1 -- SOURCE DOCUMENTS

    APPENDIX 2 -- CICAD PEER REVIEW

    APPENDIX 3 -- CICAD FINAL REVIEW BOARD

    RÉSUMÉ D'ORIENTATION

    RESUMEN DE ORIENTACION
    

    FOREWORD

         Concise International Chemical Assessment Documents (CICADs) are
    the latest in a family of publications from the International
    Programme on Chemical Safety (IPCS) -- a cooperative programme of the
    World Health Organization (WHO), the International Labour Organisation
    (ILO), and the United Nations Environment Programme (UNEP). CICADs
    join the Environmental Health Criteria documents (EHCs) as
    authoritative documents on the risk assessment of chemicals.

         CICADs are concise documents that provide summaries of the
    relevant scientific information concerning the potential effects of
    chemicals upon human health and/or the environment. They are based on
    selected national or regional evaluation documents or on existing
    EHCs. Before acceptance for publication as CICADs by IPCS, these
    documents undergo extensive peer review by internationally selected
    experts to ensure their completeness, accuracy in the way in which the
    original data are represented, and the validity of the conclusions
    drawn.

         The primary objective of CICADs is characterization of hazard and
    dose-response from exposure to a chemical. CICADs are not a summary of
    all available data on a particular chemical; rather, they include only
    that information considered critical for characterization of the risk
    posed by the chemical. The critical studies are, however, presented in
    sufficient detail to support the conclusions drawn. For additional
    information, the reader should consult the identified source documents
    upon which the CICAD has been based.

         Risks to human health and the environment will vary considerably
    depending upon the type and extent of exposure. Responsible
    authorities are strongly encouraged to characterize risk on the basis
    of locally measured or predicted exposure scenarios. To assist the
    reader, examples of exposure estimation and risk characterization are
    provided in CICADs, whenever possible. These examples cannot be
    considered as representing all possible exposure situations, but are
    provided as guidance only. The reader is referred to EHC 1701 for
    advice on the derivation of health-based guidance values.

         While every effort is made to ensure that CICADs represent the
    current status of knowledge, new information is being developed
    constantly. Unless otherwise stated, CICADs are based on a search of
    the scientific literature to the date shown in the executive summary.
    In the event that a reader becomes aware of new information that would
    change the conclusions drawn in a CICAD, the reader is requested to
    contact IPCS to inform it of the new information.

                  
    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).

    Procedures

         The flow chart shows the procedures followed to produce a CICAD.
    These procedures are designed to take advantage of the expertise that
    exists around the world -- expertise that is required to produce the
    high-quality evaluations of toxicological, exposure, and other data
    that are necessary for assessing risks to human health and/or the
    environment.

         The first draft is based on an existing national, regional, or
    international review. Authors of the first draft are usually, but not
    necessarily, from the institution that developed the original review.
    A standard outline has been developed to encourage consistency in
    form. The first draft undergoes primary review by IPCS to ensure that
    it meets the specified criteria for CICADs.

         The second stage involves international peer review by scientists
    known for their particular expertise and by scientists selected from
    an international roster compiled by IPCS through recommendations from
    IPCS national Contact Points and from IPCS Participating Institutions.
    Adequate time is allowed for the selected experts to undertake a
    thorough review. Authors are required to take reviewers' comments into
    account and revise their draft, if necessary. The resulting second
    draft is submitted to a Final Review Board together with the
    reviewers' comments.

         The CICAD Final Review Board has several important functions:

    -    to ensure that each CICAD has been subjected to an appropriate
         and thorough peer review;
    -    to verify that the peer reviewers' comments have been addressed
         appropriately;
    -    to provide guidance to those responsible for the preparation of
         CICADs on how to resolve any remaining issues if, in the opinion
         of the Board, the author has not adequately addressed all
         comments of the reviewers; and
    -    to approve CICADs as international assessments.

    Board members serve in their personal capacity, not as representatives
    of any organization, government, or industry. They are selected
    because of their expertise in human and environmental toxicology or
    because of their experience in the regulation of chemicals. Boards are
    chosen according to the range of expertise required for a meeting and
    the need for balanced geographic representation.

         Board members, authors, reviewers, consultants, and advisers who
    participate in the preparation of a CICAD are required to declare any
    real or potential conflict of interest in relation to the subjects
    under discussion at any stage of the process. Representatives of
    nongovernmental organizations may be invited to observe the
    proceedings of the Final Review Board. Observers may participate in
    Board discussions only at the invitation of the Chairperson, and they
    may not participate in the final decision-making process.

    FIGURE 


    1. EXECUTIVE SUMMARY

         This CICAD on butyl benzyl phthalate was prepared jointly by the
    Environmental Health Directorate of Health Canada and the Commercial
    Chemicals Evaluation Division of Environment Canada based on
    documentation prepared concurrently as part of the Priority Substances
    Program under the  Canadian Environmental Protection Act (CEPA). The
    objective of assessments on Priority Substances under CEPA is
    to assess potential effects of indirect exposure in the general
    environment on human health as well as environmental effects. Data
    identified as of the end of April 1998 were considered in these
    reviews. Information on the nature of the peer review and availability
    of the source document 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 Tokyo, Japan, on 30 June - 2 July 1998.
    Participants at the Final Review Board meeting are listed in Appendix
    3. The International Chemical Safety Card (ICSC 0834) for butyl benzyl
    phthalate, produced by the International Programme on Chemical Safety
    (IPCS, 1993), has also been reproduced in this document.

         Butyl benzyl phthalate (CAS No. 85-68-7), or BBP, is a clear,
    oily liquid that is used as a plasticizer mainly in polyvinyl chloride
    (PVC) for vinyl floor tile, vinyl foams, and carpet backing and to a
    minor extent also in cellulose plastics and polyurethane. Most
    environmental release is to the air. Once in the environment, BBP
    partitions to the atmosphere, soil, surface water, sediments, and
    biota and has been detected in each of these compartments.

         BBP is removed from the atmosphere by photooxidation and by
    rainwater, with a half-life of a few hours to a few days. BBP is not
    persistent in water, sediments, or soil under aerobic conditions, with
    a half-life of a few days. Under anaerobic conditions, BBP is more
    persistent, with a half-life of a few months. BBP is readily
    metabolized by vertebrates and invertebrates. Reported
    bioconcentration factors (BCFs) are less than 1000 based on total
    residues and well under 100 based on intact BBP residues.

         Available data in humans are inadequate to serve as a basis for
    assessment of the effects of long-term exposure to BBP in human
    populations.

         The acute toxicity of BBP is relatively low, with oral LD50
    values in rats being greater than 2 g/kg body weight. Target organs
    following acute exposure include the haematological and central
    nervous systems.

         Available data are inadequate to assess the irritant and
    sensitizing effects of BBP in animal species.

         The repeated-dose toxicity of BBP has been well investigated in
    recent studies, primarily in the rat, in which dose-response was well
    characterized. Effects observed consistently have been decreases in
    body weight gain (often accompanied by decreases in food consumption)
    and increases in organ to body weight ratios, particularly for the
    kidney and liver. Histopathological effects on the pancreas and kidney
    and haematological effects have also been observed. At higher doses,
    degenerative effects on the testes and, occasionally,
    histopathological effects on the liver have been reported. In
    specialized investigations, peroxisomal proliferation in the liver has
    been observed, although potency in this regard was less than that for
    other phthalates, such as bis(2-ethylhexyl) phthalate (DEHP).

         The chronic toxicity and carcinogenicity of BBP have been
    investigated in US National Toxicology Program (NTP) bioassays in rats
    (including standard and feed-restricted protocols) and mice. It was
    concluded that there was "some evidence" of carcinogenicity in male
    rats, based on an increased incidence of pancreatic tumours, and
    equivocal evidence in female rats, based on marginal increases in
    pancreatic and bladder tumours. Dietary restriction prevented full
    expression of the pancreatic tumours and delayed appearance of the
    bladder tumours. There was no evidence of carcinogenicity in mice.

         The weight of evidence of the genotoxicity of BBP is clearly
    negative. However, available data are inadequate to conclude
    unequivocally that BBP is not clastogenic, although in identified
    studies it has induced, at most, weak activity of a magnitude
    consistent with secondary effects on DNA.

         Therefore, BBP has induced an increase in pancreatic tumours
    primarily in one sex of one species, the full expression of which was
    prevented in a dietary restriction protocol, and a marginal increase
    in bladder tumours in the other sex, which was delayed upon dietary
    restriction. The weight of evidence of genotoxicity is negative, and,
    although weak clastogenic potential cannot be ruled out, available
    data are consistent with the compound not interacting directly with
    DNA. On this basis, BBP can be considered, at most, possibly
    carcinogenic to humans, likely inducing tumours through a
    non-genotoxic (although unknown) mechanism.

         In a range of studies, including those designed to investigate
    the reproductive effects of BBP on the testes and endocrine hormones
    of male rats, a modified mating protocol conducted by the NTP, and a
    one-generation study, adverse effects on the testes and, consequently,
    fertility have generally been observed only at doses higher than those
    that induce effects on other organs (such as the kidney and liver),
    although decreases in sperm counts have been observed at doses similar
    to those that induce effects in the kidney and liver. This is
    consistent with the results of repeated-dose toxicity studies. 

         Reductions in testes weight and daily sperm production in
    offspring were reported at a relatively low level in rats exposed  in
     utero and during lactation in a study in which dose-response was not
    investigated. However, such effects were not observed in a recent
    study of similar, but not identical, design in another strain of rats
    in which only increases in absolute and relative liver weights were
    observed at postnatal day 90. Additional investigation of potential
    effects on the reproductive systems of male and female animals exposed
     in utero and during lactation in studies designed to address 
    dose-response is desirable and is under way. 

         Although BBP has been estrogenic in human breast cell cancer
    lines  in vitro, results in yeast cells have been mixed. Neither BBP
    nor its principal metabolites have been uterotrophic  in vivo in rats
    or mice. Although available data do not support the conclusion that
    BBP is estrogenic, other potential endocrine-mediated effects such as
    anti-androgenic activity associated with dibutyl phthalate (DBP) are
    not precluded.

         There is considerable emphasis currently on development of more
    sensitive frameworks for testing and assessment of
    endocrine-disrupting substances; compounds such as phthalates are
    likely early candidates for additional testing.

         In several well-conducted studies in rats and mice, BBP has
    induced marked developmental effects, but only at dose levels that
    induce significant maternal toxicity.

         Although the potential neurotoxicity of BBP has not been well
    investigated, histopathological effects on the central and peripheral
    nervous systems have not been observed following short-term exposure
    to relatively high dietary concentrations. Available data are
    inadequate to assess the potential immunotoxicity of BBP.

         A sample tolerable daily intake (TDI) of 1300 µg/kg body weight
    per day has been derived for BBP. It is based upon the lower 95%
    confidence limit for the benchmark dose associated with a 5% increase
    in the incidence of pancreatic lesions in male rats in an oral
    subchronic bioassay divided by an uncertainty factor of 100 (10 for
    interspecies variation and 10 for intraspecies variation). Based upon
    concentrations in various environmental media, it appears (from sample
    estimates) that food contributes all of the estimated intake, which is
    considered, for the general population, to range from 2 to 6 µg/kg
    body weight per day. These estimates are 200-650 times less than the
    TDI. Data were inadequate to estimate exposure in the occupational
    environment or from consumer products.

         A range of toxicity tests with aquatic organisms has indicated
    that adverse effects occur at exposure concentrations equal to or
    greater than 100 µg/litre. As concentrations in surface waters are
    generally less than 1 µg/litre, it is likely that BBP poses low risk
    to aquatic organisms.

         No information about the effects of BBP on sediment-dwelling
    organisms, soil invertebrates, terrestrial plants, or birds has been
    identified on which to base an estimate of risk to these organisms.
    

    2.  IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES

         The physical and chemical properties of BBP have been summarized
    by Skinner (1992). BBP (CAS No. 85-68-7) is an aromatic ester that
    conforms to the formula C19H20O4. Synonyms include
    1,2-benzenedicarboxylic acid, butyl phenylmethyl ester, and benzyl
     n-butyl phthalate. BBP is a clear, oily liquid at room temperature
    with a molecular weight of 312.4 g/mol. Reported log octanol/water
    partition coefficients (log  Kow) range from 3.6 to 5.8; 4.91 is a
    measured value, whereas the 4.77 provided in the International
    Chemical Safety Card is an estimated value. Additional physical/
    chemical properties are presented in the International Chemical Safety
    Card reproduced in this document.
    

    3.  ANALYTICAL METHODS

         Analytical methods have been reviewed by Skinner (1992). BBP may
    be analysed by gas chromatography/mass spectrometry and by
    high-performance liquid chromatography. It is determined in water by
    an enrichment procedure using sequential reverse osmosis, followed by
    extraction and analysis by gas chromatography/mass spectrometry, or
    after adsorption onto Tenax material and thermal desorption to a fused
    silica capillary gas chromatography column under whole-column
    cryotrapping conditions (Pankow et al., 1988). In air, BBP has been
    determined by liquid chromatographic separation using a florisil
    adsorbent and 10% 2-propanol in hexane as the eluent followed by gas
    chromatographic analysis with detection by 63Ni electron capture
    (Stein et al., 1987). BBP can be determined in mixtures of
    semivolatile organic pollutants using gas chromatography/Fourier
    transform infrared spectroscopy with wall-coated open tubular
    capillary columns. Combining this technique with gas
    chromatography/mass spectrometry allows for better and faster
    identification of the components of complex mixtures of environmental
    pollutants.

         In reports of analyses of environmental media for BBP, detection
    limits were 1 µg/litre for samples of drinking-water (G. Halina,
    personal communication, 1994; method not specified) and 0.2 mg/kg dry
    weight for soil (gas chromatography/mass spectrometry; Webber & Wang,
    1995). Detection limits for analyses (by gas chromatography/flame
    ionization detection) of table-ready foods were 0.5 µg/g (butter), 0.2
    µg/g (vegetables and fruits), and 0.1 µg/g (meat and fish) (Page &
    Lacroix, 1995). The detection limits varied with the fat content of
    the food and food matrix interferences.
    

    4.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         BBP is manufactured by the reaction of the monobutyl ester of
    phthalic acid with benzyl chloride (Skinner, 1992). In the USA,
    Monsanto Company is the sole manufacturer of BBP (Anon., 1996). BBP is
    used mainly as a plasticizer in PVC for vinyl floor tile, vinyl foams,
    and carpet backing. Other polymers plasticized with BBP include
    cellulose plastics, polyvinyl acetate, polysulfides, and polyurethane.
    Consumption of BBP in Europe is approximately 18 000-45 000 tonnes per
    year (Harris et al., 1997).

         BBP is released from facilities that manufacture the substance or
    blend it with PVC (Howard, 1990). Releases may also occur through
    diffusion of BBP from PVC products.

         Total on-site environmental releases of BBP reported to the
    Canadian National Pollutant Release Inventory by 11 facilities using
    BBP amounted to 3.7 tonnes in 1994, all to the atmosphere. Total
    transfers of BBP for off-site disposal were much higher, amounting to
    33.3 tonnes in 1994, with 25.1 tonnes going to incinerators and the
    remainder, 8.2 tonnes, to landfill. A reported total of 3.7 tonnes of
    BBP was sent for recovery in 1994, 2.3 tonnes for energy recovery and
    1.4 tonnes for recovery, reuse, or recycling (NPRI, 1996).

         In the USA, it was estimated that manufacturing facilities
    released approximately 176 tonnes to the environment in 1993, with
    about 99% released to the atmosphere (TRI93, 1995).

         BBP may be released to air through automobile emissions and from
    combustion of refuse (Graedel et al., 1986). It has also been detected
    in stack emissions from hazardous waste combustion facilities and from
    coal-fired power plants in the USA (Oppelt, 1987). Reasonable
    worst-case emissions of BBP from incinerators, boilers, and industrial
    furnaces burning such wastes were predicted to be 3 µg/m3 waste gas
    (Dempsey & Oppelt, 1993). In a study of four US coal-fired utility
    boiler plants, the emission rates for BBP in flue gases ranged from
    210 to 3400 mg/h (Haile et al., 1984). BBP was identified, but not
    quantified, in extracts of municipal incinerator fly ash from the
    Netherlands, but it was not detected in extracts from Japan or Ontario
    (Eiceman et al., 1979).

         In leachate from municipal landfills in the USA, BBP was
    detected, but not quantified (Brown & Donnelly, 1988). BBP has also
    been detected (detection limits not reported) in groundwater at
    disposal sites in the USA (Plumb, 1991). BBP was also detected in 2 of
    44 groundwater samples at a Superfund site in Michigan, USA, at
    estimated concentrations of 0.6 and 1.0 µg/litre (US EPA, 1996).

         In Canada, BBP has been detected in storm sewer effluents at
    concentrations up to 50 µg/litre (Hargesheimer & Lewis, 1987) and in
    effluents from municipal sewage treatment plants and industrial plants
    at concentrations up to 25 µg/litre (Munro et al., 1985; SIGMA, 1985;
    OMOE, 1988, 1990, 1991).1 BBP has also been detected in sludges from
    Canadian sewage treatment plants at concentrations up to 914 498 ng/g
    dry weight (OMOE, 1988).

         BBP can be emitted from products containing the substance. For
    example, BBP has been detected in emissions from carpets (Bayer &
    Papanicolopoulos, 1990), PVC floorings (Bremer et al., 1993), and
    vinyl wall coverings (Etkin, 1995), although quantitative data were
    not identified. It is also a component of some consumer products, such
    as nail polish (Martin, 1996). The possibility that toys made of
    plastic might contain BBP is currently being investigated, although
    quantitative data are not yet available.

