INTOX Home Page


    UNITED NATIONS ENVIRONMENT PROGRAMME
    INTERNATIONAL LABOUR ORGANISATION
    WORLD HEALTH ORGANIZATION





    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY





    Environmental Health Criteria 218



    FLAME RETARDANTS: TRIS(2-BUTOXYETHYL)
    PHOSPHATE, TRIS(2-ETHYLHEXYL)
    PHOSPHATE AND TETRAKIS(HYDROXYMETHYL)
    PHOSPHONIUM SALTS







    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, the Netherlands


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


    World Health Organization
    Geneva, 2000

    The International Programme on Chemical Safety (IPCS),
    established in 1980, is a joint venture of the United Nations
    Environment Programme (UNEP), the International Labour Organisation
    (ILO), and the World Health Organization (WHO).  The overall
    objectives of the IPCS are to establish the scientific basis for
    assessment of the risk to human health and the environment from
    exposure to chemicals, through international peer review processes, as
    a prerequisite for the promotion of chemical safety, and to provide
    technical assistance in strengthening national capacities for the
    sound management of chemicals.

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

    WHO Library Cataloguing-in-Publication Data

    Flame retardants : tris(2-butoxyethyl) phosphate, tris(2-ethylhexyl)
    phosphate, tetrakis(hydroxymethyl) phosphonium salts.

         (Environmental health criteria ; 218)

         1.Organophosphorus compounds - toxicity  2.Phosphoric acid esters
         - toxicity  3.Flame retardants - toxicity 
         4.No-observed-adverse-effect level 5.Environmental exposure  
         6.Occupational exposure  I.Series

         ISBN 92 4 157218 3              (NLM Classification: QU 131)
         ISSN 0250-863X

         The World Health Organization welcomes requests for permission to
    reproduce or translate its publications, in part or in full. 
    Applications and enquiries should be addressed to the Office of
    Publications, World Health Organization, Geneva, Switzerland, which
    will be glad to provide the latest information on any changes made to
    the text, plans for new editions, and reprints and translations
    already available.

              (c) World Health Organization 2000

         Publications of the World Health Organization enjoy copyright
    protection in accordance with the provisions of Protocol 2 of the
    Universal Copyright Convention.  All rights reserved.

         The designations employed and the presentation of the material in
    this publication do not imply the expression of any opinion whatsoever
    on the part of the Secretariat of the World Health Organization
    concerning the legal status of any country, territory, city, or area
    or of its authorities, or concerning the delimitation of its frontiers
    or boundaries.

         The mention of specific companies or of certain manufacturers'
    products does not imply that they are endorsed or recommended by the
    World Health Organization in preference to others of a similar nature
    that are not mentioned. Errors and omissions excepted, the names of
    proprietary products are distinguished by initial capital letters.

    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR FLAME RETARDANTS:
    TRIS(2-BUTOXYETHYL) PHOSPHATE, TRIS(2-ETHYLHEXYL) PHOSPHATE,
    TETRAKIS-(HYDROXYMETHYL) PHOSPHONIUM SALTS

    PREAMBLE

    ABBREVIATIONS

    PART A:  TRIS(2-BUTOXYETHYL) PHOSPHATE (TBEP)

    A1.  SUMMARY, EVALUATION AND RECOMMENDATIONS

         A1.1 Summary
         A1.2 Evaluation
         A1.3 Recommendations

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

         A2.1 Identity
         A2.2 Physical and chemicals properties
         A2.3 Conversion factors
         A2.4 Analytical methods

              A2.4.1    Air
              A2.4.2    Water
              A2.4.3    Sediment
              A2.4.4    Soils and foodstuffs
              A2.4.5    Biological media

    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

    A4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

         A4.1 Transport and distribution between media
         A4.2 Biodegradation

              A4.2.1    Migration

    A5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         A5.1 Environmental levels

              A5.1.1    Air
              A5.1.2    Water (drinking-water and surface water)
              A5.1.3    Soils and sediment
              A5.1.4    Aquatic organisms

         A5.2 Human tissue levels
         A5.3 Food
         A5.4 Occupational exposure

    A6.  KINETIC AND METABOLISM IN LABORATORY ANIMALS AND HUMANS

    A7.  EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

         A7.1 Single exposure

              A7.1.1    Oral and dermal
              A7.1.2    Inhalation

         A7.2 Short-term repeated exposure

              A7.2.1    Oral
              A7.2.2    Dermal

         A7.3 Skin and eye irritation; sensitization
         A7.4 Reproductive toxicity, embryotoxicity and
              teratogenicity
         A7.5 Mutagenicity and related end-points
         A7.6 Carcinogenicity
         A7.7 Special studies

              A7.7.1    Neurotoxicity

                        A7.7.1.1  Acute administration
                        A7.7.1.2  Repeated oral administration
                        A7.7.1.3  Effects on esterase activity

    A8.  EFFECTS ON HUMANS

    A9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         A9.1 Laboratory experiments

              A9.1.1    Aquatics organisms

                        A9.1.1.1  Invertebrates
                        A9.1.1.2  Vertebrates

    PART B:  TRIS(2-ETHYLHEXYL) PHOSPHATE (TEHP)

    B1.  SUMMARY, EVALUATION AND RECOMMENDATIONS

         B1.1 Summary
         B1.2 Evaluation
         B1.3 Recommendations

    B2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL
         METHODS

         B2.1 Identity
         B2.2 Physical and chemical properties
         B2.3 Conversion factors
         B2.4 Analytical methods

              B2.4.1    Air
              B2.4.2    Water
              B2.4.3    Sediment

    B3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         B3.1 Natural occurrence
         B3.2 Anthropogenic sources

              B3.2.1    Production levels and processes
              B3.2.2    Uses

    B4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

         B4.1 Biodegradation
         B4.2 Bioaccumulation

    B5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         B5.1 Environmental levels

              B5.1.1    Air
              B5.1.2    Surface water
              B5.1.3    Drinking-water
              B5.1.4    Effluents
              B5.1.5    Sediment
              B5.1.6    Food

    B6.  KINETICS AND METABOLISM IN LABORATORY ANIMALS

    B7.  EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

         B7.1 Single exposure
         B7.2 Repeated exposure

              B7.2.1    Oral
              B7.2.2    Dermal
              B7.2.3    Inhalation

         B7.3 Skin and eye irritation; sensitization
         B7.4 Reproductive toxicity, embryo toxicity and
              teratogenicity
         B7.5 Mutagenicity

              B7.5.1     In vitro assays
              B7.5.2     In vivo assays

         B7.6 Carcinogenicity
         B7.7 Special studies

              B7.7.1    Neurotoxicity

    B8.  EFFECTS ON HUMANS

    B9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         B9.1 Laboratory experiments

              B9.1.1    Microorganisms
              B9.1.2    Aquatic organisms

                        B9.1.2.1  Vertebrates

              B9.1.3    Terrestrial organisms

    PART C: TETRAKIS(HYDROXYMETHYL) PHOSPHONIUM SALTS

    C1.  SUMMARY AND EVALUATION

         C1.1 Summary
         C1.2 Evaluation

    C2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL
         METHODS

         C2.1 Identity

              C2.1.1    Tetrakis(hydroxymethyl) phosphonium
                        chloride (THPC)
              C2.1.2    Tetrakis(hydroxymethyl) phosphonium
                        sulfate (THPS)
              C2.1.3    Tetrakis(hydroxymethyl) phosphonium
                        chloride-urea condensate (THPC-urea)

         C2.2 Physical and chemical properties

              C2.2.1    Technical products

         C2.3 Conversion factors
         C2.4 Analytical methods

    C3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         C3.1 Natural occurrence
         C3.2 Anthropogenic sources

              C3.2.1    Production levels and processes
              C3.2.2    Uses

    C4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSPORTATION

         C4.1 Transport and distribution between media
         C4.2 Transformation

              C4.2.1    Biodegradation
              C4.2.2    Abiotic degradation

         C4.3 Migration from textiles

    C5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    C6.  KINETICS AND METABOLISM IN LABORATORY ANIMALS

    C7.  EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

         C7.1 Single exposure

              C7.1.1    Oral
              C7.1.2    Dermal
              C7.1.3    Inhalation

         C7.2 Repeated exposure

              C7.2.1    Oral

                        C7.2.1.1  THPC
                        C7.2.1.2  THPS

              C7.2.2    Dermal

         C7.3 Long-term exposure

              C7.3.1    THPC
              C7.3.2    THPS

         C7.4 Skin and eye irritation; sensitization

              C7.4.1    Skin irritation

                        C7.4.1.1  THPS
                        C7.4.1.2  THPC-urea

              C7.4.2    Eye irritation
              C7.4.3    Skin sensitization

                        C7.4.3.1  THPS
                        C7.4.3.2  THPC-urea

         C7.5 Reproductive toxicity, embryotoxicity and
              teratogenicity

              C7.5.1    THPS
              C7.5.2    THPC-urea

         C7.6 Mutagenicity and related end-points

              C7.6.1    THPC-urea

                        C7.6.1.1   In vitro studies
                        C7.6.1.2   In vivo studies

              C7.6.2    THPC
              C7.6.3    THPS
              C7.6.4    THPO
              C7.6.5    Treated fabrics

         C7.7 Carcinogenicity

              C7.7.1    Oral studies

                        C7.7.1.1  Mice
                        C7.7.1.2  Rats

              C7.7.2    Dermal studies: initiation and promotion

         C7.8 Special studies

    C8.  EFFECTS ON HUMANS

    C9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         C9.1 Laboratory experiments

              C9.1.1    Aquatic organisms
              C9.1.2    Terrestrial organisms

    C10. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    REFERENCES

    APPENDIX

    RÉSUMÉ, EVALUATION ET RECOMMANDATIONS

    RESUMEN, EVALUACION Y RECOMENDACIONES
    

    NOTE TO READERS OF THE CRITERIA MONOGRAPHS

         Every effort has been made to present information in the criteria
    monographs as accurately as possible without unduly delaying their
    publication. In the interest of all users of the Environmental Health
    Criteria monographs, readers are requested to communicate any errors
    that may have occurred to the Director of the International Programme
    on Chemical Safety, World Health Organization, Geneva, Switzerland, in
    order that they may be included in corrigenda.

