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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 173





    Tris(2,3-dibromopropyl) phosphate and
    Bis(2,3-dibromopropyl) phosphate.












    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.



    First draft prepared by Dr. G.J. van Esch,
    Bilthoven, Netherlands


    Published under the joint sponsorship of the United Nations
    Environment Programme, the International Labour Organisation, and the
    World Health Organization


    World Health Organization
    Geneva, 1995

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    WHO Library Cataloguing in Publication Data

    Tris(2,3-dibromopropyl) phosphate and Bis(2,3-dibromopropyl)
    phosphate.

    (Environmental health criteria ; 173)

    1.Phosphoric acid esters   2.Environmental exposure
    3.Flame retardants   I.Series

    ISBN 92 4 157173 X      (NLM Classification: QP 981.P49)
    ISSN 0250-863X


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    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR TRIS(2,3-DIBROMOPROPYL)
    PHOSPHATE AND BIS(2,3-DIBROMOPROPYL) PHOSPHATE

    INTRODUCTION

    TRIS(2,3-DIBROMOPROPYL) PHOSPHATE

    1. SUMMARY AND EVALUATION; CONCLUSIONS AND RECOMMENDATIONS

        1.1. Summary and evaluation
              1.1.1. Production and use
              1.1.2. Physical and chemical properties
              1.1.3. Environmental transport, distribution, and
                      transformation
              1.1.4. Environmental levels and human exposure
              1.1.5. Kinetics and metabolism in laboratory animals
                      and humans
              1.1.6. Effects on laboratory mammals and  in vitro test
                      systems
              1.1.7. Effects on humans
              1.1.8. Effects on other organisms in the laboratory
                      and field
        1.2. Conclusions
        1.3. Recommendations

    2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL
        METHODS

        2.1. Identity
              2.1.1. Technical product
        2.2. Physical and chemical properties
        2.3. Analytical methods
              2.3.1. General
              2.3.2. Urine

    3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

        3.1. Natural occurrence
        3.2. Anthropogenic sources
              3.2.1. Production levels and processes
              3.2.2. Uses
              3.2.3. Sources of human and environmental exposure

    4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

        4.1. Transport and distribution between media
        4.2. Transformation
              4.2.1. Biodegradation
              4.2.2. Abiotic degradation
              4.2.3. Bioaccumulation
        4.3. Interaction with other physical, chemical, or
              biological factors
        4.4. Ultimate fate following use

    5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

        5.1. Environmental levels
              5.1.1. Air
              5.1.2. Water
              5.1.3. Soil
              5.1.4. Fish
        5.2. General population exposure
              5.2.1. Subpopulation at special risk
        5.3. Occupational exposure

    6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS

        6.1. Absorption
        6.2. Elimination
              6.2.1. Different routes (rat and rabbit)
              6.2.2. Dermal exposure (rat and rabbit)
                      6.2.2.1   TBPP
                      6.2.2.2   TBPP-treated fibres
              6.2.3. Dermal exposure (human)
        6.3. Distribution
              6.3.1. Rat
                      6.3.1.1   Oral
                      6.3.1.2   Intravenous
              6.3.2. Dermal (rabbit)
        6.4. Metabolic transformation
              6.4.1.  In vivo studies
                      6.4.1.1   Oral (rat)
              6.4.2.  In vitro studies
        6.5. Covalent binding to macromolecules

    7. EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

        7.1. Single exposure
        7.2. Short-term exposure
              7.2.1. Oral exposure (rat)
                      7.2.1.1   TBPP
                      7.2.1.2   TBPP-treated fibres

              7.2.2. Oral exposure (dog)
                      7.2.2.1   TBPP
                      7.2.2.2   TBPP-treated fibres
              7.2.3. Dermal exposure
                      7.2.3.1   Rabbit
                      7.2.3.2   Dog
        7.3. Long-term exposure
        7.4. Skin and eye irritation; sensitization
              7.4.1. Skin irritation
              7.4.2. Eye irritation
              7.4.3. Sensitization
        7.5. Reproductive toxicity, embryotoxicity, and
              teratogenicity
              7.5.1. Reproductive toxicity
              7.5.2. Teratogenicity
        7.6. Mutagenicity and related end-points
              7.6.1. DNA damage
                      7.6.1.1    In vivo
                      7.6.1.2    In vitro
              7.6.2. Mutation assay with Salmonella
                      typhimurium strains
              7.6.3. Mutations by urine of rats treated with TBPP65
              7.6.4. Other mutation assays
              7.6.5. Chromosomal effects
              7.6.6. Cell transformation
              7.6.7. Miscellaneous tests
              7.6.8. Mechanisms of TBPP genotoxicity
        7.7. Carcinogenicity
              7.7.1. Oral
                      7.7.1.1   Mouse
                      7.7.1.2   Rat
              7.7.2. Dermal
                      7.7.2.1   Mouse
        7.8. Special studies
              7.8.1. Kidneys
        7.9. Factors modifying toxicity; toxicity of metabolites
              7.9.1. Toxicity of metabolites
              7.9.2. Mutagenicity of metabolites

    8. EFFECTS ON HUMANS

        8.1. General population exposure
        8.2. Occupational exposure

    9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

        9.1. Laboratory studies
              9.1.1. Microorganisms
              9.1.2. Aquatic organisms
                      9.1.2.1   Invertebrates
                      9.1.2.2   Vertebrates

              9.1.3. Terrestrial organisms
                      9.1.3.1   Plants

    13. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    BIS(2,3-DIBROMOPROPYL) PHOSPHATE AND SALTS

    A1. SUMMARY AND EVALUATION; CONCLUSIONS AND RECOMMENDATIONS

    A2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL METHODS

        A2.1  Identity
        A2.2  Physical and chemical properties
        A2.3  Analytical methods

    A3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

        A3.1  Natural occurrence
        A3.2  Anthropogenic sources
              A3.2.1  Production levels and processes
              A3.2.2  Uses
        A3.3  Contamination of the environment
        A3.4  Environmental transport, distribution,
              transformation, and exposure levels

    A4. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS

        A4.1  Absorption, distribution, elimination,
              and biotransformation

    A5. EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

        A5.1  Single exposure
        A5.2  Short-term exposure
        A5.3  Long-term exposure
              A5.3.1  Mutagenicity and related end-points
              A5.3.2  Carcinogenicity
        A5.4  Special studies
              A5.4.1  Kidneys
        A5.5  Effects on humans and other organisms
              in the laboratory and field

    REFERENCES

    RESUME ET EVALUATION, CONCLUSIONS ET RECOMMANDATIONS

    RESUMEN
    

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    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR TRIS- AND
    BIS(2,3-DIBROMOPROPYL)PHOSPHATE

     Members

    Dr D. Anderson, BIBRA Toxicology International, Carshalton,
       United Kingdom

    Dr D. Osborn, Institute of Terrestrial Ecology, Monks Wood,
       Huntingdon, United Kingdom

    Dr E. Soderlund, National Institute of Public Health, Oslo,
       Norway  (Rapporteur)

    Dr B. Jansson, Institute of Applied Environmental Research,
       Stockholm University, Solna, Sweden

    Dr J. Kielhorn, Fraunhofer Institute for Toxicology and
       Aerosol Research, Hannover, Germany

    Dr R.D. Kimbrough, Institute for Evaluating Health Risks,
       Washington DC, USA  (Vice-chairman)

    Dr Wai-On Phoon, Department of Occupational Health,
       University of Sydney, Sydney, Australia (Chairman)

    Dr R. Benson, Drinking Water Branch, US EPA, Denver, USA

    Dr J. Sekizawa, National Institute of Health Sciences, Tokyo,
       Japan  (Rapporteur)

     Observers

    Dr M.L. Hardy, Toxicology Advisor, Albemarle Corporation,
       Baton Rouge, USA

    Dr D.L. McAllister, Director, Quality, Environment, Health
       and Safety, and Research Support, Great Lakes Chemical
       Corporation, West Lafayette, USA

     Secretariat

    Dr K.W. Jager, International Programme on Chemical Safety,
       World Health Organization, Geneva, Switzerland  (Secretary)

    ENVIRONMENTAL HEALTH CRITERIA FOR TRIS- AND BIS(2,3-DIBROMOPROPYL)
    PHOSPHATE

         A WHO Task Group on Environmental Health Criteria for tris- and
    bis(2,3-dibromopropyl) phosphate met at BIBRA Toxicology
    International, Carshalton, United Kingdom, from 6 to 11 June 1994.
    Dr K.W. Jager, IPCS, welcomed the participants on behalf of Dr M.
    Mercier, Director of the IPCS, and the three IPCS cooperating
    organizations (UNEP/ILO/WHO).  The Group reviewed and revised the
    draft and made an evaluation of the risks for human health and the
    environment from exposure to tris- and bis(2,3-dibromopropyl)
    phosphate.

         The first draft was prepared by Dr G.J. van Esch, the
    Netherlands, who also prepared the second draft, incorporating
    comments received following circulation of the first drafts to the
    IPCS Contact Points for Environmental Health Criteria monographs.

         Dr K.W. Jager of the IPCS Central Unit was responsible for the
    scientific content of the monograph and Mrs M.O. Head of Oxford for
    the technical editing.

         The efforts of all who helped in the preparation and finalization
    of the monograph are gratefully acknowledged.

    INTRODUCTION

         The IPCS is preparing several EHC monographs on Flame Retardants,
    which will provide additional information relevant to TBPP.

         There will be one monograph, "Flame Retardants - A General
    Introduction" (in preparation), giving a general introduction to the
    use, the mode of action, and the potential risks of flame retardants,
    and listing the substances used as flame retardants with a general
    indication of the data available on them.

         Flame retardants in wide use are discussed in separate
    monographs, e.g., EHC 162: Brominated Diphenyl Ethers (IPCS, 1994a)
    and EHC 172: Tetrabromobisphenol-A (IPCS, 1995).

         Some flame retardants considered hazardous for humans and the
    environment have been reviewed in separate monographs including EHC
    152: Polybrominated Biphenyls (IPCS, 1994b), and EHC 173: Tris- and
    Bis(2,3-dibromopropyl) phosphate (this monograph).

         Because of the possibility of the formation of halogenated
    dibenzodioxins and dibenzofurans under certain circumstances, such as
    pyrolysis, the following monographs have been developed: EHC 88:
    Polychlorinated Dibenzodioxins and Dibenzofurans (IPCS, 1989) and
    Polybrominated Dibenzodioxins and Dibenzofurans (in preparation).

         The reader should consult these monographs for further
    information.

         Tris(2,3-dibromopropyl) phosphate was an important commercial
    flame retardant ("TRIS"), especially for children's sleepwear.  In
    1977, the US Consumer Product Safety Commission banned children's
    clothing treated with tris(2,3-dibromopropyl) phosphate.  Since then,
    in several other countries, the use of this compound as a flame
    retardant has been severely restricted in consumer products and
    prohibited in textiles.

         Because tris(2,3-dibromopropyl) phosphate can also be used for
    other applications, the information available on physical and chemical
    properties, behaviour in the environment, occurrence in the
    environment and humans, kinetics and metabolism, toxicity for
    laboratory animals and in the field, and the exposure of the general
    population and workers, is summarized in this Environmental Health
    Criteria monograph.  General properties and uses of brominated flame
    retardants are given in "Flame Retardants - A General Introduction"
    (in preparation).

    ABBREVIATIONS

    BA            2-bromoacrolein

    BBPP          bis(2,3-dibromopropyl) phosphate

    DBCP          1,2-dibromo-3-chloropropane

    DBP           2,3-dibromopropanol

    DMBA          dimethylbenzanthracene

    mono-BPP      mono(2,3-dibromopropyl) phosphate

    TBPP          tris(2,3-dibromopropyl) phosphate

    TPA           tetradecanoyl phorbolacetate

    TRIS-(2,3-DIBROMOPROPYL) PHOSPHATE

    1.  SUMMARY AND EVALUATION; CONCLUSIONS AND RECOMMENDATIONS

    1.1  Summary and evaluation

    1.1.1  Production and use

         Tris(2,3-dibromopropyl) phosphate (TBPP) was first produced in
    about 1950; commercial production was reported in 1959.  Production of
    TBPP, in the USA, in 1975, was estimated to be between 4100 and
    5400 tonnes.  As far as is known, TBPP is not produced or used
    currently in the world as a flame retardant in textiles, but may be
    added to polymers used for other purposes.  TBPP was an important
    flame retardant for cellulose and tri-acetate and polyester fabrics,
    especially in children's sleepwear, but has been banned for these
    applications in several countries in Europe, the USA (1977), and Japan
    (1978).

         TBPP exists both in, and on, the fabric.  When it is in the
    fabric, it is not extractable with solvents and, therefore, probably
    not available for dermal absorption. However, when it is on the fibre
    surface, it can be extracted during laundering, and by acetic acid,
    other solvents, and saliva, and is available for dermal absorption. In
    this case, substantial losses of surface TBPP from fabrics during use
    and/or laundering of the finished products, will occur, and will
    contaminate the environment. Furthermore, release of TBPP into the
    environment has been reported from textile-finishing plants and the
    ultimate disposal of solid wastes, containing TBPP.

    1.1.2  Physical and chemical properties

         TBPP is available in at least two grades. The high-purity grade
    is a clear, pale-yellow, viscous liquid, with up to 1.5% volatiles. 
    The low-purity grade may contain up to 10% volatiles.

         TBPP (purity > 97%), has a boiling point of 390°C, a melting
    point of 5.5°C, and a vapour pressure of 1.9 × 10-4mmHg at 25°C. 
    The solubility of TBPP in water is low (8 mg/litre).

         When heated to decomposition, above 260-300°C, TBPP emits
    compounds containing bromine and phosphorus.  The  n-octanol/water
    partition coefficient (log Pow) is 3.02.

         Analytical methods to determine TBPP and its metabolites in
    biological samples and other matrices are available.

    1.1.3  Environmental transport, distribution, and transformation

         The limited information available suggests that TBPP is
    relatively persistent in the environment. Oxidation and
    photodegradation are not likely to be significant fate processes.
    However, hydrolysis involving the bromine atoms on the propyl group

    may occur, especially under basic conditions. Volatilization from
    water may occur, but no actual data are available. Although
    biodegradation of TBPP (half-life 19.7 h) in activated sewage is
    reported to occur, it is not thought to be an important process in
    natural soils and waters.  In sterilized sludge, almost no breakdown
    takes place.  Bis(2,3-dibromopropyl) phosphate (BBPP) was found as a
    major breakdown product.  Because TBPP is virtually insoluble in
    water, adsorption on particulate matter and sediment may be an
    important process.

         An estimated log Koc (3.29) suggests strong adsorption on soil.
    On the basis of this Koc value and the low measured water
    solubility, TBPP is expected to leach only slowly to groundwater. TBPP
    will tend to accumulate in rubbish dumps and other disposal sites,
    which may result in biological accumulation.  A bioaccumulation study
    with fathead minnow showed a bioconcentration factor of 2.7, which is
    low, while the  n-octanol/water partition coefficient (Log Pow) was
    3.02.  Because of its low vapour pressure, TBPP is expected to be
    mostly sorbed on particulate matter in air. Thermal oxidative
    degradation of TBPP at 370°C showed that hydrogen bromide and
    C3-brominated compounds, such as bromopropenes, dibromopropenes, and
    diand tribromopropanes, are formed.

    1.1.4  Environmental levels and human exposure

         Data on environmental levels and human exposure are limited. 
    Studies carried out in Japan in 1975 showed that 20 samples of water,
    soil, and fish did not contain TBPP.  TBPP was identified, but not
    quantified, in air particulates in the surroundings of an industry.

         Children wearing TBPP-treated sleepwear were the group of the
    general population particularly exposed to this flame retardant. The
    estimated intake via the skin of children wearing TBPPtreated
    sleepwear in the USA was calculated to be 9 µg/kg body weight per day.
    The Consumer Product Safety Commission of the USA calculated that,
    over a 6-year period, a child wearing TBPP-treated clothing could
    absorb a total of 2-77 mg TBPP/kg body weight or more.

    1.1.5  Kinetics and metabolism in laboratory animals and humans

         TBPP is absorbed readily from the gastrointestinal tract and at a
    moderate rate via the skin in rats and rabbits. In rats, TBPP or its
    metabolites are eliminated within 5 days.  Approximately 50% is
    eliminated via the urine, 10% via the faeces, and 10-20% is exhaled as
    CO2.

         One day after oral administration of labelled TBPP to rats,
    radioactivity was found in the blood, liver, kidneys, muscles, fat,
    and skin, in a range of 0.2-6.6%. The half-life of clearance of
    radioactivity from these organs was approximately 2-4 days.  After 8
    h, only bis(2,3-dibromopropyl) (BBPP) phosphate was still present in
    substantial concentrations in most tissues.

         After oral administration of TBPP to rats, six metabolites
    were identified in the urine and bile.  The main metabolite in
    the urine, faeces, bile, and tissues was BBPP.  The metabolite
    2,3-dibromopropanol (DBP) was also identified in rats and in children
    wearing TBPP-treated clothing.

         Liver microsomes metabolize TBPP in the presence of NADPH and
    oxygen.  The main metabolites are BBPP and 2,3-dibromopropanol (DBP). 
    It has been shown that BBPP is formed by oxidation at the C3 and,
    possibly, also at the C2 position of TBPP. In addition to BBPP,
    2-bromoacrolein, 2-bromoacrylic acid, and propyl-hydroxylated
    compounds and metabolites conjugated with glutathione have been found.

          S-(2,3-dihydroxypropyl) glutathione was identified in the bile
    of rats, and, it was suggested that TBPP and/or BBPP are conjugated
    directly with glutathione by glutathione  S-transferase with the
    formation of episulfonium ion metabolites.

         TBPP has been shown to be activated to form products that bind
    covalently to proteins and DNA  in vivo and  in vitro. After
    intraperitoneal injections of tritiated-TBPP, male mice, hamsters, and
    guinea-pigs, which are less sensitive to TBPP-induced nephrotoxicity
    than rats, showed similar levels of covalent binding to proteins in
    the liver and kidneys. In the male rat, which is highly susceptible to
    TBPP-induced nephrotoxicity, much higher amounts of radiolabel were
    bound to kidney proteins than to liver proteins.

         Liver microsomes from mice, guinea-pigs, hamsters, and humans all
    metabolized TBPP to genotoxic intermediates.  However, the rate of
    formation of reactive TBPP metabolites with human liver microsomes was
    lower than with liver microsomes from the rodents.

         The binding of labelled TBPP and analogues in rats at a
    nephrotoxic dose showed that the covalent protein binding was highest
    in the kidneys followed by the liver and testes.  The results of
    comparative  in vitro and  in vivo studies on renal DNA damage
    suggested that BBPP is formed in the liver by P450-mediated oxidation
    at either C2 or C3 of TBPP.  BBPP is transported to the kidneys, where
    it is metabolized to reactive intermediates that cause DNA damage and
    bind to kidney proteins. The activation occurring in the kidney
    appears not to involve P450 but seems to be mediated by GSH-dependent
    metabolism.   In vitro studies with labelled TBPP and analogues
    showed that oxidation of TBPP incorporates one atom of oxygen from
    water.  This implies that oxidation at C2 of the propyl moiety yields
    a reactive alphabromoketone that can alkylate protein directly or
    hydrolyse to BBPP and a reactive bromo-alpha-hydroxyketone.

    1.1.6  Effects on laboratory mammals and  in vitro test systems

         The acute and short-term oral, and the acute dermal, toxicities
    of TBPP are low.  The oral LD50 for the rat > 2 g/kg and the dermal
    LD50 for the rabbit > 8 g/kg body weight.  Extensive kidney damage
    (necrosis of renal proximal tubular cells) was noted in male rats
    following a single ip injection of 100 mg TBPP/kg body weight.

         Four-week, and 90-day, oral toxicity tests with TBPP (by gavage
    or in the diet) in rats showed a dose-related increase in the
    incidence and severity of chronic nephritis at dose levels of 25 mg/kg
    body weight or more.

         In rabbits, daily dermal applications of 2.2 g TBPP/kg body
    weight or more, for 4 weeks, resulted in degenerative changes in the
    liver and kidneys. All rabbits died within four weeks. No deaths
    occurred in another study with dose levels of up to 250 mg/kg body
    weight.

         In a 90-day test on rabbits, weekly application of 2.27 g/kg body
    weight to the skin resulted in kidney changes, testicular atrophy, and
    aspermatogenesis.

         No skin or eye irritation was observed in rabbits with dose
    levels of 1.1 g or 0.22 g TBPP and no skin sensitization was observed
    in guinea-pigs.

         Two teratogenicity studies were carried out on rats.  In one
    study with dose levels of up to 125 mg/kg body weight, no
    teratogenicity was observed. In another study with a dose level of
    200 mg/kg body weight, a significant increase in skeletal variations
    in the fetuses was observed, and, with 50 and 100 mg/kg body weight, a
    significantly lower viability index was found.  The authors concluded
    that the observed effect resulted from maternal toxicity.

         Extensive DNA damage was found in various organs of rats
    administered TBPP.   In vitro, TBPP has been shown to induce DNA
    strand breaks in human KB cells.  It induced unscheduled DNA synthesis
    in rat liver hepatocytes, but not in human foreskin epithelial cells.

         TBPP was mutagenic in several studies on  Salmonella typhimurium,
    especially in base-pair substituting strains with, and without,
    metabolic activation.

         Forward gene mutation assays using Chinese hamster V79 cells,
    with, and without, metabolic activation were negative. However, a
    positive effect in the presence of liver microsomes of rats pretreated
    with phenobarbital was obtained. A weak positive effect was obtained
    with mouse lymphoma cells (L5178YTK locus).

         TBPP increased the number of sister chromatid exchanges (SCEs) in
    Chinese hamster V 79 cells, but no chromosomal aberrations were
    induced in Chinese hamster cells, mouse bone marrow cells, or in
    cultured human lymphoid cells.  SCEs but no chromosomal aberrations
    were found with diploid human fibroblastic cells (line HE 2144)
    without metabolic activation.  However, in an  in vitro chromosome
    aberration test with the Chinese hamster cell line (CHL), TBPP was
    positive.

         A positive result was obtained with TBPP in a micronucleus test
    on Chinese hamster bone marrow cells. Another micronucleus study with
    mice showed a weak positive effect.

         Studies with  Drosophila melanogaster showed that TBPP increased
    sex-linked recessive lethals in male germ cells and in adult males,
    reciprocal translocations were induced. TBPP showed a strong positive
    response in the w/w+ eye mosaic assay.

         Several studies have been directed towards the elucidation of the
    mechanisms involved in TBPP-induced mutagenicity and/or genotoxicity. 
    Bacterial mutagenicity of TBPP is mediated by the microsomal
    monooxygenase system.  TBPP is activated by cytochrome P450 in a
    reaction depending on NADPH and oxygen.  Microsomes prepared from
    livers of animals treated with phenobarbital or PCBs give increased
    mutagenicity.  The mono-and bis(2,3-dibromopropyl) phosphates are less
    mutagenic than TBPP.   In vitro studies have shown that oxidation at
    C3 of the TBPP molecule yields the potent direct acting mutagen
    2bromoacrolein that also binds to DNA.

         Species differences in the bioactivation of TBPP to metabolites
    mutagenic to  Salmonella typhimurium TA 100 have been reported. Liver
    microsomes from mice were more effective than those from guinea-pigs,
    hamsters, and rats.

         Three studies in which C3H/10T1/2 cells were used to study cell
    transformation were carried out. In one study, a positive effect was
    noted, but, in the other two studies, the results were negative.