                  
    1 Additional data from ENVIRODAT, Surveys and Information Systems
      Branch, Environment Canada, 1993.
    

    5.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

         Fugacity modelling was based upon the assumption of continuous
    emissions of 1000 kg/h to air, water, or soil (DMER & AEL, 1996). Most
    environmental releases of BBP are to the atmosphere. The Level III
    calculations of the EQC fugacity model predict that when BBP is
    emitted into air, approximately 72% is found in soil, 22% in air, 4%
    in water, and 2% in sediment. When BBP is emitted into water, 65% is
    found in water, while about 35% partitions to sediment and a very
    small fraction to soil. When BBP is released to soil, more than 99% is
    found in the soil. Values for input parameters were as follows:
    molecular weight, 312.4 g/mol; vapour pressure, 0.001 15 Pa; water
    solubility, 2.69 mg/litre; melting point, -35°C; and log  Kow, 4.9.
    Average degrading reaction half-lives were assumed to be 55 h in air,
    170 h in water, 550 h in soil, and 1700 h in sediment (Mackay et al.,
    1995). The calculated organic carbon/water partition coefficient (log
     Koc) is 4.51 (based on the correlation  Koc = 0.41  Kow), and
    the Henry's law constant is 0.133 Pa.m3/mol at 25°C.

         Photooxidation is the most important process for the breakdown of
    BBP in the atmosphere (Atkinson, 1987). Howard et al. (1991) estimated
    a half-life in air of 6-60 h for BBP based on photooxidation rates.
    BBP is also readily removed from air by rain (Ligocki et al., 1985a).

         BBP is readily biodegraded in aerobic surface water, with a
    half-life of about 1-7 days (Saeger & Tucker, 1976; Gledhill et al.,
    1980; Howard et al., 1991; Adams & Saeger, 1993). Biodegradation is
    considerably slower in cold water, as BBP was almost completely
    biodegraded after 7 days in Rhine River water at 20°C but was not
    biodegraded in the same water after 10 days at 4°C (Ritsema et al.,
    1989). BBP is expected to adsorb to suspended matter, sediments, and
    biota.

         Biodegradation is the most important degradation pathway in
    sediments (Gledhill et al., 1980; Adams & Saeger, 1993). In a river
    water/sediment microcosm, the degradation pathway appeared to be
    BBP -> monobutyl/monobenzyl phthalate -> phthalic acid ->
    4,5-dihydroxyphthalic acid -> oxalic acid -> formic acid -> carbon
    dioxide (Adams et al., 1986, 1989; Adams & Saeger, 1993). The
    half-life for complete mineralization of BBP in this study was 13 days
    (Adams & Saeger, 1993). BBP can also be biodegraded in sediment under
    anaerobic conditions (Shelton & Tiedje, 1984; Painter & Jones, 1990;
    Ejlertsson et al., 1996), with an estimated half-life of about 1 day
    to 6 months (Howard et al., 1991).

         Biodegradation of BBP occurs readily in aerobic soils, with a
    half-life of about 1-7 days at room temperature (Howard et al., 1991).
    It is also biodegraded in anaerobic soils. For the removal of BBP in a
    silt loam, Kincannon & Lin (1985) determined a half-life of 59.2 days.
    BBP sorbs to soil, so soil leaching should not be significant (Zurmhhl
    et al., 1991).

         With reported log  Kow values ranging from 3.6 to 5.8, BBP
    would appear to have a high potential for bioaccumulation. However,
    reported BCFs in oysters, microorganisms, and several species of fish
    are less than 1000, because BBP is readily metabolized, with a
    depuration half-life of less than 2 days (Barrows et al., 1980; Veith
    et al., 1980). The highest reported BCF was 776 for bluegill
    ( Lepomis  macrochirus) (Veith et al., 1980).

         Based on physical/chemical properties of BBP, Wild & Jones (1992)
    predicted that retention of the substance by root surfaces of plants
    would be high, but that subsequent uptake by plants would be low. This
    prediction was confirmed by Müller and Kördel (1993), who demonstrated
    that plants grown on phthalate-enriched soil did not take up BBP from
    the soil through the roots. However, plants exposed to
    phthalate-treated dust did take up BBP through leaf cuticles
    (quantitative data not available).
    

    6.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    6.1  Environmental levels

         In air samples from Greater Vancouver, British Columbia, Canada,
    BBP was detected at concentrations ranging from 0.38 to 1.78 ng/m3
    (W. Belzer, personal communication, 1997). Concentrations of BBP in
    air up to 9.6 ng/m3 (in the aerosol phase at Portland, Oregon, USA)
    have been reported (Ligocki et al., 1985a,b). BBP has been identified
    in ambient air in Barcelona, Spain; concentrations of 1.0 and 8.0
    ng/m3 in winter and 0.25 and 2.0 ng/m3 in summer, associated with
    coarse (>7.2 µm) and fine (<0.5 µm) aerosol fractions, respectively,
    have been reported (Aceves & Grimalt, 1993).

         In Canadian surface waters, BBP was detected at concentrations up
    to 1 µg/litre.1 Gledhill et al. (1980) reported a concentration of
    2.4 µg/litre in the Mississippi River south of St. Louis, Missouri,
    USA. In central Italy, BBP was detected at concentrations up to
    6.6 µg/litre in Lake Scandarello (Vitali et al., 1997). In water
    samples collected from the Rhine River and its tributaries, levels
    ranged up to 5.2 µg/litre (ECPI, 1996). In samples of inflow and
    outflow from sewage treatment plants in Sweden and Norway,
    concentrations of BBP up to 2.4 µg/litre and 0.58 µg/litre,
    respectively, were reported (ECPI, 1996; NIWR, 1996).

         BBP has been reported in marine sediments from British Columbia,
    Canada, at concentrations up to 370 ng/g dry weight (Axys Analytical
    Services Limited, 1992; D. Goyette, personal communication, 1993).
    Outside Canada, the highest reported concentration of BBP in sediments
    was 3800 ng/g dry weight, in sediments from the Lower Passaic River,
    Newark, New Jersey, USA, adjacent to combined sewer overflow outfalls
    (Iannuzzi et al., 1997).

         In limited surveys of soils from agricultural and typical urban
    residential and parkland locations in Canada, concentrations of BBP
    were less than 0.3 µg/g (Golder Associates, 1987; Webber & Wang,
    1995).

         At a lime disposal area of a refinery in Regina, BBP
    concentrations in soil of 0.15 and 0.55 µg/g were reported.2 In soil
    in the neighbourhood of three phthalate-emitting plants in Germany
    from 1986 to 1989, the highest concentration in an individual sample
    was 100 µg/kg; the highest mean value for a single site was 30 µg/kg
    (Müller & Kördel, 1993).

                  
    1 Data from ENVIRODAT, Surveys and Information Systems Branch,
      Environment Canada, 1993.

    2 Letter from D. Fast, Saskatchewan Department of Environment and
      Public Safety, to Senes Consultants Limited, Richmond Hill, Ontario,
      1989.

         In Canadian biota, BBP has been detected at concentrations up to
    1470 ng/g wet weight (in butter sole,  Isopsetta [ Pleuronectes]
     isolepis, from Boundary Bay, British Columbia; Swain & Walton,
    1990). BBP was detected in US biota at 3% of 182 STORET stations, with
    a median concentration of <2500 ng/g (Staples et al., 1985).

    6.2  Human exposure

         In 125 homes in California, USA, two 12-h indoor air samples were
    collected during daytime and overnight periods. In indoor air, median
    daytime and nighttime concentrations were 34 and 35 ng/m3,
    respectively. In a subset of 65 homes, outdoor air samples were also
    collected. In outdoor air, the median (for both daytime and nighttime
    sampling) was below the method quantifiable limit of 5.1 ng/m3; the
    90th percentiles were 5.3 and 6.7 ng/m3 for daytime and nighttime
    sampling, respectively (California Environmental Protection Agency,
    1992). In an early study, BBP concentrations of 1 and 20 ng/m3 were
    reported in office air at two locations in the USA, although the
    compound was not detected (detection limit not reported) in ambient
    air (Weschler, 1984).

         In surveys of drinking-water primarily from surface water
    supplies conducted at over 300 sites in two provinces in Canada
    between 1985 and 1994, BBP was detected in only one sample in 1991
    (2.8 µg/litre; limits of detection 1-3 µg/litre) (D. Spink, personal
    communication, 1986; G. Halina, personal communication, 1994; A.
    Riopel, unpublished data, 1994, 1996).

         Of approximately 100 foodstuffs (generally single composite
    samples from four supermarkets) purchased in Ontario, Canada, in 1985
    and 1988 in a total diet study, BBP was detected only in yoghurt 
    (0.6 µg/g), cheddar cheese (1.6 µg/g), butter (0.64 µg/g), and 
    crackers (0.48 µg/g) (detection limits ranged from 0.005 to 0.5 µg/g; 
    Page & Lacroix, 1995).

         In foods purchased at retail stores in the United Kingdom and
    stored in their packaging until their "best before" date, BBP was not
    detected in chocolate or sugar confectioneries, although it was
    detected in baked savouries (1.5 mg/kg), meat pies (4.8 mg/kg), and
    sandwiches (14 mg/kg) (MAFF, 1987). In stored samples of composite
    fatty foods in a total diet study in the United Kingdom, BBP was
    detected in carcass meat (0.09 mg/kg), poultry (0.03 mg/kg), eggs
    (0.09 mg/kg), and milk (0.002 mg/kg) (MAFF, 1996a). Concentrations in
    59 individual samples of 15 different brands of infant formula from
    retail outlets in five towns across the United Kingdom ranged from
    <0.004 to 0.25 mg/kg (MAFF, 1996b).

         An example of indirect exposure in the general environment is
    presented here. Exposure of the general population to BBP in
    environmental media may be estimated based upon concentrations
    determined in various media and reference values for body weight and

    consumption patterns. Owing to the availability of relevant data,
    exposure has been estimated based primarily upon data from Canada.
    However, countries are encouraged to estimate total exposure on the
    basis of national data, possibly in a manner similar to that outlined
    here. Indeed, estimates based on the data on concentrations in
    foodstuffs determined in the United Kingdom presented above would be
    higher than those provided as examples here.

         Although concentrations of BBP in air (both ambient and indoor),
    drinking-water, and soil have been reported, they are so low that
    intakes from these routes are essentially negligible. Estimates of
    exposure for the general population are based almost entirely upon the
    estimates for intake from food. The estimates presented here are based
    upon identified concentrations for foodstuffs in Canada, as well as
    assumed concentrations of zero or method detection limits for foods in
    which BBP was not identified (minimum and maximum estimates,
    respectively). Adults are assumed to breathe 15.8 m3 of air per day
    (Allan, 1995), weigh 70 kg, drink 1.4 litres of water per day, ingest
    20 mg soil per day, and consume, on a daily basis, 13.61 g butter,
    3.81 g processed cheddar cheese, 1.54 g yoghurt, 22.73 g fresh pork,
    and 3.45 g crackers (Health Canada, 1994). Estimated intake for adults
    is 2 µg/kg body weight per day; intake values for infants and children
    are up to threefold higher. Data are inadequate to estimate intake in
    breast-fed infants.

         Identified data on concentrations of BBP in the occupational
    environment are inadequate as a basis for estimation of exposure.
    Similarly, data are inadequate for estimation of exposure from
    consumer products, although it should be noted that inclusion of
    information on levels in indoor air in the estimates of exposure for
    the general population presented here should account at least
    partially for exposure from consumer products.
    

    7.  COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND
        HUMANS

         No data were identified concerning the absorption, metabolism, or
    elimination of BBP in humans.

         Based upon a limited number of studies (Erickson, 1965; Kluwe,
    1984; Eigenberg et al., 1986; Mikuriya et al., 1988; Elsisi et al.,
    1989) conducted principally in rats following oral administration, BBP
    is readily hydrolysed in the gastrointestinal tract and the liver to
    the corresponding monobutyl or benzyl ester. These phthalate
    monoesters are then rapidly eliminated (90% in 24 h) in the excreta in
    ratios of approximately 80% in urine and 20% in faeces, although
    results of one study indicate that the fraction eliminated in faeces
    increases at higher doses (of approximately 2 g/kg body weight)
    (Eigenberg et al., 1986). The monobutyl ester is generally present in
    highest amounts; for example, the ratio of monobutyl to monobenzyl
    phthalate in rats in one study was 5:3 (Mikuriya et al., 1988). 
    

    8.  EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

    8.1  Single exposure

         The acute toxicity of BBP is relatively low. Reported oral LD50
    values for rats range from 2 to 20 g/kg body weight (NTP, 1982;
    Hammond et al., 1987); a dermal LD50 of 6.7 g/kg in both rats and
    mice has been reported (Statsek, 1974). Clinical signs at or near
    lethal doses following oral exposure of rats included weight loss,
    apathy, and leukocytosis. Histological examination revealed toxic
    splenitis and degenerative lesions of the central nervous system with
    congestive encephalopathy, myelin degeneration, and glial
    proliferation.

    8.2  Irritation and sensitization

         No tests have been conducted according to validated international
    protocols.

         Exposure to BBP did not cause immediate or delayed
    hypersensitivity in mice in a series of studies following
    administration of an initiating dose either intraperitoneally or by
    application to the abdomen or footpad and a challenging dose to the
    dorsal side of the ear up to 15 days later. Similarly, there was no
    immediate or delayed hypersensitivity in guinea-pigs initiated on the
    footpad and receiving a challenge dose on shaved abdominal skin. BBP
    did not form a detectable amount of hapten-protein complex when
    assayed with bovine serum albumin, although results were equivocal
    following intradermal initiation and challenge (24 h later) of mice
    with serum from BBP-exposed (intraperitoneally) mice (Little & Little,
    1983).

         Data reported in accounts of early studies on the irritancy of
    BBP, the results of which were inconsistent, are inadequate for
    evaluation (Dueva & Aldyreva, 1969; Hammond et al., 1987). Calley et
    al. (1966) injected BBP intradermally into the backs of rabbits,
    followed by trypan blue into the ear vein. Moderate irritation was
    indicated by extravasated trypan blue at the site of administration.

    8.3  Short-term exposure

         In short-term investigations by the oral route (excluding those
    addressing specifically reproductive effects or peroxisomal
    proliferation, which are addressed elsewhere) for which the range of
    end-points examined was often limited, consistent effects on body
    weight gain in rats were observed at doses of approximately 1000 mg/kg
    body weight per day and above, sometimes accompanied by a decrease in
    food consumption (NTP, 1982; Hammond et al., 1987). Although some
    effects on body weight gain were observed at lower doses, the pattern
    was inconsistent. In one study, minimal testicular changes were

    observed in one of six male rats at 480 mg/kg body weight per day
    (Bibra, 1978; Hammond et al., 19871). In general, though, testicular
    effects were observed only at much higher doses (i.e., atrophy at 1600
    mg/kg body weight per day; Hammond et al., 1987). In a 6-week
    investigation, there were no adverse histopathological effects on the
    nervous system of rats exposed to 3000 mg/kg body weight per day,
    although reversible clinical signs were observed (Robinson, 1991).

         In an inhalation study in rats, there were no effects upon
    haematology, urinalysis, blood chemistry, or histopathology following
    exposure for 4 weeks to 144 mg/m3 (Hammond et al., 1987). At 526
    mg/m3, effects included reduced body weight gain and reduced serum
    glucose. In a similar study, exposure to 2100 mg/m3 resulted in death
    of some animals; effects after 4 weeks included reduced body weight
    gain and atrophy of the spleen and testes (Hammond et al., 1987).

    8.4  Long-term exposure

         Detailed descriptions of the protocol and effect levels are
    presented here for critical studies only. Experimental details and
    effect levels for all key subchronic and chronic studies via ingestion
    are provided in Table 1.

    8.4.1  Subchronic exposure

         The protocol of an early study in Charles River rats included
    examination of body weight, clinical signs, organ weight, and limited
    histopathology of liver, spleen, kidney, adrenal, stomach, and small
    and large intestine (Hazleton Laboratories, 1958). The only effect
    observed was a decrease in body weight gain in males at the highest
    dose (1253 mg/kg body weight per day).

         In a range-finding NTP subchronic (13-week) dietary bioassay in
    F344 rats, the only adverse effects observed upon examination of body
    weight and clinical signs and histopathological examination of control
    and high-dose animals were depressed weight gain and testicular
    degeneration (nature of degeneration not specified) at the highest
    dose (1250 mg/kg body weight per day) (NTP, 1982).

         Sprague-Dawley rats were administered BBP in the diet for 3
    months at dose levels of 0, 188, 375, 750, 1125, or 1500 mg/kg body
    weight per day in males and females (Hammond et al., 1987). End-points
    examined included body weight gain, haematology, urinalysis, and
    histopathology (control and high-dose groups only). No
    compound-related lesions were observed at necropsy or upon
    histopathological examination. In females, the increase in liver to
    body weight ratio was significant at 750 mg/kg body weight per day and
    higher; in males, the increase was significant at 1125 mg/kg body

                  
    1 Full study reports for several of the investigations described
      therein were available to the authors.

    weight per day and higher. No change occurred in kidney to body weight
    ratio in females, but there was a significant increase in males at 750
    mg/kg body weight per day and higher.

         A subchronic dietary study was also conducted in Wistar rats
    (Monsanto Company, 1980a; Hammond et al., 1987) at dose levels of 0,
    151, 381, or 960 mg/kg body weight per day in males and 0, 171, 422,
    or 1069 mg/kg body weight per day in females for 3 months. Intake of
    BBP, based on body weight and food consumption, was calculated at
    4-day intervals throughout the study. Observations included slight
    anaemia in males at the highest dose and decreased urinary pH in males
    at the mid and high doses. At the highest dose, no reduction in food
    consumption was apparent, suggesting that the reduced body weight gain
    in those groups may have been compound related. Liver to body weight
    ratio was significantly increased at all dose levels in females and at
    the highest dose in males. A significant increase in kidney to body
    weight ratio occurred in a dose-related manner in both sexes at the
    mid and high doses. The caecum to body weight ratio was unaffected in
    males but increased at all dose levels in females in a dose-related
    manner. Gross pathological lesions were limited to increased incidence
    of red spots on the liver of mid- and high-dose males.
    Histopathological lesions of the pancreas were observed in males at
    the mid and high doses and included islet enlargement with cell
    vacuolization and peri-islet congestion. The liver of high-dose males
    had small areas of cellular necrosis. No histopathological lesions
    were described for females. The lowest-observed-adverse-effect level
    (LOAEL) is 381 mg/kg body weight per day, based upon histopathological
    effects in the pancreas in males. The lowest-observed-effect level
    (LOEL) in females is 171 mg/kg body weight per day, based upon
    increases in organ to body weight ratio at all doses for the liver and
    caecum (the no-observed-effect level, or NOEL, in males is 151 mg/kg
    body weight per day).