                              *     *     *

         A detailed data profile and a legal file can be obtained from the
    International Register of Potentially Toxic Chemicals, Case postale
    356, 1219 Châtelaine, Geneva, Switzerland (telephone no. + 41 22
    - 9799111, fax no. + 41 22 - 7973460, E-mail irptc@unep.ch).

                              *     *     *

         This publication was made possible by grant number
    5 U01 ES02617-15 from the National Institute of Environmental Health
    Sciences, National Institutes of Health, USA, and by financial support
    from the European Commission.

    Environmental Health Criteria

    PREAMBLE

    Objectives

         In 1973 the WHO Environmental Health Criteria Programme was
    initiated with the following objectives:

    (i)       to assess information on the relationship between exposure
              to environmental pollutants and human health, and to provide
              guidelines for setting exposure limits;

    (ii)      to identify new or potential pollutants;

    (iii)     to identify gaps in knowledge concerning the health effects
              of pollutants;

    (iv)      to promote the harmonization of toxicological and
              epidemiological methods in order to have internationally
              comparable results.

         The first Environmental Health Criteria (EHC) monograph, on
    mercury, was published in 1976 and since that time an ever-increasing
    number of assessments of chemicals and of physical effects have been
    produced.  In addition, many EHC monographs have been devoted to
    evaluating toxicological methodology, e.g., for genetic, neurotoxic,
    teratogenic and nephrotoxic effects.  Other publications have been
    concerned with epidemiological guidelines, evaluation of short-term
    tests for carcinogens, biomarkers, effects on the elderly and so
    forth.

         Since its inauguration the EHC Programme has widened its scope,
    and the importance of environmental effects, in addition to health
    effects, has been increasingly emphasized in the total evaluation of
    chemicals.

         The original impetus for the Programme came from World Health
    Assembly resolutions and the recommendations of the 1972 UN Conference
    on the Human Environment.  Subsequently the work became an integral
    part of the International Programme on Chemical Safety (IPCS), a
    cooperative programme of UNEP, ILO and WHO.  In this manner, with the
    strong support of the new partners, the importance of occupational
    health and environmental effects was fully recognized. The EHC
    monographs have become widely established, used and recognized
    throughout the world.

         The recommendations of the 1992 UN Conference on Environment and
    Development and the subsequent establishment of the Intergovernmental
    Forum on Chemical Safety with the priorities for action in the six
    programme areas of Chapter 19, Agenda 21, all lend further weight to
    the need for EHC assessments of the risks of chemicals.

    Scope

         The criteria monographs are intended to provide critical reviews
    on the effect on human health and the environment of chemicals and of
    combinations of chemicals and physical and biological agents.  As
    such, they include and review studies that are of direct relevance for
    the evaluation.  However, they do not describe  every study carried
    out.  Worldwide data are used and are quoted from original studies,
    not from abstracts or reviews.  Both published and unpublished reports
    are considered and it is incumbent on the authors to assess all the
    articles cited in the references.  Preference is always given to
    published data.  Unpublished data are only used when relevant
    published data are absent or when they are pivotal to the risk
    assessment.  A detailed policy statement is available that describes
    the procedures used for unpublished proprietary data so that this
    information can be used in the evaluation without  compromising its
    confidential nature (WHO (1990) Revised Guidelines for the Preparation
    of Environmental Health Criteria Monographs. PCS/90.69, Geneva, World
    Health Organization).

         In the evaluation of human health risks, sound human data,
    whenever available, are preferred to animal data.  Animal and  in
     vitro studies provide support and are used mainly to supply evidence
    missing from human studies.  It is mandatory that research on human
    subjects is conducted in full accord with ethical principles,
    including the provisions of the Helsinki Declaration.

         The EHC monographs are intended to assist national and
    international authorities in making risk assessments and subsequent
    risk management decisions.  They represent a thorough evaluation of
    risks and are not, in any sense, recommendations for regulation or
    standard setting.  These latter are the exclusive purview of national
    and regional governments.

    Content

         The layout of EHC monographs for chemicals is outlined below.

    *    Summary -- a review of the salient facts and the risk evaluation
         of the chemical
    *    Identity -- physical and chemical properties, analytical methods
    *    Sources of exposure
    *    Environmental transport, distribution and transformation
    *    Environmental levels and human exposure
    *    Kinetics and metabolism in laboratory animals and humans
    *    Effects on laboratory mammals and  in vitro test systems
    *    Effects on humans
    *    Effects on other organisms in the laboratory and field
    *    Evaluation of human health risks and effects on the environment
    *    Conclusions and recommendations for protection of human health
         and the environment

    *    Further research
    *    Previous evaluations by international bodies, e.g., IARC, JECFA,
         JMPR

    Selection of chemicals

         Since the inception of the EHC Programme, the IPCS has organized
    meetings of scientists to establish lists of priority chemicals for
    subsequent evaluation.  Such meetings have been held in: Ispra, Italy,
    1980; Oxford, United Kingdom, 1984; Berlin, Germany, 1987; and North
    Carolina, USA, 1995. The selection of chemicals has been based on the
    following criteria: the existence of scientific evidence that the
    substance presents a hazard to human health and/or the environment;
    the possible use, persistence, accumulation or degradation of the
    substance shows that there may be significant human or environmental
    exposure; the size and nature of populations at risk (both human and
    other species) and risks for environment; international concern, i.e.
    the substance is of major interest to several countries; adequate data
    on the hazards are available.

         If an EHC monograph is proposed for a chemical not on the
    priority list, the IPCS Secretariat consults with the Cooperating
    Organizations and all the Participating Institutions before embarking
    on the preparation of the monograph.

    Procedures

         The order of procedures that result in the publication of an EHC
    monograph is shown in the flow chart.  A designated staff member of
    IPCS, responsible for the scientific quality of the document, serves
    as Responsible Officer (RO).  The IPCS Editor is responsible for
    layout and language.  The first draft, prepared by consultants or,
    more usually, staff from an IPCS Participating Institution, is based
    initially on data provided from the International Register of
    Potentially Toxic Chemicals, and reference data bases such as Medline
    and Toxline.

         The draft document, when received by the RO, may require an
    initial review by a small panel of experts to determine its scientific
    quality and objectivity.  Once the RO finds the document acceptable as
    a first draft, it is distributed, in its unedited form, to well over
    150 EHC contact points throughout the world who are asked to comment
    on its completeness and accuracy and, where necessary, provide
    additional material.  The contact points, usually designated by
    governments, may be Participating Institutions, IPCS Focal Points, or
    individual scientists known for their particular expertise.  Generally
    some four months are allowed before the comments are considered by the
    RO and author(s).  A second draft incorporating comments received and
    approved by the  Director,  IPCS, is then  distributed to Task Group
    members, who carry out the peer review, at least six weeks before
    their meeting.

         The Task Group members serve as individual scientists, not as
    representatives of any organization, government or industry.  Their
    function is to evaluate the accuracy, significance and relevance of
    the information in the document and to assess the health and
    environmental risks from exposure to the chemical.  A summary and
    recommendations for further research and improved safety aspects are
    also required.  The composition of the Task Group is dictated by the
    range of expertise required for the subject of the meeting and by the
    need for a balanced geographical distribution.

         The three cooperating organizations of the IPCS recognize the
    important role played by nongovernmental organizations.
    Representatives from relevant national and international associations
    may be invited to join the Task Group as observers.  While observers
    may provide a valuable contribution to the process, they can only
    speak at the invitation of the Chairperson. Observers do not
    participate in the final evaluation of the chemical; this is the sole
    responsibility of the Task Group members.  When the Task Group
    considers it to be appropriate, it may meet  in camera.

         All individuals who as authors, consultants or advisers
    participate in the preparation of the EHC monograph must, in addition
    to serving in their personal capacity as scientists, inform the RO if
    at any time a conflict of interest, whether actual or potential, could
    be perceived in their work.  They are required to sign a conflict of
    interest statement. Such a procedure ensures the transparency and
    probity of the process.

         When the Task Group has completed its review and the RO is
    satisfied as to the scientific correctness and completeness of the
    document, it then goes for language editing, reference checking, and
    preparation of camera-ready copy.  After approval by the Director,
    IPCS, the monograph is submitted to the WHO Office of Publications for
    printing.  At this time a copy of the final draft is sent to the
    Chairperson and Rapporteur of the Task Group to check for any errors.

         It is accepted that the following criteria should initiate the
    updating of an EHC monograph: new data are available that would
    substantially change the evaluation; there is public concern for
    health or environmental effects of the agent because of greater
    exposure; an appreciable time period has elapsed since the last
    evaluation.

         All Participating Institutions are informed, through the EHC
    progress report, of the authors and institutions proposed for the
    drafting of the documents.  A comprehensive file of all comments
    received on drafts of each EHC monograph is maintained and is
    available on request.  The Chairpersons of Task Groups are briefed
    before each meeting on their role and responsibility in ensuring that
    these rules are followed.

    FIGURE 1


    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR FLAME RETARDANTS:
    TRIS(2-BUTOXYETHYL) PHOSPHATE, TRIS(2-ETHYLHEXYL) PHOSPHATE AND
    TETRAKIS(HYDROXYMETHYL) PHOSPHONIUM SALTS

     Members

    Dr R. Benson, US Environmental Protection Agency, Denver, Colorado,
    USA

    Dr P. Brantom, British Industry Biological Research Association
    (BIBRA) International, Carshalton, Surrey, United Kingdom

    Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood,
    Huntingdon, Cambridgeshire, United Kingdom  (Chairman)

    Professor J. Liesivuori, Department of Pharmacology and Toxicology,
    University of Kuopio, Kuopio, Finland

    Mr D. Renshaw, Department of Health, Elephant and Castle, London,
    United Kingdom

    Dr E. Söderlund, National Institute of Public Health, Department of
    Environmental Medicine, Oslo, Norway  (Rapporteur)

     Observers

    Dr L. Kotkoskic, FMC Corporation, Princetown, New Jersey, USA

    Dr P. Martin, Albright and Wilson UK Limited, European Business
    Services - Product Stewardship, Oldbury, West Midlands, United Kingdom

     Secretariat

    Dr M. Baril, International Programme on Chemical Safety, Montreal,
    Quebec, Canada

    ENVIRONMENTAL HEALTH CRITERIA FOR FLAME RETARDANTS:
    TRIS(2-BUTOXYETHYL) PHOSPHATE, TRIS(2-ETHYLHEXYL) PHOSPHATE AND
    TETRAKIS(HYDROXYMETHYL) PHOSPHONIUM SALTS

         A WHO Task Group on Environmental Health Criteria for Flame
    retardants: tris(2-butoxyethyl) phosphate, tris(2-ethylhexyl)
    phosphate and tetrakis(hydroxymethyl) phosphonium salts met at the
    British Industrial Biological Research Association, Carshalton, United
    Kingdom from 18 to 22 January 1999. Dr P. Brantom opened the meeting
    and welcome the participants on behalf of the host institute. Dr M.
    Baril, IPCS, welcomed the participants on behalf of IPCS and the three
    cooperating organizations (UNEP/ILO/WHO). The Task Group reviewed and
    revised the draft criteria monograph and made an evaluation of the
    risk to human health and the environment from exposure to these flame
    retardants.