         TBPP was tested on mice and rats by oral administration and on
    female mice by skin application in long-term studies. In mice,
    following oral administration, TBPP produced tumours of the
    fore-stomach and lung in the animals of both sexes, benign and
    malignant liver tumours in females, and benign and malignant tumours
    of the kidneys in males. In rats, TBPP produced benign and malignant
    tumours of the kidneys in males and benign kidney tumours in females.
    After skin application to female mice, TBPP produced tumours of the
    skin, lung, fore-stomach, and oral cavity.  From these studies, it can
    be concluded that TBPP has carcinogenic potential in mice and rats.

         When the TBPP metabolite BBPP was administered to rats orally, it
    caused tumours in both sexes in the digestive system.  The tumours
    found included papillomas and adenocarcinomas of the tongue,
    oesophagus, and forestomach, adenocarcinomas of the intestine, and
    hepatocellular adenomas and carcinomas.

         Another metabolite of TBPP, DBP, was tested on rats and mice by
    dermal application.  In male rats, there was an increased incidence of
    neoplasms in skin, nose, oral mucosa, oesophagus, forestomach, small
    and large intestine, Zymbal's gland, liver, kidney, tunica vaginalis,
    and spleen.  In female rats, there was an increased incidence of
    neoplasms of the skin, nose, oral mucosa, oesophagus, forestomach,
    small and large intestine, Zymbal's gland, liver, kidney, clitoral
    gland, and mammary gland.  In male mice, there was an increased
    incidence of neoplasms in the skin, forestomach, liver, and lung, and
    in female mice, there was an increased incidence of neoplasms of the
    skin and the forestomach.

    1.1.7  Effects on humans

         Limited data are available regarding the effects of TBPP on
    humans.

         TBPP has been tested for skin sensitization potential in a few
    studies on humans.  The results of these studies indicate that TBPP
    has a low sensitization potential and no skin irritation was reported. 
    However, persons who showed a positive sensitization response to pure
    TBPP also reacted when exposed to fabrics
    treated with TBPP.

    1.1.8  Effects on other organisms in the laboratory and field

         There are very few data on the effects of TBPP on other
    organisms.  All 6 goldfish  (Carassius auratus), exposed to 1 mg
    TBPP/litre, died within 5 days.

         The EC50 for growth inhibition in oat seed was 1000 mg/kg soil. 
    This concentration caused a 100% inhibition of growth in turnip seed
     (Brassica rapa sp.).

    1.2  Conclusions

         TBPP has been used as a flame retardant in fabrics, particularly
    in children's sleepwear, but there is inadequate information on its
    use in other applications.  Exposure of the general population was
    primarily through contact with fabrics treated with TBPP.

         There is little information on the exposure of, and hazards to,
    workers from the commercial production of TBPP and its use in a
    variety of products.

         Because of the paucity of data, no firm conclusions can be drawn
    as to the exposure levels and hazards of TBPP for organisms in the
    environment, other than humans.

         Animal studies have shown that TBPP can be absorbed from the
    gastrointestinal tract and, to a lesser extent, from the skin.  TBPP
    can also be absorbed through the skin of humans.  In the rat, TBPP
    appears to be extensively metabolized in the liver to BBPP, which is
    the major metabolite detected in the urine and, to a lesser extent, to
    DBP.  In addition, other brominated metabolites of TBPP have been
    found in small amounts.  DBP has also been detected in humans wearing
    TBPP-treated fabrics.  The main route of elimination is the urine and
    very little is excreted as the parent compound.  The main metabolic
    pathway seems to be through metabolism by cytochrome P450 and
    glutathione  S-transferases.

         From the available data, it can be concluded that TBPP has a low
    acute toxicity for experimental animals.  Repeated dose studies with
    relatively high doses of TBPP have revealed kidney and liver damage in
    rats and also testicular toxicity in rabbits.  TBPP has elicited a
    clear genotoxic effect in several test systems, both  in vitro and
     in vivo.  Carcinogenic effects were found in rats and mice.  The
    metabolites BBPP and DBP have also been shown to produce carcinogenic
    effects in experimental animals.  No irritation effects were found in
    animals and a low sensitization potential in humans was noted.

         In 1977, the US Consumer Product Safety Commission banned
    children's clothing treated with TBPP, because of concerns that the
    chemical might be a human carcinogen, and, because of the possibility
    of significant human exposure through contact with treated fabrics. 
    Since then, the use of this substance as a flame retardant in consumer
    products has been severely restricted in several other countries  and
    it has been prohibited in textiles.

    1.3  Recommendations

         Because of its toxic effects, TBPP should no longer be used
    commercially.

         If uses are identified for which there are no less hazardous
    alternatives to TBPP, studies to demonstrate the absence of exposure
    of, and hazards for, humans and the environment should be conducted.

    2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL
        METHODS

    2.1  Identity

    Chemical formula           C9H15Br6O4P

    Chemical structure

                                  BrCH2-CHBr-CH2O
                                                 \
                                BrCH2-CHBr-CH2O  -  P = O
                                                 /
                                  BrCH2-CHBr-CH2O

    Relative molecular mass    697.7

    Synonyms                   tris(2,3-dibromopropyl) phosphate;
                               tris(2,3-dibromopropyl) phosphoric
                               acid ester; phosphoric acid, tris(2,3-
                               dibromo-propyl) ester;
                               tris(dibromopropyl) phosphate

    CAS registry number        126-72-7

    CAS chemical name          2,3-dibromo-1-propanol-phosphate (3:1)

    RTECS registry number      UB0350000

    Trade names                T 23 P; TP-69; DBP-TP; Apex
                               (emulsion) 462-5; Hamcogard FR;
                               Fyrol 59; Tanotard PN-2; Cav Gard
                               FR 1811 and FR 1812; Pyrosan 497;
                               Firemaster LV-T23P and T23P-LV;
                               Firemaster 200; Glotard PE-2; PE 10;
                               Anfram 3PB; Bromkal P 67-6HP; ES
                               685; Firemaster T23 and T23P;
                               Flacavon R; Flamex T23P; Flammex
                               AP; Zetofex ZN; Fyrol  HB-32; NCI-
                               CO3270; Phoscon PE60; Phoscon UF-
                               S; RCRA waste number U 235;
                               USAF-DO-41 (LeBlanc, 1976; IARC,
                               1979; Ulsamer et al., 1980; IRPTC,
                               1987).  FR 2406; Berkflam T23 P;
                               Flammex LVT 23P; 3PBR; TDBP;
                               TDBPP; TRIS; TRIS-BP; Zetifex ZN;
                               (Andersen, 1977).

    2.1.1  Technical product

         Commercial TBPP contains up to 0.2% of the following impurities:
    2,3-dibromopropanol, 1,2,3-tribromopropane, and 1,2-dibromo-
    3-chloropropane (DBCP) (Blum & Ames, 1977; Van Duuren et al., 1978;
    Ulsamer et al., 1980).

    2.2  Physical and chemical properties

         Two grades of TBPP were available in the USA.  The highpurity
    grade had the following typical properties: a clear, pale-yellow,
    viscous liquid; relative density at 25°C, 2.20-2.26; refractive index
    at 25°C, 1.576-1.577; viscosity at 25°C, 3900-4200 centistokes; acid
    number (mg KOH/g), 0.05 max; volatiles, 1.5% max; bromine content,
    68.7%, and phosphorus content, 4,0%. Typical properties for a lower
    grade are as follows: density at 25°C, 2.2-2.3; viscosity at 25°C,
    1400-1700 centistokes; acid number (mg KOH/g), 0.05 max; and
    volatiles, 10% max. (US EPA, 1976; IARC, 1979).

         Osterberg et al. (1977) reported a viscosity of 9200 cP (25°C)
    for TBPP of a purity of 99.76%. Firemaster LVT 23P has a viscosity of
    9200 cP (Kerst, 1974).

         Specific gravity           2.27 (2.2-2.3) g/ml at 25°C

         (density)                  (Kerst, 1974)

         Boiling point:             390°C  (Dybing et al., 1989)

         Melting point:             5.5°C  (Dybing et al., 1989)

         Vapour pressure:           1.9 × 10-4 mmHg at 25°C
                                    1.2 × 10-3 mmHg at 45°C
                                    4.8 × 10-3 mmHg at 65°C
                                    (Kerst, 1974)

         Solubility:                Virtually insoluble in water
                                    (6.3 mg/litre at 20°C) and hexane;
                                    miscible in organic solvents, such
                                    as carbon tetrachloride, acetone,
                                    chloroform, methylene chloride,
                                    dimethyl formamide, methanol,
                                    xylene, benzene, toluene, and ethyl
                                    acetate (Kerst, 1974)

         Stability:
         Heat stability:            Major decomposition begins at
                                    about 260-300°C; when heated to
                                    decomposition, TBPP emits toxic
                                    fumes of Br- and POx (Sax, 1984)

         Light stability:           Stable in sunlight

         Hydrolytic stability:      Hydrolysed by acids and bases
                                    (IRPTC, 1987)

          n-Octanol/water partition
         coefficient (log Pow):     3.02  (IARC, 1979)

    2.3  Analytical methods

    2.3.1  General

         TBPP is determined using a gas chromatograph equipped with a
    flame photometric detector with possible cleaning processes. Direct
    mass spectrometry, GC-MS, and HPLC are also used for the analysis of
    biological samples containing TBPP and its metabolites (Cope, 1973;
    Lynn et al., 1980, 1982; Pearson et al., 1993a).

         Recovery and limits of determination vary, depending on sampling
    procedures and matrices.  GC analysis shows that TBPP can be
    determined at the 10 ng level by using a column packed with a high
    liquid loaded support. In an indirect analytical method, TBPP is
    determined by spectrophotometry, by complexing phosphor with
    molybdenum blue after hydrolysis of the TBPP by hydrobromic acid
    (Nakamura, 1980; Gutenmann & Lisk, 1975).

         Gardner (1979) described a densitometric method using thin-layer
    chromatography.  TBPP was chromatographed on silicagel thin-layer
    plates, using ethyl acetate hexane (30:70) as a developing solvent. 
    TBPP was visualized by spraying the chromatograms with 1% aqueous
    silver nitrate followed by exposure to UVR for 40 min.  The spots were
    quantified by densitometry at 600 nm. The lower level of sensitivity
    was 50 ng; calibration plots were linear from 50 to 800 ng.  The
    recovery of TBPP from sewage sludge samples fortified at the 1.0 ppm
    level was 97%.

         Techniques for the qualitative detection of TBPP in textiles have
    been described, including thin-layer chromatography, HPLC, and NMR
    (Iliano et al., 1982).

    2.3.2  Urine

         In mammalian species, organophosphates undergo enzymatic or
    chemical hydrolysis to form the corresponding acids and alcohols.  The
    alcohols are often excreted in the urine as soluble conjugates.  Since
    the hydrolysis of TBPP yields 2,3-dibromopropanol (DBP), an analytical
    method has been developed to determine free, and conjugated, DBP. 
    Extraction of urine by diethylether/hydrochloric acid, followed by
    methylation with diazomethane gives the methylether of DBP.
    Determination is by electron affinity gas chromatography.  The limits
    of determination in rat and human urine were 0.4 and 0.2 mg/litre,
    respectively (St. John et al., 1976).

    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1  Natural occurrence

         TBPP is not known to occur naturally.

    3.2  Anthropogenic sources

    3.2.1  Production levels and processes

         It is estimated that TBPP was first produced in 1950, when it was
    prepared by the addition of bromine to a solution of triallyl
    phosphate in benzene.  However, it is synthesized in the USA by a
    two-step process in which bromine is added to allyl alcohol to give
    2,3-dibromopropanol (DBP).  This is then reacted with phosphorus
    oxychloride, in the presence of a Lewis acid such as,  aluminum
    chloride or stannium chloride as a catalyst (Overbeek & Nametz, 1962).

         The commercial production of TBPP was reported in 1959 and US
    production in 1975 has been estimated to have been between 4100-5400
    tonnes (US EPA, 1976).  Prior to 1977, 4500 tonnes of TBPP were
    produced annually in the USA by 6 manufacturers.  There was no
    evidence of production of TBPP in the USA in 1986.

         Production of TBPP in Japan in 1976 and 1977 is estimated to have
    been 100 and 300 tonnes per year, respectively, made by one
    manufacturer.  No TBPP is produced in Japan at present.

         It has not been possible to assess whether TBPP is currently
    produced.  However, no reports are available that describe any
    production of TBPP.

    3.2.2  Uses

         TBPP has been used as a flame retardant for cellulose and
    triacetate and polyester fabrics,  which are widely used in children's
    sleepwear.  It has also been used as a flame retardant in other
    materials, such as urethane foam and acrylic carpets and sheets,
    polyvinyl- and phenolic resins, polystyrene foam, paints, lacquers,
    paper coatings and styrene-butadiene rubber, latexes, and cured
    unsaturated polyesters products.  Rigid foams containing TBPP were
    used in insulation, furniture, automobile interior parts, and water
    flotation devices.  About 65% of the 4500 tonnes of TBPP that were
    produced annually in the USA by 6 manufacturers was applied to fabrics
    used for children's clothing.  TBPP was added to these children's
    garments to an extent of 5-10% by weight (US EPA, 1976; Kirk-Othmer,
    19781984).

         TBPP was applied to cellulose acetate and triacetate by addition
    to the melt prior to spinning.  The process involved the thermal
    diffusion of TBPP by driving it into the fibre under pressure dying.

    For materials such as, polyesters, nylons, and acrylics, the TBPP was
    either "padded on" at 5-10% by weight with heat fixation to the woven
    or knitted material or applied via emulsion from conventional batch
    dying equipment (Prival, 1975).

         Fire-retarded polyurethane required about 0.5% phosphor and 4-7%
    bromine; being equivalent to about 10% TBPP by weight in the product
    (US EPA, 1976).

         By actions taken on 8 April and 1 June 1977, on the basis of the
    genotoxic and possible carcinogenic effects of TBPP, the US Consumer
    Product Safety Commission banned children's clothing treated with
    TBPP, the chemical itself when used or intended to be used in
    children's clothing, and fabric, yarn, or fibre containing it, when
    intended for use in such clothing (US Consumer Product Safety
    Commission, 1977a,b; US Consumer Product Safety Commission, 1977a,b). 
    In March 1978, The Consumer Product Safety Commission listed 22
    products that contained TBPP and were available to USA consumers. 
    These included children's clothing, industrial uniforms, draperies,
    tent fabric, automobile headliners, epoxy resins for the electronics
    industry, Christmas decorations, and polyester thread (IARC, 1979).

         In Japan, the use of TBPP as a fire-retardant in textile products
    was banned in 1981, because the chemical might be a human carcinogen
    and genotoxicant.

         As from December 1987, TBPP could not be used in the EC in
    textile articles such as, garments, under-garments, and linen intended
    to come into contact with the skin (EEC, 1976, 1979).

         Several other countries including Finland, New Zealand, and
    Sweden have also banned, or severely restricted, the use of TBPP in
    textiles and textile articles (UN, 1991).

    3.2.3  Sources of human and environmental exposure

         Potential sources of human exposure and environmental
    contamination include: the manufacturing of the flame retardant, its
    application to materials, leaching out of the flame retardant during
    use and/or washing, and ultimate disposal of the material.

         Studies indicated substantial losses of surface TBPP from fabrics
    after laundering, but TBPP was not completely removed after repeated
    laundering.  For example, acetate fabrics (65-600 mg TBPP/kg) showed
    up to 85% reduction in surface concentration after one laundering,
    and, polyester fabrics (260-37 500 mg TBPP/kg), from 21 to 82%
    reduction after one laundering.  A significant portion, approximately
    10% of the total production reached the environment from
    textile-finishing plants and laundries.  Most of the rest will find
    its way into solid wastes (US EPA, 1976).

         Surface TBPP can be extracted from treated fabric by saliva (up
    to 3%) as well as by water, acetic acid, sodium bicarbonate, and salt
    (Ulsamer et al., 1980).

         Gutenmann & Lisk (1975) heated polyester flannel material,
    treated with TBPP, in distilled water at 60°C for 20 min, simulating
    a laundering operation.  It was calculated from the extraction rate
    that laundering of flame-retarded sheets could result in a
    concentration of 6 mg/litre in combined washing and rinsing water. 
    This release was maintained during several subsequent launderings. 
    The presence of detergents may increase the extraction rate.

         TBPP exists both in, and on, the fabric.  In the fabric fibres,
    it is not extractable with a benzene/hexane mixture and, therefore, 
    is probably not available for dermal absorption.  However, when it is
    on the fibre surface, it is extractable and is available for dermal
    absorption (Morrow et al., 1976; Ulsamer et al., 1980).

         While most of the TBPP is within the fabric in both polyester and
    acetate, polyester contains considerably more surface TBPP as a result
    of differences in methods of addition.  Concentrations of surface
    bromine in polyester fabric ranged from 2000 to 37 500 mg/kg with the
    actual TBPP content ranging from 20 to 90% of the bromine value.  The
    non-TBPP organic bromides have not yet been identified (Ulsamer et
    al., 1980).

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    4.1  Transport and distribution between media

         An estimated log Koc (3.29) suggests strong adsorption on soil. 
    On the basis of this Koc value and the low measured water solubility
    of the technical chemical (8.0 mg/litre), TBPP is expected to leach
    only slowly into groundwater.  The water solubility of pure TBPP may
    be lower than the solubility of the technical grade chemical and so
    the extent of leaching of the pure chemical may be even lower than the
    Koc above suggests (Kenaga, 1980; Lyman, 1982; Verschueren, 1983; US
    EPA, 1985).

         Although hydrolysis of the phosphate ester is not expected to be
    significant, hydrolysis involving the bromine atoms on the propyl
    groups may occur, especially under basic conditions.  Direct
    photolysis is not expected to be a major process, since TBPP should
    not absorb light of wavelengths found in sunlight (> 290 nm) (Mabey &
    Mill, 1978).

         No data on volatilization from water or soil are available. Using
    measured water solubility (8.0 mg/litre) and vapour pressure of 1.9 ×
    10-4 mmHg, volatilization half-life values were estimated. The
    half-life values for TBPP volatilization from streams, rivers, and
    lakes were 3.64, 4.66, and 392 days, respectively, assuming current
    velocities of 3, 1, and 0.01 m/second, respectively.  The river and
    stream depths were assumed to be 1 m, while the lake was assumed to be
    50 m deep (Verschueren, 1983).

    4.2  Transformation

    4.2.1  Biodegradation

         The biodegradability of TBPP was determined following a
    shake-flask test.  TBPP was incubated with a microbial inoculum of raw
    sewage.  Samples of the test solutions were taken at 0, 5, 10, and 15
    days for final analysis using neutron activation to determine the
    bromine content of the liquid.  Assuming the increased bromide content
    of the inoculated samples relative to the blank samples is due to
    biodegradation, and the solubility of TBPP is 1.6 mg/litre, an amount
    of TBPP equal to 2.4 times the dissolved TBPP was degraded in 5 days
    (Kerst, 1974).

         Activated return sludge (at 21°C), used within 1 h of
    collection, diluted with a basal medium, with an added 2 mg
    14C-labelled TBPP/kg, showed that 6% of the added radio-activity was
    evolved as 14CO2.  A major metabolite bis(2,3-dibromopropyl)
    phosphate (BBPP) was identified, but neither dibromopropanol (DBP) nor
    dibromopropionic acid was detected.  The half-life of TBPP was 19.7 h
    (by least squares regression analysis).  In a sterilized sludge
    control study, 93% of the added TBPP was found and metabolites were
    not identified (Alvarez et al., 1982).

         A biodegradation study on TBPP (100 mg/litre) was carried out
    under sewage treatment condition with sludge (30 mg/litre).  The
    degree of biodegradation, as measured by BOD, was 1.8% of TBPP after a
    2-week incubation period (Chemicals Inspection & Testing Institute,
    1992).

    4.2.2  Abiotic degradation

         No data available.

    4.2.3  Bioaccumulation

         Tissue residue analysis of rats fed TBPP for a period of 28 days
    at levels of 100 or 1000 mg/kg diet has shown dose-related residue
    levels (measured as total bromine) in the muscle, liver, and body fat,
    of the treated animals (see section 7.2.1.).

         Groups of 30 adult fathead minnow  (Pimephales promelas) (six
    months old), were exposed to 47.7 µg TBPP/litre for 2-32 days in a
    flow-through system.  The temperature of the water was 25°C, pH 7.49,
    dissolved oxygen > 5 mg/litre, and hardness
    45.5 mg/litre.  The bioconcentration factor determined was 2.7 (Veith
    et al., 1979).

         Bioconcentration of TBPP (0.1 mg/litre, 0.03 mg/litre) from water
    to carp was estimated to be between < 0.7 to 1.9, and < 2.2 to 4.3,
    respectively, after 6 weeks of exposure (Chemicals Inspection &
    Testing Institute, 1992).

    4.3  Interaction with other physical, chemical, or biological factors

         The thermal oxidative degradation at 370°C of TBPP produced
    hydrogen bromide and the C3-brominated species - bromopropenes,
    dibromopropenes, dibromopropanes and tribromopropanes, accounting for
    87% of the volatiles.  The detection of chlorinated species can only
    be explained by the presence of chlorinated impurities in the original
    ester.  The residue (ether soluble aliquot) was composed mainly of
    1,2,3-tribromopropane, whereas the aqueous layer contained the
    phosphoric acid produced.  The gas chromatographic analyses of the
    volatiles showed a number of isomeric dibromopropenes.  It was
    established that 1,3-dibromopropene was the major dibromopropene
    formed (Paciorek et al., 1978).

    4.4  Ultimate fate following use

         It is to be expected that TBPP would be released into the
    environment in wastewater after laundering articles coated with TBPP
    flame retardant.

         With regard to disposal, it must be assumed that clothes and
    other products containing TBPP ultimately end up in landfills, which
    may result in some biological accumulation.  Incineration should be
    carried out at high temperature with scrubbers or the  equivalent.

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1  Environmental levels

    5.1.1  Air

         TBPP was identified, but not quantified, in Arkansas air
    particulates (DeCarlo, 1979).

    5.1.2  Water

         In 1975, 20 water samples were collected at different places in
    Japan and analysed for the presence of TBPP.  None of the samples
    contained the compound (limit of determination 1 µg/litre)
    (Environment Agency Japan, 1978, 1987).

    5.1.3  Soil

         In 1975, 20 sediment samples were collected at different places
    in Japan and analysed for the presence of TBPP.  None of the samples
    contained TBPP (limit of determination 0.4-10 mg/kg) (Environment
    Agency Japan, 1978, 1987).

         TBPP was identified, but not quantified, in Arkansas soil
    (DeCarlo, 1979).

    5.1.4  Fish

         In 1975, 20 fish samples, collected at different places in Japan, 
    were analysed for the presence of TBPP.  None of the samples contained
    TBPP (limit of determination 1 mg/kg) (Environment Agency Japan, 1978,
    1987).

    5.2  General population exposure

    5.2.1  Subpopulation at special risk

         Tests for the extraction of TBPP from fabrics by water at various
    pH values and by a simulated saliva solution failed to reveal any TBPP
    in the extracts, but sodium bromide and hydrobromic acid were detected
    (limits of determination not mentioned) (Prival, 1975).  However,
    surface TBPP can be extracted from treated fabric by saliva (up to 3%)
    as well as by water, acetic acid, sodium bicarbonate, and salt
    (Ulsamer et al., 1980).

         In the USA, the estimated intake via the skin of children,
    wearing sleepwear treated with the compound, was estimated to be
    9 µg/kg body weight (Blum et al., 1978).

         The Consumer Product Safety Commission of the USA stated that,
    over a 6-year period, a child wearing TBPP-treated clothing could
    absorb a total of 2-77 mg TBPP/kg body weight and there are
    indications that this may be even higher (IRPTC, 1987).