         In a 6-month dietary study in male F344 rats (NTP, 1997a),
    effects on haematological parameters were reported at 550 mg/kg body
    weight per day. Only transitory changes in haematological parameters
    were reported at 180 mg/kg body weight per day.

         In a 3-month dietary study in dogs (Hammond et al., 1987),
    decreases in body weight gain were associated with decreases in food
    consumption at the highest dose (1852 and 1973 mg/kg body weight per
    day for males and females, respectively).

         In a 90-day study in mice, there were decreases in body weight
    gain at 208 mg/kg body weight per day and greater in males, although
    no histopathological effects were observed and food consumption was
    not reported (NTP, 1982). End-points included clinical observations,
    body weight, and histopathology (control and high dose). 

         One subchronic inhalation bioassay was identified, in which
    groups of 25 male or 25 female Sprague-Dawley rats were exposed to
    concentrations of 0, 51, 218, or 789 mg/m3 for 6 h/day, 5 days/week,
    for a total of 59 exposures. End-points examined were limited to organ
    weight changes and histopathological examination of control and
    high-dose groups (Monsanto Company, 1982a; Hammond et al., 1987). A
    LOEL of 218 mg/m3 was reported for male rats, based upon increases in
    kidney weight, measured at interim sacrifice only, although no
    dose-related histopathological changes were observed in any group. The
    NOEL was 51 mg/m3.

    8.4.2  Chronic exposure and carcinogenicity

         A carcinogenicity bioassay was conducted by the NTP (1982) in
    F344 rats. Fifty rats per sex per group were administered BBP via the
    diet, at levels of 0, 6000, or 12 000 ppm (0, 300, and 600 mg/kg body
    weight per day,1 respectively).  Females were exposed for 103 weeks.
    Because of poor survival, all males were sacrificed at weeks 29-30;
    this part of the study was later repeated (NTP, 1997a).

         Only females were examined histopathologically. The incidence of
    mononuclear cell leukaemias was increased in the high-dose group
    ( P = 0.011); the trend was significant ( P = 0.006). (Incidences
    for the control, low-dose, and high-dose groups were 7/49, 7/49, and
    18/50, respectively.) The incidence in the high-dose group and the
    overall trend remained significant ( P = 0.008 and  P = 0.019,
    respectively) when compared with historical control data. The NTP
    concluded that BBP was "probably carcinogenic for female F344/N rats,
    causing an increased incidence of mononuclear cell leukemias" (NTP,
    1982).

         However, these results were not repeated in the 2-year dietary
    study in F344/N rats recently completed by the NTP (1997a). The
    average daily doses (reported by the authors) were 0, 120, 240, or 500
    mg/kg body weight per day for males and 0, 300, 600, or 1200 mg/kg
    body weight per day for females. The protocol included periodic
    haematological evaluation and hormonal assays and a 15-month interim
    sacrifice.

         There were no differences in survival between exposed groups and
    their controls. A mild decrease in triiodothyronine concentration in
    the high-dose females at 6 and 15 months and at termination was
    considered to be related to a non-thyroidal disorder. Changes in
    haematological parameters were sporadic and minor. In this bioassay,
    there was no increase in the incidence of mononuclear cell leukaemia
    in female rats, as was reported in the earlier bioassay (NTP, 1982),
    although the level of exposure (600 mg/kg body weight per day) at
    which the incidence was observed in the early bioassay was common to
    both studies.
                 
    1 Conversion factor; 1 ppm in food = 0.05 mg/kg body weight per day
      (Health Canada, 1994).


        Table 1: Effect levels in subchronic, chronic, reproductive, and developmental studies by the ingestion route.
                                                                                                                                      

    Study protocol                  Effect levela                        Critical end-point/comments              Reference
                                                                                                                                      
    Subchronic exposure

    Charles River rats              LOAEL (males) = 1253 mg/kg           Limited range of end-points,             Hazleton
    (10/sex/group)                  body weight per day                  including body weight, food              Laboratories, 1958
    90 days                         NOEL (females) = 1270 mg/kg          consumption, organ weight, and
    median intake                   body weight per day                  histopathological examination of
    in diet:                        (highest doses administered)         only seven organs/tissues, 
    males: 0, 447, or                                                    excluding the testes.
    1253 mg/kg body weight
    females: 0, 462, or
    1270 mg/kg body weight

    F344/N rats                     LOAEL (males) = 1250 mg/kg body      Histopathological degeneration of        NTP, 1982
    (10/sex/group)                  weight per day                       the testes and depressed weight
    13 weeks                        NOEL = 625 mg/kg body weight         gain. End-points examined were
    approximate intake in           per day                              restricted to clinical
    diet: 0, 80, 155, 315,                                               observations, body weight gain,
    625, or 1250 mg/kg body                                              and histopathological observation
    weight per day                                                       of control and high-dose animals.

    Sprague-Dawley rats             LOEL (females) = 750 mg/kg           Significant increases in liver to        Hammond et al., 1987
    (10/sex/group)                  body weight per day                  body weight ratio (females) and
    3 months                        NOEL = 375 mg/kg body                kidney to body weight ratio
    approximate intake in           weight per day                       (males). No histopathological 
    diet: 0, 188, 375, 750,                                              changes.
    1125, or 1500 mg/kg
    body weight per day

    Wistar rats                     LOAEL (males) (pancreas) = 381       Histopathological changes in             Monsanto Company,
    (27-45/sex/group)               mg/kg body weight per day            the pancreas in males from               1980a;
    (15-27 exposed for              LOEL (females) = 171 mg/kg body      the two highest dose groups.             Hammond et al.,
    entire period)                  weight per day (lowest dose          Increases in organ to body               1987
    3 months                        administered)                        weight ratio at all doses

    Table 1 (continued)
                                                                                                                                      

    Study protocol                  Effect levela                        Critical end-point/comments              Reference
                                                                                                                                      
    approximate intake                                                   for the liver (females) and
    in diet:                                                             caecum (females). No
    males: 0, 151, 381,                                                  histopathological effects in either
    or 960 mg/kg body                                                    of these organs at higher doses in
    weight per day                                                       the same sex.
    females: 0, 171, 422,
    or 1069 mg/kg body
    weight per day

    Male F344 rats                  LOEL = 550 mg/kg body weight         Effects on haematological parameters     NTP, 1997a
    (15/group) 26 weeks             per day                              (significant increase in mean cell
    approximate intake              NOAEL = 180 mg/kg body weight        haemoglobin and mean cell
    in diet for four                per day                              haemoglobin concentration) and
    lowest doses: 0, 30,                                                 increased relative liver weight.
    60, 180, or 550 mg/kg                                                Transitory changes only in 
    body weight per day                                                  haematological parameters at the
                                                                         lower dose (NOAEL).

    Beagle dogs (3 males            NOAEL (males) = 1852 mg/kg           Decreases in body weight gain at         Hammond et al., 1987
    and 3 females)                  body weight per day                  the highest doses associated with
    3 months                        NOAEL (females) = 1973 mg/kg         decreases in food consumption.
    approximate intake in           body weight per day                  (Body weight increased but remained
    diet or by capsule              (highest doses administered)         depressed in relation to controls
    (high-dose group):                                                   during 2 months of administration
    males: 0, 400, 1000,                                                 by capsule.)
    or 1852 mg/kg body
    weight per day
    females: 0, 700, 1270,
    or 1973 mg/kg body
    weight per day

    Table 1 (continued)
                                                                                                                                      

    Study protocol                  Effect levela                        Critical end-point/comments              Reference
                                                                                                                                      

    B6C3F1 mice                     LOEL (males) = 208 mg/kg             Decreases in body weight (of             NTP, 1982
    (10/sex/group)                  body weight per day                  unspecified statistical
    13 weeks                        LOEL (females) = 1625 mg/kg          significance), but no
    approximate intake              body weight per day                  histopathological effects;
    in diet: 0, 208, 403,                                                food consumption was not
    819, 1625, or 3250                                                   reported. End-points examined
    mg/kg body weight                                                    restricted to body weight gain,
    per day                                                              clinical observations, and
                                                                         histopathology in control
                                                                         and high-dose groups.

    Chronic exposure

    F344/N rats                     LOEL (females) = 300 mg/kg           Increased nephropathy (the latter        NTP, 1997a
    (60/sex/group)                  body weight per day                  observed at all dose levels
    2 years                         LOEL (males) = 120 mg/kg             in females). Relative kidney weight
    approximate intake in           body weight per day                  increased at all doses in males at
    diet:                                                                interim sacrifice (not determined
    males: 0, 120, 240,                                                  at terminal sacrifice). At high 
    or 500 mg/kg body                                                    dose, increase in severity of renal
    weight per day                                                       tubular pigmentation in both sexes.
    females: 0, 300, 600,
    or 1200 mg/kg body
    weight per day

    B6C3F1 mice                     LOEL = 780 mg/kg                     Decrease in body weight gain             NTP, 1982
    (50/sex/group)                  body weight per day                  (unspecified statistical
    103 weeks                                                            significance). End-points
    approximate intake                                                   examined restricted to clinical
    in diet: 0, 780, or                                                  signs, body weight, and
    1560 mg/kg body weight                                               histopathology.
    per day

    Table 1 (continued)
                                                                                                                                      

    Study protocol                  Effect levela                        Critical end-point/comments              Reference
                                                                                                                                      

    Reproductive/developmental studies


    RIVM-bred WU rats               LOAEL = 1000 mg/kg body weight       At top dose, reduction in body weight    Piersma et al., 
    (10/sex/group)                  per day                              gain, fluctuation in food consumption,   1995
    14 days prior to and            NOAEL = 500 mg/kg body weight        reduction in weight of testis and
    throughout mating               per day                              epididymis, and increase in testicular
    (OECD 421 - combined                                                 degeneration (males). At top dose,
    reproductive/developmental                                           decrease in body weight gain and 
    toxicity screening protocol)                                         effects on food consumption; adverse
    gavage in corn oil: 0, 250,                                          effects on reproductive indices
    500, or 1000 mg/kg body                                              (females). The only effect observed at
    weight per day                                                       500 mg/kg body weight per day was a
                                                                         transient decrease (day 1) in
                                                                         pup weight.

    Male F344 rats                  LOAEL = 312.5 mg/kg body weight      Dose-related increases in relative       Kluwe et al., 1984;
    (10/group)                      per day                              weights of kidney and liver at all       Agarwal et al., 1985
    14 days                                                              doses; increase in absolute kidney
    approximate intake in diet:                                          weight at two lowest doses, and
    0, 312.5, 625, 1250, or                                              decrease in absolute kidney weight
    2500 mg/kg body weight                                               at two highest doses. Proximal
    per day                                                              tubular regeneration and
                                                                         histopathological changes in the
                                                                         thymus were also observed at all
                                                                         dose levels; however, latter was
                                                                         minimal and not considered dose
                                                                         related. Histopathological effects
                                                                         on the liver, testes, epididymis,
                                                                         seminal vesicles, and prostate were
                                                                         observed only at higher concentrations.

    Table 1 (continued)
                                                                                                                                      

    Study protocol                  Effect levela                        Critical end-point/comments              Reference
                                                                                                                                      

    Male F344/N rats                NOEL = 20 mg/kg body weight          Significant dose-related decrease in     NTP, 1997a
    (15/group)                      per day                              epididymal spermatozoal concentration
    10 weeks prior to mating        LOAEL = 200 mg/kg body weight        at the two highest dose levels.
    (modified mating protocol)      per day                              Histopathological evidence of
    approximate intake in diet:     (it should be noted that             hypospermia and a decrease in fertility
    0, 20, 200, or 2200 mg/kg       dose spacing was poor in             index were observed at the highest dose
    body weight per day             the study)                           only (2200 mg/kg body weight per day).

    Wistar rats (12 males,          Reproductive effects:                No effects on reproductive performance   
    24 females per group)           NOAEL (males) = 418 mg/kg body       and development of offspring.
    one-generation reproductive     weight per day                                                                TNO Biotechnology and
    study approximate intake        NOAEL (females) = 446 mg/kg body                                              Chemistry Institute,
    in diet:                        weight per day                                                                1993
    males: 0, 108, 206, or          (highest doses administered)
    418 mg/kg body weight per day
    females: 0, 106, 217, or        Parental effects:                    At top dose, significant increase in     
    446 mg/kg body weight           NOEL (males) = 418 mg/kg body        relative weight of livers and            
    per day                         weight per day                       decrease in food consumption             
                                    NOAEL (females) = 217 mg/kg          and body weight (females).
                                    body weight per day                  
                                    LOEL (females) = 446 mg/kg
                                    body weight per day

    Examination of effects on       Reduction in testes weight           Dose-response was not investigated.      Sharpe et al., 1995
    the testes of offspring of      and daily sperm production;
    female Wistar rats (number      effects were not replicated
    unspecified) administered       in the study of similar design
    0 or 1000 µg BBP/litre in       in another strain of rats
    drinking-water (estimated       by Ashby et al. (1997a)
    to be approximately 126-366
    µg/kg body weight per day)
    for 2 weeks prior to mating,
    throughout mating and
    gestation, and until 22
    days after giving birth

    Table 1 (continued)
                                                                                                                                      

    Study protocol                  Effect levela                        Critical end-point/comments              Reference
                                                                                                                                      

    Examination of effects on       Reversible increase in absolute and  Dose-response was not investigated.      Ashby et al., 1997a
    reproductive systems of         relative liver weight at postnatal
    male and female offspring       day 90 in male offspring
    of female Alpk:APfSD rats
    (n = 19) exposed during
    gestation and lactation
    to 0 or 1000 µg BBP/litre
    in drinking-water (estimated
    to be 183 µg/kg body weight
    per day)

    Sprague-Dawley rats             NOAEL (maternal and offspring)       An increase in the percentage of         NTP, 1989; Price et 
    (30 females/group)              = 420 mg/kg body weight per day      fetuses with variations per litter.      al., 1990
    gestational days 6-15           LOAEL (significant maternal and      Maternal toxicity was evident at the
    approximate intake in diet:     minimal developmental effects)       mid and high dose levels (decreased
    0, 420, 1100, or 1640 mg/kg     = 1100 mg/kg body weight per day     maternal weight gain, increased 
    body weight per day                                                  relative liver weight, increased food
                                                                         and water consumption).

    Swiss albino mice (30           NOAEL (maternal and                  Increased percentage of late fetal       NTP, 1990; Price et 
    females/group) gestational      developmental) = 182 mg/kg body      deaths per litter and non-live           al., 1990
    days 6-15                       weight per day                       implants per litter, decreased number
    approximate intake in diet:     LOAEL (maternal and developmental)   of live fetuses per litter, increased
    0, 182, 910, or 2330 mg/kg      = 910 mg/kg body weight per day      percentage of litters with malformed
    body weight per day                                                  fetuses, and an increased percentage
                                                                         of malformed fetuses per litter.
                                                                         Decreased maternal weight gain at two
                                                                         highest doses; increased relative
                                                                         kidney and liver weight in mothers
                                                                         at top dose.

    Table 1 (continued)
                                                                                                                                      

    Study protocol                  Effect levela                        Critical end-point/comments              Reference
                                                                                                                                      

    Wistar rats (15-19              LOAEL (maternal) = 654 mg/kg         Significant dose-related reduction       Ema et al., 1990
    females/group)                  body weight per day                  in maternal body weight gain and
    gestational days 0-20           NOEL (embryo/fetal toxicity)         reduced food consumption at three
    approximate intake in           = 654 mg/kg body weight per day      highest doses (significant only at
    diet: 180, 375, 654,            Significant reduction in the         two highest doses when adjusted
    or 974 mg/kg body               number of live fetuses per           for gravid uterus). Additional
    weight per day                  litter at 375 and 654 mg/kg          studies conducted by these
                                    body weight per day                  investigators in which effects
                                    (administration on days 0-20         in offspring were examined
                                    in study of unconventional design)   following administration of
                                    (maternal LOEL)                      doses greater than 500 mg/kg
                                    NOEL (reproduction) = 185 mg/kg      body weight per day either in
                                    body weight per day                  the diet or by gavage during
                                                                         various periods of gestation are
                                                                         not additionally informative with
                                                                         respect to effect levels.

    Peroxisomal proliferation

    F344 rats (5/sex/group)         LOEL (males) = 639 mg/kg             Increase in relative liver               BIBRA, 1985
    21 days                         body weight per day                  and kidney weights in males
    approximate intake              LOEL (females) = 679 mg/kg           and females; increase in
    in diet:                        body weight per day                  cyanide-insensitive
    males: 0, 639, 1277, or         (lowest doses administered)          palmitoyl-CoA oxidation;
    2450 mg/kg body weight                                               increase in lauric acid
    per day                                                              11- and 12-hydroxylase activity
    females: 0, 679, 1346,                                               in males.
    or 2628 mg/kg body weight
    per day

    Table 1 (continued)
                                                                                                                                      

    Study protocol                  Effect levela                        Critical end-point/comments              Reference
                                                                                                                                      

    female F344/N rats (5 or 10)    LOEL = 300 mg/kg body weight         Increase in peroxisomal                  NTP, 1997a
    1 or 12 months in the diet      per day                              proliferation (carnitine
    approximate intake in diet:     (lowest dose administered)           acetyl transferase activity).
    300, 600, or 1200 mg/kg body
    weight per day

                                                                                                                                      

    a NOEL = no-observed-effect level; NOAEL = no-observed-adverse-effect level; LOEL = lowest-observed-effect level;
      LOAEL = lowest-observed-adverse-effect level.
    