         Financial support for this Task Group was provided by the United
    Kingdom Department of Health as part of its contribution to the IPCS.

         The first draft of this monograph was prepared by Dr G. J. van
    Esch, Bilthoven, the Netherlands. The second draft prepared by Dr M.
    Baril incorporated the comments received following circulation of the
    first draft to the IPCS contact points for Environmental Health
    Criteria.

         Dr P.G. Jenkins (IPCS Central Unit, Geneva) and Dr M. Baril (IPCS
    technical advisor, Montreal) were responsible for the overall
    technical editing and scientific content,respectively.

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

                              *  *  *

    ABBREVIATIONS

    AChE      acetylcholinesterase
    ALAT      alanine aminotransferase
    ASAT      aspartate aminotransferase
    BCME      bis(chloromethyl) ether
    BEHP      bis(2-ethylhexyl) phosphate
    BMPA      bishydroxymethyl phosphonic acid
    BuCHE     butyrylcholinesterase
    CHO       Chinese hamster ovary
    DMSO      dimethyl sulfoxide
    EC50      median effective concentration
    FDA       Food and Drug Administration (USA)
    GC        gas chromatography
    HPLC      high performance liquid chromatography
    IC50      median inhibitory concentration
    LC50      median lethal concentration
    LD50      median lethal dose
    LOAEL     lowest-observed-adverse-effect level
    LOEL      lowest-observed-effect level
    MS        mass spectrometry
    nd        not detected
    NOAEL     no-observed-adverse-effect level
    NOEC      no-observed-effect concentration
    NOEL      no-observed-effect level
    NPD       nitrogen-phosphorus sensitive detector
    NTE       neuropathy target esterase
    NTP       National Toxicology Program (USA)
    OECD      Organisation for Economic Co-operation and Development
    PVC       polyvinyl chloride
    SCE       sister-chromatid exchange
    TBEP      tris(2-butoxyethyl) phosphate
    TEHP      tris(2-ethylhexyl) phosphate
    THP       tetrakis(hydroxymethyl) phosphonium
    THPC      tetrakis(hydroxymethyl) phosphonium chloride
    THPO      trihydroxymethyl phosphine oxide
    THPS      tetrakis(hydroxymethyl) phosphonium sulfate
    TOCP      tri- ortho-cresyl phosphate

    PART A

    Tris(2-butoxyethyl) phosphate

    (TBEP)

    A.  SUMMARY, EVALUATION AND RECOMMENDATIONS

    A1.  Tris(2-butoxyethyl) phosphate (TBEP)

    A1.1  Summary

         Tris(2-butoxyethyl) phosphate (TBEP) is used in floor polishes
    and as a plasticizer in rubber and plastics. The worldwide production
    volume is not available but is estimated to be in the range of 
    5000-6000 tonnes.

         TBEP occurs in the environment only as a result of human
    activity. Its distribution in the environment has been investigated in
    certain industrialized countries. Concentrations in surface water were
    found to be below 300 ng/litre, whereas concentrations in sediment
    were between 100 and 1000 µg/kg. None of 167 analyses detected TBEP in
    fish. It has been detected in outdoor air in a single study (<200
    ng/m3). Measurement of TBEP in indoor air in offices showed
    concentrations of 25 ng/m3 or less. TBEP is associated with
    particulates and the source is considered to be the application of
    floor polish. It has been detected at µg/kg levels in human adipose
    tissue. The reported daily dietary intake from market basket studies,
    for a range of age groups, was <0.02 µg/kg body weight per day.
    Drinking-water concentrations of up to 270 µg/litre have been
    reported, this is considered to arise from migration from rubber
    gaskets in the plumbing.

         TBEP is considered to be readily biodegradable. Sewage treatment
    plant measurements and semi-continuous sludge laboratory tests have
    indicated substantial elimination of TBEP (>80%). In river and
    coastal water TBEP was completely degraded. The half-life in estuarine
    water was reported to be about 50 days and there was little
    degradation in unadapted seawater.

         The acute systemic mammalian toxicity and irritation potential
    are low.

         Several subchronic studies in laboratory animals have shown that
    the liver is the target organ for TBEP toxicity. One study in male
    Sprague-Dawley rats suggested that TBEP might cause focal myocarditis.
    Neurotoxic effects in rats after single doses of TBEP are
    inconsistent. In rats repeatedly given high doses by gavage, TBEP
    decreased nerve conduction velocity and increased the refractory
    period. It did not cause delayed neurotoxicity in hens but did inhibit
    brain and plasma cholinesterases.

         Based on an 18-week repeated dose study in rats, the 
    no-observed-effect level (NOEL) for liver effects was reported to be 
    15 mg/kg body weight per day, while the lowest-observed-effect level 
    (LOEL) was 150 mg/kg body weight per day.

         The long-term toxicity and carcinogenicity of TBEP have not been
    studied.

         Bacterial and mammalian cell tests for gene mutation gave
    negative results, but no tests for chromosomal damage have been
    reported.

         Teratogenicity was not observed in one study in rats. Other
    aspects of reproductive toxicity have not been reported.

         A Repeat Human Insult Patch Test indicated no skin sensitization
    and minimal skin irritation.

         The toxicity of TBEP to aquatic organisms is moderate. The 48-h
    LC50 in  Daphnia magna is 75 mg/litre and the 96-h LC50 values in
    fish range between 16 and 24 mg/litre.

    A1.2  Evaluation

         Occupational exposure to TBEP is likely to be by the dermal route
    during manufacture (accidental exposure) and from the use of floor
    polishes. The compound is absorbed dermally in experimental animals
    but no information is available on its kinetics and metabolism. Dermal
    exposure cannot, therefore, be quantified but is expected to be low.
    Inhalation exposure in the office environment has been measured to be
    25 ng/m3 or less.

         Exposure of the general population is principally via food (from
    use of TBEP as a plasticizer in packaging plastics) and drinking-water
    (contaminated by leaching from synthetic rubbers used in plumbing
    washers). Exposure from both sources is very low (estimated to be
    <0.2 µg/kg body weight per day from the diet and concentrations in
    drinking-water of <270 µg/litre).

         Given the reported NOEL from animal studies of 15 mg/kg body
    weight per day from a repeated dose oral study, the risk to the
    general population is very low. The risk to the occupationally exposed
    is also considered to be very low, though this cannot be quantified.

         In the environment, TBEP is expected (from its low volatility,
    high adsorption coefficient and moderate water solubility) to
    partition to sediment. The few measured data confirm this. Degradation
    in environmental media is expected to be rapid. No information is
    available on breakdown products; phosphate released during breakdown
    is not expected to contribute significantly to environmental nutrient
    levels. Fig. 1 plots measured environmental concentrations in surface
    water against reported acute toxicity values. The margin of safety
    between highest reported concentrations and lowest reported toxicity
    values is several orders of magnitude, indicating low risk to
    organisms in the aquatic environment. No assessment of risk can be
    made for the terrestrial compartment.

    A1.3  Recommendations

         For a full scientific evaluation of the compound, identification
    and assessment of metabolites in mammals would be required, given the
    toxicological profile of one of the suggested metabolites,
    2-butoxyethanol.


    FIGURE 2
    

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

    A2.1  Identity

    Molecular structure:

    CHEMICAL STRUCTURE 1

    Empirical formula:       C18H39O7P

    Relative molecular mass: 398.54

    Common name:             tris(2-butoxyethyl) phosphate

    Synonyms:                phosphoric acid, tris(2-butoxyethyl) ester;
                             tri(2-butoxyethanol) phosphate;
                             tris(2- n-butoxyethyl) phosphate;
                             tributoxyethyl phosphate; TBOP; TBEP; TBXP
                             (only in Japanese literature);
                             2-butoxyethanol phosphate (RTCES, 1989);
                             tri(2-butylethylether) phosphate;
                             tris(butylglycol) phosphate; tributyl cello
                             solve phosphate

    Trade names:             Kronitex KP-140; KP-140; Phosflex T-BEP;
                             Phosflex 176C; Amgard TBEP

    CAS registry number:     78-51-3

    CAS name:                Ethanol, 2-butoxy, phosphate (3:1)

    EINECS number:           201-122-9

    RTECS number:            KJ9800000

    A2.2  Physical and chemical properties

         TBEP is a technical product that may contain as impurities
    tributyl phosphate (about 3%) and traces of 2-butoxyethanol and
    phosphoric acid (FMC, 1990; Albright & Wilson (1999) personal
    communication to IPCS). There is no information on the concentration
    of mono- or diesters or other impurities in the technical product.

         TBEP is a light-coloured, high-boiling, non-flammable viscous
    liquid with a butyl-like odour under normal conditions. It is more
    soluble in non-polar than in polar solvents. 