    5.3  Occupational exposure

         There are no data on levels of exposure to TBPP during
    manufacture or further processing.

    6.  KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS

    6.1  Absorption

         TBPP is absorbed readily by the gastrointestinal tract and at a
    moderate rate via the skin in rats and rabbits.  Studies on children
    revealed that TBPP is dermally absorbed from TBPP-treated sleepwear
    (Kerst, 1974; Blum et al., 1978; Ulsamer et al., 1978, 1980).

         Following the dermal application of 14C-TBPP to the clipped
    backs of New Zealand White rabbits (2-3 kg), 3.5-3.8% of the 0.9 ml/kg
    dose and 15.2% of the 0.05 ml/kg dose were absorbed over 96 h. 
    Osborne Mendel rats (200-250 g) absorbed approximately 1/6 as much
    14C-TBPP at each dose, when TBPP was applied to an equivalent area
    of skin/kg.  The dermal uptake of 14C-TBPP by rats and rabbits
    showed that the primary elimination was via the kidneys (Ulsamer et
    al., 1980).

    6.2  Elimination

    6.2.1  Different routes (rat and rabbit)

         Four male Sprague-Dawley rats (290-310 g) were administered
    14C-TBPP (98%) intravenously.  The animals were housed in metabolism
    cages for 5 days.  Urine, faeces, and air samples were collected for
    5 days, and bile for 1 day.  In 5 days, 58% of the administered
    radioactivity was found in the urine; 9% in the faeces and 19% in the
    air as CO2. In 24 h, bile contained 34% of the radioactivity while
    9% was found in the bodies of the rats.  In three additional rats,
    it was found that biliary excretion and enterohepatic recirculation
    was a major route in the disposition of TBPP.  Bis(2,3-dibromopropyl)
    phosphate (BBPP) was detected in the urine of male rats (290-310 g)
    dosed iv with 25 mg 14C-TBPP (98%)/animal (in Emulphor) in
    amounts of 7.8% of the dose during 5 days following administration. 
    BBPP was identified in the urine, faeces, bile, and tissues. 
    2,3-Dibromopropanol (DBP) was found in tissues and DBP and a few other
    metabolites were found in urine, but TBPP was not detected (Lynn et
    al., 1980, 1982).

         An adult male Sprague-Dawley rat (150-200 g) was administered
    (iv or orally) 1.39 mg 14C(propyl)-TBPP (99%)/kg body weight.  One
    day after iv administration, 17% of the administered radioactivity was
    found in the urine, 7.4% in the faeces and 20% in the air (as CO2). 
    One day after oral administration of TBPP, the concentrations were 24%
    in the urine and 11.5% in the faeces, but no radioactivity was
    detected in the air.  Mainly metabolites were excreted in the urine
    and bile (Nomeir & Matthews, 1983).

         Small amounts of DBP and conjugates appeared in urine, when the
    rat was allowed to chew on TBPP-finished polyester fabric (St. John et
    al., 1976).

         Radiolabel from 14C-TBPP, applied to the skin, was excreted
    primarily in the urine (70% for rabbits and 50% for rats) with lesser
    amounts appearing in the faeces and 12 and 18% exhaled as CO2,
    respectively.  TBPP itself did not appear in the urine, but a number
    of metabolites including DBP were found (section 6.4) (Ulsamer et al.,
    1980).

    6.2.2  Dermal exposure (rat and rabbit)

    6.2.2.1  TBPP

         One hundred mg of TBPP was spread over the surface of a gauze pad
    (one square inch) bandage and pressed tightly against the shaved skin
    of a rat.  Urine was assayed for free and conjugated (released by acid
    hydrolysis) DBP.  By day 7, the total concentrations of free and
    conjugated DBP in the urine were 17.61 and 23.58 mg/litre,
    respectively (St. John et al., 1976).

    6.2.2.2  TBPP-treated fibres

         TBPP has been shown to penetrate rabbit skin from 14C-TBPP
    labelled polyester cloth containing 15 000 mg TBPP/kg of surface (4.3%
    of the radioactivity in 96 h) (Ulsamer et al., 1980).

         A shaved rat wore a garment made of 100% polyester flannel
    (4 × 6 inches), treated with TBPP, for 9 days.  No DBP could be
    detected in the urine (limit of determination 0.4 mg/litre) (St. John
    et al., 1976).

    6.2.3  Dermal exposure (human)

         The skin of a 7-year-old child was exposed on days 1, 2, and
    8-12, by wearing repeatedly washed sleepwear that may have been
    TBPP-treated.  On days 3-7, she wore new TBPP-treated pyjamas.  Urine
    samples were collected daily from the child.  In the urine, a maximum
    concentration of DBP of 29 µg/litre was found 2 days after wearing the
    new treated pyjamas.  DBP at a concentration of 0.4 µg/litre was
    present in the urine, prior to wearing the new treated pyjamas.  DBP
    was still excreted 5 days after the child stopped wearing the new
    TBPP-treated pyjamas.  Urine samples were collected from 10 other
    children and one adult.  All samples were analysed for DBP; it was not
    found in the urine of one child and one adult (who had never used
    washed TBPP-treated sleepwear).  Seven children had levels of about
    0.5 µg DBP/litre in the urine and one child had a level of 5 µg/litre. 
    Approximately 180 µg/day (9 µg/kg body weight) was absorbed through
    the skin of children wearing pyjamas treated with TBPP (Blum et al.,
    (1978).

         No DBP could be detected in the urine of an adult or in the urine
    of a 5-year-old boy who wore 100% polyester knit pyjamas, treated with
    TBPP, for 7 nights.  Morning urine samples were collected daily
    throughout this period and up to 8 days thereafter (limit of
    determination 0.2 mg/litre) (St. John et al., 1976).

    6.3  Distribution

    6.3.1  Rat

    6.3.1.1  Oral

         Male adult Sprague-Dawley rats (150-200 g) were administered
    1.39 mg 14C(propyl)-TBPP (99%) orally.  The percentages of the total
    dose of radioactivity, found after one day, in the blood, liver,
    kidneys, lung, muscles, fat, and skin, were 6.6, 3.4, 0.7, 0.2, 5.5,
    1.3, and 3.4%; 24 and 11.5% of the total dose were found in the urine
    and faeces, respectively.  The terminal clearance of TBPP-derived
    radioactivity from most of the tissues was described by a single
    component exponential decay with a half-life of 2.5 days.  The
    half-life of TBPP in the liver and kidneys was 3.8 days (Nomeir &
    Matthews, 1983).

         Dose-related bromine concentrations were detected by neutron
    activation analysis in the muscles, liver, and fat of male rats fed
    TBPP for 28 days.  The levels decreased to control levels during the
    six-week withdrawal period (Kerst, 1974).

    6.3.1.2  Intravenous

         Eight male Sprague-Dawley rats (290-310 g) were administered
    14C-TBPP (98%) by the iv route and the distribution was studied. 
    All tissues contained TBPP-derived radioactivity.  The concentrations
    of TBPP-derived radioactivity declined rapidly in most tissues, but
    the concentration of radioactivity in kidneys was 11 times the average
    body concentration, five days after dosing.  No TBPP was detected,
    though bis(2,3-dibromopropyl) phosphate (BBPP) was still present in
    substantial concentrations.  By day five, only small quantities of
    this metabolite were detected.  The concentration of TBPP increased
    in the fat during the first 5-30 min, but, after 8 h, TBPP was no
    longer detectable.  In contrast to the rapid disappearance of TBPP,
    the half-life of BBPP was relatively long in most tissues.  BBPP
    represented a major portion of the radioactivity in several tissues
    including the lung, muscles, fat, and blood.  In blood, it accounted
    for 90% of the radioactivity at 30 min and 8 h.  By 5 min, 75% of the
    radioactivity in plasma was BBPP.  The initial plasma half-life of
    this metabolite was 6 h.  For 5 days it was 36 h.  TBPP was not
    detectable in plasma after 1 h (Lynn et al., 1982).

    6.3.2  Dermal (rabbit)

         Substantially more TBPP-derived radiolabel was detected in the
    kidneys and liver than in other organs of New Zealand rabbits,
    dermally treated with polyester fabrics containing 14C-TBPP (Ulsamer
    et al., 1978).

    6.4  Metabolic transformation

    6.4.1  In vivo studies

    6.4.1.1  Oral (rat)

         TBPP was readily metabolized in rats.  The main metabolite found
    in the urine, faeces, bile, and tissues of rats was BBPP. 
    2,3-Dibromopropanol (DBP) was also identified in tissues and urine. 
    Only small amounts of unchanged TBPP were found in the excreta (Lynn
    et al., 1982; Nomeir & Matthews, 1983).

         Male adult rats (150-200 g) were administered 1.39 mg
    14C(propyl)-TBPP (99%) orally (by intubation), and the urine and
    bile were analysed for metabolites.  Six metabolites were identified
    in urine and bile, respectively:

         -  2,3-dibromopropanol; 1.0 and 1.1%;
         -  bis(2,3-dibromopropyl) phosphate; 2.8 and 25.8%;
         -  2-bromo-2-propenyl 2,3-dibromopropyl phosphate; 4.8 and 13.8%;
         -  bis(2-bromo-2-propenyl) phosphate; 10.3 and 5.2%;
         -  2,3-dibromopropyl phosphate; 4.1 and 2.6%;
         -  2-bromo-2-propenyl phosphate; 9.5 and 2.4%

    and TBPP was found in concentrations of 0.8 and 2.0%, respectively.

         These data are expressed as a percentage of total radioactivity
    excreted in the urine in 24 h, and, bile in 3 h.  The total quantity
    of metabolites eliminated in the urine and bile were, in these
    periods, 33.3 and 52.9% of the radioactivity administered,
    respectively (Nomeir &  Matthews, 1983).

         The formation of BBPP has been studied using selectively
    deuterated analogues of TBPP.  Plasma concentrations of BBPP in rats
    dosed with either C2-D1- or C3-D2-TBPP were substantially lower than
    levels obtained with TBPP up to 4-6 h after administration.  This
    indicates that oxidative metabolism of TBPP to form BBPP is important
     in vivo.  Furthermore, in addition to oxidation at C3, BBPP
    formation may result from oxidation at C2.  This latter reaction may
    be of particular importance with phenobarbital-pretreated microsomes
    (Pearson et al., 1993a; Dybing et al., 1989).

         In addition to these TBPP metabolites, 2-bromoacrolein,
    2-bromoacrylic acid, bis(2,3-dibromopropyl)-3-hydroxypropyl phosphate,
     S-(2,3-dihydroxypropyl) glutathione,  S-(3hydroxypropyl)
    glutathione and  S-(2-carboxyethyl) glutathione have been detected
     in vitro and/or  in vivo (Marsden & Casida, 1982; Nelson et al.,
    1984).

         2-Bromoacrylic acid has been detected in the urine of rats
    administered TBPP.  It was suggested that 2-bromoacrylic acid is an
    oxidation product of 2-bromoacrolein and that 2-bromoacrolein is
    formed spontaneously from DBP generated via initial cytochrome
    P450-mediated oxidation of TBPP (Marsden & Casida, 1982; Soderlund et
    al., 1984).

         Recent data indicate that the formation of 2-bromoacrolein occurs
    mainly from oxidative dehalogenation at the C3 position (Pearson et
    al., 1993a).

         Although glutathione acts as a detoxifying agent for reactive
    TBPP metabolites (Soderlund et al., 1984), conjugation could also
    result in the formation of reactive episulfonium ion intermediates
    (Pearson et al., 1993b).  Van Beerendonk (1994) noted that there is
     S-(2,3-dihydroxypropyl) glutathione in the bile of Sprague-Dawley
    rats.  They suggested that TBPP and/or BBPP are conjugated directly
    with glutathione by glutathione  S-transferases, with subsequent
    formation of episulfonium ions.

    6.4.2  In vitro studies

         TBPP is readily metabolized by microsomal and cytosolic rat liver
    fractions.  Liver microsomes metabolized TBPP in the presence of NADPH
    and oxygen, as evidenced by the release of bromine and the formation
    of BBPP (Kerst, 1974; Nomeir & Matthews, 1983).

         The role of debromination in the formation of reactive
    metabolites was demonstrated in a series of TBPP analogues (Soderlund
    et al., 1984).  The rate of NADPH-dependent metabolism was increased
    5-10 times with microsomes from phenobarbital-pretreated rats compared
    with control microsomes and was reduced in the presence of cytochrome
    P450 inhibitors, indicating that cytochrome P450 is responsible for
    microsomal TBPP biotransformation (Soderlund et al., 1979, 1981, 1984;
    Nomeir & Matthews, 1983).

         Liver microsomes from mice, guinea-pigs, hamsters, and humans all
    metabolized TBPP to reactive intermediates.  However, the rate of
    formation of reactive TBPP metabolites with human liver microsomes was
    lower than with liver microsomes from rodents (Soderlund et al.,
    1982a).

         In addition, a 1.5 to 2-fold increase in the rate of TBPP
    metabolism occurred when phenobarbital-pretreated microsomes were
    fortified with GSH, indicating that microsomal GSH- S-tranferases are
    able to conjugate TBPP with GSH.  Dialysed rat liver cytosolic
    fractions, supplemented with GSH, metabolized TBPP at rates that were
    3 times higher than those observed with control microsomes and NADPH
    (Nomeir & Matthews, 1983; Soderlund et al., 1981, 1984).  Thus, in
    animals, GSH-dependent metabolism may be an important route in the  in
     vivo biotransformation of TBPP to more water-soluble products.

         Soderlund et al. (1984) detected the  in vitro formation of
    2-bromoacrolein, by a reaction catalysed by cytochrome P450, in a
    process liberating bromide ions with subsequent formation of BBPP
    using rat liver microsomes (Soderlund et al., 1984).  Mass spectral
    analysis of 2-bromoacrolein, formed from selectively deuterated
    analogues of TBPP, revealed that the primary mechanism for the
    formation of 2-bromoacrolein involves the initial oxidative
    dehalogenation at C-3 followed by a betaelimination reaction (Nelson
    et al., 1984).

          In vitro studies were carried out with deuterated analogues of
    TBPP, or, analogues labelled at specific positions with carbon-14,
    phosphorus-32, or oxygen-18, or dual-labelled with both deuterium and
    tritium.  These were used as metabolic probes to study the chemical
    and metabolic events in the bioactivation of TBPP to chemically
    reactive metabolites in the liver microsomal preparations of male
    Sprague-Dawley rats.  Studies with deuterated analogues of TBPP
    implicated oxidation at C-2 of the propyl moiety as a major pathway
    that leads to protein binding, which is enhanced by phenobarbital
    pretreatment of rats. Investigations with 18O-TBPP and H218O
    showed that the BBPP that is formed from the oxidation of TBPP
    incorporates one atom of oxygen from water.  These results imply that
    oxidation at C-2 yields a reactive alpha-bromoketone that can alkylate
    proteins directly, or, hydrolyse to BBPP and a reactive alpha-
    bromoalpha'-hydroxyketone that alkylates microsomal proteins (Pearson
    et al., 1993a).  These studies also showed that TBPP is oxidized at
    C-3, yielding the direct acting mutagen 2-bromoacrolein as the major
    metabolite that binds to DNA.  This is consistent with earlier studies
    that indicate that 2-bromoacrolein is the major reactive metabolite
    formed in  in vitro microsomal incubations (Nelson et al., 1984;
    Dybing et al., 1989).

    6.5  Covalent binding to macromolecules

         TBPP has been shown to be activated to products that bind
    covalently to proteins (total macromolecules) and DNA  in vitro and
     in vivo (Soderlund et al., 1981, 1984; Pearson et al., 1993a,b). 
    The covalent binding of radiolabel TBPP to macromolecules was
    dependent on microsomes and NADPH, and was reduced by carbon monoxide,
    inhibitors of P450, and glutathione (Soderlund et al., 1981).  The

    extent of TBPP covalent binding  in vivo was five times higher in the
    kidneys than in the liver, whereas the rate of  in vitro covalent
    binding was much higher with liver microsomes than with kidney
    microsomes.  The low levels of TBPP binding in the liver  in vivo may
    be the result of an extensive detoxification of TBPP to non-reactive
    metabolites or to low tissue concentrations of the proximate
    metabolite(s).

         Male NMRI and female B6C3F1 mice (20-25 g), male F344 rats
    (200-250 g), and guinea-pigs (80-100 g) were injected ip once with
    250 mg 3H-TBPP/kg body weight in DMSO.  The animals were killed 9 h
    after injection.  All species showed similar levels of covalent
    binding to proteins in the liver and kidneys except for the rat which
    had much higher amounts of radiolabel bound to kidney proteins
    (Soderlund et al., 1982a).

         The binding of TBPP and analogues has also been studied  in
     vivo.  Analogues of TBPP either labelled at specific positions with
    carbon-14, and phosphorus-32 or dual-labelled with both deuterium and
    tritium were administered to male Wistar rats at a nephrotoxic dose of
    360 µmol/kg body weight.  The covalent binding of TBPP metabolites to
    rat hepatic, renal, and testicular proteins was determined after 9 and
    24 h.  The covalent protein binding was 5 times higher in the kidneys
    than in the liver and approximately 25 times higher than that in the
    testes.  The results of comparative studies on renal DNA damage
    induced by TBPP and BBPP labelled with deuterium at C-2 or C-3
    suggested that BBPP is formed in the liver by P450-mediated oxidation
    at either C-2 or C-3 of TBPP.  BBPP is then transported to the
    kidneys, where it is subsequently metabolized to reactive
    intermediates that cause DNA damage and bind to kidney proteins in a
    process, independent of cytochrome P450, involving activation by
    conjugation with glutathione (Pearson et al., 1993b).

         Van Beerendonk et al. (1992) studied the formation of thymidine
    adducts and the cross-linking  potential of  2-bromoacrolein (BA), a
    reactive metabolite of TBPP.  In this study, [3-3H]BA was reacted
    with single-stranded (ss) DNA or double-stranded (ds) DNA and
    subsequently incubated with methoxylamine to covert the reaction
    product to an unstable BA:thymidine adduct.  Because the unstable
    BA:thymidine adduct may have the potential to form cross-links, the
    reaction with various nucleophiles  in vitro was studied.  A reaction
    occurred between the adduct and cystein, but not with lysine or
    desoxynucleosides.  Reaction of BA with ssDNA in the presence of
    [3H]glutathione also resulted in the binding of radiolabelled GSH to
    DNA.  The results indicated that the reactive aldehyde group of the
    adduct can react with thiol groups in proteins to form protein-DNA
    cross-links.  When the possibility that tris- and bis-(2,3-
    dibromopropyl) phosphates form such cross-links was examined  in vivo
    in  Drosophila, it was found that TBPP was a cross-linking agent,
    whereas BBPP was not.

    7.  EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

    7.1  Single exposure

         The oral LD50 for TBPP was calculated to be 5.24 g/kg body
    weight, when administered as a suspension in propyleneglycol to male
    albino Spartan rats with a weight of 202-250 g.  The observation
    period was 14 days (Kerst, 1974).  In another study, TBPP dissolved in
    propyleneglycol or in ethanol was given to Osborn-Mendel rats.  Oral
    LD50s of 1.88 and 3.12 g/kg body weight, respectively, were obtained
    (Ulsamer et al., 1980).

         A dermal toxicity study showed an acute LD50 for rabbits of
    17.6 g/kg body weight (Ulsamer et al., 1980).  In another study, TBPP
    was applied once to the back of four groups of two male and two female
    New Zealand white rabbits (2.56-2.96 kg) in concentrations of 1, 2, 4,
    or 8 g/kg body weight.  The application area was wrapped with a gauze
    bandage and occluded; after 24 h, the bandages were removed and the
    skin washed with water.  The observation time was 14 days.  An LD50
    of > 8 g/kg body weight was found (Kerst, 1974).

         A dose of 2 g TBPP was applied to the intact and abraded skin of
    10 albino rabbits.  No deaths were observed during a 14-day
    observation period (Moldovan, 1972).

    7.2  Short-term exposure

    7.2.1  Oral exposure (rat)

    7.2.1.1  TBPP

         Groups of male rats received daily doses of 250 mg TBPP/kg in
    either propyleneglycol or saline, by gavage, and were sacrificed after
    1, 2, 4, 6, 8, or 10 days.  Liver and testes were unaffected by any
    treatment, but nephrotic changes were observed to commence on day 2
    and to become progressively more severe with time.  In addition to the
    tubular lesions, the glomeruli were adversely affected, an observation
    not seen in the 13-week study (Osterberg et al., 1979).

         In a pilot study, groups of 10 non-pregnant rats were
    administered TBPP for 10 days at dose levels of 100, 150, 500, or
    1000 mg/kg body weight per day.  Mortality rates were 0, 0, 70, and
    100%, respectively (Seabaugh et al., 1981).

         Male weanling rats were fed TBPP at concentrations of 100 or
    1000 mg/kg diet for 28 days.  The animals were then sacrificed
    immediately or after 2 or 6 additional weeks of recovery.  The results
    showed a decrease in food efficiency (approximately 10%  at the
    highest dose), decreased body weight gain (approximately 20% at the
    highest dose), and decreased organ to body weight ratios for heart,

    liver, spleen, kidney, and gonads (approximately 20% for each organ at
    the highest dose).  Haematology, blood chemistry, urinalysis, and
    histopathology did not differ from the control values.  In the
    recovery period, the body weight gain became normal.  The authors
    suggested that the effect might be because of the palatability of the
    substance.  Tissue residues (measured as bromine) increased 40-50
    times in the first 4 weeks of treatment in the fat, liver, and
    muscles.  By the end of the 6-week withdrawal period, the residues
    were at control levels (Kerst, 1974).

         Groups of rats were gavaged with TBPP in corn oil at 10, 50, or
    100 mg/kg per day for 4 weeks.  One half of each group was sacrificed
    at 4 weeks and the remainder at 6 weeks.  While no adverse responses
    were observed, elevated bromine levels in blood were reported (Brieger
    et al., 1968).

         A 90-day study was carried out on rats administered TBPP in
    propylene glycol, daily (by gavage), at 25, 100, or 250 mg/kg body
    weight.  The control groups received either the vehicle, normal
    saline, or no treatment.  Weight gain for males was 34-50% less and,
    for females, 40% less in the test groups and vehicle group compared
    with the control values.  Liver/body weight ratios were lower for both
    sexes in the low TBPP group, but higher in females in the highest dose
    group, compared with those in the control group.  Kidney/body weight
    ratios were 18% lower than in controls.  Testes/body weight ratios in
    the TBPP groups were 25% lower.  There was an increased incidence and
    severity of chronic nephritis associated with regenerative epithelium,
    hypertrophy, and dysplasia of renal tubular epithelial cells in all
    TBPP-treated rats.  The complex of changes was more severe with higher
    dose, and among males (Osterberg et al., 1978).

    7.2.1.2  TBPP-treated fibres

         The results of a 2-week study on rats fed 15% shredded
    TBPP-treated acetate fibres in their food (3 times/week) showed no
    changes in blood-bromine levels and no adverse effects (Ulsamer et
    al., 1980).

    7.2.2  Oral exposure (dog)

    7.2.2.1  TBPP

         In a study on dogs, doses of 50 or 100 mg TBPP/kg body weight
    were given in the diet for four weeks.  A decrease in body weight was
    noted in the treated dogs as well as increased blood-bromine levels. 
    Cholinesterase activity was reported to be unaffected (Brieger et al.,
    1968).  No further details were available for this study.