         At the 15-month interim sacrifice, the absolute weight of the
    right kidney in the females at 600 mg/kg body weight per day and the
    relative weight in all exposed males were significantly greater than
    in controls. The severity of renal tubule pigmentation in high-dose
    males and females was greater than in controls, both at 15 months and
    at 2 years. The incidence of mineralization in kidney was
    significantly less than in controls in low- and high-dose females at 2
    years; severity decreased in all groups of exposed females. The
    incidence of nephropathy was significantly increased in all groups of
    exposed females (34/50, 47/50, 43/50, and 45/50 in control, 300, 600,
    and 1200 mg/kg body weight per day groups, respectively) (see Table 3
    in section 11.1.2). The incidence of transitional cell hyperplasia
    (0/50, 3/50, 7/50, and 4/50 in control, 300, 600, and 1200 mg/kg body
    weight per day groups, respectively) was significantly increased at
    600 mg/kg body weight per day.

         At final necropsy, the incidences of pancreatic acinar cell
    adenoma (3/50, 2/49, 3/50, and 10/50 in control, 120, 240, and 500
    mg/kg body weight per day groups, respectively) and pancreatic acinar
    cell adenoma or carcinoma (combined) (3/50, 2/49, 3/50, and 11/50 in
    control, 120, 240, and 500 mg/kg body weight per day groups,
    respectively) in the high-dose males were significantly greater than
    in the controls and exceeded those in the ranges of historical
    controls from NTP 2-year feeding studies. One carcinoma was observed
    in a high-dose male; this neoplasm had never been observed in the
    historical controls. The incidence of focal hyperplasia of the
    pancreatic acinar cell in the high-dose males was also significantly
    greater than in the controls (4/50, 0/49, 9/50, and 12/50 in control,
    120, 240, and 500 mg/kg body weight per day groups, respectively). Two
    pancreatic acinar cell adenomas were observed in the high-dose
    females.

         The incidences of transitional cell papilloma of the urinary
    bladder in female rats at 2 years were 1/50, 0/50, 0/50, and 2/50 in
    control, 300, 600, and 1200 mg/kg body weight per day groups,
    respectively.

         The authors concluded that there was "some evidence of
    carcinogenic activity" in male rats, based upon the increased
    incidences of pancreatic acinar cell adenoma and of acinar cell
    adenoma or carcinoma (combined). There was "equivocal evidence of
    carcinogenic activity" in female rats, based upon the marginally
    increased incidences of pancreatic acinar cell adenoma and of
    transitional cell papilloma of the urinary bladder.

         The NTP (1997b) has released a technical report of a study that
    compared outcomes when chemicals were evaluated under typical NTP
    bioassay conditions as well as under protocols employing dietary
    restriction. The experiments were designed to evaluate the effect of
    dietary restriction on the sensitivity of bioassays towards

    chemical-induced chronic toxicity and carcinogenicity and to evaluate
    the effect of weight-matched control groups on the sensitivity of the
    bioassays. BBP was included in the protocol; the results were
    summarized as follows:

    "Butyl benzyl phthalate caused an increased incidence of pancreatic
    acinar cell neoplasms in  ad libitum-fed male rats relative to  ad
     libitum-fed and weight-matched controls. This change did not occur
    in rats in the restricted feed protocol after 2 years ... Butyl benzyl
    phthalate also caused an increased incidence of urinary bladder
    neoplasms in female rats in the 32-month restricted feed protocol. The
    incidences of urinary bladder neoplasms were not significantly
    increased in female rats in any of the 2-year protocols, suggesting
    that the length of the study, and not body weight, was the primary
    factor in the detection of this carcinogenic response."

         Fifty B6C3F1 mice per sex per group were exposed to 0, 6000, or
    12 000 ppm BBP (0, 780, or 1560 mg/kg body weight per day1) via the
    diet for 103 weeks (NTP, 1982). Approximately 35 tissues were examined
    histopathologically. The only compound-related sign of exposure was a
    dose-related decrease (statistical significance not specified) in body
    weight in both sexes. Survival was not affected, and there was no
    increased incidence of any neoplasm that was compound related. As
    well, non-neoplastic changes were all within the normal limits of
    incidence for B6C3F1 mice. The NTP concluded that, under the
    conditions of the bioassay, BBP "was not carcinogenic for B6C3F1 mice
    of either sex."

    8.5  Genotoxicity and related end-points

         In the (few) published reports of Ames assays with BBP, results
    have been negative (Litton Bionetics Inc., 1976; Rubin et al., 1979;
    Kozumbo et al., 1982; Zeiger et al., 1982, 1985). Negative results
    have also been reported for mouse lymphoma assays (Litton Bionetics
    Inc., 1977; Hazleton Biotechnologies Company, 1986), although
    equivocal findings have also been published (Myhr et al., 1986; Myhr &
    Caspary, 1991). In an assay for  in vitro transformation of
    Balb/c-3T3 cells (Litton Bionetics Inc., 1985), results were negative.
    In an assay for chromosomal aberrations and sister chromatid exchanges
    in Chinese hamster ovary cells (Galloway et al., 1987), there was
    slight evidence for a trend in one sister chromatid exchange test
    without activation, but no convincing evidence for positive results
    for sister chromatid exchanges or aberrations.

                  
    1 Conversion factor: 1 ppm in food = 0.13 mg/kg body weight per day
      (Health Canada, 1994).

         The results from the mouse lymphoma (Myhr et al., 1986; Myhr &
    Caspary, 1991) and chromosomal aberration (Galloway et al., 1987)
    assays are equivocal. For the mouse lymphoma assay, the NTP concluded
    that "Increases in mutant colonies were observed in the absence of S9
    in cultures treated with concentrations that produced precipitation,
    but such responses were not considered valid by experimental quality
    control parameters." However, it is difficult to dismiss the observed
    dose-response in several studies as spurious, although the repeat
    tests were negative, particularly in view of inconsistencies of
    results of the latter. In repeat studies ( n = 5) in the absence of
    S9, there was limited evidence of activity in only one case; however,
    although BBP was positive at 80 nl/ml in the second trial, it was
    toxic at concentrations above 30 nl/ml in the third. The
    inconsistently observed increase in small colony mutants and percent
    damaged Chinese hamster ovary cells may be indicative of weak
    clastogenic activity, which warrants proper confirmation in
    well-conducted assays.

         A negative response was reported for an assay for the induction
    of sex-linked recessive lethals in  Drosophila melanogaster (Valencia
    et al., 1985). Recently, the NTP (1997a) published summary results of
    mouse bone marrow tests for sister chromatid exchanges and induction
    of chromosomal aberrations; responses were weak, and the sister
    chromatid exchange test was not repeated. Both of these responses,
    although statistically significant, were small and indicative of only
    weak clastogenic activity. Ashby et al. (1997a) reported negative
    results in a micronucleus assay in rats.

    8.6  Reproductive and developmental toxicity

         Detailed descriptions of the protocol and effect levels are
    presented here for critical studies only. Experimental details and
    effect levels for all key reproductive and developmental studies via
    ingestion are provided in Table 1.

         With respect to reproductive effects, in repeated-dose toxicity
    studies by the oral route, decreases in the weight of the testes and
    histopathological effects in the testes have been observed, although
    only at doses greater than those that induce other effects, such as
    variations in organ to body weight ratios for the kidney and liver or
    histopathological effects in the pancreas or kidney. With the
    exception of a short-term gavage study in which minimal
    histopathological effects in the testes of rats were observed at 480
    mg/kg body weight per day in one of six animals (control data not
    presented, and no statistical analysis) (Hammond et al., 1987),
    testicular atrophy or degeneration has been observed only in rats only
    at doses exceeding 1250 mg/kg body weight per day (NTP, 1982, 1997a;
    Hammond et al., 1987).

         In a combined reproductive/developmental screening protocol, at
    1000 mg/kg body weight per day there was a decrease in body weight
    gain, fluctuation in food consumption, reduction in the weight of
    testis and epididymis, and increase in testicular degeneration in
    males. In females at this dose, there was a decrease in body weight
    gain, effects on food consumption, and adverse effects on reproductive
    indices. With the exception of a transient decrease in pup weight,
    there were no effects on the parental generation or offspring at
    500 mg/kg body weight per day (Piersma et al., 1995).

         Reproductive effects of BBP in male Fischer 344 rats have been
    investigated by the NTP (Kluwe et al., 1984; Agarwal et al., 1985).
    Groups of 10 males were administered 0, 0.625, 1.25, 2.5, or 5.0% (0,
    312.5, 625, 1250, or 2500 mg/kg body weight per day1) in the diet
    for 14 days. The protocol included measurement of endocrine hormones
    and histopathological examination of brain, liver, kidney, spleen,
    thyroid, thymus, pituitary, testes, epididymis, prostate, seminal
    vesicles, and mesenteric lymph nodes. Bone marrow was also examined.

         No deaths occurred during the study. Body weight was reduced in
    the two highest dose groups. Food consumption was consistently reduced
    in the highest dose group throughout the experiment. Absolute weights
    of testis, epididymis, prostate, and seminal vesicles were
    significantly reduced at the two highest dose levels in a dose-related
    manner and were accompanied by "generalized histological atrophy."
    Statistical analyses were presented for histopathological changes in
    testis (aspermatogenesis/seminiferous tubular atrophy), seminal
    vesicles (atrophy), and prostate (atrophy); significant changes were
    consistently observed at the two highest doses. The authors noted a
    "clear relationship" between dose and severity of morphological
    changes in testis, seminal vesicles, and prostate; the changes
    occurred only at the two highest dose levels. Similarly, effects on
    the epididymis were observed in only the two highest dose groups.

         Absolute weight of liver was increased at the two lowest doses
    and decreased at the highest dose. The relative weight was increased
    at all levels of exposure, in a dose-related manner. Histopathological
    changes (mild multifocal chronic hepatitis) were described only for
    the highest dose. Absolute weight of kidney was also increased at the
    two lowest doses and decreased at the two highest. The relative weight
    was increased at all levels of exposure, in a dose-related manner.
    Proximal tubular regeneration was observed at all dose levels. Thymic
    weight was reduced at the two highest doses in a dose-related manner.
    Although histopathological changes were described for all dose groups,
    atrophy was observed only in the highest dose group. There were no
    effects upon absolute or relative pituitary weight, nor were
    morphological changes observed in thyroid, pituitary, spleen, or lymph
    nodes. Statistical analyses were not presented for histopathological
    observation of these organs.

                  
    1 Conversion factor: 1 ppm in food = 0.05 mg/kg body weight per day
      (Health Canada, 1994).

         Plasma testosterone was decreased at the highest dose.
    Follicle-stimulating hormone was increased at the two highest doses in
    a dose-related manner. Luteinizing hormone was increased at the lowest
    dose and at the two highest doses; there was a limited number of
    samples at the high dose. No effects were observed upon such
    haematological parameters as red blood cell count, packed cell volume,
    haemoglobin, mean corpuscular volume, or white blood cell count. There
    was no significant effect upon blood clotting ability, as measured by
    prothrombin time. Bone marrow cell count was reduced at the two
    highest doses.

         At the lowest dose (312.5 mg/kg body weight per day), there was a
    significant increase in both the absolute and relative weights of both
    liver and kidney. There was proximal tubular regeneration at all
    levels of exposure. Focal thymic medullary haemorrhage (minimal
    severity) was observed in a small number of animals in all BBP-exposed
    groups, but the incidences were not dose related. Based upon these
    observations, the LOAEL is 312.5 mg/kg body weight per day for effects
    on the liver and kidney.

         Male F344/N rats (15 per group) were administered BBP via the
    diet for 10 weeks, then each mated to 2 unexposed females (NTP,
    1997a). Dietary concentrations were relatively widely spaced at 0,
    300, 2800, or 25 000 ppm, which were reported by the authors to be
    equivalent to 0, 20, 200, or 2200 mg/kg body weight per day. The final
    body weight and body weight gain of the high-dose group were
    significantly lower than in the controls. Minimal changes in
    haematological parameters were observed in the high-dose group. Both
    the absolute and relative weights of prostate and testis were
    significantly decreased in the high-dose group (2200 mg/kg body weight
    per day). (Other lower organ weights in this group were attributed to
    the lower mean body weight.) Other effects observed at the high dose
    included degeneration of the seminiferous tubular germinal epithelium
    and significantly reduced weight of right cauda, right epididymis, and
    right testis. Epididymal spermatozoal concentrations were
    significantly reduced in a dose-related manner at the two highest
    doses. However, histopathological evidence of hypospermia and a
    decrease in fertility index were observed only at the highest dose.
    Ten of 30 females mated to high-dose males were found to be sperm
    positive, but none was pregnant at necropsy. Fertility indices were
    significantly lower at the high dose. At the lower two doses, there
    were no exposure-related effects observed on maternal body weight,
    maternal clinical observations, or litter data. A NOEL of 20 mg/kg
    body weight per day can be designated, based upon a significant and
    dose-related decrease in epididymal spermatozoal concentration at the
    two highest doses and associated effects on fertility at the highest
    dose (LOAEL = 200 mg/kg body weight per day).

         Concentrations of BBP of 0.2, 0.4, and 0.8% (108, 206, and 418
    mg/kg body weight per day for males; 106, 217, and 446 mg/kg body
    weight per day for females) were administered in the diet to males for
    10 weeks and to females for 2 weeks premating. Two litters were

    produced, and no adverse effects were observed on fertility,
    pregnancy, or offspring development (TNO Biotechnology and Chemistry
    Institute, 1993).

         Sharpe et al. (1995) administered a single dose level of BBP via
    drinking-water to pregnant Wistar rats, to determine the effects of
    gestational and lactational exposure upon male offspring. Dams were
    exposed for 2 weeks prior to mating and throughout gestation until
    weaning. This procedure was then repeated on the same dams, and
    observations were also carried out on the second litters. Based upon
    measurement of drinking-water consumption in six animals, intake of
    BBP was estimated to range from 126 to 366 µg/kg body weight per day,
    from postnatal days 1-2 to postnatal days 20-21, respectively. There
    was a significant reduction in daily sperm production in the
    BBP-exposed animals examined at 90-95 days. Sperm production in the
    positive control group, which received 100 µg diethylstilbestrol
    (DES)/litre in drinking-water, was also reduced ( P < 0.01); the
    negative control group (which received 1000 µg octylphenol
    polyethoxylate/litre) was not evaluated. The authors questioned the
    relevance of the effects to humans on the basis that this would
    require detailed dose-response data and measurement of the actual
    levels of the administered chemical in the male rats. Moreover, these
    results vary from those reported by Sharpe et al. (1995) in an
    investigation of effects on male offspring.

         Ashby et al. (1997a) exposed Alpk:APfSD rats during gestation
    and lactation to 1000 µg BBP/litre in drinking-water or 50 µg
    DES/litre in drinking-water (positive control). Negative controls
    received 100 µl ethanol/litre in drinking-water. Glass drinking-water
    bottles were used in the experiment, as the authors had determined
    that 60% of BBP was adsorbed onto plastic drinking-water bottles
    within 24 h (Ashby et al., 1997b). The authors reported that the
    overall exposures were 183 µg BBP/kg body weight per day and 8.6 µg
    DES/kg body weight per day. There were no effects upon weight of right
    testis after decapsulation, total sperm count (right testis), sperm
    count per gram of right testis, or total sperm count in right cauda on
    either postnatal day 90 or postnatal day 137. The authors noted the
    contrast between these results and those reported by Sharpe et al.
    (1995).1

                  
    1 It is noted that TNO Nutrition and Food Research Institute (1997)
      is conducting an experiment in which the protocol was designed "to
      investigate the reproducibility of, and expand on, the findings of
      Sharpe et al. ... related to the development of the reproductive
      system in Wistar rats exposed  in utero and during lactation to 
      butyl benzyl phthalate in drinking water." Data from this study have 
      not yet been published.

         It should be noted that there were significant differences
    between these studies with respect to exposure of the dams. In the
    Sharpe et al. (1995) study, the dams were exposed for 2 weeks prior to
    mating, throughout gestation and weaning, and subsequently for another
    2 weeks prior to mating, during gestation, and during lactation. In
    the study by Ashby et al. (1997a), dams were exposed only during
    gestation and lactation.

         Although BBP has been estrogenic in human breast cancer cells
     in  vitro (Jobling et al., 1995; Soto et al., 1995; Meek et al.,
    1996), results in yeast have been both positive (Coldham et al., 1997;
    Harris et al., 1997) and negative, the latter for both BBP and its
    principal metabolites (Gaido et al., 1997); it should be noted,
    however, that administered concentrations were unclear in two of the
    studies (Coldham et al., 1997; Harris et al., 1997). However, neither
    BBP nor its metabolites monobutyl benzyl phthalate and monobenzyl
    phthalate have been uterotrophic  in vivo in rats (Monsanto Europe
    SA, 1995a, 1996a) or in rats and mice (Monsanto Europe SA, 1995b,
    1996b), respectively. There was no estrogenic effect in an acute  in
     vivo assay (Milligan et al., 1998) in mice (stimulation of increased
    uterine vascular permeability).

         The developmental toxicity of BBP following dietary
    administration has been well investigated by the NTP in studies in
    both rats and mice (NTP, 1989, 1990; Price et al., 1990) and in a
    series of investigations in rats by Ema et al. (1990, 1991a,b,c, 1993,
    1994, 1995) following both dietary and gavage administration. In
    general, developmental effects of BBP have been observed only at dose
    levels that induced significant maternal toxicity; in pair feeding
    studies, however, malformations observed at high doses were not fully
    attributable to maternal toxicity (Ema et al., 1992). In a
    well-conducted NTP (1989) study in rats, at 1100 mg/kg body weight per
    day there were significant effects in the mothers but minimal effects
    in the offspring. At the highest dose (1640 mg/kg body weight per
    day), there was an increased incidence of rudimentary extra lumbar
    ribs. Results of studies by Ema and colleagues in which BBP was
    administered in the diet to rats for various periods, including the
    full 21 days of gestation, were similar. Although the
    no-observed-adverse-effect levels (NOAELs) for both maternal and
    developmental toxicity were less in the NTP (1990) study in mice (182
    mg/kg body weight per day), this was primarily a function of wide dose
    spacing, with maternal (decreased weight gain) and developmental
    effects being observed at 910 mg/kg body weight per day. At both 910
    and 2330 mg/kg body weight per day, there was a significant increase
    in the percentage of fetuses malformed per litter. Ema et al. (1998)
    observed a significant decrease in uterine decidual growth at 750
    mg/kg body weight and higher following administration on days 0-8 to
    pseudopregnant rats. Functional effects have not been investigated in
    available studies.