    Boiling point:              200-230°C at 5.0-5.3 hPa

    Melting point:              -70°C

    Density:                    1.02 g/ml at 20°C

    Viscosity:                  11-15 mPa.s at 20°C

    Vapour pressure:
         at 25°C                2.8 × 10-7 hPa
         at 150°C               0.33 hPa (0.03 mmHg)

    Refractive index:           1.434 at 25°C

    Solubility:                 1.1-1.3 g/litre water at 20°C; miscible
                                in petroleum at 20°C

    Acidity/alkalinity:         neutral
    (1 g/litre water at 20°C)

    Flashpoint:                 210°C (approximately);
                                159 ± 2°C

    Ignition point:             251-52°C

    Auto-ignition
    temperature:                322 ± 5°C; 261°C

    Log Koc:                    4.38 (calculated)

     n-Octanol/water
    partition coefficient:      4.78 (calculated); 3.65

    References: Eldefrawi et al. (1977); Keith & Walters (1985); Laham et
    al. (1985b); Hoechst (1987); Watts & Moore (1988); Leo (1989); FMC
    (1990); Hinckley et al. (1990); Lenga (1993); Tremain & Bartlett
    (1994).

    A2.3  Conversion factors

         1 ppm = 16.53 mg/m3 at 20°C
         1 mg/m3 = 0.0605 ppm at 20°C

    A2.4  Analytical methods

         TBEP is usually analysed by gas chromatography (GC) coupled with
    mass spectrometry (MS), infrared spectroscopy or nuclear magnetic
    resonance spectrometry. The detection limit is <1 ng/g (adipose
    tissue) using any of these methods or a nitrogen/phosphorus-selective
    detector (LeBel et al., 1981; Rivera et al., 1987).

    A2.4.1  Air

         TBEP has been found associated with particulate matter in the air
    of offices. Of the methods that can be used to collect the particles,
    Weschler (1980) used a four-stage impactor with a back-up filter and
    extracted with a mixture of water and methanol. Later Weschler (1984)
    and Weschler & Fong (1986) collected particles on Teflon(R) membranes,
    separating the particles according to whether the aerodynamic diameter
    was greater or less than 2.5 µm. The samples were analysed by GC/MS
    after thermal desorption of the collector membranes. Sometimes samples
    were desorbed or dissolved with toluene.

    A2.4.2  Water

         TBEP has been extracted either with dichloromethane after
    acidification to pH 2 or by passage through a column filled with
    Amberlite XAD-2 resin which is subsequently extracted with acetone and
    hexane. After dehydration and concentration, extracts are analysed.
    The concentrated extracts are determined by GC/MS, or with other
    detection methods, as described above (LeBel et al., 1981; Watts &
    Moore, 1988). LeBel et al. (1987) used large-volume resin sampling
    cartridges to obtain sufficient organic extracts from water for
    analysis. Recovery at 10 ng TBEP/litre fortification level was 103.4%.

         Frimmel et al. (1987) described an analytical method to determine
    TBEP in water by extracting TBEP with granulated activated carbon and
    analysing the extract with GC/MS.

         Rivera et al. (1987) analysed water samples with different
    procedures, liquid-liquid extraction, adsorption on granular activated
    carbon, extraction with dichloromethane, followed by GC/MS/DS
    (Daughter spectral) detection. Ether-insoluble organic fractions were
    analysed and fractionated by high-performance liquid chromatography
    (HPLC) and ultraviolet absorbency detection was carried out with a
    2140 diode-array detector, followed by fast atom bombardment (FAB) and
    FAB-collision-induced dissociation - mass analysis kinetic energy
    spectroscopy (CID-MIKES) mass spectrometry.

    A2.4.3  Sediment

         After decanting the supernatant water, the sediment samples are
    mixed with an equal volume of pre-extracted anhydrous sodium sulfate
    and transferred to a Soxhlet thimble. Soxhlet extraction is carried
    out overnight using dichloromethane (300 ml) (Watts & Moore, 1988).

    A2.4.4  Soils and foodstuffs

         There are no reports of extraction or clean-up methods for soil
    or food (ECETOC, 1992b).

    A2.4.5  Biological media

         LeBel & Williams (1983b, 1986) and LeBel et al. (1989) analysed
    human adipose tissue for TBEP by extraction with a mixture of
    acetone/hexane in the presence of anhydrous sodium sulfate. The
    solution was centrifuged and the supernatant filtered and evaporated.
    The resulting extract was dissolved in a mixture of 5% dichloromethane
    in cyclohexane for gel permeation chromatography (GPC) to separate
    residual lipids from phosphate esters. Using this method the recovery
    of TBEP from adipose tissue was approximately 90%.

         Anderson et al. (1984) measured peaks of TBEP determined by HPLC
    in spiked samples of serum during the development of an analytical
    refinement. There was a marked inter-individual variation in peak
    height, which correlated with serum lipoprotein concentration.
    

    A3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    A3.1  Natural occurrence

         TBEP has not been found to occur naturally in the environment
    (ECETOC, 1992b).

    A3.2  Anthropogenic sources

    A3.2.1  Production levels and processes

         TBEP is produced by reacting phosphorus oxychloride and
    butoxyethanol (butyl glycol) and stripping hydrochloric acid and
    excess of butoxyethanol. Another production method uses the sodium
    salt of the glycol. In this case, the by-product is sodium chloride
    (ECETOC, 1992b).

         The world global production has been estimated to be 5000-6000
    tonnes, with less than 1000 tonnes in Europe.

    A3.2.2  Uses

         TBEP is used mainly as a component in floor polishes, a solvent
    in some resins, a viscosity modifier in plastisols, an antifoam and
    also as a plasticizer in synthetic rubber, plastics and lacquers. TBEP
    is widely used as a plasticizer in rubber stoppers for vacutainer
    tubes and plastic ware.
    

    A4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

    A4.1  Transport and distribution between media

         All environmental TBEP derives from human activities but the
    input rate to the environment cannot be estimated from the available
    data. The input is expected to be mainly to soil, sediments and
    surface waters from leachates from plastics on landfills, from
    spillages and from effluents (ECETOC, 1992b).

         The low vapour pressure, the high soil sorption coefficient
    (Koc) and the water solubility of approximately 1 g/litre suggests
    that TBEP in the environment will be found mainly in water and
    sediment. TBEP has been detected in surface water and sediments
    (ECETOC, 1992b).

    A4.2  Biodegradation

         No data are available on mechanisms of abiotic or biotic
    transformation. Analogy with other phosphate esters suggests that
    enzymatic hydrolysis would be expected to dominate (ECETOC, 1992b).

         TBEP was readily biodegradable when tested in the OECD 301B
    assay, achieving 87% degradation within 28 days (Mead & Handley 1998).

         In a test of primary biodegradation using the semi-continuous
    activated sludge procedure and an addition rate of 3 mg TBEP/litre per
    test cycle, 88% of TBEP was eliminated. The ultimate biodegradability
    (using the Monsanto shake-flask procedure) was 51% of the theoretical
    CO2 generated after 28 days (Monsanto, 1976).

         Hattori et al. (1981) studied the degradation of TBEP in
    environmental water in 1979-1980. Using the molybdenum blue
    colorimetric method, the increase of phosphate ions was analysed in Oh
    and Neya river water and seawater from Osaka Bay to which
    1 mg TBEP/litre had been added. The degradation depended on the source
    of the water (Table 1).

        Table 1.  Biodegradation of TBEP in water in percentages
              (from Hattori et al., 1981)
                                                                                 

    Test            Oh River          Neya River              Osaka Bay       
    duration                                            Tomagashima    Senboku
    (days)                                              seawater       seawater
                                                                                 

    7               29.1              0                 1.9a           0

    14              100b              100               17.6           100
                                                                                 
    a  Test duration 8 days
    b  Test duration 15 days
    
         A sterilized distilled water control did not show any degradation
    after 15 days. TBEP was rapidly degraded in less than 14 days after an
    acclimatization period of several days in water containing
    micro-organisms. Where degradation was rapid, the phosphatase activity
    increased during the test period.

         TBEP was eliminated from estuarine water with a half-life of
    approximately 50 days (Ernst, 1988).

    A4.2.1  Migration

         LeBel & Williams (1983a) investigated the difficulties of
    obtaining representative water samples and the importance of designing
    suitable sampling protocols. TBEP was detected in tap water at
    concentrations from 11.0 to 5400 ng/litre. The authors suggested that
    the TBEP originated from the O-ring and seal in the tap.
    

    A5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    A5.1  Environmental levels

    A5.1.1  Air

         An indoor aerosol sample was collected in a large building in New
    Jersey, USA. The abundance of TBEP was greatest both for particles
    larger than 7.0 µm diameter and for those smaller than 1.1 µm; there
    was considerably less material present in the intermediate size
    ranges. This pattern is consistent with its use in floor polish.
    Buffing operations generate relatively large particles which are
    likely to contain TBEP. However, this compound may also migrate from
    the floor polish and be attached to particles. In this case the
    majority of the adsorbed TBEP would accumulate in the submicron size
    range (Weschler, 1980). The mean concentrations measured in
    representative samples of dust from air in 7 offices in the USA was
    reported to be 15 ng/m3 (Weschler & Shields, 1986). The significance
    of floor polish, which may contain 1% TBEP (Nakashima et al., 1993),
    as a source of these particulates is suggested by the fact that the
    highest concentration measured (25 ng/m3) was found immediately
    following floor polishing work by a night crew.

         Airborne concentrations of fine (2.5 µm) and coarse aerosol
    (2.5-15 µm) particles were simultaneously measured outside and inside
    two buildings, one in Wichita, Kansas, USA, during the fall and early
    winter (1981-1982) and the second one in Lubbock, Texas, USA, during
    late winter and spring 1982. The average indoor concentrations of TBEP
    in Wichita and Lubbock were 4 and 25 ng/m3, mainly in fine aerosol
    particles. TBEP was not found in outdoor aerosol particles (Weschler,
    1984).

         Yasuda (1980) reported the results of a study of 19 outdoor air
    samples from 7 locations in 1976. Two samples from Kawauchi Town
    contained 149.1 and 176.8 ng TBEP/m3 and one from Ehime University
    9.6 ng TBEP/m3. TBEP was not detected in the other 16 samples.

    A5.1.2  Water (drinking-water and surface water)

         Levels of TBEP have been determined in rivers, sewage, tap water,
    lakes and estuaries. The investigations have been carried out in the
    Great Lakes area of Canada, USA, Japan, Germany and the United
    Kingdom.