    7.2.2.2  TBPP-treated fibres

         In a 2-week study on dogs fed 15% shredded TBPP-treated acetate
    fibres in their food (3 times/week), no changes in blood-bromine
    levels or adverse effects were seen.  Two additional, 3-week studies
    on dogs using TBPP-treated shredded rayon and acetate fibres added to
    foods did not show any detectable changes in health or in
    blood-bromine levels (Brieger et al., 1968).

    7.2.3  Dermal exposure

    7.2.3.1  Rabbit

         Short-term dermal studies have been performed using groups of
    clipped rabbits dosed with 2.2, 4.4, or 8.8 g TBPP/kg body weight,
    daily, for 4 weeks.  A dose-related increase in bromine was found in
    the blood and urine.  All rabbits died within 4 weeks.  Significant
    degenerative changes in the kidneys and the liver were found.  Slight
    decreases in cholinesterase activity were recorded (Brieger et al.,
    1968).  In another study in which the animals were administered dose
    levels of 50 and 250 mg/kg body weight, bromide levels in the blood
    and urine were increased, but no deaths occurred (Ulsamer et al.,
    1980).

         A 13-week study was carried out on 12 young (3 months old) New
    Zealand white rabbits, 6 with intact, and 6 with abraded, dorsal skin. 
    They were treated with a weekly application of 2.27 g TBPP (99.76%)/kg
    body weight for 13 weeks.   In a third group, 6 rabbits were initially
    clipped and maintained untreated as controls.  The TBPP-treated sites
    were not occluded with a patch, but the animals were fitted with a
    collar.  Besides a statistically significant increase in relative
    liver weights in the rabbits with intact and abraded skin (53% and
    59%, respectively), a significant decrease in testes weight (54% and
    40%, respectively) was observed.  Microscopically, chronic
    interstitial nephritis (in 6/8 males) with tubule involvement and
    bizarre nuclei as well as testicular atrophy and aspermatogenesis
    (spermatogonia were present in seminiferous tubules, and also
    secondary spermatocytes,  but no spermatozoa) were observed in 7/8
    males of the test groups. Female rabbits did not exhibit any adverse
    responses.  No histopathological changes were seen in the liver
    (Osterberg et al., 1977, 1978).

         In a study in which TBPP-treated rayon cloth was applied to the
    clipped skin of rabbits for 4 weeks, no significant effects were found
    (bromine levels were not increased) in treated animals (Ulsamer et
    al., 1980).  No further details were available for this study.

    7.2.3.2  Dog

         When TBPP-treated rayon cloth was applied to the clipped skin of
    dogs for 4 weeks, no significant effects (no increased bromine levels)
    were found in the treated animals (Brieger et al., 1968).  No further
    details were available for this study.

    7.3  Long-term exposure

         Apart from carcinogenicity studies, no long-term toxicity studies
    are available (see section 7.7).

    7.4  Skin and eye irritation; sensitization

    7.4.1  Skin irritation

         TBPP (1.1 g) was applied to the abraded or intact skin of six
    albino rabbits.  The animals were fitted with collars for 24 h. After
    this period, the coverings were removed and the test material washed
    off.  The extent of erythema and oedema was determined after 24 and
    72 h.  No signs of irritation were observed (Kerst, 1974).

    7.4.2  Eye irritation

         Administration of 0.22 g TBPP to the eyes of 6 adult rabbits did
    not cause noticeable irritation or damage to the cornea, iris, or
    palpebral conjunctiva during a 72-h observation period (Kerst, 1974;
    US EPA, 1976).

    7.4.3  Sensitization

         TBPP was tested for skin sensitization in groups of 5-10
    guinea-pigs using a modified Landsteiner method and the footpad
    technique.  No sensitization was noted in either test (no details
    given) (Morrow et al., 1976).

    7.5  Reproductive toxicity, embryotoxicity, and teratogenicity

    7.5.1  Reproductive system

         Groups of 6 adult male Sprague-Dawley rats (56-60 days of age)
    were used in a study to investigate the effects of TBPP on the
    reproductive system.  Six rats were injected with 0.1 ml
    propyleneglycol intraperitoneally, three times/week, and, six rats
    were untreated controls.  Nine groups of 6 rats were given (ip
    injection), three times/week, 0.4, 0.9, 1.8, 3.5, 7.1, 14.2, 28.4,
    56.8, or 113.5 mg TBPP in propyleneglycol for a period of 72 days. The
    four highest dose levels of TBPP did not dissolve completely and were
    injected as an emulsion.  The rats were treated for a minimum of 72
    days (6 cycles of the germinal epithelium) before being killed.  The
    three highest dose levels (28.4-113.5 mg/injection) caused significant
    dose-related declines in the weights of the testes and prostate,

    epididymides, and seminal vesicles.  Sperm production of testes and
    sperm storage in the epididymides were reduced, and the percentage of
    the motile sperm and the motility index were decreased.  Histological
    examination of the testes revealed that the seminiferous tubules were
    affected.  The affected tubules contained very few germinal cells and
    the macrophages in the interstitium of the affected testes appeared to
    be phagocytically active.  The Leydig cells were normal.  TBPP did
    not have any significant effects on the serum concentration of
    testosterone or on the  in vitro testicular capacity for testosterone
    secretion (Cochran & Wiedow, 1986).

         The effects on the testes were also reported in a 13-week study
    on New Zealand white rabbits, treated with weekly dermal applications
    of 2.27 g TBPP on the intact or abraded skin.  Decreased testes
    weights and, microscopically, testicular atrophy and aspermatogenesis
    were found in male rabbits (Osterberg et al., 1977).

         B6C3F1 mice (15 weeks old) were administered (ip) TBPP in corn
    oil at dose levels of 0, approximately 200, 400, 600, 800, and
    1000 mg/kg body weight daily, for 5 days.  The mice were killed 35
    days after the fifth treatment.  Their epididymides were removed and
    abnormal sperm heads determined.  The frequency of abnormal sperm
    heads in TBPP-treated mice was significantly greater than in controls,
    predominantly at dose levels of 800 mg/kg body weight or more
    (Salamone & Katz, 1981).

    7.5.2  Teratogenicity

         In a pilot study on groups of ten pregnant Sprague-Dawley rats,
    orally intubated with 0, 250, or 1000 mg TBPP/kg body weight on days
    6-15 of gestation, an increase in maternal mortality was observed. 
    The mortality rates were 0, 10, and 100% respectively.  The rats given
    1000 mg/kg died on days 9-11 of gestation (Seabaugh et al., 1981).

         Sexually mature, timed-pregnant Sprague-Dawley rats, 30 animals
    per group, were intubated on days 6-15 of gestation with TBPP (99.7%
    TBPP, 0.14% 1,2,3-tribromopropane, and 0.17% 2,3-dibromopropanol) in
    undiluted propyleneglycol at levels of 0, 5, 25, or 125 mg/kg body
    weight per day.  Maternal body weight gain was decreased at the
    highest dose level.  No effects of treatment were apparent on the
    number of corpora lutea, implantations, or early or late deaths. 
    Furthermore, the percentage of females with resorptions, the number of
    viable fetuses, the percentage of resorptions, and the percentage of
    pre-implantation losses, did not show compound-related changes.  Fetal
    body weight and crown-rump length were not affected.  Some fetal soft
    tissue and skeletal variations found were not dose-related or
    statistically significant.  It was concluded that TBPP was not
    teratogenic in this study (Seabaugh et al., 1981).

         Female Wistar rats were exposed orally to 25, 50, 100, or 200 mg
    TBPP in olive oil/kg body weight on days 7-15 of gestation.  A
    significant increase in skeletal variation was found in the fetuses at
    200 mg/kg.  A significantly lower viability index was observed in the
    50 and 100 mg/kg groups.  The authors concluded that TBPP did not
    produce teratogenic effects in rats.  A dose of 200 mg/kg elicited
    maternal toxicity (Kawashima et al., 1983).

    7.6  Mutagenicity and related end-points

    7.6.1  DNA damage

    7.6.1.1  In vivo

         When male Wistar rats (250-320 g) were given a single ip
    injection of 350 µmol TBPP/kg (250 mg/kg) body weight and assayed for
    DNA damage 2 h later, single strand breaks/alkali labile sites were
    found in the DNA from nuclei isolated from several organs.  DNA damage
    was detected using an automated alkaline elution system.  Extensive
    DNA damage was detected in the liver, kidneys, and small intestines. 
    In addition, substantial DNA damage was found in the brain and lungs;
    less DNA damage was detected in the testes, spleen, and large
    intestines (Holme et al., 1983; Soderlund et al., 1992).  DNA damage
    was clearly detectable in the kidneys 20 min after a single ip dose of
    36 µmol TBPP/kg (25 mg/kg) body weight (Pearson et al., 1993b).

    7.6.1.2  In vitro

         Monolayer cultures of human (KB) cells were grown with
    [3H]-thymidine for 30 h, and without, for another 17 h.  The cells
    were then exposed to TBPP (2 µl/ml of growth medium devoid of serum)
    for 4.5 h and processed for analysis of the DNA on alkaline-sucrose
    gradients.  They were re-incubated for various intervals to permit DNA
    repair.  TBPP was shown to have induced DNA repair, which indicated a
    specific action on human cellular DNA.  TBPP was found to damage human
    DNA  in vitro and to cause unscheduled DNA synthesis in human cells
    in tissue culture (Gutter & Rosenkranz, 1977; Blum & Ames, 1977).

         A semiquantitative,  in vitro method for measuring unscheduled
    DNA synthesis (UDS) was developed by Lake et al. (1978).  Normal
    foreskin epithelial cells from a cryopreserved skin pool were grown
    from explants and replanted in replicate culture wells.  Cultures were
    then treated for 3 days in an arginine-deficient medium and further
    inhibited in S-phase DNA-synthesis by a 2-h (10 mmol/litre)
    hydroxyurea treatment.  3H-Thymidine and TBPP were added
    simultaneously and the UDS, accumulated over a 24-h incubation period,
    was determined by direct scintillation counting of acid-precipitable
    whole-cell radioactivity.  TBPP did not induce an UDS response in this
    assay, with input dose ranges of 10-99 and 100-400 µg/ml.

         UDS was detected in rat liver hepatocytes, grown as monolayer
    cultures, exposed to 0.01-0.1 mmol TBPP/litre for 18-19 h in the
    presence of [3H]-thymidine and hydroxyurea.  UDS was determined by
    scintillation counting (Holme et al., 1983; Holme & Soderlund, 1984;
    Gordon et al., 1985; Soderlund et al., 1985).

         In  in vitro test systems, DNA damage was detected in isolated
    rat hepatocytes exposed to concentrations as low as 5 µmol TBPP/litre,
    while a 10-fold higher concentration was necessary to induce DNA
    damage in testicular cells (Soderlund et al., 1992).  No DNA damage
    was found in cultured Reuber rat hepatoma cells, without the addition
    of an exogenous metabolism system (Gordon et al., 1985).

    7.6.2  Mutation assay with Salmonella typhimurium strains

         Species differences in the bioactivation of TBPP to metabolites,
    mutagenic to  Salmonella typhimurium TA 100, have been reported. 
    Liver microsomes from mice (NMRI strain) were more effective in
    activating TBPP to mutagenic intermediates than those from
    guinea-pigs, hamsters, and rats.  Phenobarbitalinduced liver
    microsomes from NMRI mice were especially effective (Soderlund et al.,
    1982a).

         TBPP was activated to mutagens in the  Salmonella/microsome
    test.  S9-fractions from rats pretreated with phenobarbital increased
    the mutagenicity of 0.05 mmol TBPP/litre in TA 100 strain  compared
    with liver microsomes from untreated rats (Holme et al., 1983).

         It was demonstrated that the metabolic activation is dependent on
    the presence of NADPH and oxygen, which indicates that TBPP is
    metabolized by cytochrome P450 enzymes to mutagenic products.  In
    studies conducted in an anaerobic atmosphere or in  the presence of
    GSH, the mutagenicity of TBPP was significantly decreased (Soderlund
    et al., 1979, 1984).

         TBPP (97%) in DMSO was tested in concentrations of 0.0110 µlitre
    on  Salmonella typhimurium TA 100, TA 1535, TA 1537, and TA 1538,
    using the plate assay, in the absence, and presence, of a metabolic
    activation system from rat liver.  A mutagenic effect was found with
    TA 100 and TA 1535 with, and without, metabolic activation.  TA 1537
    and TA 1538 gave negative results (Blum & Ames, 1977; Brusick et al.,
    1978; Prival et al., 1977).

         TBPP was tested on  Salmonella typhimurium tester strains
    TA 1535 and TA 1538 in the absence, and presence, of metabolic
    activation derived from Aroclor-induced rat liver.  Dose levels of 0,
    0.1, and 1.0 µlitre/plate were used.  Weak mutagenic activity was
    observed in TA 1535 without activation, but a strong effect was seen
    with microsomal activation.  TA 1538 gave negative results (Carr &
    Rosenkranz, 1978).

         MacGregor et al. (1980) confirmed the mutagenicity of TBPP in the
     Salmonella typhimurium strains TA 100, TA 98, and TA 1535, with dose
    levels ranging from 10 to 1000 µg/plate, with metabolic activation. 
    Without activation, no mutagenicity was found.  A negative result was
    obtained in strain TA 1537 with, and without, activation.

         Nakamura et al. (1979) tested TBPP on  Salmonella typhimurium
    strains TA 100 and TA 1535 with, and without, metabolic activation at
    dose levels of 0.3-100 µmol/plate.  A positive effect was seen in both
    strains, without and with S9 mix.  McCann & Ames (1977) found a
    mutagenic effect in  Salmonella typhimurium TA 100 with dose levels
    up to 100 µg/plate, in the presence of liver S9 fraction of rats
    treated with Aroclor.

         TBPP at dose levels of 0, 112, 224, 2240, 4480, and
    11 200 µg/plate was tested on  Salmonella typhimurium strain TA100
    with, and without, metabolic activation by Aroclor 1254-induced rat
    liver S9 fraction.  With the S9 fraction, all dose levels showed a
    mutagenic effect.  Without the S9 fraction, TBPP showed direct-acting
    properties only at dose levels of 2240 µg/plate or more (Salamone &
    Katz, 1981).

         In an interlaboratory study, TBPP and 62 other chemicals were 
    tested for mutagenic activity.  TBPP was tested on the  Salmonella
     typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538, and on
     Escherichia coli WP2uvrA.  The dose levels were between 0.3 and
    10 000 µg/plate.  TBPP was tested without metabolic activation and
    with liver S9 fractions from uninduced and Aroclor 1254-induced F344
    rats, B6C3F1 mice, and Syrian hamsters.  TBPP tested positive in all
    four laboratories involved in this study (Dunkel et al., 1985).

         Results obtained by Prival et al. (1977) indicated that TBPP
    induces mutations of the base-pair substitution type in  Salmonella
     typhimurium TA100.  Although, at higher concentrations
    (> 1 µl/plate), TBPP behaves as a direct acting mutagen not requiring
    metabolic activation, at a much lower concentration (0.01 µl/plate) it
    demonstrates significant genetic activity only with metabolic
    activation.

         Brusick and coworkers demonstrated that amounts of 50 µg/plate or
    more were clearly mutagenic for  Salmonella typhimurium TA 100
    (Brusick et al., 1980).  When tested for bacterial mutagenicity in
     Salmonella typhimurium TA 100, a 4-fold interindividual variation in
    the capability to activate TBPP was noted with human liver microsomes
    prepared from 5 liver donors (Soderlund et al., 1982a).

         The CASE structure-activity method was applied to a Gene-Tox
    derived  Salmonella mutagenicity data base.  Strains TA 97, TA 98, TA
    100, TA 1535, TA 1537, and TA 1538 with, or without, exogenous
    metabolic activation, were used.  TBPP was found to be positive
    (Klopman et al., 1990).

    7.6.3  Mutations by urine of rats treated with TBPP

         The urine was collected of rats exposed to TBPP directly by
    either the oral or dermal route, or from treated fabric.   Salmonella
     typhimurium TA 1535 was used as indicator organism.  TBPP was
    dermally applied at doses of 5, 50, 500, or 5000 mg/kg body weight or
    given orally at 5, 50, or 500 mg/kg body weight.  In the oral study,
    only 500 mg/kg produced a positive response.  In the dermal studies, a
    dose of 500 mg/kg produced a weak positive response, while 5000 mg/kg
    produced a definitive positive response.  When fabrics with surface
    TBPP levels of 3000, 28 000, and 67 000 mg/kg product were applied
    dermally, no mutagenic responses were detected in the urine of the
    rats over the 5-day period (data were lacking on whether or not
    metabolic activation was used) (Brusick et al., 1978; Ulsamer et al.,
    1980).

         TBPP at 500 mg/kg body weight in corn oil was applied dermally to
    CD-1 mice.  Urine was collected over approximately 16 h and the
    bacterial mutagenicity of 0.3 ml urine samples was assayed in
     Salmonella typhimurium TA1535, TA1537, and TA100.  A positive
    response was found only with TA100 (Brusick et al., 1982).

    7.6.4  Other mutation assays

         TBPP was tested in the forward mutation assay with mouse-lymphoma
    cells (L5178YTK locus).  While the results at lower doses were
    inconclusive, a 2 to 3-fold increase in mutations was consistently
    produced at 5 mg/litre (Brusick et al., 1978; Ulsamer et al., 1980).

         TBPP has been reported to induce increased mutation frequencies
    (6-TG resistance) in V79 Chinese hamster cells incubated with
    0.02 mmol TBPP/litre in the presence of liver microsomes of rats
    pretreated with phenobarbital as an exogenous metabolism system (Holme
    et al., 1983; Soderlund et al., 1985).   However, in a similar study,
    concentrations of TBPP up to 150 µg/ml did not increase the frequency
    of 6-TG resistance, both with, and without, an exogenous metabolism
    system (Sala et al., 1982).

    7.6.5  Chromosomal effects

         Using Chinese hamster V79 cells, TBPP severely inhibited the
    colony-forming activity and significantly increased sisterchromatid
    exchanges, but no significant increase in chromosome aberrations was
    found (Furukawa et al., 1978).  Interestingly, chromosomal aberrations
    were not significantly increased in Chinese hamster cells, in mouse
    bone-marrow cells, or in cultured human lymphoid cells.  The lack of a
    TBPP effect on rat bone-marrow chromosomes was also observed after
    rats received 25, 250, or 2500 mg TBPP/kg body weight, by gavage,
    after either a single dose, or, 5 daily doses/week for 13 weeks
    (Osterberg, 1977; Nakanishi & Schneider, 1979).

         TBPP was tested for the induction of chromosome aberrations, and
    sister chromatid exchanges in the diploid human fibroblastic cell line
    HE 2144 (from a 10-week-old male embryo) without metabolic activation
    (Sasaki et al., 1980).  The dose levels used were 0.349, 0.070, and
    0.035 mg/ml.  Sister chromatid exchanges were induced with 0.070 mg
    TBPP/ml in the human HE 2144 cell line.  No chromosomal aberrations
    were found.

         In a comparative study, Brusick and coworkers found that TBPP
    gave a positive response in tests for sister chromatid exchanges and
    chromosomal aberrations in the mouse lymphoma L5178Y cell line at
    concentrations of 0.005 and 0.01 µlitre/ml, respectively (Brusick et
    al., 1980).

         TBPP was tested in an  in-vitro test for sister chromatid
    exchanges in Chinese hamster V79 cells with, and without, S9 fraction
    of livers of Wistar rats administered (ip) methylcholanthrene. 
    Acetone was used as solvent.  The dose levels 17.2, 35, 100, and
    200 µg/ml were tested only without S9 fraction, while levels of 24.5
    and 50 µg/ml were tested with, and without, metabolic activation.  A
    significant increase in sister chromatid exchanges was found at dose
    levels of more than 35 µg/ml (Sala et al., 1982).

         Two male and two female Chinese hamsters per group were used in a
    micronucleus test.  The dose levels were 200, 400, and 800 mg TBPP/kg
    body weight administered by ip injection.  The solvent was DMSO. 
    Bone-marrow samples were obtained after 24 h.  Two thousand
    polychromatic erythrocytes/animal were analyzed for the presence of
    micronuclei.  Levels of 400 and 800 mg/kg body weight showed a
    positive effect (Sala et al., 1982).

         Salamone & Katz (1981) studied the clastogenic effect of TBPP in
    a bone marrow micronucleus test.  B6C3F1 mice (15 weeks old) were
    given two ip treatments of TBPP in corn oil.  Dose levels of 0, 204,
    408, 612, 816, 1020, 1275, and 1530 mg/kg body weight were tested.  In
    this test, TBPP showed a weak clastogenic effect.

         An  in vitro chromosome aberration test was carried out with
    TBPP, using a Chinese hamster CHL cell line of lung fibroblast origin. 
    CHL cells cultured in plates were exposed to different dose levels of
    TBPP including the 50% growth inhibition dose.  The number of
    polyploid cells and cells with structural aberrations, such as
    chromatid-type gaps, breaks, exchanges, and rings, were scored.  A
    microsome fraction (S9-mix) from the liver of Wistar rats, pretreated
    with the PCB; KC-400, was used.  TBPP was positive in this test.  A
    dose level of 0.25 mg/ml showed chromosomal aberrations in 20% of the
    metaphases (Ishidate et al., 1981).

         Vogel & Nivard (1993) studied the effects of TBPP in the
    (white/white+) (w/w+) eye mosaic assay, and an  in vivo, short-term
    test measuring genetic damage in the somatic cells of  Drosophila
     melanogaster, after treatment of the larvae.  The genetic principle
    of this system is the loss of heterozygosity for the wild-type
    reporter gene w+, an event predominantly resulting from homologous,
    interchromosomal, mitotic recombination between the two X-chromosomes
    of female genotypes.  The w/w+ eye mosaic test detects a broad
    spectrum of DNA modifications. Between 12 and 15 pairs of flies were
    permitted to lay eggs for three days on food supplemented with 0.25,
    0.5, or 1.0 mmol TBPP/litre (dissolved in 3% ethanol).  TBPP gave a
    strong positive response in the w/w+ bioassay.

    7.6.6  Cell transformation

         TBPP was tested for its ability to induce malignant
    transformation  in vitro using mouse BALB/3T3 cells.  The results of
    this test showed that TBPP can transform mammalian cells  in vitro,
    perhaps indicating a potential for the induction of carcinogenic
    responses (Brusick et al., 1978; Ulsamer et al., 1980).

         C3H/10T1/2 cells were treated with TBPP, with or without S9 mix
    from the liver of Wistar rats administered methylchloanthrene
    intraperitoneally.  Some cell samples were additionally treated
    several times with tetradecanoyl phorbolacetate (TPA) (0.1 µg/ml). 
    The TBPP concentrations tested were 40 µg/ml (with and without  S9
    fraction) and 80 µg/ml (without S9 fraction).  A very low frequency of
    transformed type 3 foci was obtained and the authors considered the
    results of this study to be  negative (Sala et al., 1982).  Dunkel et
    al. (1988) also found a negative result for TBPP in the C3H/10T1/2
    cell transformation assay.  The dose levels tested were between 0.16
    and 20 µg/ml.

    7.6.7  Miscellaneous tests

         TBPP induced a significant increase in sex-linked recessive
    lethal mutations in male germ-cell stages of  Drosophila melanogaster
    at a dose of 1000 mg/kg.  The spermatids were the most sensitive
    (Valencia, 1978).

         Adult Canto-S male  Drosophila flies aged 7 days were fed for
    48 h on a 1% solution of glucose containing 1000 or 10 000 mg
    TBPP/litre.  The TBPP-exposed males were mated immediately after
    treatment to brown ebony virgin females.  The results showed that TBPP
    caused reciprocal translocations in  Drosophila.  There was no
    difference between the translocation recoveries at the two dose levels
    (Berkowitz, 1978).