         Metabolites of BBP have induced effects on the testes similar to
    those of BBP, with the monobutyl ester being more potent in this
    regard (Mikuriya et al., 1988). Similarly, profiles of effects (e.g.,
    fusion of sternebrae, cleft palate) in the offspring observed at
    maternally toxic doses of the metabolites of BBP are similar to those
    induced by BBP itself, with effects being observed at lower doses of
    monobenzyl than of monobutyl phthalate (see, for example, Ema et al.,
    1996a,b,c).

         In a recent multigeneration study by continuous breeding in rats
    exposed to DBP for which the sole metabolite is monobutyl phthalate,
    testicular effects observed in the F1 generation were attributed to
    impairment of normal androgen signalling in the fetus, although
    available data were considered insufficient to conclude that the
    monoester was responsible (Foster, 1997). Multigeneration studies for
    BBP have not been identified.

    8.7  Peroxisomal proliferation

         BIBRA (1985) investigated peroxisomal proliferation of BBP and
    reported an increase in relative liver and relative kidney weights, an
    increase in cyanide-insensitive palmitoyl-CoA oxidation, and an
    increase in lauric acid 11- and 12-hydroxylase activity in male F344
    rats at 639 mg/kg body weight per day. In female rats, an increase in
    relative liver and relative kidney weights was reported at 679 mg/kg
    body weight per day. These were the lowest levels of exposure. The NTP
    (1997a) reported an increase in peroxisomal proliferation in female
    F344/N rats after exposure to 300 mg/kg body weight per day for either
    1 or 12 months. In a comparative study, whereas DEHP induced a "very
    marked" increase in peroxisomal proliferation, that for BBP was
    considered "moderate" (Barber et al., 1987).

    8.8  Immunological and neurological effects

         Data additional to those presented in sections 8.2 and 8.3
    relevant to assessment of the potential immunotoxicity and
    neurotoxicity of BBP were not identified.
    

    9.  EFFECTS ON HUMANS

         Although in an early study (Mallette & von Haam, 1952) BBP was
    reported to have a moderately irritating effect upon 15-30 volunteers,
    Hammond et al. (1987) observed neither primary irritation nor
    sensitization reactions in a patch test with 200 volunteers. Other
    identified data in humans relevant to the assessment of the potential
    adverse effects of BBP are restricted to limited studies of
    respiratory/neurological effects or cancer in populations of workers
    generally exposed to mixtures of plasticizers, of which BBP was a
    minor component (Nielsen et al., 1985; Hagmar et al., 1990).
    

    10.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

    10.1  Aquatic environment

    10.1.1  Pelagic organisms

         Data on acute toxicity are available for approximately two dozen
    species, including microorganisms, algae, invertebrates, and fish
    (Table 2). The lowest reported acute toxicity value was a 96-h LC50
    of 510 µg/litre for the shiner perch ( Cymatogaster aggregata) in a
    flow-through study using measured concentrations (Ozretich et al.,
    1983). Values of the LC50 for most other fish species exceeded 1000
    µg/litre. The most sensitive invertebrate species in acute toxicity
    tests was the mysid shrimp ( Mysidopsis bahia), with a 96-h LC50 of
    900 µg/litre in a static bioassay using nominal concentrations
    (Gledhill et al., 1980). Reported LC50 values for other invertebrates
    exceeded 1000 µg/litre.

         Data on chronic toxicity are available for about a dozen species,
    including algae, invertebrates, and fish. The lowest reported chronic
    toxicity value was a 96-h EC50 of 110 µg/litre, reported for the
    green alga  Selenastrum, based on chlorophyll  a measurements and
    cell number reductions using nominal concentrations (Suggatt & Foote,
    1981). The most sensitive invertebrate species in chronic toxicity
    tests was the mysid shrimp ( Mysidopsis bahia), with a 28-day
    lowest-observed-effect concentration (LOEC) of 170 µg/litre, based on
    reproduction and growth in a flow-through study using measured
    concentrations (Springborn Bionomics, 1986a). The most sensitive fish
    species in chronic toxicity tests was the fathead minnow ( Pimephales
     promelas), with a 30-day LOEC of 360 µg/litre based on hatching of
    eggs and survival and growth of larvae using measured concentrations
    (LeBlanc, 1984).


        Table 2: Toxicity to aquatic organisms.
                                                                                                                              

    Organism                                            Effect                                        Reference
                                                                                                                              

    Acute toxicity

    mixed microbial cultures                            8% inhibition of oxygen consumption           Volskay & Grady, 1988;
                                                        at solubility limit (2900 µg/litre)           Volskay et al., 1990
                                                        with Organisation for Economic 
                                                        Co-operation and Development (OECD) 
                                                        Method 209 and Respiration Inhibition
                                                        Kinetic Analysis (RIKA)a Screening Test

    selected pure bacterial cultures                    little or no inhibition of growth in          Painter & Jones, 1990
                                                        cultures amended with 625-625 000
                                                        µg/litre

    unacclimated wastewater treatment                   8.4% chemical oxygen demand (COD) removal     Adams 
    plant sludge                                        inhibition after 3 h at 3000 µg/litre,        & Bianchini-Akbeg, 
                                                        no effect on nitrification of ammonia         1989

    Photobacterium phosphoreum                          5-min Apparent Effects Thresholdb (AET),      Tetra Tech Inc., 1986;
                                                        Puget Sound (reduced sediment                 Barrick et al., 1988
                                                        luminescence), 63 ng/g dry weight
                                                        sediment

    Photobacterium phosphoreum                          5-min, Puget Sound (reduced sediment
                                                        luminescence), 4900 ng/g organic carbon       Barrick et al., 1988

    variety of algae, invertebrates, and fish           acute toxicity = 500-5000 µg/litre            TOXNETc

    Hydra littoralis                                    96-h EC50 = 1100 µg/litre (mortality          Monsanto Company, 1986a
                                                        and presence of "tulip" stage)

    polychaetes (Nereis/Neanthes virens)                96-h LC50 > 3000 µg/litre                     Monsanto Company, 1986b

    Table 2 (continued)
                                                                                                                              

    Organism                                            Effect                                        Reference
                                                                                                                              

    oyster (Crassostrea gigas)                          AET, Puget Sound (increased                   Tetra Tech Inc., 1986;
                                                        abnormalities), >470 ng/g dry weight          Barrick et al., 1988
                                                        sediment

    oyster (Crassostrea gigas)                          AET, Puget Sound (increased                   Barrick et al., 1988
                                                        abnormalities), >9200 ng/g organic carbon

    oyster (Crassostrea virginica)                      96-h EC50 (shell deposition)                  Monsanto Company, 1986c
                                                        = 1300 µg/litre

    amphipod (Rhepoxynius abronius)                     AET, Puget Sound (increased mortality),       Tetra Tech Inc., 1986
                                                        >470 ng/g dry weight sediment

    amphipod (Rhepoxynius abronius)                     AET, Puget Sound (increased mortality),       Barrick et al., 1988
                                                        900 ng/g dry weight sediment

    amphipod (Rhepoxynius abronius)                     AET, Puget Sound (increased mortality),       Barrick et al., 1988
                                                        42 000 ng/g organic carbon

    daphnids                                            48-h LC50 = 1000-3700 µg/litre                Nabholz, 1987

    Daphnia magna                                       24-h LC50 > 460 000 µg/litre                  LeBlanc, 1980

    Daphnia magna                                       24-h EC50 = 3800 µg/litre                     Adams & Heidolph, 1985

    Daphnia magna                                       48-h EC50 > 960 µg/litre                      Adams et al., 1995

    Daphnia magna                                       48-h EC50 > 1400 µg/litre                     CMA, 1984

    Daphnia magna                                       48-h LC50 = 1800 µg/litre                     Zeigenfuss et al., 1986

    Daphnia magna                                       48-h EC50 = 1800 µg/litre                     Adams & Heidolph, 1985

    Daphnia magna                                       48-h EC50 = 3700 µg/litre                     Gledhill et al., 1980

    Table 2 (continued)
                                                                                                                              

    Organism                                            Effect                                        Reference
                                                                                                                              

    Daphnia magna                                       48-h LC50 = 92 000 µg/litre                   LeBlanc, 1980

    Daphnia magna                                       48-h LC50 = 1600 µg/litre (no food) to        Barera & Adams, 1983
                                                        >10 000 µg/litre (2000 µg/litre algae
                                                        or 30 000 µg/litre
                                                        trout chow/alfalfa yeast as food)

    Daphnia magna                                       48-h LC50 = 1000 µg/litre (no organic         Barera & Adams, 1983
                                                        solvent) to 2200 µg/litre (triethylene
                                                        glycol solvent)

    Daphnia magna                                       2-, 7-, 14-, and 21-day EC50 > 760            Adams & Heidolph, 1985
                                                        µg/litre (flow-through); 21-day EC50
                                                        = 680 µg/litre (static renewal)

    Daphnia magna                                       48-h LC50 = 3700 µg/litre (no fulvic acid)    Monsanto Company, 1978
                                                        48-h LC50 = 2430 µg/litre (250 mg natural
                                                        fulvic acid/litre)
                                                        48-h LC50 = 1910 µg/litre (250 mg
                                                        purchased fulvic acid/litre)

    Mysid shrimp (Mysidopsis bahia)                     48-h LC50 = 1700 µg/litre                     CMA, 1984

    Mysid shrimp (Mysidopsis bahia)                     96-h LC50 = 900 µg/litre                      Gledhill et al., 1980

    Mysid shrimp (Mysidopsis bahia)                     96-h LC50 > 740 µg/litre                      Monsanto Company, 1988
                                                        (estimate = 1100 µg/litre)

    Mysid shrimp (Mysidopsis bahia)                     96-h LC50 = 9630 µg/litre                     Suggatt & Foote, 1981

    Grass shrimp (Paleomonetes vulgaris)                96-h LC50 > 2700 µg/litre                     Monsanto Company, 1986d

    Pink shrimp (Penaeus duorarum)                      96-h LC50 > 3400 µg/litre                     Springborn Bionomics, 1986b

    Table 2 (continued)
                                                                                                                              

    Organism                                            Effect                                        Reference
                                                                                                                              

    Crayfish (Procambarus sp.)                          96-h LC50 > 2400 µg/litre                     Monsanto Company, 1986e

    Chironomus tentans                                  48-h LC50 = 1600 µg/litre                     Zeigenfuss et al., 1986

    Chironomus tentans                                  48-h LC50 = 1640 µg/litre                     Monsanto Company, 1982b

    Chironomus tentans                                  48-h LC50 = 3600 µg/litre                     Monsanto Company, 1981a

    Paratanytarsus dissimilis                           48-h LC50 > 3600 µg/litre                     Monsanto Company, 1981a

    Midge (Paratanytarsus parthenogenetica)             48-h LC50 = 7200 µg/litre                     Monsanto Company, 1981b;
                                                                                                      CMA, 1984

    Midge (Paratanytarsus parthenogenetica)             48-h LC50 = 13 400 µg/litre                   Monsanto Company, 1981c

    Midge (Paratanytarsus parthenogenetica)             96-h LC50 > 3600 µg/litre                     Adams et al., 1995

    Mayfly (Hexagenia sp.)                              96-h LC50 = 1100 µg/litre                     Monsanto Company, 1986f

    Fathead minnow (Pimephales promelas)                96-h LC50 = 2100 µg/litre (hardness           Gledhill et al., 1980
                                                        40 000 µg calcium carbonate/litre)

    Fathead minnow (Pimephales promelas)                96-h LC50 = 5300 µg/litre (hardness           Gledhill et al., 1980
                                                        160 000 µg calcium carbonate/litre)

    Fathead minnow (Pimephales promelas)                96-h LC50 > 780 µg/litre (static test)        Adams et al., 1995

    Fathead minnow (Pimephales promelas)                96-h LC50 = 1500 µg/litre                     CMA, 1984; Adams et al., 1995
                                                        (flow-through test)

    Fathead minnow (Pimephales promelas)                96-h LC50 > 1600 µg/litre (static test)       CMA, 1984

    Fathead minnow (Pimephales promelas)                96-h LC50 = 2320 µg/litre                     Gledhill et al., 1980

    Fathead minnow (Pimephales promelas)                14-day LC50 = 2250 µg/litre                   Gledhill et al., 1980

    Table 2 (continued)
                                                                                                                              

    Organism                                            Effect                                        Reference
                                                                                                                              

    Bluegill (Lepomis macrochirus)                      24-h LC50 = 62 000 µg/litre                   Buccafusco et al., 1981

    Bluegill (Lepomis macrochirus)                      96-h LC50 = 43 000 µg/litre                   Buccafusco et al., 1981

    Bluegill (Lepomis macrochirus)                      96-h LC50 = 1700 µg/litre                     Gledhill et al., 1980; 
                                                                                                      CMA, 1984

    Rainbow trout (Oncorhynchus mykiss)                 96-h LC50 = 3300 µg/litre                     Gledhill et al., 1980

    Rainbow trout (Oncorhynchus mykiss)                 96-h LC50 = 820 µg/litre (flow-through test)  CMA, 1984; Adams et al., 1995

    Sheepshead minnow (Cyprinodon variegatus)           48-h LC50 = 3300 µg/litre                     AQUIREd

    Sheepshead minnow (Cyprinodon variegatus)           96-h LC50 > 680 µg/litre (static test)        CMA, 1984; Adams et al., 1995

    Sheepshead minnow (Cyprinodon variegatus)           96-h LC50 = 3000 µg/litre                     Gledhill et al., 1980

    Sheepshead minnow (Cyprinodon variegatus)           96-h LC50 = 440 000 µg/litre                  Heitmuller et al., 1981

    Shiner perch (Cymatogaster aggregata)               96-h LC50 = 510 µg/litre                      Ozretich et al., 1983

    English sole (Parophrys vetulus)                    96-h LC50 = 660 µg/litre (static              Randall et al., 1983
                                                        replenish), 550 µg/litre (flow-through)

    Chronic toxicity

    Algae                                               96-h EC50 = 200 µg/litre                      CMA, 1984

    Anacystis                                           96-h EC50 = 1000 µg/litre (cell count)        AQUIREd

    Microcystis                                         96-h EC50 = 1 000 000 µg/litre (cell count)   Gledhill et al., 1980

    Dunaliella                                          96-h EC50 = 1000 µg/litre (cell count)        Gledhill et al., 1980

    Navicula                                            96-h EC50 = 600 µg/litre (cell count)         Gledhill et al., 1980

    Table 2 (continued)
                                                                                                                              

    Organism                                            Effect                                        Reference
                                                                                                                              

    Skeletonema                                         96-h EC50 = 600 µg/litre (cell count)         Gledhill et al., 1980

    Skeletonema                                         EC50 = 190 µg/litre (cell count)              Suggatt & Foote, 1981

    Skeletonema                                         EC50 = 170 µg/litre (chlorophyll a)           Suggatt & Foote, 1981

    Selenastrum                                         96-h EC50= 400 µg/litre (cell count)          Gledhill et al., 1980

    Selenastrum                                         96-h EC50= 110 µg/litre (chlorophyll a)       Suggatt & Foote, 1981

    Selenastrum                                         96-h EC50 = 130 µg/litre (cell count)         Suggatt & Foote, 1981

    Selenastrum                                         96-h EC50 = 600 µg/litre (cell count)         AQUIREd

    Selenastrum capricornutum                           96-h EC50 = 210 µg/litre (cell count)         Adams et al., 1995

    Selenastrum capricornutum                           96-h EC50 = 520 µg/litre (red blood cells,    Tucker et al., 1985
                                                        reduced dry weight)

    Selenastrum capricornutum                           5-day EC50 = 720 µg/litre (cell count)        Monsanto Company, 1980b

    Selenastrum capricornutum                           14-day EC50 = 520 µg/litre (cell count)       Monsanto Company, 1980b

    Daphnids                                            21-day NOEC = 440-630 µg/litre                Nabholz, 1987

    Daphnia and fathead minnow (Pimephales promelas)    chronic toxicity = 100-800 µg/litre           TOXNETc

    Daphnia magna                                       21-day LOEC = 350 µg/litre; NOEC = 220
                                                        µg/litre (reproduction) (chronic renewal)     Monsanto Company, 1982c

    Daphnia magna                                       21-day LOEC = 760 µg/litre; NOEC = 260        Adams & Heidolph, 1985
                                                        µg/litre (reproduction) (flow-through)

    Table 2 (continued)
                                                                                                                              

    Organism                                            Effect                                        Reference
                                                                                                                              

    Daphnia magna                                       21-day LOEC = 700 µg/litre; NOEC = 350        Adams & Heidolph, 1985
                                                        µg/litre (growth, survival, and
                                                        reproduction) (static)

    Daphnia magna                                       14-day (Springborn = 21-day) LOEC = 1400      CMA, 1984; Springborn Bionomics, 
                                                        µg/litre; NOEC = 280 µg/litre (survival       1984; Rhodes et al., 1995
                                                        and reproduction)

    Daphnia magna                                       42-day LOEC = 760 µg/litre; NOEC =            Gledhill et al., 1980
                                                        260 µg/litre (decreased reproduction,
                                                        both generations; decreased survival in
                                                        second generation)

    Mysid shrimp (Mysidopsis bahia)                     28-day LOEC = 170 µg/litre; NOEC =            Springborn Bionomics, 1986a
                                                        75 µg/litre (reproduction and growth)

    Fathead minnow (Pimephales promelas)                30-day LOEC = 360 µg/litre; NOEC =            LeBlanc, 1984
                                                        140 µg/litre (decreased growth,
                                                        embryo-larvae study)

    Fathead minnow (Pimephales promelas)                maximum acceptable toxicant concentration     Sun et al., 1995
                                                        (MATC) > 360 µg/litre; chronic LC01 =
                                                        547 µg/litre (estimated)

    Fathead minnow (Pimephales promelas)                30-day mean chronic value = 220 µg/litre      Pickering, 1983

    Bluegill (Lepomis macrochirus)                      NOEC = 380 µg/litre                           Verschueren, 1983

    Table 2 (continued)
                                                                                                                              

    Organism                                            Effect                                        Reference
                                                                                                                              

    Rainbow trout (Oncorhynchus mykiss)                 109-day NOEC > 200 µg/litre (hatchability,    Monsanto Company, 1986g;
                                                        growth, survival)                             Rhodes et al., 1995

    English sole (Parophrys vetulus)                    sublethal effects at all exposures,           TOXNETc
                                                        lowest = 100 µg/litre
                                                                                                                              
    a According to Volskay et al. (1990).
    b The concentration above which statistically significant adverse effects are always expected relative
      to appropriate reference conditions.
    c Toxicology Data Network, National Library of Medicine, US Department of Health and Human Services,
      Bethesda, MD. 
    d Aquatic Information Retrieval Database, US Environmental Protection Agency.
    