         The lower part of the River Weser (over 33 km), Germany, was
    examined for the presence of TBEP during the period May 1985 to April
    1987. TBEP was found at a mean concentration of 125 ng/litre.
    Systematic measurements of effluent samples from five sewage treatment
    plants in the Bremen region showed concentrations of TBEP ranging from
    800 to 34 900 ng/litre (Bohlen et al., 1989).

         Ernst (1988) analysed water of the estuary of the Rivers Elbe and
    Weser, Germany, for the presence of TBEP during the period 1983-1985.
    The concentrations that were found ranged from 5 to 70 ng/litre.

         One hundred samples of surface water were collected from various
    locations throughout Japan in 1975 and analysed for the presence of
    TBEP. TBEP was identified in none of the samples (the limit of
    determination ranged from 0.02 to 0.5 µg/litre). In 1978, 114 samples
    were analysed in Japan and TBEP was not identified (the limit of
    determination ranged from 0.005 to 1.5 µg/litre) (Environmental Agency
    Japan, 1978, 1983, 1987).

         In a survey conducted between 1989 and 1990, Fukushima et al.
    (1992) identified TBEP in Lake Biwa, Yodo River and also in the Yamato
    Osaka Rivers and Osaka Bay at levels of about 0.2-2.5 µg/litre.

         Drinking-water was collected in Japan over a 12-month period and
    analysed. Concentrations ranging up to 0.0585 ng/litre were found
    (Adachi et al., 1984).

         Two samples of drinking-water collected from six Eastern Ontario
    water treatment plants in the period June-October 1978 contained
    0.9-75.4 ng/litre (LeBel et al., 1981). In another study two samples
    of drinking-water were collected from five Great Lakes water treatment
    plants of Eastern Ontario and analysed for TBEP. The concentration
    found in surface water samples ranged from 9.8 to 54.4 ng/litre as
    determined by GC/MS. When determined by GC/NPD, concentrations of 0.4
    to 73.8 ng/litre were found (LeBel et al., 1987).

         Williams et al. (1982) collected samples of drinking-water from
    12 Ontario municipal water treatment plants which draw their water
    from the Great Lakes system in January and August 1980. All samples
    contained TBEP at concentrations ranging from 1.6 to 271.6 µg/litre.
    The authors noted that TBEP is a common constituent of rubber gaskets
    and washers and can be introduced into water from components of the
    tap used for sampling.

         In 1983, LeBel et al. (1983a) found up to 5400 ng/litre in a
    sample of drinking-water taken after non-use of the tap for 65 h.

         In the period August 1976 to March 1977, 16 grab samples of river
    water were collected from the Delaware River, USA (between river mile
    78 and 132). In addition to other compounds, TBEP was identified in
    all samples. The concentrations ranged from 0.3 to 3.0 µg/litre in the
    winter and from 0.4 to 2.0 µg/litre in the summer (Sheldon & Hites,
    1978).

    A5.1.3  Soils and sediment

         TBEP was detected in 7 out of 80 samples of sediment collected at
    different locations in Japan in 1975. The concentrations ranged from
    0.22 to 0.54 mg/kg and the limit of determination was 0.002-0.1 mg/kg.
    In 1978, none of the 114 sediment samples collected at different
    places in Japan contained TBEP (limit of determination 0.0005-0.12
    mg/kg) (Environmental Agency Japan, 1978, 1983).

         Watts & Moore (1988) did not detect TBEP in suspended particles
    or bottom sediments in a river in the United Kingdom, even though TBEP
    was found in corresponding water columns.

    A5.1.4  Aquatic organisms

         No TBEP could be detected in 74 samples of fish from numerous
    locations throughout Japan (limit of determination 0.005-0.1 mg/kg).
    Another report from the same agency stated that TBEP was not found in
    93 fish samples (limit of determination 0.0005-0.15 mg/kg)
    (Environmental Agency Japan, 1978).

    A5.2  Human tissue levels

         LeBel & Williams (1983b) analysed 16 samples of human adipose
    tissue for TBEP. Four of sixteen samples contained TBEP at
    concentrations of 4.0-26.8 µg/kg. LeBel & Williams (1986) reported the
    results of 115 human adipose tissue (omentum) samples for TBEP,
    obtained at autopsy of humans from the Eastern Ontario cities,
    Kingston and Ottawa, Canada. TBEP was detectable in 21 out of 68 male
    adipose tissue samples and in 20 out of 47 female samples. Although
    the frequency of detection was similar in the two cities, mean
    concentrations in Ottawa were about 2.5 times those in Kingston. In
    both cities the concentrations in women were 2-3 times greater than in
    men. The arithmetic mean concentration of TBEP in the 41 detectable
    samples was 11.3 µg/kg in extracted fat (in males 6.3 µg/kg and in
    females 16.6 µg/kg). The mean concentration overall was 4.2 µg/kg in
    extracted fat. In a different study, LeBel et al. (1989) showed the
    presence of TBEP in human adipose tissue autopsy samples from 3 out of
    6 Ontario (Canada) municipalities (based on a detection limit of 20
    ng/g). No statistical difference between sexes was found, the mean
    concentration being 396 ± 56 ng/g in Toronto and 173 ± 32 ng/g in
    Cornwall.

    A5.3  Food

         In a series of articles Gunderson (1988, 1995a,b) reported data
    on daily intake of TBEP for a range of age groups and for a period
    between 1982 and 1991 from the USA FDA Total Diet Study (see Table 2).

         Similar data were collected in a parallel study on ready-to-eat
    food from 1982 to 1991. TBEP was found in 5 out of 230 food items
    (baby food, ketchup, grapefruit juice, strawberries, tomatoes) and in
    5 out of 17 050 chemical or pesticide samples, with an average
    concentration per residue of 0.28 µg/g (Kan-Do Office and Pesticides
    Team, 1995).

    A5.4  Occupational exposure

         The only data on occupational exposure to TBEP is from an office
    environment. Weschler & Shields (1986) measured a mean concentration
    of 15 ng/m3 in dust samples from some offices in the USA. NIOSH (USA)
    has estimated that the number of workers exposed to TBEP is more than
    200 000.

    

    Table 2.  Mean daily intake of TBEP per unit body weight (µg/kg body weight per day)
              according to age and gender
                                                                                                             

                 6-11        2 years      14-16 years old           25-30 years old         60-65 years old
                 months      old        females     males         females      males       females   males
                 old
                                                                                                             

    1982-1984    0.0029      0.0144     0.0084      0.0077        0.0129       0.0107      0.0168    0.0137

    1984-1986    0.0002      0.0015     0.0007      0.0011        0.0004       0.0008      0.0002    0.0002

    1986-1991    0.0052      0.0037     0.0012      0.0011        0.0020       0.0009      0.0034    0.0028
                                                                                                             

        


    A6.  KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS

         No data are available on the kinetics or metabolism of TBEP
    either in animals or humans.

         The Task Group considered that 2-butoxyethanol is a metabolite.
    Information on the toxicity of 2-butoxyethanol is given in IPCS
    (1998).
    

    A7.  EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

    A7.1  Single exposure

    A7.1.1  Oral and dermal

         The acute toxicity of TBEP following oral or dermal
    administration is low (Table 3).

        Table 3.  Acute toxicity of TBEP
                                                                              

    Species    Route       LD50                       Reference
                           (mg/kg body weight)
                                                                              

    Rat        oral        3000                       Eldefrawi et al. (1977)
    Rat        oral        4700                       Monsanto (1984c)
    Rabbit     dermal      >5000                      Gabriel (1980c)
    Rabbit     dermal      >10 000                    Report ICD/T.76.019
                                                      by FMC Corporation,
                                                      Princeton, NJ, USA (1976)
                                                                              
    
         An acute oral toxicity study was conducted according to the
    "fixed dose" procedure. Two out of three male rats but no females died
    at 5000 mg/kg body weight; no rats died at 500 mg/kg body weight.
    Signs of toxicity included chromorhinorrhoea, dyspnoea and decreased
    locomotion (Freeman, 1991a).

    A7.1.2  Inhalation

         The median lethal concentration in air has been investigated in a
    4-h aerosol inhalation test (Hoechst, 1989). Groups of five male and
    five female Wistar rats were exposed to measured TBEP concentrations
    of 3.3, 3.4 or 6.4 mg/litre. No animal died but at all concentrations
    the animals exhibited depressed and irregular respiration, increased
    salivation, sneezing, unsteadiness and tremor, but these symptoms had
    cleared in most animals 9 days later. There were no body weight
    changes and gross necropsy revealed no abnormality. The 4-h LC50 was
    thus >6.4 mg/litre.

         The 4-h LC50 in rats was reported to be greater than 4.43
    mg/litre determined gravimetrically (particle size 2.46 ± 2.52 µm)
    (Mount 1991).

    A7.2  Short-term repeated exposure

    A7.2.1  Oral

         In a 14-day oral dosing regime using male and female rats, where
    the highest dose was 100 mg/kg body weight per day, a comprehensive
    biochemical, haematological and histopathological evaluation showed no
    changes (Komsta et al., 1989).

         In a 4-week study, diets containing 0, 500, 2000, 7500 or 
    15 000 mg TBEP/kg were fed to male and female Sprague-Dawley rats. 
    No signs of toxicity were found in male rats of any group whereas 
    there was a slight decrease in body weight and food consumption in 
    females receiving diets containing 7500 or 15 000 mg/kg diet. No
    compound-related changes were observed at necropsy (Monsanto, 1985a).

         In a 14-week oral toxicity study with TBEP, Wistar rats (5 weeks
    old, male and female, 15 rats/group) were given a diet containing 0,
    0.3, 3 or 30 g TBEP/kg. Suppression of body weight gain was observed
    in both sexes at 30 g/kg. Serum cholinesterase activity was
    significantly decreased in both sexes at 3 and 30 g/kg, and serum
    gammaglutamyl transferase activity was significantly increased in both
    sexes at 30 g/kg. Examination of the liver in both sexes revealed
    moderate periportal hepatocyte swelling in male rats at 30 g/kg after
    14 weeks of exposure but this change was not found in male rats given
    3 g/kg or less. The no-observed-effect level (NOEL) of TBEP in the
    diet was 0.3 g/kg diet (for males 20 mg/kg body weight per day and for
    females 22 mg/kg body weight per day. The Task Group considered the
    NOAEL of this study to be 3 g/kg diet (Tsuda et al., 1993; Saitoh et
    al., 1994).