    7.6.8  Mechanisms of TBPP genotoxicity

         Following the initial mutagenicity reports, several studies have
    been directed towards the elucidation of the mechanisms involved in
    TBPP-induced genotoxicity.  Such studies include investigations into
    the enzyme systems involved in the bioactivation of TBPP to genotoxic
    metabolites, delineating structural requirements for genotoxicity, and
    the characterization and identification of the genotoxicity of
    possible TBPP metabolites.  Some of these investigations have recently
    been reviewed (Dybing et al., 1989).

         The bacterial mutagenicity of TBPP is mediated by the microsomal
    monooxygenase system.  Several studies have shown that TBPP is
    activated to metabolites, mutagenic to  Salmonella typhimurium TA100,
    by cytochrome P450 in a reaction depending on NADPH and oxygen
    (Soderlund et al., 1979; Dybing et al., 1989).  The mutagenicity of
    TBPP was increased in the presence of microsomes prepared from livers
    of rodents pretreated with phenobarbital or PCBs, but not from those
    pretreated with 3-methylcholanthrene or beta-naphthoflavone (Soderlund
    et al., 1979; 1982a).

         The metabolism of TBPP by soluble enzymes (e.g., glutathione
     S-transferase) appears to be of minor importance in the
    bioactivation of TBPP to mutagenic species.  The available data
    indicate that reductive metabolism and episulfonium ion formation are
    not major activation pathways in TBPP-induced mutagenicity (Dybing et
    al., 1989).  However, it has recently been suggested that human
    glutathione transferases may further metabolize P-450-generated TBPP
    intermediates to more potent mutagenic species (Simula et al., 1993). 
    Interestingly, singlet oxygen, obtained from the illumination of
    riboflavin, may also activate TBPP to mutagenic metabolites (McCoy et
    al., 1980).

         Studies investigating the bacterial mutagenicity of known and
    postulated metabolites of TBPP have given little information regarding
    the mechanisms of its bioactivation.  With the exception of
    2-bromoacrolein (BA) and DBP, other postulated or identified TBPP
    metabolites were less mutagenic than TBPP when tested with, or
    without, an exogenous metabolism system (Prival et al., 1977;
    Soderlund et al., 1979; Zeiger et al., 1982; Holme et al., 1983;
    Gordon et al., 1985).  Such metabolites include the two major TBPP
    metabolites 2,3-dibromopropanol (DBP) and bis(2,3-dibromopropyl)
    phosphate (BBPP) as well as mono(2,3-dibromopropyl) phosphate (mono-
    BP) (McCann & Ames, 1977; Prival et al., 1977; Soderlund et al.,
    1982b; Holme et al., 1983).  These metabolites were also less
    mutagenic than TBPP in V79 Chinese hamster lung cells with microsomal
    activation (Holme et al., 1983).

         Eight coded samples of different lots of TBPP from different
    manufacturers were tested in TA 1535.  All were positive (Prival,
    1975).

         Several commercial TBPP samples and a few known contaminants
    (1,2,3-tribromopropane, DBP, and 1,2-dibromo-3-chloropropane) were
    tested in amounts of 0.01 up to 10 µl/plate on Salmonella strains TA
    100, TA 1535, and TA 1538 with, and without, Aroclor 1254-activated,
    or non-activated, rat liver S9 fractions.  The results indicated that
    the highest levels of mutagenicity obtained with commercial TBPP were
    probably not due to the presence of the contaminants (Prival et al.,
    1977).

         The bacterial mutagenicity of compounds structurally related to
    TBPP, including monobrominated and chlorinated analogues, unsaturated
    and saturated methyl esters, and halogenated propanols, indicate the
    following structural effects on mutagenic activity: (a) a decrease in
    the number of alkyl chains decreases mutagenicity; (b) a decrease in
    the number of halogens in the alkyl chain decreases mutagenicity; (c)
    compounds with vicinal halogens are more mutagenic than 1,3-dihalo-
    isopropyl analogues; (d) brominated compounds are more mutagenic than
    the corresponding chlorinated ones; and (e) salts of mono- and
    diphosphate esters are more mutagenic than the free base (Carr &
    Rosenkranz, 1978; Nakamura et al., 1979, 1983; Zeiger et al., 1982;
    Holme et al., 1983).

         Mutagenicity testing of TBPP metabolites has yielded little
    information on the mechanisms of activation of TBPP to mutagenic
    metabolites, since none of the metabolites were more mutagenic than
    the parent compound.  The first evidence for the possible formation of
    a potent bacterial mutagen from TBPP came when 2-bromoacrylic acid was
    found in the urine of rats, administered large doses of TBPP (Marsden
    & Casida, 1982).  These authors proposed that TBPP is initially
    oxidized at the C-1 position to yield 2,3-dibromopropanal, which
    then spontaneously dehydrobrominates to give BA.  BA and 2,3-
    dibromopropanal, which are potent, direct-acting, bacterial mutagens
    in  Salmonella typhimurium TA100, caused DNA damage in Reuber rat
    hepatoma cells, and transformation of Syrian hamster embryo cells
    (Rosen et al., 1980; Gordon et al., 1985).

         In 1984, BA was detected in incubations of TBPP with rat liver
    microsomes, using GC/MS.  In these experiments, substitution of
    deuterium atoms for hydrogen at the C-3 position decreased the
    mutagenicity of TBPP by approximately 80%, whereas only a small
    deuterium isotope effect was noted at C-2 and C-1.  These data
    indicate that an initial oxidation at the terminal carbon atom is the
    key step in the formation of mutagenic metabolites from TBPP (Nelson
    et al., 1984; Soderlund et al., 1984).  Subsequent experiments with
    variously deuterated TBPP analogues revealed that, according to the
    number of deuteriums retained in the BA formed, oxidation at C-3 is
    the major pathway for BA formation (Nelson et al., 1984).  The results
    of the studies with deuterated TBPP analogues were later substantiated
    with selectively methylated analogues.  These findings demonstrated
    that the initial oxidation of TBPP at C-3 was followed by spontaneous

    dehydrohalogenation and dehydrophosphorylation, with the subsequent
    formation of BA and BBPP (Omichinski et al., 1987).

         Although BA is the most potent TBPP metabolite with regard to
    bacterial mutagenicity  in vitro, additional TBPP metabolites appear
    to be involved in TBPP-induced DNA damage in mammalian cells.  The
    formation of these metabolites has not yet been elucidated, but is
    likely to involve conjugation with glutathione (Soderlund et al.,
    1992).

         All the known metabolites, including the two major metabolites,
    DBP and BBPP, are considerably less mutagenic than the parent
    compound, when tested directly or in the presence of an activation
    system (Blum et al., 1978; Soderlund et al., 1979, 1982b; Zeiger et
    al., 1982).  However, BA is a more potent mutagen than TBPP (Rosen et
    al., 1980; Nelson et al., 1984; Gordon et al., 1985).

    7.7  Carcinogenicity

    7.7.1  Oral

    7.7.1.1  Mouse

         Groups of 50 male, and 50 female, B6C3F1 hybrid mice, 6 weeks
    old, were fed technical TBPP (containing no detectable 1,2-dibromo-3-
    chloropropane) at concentrations of 500 or 1000 mg/kg diet in the diet
    for 103 weeks followed by a 1-week observation period.  The
    experimental design of the study is shown in Table 1.  Of the males,
    44/55 matched controls, 38/50 low-dose mice and 43/50 high-dose mice
    survived until the end of the study; of the females 44/55 controls,
    37/50 low-dose mice, and 38/50 high-dose mice survived.  TBPP
    increased the incidence of squamous-cell carcinomas and papillomas of
    the fore-stomach and of adenomas and carcinomas of the lungs in both
    male and female treated animals compared with the controls.  There was
    also an increased incidence of renal tubular cell adenomas and
    adenocarcinomas in treated male mice and liver cell adenomas and
    carcinomas in treated female mice.  Neoplastic lesions associated with
    the administration of TBPP are summarized in Table 1.  The incidence
    of "preneoplastic" kidney changes, dysplasia, and hyperplasia, were:
    controls (males and females) 0/109, low-dose females 20/50, low-dose
    males 46/50, high-dose females 40/46 and high-dose males 49/50 (US
    NCI, 1978; Reznik et al., 1979; IARC, 1979).

    7.7.1.2  Rat

         Groups of 55 male, and 55 female Fischer 344 rats, 6 weeks old,
    were fed diets containing concentrations of 50 or 100 mg technical
    TBPP/kg for 103 weeks, followed by a 1- or 2-week observation period. 
    The experimental design of the study is shown in Table 1.  Of the
    males 39/55 control, 35/55 low-dose, and 40/55 high-dose rats survived
    until the end of the study; of the females 36/55 control, 44/55
    low-dose, and 36/55 high-dose rats survived.  The compound increased
    the incidences of both renal tubular cell adenomas in rats of both
    sexes and tubular cell  adenocarcinomas in high-dose males. 
    Neoplastic lesions associated with the administration of TBPP are
    summarized in Table 1. The incidence of "preneoplastic" kidney
    changes, dysplasia, and hyperplasia, were; controls (males and
    females) 0/105, low-dose females 25/54, low-dose males 53/54,
    high-dose females 46/54, and high-dose males 39/54 (US NCI, 1978;
    IARC, 1979; Reznik et al., 1979).

    
    Table 1.  Tumour incidences in mice and rats fed tris(2,3-dibromopropyl) phosphate (TBPP)

                                                                                                                                     
    Species   Sex       Number       Concentration   Duration    Number of tumour-bearing animals/number of animals examined
                        of animals   (mg/kg          (weeks)                                                                         
                        treated      diet)                       Forestomach**     Lung**         Kidneys*          Liver**
                                                                 (squamous-cell    (adenomas or   (tubular-cell     (adenomas or
                                                                 carcinomas or     carcinomas)    adenomas or       carcinomas)
                                                                 papillomas)                      adenocarcinomas)
                                                                                                                                     
    Mouse     male      55           0               105         0/51              12/54          0/54              28/54
              male      50           500             103         10/47a            18/44c         6/50              31/49
              mate      50           1000            103         13/48b            25/50d         17/49e            23/49

              female    55           0               105         2/53              4/55           0/55              11/54
              female    50           500             103         14/48b            9/50           3/50              23/50f
              female    50           1000            103         22/44b            17/50d         3/46              35/49f

    Rat       male      55           0               107         -                 0/54           0/53              0/54
              male      55           50              103         -                 3/55           30/54e            1/55
              male      55           100             103         -                 0/55           30/54a            4/54

              female    55           0               107         -                 -              0/52              -
              female    55           50              103         -                 -              4/54              -
              female    55           100             103         -                 -              13/54a            -
                                                                                                                                     

    From:   * Reznik et al. (1979);      ** US-NCI (1978).
    Fisher analysis of treated group versus control:
    a Squamous-cell papillomas;  P < 0.01; b Squamous-cell carcinomas and papillomas;  P < 0.01; c Alveolar/bronchiolar
    adenomas and carcinomas;  P < 0.05; d Alveolar/bronchiolar adenomas and carcinomas:  P < 0.01: e Tubular-cell adenomas
    and adenocarcinomas:  P < 0.01; f Hepatocellular adenomas and carcinomas;  P < 0.01.
    
         Male F344 rats, 4 weeks old, were administered (by gavage) 0
    (untreated), and 0 (vegetable oil), or 100 mg TBPP in vegetable oil/kg
    body weight per day.  Treatment was given for 5 days per week and
    continued for 4 or 52 weeks.  Selected rats of the treated and control
    groups were killed at various time intervals.  Control and treated
    animals (2-9 animals) were killed after 1, 5, 10, 20, 50, 75, and 260
    treatments.  After 4 weeks (20 treatments), the TBPP group was divided
    into two subgroups; TBPP administration was continued in one subgroup
    of 15 rats and, in the second subgroup, 15 other rats (treated for
    four weeks) received only vegetable oil for the remainder of the
    study.  The histomorphology and ultrastructure of the kidneys were
    studied. Twenty-four hours after the first TBPP treatment, the
    epithelial cells at the corticomedullary junction developed increased
    nucleus/cytoplasm ratios, cytomegaly, and nuclear vacuolization and
    pleomorphism.  These changes increased in severity to a toxic tubular
    nephrosis as treatment continued, and extended to the peripheral
    cortex by 52 weeks.  After 52 weeks of TBPP treatment, small tubular
    papillary hyperplasia had developed in three animals and an
    adenocarcinoma was observed in one of the five animals killed at the
    end of the study.  Electron microscopy showed loss of microvilli and
    polarity in the epithelium of the proximal convoluted tubules.  At the
    ultrastructural level, the cytoplasm of the neoplastic cells was
    poorly differentiated and, in many areas, the surfaces of the cells
    were covered by microvilli.  In the animals in which treatment was
    discontinued after 4 weeks, a gradual, but incomplete, restoration of
    the tubular epithelia to nearly normal morphology was observed. 
    Nuclear changes persisted after cytoplasmic abnormalities had
    disappeared.  At 52 weeks, three out of five surviving rats,
    administered TBPP throughout the study, were found to have polyploid
    adenomas of the descending colon (Reznik et al., 1981).

         Cunningham et al. (1992, 1993) examined the mechanisms whereby
    chemicals produce mutagenicity in short-term  in vitro assays, yet
    fail to produce carcinogenicity in long-term rodent bioassays. 
    Previous studies indicated that mutagenic carcinogens increased the
    amount of cell turnover in the target organ, but that mutagenic
    noncarcinogens failed to do so.  An association of cell-proliferation,
    as determined by labelling with bromodeoxyuridine, and tumour
    development was investigated in groups of five male Fischer 344 rats
    (150 g).  Administration of TBPP in the diet at dose levels of 0, 50,
    or 100 mg/kg, for 14 days, resulted in increased incidences of cell
    proliferation in the kidneys.  A further association of cell
    proliferation with tumour development in the kidneys was suggested by
    their similar location in the kidneys, i.e., the renal outer medulla.

    7.7.2  Dermal

    7.7.2.1  Mouse

         Female ICR/Ha Swiss mice (29 or 30 per group) (6-8 weeks old)
    were treated with 10 or 30 mg TBPP (97%) in 0.2 ml acetone, 3 times
    weekly, on the shaved skin, for 496 and 474 days, respectively.  Two
    control groups were used; 30 mice received the acetone and 249 mice
    were untreated.  Besides a significant increase in skin tumours
    (papillomas and/or carcinomas), a substantial number of tumours were
    also found at distant sites, such as squamous cell carcinomas of the
    tongue and in the gingival area; papillomas and carcinomas were
    observed in the forestomach (Table 2) (Van Duuren et al., 1978).

         TBPP was tested in an  in vivo, short-term skin test for
    sebaceous gland suppression and the induction of epidermal
    hyperplasia.  Groups of 25 Swiss mice (aged 45 days) received dorsal
    applications of TBPP in acetone on days 1, 3, and 5.  The dose levels
    applied on the skin were 49.5, 82.5, and 115.5 mg (total dose applied
    in three applications in acetone).  TBPP did not suppress the
    sebaceous gland and did not induce hyperplasia (Sala et al., 1982).

         Groups of 28-34 female (60 days old) Swiss mice were given a
    single application of dimethylbenzanthracene (DMBA) (50 µg) or TBPP
    (110 µg) in acetone, on the dorsal skin.  In the tumour promotion
    studies, the mice received, for 78 weeks, twice weekly applications to
    the same area of the dorsal skin of an acetone solution of
    tetradecanoyl phorbolacetate (TPA) (1 µg) or TBPP (33 mg), started one
    week after the initiation with DMBA or TBPP.  In order to test TBPP
    for its ability to act as a complete carcinogen, a second series of
    mice received the same twice weekly applications as the promoted mice,
    but without any initiation treatment.  The total TPA dose applied, was
    156 µg/mouse and that of TBPP, 5.1 g/mouse.  TBPP did not have any
    effect as a complete carcinogen on the skin, with a total dose of
    5.1 g/mouse.  The same dose did not have a promoting activity after
    DMBA initiation.  However, TBPP initiated a significant number of skin
    tumours, when TPA was used as promoter.  Furthermore, the number of
    lung adenomas increased significantly (Table 3) (Sala et al., 1982).


        Table 2.  Tumour incidences in female Swiss mice after dermal application of
              tris(2,3-dibromopropyl) phosphate (TBPP)a

                                                                                      

    Number of    Dose            Number of mice with tumours/number necropsiedb
    animals      (mg/animal)                                                       
    treated                      Forestomach     Lung       Skin      Oral cavity
                                                                                      

    29           0               1/29            7/29       0/29      0/29
    29           10              10/29           26/29      2/29      2/29
    30           30              20/30           28/30      5/30      4/30
                                                                                      

    a   From: Van Duuren et al. (1978).

    b   Increases in incidences of tumours of the forestomach, lung, skin, and oral
        cavity in treated animals were statistically significant compared with those
        in controls ( P < 0.05).

    7.8  Special studies

    7.8.1  Kidneys

         Osterberg et al. (1978) found an increased incidence and severity
    of chronic nephritis in a 90-day gavage study on rats, administered
    TBPP at dose levels of 25, 100, or 250 mg/kg body weight in
    propyleneglycol.  The renal changes were associated with regenerative
    epithelium, hypertrophy, and dysplasia of renal tubular epithelial
    cells and were found at all three dose levels (section 7.2.1.1).

         TBPP caused proximal tubular damage and acute renal failure in
    rats, with elevation of serum creatinine and urea, and depression of
    organic anion and cation transport (Soderlund et al., 1980; Elliott et
    al., 1982; Lynn et al., 1982).  It has been demonstrated that TBPP
    caused urinary excretion of renal cytoplasmic enzymes associated with
    the initial damage (characterized by increased membrane permeability),
    followed by the excretion of cell organelle-linked enzymes with
    necrosis of the renal tubular epithelium (Nomiyama et al., 1974;
    Emanuelli et al., 1979; Fukuoka et al., 1987, 1988a,b).  TBPP also
    produced impairment of the tubular reabsorption capacity for metabolic
    fuels such as, lactate, glucose, and citrate, maintained across the
    brush border membrane by the sodium co-transport system (Kurokawa et
    al., 1985; Pitts, 1987).

         Male Wistar rats (56 rats in test group and 15 as controls; 7
    weeks of age) were given a single oral dose in olive oil of 286.8 µmol
    TBPP (98%)/kg, to study TBPP nephrotoxicity.  TBPP caused tubular
    necrosis.  The animals received a single dose and some were killed
    daily for 10 days.  The following effects were observed: on day 1,
    pyknosis of the renal tubular epithelial cells, necrosis on day 2,
    regeneration from day 3 and large nuclei formation from day 4. 
    13C-NMR spectra were applied to clarify changes of the renal
    low-molecular weight components in the kidneys injured by TBPP; sialic
    acid and inositol were found to be the desired marker components.  The
    lesions produced by TBPP were characterized by changes in the renal
    components and enzyme activities.  Increases in the sialic acid
    content of the kidneys were observed on day 1, suggesting destruction
    of the epithelial cell membrane.  On day 5, regeneration accompanied
    by an increase in inositol contents was found.  Renal activity of the
    cytoplasmic enzyme, alanine aminopeptidase, was increased on days 2,
    5, 6, and 7 (Fukuoka et al., 1988a).

         There are large species differences in TBPP nephrotoxicity, since
    neither hamsters, guinea-pigs, nor mice developed acute kidney damage
    at doses of 500-1000 mg/kg body weight (Soderlund et al., 1982a).

        Table 3.  Development of tumours in female Swiss mice in initiation-promotion studies carried out with TBPPa

                                                                                                                           
                      Treatment                                                       Number of mice with tumours

    Group    Initiation    Promotion or          Number        Skin          Lung         Number      Other tumours
                           repeated treatment    of mice       tumours       adenomas                 Type
                                                                                                                           

    1        -             TBPPb                 33            0             14           3           2: lymphosarcoma,
                                                                                                      hepatoma

    2        TBPP          TPAc                  34            26d           7            0

    3        DMBA          TBPPa                 33            3             11           2           mammary tumour,
                                                                                                      perianal carcinoma

    7        -             TPAc                  28            12            5            0
                                                                                                                           

    a   From: Sala et al. (1982).
    b   TBPP: Total dose, 5.1 g/animal (170 g/kg body weight).
    c   TPA: Total dose, 156 µg/animal.
    d   Two squamous cell carcinomas in each group.
    
         BBPP was clearly more nephrotoxic for Wistar and Sprague-Dawley
    rats than TBPP, whereas mono(2,3-dibrompropyl) phosphate (mono-BPP)
    was less nephrotoxic (Elliott et al., 1982; Soderlund et al., 1982b). 
    However, female Sprague-Dawley rats appeared to be resistant to BBPP
    nephrotoxicity (Elliott et al., 1982), paralleling the carcinogenicity
    of TBPP in female animals.

         The nephrotoxicity of TBPP has been compared to that of BBPP,
    using equimolar doses.  Both chemicals caused reversible acute renal
    failure, accompanied by tubular necrosis.  Polyuria, high urinary
    glucose, lactate, and enzyme levels, and increased serum creatinine
    levels were observed.  It was suggested, therefore, that BBPP or a
    metabolite of this compound, mediated the nephrotoxicity associated
    with TBPP (Takada et al., 1991a).

         The finding that BBPP was a major urinary metabolite of TBPP and
    that this compound was at least as nephrotoxic as TBPP, indicates that
    it is a proximate nephrotoxic metabolite of TBPP (Lynn et al., 1980;
    Soderlund et al., 1982b).

         Generally, attempts to modulate TBPP nephrotoxicity by various
    pretreatments have not been very successful. Pretreatment of Wistar
    rats with the cytochrome P-450 inducers, phenobarbital and
    polychlorinated biphenyls, known to increase the metabolism of TBPP,
    had no effect on its nephrotoxicity.  However, pretreatment with
    cobaltous chloride resulted in a moderate reduction in TBPP
    nephrotoxicity.  Interestingly, depletion of glutathione  in vivo
    with diethyl maleate did not alter TBPP nephrotoxicity (Soderlund et
    al., 1980).

         The indication that the oxidative metabolism of TBPP or BBPP
    plays only a minor role in its nephrotoxicity, is confirmed by the
    findings that none of the selectively deuterated analogues (see below)
    significantly altered morphological evidence of nephrotoxicity
    compared with the protio compounds.  It appears that C-H bond cleavage
    was not the rate-limiting step in the overall process leading to
    nephrotoxicity (Soderlund et al., 1988).  However, recent studies have
    revealed that deuterium substitution at C-2 and C-3 of TBPP results in
    a considerable decrease in the plasma levels of BBPP at earlier time
    points compared with those after protio TBPP.  The time-integrated
    plasma concentrations of the resulting deuterated BBPP analogues at
    later time points are not significantly different from that of BBPP,
    indicating that the target organ exposures to BBPP and deuterated BBPP
    analogues are similar (Pearson et al., 1993b).  This may explain the
    lack of deuterium isotope effect on nephrotoxicity.  Thus, a role of
    oxidative metabolism cannot be completely ruled out.

         Activation of nephrotoxic alkyl halides with glutathione by the
    beta-lyase pathway is documented.  However, known inhibitors of the
    beta-lyase pathway (e.g., AT-125 and aminooxyacetic acid) did not
    affect the extent of nephrotoxicity in rats caused by a single ip dose
    of TBPP (Soderlund et al., 1988).

         Because of its acidic nature, BBPP may be the species transported
    into the renal tubular cells.  Probenecid, an inhibitor of the organic
    anion transport system in the kidneys, reduces the nephrotoxicity of
    BBPP (Soderlund et al., 1988).  The nature of the toxic metabolites
    formed from BBPP has not been identified.  One possible candidate is
    an episulfonium ion generated by the conjugation of BBPP with
    glutathione.