    10.1.2  Benthic organisms

         There were no acute or chronic toxicity studies identified for
    BBP in sediments.

         Tetra Tech Inc. (1986) calculated a sediment quality value1 of
    55 000 ng BBP/g dry weight for sediment containing 1% organic carbon
    using the equilibrium partitioning approach. The assumption behind
    this approach is that non-polar organic compounds partition to the
    organic carbon fraction of the sediments to varying degrees depending
    upon their organic carbon/water partition coefficients (Di Toro et
    al., 1991).

    10.2  Terrestrial environment

         No studies on the effects of BBP on wild mammals were identified.
    Information about the effects of BBP on laboratory mammals is
    presented in section 8.

         No studies on the effects of BBP on plants were identified.
                  
    1 Sediment quality values represent concentrations of chemicals in
      sediments that are expected to be associated with adverse biological
      effects based either on field evidence or on theoretical predictions
      (Tetra Tech Inc., 1986).
    

    11.  EFFECTS EVALUATION

    11.1  Evaluation of health effects

    11.1.1  Hazard identification and dose-response assessment

         Following oral administration to rats, BBP is readily hydrolysed
    in the gastrointestinal tract and the liver to phthalate monoesters
    (monobutyl and monobenzyl phthalate), which are rapidly eliminated,
    predominantly in urine.

         Available data in humans are inadequate to serve as a basis for
    assessment of the effects of long-term exposure to BBP in human
    populations. The remainder of this section, therefore, addresses
    effects in experimental animals.

         The acute toxicity of BBP is relatively low, with oral LD50
    values in rats being greater than 2 g/kg body weight. Target organs
    following acute exposure include the haematological and central
    nervous systems.

         Available data are inadequate to assess the irritant or
    sensitizing effects of BBP in animal species.

         The repeated-dose toxicity of BBP has been well investigated in
    recent studies, primarily in the rat, in which dose-response was well
    characterized. Effects observed consistently have been decreases in
    body weight gain (often accompanied by decreases in food consumption)
    and increases in organ to body weight ratios, particularly for the
    kidney and liver. In addition, histopathological effects on the
    pancreas and kidney and haematological effects have also been
    observed. At higher doses, degenerative effects on the testes and,
    occasionally, histopathological effects on the liver have been
    reported. In specialized investigations, peroxisomal proliferation in
    the liver has been observed, although potency in this regard was less
    than that for other phthalates, such as DEHP.

         The chronic toxicity and carcinogenicity of BBP have been
    investigated in NTP bioassays in rats (including standard and
    feed-restricted protocols) and mice. An increase in mononuclear cell
    leukaemias observed in female F344 rats was not confirmed in a repeat
    study. It was concluded that there was "some evidence" of
    carcinogenicity in male rats, based on an increased incidence of
    pancreatic tumours, and equivocal evidence in female rats, based on
    marginal increases in pancreatic and bladder tumours. Dietary
    restriction prevented full expression of the pancreatic tumours and
    delayed appearance of the bladder tumours. There was no evidence of
    carcinogenicity in mice.

         The weight of evidence of the genotoxicity of BBP is clearly
    negative. However, available data are inadequate to conclude
    unequivocally that BBP is not clastogenic, although in identified
    studies it has induced, at most, weak activity of a magnitude
    consistent with secondary effects on DNA.

         Therefore, BBP has induced an increase in pancreatic tumours
    primarily in one sex of one species, the full expression of which was
    prevented in a dietary restriction protocol, and a marginal increase
    in bladder tumours in the other sex, which was delayed upon dietary
    restriction. Available data are consistent with the compound not
    interacting directly with DNA. On this basis, BBP can be considered,
    at most, possibly carcinogenic to humans, likely inducing tumours
    through a non-genotoxic (although unknown) mechanism.

         In a range of studies, including those designed to investigate
    the reproductive effects of BBP on the testes and endocrine hormones
    of male rats, a modified mating protocol conducted by the NTP, and a
    one-generation study, adverse effects on the testes and, consequently,
    fertility have generally been observed only at doses higher than those
    that induce effects on other organs (such as the kidney and liver),
    although decreases in sperm counts have been observed at doses similar
    to those that induce effects in the kidney and liver. This is
    consistent with the results of repeated-dose toxicity studies.

         Reductions in testes weight and daily sperm production in
    offspring were reported at a relatively low level in rats exposed  in
     utero and during lactation in a study in which dose-response was not
    investigated. However, such effects were not observed in a recent
    study in another strain of rats in which only increases in absolute
    and relative liver weights were observed at postnatal day 90.
    Additional investigation of potential effects on the reproductive
    systems of male and female animals exposed  in utero and during
    lactation in studies designed to address dose-response is desirable
    and under way.

         Although BBP has been estrogenic in human breast cell cancer
    lines  in vitro, results in yeast cells have been mixed. Neither BBP
    nor its principal metabolites have been uterotrophic  in vivo in rats
    or mice. Although available data do not support the conclusion that
    BBP is estrogenic, other potential endocrine-mediated effects such as
    anti-androgenic activity associated with DBP are not precluded.

         There is considerable emphasis currently on development of more
    sensitive frameworks for testing and assessment of
    endocrine-disrupting substances; compounds such as phthalates are
    likely early candidates for additional testing.

         In several well-conducted studies in rats and mice, BBP has
    induced marked developmental effects, but only at dose levels that
    induce significant maternal toxicity.

         Although the potential neurotoxicity of BBP has not been well
    investigated, histopathological effects on the central and peripheral
    nervous systems have not been observed following short-term exposure
    to relatively high dietary concentrations. Available data are
    inadequate to assess the potential immunotoxicity of BBP.

         Effect levels in available studies for the oral route are
    summarized in Table 1. Based on consideration of the complete database
    on repeated-dose toxicity by the oral route (including subchronic,
    chronic, and reproductive/developmental studies), effects that occur
    at lowest concentrations in rats are increases in organ to body weight
    ratios, primarily for the liver and kidney, and histopathological
    effects on the pancreas and kidney at dose levels in the range of 120
    to just greater than 300 mg/kg body weight per day. Specifically,
    these include increases in ratios of liver to body weight and
    pancreatic lesions in the Wistar rat observed in a 90-day study
    (Hammond et al., 1987), increases in (absolute and relative) kidney
    weight and relative liver weight and proximal tubular regeneration in
    a 2-week reproductive study (Agarwal et al., 1985), and increased
    relative kidney weight at interim (15 month; not determined at
    termination) sacrifice in male F344 rats in the 2-year NTP bioassay
    (NTP, 1997a). Although nephropathy was also increased at all doses
    (300 mg/kg body weight per day and higher) in the kidney of female
    F344 rats in the 2-year NTP bioassay (NTP, 1997a), incidence was high
    in all groups, with no evidence of dose-response (incidence or
    severity) and no increase in severity between the interim and final
    sacrifices.

         Increases in hepatic peroxisomal proliferation in F344 rats also
    occur at doses similar to those at which the effects mentioned above
    have been observed following exposure for 1 or 12 months (NTP, 1997a).
    Decreases in body weight in mice (of unspecified statistical
    significance) have also been observed in this dose range in a 90-day
    study, although food consumption was not reported (NTP, 1982).
    Decreases in epididymal spermatozoal concentrations have also been
    reported at these levels, although without accompanying
    histopathological effects on the testes or adverse impact on fertility
    (NTP, 1997a).

    11.1.2  Criteria for setting guidance values for BBP

         The following guidance is provided as a possible basis for
    derivation of limits of exposure and judgement of the quality of
    environmental media by relevant authorities.

         Benchmark doses have been developed for histopathological lesions
    in the pancreas of male Wistar rats in the 90-day study (Hammond et
    al., 1987) and renal lesions in male F344 rats in the 2-week
    reproductive study conducted by the NTP (Agarwal et al., 1985).
    Primarily for purposes of comparison, a benchmark dose for renal
    lesions in female F344/N rats in the 2-year carcinogenesis bioassays
    conducted by the NTP is also presented (NTP, 1997a). Information on

    the incidence of these lesions, resulting benchmark doses calculated
    using the THRESH program (Howe, 1995), and associated parameter
    estimates and statistics of fit are presented in Table 3. Each
    benchmark dose is based upon a 5% effect level; 95% lower confidence
    limits are also presented.

         Histopathological effects have not been associated with increases
    in organ to body weight ratios in the same sex except at much higher
    doses, nor have decreases in epididymal spermatozoal concentrations at
    lowest doses been accompanied by histopathological effects and adverse
    impact on fertility. Owing principally to these considerations and
    less to the inadequacy of current statistical techniques to adequately
    model continuous data for these end-points and for peroxisomal
    proliferation, benchmark doses for these end-points have not been
    developed; for completeness, however, relevant effect levels are
    included in Table 3 for comparison.

         The fit of the model was best for pancreatic lesions in male
    Wistar rats in the subchronic study by Hammond et al. (1987)
    ( P = 0.98), adequate for proximal tubular regeneration in the kidney
    of male rats in the 2-week reproductive protocol (Agarwal et al.,
    1985) ( P = 0.39), and inadequate for nephropathy in female rats in
    the 2-year bioassay (NTP, 1997a) ( P = 0.03). Inadequate fit for the
    latter is attributable to high incidence in all dose groups and little
    evidence of dose-response. On this basis and consideration of the fact
    that pancreatic lesions and tumours were also observed in the NTP
    2-year bioassay in males of another strain of rats, the pancreatic
    lesions in the Hammond et al. (1987) study have been selected as the
    point of departure for development of a tolerable intake.

         For comparison, a benchmark dose calculated using the THRESH
    program (Howe, 1995) and associated parameter estimates and statistics
    of fit for pancreatic focal hyperplasia (acinus) in male F344 rats in
    the 2-year NTP bioassay are presented in Table 4. Although the
    benchmark dose and associated lower 95% confidence limit are slightly
    less than those calculated on the basis of the Hammond et al. (1987)
    study in Wistar rats, it should be noted that the distinction between
    hyperplasia and adenomas in the carcinogenesis bioassay was not
    readily apparent. A tumorigenic dose (TD05) calculated on the basis
    of multistage modelling (Global 82) of the incidence of pancreatic
    adenomas or carcinomas (acinus) in male rats in the NTP bioassay is
    also presented in Table 4 and, as would be expected, is greater than
    the benchmark dose for hyperplasia. Data presented in the published
    account were insufficient to develop a benchmark dose on the basis of
    hyperplasia and adenomas combined.


        Table 3: Benchmark doses for non-neoplastic effects.
                                                                                                                                           

    Study                                                   Data for calculating                        Parameter estimates
                                                            benchmark dosea

    (reference)             Effect levels              Dose                Response           Benchmark dose           Goodness of fit
                                                                                                                                           

    Subchronic dietary      LOAEL = 381 mg/kg body     Males:              Lesions in         5% dose: 167 mg/kg       Chi-square goodness
    study                   weight per day (based                          pancreas:          body weight per day      of fit: 9.3 × 10-4
    Wistar rats,            upon histopathological
    27-45/group             lesions in males in        control             0/27 (0%)          95% lower confidence     Degrees of freedom:
    3-month duration        pancreas at two highest    151 mg/kg body      0/14 (0%)          limit: 132 mg/kg body    1
                            doses) (males)             weight per day      8/15 (53%)         weight per day           P-value: 0.98
                                                       381 mg/kg body      13/14 (93%)
                                                       weight per day
                                                       960 mg/kg body
                                                       weight per day
    (Monsanto Company,      LOEL = 171 mg/kg body
    1980a; Hammond et al.,  weight per day (based
    1987)                   on increases in organ
                            to body weight ratios
                            at all doses for the
                            kidney, liver, and
                            caecum) (females)

    Reproductive study      LOAEL = 312.5 mg/kg        Males:              Kidney, 
    F344 male rats,         body weight per day                            proximal
    10/group                (based upon significant    control             tubular            5% dose: 228 mg/kg       Chi-square goodness
    14-day dietary          increase in the relative                       regeneration:      body weight per day      of fit: 3.01
    administration          weight of liver and both   312.5 mg/kg body    0/10
                            the absolute and           weight per day      2/10
    (Kluwe et al., 1984;    relative weights of        625 mg/kg body      2/10               95% lower confidence     Degrees of freedom: 3
    Agarwal et al., 1985)   kidney and proximal        weight per day      4/10               limit:
                            tubular regeneration       1250 mg/kg body     3/10               117 mg/kg body weight    P-value: 0.39
                            at all levels of           weight per day                         per day                  
                            exposure)                  2500 mg/kg body                        
                                                       weight per day

    Table 3 (continued)
                                                                                                                                           

    Study                                                   Data for calculating                        Parameter estimates
                                                            benchmark dosea

    (reference)             Effect levels              Dose                Response           Benchmark dose           Goodness of fit
                                                                                                                                           

    Carcinogenicity         LOEL = 120 mg/kg body      Females:            2-year sacrifice;  5% dose: 50 mg/kg body   Chi-square goodness
    bioassay                weight per day (based                          kidney             weight per day           of fit: 7.09
    F344/N rats,            on increased relative                          nephropathy:
    60/sex/group            kidney weight in males
    Dietary                 at interim sacrifice)
    administration          (not determined at
    for 2 years             terminal sacrifice)

    (NTP, 1997a)            Increase in renal          control             34/50              95% lower confidence     Degrees of freedom: 2
                            nephropathy in females     300 mg/kg body      47/50 (P < 0.01)   limit: 28 mg/kg body
                            at all doses (300 mg/kg    weight per day      43/50 (P < 0.05)   weight per day           P-value: 2.9 × 10-2
                            body weight and above);    600 mg/kg body      45/50 (P < 0.01)
                            however, unacceptable      weight per day
                            goodness of fit for        1200 mg/kg body
                            benchmark dose             weight per day


    F344/N female           LOEL = 300 mg/kg body
    rats, 5/group           weight per day (based
    Dietary administration  on increase in
    for 1 or 12 months      peroxisomal
                            proliferation)

    (NTP, 1997a)

    Table 3 (continued)
                                                                                                                                           

    Study                                                   Data for calculating                        Parameter estimates
                                                            benchmark dosea

    (reference)             Effect levels              Dose                Response           Benchmark dose           Goodness of fit
                                                                                                                                           

    F344 males, 15/group    LOAEL = 200 mg/kg body
    Modified mating         weight per day (decrease
    protocol                in epididymal
                            spermatozoal
                            concentration without
                            histopathological
                            evidence of hypospermia
    (NTP, 1997a)            or decrease in fertility)
                            (It should be noted that
                            the dose levels in this
                            protocol increase by a
                            factor of 10.)
                                                                                                                                           
    a Benchmark doses were calculated with the THRESH program (Howe, 1995). The approach to the use of benchmark doses in risk
      assessment is described by US EPA (1995).
    

         The TDI is developed, therefore, as follows:

    TDI  =    132 mg/kg body weight per day
                           100

         =    1.3 mg/kg body weight per day

    where:

    132 mg/kg body weight per day is the lower 95% confidence limit for
    the benchmark dose (167 mg/kg body weight per day) associated with a
    5% increase in the incidence of pancreatic lesions in male Wistar rats
    in the subchronic study of Hammond et al. (1987). It is noted that
    increased excretion in faeces at higher doses observed in one study
    might impact on the dose-response curve and resulting benchmark dose,
    although it was not possible to address this quantitatively.

    100 is the uncertainty factor (×10 for intraspecies variation; ×10 for
    interspecies variation). An additional factor for extrapolation from
    subchronic to chronic has not been incorporated as, on the basis of a
    fairly robust database, there is no indication that effect levels are
    lower in chronic studies than in investigations of shorter duration;
    moreover, the compound is rapidly eliminated. Also, the incidence of
    pancreatic lesions in the Wistar rat in the subchronic study on which
    the benchmark dose is based is higher than that observed in the F344/N
    rat in the 2-year carcinogenesis bioassay. Available data were
    considered insufficient to replace default values for toxicokinetic
    and toxicodynamic components of interspecies and intraspecies
    variation with data-derived values.

         This TDI is similar to values that could be developed based on
    the LOELs for the continuous end-points such as peroxisomal
    proliferation and increases in organ to body weight ratios included in
    Table 1.

         Data on the toxicity of BBP following repeated exposure by
    inhalation are limited, with information relevant to characterization
    of exposure-response being confined to results of two short-term and
    one subchronic study in rats, with the range of end-points examined in
    the latter investigation being more limited (Hammond et al., 1987). In
    the short-term study with lowest concentrations, effects on body
    weight gain and serum glucose were observed at 526 mg/m3; there were
    no effects on haematology, blood chemistry, urinalysis, organ weights,
    or histopathology at 144 mg/m3. Increases in organ weights were
    observed at 218 mg/m3 in the subchronic study, although there were no
    histopathological effects at the highest dose (789 mg/m3); the NOEL
    was 51 mg/m3. Although the database for inhalation is somewhat
    limited, it is of interest to note that the NOELs for effects by this
    route are similar to those for ingestion. For example, the NOEL in the

    investigation in which the range of end-points examined was more
    extensive (144 mg/m3) is equivalent to a dose approximately threefold
    less than the point of departure (i.e., the 95% lower confidence
    limit) for the TDI presented above.1

    11.1.3  Sample risk characterization

         Based upon a sample estimate (section 6.2), intake of BBP for the
    general population ranges from 2 µg/kg body weight per day in adults
    to 6 µg/kg body weight per day in children. Food is by far the
    greatest source, contributing essentially all of the intake.

         The maximum and minimum estimates of total daily intake are 200
    and 650 times less, respectively, than the TDI derived above for the
    general population.