         In a gavage study, groups of 12 male and 12 female Sprague-Dawley
    rats were administered 0, 0.25 or 0.5 ml/kg body weight undiluted TBEP
    on 5 days/week for 18 weeks. During the first week, two high-dose
    females showed muscular weakness and ataxia which had disappeared by
    the end of the fourth week. After about 7 weeks, nearly all animals
    exhibited some signs of toxicity, which seemed to be treatment
    related. All treated animals appeared less active, and one female died
    during week 13. Breathing difficulties and ataxia were present in
    several males and females in both treatment groups, though the
    low-dose group was affected to a lesser extent. Tremors, piloerection,
    lacrimation and increased urination were observed in both males and
    females of the high-dose group. After the last dose, the clinical
    signs observed in the high-dose group decreased in intensity.
    High-dose females had significantly elevated level of serum
    gamma-glutamyltransferase. Red cell acetylcholinesterase (AchE)
    activity was significantly reduced in males at both doses. There were
    no haematological changes. Animals were necropsied one week after the
    last dose. Liver weight was significantly increased (about 20%) in
    both high- and low-dose groups. Kidney weight was increased by about
    20% in both groups and the increase was statistically significant in
    high-dose groups. Histopathological changes were confined to the heart
    of male rats of both groups. Three of six high-dose and two of six

    low-dose animals had multiple foci of mononuclear cell infiltration,
    haemorrhages and/or myocardial fibre degeneration. Two of six
    high-dose, three of six low-dose and one of six control rats
    demonstrated multifocal interstitial fibrosis with or without
    macrophage containing haemosiderin pigment. The authors concluded that
    TBEP may have accelerated the development of focal myocarditis, which
    is a normal feature of older male Sprague-Dawley rats. A NOAEL was not
    ascertained in this study (Laham et al., 1984a, 1985a).

         In an 18-week study, four groups of 20 male and 20 female
    Sprague-Dawley rats were fed diets containing 0, 300, 3000 or 10 000
    mg TBEP/kg. Body weight, food intake and clinical observations were
    similar in treated and control rats. Haematological and clinical
    chemistry parameters were normal except for increased platelet counts
    in the 10 000 mg/kg group, and increased serum
    gamma-glutamyl-transpeptidase and decreased plasma cholinesterase
    activity in the 3000 and 10 000 mg/kg groups. Liver weight was
    increased in the 10 000 mg/kg group. Microscopic examination showed
    mild periportal hepatocellular hypertrophy and periportal
    vacuolization in males receiving 3000 and 10 000 mg/kg in the diet.
    The NOEL was 300 mg/kg diet, equivalent to 15 mg/kg body weight per
    day (Monsanto, 1987a).

    A7.2.2  Dermal

         In a 21-day dermal toxicity study on New Zealand White rabbits,
    groups of 6 male and 6 female animals were treated with TBEP
    applications of 0, 10, 100 or 1000 mg/kg body weight per day,
    5 days/week for 3 weeks. The unabraded dorsal clipped skin was used.
    The tests sites were occluded for 6 h after each exposure. No animals
    died and no adverse clinical signs of pharmacological/toxicological
    effects were observed. There was no indication that dermal exposure to
    1000 mg/kg body weight per day resulted in any adverse systemic
    effect, but local irritation, oedema, atonia and desquamation occurred
    at all dose levels (Monsanto, 1985b).

    A7.3  Skin and eye irritation; sensitization

         In three studies TBEP was non-irritating to intact and abraded
    skin when applied topically to albino rabbits. (Gabriel 1980b;
    Monsanto, 1984c; Freeman, 1991b).

         In the 21-day dermal toxicity study on New Zealand White rabbits,
    slight to moderate erythema was noted. The skin irritation was 
    dose-related and severity progressed over time. Microscopic 
    observations of the skin (of the 1000 mg/kg group) showed squamous 
    cell hyperplasia, hyperkeratosis, hair follicles distended with 
    keratin and surface accumulation of keratin and cellular debris, 
    erosions ulcers, acute/subacute inflammation and congestion and 
    haemorrhages in various combinations (Monsanto, 1985b) (see also
    section A7.2.2).

         In four studies TBEP was non-irritating to the eyes of albino
    rabbits (Gabriel 1980a; Monsanto, 1984c; Freeman, 1991c; personal
    communication from Hoechst AG, Frankfurt, Germany entitled: Eye
    irritation test on New Zealand rabbit with TBEP, 1988).

         No animal data are available on skin sensitization potential.

    A7.4  Reproductive toxicity, embryotoxicity and teratogenicity

         TBEP was administered by gavage in corn oil to three groups of 25
    mated Charles River CD female rats at dose levels of 0 (corn oil),
    250, 500 or 1500 mg/kg body weight per day on days 6 to 15 of
    gestation. The treatment had no effect at any dose level on fetal
    resorption, fetal viability, post-implantation loss, total
    implantations or the incidence of fetal malformations. The NOEL was
    the highest dose level tested, 1500 mg/kg body weight (Monsanto,
    1985e). In an earlier range-finding study maternal weight loss was
    observed in animals receiving 2000 mg/kg but not 1000 mg/kg body
    weight per day (Monsanto, 1985d).

    A7.5  Mutagenicity and related end-points

         A mutagenicity test was carried out with  Salmonella
     typhimurium strains TA1535, TA1538, TA1537, TA98 and TA100, with and
    without metabolic activation. Liver S9 fractions were used from male
    Sprague-Dawley rats or from male Syrian hamsters induced by Aroclor
    1254. TBEP was non-mutagenic (MacKeller, 1978)

         TBEP was tested for mutagenic activity with  Salmonella
     typhimurium strains TA98, TA100, TA1535 and TA1537, in the presence
    and absence of rat liver metabolic system, in comparison with positive
    controls. The concentrations tested were 0, 50, 100, 500, 1000, 5000
    and 10 000 µg/plate with and without S9. Toxicity to strain TA100 was
    observed at 5000 and 10 000 µg/plate in the presence and absence of
    metabolic activation. The same effect was seen at 10 000 µg/plate with
    TA1535 and TA98 in the absence of S9 mix. TBEP did not cause any
    mutagenic response either with or without metabolic activation
    (Monsanto, 1984d).

         A CHO/HGPRT mammalian cell forward gene mutation assay with TBEP
    was carried out. The tests were conducted at 50, 100, 150, 225 and 300
    µg/ml with S9 and at 5, 50, 75, 100 and 130 µg/ml without S9. TBEP was
    not mutagenic (Monsanto, 1985c).

    A7.6  Carcinogenicity

         No data on the carcinogenicity of TBEP are available.

    A7.7  Special studies

    A7.7.1  Neurotoxicity

    A7.7.1.1  Acute administration

         An acute delayed neurotoxicity study was carried out using groups
    of 20 hens. Dermal or oral (in gelatin capsules) TBEP doses of 5000
    mg/kg body weight were administered at the start of the study and
    again 21 days later. Positive control hens were given 750 mg/kg body
    weight of tri- ortho-cresyl phosphate (TOCP) at the same time
    intervals. Negative controls were either untreated (dermal study) or
    given empty capsules (oral study). All hens were treated with 15 mg/kg
    body weight of atropine sulfate three times a day for 5 days following
    each dosing. Hens were killed 21 days after being given the final
    dose, and histological preparations were made from brain, spinal cord
    and peripheral nerves. No treatment-related lesions were detected in
    the nerves of TBEP-treated hens. TBEP had no effect on neuropathy
    target esterase (NTE). Brain and plasma cholinesterases were inhibited
    in treated hens (Carrington et al., 1990).

         In another study, groups of five hens were treated orally with
    TBEP (5000 mg/kg), with TOCP (750 mg/kg) as positive control group, or
    with the capsules alone. The animals were killed 24 h after treatment.
    Brain AChE, brain neuropathy target esterase (NTE) and plasma
    butyrylcholinesterase (BuChE) activity was measured. No differences
    were seen between control and TBEP-treated brain NTE activity,
    although plasma BuChE and brain AChE levels in TBEP-treated hens were
    depressed to 5% and 13% of the control group, respectively (Monsanto,
    1986).

         Laham et al. (1985b) reported the results of the administration
    by gavage to Sprague-Dawley rats of a single dose of TBEP (98.2%).
    Groups of randomized female and male rats (10 rats of each sex per
    dose level) were used. The doses were 1.0, 1.5, 1.75, 2.0 and 3.2 g/kg
    for females and 1.0, 3.2, 6.8, 8.0 and 9.0 g/kg body weight for males.
    Three weeks after the administration of TBEP, electrophysiological
    parameters were determined in four or less surviving animals for each
    group, selected from survivors showing overt clinical signs.
    Reductions in caudal nerve conduction velocity and increases in
    refractory period (in males) were observed. Sciatic nerve sections
    showed degenerative changes in some myelinated and unmyelinated
    fibres. It should be noticed that the doses were in the region of or
    greater than the LD50. There was a high mortality. Survivors were ill
    and had marked weight loss.

         The Task Group considered this study of inadequate quality for
    use in risk evaluation.

         A study of similar design as the oral study of Monsanto (1986)
    but with dermal application of 5000 mg/kg body weight both on day 0
    and on day 21 showed no clinical signs of toxicity in chickens
    (Monsanto, 1986).

    A7.7.1.2  Repeated oral administration

         In a 14-day repeated-dose study on Sprague-Dawley rats dosed at
    0.8 to 2.24 ml/kg body weight (08-2.28 g/kg), electro-physiological
    measurements were made on days 15 and 28. Apart from a significant
    decrease in the body weight of low-dose females at 7 days, there were
    no clinical signs or significant differences between dosed groups and
    controls in the 14-day study. Minor and inconsistent changes in
    electro-physiological parameters were reported. No morphological
    changes were found using light or electron microscopy (Laham et al.,
    1984b).