         At present, the mechanisms involved in TBPP organ toxicity are
    not known with certainty.  DNA damage, as measured by alkaline
    elution, was detected after 20 min in the kidneys of Wistar rats given
    a single ip dose of 25 mg/kg body weight.  Thus, DNA appears to be an
    early target in TBPP nephrotoxicity, leading to cell death (Pearson et
    al., 1993b).

    7.9  Factors modifying toxicity; toxicity of metabolites

    7.9.1  Toxicity of metabolites

         2,3-Dibromo-1-propanol (DBP), a metabolite of TBPP, was tested in
    2-year dermal carcinogenicity studies on F344/N rats and B6C3F1
    mice.  The doses used were 0, 188, or 375 mg/kg body weight in rats
    and 0, 88, or 177 mg/kg body weight in mice.  Under the conditions of
    these studies, there was clear evidence of carcinogenic activity in
    both sexes of both species in a variety of organs (US NTP, 1992).  In
    male rats, there was an increased incidence of neoplasms of the skin,
    nose, oral mucosa, oesophagus, forestomach, small and large intestine,
    Zymbal's gland, liver,  kidney, tunica vaginalis, and spleen.  In
    female rats, there was an increased incidence of neoplasms of the
    skin, nose, oral mucosa, oesophagus, forestomach, small and large
    intestine, Zymbal's gland, liver, kidney, clitoral gland, and mammary
    gland.  In male mice, there was an increased incidence of neoplasms of
    the skin, forestomach, liver, and lung.  In female mice, there was an
    increased incidence of neoplasms of the skin and forestomach.

         BBPP, DBP, as well as TBPP, are acute nephrotoxins, BBPP  being
    the most potent (Lynn et al., 1982).  In three groups of rats, the
    24-h urine volume was measured after ip injection of equimolar amounts
    (in 1 ml Emulphor) of TBPP (50 mg), BBPP (36 mg), or DBP (39 mg).  The
    single dose of TBPP caused a 5-fold increase in urine volume after two
    days.  After one week, urine volume had returned to normal.  In
    contrast, the single dose of BBPP resulted in a 7 to 8-fold increase
    in urine volume from days 2-5.  Urine volume had not returned to
    normal after 10 days.  The single dose of DBP produced a 2 to 3-fold
    increase in urine volume, which rapidly returned to normal.

         In another study, rats received a single ip injection of TBPP,
    BBPP, or mono-BPP (in dimethyl-sulfoxide, 0.25 ml per 100 g) of 0, 10,
    25, 50, 100, or 200 mg/kg body weight; the animals were killed 48 h
    later (except the high dose group which was killed 40 h later).  A
    significant increase in kidney/body weight ratio occurred with all
    three compounds at the 200 mg/kg dose.  Enlarged kidneys were pale,

    oedematous, and showed a prominent necrotic band in the inner part of
    the cortex.  Histologically, tubular kidney necrosis was demonstrated
    in rats receiving 100 mg TBPP or mono-BP/kg or more and, in animals
    receiving 50 mg BBPP/kg or more.  Plasma creatinine was significantly
    elevated at doses from 10 mg BBPP/kg, 25 mg mono-BP/kg, and 50 mg
    TBPP/kg upwards.  Plasma urea was significantly elevated after doses
    of 100 mg mono-BP/kg or more and 200 mg BBPP/kg.  Plasma GDT was also
    significantly increased at the highest doses of BBPP and mono-BP
    (Soderlund et al., 1982b).

         Comparable results were reported by Fukuoka et al. (1988b).
    Rats received a single oral dose of 0, 71.7, 143.4, or 286.8 µmol
    BBPP/kg and were evaluated for seven days after the dose.  In
    addition to polyuria, changes in the excretion of lactate, uric acid,
    and glucose, and changes in the activities of urinary enzymes
    (alkaline phosphatase, aspartate aminotransferase, and gamma-
    glutamyltransferase) at various times after dosing, histopatho-logical
    changes occurred in the kidney.  The histopathological changes
    included pyknosis, necrosis, and desquamation.

    7.9.2  Mutagenicity of metabolites

         The following TBPP metabolites have been identified in  in vivo
    and  in vitro test systems: BBPP, mono(2,3-dibromopropyl) phosphate
    (mono-BPP), 2-bromoacrolein (BA), 2,3-dibromo-1propanol (DBP),
    2,3-dibromopropyl-2-bromopropen-2-yl, bis(2-bromopropen-2-yl)
    phosphate and 3,3-dibromopropyl phosphate (Lynn et al., 1980, 1982;
    Zeiger et al., 1982; Nelson et al., 1984). Several of these TBPP
    metabolites have been tested for their mutagenic potential.

         All the identified TBPP metabolites were mutagenic in  Salmonella
     typhimurium TA 100 (Prival et al., 1977; Zeiger et al., 1982; Holme
    et al 1983; Nakamura et al., 1983; Gordon et al., 1985).  DBP was
    mutagenic in  Salmonella typhimurium TA 100 and TA 1535, but not in
    TA 1538 (Carr & Rosenkranz, 1978).  However, only BA was more
    mutagenic than the parent compound (Gordon et al., 1985). Unscheduled
    DNA synthesis was induced in monolayer cultures of rat hepatocytes by
    DBP and, to a lesser extent, by BBPP and mono(2,3-dibromopropyl)
    phosphate (mono-BPP).  A similar relative response of DBP, BBPP, and
    mono-BPP was found with respect to mutagenicity in V79 Chinese hamster
    lung cells with liver microsomal activation.  The concentration of
    BBPP that was tested was 0.05 mmol/litre (Holme et al., 1983).

         BBPP was less potent than TBPP in causing DNA damage in both the
    liver and testicular cells.  DNA damage, as measured by alkaline
    elution, was found in isolated rat liver cells exposed to 100
    micromolar BBPP and to a lesser extent in testicular cells. DNA damage
    caused by BBPP phosphate could be decreased by diethyl maleate-
    pretreatment in testicular cells,  but not in the liver cells
    (Soderlund et al., 1992).

    8.  EFFECTS ON HUMANS

    8.1  General population exposure

         Fifty-two out of 61 (22 males and 39 females) human volunteers
    completed a repeated insult patch study in which TBPP (1.1 g) was
    applied 10 times over a 24-day period, followed by a single challenge
    patch 14 to 21 days later.  Fifty persons showed no reaction.  After
    the 6th or 7th application 2 showed itching (or pruritis), and
    urticaria.  The study was stopped for a month in these 2 subjects, and
    then restarted.  No adverse effects were seen the second time.  The
    conclusion of the author was that TBPP did not produce primary skin
    irritation, skin fatigue, or skin sensitization (Kerst, 1974; US EPA,
    1976).

         A maximization test was carried out and 8 out of 24 human
    volunteers, exposed to a 100% TBPP solution, showed a sensitization
    reaction; while a 20% solution in a petroleum ether sensitized 2 out
    of 25 subjects.  The TBPP was considered to be a mild skin sensitizer
    in humans.  Subjects who had been sensitized by the 20% solution also
    showed reactions when tested with TBPP-treated fabrics.  The response
    varied with the type of fabric substrate.  The degree of sensitization
    appeared to depend upon the availability of the agent at the surface
    of the fibre.  This is different for different types of fibres and the
    methods in which the flame retardant is applied.  Washing the fibre
    reduced surface concentrations (Morrow et al., 1976).

         Andersen (1977) reported the incidence of sensitization to TBPP
    in human subjects from seven European countries, patch-tested with
    TBPP (5% in petrolatum), and found two positives among 1103 patients.

         Since TBPP-treated fabrics can be expected to contact the skin
    for long exposure periods, patches from both rayon and acetate
    fabrics, previously treated with TBPP were applied to humans, but skin
    reactions were not elicited (Brieger et al., 1968).

    8.2  Occupational exposure

         No case reports or epidemiological studies are available.

    9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

    9.1  Laboratory studies

    9.1.1  Microorganisms

         Nitrifying return activated sludge diluted with fresh settled
    sewage, filtered, aerated and containing Nitromonas and Nitrobacter
    was used to test nitrification.  No inhibition was found with 300 mg
    TBPP/litre and no depression of the BOD was noticed  at 170 mg/litre
    (Wood et al., 1981).

    9.1.2  Aquatic organisms

    9.1.2.1  Invertebrates

         A 57% inhibition of southern armyworm  (Spodoptera eridania)
    microsomal  p-chloro- N-methylanaline  N-demethylase was measured
    at 1 mg TBPP/ml, in an  in vitro incubation mixture (Eldefrawi et
    al., 1977).

    9.1.2.2  Vertebrates

         Six goldfish  (Carassius auratus) were exposed to 1 mg TBPP
    (dissolved in acetone) per litre water.  All died within 5 days.  The
    fish appeared to swim in a disoriented manner prior to death.  The
    fish showed necrosis of the kidneys (Gutenmann & Lisk, 1975).

         TBPP (1 mmol/litre) inhibited by 19% the acetylcholinesterase
    (AChE) activity in the electric organ of the electric ray  (Torpedo
     ocellata).  The binding of acetylcholine to its electric organ
    receptor was not inhibited (Eldefrawi et al. 1977).

    9.1.3  Terrestrial organisms

    9.1.3.1  Plants

         Seed of oat  (Avena sativa) was added to loamy sand soil (1.5%
    organic carbon) and exposed to 1, 10, 100 or 1000 mg TBPP/kg soil for
    14 days.  The temperature of the soil was 20°C, the pH 6.0 and 16 h
    light/8 h dark cycle was used.  The study was performed according to a
    modified OECD terrestrial plant-growth test.  The EC50 for growth
    inhibition was at 1000 mg/kg soil (Pestemer, 1988).  In a comparable
    study, turnip seed  (Brassica rapa sp.) was tested under the same
    conditions as the oat seed.  With 1000 mg TBPP/kg soil, 100%
    inhibition of growth was obtained (Pestemer, 1988).

    10.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         IARC concluded in 1979 that there is sufficient evidence that
    TBPP is carcinogenic in mice and rats.  In the absence of adequate
    data on humans, it is reasonable, for practical purposes, to regard
    TBPP as if it presented a carcinogenic risk to humans (IARC, 1979). 
    In 1987, colon tumours were reported in a short-term study on male
    rats.  The overall evaluation made by IARC (1987) was that TBPP is
    probably carcinogenic to humans (Group 2A) (IARC, 1987).

    BIS(2,3-DIBROMOPROPYL) PHOSPHATE AND SALTS

    A1.  SUMMARY AND EVALUATION; CONCLUSIONS AND RECOMMENDATIONS

         The data base on bis(2,3-dibromopropyl) phosphate (BBPP) and its
    salts is inadequate for an evaluation, and to support its commercial
    use.

         From the available data, there is some indication that the
    substance may be mutagenic and carcinogenic.

         The substance cannot be evaluated unless additional data become
    available on physical and chemical properties, production and use,
    environmental transport, distribution, and transformation,
    environmental levels and human exposure, kinetics and metabolism in
    animals and humans, effects on laboratory mammals, humans, and  in
     vitro test systems, and effects on other organisms in the laboratory
    and field.  More mutagenicity data on at least two end-points are also
    needed.

    A2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL
         METHODS

    A2.1  Identity

    Chemical formula         C6H11Br4O4P

    Chemical structure

                             (BrCH2-BrCH-CH2O)2P - OH
                                                   '
                       (BrCH2-BrCH-CH2O)2P -  O -  P = O
                                              H    '
                                                   OH

    Relative molecular       497.8
    mass

    CAS Chemical name        2,3-dibromo-1-propanol-hydrogen
                             phosphate

    Common name              bis(2,3-dibromopropyl) phosphate;

    Synonyms                 bis(2,3-dibromopropyl)hydrogen
                             phosphate; bis(2,3-dibromopropyl)
                             phosphoric acid

    CAS registry number      5412-25-9

         The ammonium, magnesium, potassium, and sodium salts have also
    been proposed.

    A2.2  Physical and chemical properties

         No data are available on this subject.

    A2.3  Analytical methods

         See section 2.3, TBPP.

    A3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    A3.1  Natural occurrence

         BBPP and its salts are not known to occur as natural products.

    A3.2  Anthropogenic sources

    A3.2.1  Production levels and processes

         Bis(2,3-dibromopropyl)ammonium phosphate has been prepared by a
    reaction of bis(2,3-dibromopropyl) phosphate with NH4OH (Mischutin,
    1972).

    A3.2.2  Uses

         In the 1960s and 1970s, BBPP and its magnesium and ammonium salts
    were proposed for use as fire-proofing agents for textiles and
    plastics.

         No evidence was found that BBPP or its salts are currently used
    for commercial applications.

    A3.3  Contamination of the environment

         BBPP has been identified as a major biodegradation product of
    TBPP, in a laboratory activated sludge system (Alvarez et al., 1982).

    A3.4  Environmental transport, distribution, transformation,
          and exposure levels

         No data are available.

    A4.  KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS

    A4.1  Absorption, distribution, elimination, and biotransformation

         BBPP has been identified as a metabolite of TBPP (Lynn et al.,
    1982).  Following intravenous administration of [14C]-tris(2,3-
    dibromopropyl) phosphate to male Sprague-Dawley rats, approximately
    half of the label appeared in the urine within 120 h and 7.8% of the
    recovered urinary label was BBPP.  BBPP also constituted 21.5% of the
    biliary label (33.9% of administered dose in 24 h).  The tissue
    distribution of BBPP was studied at different intervals (5 and 30 min,
    8, 24, and 120 h, and 5 days) after administration of the tris
    compound.  BBPP was identified in nearly all organs within 5 min of
    administration.  Tissue levels declined after 5 or 30 min at all sites
    except the large intestines and carcass.  Five min after
    administration, 75% of the plasma label was BBPP.  The plasma
    concentration of BBPP increased between 0 and 1 h and declined
    biphasically thereafter, with an initial plasma half-life of 6 h,
    declining to approximately 36 h, by one to five days.

    A5.  EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

    A5.1  Single exposure

         Adult male Wistar rats, 5 per group, were administered a single
    ip injection of 0, 10, 25, 50, 100, or 200 mg BBPP/kg body weight in
    DMSO (2.5 ml/kg).  All rats were killed 40-48 h after dosing.  One rat
    of the highest dose group died.   Kidneys and body weight ratios were
    increased in 200 mg/kg rats.  The kidneys were pale and oedematous
    with necrosis of the inner cortex.  Microscopically, tubular cell
    necrosis was observed in rats with 50 mg/kg or more.  However, plasma
    creatinine was significantly elevated at doses of 10 mg/kg body weight
    or more and plasma urea and plasma-GOT were elevated at 200 mg/kg body
    weight (Soderlund et al., 1982b).

         Elliot et al. (1982) carried out a comparable study with only
    one dose level of 120 mg/kg body weight, administered to male
    Sprague-Dawley rats intraperitoneally.  Rats were killed after 48 h. 
    Serum creatinine was elevated, and renal cortical slices showed
    decreased uptake of para-aminohippuric acid and N-[14C]-
    methylnicotinamide.  Microscopically, tubular cell necrosis of the
    loops of Henle was found.

         When the Mg salt of BBPP was administered by oral intubation to
    Wistar rats, eyelid closure, crouching, shivering, and staggering gait
    were observed.  LD50 values in male and female rats were 283 and
    261 mg/kg, respectively (Takada et al., 1991b).

    A5.2  Short-term exposure

         The Mg salt of BBPP was given to Wistar rats (5/sex per group) in
    the diet at levels of 0, 30, 100, 300, or 1000 mg/kg for 45 days. 
    There was no difference between treated and control animals in body
    weight and food consumption.  At 1000 mg/kg, a significant increase in
    liver and kidney weights was observed in the males.  Desquamation,
    swelling and large nuclei formation of the tubular epithelium, and
    tubular dilation of kidney were observed.  It was concluded that
    BBPP-Mg has apparent renal toxicity (Takada et al., 1991b).

    A5.3  Long-term exposure

         No data were available on the following subjects:

    *    Skin and eye irritation; sensitization
    *    Reproductive toxicity, embryotoxicity, and teratogenicity

    A5.3.1  Mutagenicity and related end-points

         2,3-Dibromo-1-propanol (DBP) was mutagenic in  Salmonella
     typhimurium TA 100 and TA 1535, but not in TA 1538 (Carr &
    Rosenkranz, 1978).

         Magnesium BBPP at doses of  3-100 µmol/plate was more mutagenic
    to  Salmonella typhimurium TA 1535 and TA 100 in the presence of
    metabolic activation by Kanechlor 500-induced rat-liver S9 than in its
    absence; it was weakly mutagenic to TA 98 with S9, but showed no
    mutagenic activity in TA 1537 and TA 1538 (Nakamura et al., 1979). 
    The ammonium salt of BBPP was more mutagenic than the magnesium salt,
    which itself was more mutagenic than the free acid (Nakamura et al.,
    1983).

         BBPP purified as a urinary metabolite from rats treated with TBPP
    was mutagenic to  Salmonella typhimurium TA1535 and TA100 in the
    presence of metabolic activation (Aroclor 1254-induced rat liver S9)
    at doses ranging from 0.05 to 1.0 µmol (Lynn et al., 1982).

         Mutagenic activity in  Salmonella typhimurium TA100 was detected
    when BBPP at concentrations of 50 and 100 µmol/litre was incubated for
    30 min with hepatic microsomal fractions from untreated rats or rats
    pretreated with phenobarbital (Soderlund et al., 1982b).

    A5.3.2  Carcinogenicity

         Four groups of 40 Wistar rats (5 weeks old) of each sex per dose
    level were fed diets containing 0, 80, 400, or 2000 mg/kg of the
    magnesium salt of bis(2,3-dibromopropyl) phosphate (BBPP), for 24
    months.  Food consumption and body weight gain were measured
    immediately prior to the beginning of the study, and then weekly for 6
    weeks, biweekly for 6 months, and monthly, thereafter.  Blood samples
    of 8-13 rats/sex per dose were taken at 12, 18, and 24 months.  Body
    weight gain was reduced significantly at a level of 2000 mg/kg. Male
    and female rats receiving 2000 mg/kg and female rats receiving
    400 mg/kg showed a significant increase in absolute and relative liver
    and kidney weights.  A high incidence of tumours was observed in both
    sexes.  In the digestive system, papillomas and adenocarcinomas were
    found in the tongue, oesophagus, and forestomach, and adenocarcinomas
    of the intestines.  In the liver, hepatocellular adenomas (neoplastic
    nodules) and carcinomas were found (Table 4).  Pre-terminal
    mortalities were associated with an increased incidence of forestomach
    papillomas in both sexes, adenocarcinomas of the small intestines in
    male rats, and hepatocellular carcinomas in females.  Non-neoplastic
    lesions were mainly found in the kidneys of the rats of the 2000 mg/kg
    group and, in a few instances, also in the 400 mg/kg group.  The
    changes were epithelial swelling and desquamation, large bizarre
    nuclei, pyknosis, and basement membrane thickening.  Serum
    biochemistry was performed using commercially available assay kits for
    the diagnosis of liver and kidney function and of disorders of the
    digestive system.  Eighteen parameters were studied.  Significant
    increases or decreases in the parameters were mainly observed in the
    2000 mg/kg group with a few in the 400 mg/kg group.  Statistically
    significant decreases were seen in the serum, in total protein,
    albumin, and cholinesterase;  and significant increases were seen in

    blood urea nitrogen, total cholesterol, alkaline phosphatase,
    gamma-glutamyl transferase, magnesium, GOT, and GPT (Takada et al.,
    1991a).

    A5.4  Special studies

    A5.4.1  Kidneys

         Many nephrotoxic agents exert their effects primarily on the
    cells of the proximal tubules.  Isolated tubular cells were used to
    study the uptake of alpha-methylglucose as indicator of effects on the
    functional integrity of the cells.  BBPP, which is acutely nephrotoxic
     in vivo, inhibited the uptake of alpha-methylglucose at low
    concentrations (Boogaard et al., 1989).

         See also TBPP section 7.8.1 and 7.9.1 on the nephrotoxicity of
    BBPP.

    A5.5  Effects on humans and other organisms in the laboratory
          and field

         No data are available.

        Table 4.  Neoplastic lesions and tumour incidence in Wistar rats fed diets containing
              BBP magnesium salta

                                                                                          
    Organ             Sex             Dose level        Papillomas         Squamous cell
                                                        carcinomas
                                                                                          

    Tongue            male                400              1/40                 1/40
                      female              400              1/40                 1/40
                                         2000              5/40                 0/40

    Oesophagus        male                400              6/40                 1/40
                                         2000              2/40                 0/40
                      female             2000              6/40b                0/40

    Forestomach       male                400              8/40b                1/40
                                         2000              17/40c               2/40
                      female              400              4/40                 2/40
                                         2000              20/40c               4/40

                                                                                          
                                                          Adenoma           Adenocarcinoma
                                                                                          

    Small intestines  male                400              0/40                 2/40
                                         2000              2/40                14/40c
                      female             2000              0/40                 9/40c
                                                                                          

    Table 4 (contd).

                                                                                          
    Organ             Sex             Dose level        Neoplastic         Hepatic cell
                                                        nodules            carcinomas
                                                                                          

    Liver             male                  0              7/40                 1/40
                                           80              3/40                 2/40
                                          400              7/40                 2140
                                         2000              2/40                 2/40
                      female                0              1/40                 0/40
                                           80              2/40                 1/40
                                          400              5/40                 7/40b
                                         2000              5/40                24/40c
                                                                                          
                                                          Adenoma             Carcinoma
                                                                                          

    Kidneys           male                400              5/40                 1/40
                                         2000              0/40                 0/40
                      female             2000              1/40                 1/40
                                                                                          

    a  From: Takada et al, (1991a).
    No tumours were found in the groups not mentioned in the table.
    The figures given in this table are the total numbers of the tumours
    found at the end of the study.  The 2000 mg/kg treated rats did not survive
    until the end of the 18th or/and 24th month.
    b   P < 0.05.
    c   p < 0.01 compared with the controls.
    
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    Nephrotoxicity of selectively deuterated and methylated analogues of
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    RESUME ET EVALUATION, CONCLUSIONS ET RECOMMANDATIONS

    1.  Tris-2,3-dibromopropyle

    1.1  Résumé et évaluation

    1.1.1  Production et usage

         La production de phosphate de tris-2,3-dibromopropyle (TBPP) a
    commencé pour la première fois vers 1950 et sa production commerciale
    est documentée à partir de 1959.  Aux Etats-Unis, en 1975, la
    production de TBPP se situait, selon les estimations, entre 4100 et
    5400 tonnes.  Autant qu'on sache, le TBPP n'est ni produit ni utilisé
    actuellement dans le monde comme retardateur de flamme dans les
    textiles, mais il peut être incorporé à des polymères utilisés à
    d'autres fins.  Le TBPP a constitué un important retardateur de
    flamme, que l'on ajoutait aux tissus de cellulose, de triacétate et de
    polyester, en particulier pour les vêtements de nuit destinés aux
    enfants, mais il a été depuis interdit pour cet usage dans plusieurs
    pays d'Europe, aux Etats-Unis d'Amérique (1977) ainsi qu'au Japon
    (1978).