         Identified data were inadequate to provide sample estimates of
    exposure to BBP in the occupational environment or from consumer
    products and hence sample risk characterizations for these scenarios.
    It should be noted, though, that the inclusion of concentrations in
    indoor air in the estimates of exposure for the general population
    should account, at least to some extent, for exposure from consumer
    products.

    11.2  Evaluation of environmental effects

         BBP may be released to the environment from a number of
    industrial and municipal sources. Most releases are reported to be to
    the atmosphere, but BBP is also released to the aquatic environment
    from industrial and municipal liquid effluents.

         Once in the environment, BBP partitions to soil, surface water,
    sediments, and biota, and the substance has been detected in each of
    these compartments. Likely sinks are soil and sediment.

         BBP is removed from the atmosphere by photooxidation and by
    rainwater, with a half-life of a few hours to a few days. BBP is not
    persistent in water, sediments, or soil under aerobic conditions, with
    a half-life of a few days. Under anaerobic conditions, BBP is more
    persistent, with a half-life of a few months. BBP is readily
    metabolized by vertebrates and invertebrates. Reported BCFs are less
    than 1000, based on total residues, and well under 100, based on
    intact BBP residues.

                  
    1 Based on the following conversion: 1 mg/m3 in air = 0.31 mg/kg
      body weight per day ingested in rats (Health Canada, 1994).


        Table 4: Benchmark dose for pancreatic hyperplasia and tumorigenic dose (NTP 2-year bioassay).
                                                                                                                                          

    Study                                        Data for calculating benchmark dose                    Parameter estimates

    (reference)         Effect levels           Dose                     Response           Benchmark dose         Goodness of fit
                                                                                                                                          

    Carcinogenicity     Pancreas, acinus,       Males:                   Incidence:         5% dose: 130 mg/kg     P-value for lack of
    bioassay            focal hyperplasia                                                   body weight per day    fit: 0.916
    F344/N rats                                 control                  4/50
    Dietary                                     120 mg/kg body           7/49               95% lower confidence   
    administration                              weight per day           9/50               limit: 73 mg/kg body   
    for 2 years                                 240 mg/kg body weight    12/50              weight per day         
                                                per day                  (P < 0.05)
    (NTP, 1997a)                                500 mg/kg body weight
                                                per day


    Carcinogenicity     Pancreas, acinus,       Males:                   Incidence:         TD05: 320 mg/kg body   P-value for lack of
    bioassay            adenoma, or carcinoma                                               weight per day         fit: 0.854
    F344/N rats                                 control                  3/50
    Dietary                                     120 mg/kg body weight    2/49               95% lower confidence
    administration                              per day                  3/50               limit:
    for 2 years                                 240 mg/kg body weight    11/50 (P = 0.014)  160 mg/kg body weight
                                                per day                                     per day
    (NTP, 1997a)                                500 mg/kg body weight
                                                per day
                                                                         P = 0.003
                                                                         for trend
                                                                                                                                          
    

         In acute toxicity tests on approximately two dozen species and
    chronic tests on about a dozen species, adverse effects occur at
    exposure concentrations equal to or greater than 100 µg/litre.
    Although higher concentrations have sometimes been reported,
    concentrations in surface waters are generally less than 1 µg/litre.
    Therefore, it is likely that BBP poses low risk to aquatic organisms.

         No information about the effects of BBP on sediment-dwelling
    organisms, soil invertebrates, terrestrial plants, or birds has been
    identified on which to base an estimate of risk to these organisms.
    

    12.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         IARC (1987) has classified BBP in Group 3: "the agent is not
    classifiable as to its carcinogenicity to humans." There were no
    adequate data for humans, and evidence in animals was inadequate.

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

    13.  HUMAN HEALTH PROTECTION AND EMERGENCY ACTION

         Human health hazards, together with preventive and protective
    measures and first aid recommendations, are presented in the
    International Chemical Safety Card (ICSC 0834) reproduced in this
    document.

    13.1  Human health hazards

         BBP has the potential to adversely affect reproductive function,
    although effects on kidney, liver, and pancreas are noted at generally
    lower doses.

    13.2  Advice to physicians

         In case of poisoning, treatment is supportive.

    13.3  Spillage

         In the event of spillage, measures should be undertaken to
    prevent BBP from reaching drains or watercourses because of its
    toxicity to aquatic organisms.
    

    14.  CURRENT REGULATIONS, GUIDELINES, AND STANDARDS

         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.
    


    INTERNATIONAL CHEMICAL SAFETY CARD

    BUTYL BENZYL PHTHALATE                                 ICSC: 0834
                                                           March 1998

    CAS #     85-68-7                            Benzyl Butyl phthalate
    RTECS #   TH9990000           1,2-Benzenedicarboxylic acid, butyl phenymethyl ester
                                                         BBP
                                  1,2-C6H4(COOCH2C6H5)(COOC4H9)/C19H20O4

                                                 Molecular Mass: 312.4

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

    FIRE                          Combustible. Gives off        NO open flames.               Water spray, powder,
                                  irritating or toxic fumes                                   carbon dioxide.
                                  (or gases) in a fire.
                                                                                                                     

    EXPLOSION
                                                                                                                     

    EXPOSURE
                                                                                                                     

    Inhalation                    Cough. Sore throat.           Ventilation, local exhaust,   Fresh air, rest.
                                                                or breathing protection.
                                                                                                                     
    Skin                          Redness.                      Protective gloves.            Remove contaminated
                                                                                              clothes. Rinse and then
                                                                                              wash skin with water and
                                                                                              soap.
                                                                                                                     
    Eyes                          Redness.                      Safety spectacles.            First rinse with plenty
                                                                                              of water for several
                                                                                              minutes (remove contact
                                                                                              lenses if easily possible),
                                                                                              then take to a doctor.
                                                                                                                     

    Ingestion                                                   Do not eat, drink, or smoke   Rinse mouth. Rest.
                                                                during work.
                                                                                                                     
    SPILLAGE DISPOSAL                                           PACKAGING & LABELLING
                                                                                                                     
    Collect leaking and spilled liquid in sealable metal        Marine pollutant.
    containers as far as possible. Absorb remaining liquid      EU Classification
    in sand or inert absorbent and remove to safe place.        Symbol:
    Do NOT let this chemical enter the environment. (Extra      UN Classification
    personal protection: A/P2 filter respirator for organic
    vapour and harmful dust).
                                                                                                                     
    EMERGENCY RESPONSE                                          STORAGE
                                                                                                                     
    NFPA Code: H1; F1; R0;                                      Separated from strong oxidants.


                                                                                                                     
                                        IMPORTANT DATA
                                                                                                                     

    PHYSICAL STATE; APPEARANCE:                                 ROUTES OF EXPOSURE:
    COLOURLESS OILY LIQUID                                      The substance can be absorbed into the body
                                                                by inhalation of its vapour.

    CHEMICAL DANGERS:                                           INHALATION RISK:
    The substance decomposes on heating producing toxic         No indication can be given about the rate in
    fumes (phthalic anhydride). Reacts with oxidants.           which a harmful concentration in the air is
                                                                reached on evaporation of this substance
                                                                at 20°C.

    OCCUPATIONAL EXPOSURE LIMITS:                               EFFECTS OF SHORT-TERM EXPOSURE:
    TLV not established.                                        The substance irritates the eyes, the skin
                                                                and the respiratory tract.

                                                                EFFECTS OF LONG-TERM OR REPEATED EXPOSURE:
                                                                The substance may have effects on the liver and
                                                                kidneys, resulting in impaired functions.

                                                                                                                     
                                        PHYSICAL PROPERTIES
                                                                                                                     
    Boiling point:                      370°C
    Melting point:                      -35°C
    Relative density (water = 1):         1.1
    Solubility in water:                 none
    Vapour pressure, Pa at 20°C:         <0.1
    Relative vapour density (air = 1):   10.8
    Flash point:                        199°C
    Octanol/water partition
    coefficient as log Pow:              4.77
                                                                                                                     

                                          ENVIRONMENTAL DATA
                                                                                                                     
    The substance is very toxic to aquatic organisms. In the food chain important to humans,
    bioaccumulation takes place, specifically in fish.
                                                                                                                     

                                                 NOTES
                                                                                                                     
    Saniticizer 160, Sicol 160, Unimoll BB and Palatinol BB are trade names. Also consult
    ICSC #0271 Di(2-ethylhexyl)phthalate.
                                                                                                                     

                                          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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    of di(2-ethylhexyl)phthalate and related chemicals in  Salmonella.
     Environmental mutagenesis, 7(2):213-232.

    Zurmühl T, Durner W, Herrmann R (1991) Transport of phthalate-esters
    in undisturbed and unsaturated soil columns.  Journal of contaminant
     hydrology, 8:111-133.
    

    APPENDIX 1 -- SOURCE DOCUMENTS

    Government of Canada (in press)

         Copies of the Canadian Environmental Protection Act  Priority
     Substances List assessment report (Government of Canada, in press)
    and unpublished supporting documentation for BBP may be obtained from:

         Commercial Chemicals Branch
         Environment Canada
         14th Floor, Place Vincent Massey
         351 St. Joseph Blvd.
         Hull, Quebec
         Canada  K1A 0H3

    or

         Environmental Health Centre
         Health Canada
         Address Locator: 0801A
         Tunney's Pasture
         Ottawa, Ontario
         Canada  K1A 0L2

         Initial drafts of the supporting documentation and Assessment
    Report for BBP were prepared by staff of Health Canada and Environment
    Canada. 

         The environmental sections were reviewed externally by Dr G.
    Coyle (Monsanto Company), Dr T. Parkerton (Exxon Biomedical Sciences
    Inc.), Mr A. Sardella (Monsanto Canada), and Dr D. Spry (Ontario
    Ministry of Environment and Energy).

         Sections of the supporting documentation pertaining to human
    health were reviewed externally by Dr R. Nair (Solutia Inc.) to
    address adequacy of coverage. Accuracy of reporting, adequacy of
    coverage, and defensibility of conclusions with respect to hazard
    identification and dose-response analyses were considered in written
    review by staff of the Information Department of BIBRA International
    and at a panel meeting of the following members convened by Toxicology
    Excellence for Risk Assessment on 27 April 1998 in Cincinnati, Ohio,
    USA:

         Dr M. Abdel-Raman, University of Medicine and Dentistry of New
         Jersey

         Dr J. Christopher, California Environmental Protection Agency

         Dr G. Datson, Procter & Gamble Co.

         Dr J. Donohue, US Environmental Protection Agency

         Dr M. Dourson, Toxicology Excellence for Risk Assessment

         Ms D. Proctor, ChemRisk

         Ms R. Rudel, Silent Spring Institute (submitted written comments;
         not available to attend panel meeting)

         Dr A. Stern, New Jersey Department of Environmental Protection
    

    APPENDIX 2 -- CICAD PEER REVIEW

         The draft CICAD on BBP 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:

         Chemical Industry Institute of Toxicology (CIIT), Research
         Triangle Park, USA

         Department of Health, London, United Kingdom

         Fraunhofer Institute of Toxicology and Aerosol Research, Hanover,
         Germany

         Health and Safety Executive, Bootle, United Kingdom

         Health Canada, Ottawa, Canada

         József Fodor National Center of Public Health, Budapest, Hungary

         Karolinska Institute, Stockholm, Sweden

         National Chemicals Inspectorate (KEMI), Solna, Sweden

         National Food Administration, Uppsala, Sweden

         National Institute for Working Life, Solna, Sweden

         National Institute of Public Health, Oslo, Norway

         National Institute of Public Health and Environmental Protection,
         Bilthoven, The Netherlands

         Nofer Institute of Occupational Medicine, Lodz, Poland

         Norwegian University of Science and Technology, Trondheim, Norway

         Mr Frank Sullivan, Consultant Toxicologist, Brighton, United
         Kingdom

         United States Department of Health and Human Services (Agency for
         Toxic Substances and Disease Registry, Atlanta, USA; National
         Institute of Environmental Health Sciences, Research Triangle
         Park, USA)
    

    APPENDIX 3 -- CICAD FINAL REVIEW BOARD

    Tokyo, Japan, 30 June - 2 July 1998

    Members

    Dr R. Benson, Drinking Water Program, United States Environmental
    Protection Agency, Denver, CO, USA

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

    Mr R. Cary, Health Directorate, Health and Safety Executive,
    Merseyside, United Kingdom

    Dr C. DeRosa, Agency for Toxic Substances and Disease Registry, Center
    for Disease Control and Prevention, Atlanta, GA, USA

    Dr S. Dobson, Institute of Terrestrial Ecology, Cambridgeshire, United
    Kingdom

    Dr H. Gibb, National Center for Environmental Assessment, United
    States Environmental Protection Agency, Washington, DC, USA

    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,
    Germany

    Ms M.E. Meek, Environmental Health Directorate, Health Canada, Ottawa,
    Ontario, Canada ( Chairperson)

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

    Professor S.A. Soliman, Department of Pesticide Chemistry, Alexandria
    University, Alexandria, Egypt

    Ms D. Willcocks, Chemical Assessment Division, Worksafe Australia,
    Camperdown, Australia ( Rapporteur)

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

    Observers

    Professor F.M.C. Carpanini,1 Secretary-General, ECETOC (European
    Centre for Ecotoxicology and Toxicology of Chemicals), Brussels,
    Belgium
                 
    1 Invited but unable to attend.

    Dr M. Ema, Division of Biological Evaluation, National Institute of
    Health Sciences, Osakai, Japan

    Mr R. Green,1 International Federation of Chemical, Energy, Mine and
    General Workers' Unions, Brussels, Belgium

    Dr B. Hansen,1 European Chemicals Bureau, European Commission, Ispra,
    Italy

    Mr T. Jacob,1 Dupont, Washington, DC, USA

    Dr H. Koeter, Organisation for Economic Co-operation and Development,
    Paris, France

    Mr H. Kondo, Chemical Safety Policy Office, Ministry of International
    Trade and Industry, Tokyo, Japan

    Ms J. Matsui, Chemical Safety Policy Office, Ministry of International
    Trade and Industry, Tokyo, Japan

    Mr R. Montaigne,1 European Chemical Industry Council (CEFIC),
    Brussels, Belgium

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

    Dr H. Nishimura, Environmental Health Science Laboratory, National
    Institute of Health Sciences, Osaka, Japan

    Ms C. Ohtake, Chem-Bio Informatics, National Institute of Health
    Sciences, Tokyo, Japan

    Dr T. Suzuki, Division of Food, National Institute of Health Sciences,
    Tokyo, Japan

    Dr K. Takeda, Mitsubishikagaku Institute of Toxicological and
    Environmental Sciences, Yokohama, Japan

    Dr K. Tasaka, Department of Chemistry, International Christian
    University, Tokyo, Japan

    Dr H. Yamada, Environment Conservation Division, National Research
    Institute of Fisheries Science, Kanagawa, Japan

    Dr M. Yamamoto, Chem-Bio Informatics, National Institute of Health
    Sciences, Tokyo, Japan

    Dr M. Yasuno, School of Environmental Science, The University of Shiga
    Prefecture, Hikone, Japan
                 
    1 Invited but unable to attend.

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

    Secretariat

    Ms L. Regis, International Programme on Chemical Safety, World Health
    Organization, Geneva, Switzerland

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

    Dr P. Toft, Associate Director, International Programme on Chemical
    Safety, World Health Organization, Geneva, Switzerland
    

    RÉSUMÉ D'ORIENTATION

         Ce CICAD relatif au phtalate de butyle et de benzyle a été
    préparé conjointement par la Direction de l'Hygične du Milieu (Santé
    Canada) et par la Direction de l'Evaluation des Produits chimiques
    commerciaux (Environnement Canada) d'aprčs la documentation préparée
    parallčlement dans le cadre du Programme d'évaluation des substances
    d'intéręt prioritaire mené en vertu de la  Loi canadienne sur la
     protection de l'environnement (LCPE). L'objectif de l'évaluation des
    substances d'intéręt prioritaire en vertu de la LCPE est d'évaluer les
    effets potentiels sur la santé humaine de l'exposition indirecte aux
    substances présentes dans l'environnement, ainsi que les effets de ces
    substances sur l'environnement. Les analyses ont porté sur les données
    connues ŕ fin avril 1998. On trouvera ŕ l'appendice 1 des informations
    sur les modalités de l'examen par des pairs et sur les sources
    documentaires. Les renseignements concernant l'examen du CICAD par des
    pairs font l'objet de l'appendice 2. Ce CICAD a été approuvé en tant
    qu'évaluation internationale lors d'une réunion du Comité d'évaluation
    finale qui s'est tenue ŕ Tokyo (Japon) du 30 juin au 2 juillet 1998.
    La liste des participants ŕ cette réunion figure ŕ l'appendice 3. La
    fiche d'information internationale sur la sécurité chimique (ICSC
    No 0834) pour le phtalate de butyle et de benzyle, établie par le
    Programme international sur la Sécurité chimique (IPCS, 1993) est
    également reproduite dans ce document.

         Le phtalate de butyle et de benzyle (No CAS 85-68-7), ou PBB,
    est un liquide huileux limpide utilisé comme plastifiant
    principalement dans le poly(chlorure de vinyle) (PVC) pour les
    revętements de sol, les mousses de vinyle et les sous-couches de tapis
    et, dans une moindre mesure, dans les plastiques cellulosiques et le
    polyuréthane. La plupart des rejets se font dans l'air. Une fois dans
    l'environnement, le PBB se répartit entre l'atmosphčre, le sol, les
    eaux de surface, les sédiments et les biotes, et a été détecté dans
    chacun de ces compartiments.

         Le PBB est éliminé de l'atmosphčre par photo-oxydation et par la
    pluie, avec une demi-vie de quelques heures ŕ quelques jours. En
    aérobiose, il ne persiste pas dans l'eau, les sédiments ni les sols,
    sa demi-vie étant de quelques jours. En anaérobiose, il est plus
    persistant, avec une demi-vie de quelques mois. Les vertébrés et les
    invertébrés le métabolisent facilement. Les facteurs de
    bioconcentration signalés sont inférieurs ŕ 1000 si l'on tient compte
    des résidus totaux, et sont bien inférieurs ŕ 100 d'aprčs les résidus
    intacts.