         A second study (Lahman et al., 1984a) involved dosing on 5 days
    per week for 18 weeks at dose levels of 0 (0.5 ml water), 0.25 and 0.5
    ml/kg body weight (0.25-0.51 g/kg) with observations at 6, 12 and 18
    weeks. There were no significant body weight differences between
    exposed groups and their controls at any stage. A few females (2/12)
    from the high-dose group showed, at the beginning of the experiment,
    transient muscular weakness and ataxia which disappeared 4 weeks
    later. In the second half of the study almost all treated animals
    exhibited tremors, piloerection, lacrimation and increased urination.
    Males were less affected than females.

         Electro-physiological changes were observed at 18 weeks in all
    test animals (Table 4) and included a statistically significant
    reduction in nerve conduction velocity and a significant increase of
    both relative and absolute refractory periods. The increased
    refractory period and the decreased conduction velocity were 
    dose-related in females, but in males the maximum effect appears to 
    have been reached by the low dose, suggesting that the magnitude of 
    the maximum attainable neurophysiological changes is modest. Three 
    animals of each sex at each dose level were examined for 
    neurohistological abnormalities by light and electron microscopy of 
    the sciatic nerve. Most of the treated animals showed the presence of 
    some degenerative myelin sheaths accompanied by axonal swelling and an 
    advanced stage of degeneration, indicated by the presence of 
    lamellated electron-dense inclusions in unmyelinated nerve fibres
    (Laham et al., 1984a).

         In the 18-week studies of Monsanto (1987a,b), TBEP was
    administered to four groups of 20 male and 20 female Sprague-Dawley
    rats at concentrations of 0, 300, 3000 and 10 000 mg/kg diet for
    approximately 18 weeks. No clinical signs of neurotoxicity were
    observed. The only neurophysiological alteration observed was reduced
    caudal nerve conduction velocity in high-dose females, and there were
    no treatment-related changes in peripheral nerve or spinal cord
    histopathology.


        Table 4.  Electro-physiological parameters at 18 weeks in rats treated with TBEP
              (Laham et al., 1984a)a
                                                                                                    

                                    Control (water)         Low-dose TBEP        High-dose TBEP
                                 Males       Females      Males     Females    Males      Females
                                                                                                    

    Number of animals            12          12           12        12         12         12

    Dose (ml/kg
    per day)                     -           -            0.25      0.25       0.5        0.5

    Nerve conduction
    velocity (m/s)               36.3        36.3         30.7b     32.0b      30.1b      30.8b

    Absolute refractory
    period in caudal nerve (ms)  1.02        0.95         1.24b     1.26b      1.24b      1.34b

    Relative refractory
    period in caudal nerve (ms)  2.06        1.93         2.39b     2.33b      2.32b      2.43b
                                                                                                    

    a  results at 6 and 12 weeks were quantitatively similar to those at 18 weeks
    b  P<0.001
    

    A7.7.1.3  Effects on esterase activity

         Laham et al. (1984b) reported a 5-7% reduction in red cell
    cholinesterase activity at 18 weeks in male rats dosed by gavage with
    0.25 or 0.5 ml TBEP/kg body weight per day but no reductions in female
    rats.

         A study was made of the effect of TBEP on NTE, brain AChE and
    plasma BuChE in three groups of five hens. Each was administered a
    single oral dose of 5000 mg TBEP/kg body weight. All animals were
    killed 24 h after treatment. The NTE activity was unchanged but plasma
    BuChE and brain AChE levels were depressed to 5% and 13%,
    respectively, of control levels (Monsanto, 1986).

         In an acute delayed neurotoxicity study in hens, two doses of
    5000 mg TBEP/kg body weight were given 21 days apart, each followed by
    antidote treatment with atropine. There was no effect on NTE activity,
    whereas brain AChE and serum BuChE were inhibited (Carrington et al.,
    1990).
    

    A8.  EFFECTS ON HUMANS

         A repeat human insult patch test on a panel of 209 volunteers was
    undertaken by Monsanto (1984e). In the 3-week induction period, four
    applications per week of 0.2 ml of the test material were applied for
    24 h to occluded skin. During the fourth week, four similar
    applications were made to previously untreated sites. During
    induction, minimal irritation was observed in 9 of the individuals.
    The irritation was only seen once or twice during the 12 applications.
    There was no dermal reaction to challenge applications. The results
    indicate minimal skin irritation and do not indicate any sensitizing
    potential.
    

    A9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

    A9.1  Laboratory experiments

    A9.1.1  Aquatic organisms

    A9.1.1.1  Invertebrates

         The 24-h and 48-h LC50 values for TBEP in  Daphnia magna were
    84 mg/litre and 75 mg/litre, respectively. The no-observed-effect
    concentration (NOEC) was 32 mg/litre (Monsanto, 1984a).

    A9.1.1.2  Vertebrates

         The 96-h LC50 in fathead minnow  (Pimephales promelas) was
    16 mg/litre (95% confidence interval 13-22 mg/litre) at 22°C
    (Monsanto, 1984b). The 48-h LC50 values in killifish  (Oryzias
     latipes) at 10, 20 and 30°C were 44 mg, 27 mg and 6.8 mg/litre,
    respectively (Tsuji et al., 1986).

         In goldfish  (Carassius auratus) Eldefrawi et al. (1977)
    reported no death at 5 mg/litre after 168 h (temperature 20°C).

         In rainbow trout  (Oncorhynchus mykiss), a 96-h LC50 of
    24 mg/litre and a NOEC of 10 mg/litre were reported in a test
    conducted under OECD guideline 203 (Wetton & Handley, 1998).
    

    PART B


    TRIS(2-ETHYLHEXYL) PHOSPHATE
    (TEHP)

    B.  SUMMARY, EVALUATION AND RECOMMENDATIONS

    B1.  Tris (2-ethylhexyl) phosphate (TEHP)

    B1.1  Summary

         Tris(2-ethylhexyl) phosphate (TEHP) is a non-flammable,
    colourless liquid with low water solubility and very low vapour
    pressure, which is used as a flame retardant and plasticizer for PVC
    and cellulose acetate and as a solvent. It is produced from phosphorus
    oxychloride and 2-ethylhexanol. Figures for current worldwide
    production are not available. Approximately 1000 tonnes are currently
    produced in Germany.

         TEHP has not been detected in outdoor air; it has been detected
    in indoor air at concentrations of less than 10 ng/m3, in river water
    at concentrations of up to 7500 ng/litre and in sediments at 
    2-70 ng/g. TEHP was detected in a single sample of drinking-water at 
    0.3 ng/litre. Reported daily dietary intake from market basket 
    studies, from a range of age groups, was less than 0.05 µg/kg body 
    weight per day.

         TEHP is rapidly biodegraded in natural waters, but in laboratory
    tests with activated sludge the results were equivocal. There is no
    significant abiotic degradation.

         TEHP has a low acute toxicity for mammals, the oral LD50 being
    >10 000 mg/kg body weight for rats.

         TEHP is a skin irritant but not an eye irritant. Repeated
    application of 0.1 ml (93 mg) TEHP to the skin of rabbits produced no
    signs of systemic intoxication.

         Thirteen-week gavage studies in rats and mice revealed no
    significant toxic effects. The no-observed-adverse-effect level
    (NOAEL) in rats was 2860 mg/kg body weight per day and in mice was
    5710 mg/kg body weight per day, the highest dose tested in each
    species.

         In a 3-month inhalation study at concentrations up to 85.0 mg
    TEHP/m3, the lungs of dogs showed mild chronic inflammatory changes,
    and conditioned avoidance performance deteriorated in relation to the
    concentration administered.

         No studies on reproductive toxicity were available.

         TEHP gave negative results in several  in vivo and  in vitro 
    tests for mutagenicity.

         TEHP was tested for chronic toxicity and carcinogenicity in rats
    and mice. The NOAEL for chronic toxicity in male rats was 2857 mg/kg
    body weight per day and in female rats was 1428 mg/kg body weight per

    day. In male and female mice, the lowest-observed-adverse-effect level
    (LOAEL) for thyroid follicular cell hyperplasia was 357 mg/kg body
    weight per day. A NOAEL in mice was not established. The authors
    concluded there was some evidence of carcinogenicity based on an
    increased incidence of hepatocellular carcinomas in female mice at the
    high-dose level and equivocal evidence of carcinogenicity based on the
    increased incidence of adrenal phaeochromocytomas in male rats in both
    dose levels. Although there were increases in adrenal
    phaeochromocytomas in both dose groups of male rats and in
    hepatocellular carcinomas in female mice in the high-dose group, these
    results are not considered to indicate that TEHP presents a
    significant carcinogenic risk to humans. Phaeochromocytomas show a
    variable background incidence in rats. The incidences of these tumours
    in two previous National Toxicology Programme (NTP) bioassays were
    equal to the incidence observed in the TEHP bioassay. The only other
    significant neoplastic finding was hepatocellular carcinomas in the
    high-dose group of female mice. Considering the low incidence of this
    tumour, its occurrence in only one sex of one species, the lack of
    evidence of genetic toxicity, and the low exposure of humans to TEHP,
    it is unlikely that TEHP poses a significant carcinogenic risk to
    humans.

         Neurotoxicity studies have been conducted in several species.
    TEHP causes no alteration in activity of plasma or red blood cell
    cholinesterase. No studies on delayed neurotoxicity have been
    reported.

         In a study on human volunteers, no skin irritation was reported.

         The few data available indicate a low acute aquatic toxicity of
    TEHP. The IC50 for bacteria is greater than 100 mg/litre and the 96-h
    LC50 for zebra fish  (Brachydanio rerio) is greater than
    100 mg/litre, which is the solubility limit of TEHP in water.

    B1.2  Evaluation

         Occupational exposure to TEHP is likely to be by the dermal route
    during manufacture (accidental exposure) and from the use of some
    products. The compound is absorbed dermally in experimental animals
    but no information is available on its kinetics or metabolism via this
    route. Dermal exposure cannot, therefore, be quantified but is
    expected to be low. Inhalation exposure in the office environment has
    been measured to be 10 ng/m3 or less.

         Exposure of the general population is principally via food and
    drinking-water. Exposure from both sources is very low (estimated to
    be <0.05 µg/kg body weight per day from the diet; a single measured
    concentration in drinking-water was 0.3 ng/litre).