         Le TBPP peut se trouver à l'intérieur ou à la surface du tissu. 
    Lorsqu'il se trouve à l'intérieur, on ne peut pas l'extraire par
    solvants et il est donc probable qu'il ne peut pas non plus être
    absorbé par voie percutanée.  Toutefois, lorsqu'il se trouve à la
    surface de la fibre, il peut être extrait lors de la lessive ainsi
    qu'au moyen d'acide acétique ou d'autres solvants ou encore par la
    salive, et peut être alors absorbé par voie percutanée.  Dans ce cas,
    il peut y avoir en cours d'utilisation ou pendant la lessive des
    produits finis une perte importante du TBPP qui se trouve à leur
    surface, d'où contamination de l'environnement.  En outre, on a
    signalé la décharge de TBPP dans l'environnement par des ateliers de
    finissage et le rejet final de déchets solides.

    1.1.2  Propriétés physiques et chimiques

         Le TBPP existe en au moins deux qualités.  Le produit de haute
    qualité est un liquide visqueux clair, de couleur jaune pâle, qui
    contient jusqu'à 1,5% de matière volatile.  Le produit de basse
    qualité peut contenir jusqu'à 10% de matière volatile.

         Le TBPP (degré de pureté > à 97%) a un point d'ébullition égal à
    390°C, un point de fusion de 5,5°C et une tension de vapeur de
    1,9 × 10-4 mmHg à 25°C.  Il est faiblement soluble dans l'eau
    (8 mg/litre).

         Lorsqu'on le chauffe jusqu'à décomposition, c'est-à-dire au-dessus
    de 260-300°C, le TBPP libère des composés contenant du brome et du
    phosphore.  Son coefficient de partage entre le  n-octanol et l'eau
    (log Pow) est égal à 3,02.

         Il existe des méthodes d'analyse permettant le dosage du TBPP et
    de ses métabolites dans des échantillons biologiques ou d'autres
    matrices.

    1.1.3  Transport, distribution et transformation dans l'environnement

         Le peu de données dont on dispose incitent à penser que le TBPP
    est relativement persistant dans l'environnement.  Il ne semble pas
    que l'oxydation et la photodécomposition jouent un rôle important dans
    sa destinée.  Cependant, il peut y avoir une hydrolyse impliquant les
    atomes de brome du groupement propyle, en particulier en milieu
    basique.  Il peut s'évaporer de l'eau mais on ne dispose pas
    véritablement de données sur ce point.  Bien qu'on ait signalé la
    possibilité d'une biodécomposition du TBPP (demi-vie 19,7 h.) dans les
    boues activées, on ne pense pas que cela constitue un processus
    important dans les sols et les eaux naturels.  Dans la boue
    stérilisée, il n'y a pratiquement pas de décomposition.  On a constaté
    que l'un des principaux produits de décomposition du TBPP était le
    phosphate de bis-2,3-dibromo-propyle.  Le TBPP étant pratiquement
    insoluble dans l'eau, il est possible que l'adsorption sur les
    matières particulaires et sur les sédiments joue un rôle important.

         La valeur estimative du log de Koc (3,29) indique qu'il y a une
    forte adsorption au sol.  Sur la base de cette valeur de Koc et de
    la faible solubilité dans l'eau du TBPP, on pense que ce composé n'est
    que lentement lessivé vers les eaux souterraines.  Le TBPP va avoir
    tendance à s'accumuler dans les décharges publiques et autres lieux de
    ce genre, avec pour conséquence la possibilité d'une bioaccumulation. 
    D'ailleurs, une étude portant sur un cyprin,  Pimephales promelas, a
    permis de mettre en évidence un facteur de bioconcentration de 2,7, ce
    qui est faible, alors que le coefficient de partage  n-octanol/eau
    (log de Pow) est de 3,02.  En raison de sa faible tension de vapeur,
    on peut penser que le TBPP sera essentiellement sorbé sur les
    particules en suspension dans l'air.  La décomposition thermique en
    milieu oxydant du TBPP à la température de 370°C entraîne la formation
    de bromure d'hydrogène et de composés bromés en C3 tels que des
    bromopropènes, des dibromopropènes ainsi que des di-et-tribromopropanes.

    1.1.4  Concentrations dans l'environnement et exposition humaine

         On ne dispose que de données limitées sur les concentrations dans
    l'environnement et l'exposition humaine.  Lors d'études effectuées au
    Japon en 1975, on a analysé 20 échantillons d'eau, de sol et de
    poissons sans y trouver de TBPP.  En revanche, on a mis en évidence,
    sans le doser, du TBPP dans des particules en suspension dans l'air
    prélevé aux alentours d'une installation industrielle.

         Ce sont les enfants portant des vêtements de nuit traités par du
    TBPP qui, lorsque ce produit était autorisé, constituaient le groupe
    de population le plus particulièrement exposé à ce retardateur de
    flamme.  On estime qu'à l'époque, la dose absorbée à travers la peau
    par ces enfants aux Etats-Unis d'Amérique était de l'ordre de 9 µg/kg
    de poids corporel et par jour.  La Consumer Product Safety Commission
    des Etats-Unis a calculé que, sur une période de six ans, un enfant
    portant de tels vêtements pouvait absorber une dose totale d'au moins
    2 à 77 mg de TBPP/kg de poids corporel.

    1.1.5  Cinétique et métabolisme chez les animaux de laboratoire
           et l'homme

         Le TBPP est rapidement absorbé au niveau des voies digestives et
    à un rythme plus modéré par la voie percutanée chez les rats et les
    lapins.  Chez le rat, le TBPP ou ses métabolites sont éliminés dans
    les 5 jours.  L'élimination se produit à hauteur d'environ 50% dans
    les urines, 10% dans les matières fécales, 10-20% de son carbone étant
    rejetés sous forme de CO2 dans l'air expiré.

         Un jour après avoir administré par voie orale du TBPP radiomarqué
    à des rats, la radioactivité s'est retrouvée dans les limites de
    0,2-6,6% au niveau du sang, du foie, des reins, des muscles, des
    tissus adipeux et de la peau.  Le temps de demi-élimination de la
    radioactivité de tous ces organes était d'environ 2-4 jours.  Au bout
    de 8 h., il ne restait encore, en concentrations notables, que du
    phosphate de bis-2,3-dibromopropyle dans la plupart des tissus.

         Après administration orale de TBPP à des rats, on a mis en
    évidence six métabolites dans les urines et la bile.  Le principal
    métabolite urinaire, fécal, biliaire et tissulaire était le phosphate
    de bis-2,3-dibromopropyle.  Un autre métabolite, le 2,3-dibromo-
    propanol, a été également mis en évidence chez des rats et des enfants
    qui portaient des vêtements traités par du TBPP.

         Les microsomes hépatiques métabolisent le TBPP en présence de
    NADPH et d'oxygène.  Les principaux métabolites obtenus sont le
    phosphate de bis-2,3-dibromopropyle et le  2,3-dibromopropanol.  On a
    montré qu'il se formait du phosphate de bis-2,3-dibromopropyle par
    oxydation au niveau du C3 et peut-être également en position C2 du
    TBPP.  Outre le phosphate bis-2,3-dibromopropyle, on retrouve de la
    2-bromoacroléine, de l'acide 2-bromoacrylique ainsi que des composés
    propylliques hydroxylés et des métabolites conjugués avec du
    glutathion.

         Du  S-(2,3-dihydroxypropyl)glutathion ayant été mis en évidence
    dans la bile de rats, on a avancé l'hypothèse que le TBPP et/ou le
    phosphate de bis-2,3-dibromopropyle subissent une conjugaison directe
    par le glutathion en présence de glutathion  S-transférase avec
    formation, comme métabolites, d'ions épisulfonium.

         Par activation, le TBPP forme des produits qui se fixent par
    liaisons covalentes aux protéines et à l'ADN  in vivo et  in vitro. 
    Après injection intrapéritonéale de TBPP tritié à des souris, à des
    hamsters et à des cobayes mâles, qui sont moins sensibles à la
    néphrotoxicité induite par cette substance que les rats, on a observé
    un degré analogue de liaison covalente aux protéines dans le foie et
    les reins.  Chez le rat mâle, qui est beaucoup plus sensible à la
    néphrotoxicité induite par ce produit, on a constaté qu'il y avait
    beaucoup plus de composé radiomarqué fixé aux protéines rénales qu'aux
    protéines hépatiques.

         Mis en présence de microsomes hépatiques provenant de souris, de
    cobayes, de hamsters et de sujets humains, le TBPP est dans tous les
    cas métabolisé en intermédiaires génotoxiques.  Toutefois, les
    métabolites réactifs du TBPP se forment beaucoup plus lentement en
    présence de microsomes hépatiques d'origine humaine qu'en présence de
    microsomes prélevés sur rongeurs.

         Après avoir administré à des rats une dose néphrotoxique de TBPP
    et de ses analogues radiomarqués, on a constaté que le degré de
    liaison covalente aux protéines décroissait dans l'ordre suivant: 
    reins, foie et testicules.  D'après les résultats d'études  in vitro
    et  in vivo au cours desquelles on a comparé les lésions produites au
    niveau de l'ADN rénal, on est incité à penser qu'il y a formation de
    phosphate de bis-2,3-dibromopropyle au niveau du foie par oxydation,
    catalysée par le P450, du TBPP en position C2 ou C3.  Ce phosphate de
    bis-2,3-dibromopropyle est ensuite transporté vers les reins où il est
    métabolisé en intermédiaire réactif qui endommage l'ADN et se fixe aux
    protéines rénales.  L'activation qui se produit au niveau du rein ne
    semble pas impliquer le P450 mais s'effectuer plutôt par
    l'intermédiaire d'un métabolisme dépendant du GSH.  Des études  in
     vitro avec du TBPP et certains de ses analogues radiomarqués ont
    montré que l'oxydation du TBPP comportait l'incorporation d'un atome
    d'oxygène provenant de l'eau.  Cela implique que l'oxydation en
    position C2 du reste propyle donne naissance à une alpha-bromocétone
    réactive qui est capable d'alkyler directement les protéines ou de
    s'hydrolyser pour donner du phosphate de bis-2,3-dibromopropyle et une
    bromo-alpha-hydroxycétone réactive.

    1.1.6  Effets sur les mammifères de laboratoire et les systèmes
           d'épreuve  in vitro

         La toxicité du TBPP est faible, qu'il s'agisse de la toxicité
    aiguë par voie orale à court terme ou de la toxicité aiguë par voie
    percutanée.  Pour le rat, la DL50 par voie orale est > 2 g/kg et
    pour le lapin, la DL50 par voie cutanée dépasse 8 g/kg de poids
    corporel.  On a observé une atteinte rénale très étendue (nécrose
    cellulaire au niveau des tubules proximaux) chez des rats mâles à qui
    l'on avait injecté par voie intrapéritonéale une seule dose de 100 mg
    de TBPP par kg de poids corporel.

         Chez des rats soumis respectivement pendant quatre semaines ou
    90 jours à des épreuves de toxicité orale au cours desquelles du TBPP
    leur avait été administré par gavage ou mêlé à leur nourriture, on a
    observé une augmentation de l'incidence et de la gravité des néphrites
    chroniques aux doses supérieures ou égales à 25 mg/kg de poids
    corporel.

         Chez des lapins, l'application cutanée quotidienne de TBPP à des
    doses supérieures ou égales à 2,2 g/kg de poids corporel pendant 4
    semaines a entraîné une dégénérescence au niveau du foie et des reins. 
    Tous les lapins sont morts dans les quatre semaines.  En revanche,
    aucun animal n'est mort lors d'une autre étude avec des doses allant
    jusqu'à 250 mg/kg de poids corporel.

         Des lapins qui avaient subi chaque semaine pendant 90 jours une
    application cutanée de 2,27 g de TBPP/kg de poids corporel ont
    présenté des anomalies rénales, une atrophie testiculaire et une
    aspermatogénèse.

         Aux doses de 1,1 ou 0,22g de TBPP, on n'a observé aucune
    irritation cutanée ou oculaire chez les lapins et il n'y a pas eu non
    plus de sensibilisation cutanée chez des cobayes.

         Deux études de tératogénicité ont été effectuées sur des rats. 
    L'une d'entre elles comportait des doses allant jusqu'à 125 mg/kg de
    poids corporel et n'a pas permis de mettre en évidence d'effet
    tératogène.  Lors d'une autre étude où la dose administrée était de
    200 mg/kg de poids corporel, on a observé une augmentation
    significative des variations affectant le squelette chez les foetus
    et, aux doses de 50 et 100 mg/kg de poids corporel, une diminution
    sensible de l'indice de viabilité.  Les auteurs en ont conclu que
    l'effet observé était dû à l'action toxique du composé sur les
    femelles gestantes.

         Chez des rats auxquels on avait administré du TBPP, on a constaté
    des lésions étendues de l'ADN dans divers organes.   In vitro, on a
    constaté que le TBPP produisait la rupture des brins d'ADN dans des
    cellules KB d'origine humaine.  Le TBPP a également induit une
    synthèse non programmée de l'ADN dans des hépatocytes de foie de rat,
    ce phénomène n'étant toutefois pas constaté dans des cellules
    épithéliales de prépuce humain.

         Plusieurs études ont révélé que le TBPP provoquait des mutations,
    notamment par substitution des paires de base, chez des souches de
     Salmonella typhimurium, avec ou sans activation métabolique.

         L'étude des mutations géniques directes sur cellules de hamsters
    chinois V79 avec ou sans activation métabolique, a donné des résultats
    négatifs.  Toutefois, en présence de microsomes hépatiques de rats
    préalablement traités par du phénobarbital, on a observé un effet
    positif.  Un effet faiblement positif a également été observé avec des
    cellules lymphomateuses de souris (locus L5178YTK).

         Dans des cellules V79 de hamsters chinois, on a constaté que le
    TBPP augmentait le nombre d'échanges entre chromatides soeurs.  En
    revanche il n'y avait pas d'augmentation du nombre des aberrations
    chromosomiques, ni dans les cellules de hamsters chinois, ni dans les
    cellules de moelle osseuse murine, ni dans les cellules lymphoïdes
    humaines en culture.  Dans des cellules fibroblastiques humaines
    diploïdes (lignée HE 2144), on a observé des échanges entre
    chromatides soeurs mais pas d'aberrations chromosomiques, l'épreuve
    étant effectuée sans activation métabolique. Toutefois la recherche
     in vitro d'aberrations chromo-somiques dans des lignées cellulaires
    de hamsters chinois a donné un résultat positif.

         Un résultat positif a également été obtenu lors de la recherche
    de micronoyaux dans des cellules de moelle osseuse provenant de
    hamsters chinois.  Une autre épreuve de ce genre, portant cette fois
    sur des souris, a permis d'observer un effet faiblement positif.

         Les études effectuées sur  Drosophila melanogaster ont montré
    que le TBPP augmentait les mutations récessives létales liées au sexe
    dans les gamètes mâles ainsi que chez les mâles adultes et il y avait
    induction de translocations réciproques.  Dans l'épreuve de l'oeil en
    mosaïque w/w+, le TBPP a suscité une réaction fortement positive.

         Un certain nombre d'études ont été menées pour tenter d'élucider
    les mécanismes qui sont à la base de la mutagénicité et/ou de la
    génotoxicité induites par le TBPP.  Ainsi la mutagénicité du TBPP pour
    les bactéries s'effectue par l'intermédiaire du système des
    monooxygénases microsomiques.  Par ailleurs, lors d'une réaction qui
    est sous la dépendance du NADPH et de l'oxygène, il y a activation du
    TBPP par le cytochrome P450.  Des microsomes préparés à partir de
    foies d'animaux traités par du phénobarbital ou des PCBs entraînent un
    accroissement de la mutagénicité.  Le phosphate de mono- et de
    bis-2,3-dibromopropyle sont moins mutagènes que le TBPP.  Des études
     in vitro ont montré que l'oxydation de la molécule de TBPP au niveau
    du C3 donnait naissance à un puissant mutagène à action directe, la
    2-bromoacroléine qui se lie également à l'ADN.

         On a mis en évidence des différences interspécifiques dans la
    bioactivation du TBPP en métabolites mutagènes pour la souche TA 100
    de  Salmonella typhimurium.  A cet égard, les microsomes hépatiques
    de souris étaient plus efficaces que ceux de cobayes, de hamsters et
    de rats.

         Trois études de transformation cellulaire ont été menées à l'aide
    de cellules C3H/10T1/2.  Dans l'une d'entre elles, on a obtenu un
    effet positif, mais les deux autres ont donné des résultats négatifs.

         Lors d'études à long terme, on a administré par voie orale du
    TBPP à des souris et à des rats et on en a appliqué sur la peau de
    souris femelles.  Chez les souris, on a constaté, après administration
    par voie orale, qu'il se formait chez les deux sexes des tumeurs au
    niveau de la portion cardiaque de l'estomac et des poumons, ainsi que
    des tumeurs bénignes ou malignes au niveau du foie chez les femelles
    et au niveau des reins chez les mâles.  Chez les rats, des tumeurs
    bénignes ou malignes se sont formées au niveau des reins chez les
    mâles, les tumeurs rénales étant bénignes chez les femelles. 
    L'application de TBPP sur la peau de souris femelles a entraîné
    l'apparition de tumeurs de la peau, des poumons, de la portion
    cardiaque de l'estomac et de la cavité buccale.  On peut conclure de
    ces études que le TBPP est doté de pouvoir cancérogène chez la souris
    et le rat.

         Après administration d'un métabolite du TBPP, le phosphate de
    bis-2,3-dibromopropyle, par voie orale à des rats, on a constaté
    l'apparition de tumeurs digestives chez les deux sexes. Il s'agissait
    de papillomes et d'adénocarcinomes de la langue, de l'oesophage et de
    la portion cardiaque de l'estomac, ainsi que d'adénocarcinomes de
    l'intestin avec en outre des adénomes et des carcinomes
    hépatocellulaires.

         On a également procédé à l'application cutanée d'un autre
    métabolite du TBPP, le 2,3-dibromo-1-propanol, à des souris et à des
    rats.  Chez les rats mâles, on a constaté un accroissement de
    l'incidence des tumeurs malignes de la peau, du nez, de la muqueuse
    buccale, de l'oesophage, de la portion cardiaque de l'estomac, de
    l'intestin grêle et du gros intestin, de la glande de Zymbal, du foie,
    du rein, de la vaginale, et de la rate.  Chez les rats femelles, on
    constatait une incidence accrue de tumeurs malignes affectant la peau,
    le nez, la muqueuse buccale, l'oesophage, la portion cardiaque de
    l'estomac, l'intestin grêle et le gros intestin, la glande de Zymbal,
    le foie, le rein, la glande clitoridienne, et les glandes mammaires. 
    Chez les souris mâles, il y avait également une incidence plus élevée
    des tumeurs malignes au niveau de la peau, de la portion cardiaque de
    l'estomac, du foie et des poumons, tandis que chez les femelles
    l'accroissement des tumeurs malignes se manifestait au niveau de la
    peau et de la portion cardiaque de l'estomac.

    1.1.7  Effets sur l'homme

         On ne dispose que de données limitées concernant les effets du
    TBPP sur l'homme.

         Quelques études ont été consacrées à la recherche chez l'homme
    d'un effet sensibilisateur que le TBPP pourrait avoir sur la peau. 
    Les résultats obtenus montrent que ce produit n'a qu'un faible pouvoir
    sensibilisateur et aucune irritation cutanée n'a été observée. 
    Toutefois les personnes qui avaient présenté une réaction positive au
    TBPP pur ont également réagi lorsqu'on les a mises en contact avec des
    tissus qui en contenaient.

    1.1.8  Effets sur les autres êtres vivants au laboratoire et
           dans leur milieu naturel

         On ne possède que très peu de données concernant les effets du
    TBPP sur les autres êtres vivants.  Par exemple, des poissons rouges
     (Caraccius auratus) qui avaient été exposés à du TBPP à raison de
    1 mg/litre sont morts tous les 6 en l'espace de 5 jours.

         La CE50 relative à l'inhibition de la croissance de la semence
    d'avoine se situait à 1000 mg/kg de terre.  Cette concentration a
    provoqué l'inhibition totale de la croissance des semences de navet
    ( Brassica rapa sp.).

    1.2  Conclusions

         Le TBPP a été utilisé naguère comme retardateur de flamme pour en
    imprégner les tissus, en particulier destinés à la confection de
    vêtements de nuit pour enfants, mais on est guère renseigné sur ses
    autres applications.  C'est essentiellement par contact avec des
    tissus traités par ce composé que la population générale a pu être
    contaminée.

         On n'a guère de renseignements non plus sur l'exposition des
    ouvriers employés à la production commerciale du TBPP ainsi qu'à son
    utilisation pour la fabrication de divers produits, ni d'ailleurs sur
    les dangers qu'il représente.

         En raison de la rareté des données, il n'est pas possible de
    parvenir à des conclusions définitives quant aux niveaux d'exposition
    ou aux dangers que le TBPP fait courir aux êtres vivants dans leur
    milieu naturel, l'homme mis à part.

         Les études sur l'animal ont montré que le TBPP pouvait être
    absorbé au niveau des voies digestives et, dans une moindre
    proportion, par la voie percutanée.  Il peut également être résorbé
    par cette dernière voie chez l'homme.  Chez le rat, il se révèle être
    très largement métabolisé dans le foie en phosphate de bis-2,3-
    dibromopropyle, qui constitue le principal métabolite mis en évidence
    dans les urines, et, dans une moindre proportion, en 2,3-
    dibromopropanol.  En outre, on a retrouvé de petites quantités
    d'autres métabolites bromés du TBPP.  La présence de
    2,3-dibromopropanol a été également observée chez des personnes qui
    portaient des tissus traités par le TBPP.  La principale voie
    d'élimination est la voie urinaire, le composé étant excrété en très
    faible proportion sous sa forme initiale.  Quant à la principale voie
    métabolique, elle semble faire intervenir le cytochrome P450 et les
    glutathion- S-transférases.

         D'après les données dont on dispose, on peut conclure que le TBPP
    ne présente qu'une faible toxicité aiguë chez l'animal de laboratoire. 
    Des études au cours desquelles on a administré de manière répétée de
    fortes doses de TBPP, on permis de mettre en évidence des lésions
    rénales et hépatiques chez le rat ainsi qu'une atteinte testiculaire
    chez le lapin.  Le composé a également un indéniable effet génotoxique
    dans plusieurs systèmes d'épreuve, tant  in vitro qu' in vivo.  Des
    effets cancérogènes ont également été relevés chez le rat et la
    souris.  Deux de ses métabolites, le phosphate de bis-2,3-
    dibromopropyle et le 2,3-dibromopropanol, produisent également des
    effets cancérogènes chez l'animal de laboratoire.  Il n'est pas
    irritant chez l'animal et son pouvoir sensibilisateur chez l'homme est
    faible.

         En 1977, la Consumer Product Safety Commission des Etats-Unis
    d'Amérique (Commission pour protection du consommateur) a interdit
    l'utilisation de vêtements d'enfants traités par le phosphate de
    tris-2,3-dibromoproyl, par crainte que ce composé ne soit cancérogène
    pour l'homme et en raison du risque non négligeable encouru par les
    personnes portant des vêtements confectionnés à l'aide de tissus
    imprégnés.  Depuis lors, l'utilisation de ce composé comme retardateur
    de flamme dans les produits destinés à la consommation courante est
    très sévèrement réglementée dans un certain nombre d'autres pays et
    son utilisation dans les textiles est interdite.

    1.3  Recommandations

         En raison de ses effets toxiques, le TBPP ne doit plus être
    utilisé dans le commerce.

         Au cas où, pour certains usages, il n'existerait pas de
    substituts moins dangereux au TBPP, il faudrait entreprendre des
    études pour s'assurer de l'absence d'exposition et de danger pour
    l'homme et l'environnement.

    2.  Bis-2,3-dibromopropyle

         La base de données relatives au phosphate de
    bis-2,3-dibromopropyle et à ses sels est insuffisante pour en
    permettre l'évaluation ou en justifier l'usage commercial.