         Les données disponibles sur l'homme sont insuffisantes pour
    servir de base ŕ l'évaluation des effets d'une exposition ŕ long terme
    au PBB sur les populations humaines.

         La toxicité aiguë du PBB est relativement faible, la DL50 orale
    chez le rat étant supérieure ŕ 2 g/kg de poids corporel. Aprčs
    exposition aiguë, les cibles principales sont le sang et le systčme
    nerveux central.

         Les données disponibles sont insuffisantes pour évaluer les
    effets irritants et sensibilisants du PBB chez l'animal.

         La toxicité du PBB aprčs administration de doses répétées a été
    largement étudiée lors d'études récentes, principalement chez le rat,
    espčce pour laquelle une relation dose-réponse a été bien
    caractérisée. Les effets réguličrement observés consistaient en une
    diminution de la prise de poids (souvent accompagnée d'une diminution
    de la consommation alimentaire) et en une augmentation du rapport du
    poids des organes (notamment du foie et des reins) au poids total. On
    a également observé des effets histopathologiques sur le pancréas et
    les reins et des effets hématologiques. Aux fortes doses, une
    dégénérescence des testicules et parfois des effets histopathologiques
    sur le foie ont été rapportés. Des investigations spécialisées ont
    montré une prolifération des peroxysomes du foie, bien que le PBB ait
    fait preuve dans cette étude d'une activité plus faible que les autres
    phtalates, par exemple le phtalate de bis(2-éthylhexyle).

         La toxicité chronique et la cancérogénicité du PBB ont été
    étudiées lors d'essais biologiques de l'US National Toxicology Program
    (NTP) chez le rat (avec des protocoles alimentaires standard et
    restrictifs) et chez la souris. Il a été conclu qu'il y avait
    "certaines preuves" de cancérogénicité chez le rat mâle, d'aprčs une
    incidence accrue des tumeurs du pancréas, et des preuves non
    concluantes chez les rats femelles d'aprčs une augmentation marginale
    des tumeurs du pancréas et de la vessie. L'administration d'une
    alimentation restreinte empęchait l'expression complčte des tumeurs du
    pancréas et retardait l'apparition des tumeurs de la vessie. Aucune
    preuve de cancérogénicité n'a été trouvée chez la souris.

         Les résultats des études de génotoxicité portant sur le PBB sont
    clairement négatifs. Cependant, les données disponibles sont
    insuffisantes pour permettre de conclure formellement ŕ l'absence de
    clastogénicité du PBB, bien que dans certaines études il ait induit au
    maximum une activité clastogčne faible, d'une intensité compatible
    avec des effets secondaires sur l'ADN.

         En résumé, le PBB a induit une augmentation des tumeurs du
    pancréas chez les animaux d'un sexe d'une espčce, effet dont
    l'expression totale était empęchée par une restriction alimentaire, et
    une augmentation marginale des tumeurs de la vessie chez les animaux
    de l'autre sexe, effet retardé par la restriction alimentaire. En ce
    qui concerne la génotoxicité, les résultats ont été négatifs et, bien
    qu'on ne puisse exclure un faible potentiel clastogčne, les données
    disponibles permettent de penser que le composé n'exerce pas

    d'interaction directe avec l'ADN. D'aprčs ces résultats, le PBB peut
    ętre considéré au maximum comme éventuellement cancérogčne pour
    l'homme, susceptible d'induire des tumeurs par un mécanisme non
    génotoxique (mais inconnu).

         Dans diverses études, y compris celles portant sur les effets du
    PBB sur les testicules et les hormones endocrines chez le rat mâle,
    des études avec un protocole modifié d'accouplement réalisées par le
    NTP, et une étude sur une seule génération, on n'a en général observé
    d'effets indésirables sur les testicules et par conséquent sur la
    fécondité qu'aux doses supérieures ŕ celles qui induisent des effets
    sur les autres organes (comme le foie et les reins), bien qu'une
    diminution du nombre de spermatozoďdes ait été observée ŕ des doses
    analogues ŕ celles qui induisent des effets sur le rein et le foie.
    Ces résultats sont compatibles avec ceux des études de toxicité
    portant sur des doses répétées.

         Une diminution du poids des testicules et de la production
    quotidienne de spermatozoďdes chez la descendance a été observée ŕ une
    dose relativement faible chez des rats exposés  in utero et pendant
    l'allaitement lors d'une étude dans laquelle la relation dose-réponse
    n'était pas examinée. Cependant, de tels effets n'ont pas été observés
    lors d'une étude récente de conception similaire mais non identique
    réalisée sur une autre souche de rats, chez lesquels seule une
    augmentation du poids relatif et absolu du foie a été observée
    90 jours aprčs la naissance. Des investigations supplémentaires sur
    les effets potentiels du composé sur le systčme reproducteur d'animaux
    mâles et femelles exposés  in utero et pendant l'allaitement dans le
    cadre d'études portant également sur la relation dose-réponse sont
    souhaitables, et sont en cours.

         Bien que le PBB ait des effets estrogéniques dans des lignées de
    cellules humaines de cancer du sein  in vitro, les résultats en
    cellules de levure sont peu concluants. Ni le PBB ni ses principaux
    métabolites ne sont utérotrophiques  in vivo chez le rat ou la
    souris. Si les données disponibles ne permettent pas de conclure que
    le PBB a des propriétés estrogéniques, d'autres effets potentiels ŕ
    médiation endocrinienne, par exemple un effet anti-androgčne associé
    au phtalate de dibutyle, ne sont pas exclus.

         On s'intéresse actuellement ŕ la mise au point de cadres plus
    sensibles d'essai et d'évaluation des substances perturbant
    l'équilibre endocrinien; des composés comme les phtalates sont
    susceptibles d'ętre parmi les premiers candidats ŕ soumettre ŕ des
    essais supplémentaires.

         Lors de plusieurs études bien conduites chez des rats et des
    souris, le PBB a induit des effets notables sur le développement, mais
    seulement ŕ des doses qui entraînent une toxicité significative chez
    la mčre.

         Bien que la neurotoxicité potentielle du PBB n'ait pas été
    largement explorée, il n'a pas été observé d'effets histopathologiques
    sur le systčme nerveux central et périphérique aprčs exposition ŕ
    court terme ŕ des doses relativement élevées dans l'alimentation. Les
    données disponibles sont insuffisantes pour permettre d'évaluer la
    toxicité immunologique potentielle du PBB.

         Une dose journaličre tolérable estimative (DJT) de 1300 µg/kg de
    poids corporel par jour a été calculée pour le PBB, d'aprčs la limite
    inférieure de confiance ŕ 95% pour la dose associée ŕ une augmentation
    de 5% de l'incidence des lésions pancréatiques chez le rat mâle lors
    d'un essai biologique subchronique par voie orale, divisée par un
    facteur d'incertitude de 100 (10 pour la variation interspécifique et
    10 pour la variation intraspécifique). D'aprčs les concentrations
    rencontrées dans les divers milieux de l'environnement, il apparaît
    (d'aprčs des estimations) que la totalité de l'apport estimé est
    imputable ŕ l'alimentation; cet apport est évalué, pour la population
    générale, ŕ 2-6 µg/kg de poids corporel par jour. Ces estimations sont
    200 ŕ 650 fois plus faibles que la DJT. Les données sont insuffisantes
    pour estimer l'exposition dans le milieu de travail ou par des
    produits de consommation.

         Divers tests de toxicité réalisés sur des organismes aquatiques
    ont montré que des effets indésirables se produisent lors
    d'expositions ŕ des concentrations supérieures ou égales ŕ
    100 µg/litre. Comme les concentrations de PBB dans les eaux de surface
    sont en général inférieures ŕ 1 µg/litre, il est probable que ce
    composé comportera peu de risques pour les organismes aquatiques.

         On ne dispose d'aucune information sur les effets du PBB sur les
    organismes benthiques, les invertébrés du sol, les plantes terrestres
    ou les oiseaux, qui permettrait d'estimer le risque pour ces
    organismes.
    

    RESUMEN DE ORIENTACION

         Este CICAD sobre el butil-bencil-ftalato, preparado conjuntamente
    por la Dirección de Higiene del Medio del Ministerio de Sanidad del
    Canadá y la División de Evaluación de Productos Químicos Comerciales
    del Ministerio de Medio Ambiente del Canadá, se basa en la
    documentación preparada al mismo tiempo como parte del Programa de
    Sustancias Prioritarias en el marco de la  Ley Canadiense de
     Protección del Medio Ambiente (CEPA). Las evaluaciones de sustancias
    prioritarias prevista en la CEPA tienen por objeto valorar los efectos
    potenciales para la salud humana de la exposición indirecta en el
    medio ambiente general, así como los efectos ecológicos. En estos
    exámenes se incluyen los datos identificados hasta el final de abril
    de 1998. La información relativa al carácter del examen colegiado del
    documento original y su disponibilidad 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 Tokio (Japón)
    del 30 de junio al 2 de julio de 1998. La lista de participantes en
    esta reunión figura en el apéndice 3. La ficha internacional de
    seguridad química (ICSC 0834) para el butil-bencil-ftalato, preparada
    por el Programa Internacional de Seguridad de las Sustancias Químicas
    (IPCS, 1993), también se reproduce en este documento.

         El butil-bencil-ftalato (CAS No 85-68-7) o BBP es un líquido
    oleoso transparente que se utiliza como plastificante sobre todo en el
    cloruro de polivinilo (PVC) para la fabricación de baldosas de vinilo,
    espumas de vinilo y entramado para alfombras y en menor medida también
    en los plásticos de celulosa y el poliuretano. La mayor parte del que
    se libera en el medio ambiente va al aire. Una vez en el medio
    ambiente, el BBP se distribuye entre la atmósfera, el suelo, el agua
    superficial, los sedimentos y la biota, y se ha detectado en cada uno
    de estos compartimentos.

         El BBP se elimina de la atmósfera por fotooxidación y por el agua
    de lluvia, con una semivida que oscila entre algunas horas y varios
    días. No es persistente en el agua, los sedimentos o el suelo en
    condiciones aerobias, con una semivida de varios días. En condiciones
    anaerobias, el BBP es más persistente, siendo su semivida de varios
    meses. Los vertebrados e invertebrados lo metabolizan fácilmente. Se
    han notificado factores de bioconcentración inferiores a 1000, tomando
    como base los residuos totales, y muy por debajo de 100 a partir de
    los residuos de BBP intactos.

         Los datos disponibles en el ser humano son insuficientes para
    poder evaluar los efectos de la exposición prolongada al BBP en
    poblaciones humanas.

         La toxicidad aguda del BBP es relativamente baja, con valores de
    la DL50 por vía oral superiores a 2 g/kg de peso corporal en ratas.
    Los órganos afectados tras la exposición aguda son el sistema
    hematológico y el sistema nervioso central.

         Los datos disponibles son insuficientes para evaluar los efectos
    irritantes y sensibilizantes del BBP en especies de animales.

         En estudios recientes se ha investigado a fondo la toxicidad de
    dosis repetidas de BBP, particularmente en la rata, en la cual está
    bien caracterizada la relación dosis-respuesta. Los efectos observados
    han sido siempre una disminución del aumento del peso corporal (con
    frecuencia acompańada de una reducción del consumo de alimentos) y un
    incremento de la razón peso de los órganos/peso corporal,
    especialmente para el rińón y el hígado. Se han observado asimismo
    efectos en el páncreas y el rińón, así como hematológicos. Con dosis
    más elevadas, se han notificado efectos degenerativos en los
    testículos y, ocasionalmente, efectos histopatológicos en el hígado.
    En investigaciones especializadas se ha observado proliferación de
    peroxisomas en el hígado, aunque la potencia a este respecto fue
    inferior a la de otros ftalatos, como el bis(2-etilhexil)ftalato
    (DEHP).

         Se han investigado la toxicidad crónica y la carcinogenicidad del
    BBP en biovaloraciones realizadas por el Programa Nacional de
    Toxicología de los Estados Unidos de América (con inclusión de
    protocolos normales y de alimentación limitada) en ratas y en ratones.
    Se llegó a la conclusión de que había "algunos indicios" de
    carcinogenicidad en ratas macho, basados en una mayor incidencia de
    tumores pancreáticos, e indicios equívocos en ratas hembra, basadas en
    un aumento marginal de la incidencia de tumores pancreáticos y de
    vejiga. La limitación de la alimentación impidió la expresión completa
    de los tumores pancreáticos y retrasó la aparición de los tumores de
    vejiga. No hubo indicios de carcinogenicidad en ratones.

         El valor demostrativo de los indicios de genotoxicidad del BBP es
    claramente negativo. Sin embargo, los datos disponibles son
    insuficientes para llegar a la conclusión inequívoca de que el BBP no
    es clastogénico, aunque en determinados estudios ha inducido, como
    máximo, una actividad débil de magnitud compatible con los efectos
    secundarios en el ADN.

         Por consiguiente, el BBP ha inducido un aumento de los tumores
    pancreáticos fundamentalmente en un sexo de una especie, cuya
    expresión completa se evitó mediante un protocolo de alimentación
    limitada, y un aumento marginal de los tumores de vejiga en el otro
    sexo, que se retrasó con la limitación de la alimentación. El valor
    demostrativo de los indicios de genotoxicidad es negativo y, aunque no
    se puede descartar el potencial clastogénico, los datos disponibles
    son compatibles con el hecho de que el compuesto no tiene una
    interacción directa con el ADN. De acuerdo con esto, el BBP puede
    considerarse, como máximo, posiblemente carcinogénico para el ser
    humano, probablemente induciendo tumores a través de un mecanismo no
    genotóxico (aunque desconocido).

         En una serie de estudios, en particular los diseńados para
    investigar los efectos reproductivos del BBP en los testículos y las
    hormonas endocrinas de las ratas macho, un protocolo modificado de
    acoplamiento realizado por el NTP y un estudio de una generación, en
    general se han observado efectos adversos en los testículos y, por
    consiguiente, en la fecundidad sólo con dosis superiores a las que
    inducen efectos en otros órganos (como el rińón y el hígado), si bien
    se ha puesto de manifiesto una reducción en el recuento de
    espermatozoides con dosis semejantes a las que inducen efectos en el
    rińón y el hígado. Esto está en consonancia con los resultados de los
    estudios de toxicidad con dosis repetidas.

         En un estudio en el que no se investigó la relación
    dosis-respuesta se observó una reducción del peso de los testículos y
    de la producción diaria de espermatozoides en crías de ratas expuestas
    a una concentración relativamente baja en el útero y durante la
    lactancia. Sin embargo, estos efectos no se observaron en un estudio
    reciente de diseńo parecido, pero no idéntico, realizado con otra
    estirpe de ratas en la cual sólo se observó un aumento del peso
    absoluto y relativo del hígado a los 90 días del nacimiento. Son
    convenientes, y se han emprendido ya, nuevas investigaciones de los
    efectos potenciales en el sistema reproductor de animales machos y
    hembras expuestos en el útero y durante la lactancia en estudios
    encaminados a examinar la relación dosis-respuesta.

         Si bien el BBP ha sido estrogénico en líneas de células de cáncer
    de mama humano  in vitro, los resultados en células de levadura han
    sido contradictorios. Ni el BBP ni sus principales metabolitos han
    sido uterotróficos  in vivo en ratas o ratones. Aunque los datos
    disponibles no permiten llegar a la conclusión de que el BBP es
    estrogénico, no se pueden descartar otros posibles efectos debidos a
    factores endocrinos, como la actividad antiandrogénica asociada al
    dibutil-ftalato (DBP).

         En la actualidad se concede una importancia considerable a la
    creación de sistemas más sensibles de prueba y evaluación de
    sustancias perturbadoras del sistema endocrino; compuestos como los
    ftalatos probablemente serán de los primeros que se someterán a
    pruebas adicionales.

         En varios estudios bien realizados en ratas y ratones, el BBP
    indujo efectos pronunciados en el desarrollo, pero sólo a
    concentraciones que producen una toxicidad materna significativa.

         Aunque no se ha investigado bien la posible neurotoxicidad del
    BBP, no se han observado efectos histopatológicos en los sistemas
    nerviosos central y periférico tras una exposición breve a
    concentraciones relativamente altas en los alimentos. Los datos
    disponibles son insuficientes para evaluar la posible inmunotoxicidad
    del BBP.

         Se ha estimado para el BBP una ingesta diaria tolerable (IDT)
    muestral de 1300 µg/kg de peso corporal al día. Se basa en un límite
    de confianza inferior del 95% para la dosis de referencia asociada con
    un aumento del 5% de la incidencia de lesiones pancreáticas en ratas
    macho en una biovaloración subcrónica por vía oral, dividido por un
    factor de incertidumbre de 100 (10 por la variación interespecífica y
    10 por la intraespecífica). Teniendo en cuenta las concentraciones en
    diversos medios parece (a partir de estimaciones muestrales) que los
    alimentos son la fuente de toda la ingesta estimada, que se considera
    que oscila, para la población general, entre 2 y 6 µg/kg de peso
    corporal al día. Estas estimaciones son 200-650 veces inferiores a la
    IDT. Los datos fueron insuficientes para estimar la exposición en el
    entorno ocupacional o a partir de productos de consumo.

         En una serie de pruebas de toxicidad con organismos acuáticos se
    ha puesto de manifiesto que se producen efectos adversos a
    concentraciones de exposición iguales o superiores a 100 µg/l. Habida
    cuenta de que la concentración en el agua superficial suele ser
    inferior a 1 µg/l, es probable que el BBP represente un riesgo bajo
    para los organismos acuáticos.

         No se dispone de información acerca de los efectos del BBP en los
    organismos de los sedimentos, los invertebrados del suelo, las plantas
    terrestres o las aves en la que pueda basarse una estimación del
    riesgo para estos organismos.
    


    See Also:
       Toxicological Abbreviations
       Butyl benzyl phthalate (ICSC)
       Butyl Benzyl Phthalate  (IARC Summary & Evaluation, Volume 29, 1982)
       Butyl Benzyl Phthalate  (IARC Summary & Evaluation, Volume 73, 1999)