         D'après les données disponibles on peut penser que ce composé
    pourrait être mutagène et cancérogène.

         Il ne sera pas possible d'évaluer ce produit tant qu'on ne
    disposera pas de données complémentaires sur ses propriétés physiques
    et chimiques, sa production et son usage, son transport, sa
    distribution, sa transformation et sa concentration dans
    l'environnement ainsi que l'exposition humaine auxquels il donne lieu,
    sa cinétique et son métabolisme chez l'animal et l'homme, ses effets

    sur les animaux de laboratoire, l'homme et les systèmes d'épreuve  in
     vitro ainsi que son action sur les autres êtres vivants au
    laboratoire et dans leur milieu naturel.  Il est également nécessaire
    d'obtenir davantage de données concernant son pouvoir mutagène sur au
    moins deux points d'aboutissement.

    RESUMEN Y EVALUACION; CONCLUSIONES Y RECOMENDACIONES

    1.  El fosfato de tris(2,3-dibromopropilo)

    1.1  Resumen y evaluación

    1.1.1  Producción y utilización

         El fosfato de tris(2,3-dibromopropilo) (FTBP) se produjo por
    primera vez hacia 1950.  Se sabe que en 1959 hubo producción con fines
    comerciales.  En 1975 la producción de FTBP en los Estados Unidos de
    América se estimó entre 4100 y 5400 toneladas.  Que se sepa, el FTBP
    no se produce ni utiliza corrientemente en la actualidad a nivel
    mundial como retardador de ignición en productos textiles, pero puede
    utilizarse en polímeros empleados para otros fines. El FTBP era un
    importante retardador de ignición de la celulosa y de tejidos de
    triacetato y de poliéster, especialmente en ropa de dormir para
    niños, pero este empleo se ha prohibido en varios países de Europa,
    los Estados Unidos de América (1977) y el Japón (1978).

         El FTBP se utiliza tanto dentro del tejido como sobre el mismo. 
    Si se encuentra dentro del tejido, no puede extraerse con disolventes
    y, por consiguiente, probablemente no esté disponible para su
    absorción cutánea.  Sin embargo, si se halla en la superficie de la
    fibra, puede extraerse durante el lavado o por acción del ácido
    acético, de otros disolventes y de la saliva y está disponible para la
    absorción cutánea.  En este caso habrá pérdida sustancial de FTBP
    superficial del tejido durante la utilización y/o el lavado de los
    productos acabados, y se contaminará el medio ambiente.  Además, se
    sabe que hay emisión de FTBP al medio ambiente en las operaciones de
    acabado de textiles y en la evacuación final de desechos sólidos que
    contienen FTBP.

    1.1.2  Propiedades físicas y químicas

         Puede obtenerse FTBP de dos calidades por lo menos.  El producto
    de alto grado de pureza es un líquido transparente, amarillo pálido y
    viscoso, que tiene hasta un 1,5% de componentes volátiles.  La calidad
    de baja pureza puede contener hasta un 10% de componentes volátiles.

         El punto de ebullición del FTBP (pureza > 97%) es de 390°C, su
    punto de fusión de 5,5°C y su presión de vapor de 1,9 × 10-4 mmHg a
    25°C.  La solubilidad del FTBP en el agua es baja (8 mg/litro).

         Cuando se calienta hasta su descomposición, a una temperatura
    superior a 260-300°C el FTBP emite compuestos que contienen bromo y
    fósforo.  El coeficiente de reparto  n-octanol/agua (log Pow) es de
    3,02.

         Se dispone de métodos analíticos para determinar la presencia de
    FTBP y sus metabolitos en muestras biológicas y otras matrices.

    1.1.3  Transporte, distribución y transformación en el medio ambiente

         La limitada información disponible sugiere que el FTBP es
    relativamente persistente en el medio ambiente.  La oxidación y la
    fotodegradación probablemente no tengan un efecto significativo en su
    destino.  Sin embargo, puede haber hidrólisis de los átomos de bromo
    del grupo propílico, especialmente en condiciones básicas.  Puede
    producirse volatilización a partir del agua, pero no se dispone de
    datos efectivos.  Aunque se han notificado casos de biodegradación del
    FTBP (semivida 19,7 h) en aguas residuales activadas, no se considera
    que ésta constituya un proceso importante en suelos y aguas naturales.
    En fangos esterilizados casi no se produce descomposición.  Se
    encontró fosfato de bis(2,3-dibromopropilo) como principal producto de
    la descomposición.  Como el FTBP es prácticamente insoluble en agua,
    la adsorción en partículas en sedimento puede ser un proceso
    importante.

         Un log Koc estimado (3,29) sugiere una fuerte adsorción en el
    suelo.  Sobre la base de este valor de Koc y de la baja solubilidad
    medida en agua, sólo se prevé una lixiviación lenta del FTBP a las
    aguas subterráneas.  El FTBP tenderá a acumularse en basureros y otros
    vertederos de desechos, lo que tal vez dé lugar a la acumulación
    biológica.  Un estudio sobre bioacumulación en  Pimephales
     promelas mostró un factor de bioconcentración de 2,7, que
    es bajo, mientras que el coeficiente de reparto  n-octanol/agua (Log
    Pow) es de 3,02.  Debido a su baja presión de vapor, se prevé que el
    FTBP sea principalmente objeto de sorción en las partículas en
    suspensión en el aire.  La degradación oxidativa térmica del FTBP a
    370 oC mostró que se forman bromuro de hidrógeno y compuestos
    C3-bromados, tales como bromopropenos, dibromopropenos, y
    dibromopropanos y tribromopropanos.

    1.1.4  Niveles ambientales y exposición humana

         Los datos sobre los niveles ambientales y la exposición humana
    son limitados.  Estudios realizados en el Japón en 1975 mostraron que
    20 muestras de agua, suelo y peces no contenían FTBP.  Se identificó
    la presencia de FTBP en partículas en suspensión en el aire en los
    alrededores de una planta industrial, pero no se cuantificaron.

         Los niños que llevaban ropa de dormir tratada con FTBP fueron el
    grupo de la población general particularmente expuesto a este
    retardador de ignición.  La absorción estimada a través de la piel de
    los niños que llevaban ropa de dormir tratada con FTBP en los Estados
    Unidos de América se calculó en 9 µg/kg de peso corporal por día.  La
    Comisión de Seguridad de los Productos de Consumo de los Estados
    Unidos de América calculó que, en un periodo de seis años, un niño que
    lleve ropa tratada con FTBP podría absorber en total 2-77 mg de
    FTBP/kg de peso corporal o más.

    1.1.5  Cinética y metabolismo en animales de laboratorio y en
           seres humanos

         El FTBP se absorbe rápidamente a través del tracto gastro-
    intestinal y a una velocidad moderada a través de la piel en la rata y
    el conejo.  En la rata, el FTBP o sus metabolitos se eliminan en cinco
    días.  Aproximadamente el 50% se elimina por la orina, el 10% por las
    heces y el 10-20% se exhala en forma de CO2.

         Un día después de la administración oral de FTBP marcado a ratas,
    se encontró radiactividad en la sangre, el hígado, los riñones, los
    músculos, la grasa y la piel con valores comprendidos entre el 0,2% y
    el 6,6%.  El periodo de semieliminación de la radiactividad de dichos
    órganos fue de aproximadamente 2-4 días.  Después de ocho horas,
    solamente el fosfato de bis(2,3-dibromopropilo) seguía presente en
    concentraciones sustanciales en la mayor parte de los tejidos.

         Después de la administración oral de FTBP a ratas, se
    identificaron seis metabolitos en la orina y en la bilis.  El
    principal metabolito en la orina, las heces, la bilis y los tejidos
    fue el fosfato de bis(2,3-dibromopropilo).  También se identificó el
    metabolito 2,3-dibromopropanol en ratas y en niños que llevaban ropa
    tratada con FTBP.

         Los microsomas del hígado metabolizan el FTBP en presencia de
    NADPH y oxígeno.  Los principales metabolitos son el fosfato de
    bis(2,3-dibromopropilo) y el 2,3-dibromopropanol.  Se ha mostrado que
    el fosfato de bis(2,3-dibromopropilo) se forma por oxidación en la
    posición C3 y posiblemente también en la posición C2 del FTBP.
    Además del fosfato de bis(2,3-dibromopropilo), se han encontrado
    2-bromoacroleína, ácido 2-bromoacrílico, y compuestos propil-
    hidroxilados y metabolitos conjugados con glutatión.

         Se identificó la presencia de S-(2,3-dihidroxipropil)glutatión en
    la bilis de ratas y se sugirió que el FTBP y/o el fosfato de bis(2,3-
    dibromopropilo) son conjugados directamente con el glutatión por la
    glutatión  S-transferasa, formándose iones episulfonio como
    metabolitos.

         Se ha mostrado que el FTBP se activa para formar productos que se
    enlazan de forma covalente con las proteínas y el ADN  in vivo e  in
     vitro.  Después de inyecciones intraperitoneales de FTBP tritiado,
    el ratón, el hámster y el cobayo machos, que son menos sensibles a la
    nefrotoxicidad inducida por el FTBP que la rata, mostraron niveles
    semejantes de enlace covalente con las proteínas en el hígado y los
    riñones.  En la rata macho, muy susceptible a la nefrotoxicidad
    inducida por el FTBP, los átomos marcados se habían fijado a las
    proteínas de riñon en cantidad mucho mayor que las proteínas del
    hígado.

         Los microsomas del hígado de ratón, cobayo, hámster y humano
    metabolizaron todos ellos el FTBP formando productos intermedios
    genotóxicos.  Sin embargo, la tasa de formación de metabolitos
    reactivos del FTBP por acción de los microsomas del hígado humano fue
    menor a la de los microsomas del hígado de roedores.

         El enlace del FTBP marcado y análogos en ratas a las que se había
    administrado una dosis nefrotóxica mostró que el número de enlaces
    covalentes a las proteínas era máximo en los riñones; les seguían el
    hígado y los testículos.  Los resultados de estudios comparativos  in
     vitro e  in vivo sobre lesiones del ADN renal parecen indicar que
    el fosfato de bis(2,3-dibromopropilo) se forma en el hígado por
    oxidación mediada por el P450 en las posiciones C2 o C3 del FTBP.  El
    fosfato de bis(2,3 dibromopropilo) se transporta a los riñones, donde
    se metaboliza formando productos intermedios reactivos que lesionan el
    ADN y se enlazan con las proteínas del riñón.  La activación en el
    riñón no parece realizarse con intervención del P450 sino por medio
    del metabolismo depen-diente del glutatión.  Estudios  in vitro con
    FTBP marcado y productos análogos mostraron que, en la oxidación, al
    FTBP se incorpora un átomo de oxígeno del agua.  Ello significa que la
    oxidación en la posición C2 del grupo propílico produce una alpha-
    bromocetona reactiva que puede alkilizar la proteína directamente o
    hidrolizarla produciendo fosfato de bis(2,3-dibromopropilo) y una
    bromo-alpha-hidroxicetona reactiva.

    1.1.6  Efectos en mamíferos de laboratorio y en sistemas de
           prueba  in vitro

         La toxicidad oral aguda y de corto plazo y la toxicidad cutánea
    aguda del FTBP son bajas.  La DL50 oral para la rata es > 2 g/kg y
    la DL50 dérmica para el conejo es > 8 g/kg de peso corporal en
    ambos casos.  Se observaron lesiones renales extensas (necrosis de las
    células de los tubos proximales) en ratas macho después de una sola
    inyección intraperitoneal de 100 mg de FTBP/kg de peso corporal.

         Estudios de cuatro semanas y de 90 días sobre toxicidad oral del
    FTBP (administrado por sonda o en la alimentación) a ratas mostraron
    un aumento relacionado con la dosis en la incidencia de nefritis
    crónica y su gravedad a niveles de dosis de 25 mg/kg de peso corporal
    o más.

         En conejos, aplicaciones cutáneas cotidianas de 2,2 g de FTBP/kg
    de peso corporal o más durante cuatro semanas ocasionaron cambios
    degenerativos en el hígado y los riñones.  Todos los conejos murieron
    en cuatro semanas.  No se registraron muertes en otro estudio con
    niveles de dosis de hasta 250 mg/kg de peso corporal.

         En una prueba de 90 días en conejos, aplicaciones cutáneas
    semanales de 2,27 g/kg de peso corporal dieron lugar a cambios
    renales, atrofia testicular y aspermatogénesis.

         No se observó irritación cutánea ni ocular en conejos a niveles
    de dosis de 1,1 g ó 0,22 g de FTBP y tampoco se observó
    sensibilización cutánea en cobayos.

         Se realizaron dos estudios sobre teratogenicidad en ratas.  En un
    estudio, a niveles de dosis de hasta 125 mg/kg de peso corporal no se
    observó teratogenicidad.  En otro estudio, a un nivel de dosis de
    200 mg/kg de peso corporal se observó un aumento significativo en las
    variaciones esqueléticas de los fetos, y con 50 y 100 mg/kg de peso
    corporal se obtuvo un índice de viabilidad  significativamente más
    bajo.  Los autores llegaron a la conclusión de que el efecto observado
    se debía a toxicidad materna.

         Se encontraron lesiones extensas del ADN en diversos órganos de
    ratas a las que se había administrado FTBP.   In vitro, se ha
    mostrado que el FTBP induce ruptura de las hebras de ADN en las
    células KB humanas.  Indujo síntesis imprevista del ADN en hepatocitos
    de ratas, pero no en células epiteliales del prepucio en el hombre.

         El FTBP resultó mutagénico en varios estudios realizados en
     Salmonella typhimurium, especialmente en cepas sensibles a la
    sustitución de pares de bases, con y sin activación metabólica.

         Las valoraciones de mutación génica anterógrada efectuadas en
    células V79 de hámster de China, con y sin activación metabólica,
    dieron resultados negativos.  Sin embargo, se obtuvo un efecto
    positivo en presencia de microsomas del hígado de ratas tratadas
    previamente con fenobarbital.  Se obtuvo un efecto positivo débil con
    células de linfoma de ratón (locus L5178YTK).

         El FTBP aumentó el número de intercambios de cromátides hermanas
    en células V79 de hámster de China, pero no indujo aberraciones
    cromosómicas en células de hámster de China, células de médula ósea de
    ratón y células linfoides humanas de cultivo.  Se encontraron
    intercambios de cromátides hermanas, pero no aberraciones
    cromosómicas, en fibroblastos humanos diploides (línea HE 2144) sin
    activación metabólica.  Sin embargo, en una prueba  in vitro sobre
    aberración cromosómica con la línea celular de hámster de China, el
    FTBP dio resultados positivos.

         Se obtuvo un resultado positivo con FTBP en una prueba de
    formación de micronúcleos en células de médula ósea de hámster de
    China.  Otro estudio en ratones sobre formación de micronúcleos mostró
    un efecto positivo débil.

         Estudios con  Drosophila melanogaster mostraron que el FTBP
    hacía aumentar el número de efectos recesivos letales ligados al sexo
    en células germinales masculinas y en machos adultos y se inducían
    traslocaciones recíprocas.  El FTBP mostró una respuesta fuertemente
    positiva en la valoración de mosaicismo ocular w/w+.

         Se han realizado varios estudios para dilucidar los mecanismos de
    la mutagenicidad y/o la genotoxicidad inducidas por el FTBP.  La
    mutagenicidad bacteriana ocasionada por el FTBP está mediada por el
    sistema de la monooxigenasa microsómica.  El citocromo P450 activa el
    FTBP en una reacción que depende del NADPH y del oxígeno.  Los
    microsomas preparados a partir del hígado de animales tratados con
    fenobarbital o con bifenilos policlorados acusaron un aumento de la
    mutagenicidad. Los fosfatos de mono(2,3-dibromopropilo) y
    bis(2,3-dibromopropilo) son menos mutagénicos que el FTBP.  Estudios
     in vitro han mostrado que la oxidación en la posición C3 de la
    molécula de FTBP produce el potente mutágeno 2-bromoacroleína de
    acción directa, que también se enlaza con el ADN.

         Se han notificado diferencias entre especies en la bioactivación
    del FTBP con transformación en metabolitos mutagénicos para cepas
    TA 100 de  Salmonella typhimurium.  Los microsomas del hígado de
    ratones fueron más eficaces que los de cobayos, hámsters y ratas.

         Se realizaron tres estudios sobre transformación celular en los
    que se utilizaron células C3H/10T1/2.  En un estudio se observó un
    efecto positivo, pero en los otros dos los resultados fueron
    negativos.

         Se probó el FTBP en ratones y ratas por administración oral y en
    ratones hembra por aplicación cutánea en estudios a largo plazo.  En
    los ratones, el FTBP administrado por vía oral produjo tumores de
    preestómago y pulmón en los animales de ambos sexos, tumores hepáticos
    benignos y malignos en las hembras y tumores renales benignos y
    malignos en los machos.  En ratas, el FTBP produjo tumores renales
    benignos y malignos en los machos y tumores renales benignos en las
    hembras.  Después de la aplicación cutánea a ratones hembra, el FTBP
    produjo tumores en la piel, el pulmón, el preestómago y la cavidad
    bucal.  De esos estudios puede concluirse que el FTBP tiene un
    potencial carcinogénico en ratones y ratas.

         El fosfato de bis(2,3-dibromilpropilo), un metabolito del FTBP
    administrado por vía oral a ratas produjo tumores del sistema
    digestivo en ambos sexos.  Entre los tumores encontrados había
    papilomas y adenocarcinomas de lengua, esófago y preestómago,
    adenocarcinomas de intestino, y adenomas y carcinomas
    hepato-celulares.

         Otro metabolito del FTBP, el 2,3-dibromo-1-propanol, se ensayó en
    ratas y ratones por aplicación cutánea.  En ratas macho se observó
    mayor incidencia de neoplasias de piel, nariz, mucosa bucal, esófago,
    preestómago, intestino delgado y grueso, glándula de Zymbal, hígado,
    riñón, túnica vaginal y bazo.  En ratas hembra se registró mayor
    incidencia de neoplasias de piel, nariz, mucosa bucal, esófago,
    preestómago, intestino delgado y grueso, glándula de Zymbal, hígado,
    riñón, glándula clitorídea y mama.  En ratones macho se observó un

    aumento de la incidencia de neoplasias de piel, preestómago, hígado y
    pulmón, y en ratones hembra, un aumento de la incidencia de neoplasias
    de piel y preestómago.

    1.1.7  Efectos en el ser humano

         Se dispone de datos limitados sobre los efectos del FTBP en el
    ser humano.

         Se ha ensayado el FTBP para determinar su potencial de
    sensibilización cutánea en unos pocos estudios en seres humanos.  Los
    resultados de éstos indican que el FTBP tiene un bajo potencial de
    sensibilización y no ha habido irritación cutánea.  Sin embargo, las
    personas que mostraron una respuesta positiva de sensibilización al
    FTBP puro también reaccionaron cuando se expusieron a tejidos tratados
    con FTBP.

    1.1.8  Efectos en otros organismos en laboratorio y en el medio
           natural

         Hay muy pocos datos sobre los efectos del FTBP en otros
    organismos.  Seis carpas doradas  (Carassius auratus) expuestas a
    1 mg de FTBP/litro murieron todas a los cinco días.

         La CE50 de inhibición del crecimiento en semillas de avena fue
    de 1000 mg/kg de suelo.  Esta concentración causó una inhibición del
    100% del crecimiento en semillas de nabo ( Brassica rapa sp.).

    1.2  Conclusiones

         El FTBP se ha utilizado como retardador de ignición en tejidos,
    en particular en ropa de dormir para niños, pero hay información
    insuficiente sobre su utilización para otros fines.  La exposición de
    la población general se ha efectuado principalmente por contacto con
    tejidos tratados con FTBP.

         Hay poca información sobre la exposición de los trabajadores y
    los riesgos que para éstos entrañan la producción comercial de FTBP y
    su utilización en diversos productos.

         Debido a la escasez de datos, no pueden sacarse conclusiones
    firmes respecto de los niveles de exposición y los riesgos del FTBP
    para organismos en el medio ambiente distintos del ser humano.


         Estudios en animales han mostrado que el FTBP puede absorberse a
    través del tracto gastrointestinal y, en menor medida, de la piel.  El
    FTBP también puede absorberse a través de la piel en el ser humano. 
    En la rata, el FTBP parece metabolizarse extensamente en el hígado
    convirtiéndose en fosfato de bis(2,3-dibromopropilo), que es el

    principal metabolito detectado en la orina, y, en menor medida, en
    2,3-dibromopropanol.  Además, se han encontrado pequeñas cantidades de
    otros metabolitos bromados del FTBP.  También se ha detectado
    2,3-dibromopropanol en seres humanos que llevaron tejidos tratados con
    FTBP.  La principal vía de eliminación es la orina y una cantidad muy
    pequeña se excreta en la forma del compuesto originario.  La principal
    vía metabólica parece ser la del metabolismo de las  S-transferasas
    del citocromo P450 y del glutatión.

         Sobre la base de los datos disponibles se puede concluir que el
    FTBP tiene una baja toxicidad aguda para animales de experimentación. 
    Estudios sobre la administración repetida de dosis relativamente
    elevadas de FTBP han revelado lesiones renales y hepáticas en ratas y
    también toxicidad testicular en conejos.  El FTBP ha producido un
    claro efecto genotóxico en varios sistemas de prueba, tanto  in vitro
    como  in vivo.  Se observaron efectos carcinogénicos en ratas y
    ratones. Se ha observado que los metabolitos fosfato de
    bis(2,3-dibromopropilo) y 2,3-dibromopropanol también tienen efectos
    carcinogénicos en animales de experimentación.  No se registraron
    efectos irritativos en animales y se observó un bajo potencial de
    sensibilización en seres humanos.

         En 1977, la Comisión de Seguridad de los Productos de Consumo de
    los Estados Unidos de América prohibió las prendas de vestir para
    niños tratadas con fosfato de tris(2,3-dibromo-propilo), debido a la
    preocupación de que esta sustancia química pudiera ser carcinogénica
    para el ser humano y a la posibilidad de una exposición humana
    significativa por contacto con los tejidos tratados.  Desde entonces,
    la utilización de esta sustancia como retardador de ignición en
    productos de consumo se ha restringido rigurosamente en varios otros
    países y se ha prohibido en los productos textiles.

    1.3  Recomendaciones

         Debido a sus efectos tóxicos, el FTBP no se debería utilizar ya
    comercialmente.

         Si se identifican aplicaciones para las cuales no hay
    alternativas menos peligrosas que el FTBP, deberían realizarse
    estudios para demostrar la ausencia de exposición humana y ambiental y
    de riesgos para el ser humano y para el medio ambiente.

    2.  El fosfato de bis(2,3-dibromopropilo)

         La base de datos sobre el fosfato de bis(2,3-dibromopropilo) y
    sus sales es insuficiente para hacer una evaluación y para respaldar
    su utilización comercial.

         Sobre la base de los datos disponibles, hay algunos indicios de
    que esta sustancia puede ser mutagénica y carcinogénica.

         Esta sustancia no puede evaluarse a menos que llegue a disponerse
    de datos adicionales sobre sus propiedades físicas y químicas; su
    producción y utilización; su transporte, distribución y transformación
    en el medio ambiente; los niveles ambientales y la exposición humana;
    su cinética y metabolismo en animales y en seres humanos; sus efectos
    en mamíferos de laboratorio, en seres humanos y en sistemas de prueba
     in vitro; y sus efectos en otros organismos en el laboratorio y en
    el medio natural.  También se necesitan más datos sobre mutagenicidad
    en relación con dos variables de evaluación por lo menos.
    


    See Also:
       Toxicological Abbreviations