         Given the reported LOAEL for thyroid hyperplasia of 357 mg/kg
    body weight per day in mice, the risk to the general population is
    very low. The risk to those exposed occupationally is also considered
    to be very low, although this cannot be quantified.

         TEHP is not considered to be carcinogenic in humans.

         In the environment, TEHP is expected (from its low volatility,
    high adsorption coefficient and low water solubility) to partition to
    sediment. Measured data are too few to confirm this. Degradation in
    environmental media is expected, although laboratory data on
    degradation in sewage sludges are equivocal. No information is
    available on breakdown products; phosphate released during breakdown
    is not expected to contribute significantly to environmental nutrient
    levels. Fig. 2 plots measured environmental concentrations in
    environmental media against reported acute toxicity values (the latter
    indicating no toxic effects at the limit of water solubility). The
    margin of safety between highest reported concentrations and lowest
    reported toxicity values is several orders of magnitude, indicating
    low risk to organisms in the aquatic environment. No assessment of
    risk can be made for the terrestrial compartment.

    B1.3  Recommendations

         For full scientific evaluation of the compound, identification
    and assessment of metabolites in mammals would be required, given
    the toxicological profile of one of the suggested metabolites,
    2-ethylhexanol.

         Reproductive toxicity needs to be investigated, in particular the
    potential for developmental effects.

    FIGURE 3
    

    B2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL
         METHODS

    B2.1  Identity

    Chemical structure:

    CHEMICAL STRUCTURE 2

    Chemical formula:          C24H51O4P

    Relative molecular mass:   434.64

    CAS registry number:       78-42-2

    EINECS number:             201-116-6

    RTECS number:              MP-0770000

    CAS name:                  phosphoric acid, tris(2-ethylhexyl) ester

    Synonyms:a                 1-hexanol 2-ethyl-phosphate;
                               2-ethyl-1-hexanol phosphate; triethylhexyl
                               phosphate; tri(2-ethylhexyl) phosphate;
                               tris(isooctyl) phosphate 

    Trade names:               Disflamoll TOF; Flexol TOF; Reomol TOP;
                               Amgard TOF; Antiblaze TOF


                   

    a  The synonym trioctyl phosphate has also been
       used. However, this chemical has a different
       chemical abstracts (CAS) registry number 
       (1806-54-8).

    B2.2  Physical and chemical properties

         Tris(2-ethylhexyl) phosphate (TEHP) is a colourless to light
    yellow liquid, non-flammable and nearly odourless (Arias, 1992).

    Boiling point:         220°C at 6.67 hPa;
                           210°C at 5 hPa

    Melting point:         -74°C

    Pour point:            -70°C

    Relative density:      0.926 at 20°C

    Refractive index:      1.4426 at 20°C

    Vapour pressure:       <0.1 hPa at 20°C

    Viscosity:             10.2 cP

    Stability:             stable under normal storage conditions; can
                           react with oxidizers

    Flash point:           190-195°C

    Solubility:            soluble in acetone, ether and ethanol;
                           in DMSO 1.0 mg/litre at 18°C;
                           in water less than 0.1 g/litre at 20°C

     n-Octanol/water
    partition coefficient  4.22

    From: MacFarland & Punte (1966); Saeger et al. (1979); Keith & Walters
    (1987); Hinckley et al. (1990); FMC (1998).

    B2.3  Conversion factors

         1 ppm          =    17.78 mg/m3
         1 mg/m3        =    0.056 ppm

    B2.4  Analytical methods

         The analytical methods for TEHP are based on gas chromatography
    combined with flame ionization detection (FID), flame photometric
    detection (FPD), mass spectroscopy (MS) or nitrogen-phosphorus
    sensitive detection (NPD). The detection limits are in the ng/m3
    (air) and ng/litre (water) range.

         Lerche & Morch (1973) determined TEHP using GC combined with FID
    with a detection limit of 5-30 ng/litre. The separation of various
    phosphoric acid esters by GC was achieved using columns filled with
    various liquid silicone phases.

    B2.4.1  Air

         In a method described by Krzymien (1981), TEHP vapour and aerosol
    were collected in glass absorber tubes packed with a plug of fine
    platinum mesh coated with silicone packing material and subsequently
    thermally desorbed into a GC for analysis. The capacity of the
    absorber was found to be 2.1 ng pure TEHP when presented with 3 ng
    TEHP/litre. Concentrations of 20 pg/litre were determined with a
    precision of better than 10%. The aerosol concentration and its
    drop-size distribution were determined at the picogram level with
    around 5% precision using a cascade impactor. Armstrong & Yule (1978)
    determined TEHP deposited on foliage and twigs by extraction with
    toluene, drying with anhydrous sodium sulfate and using GC with FPD.

    B2.4.2  Water

         LeBel et al. (1981) used Amberlite(R) XAD-2 macroreticular resin
    to collect TEHP from drinking-water. The resin was extracted with an
    acetone/hexane mixture. TEHP was identified by GC and by GC/MS at
    ng/litre levels. The recovery by direct fortification was 62%.
    Determination of TEHP in extracts of activated carbon by means of
    GC/MS was described by Frimmel et al. (1987). TEHP was extracted from
    activated charcoal using a mixture of acetone, dichloromethane and
    toluene.

         Kawagoshi & Fukunaga (1994, 1995) showed, by extracting leachate
    with dichloromethane and analysing the residue by GC-FPD, that it was
    possible to detect organophosphoric acid triesters, including TEHP, at
    a limit of detection of 2 ng/litre.

    B2.4.3  Sediment

         Sediment samples were extracted with acetone and dried,
    concentrated and analysed by Ishikawa et al. (1985) in a similar way
    to that used for water samples. The limit of determination was 10
    ng/g.
    
    

    B3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    B3.1  Natural occurrence

         TEHP does not occur naturally in the environment.

    B3.2  Anthropogenic sources

    B3.2.1  Production levels and processes

         In 1992, approximately 1000 tonnes of TEHP were manufactured in
    Germany (BUA, 1997).

         Figures for the world production of TEHP are not available.
    ECETOC (1992a) estimated the world production to be between 1000 and
    5000 tonnes/year.

         TEHP is produced by reaction of phosphorus oxychloride and
    2-ethylhexanol. The triester is separated by vacuum distillation.
    Technical grade TEHP is usually 99% pure. The impurities are
    2-ethylhexanol, bis(2-ethylhexyl) phosphate (BEHP) and traces of water
    (ECETOC, 1992a).

    B3.2.2  Uses

         TEHP is used in PVC plastisols, as a flame retardant in cellulose
    acetate and as a solvent for certain chemical reactions. It is also
    used as a flame retardant plasticizer, particularly for PVC, in low
    temperature application (ECETOC, 1992a).
    

    B4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

    B4.1  Biodegradation

         Biodegradation of phosphoric acid esters involves stepwise
    hydrolysis to  ortho-phosphate and alcohol moieties. The alcohol
    would then be expected to undergo further degradation (Saeger et al.,
    1979).

         In a ready biodegradability closed bottle test (OECD Guideline
    301D), no biodegradation of TEHP was observed after 28 days (Bayer,
    1982a).

         An activated sludge method, based on a semi-continuous procedure,
    was used to test primary degradation of TEHP. The addition rate of the
    compound was 3 mg/litre per 24 h and the biodegradation was 20 (± 8)%
    after 34 weeks (Saeger et al., 1979).

         TEHP was rapidly biodegraded (50% in 48 h) by activated sludge
    (Ishikawa et al., 1985). After a 48-h acclimation period, the
    biodegradation increased to 60% during a further 48-h test period.

         Hattori et al. (1981) studied the fate of TEHP in river water and
    seawater from the Osaka Bay area, Japan. After addition of TEHP at a
    level of 1 mg/litre, the biodegradation was followed by analysing the
    increase in phosphate ion concentration using the molybdenum blue
    colorimetric method. The percentages of biodegradation are given in
    Table 5.

        Table 5.  Biodegradation of TEHP in river water and seawater
              (in percentages)
                                                                             

    Test duration    Oh River        Neya River              Osaka Bay    
    (days)                                          Tomogashima      Senboku
                                                    seawater         seawater
                                                                             

    7                35.9            24.4           1.2b             9.9
    14               65.2a           42.2           32.5             73.2
                                                                             

    a   Test period 15 days
    b   Test period 8 days
    
         In sterilized water TEHP did not show any degradation after
    15 days. The authors (Hattori et al., 1981) stated that the
    degradation rate depended on the microbial content of the water, and
    this view was supported by the increase of phosphatase activity
    observed during the test period.

         Similar results were reported by Kawai et al. (1985, 1986) for
    river die-away tests with TEHP in water samples from rivers of the
    Osaka City area, Japan. Depending on the bacterial content of the
    water, up to 80% degradation was observed. Usually the TEHP
    concentration decreased rapidly during the first 10 days. Fukushima &
    Kawai (1986) found that the removal of TEHP in a wastewater treatment
    plant (Osaka City) with aquatic bacteria was up to 99%.

    B4.2  Bioaccumulation

         Saeger et al. (1979) estimated the bioconcentration factor (BCF)
    of TEHP to be 250, suggesting that some uptake by biota could occur.
    

    B5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    B5.1  Environmental levels

    B5.1.1  Air

         In New Brunswick, Canada, forest ambient concentrations of TEHP
    in air were below the limit of determination (20 ng/m3 with a
    precision of ± 5%) (Krzymien, 1981).

         When samples of particulates in air were collected in a large
    building in New Jersey, USA, the relative abundance of TEHP in the
    submicron particle size range was much higher than in any larger size
    range, suggesting that its presence did not result from abrasion
    (Weschler, 1980). Airborne concentrations of TEHP were measured in
    fine (2.5 µm) and coarse (2.5 to 15 µm) particulate fractions
    collected on filters simultaneously outdoors and indoors in Wichita,
    Kansas, USA during the autumn and early winter of 1981-1982. The
    average indoor concentration was 6 ng/m3, but TEHP was not detected
    in outdoor air (Weschler, 1984). The mean concentration measured in
    representative samples of dust of seven office buildings in the USA
    was reported to be 5 ng/m3 (Weschler & Shields, 1986).

    B5.1.2  Surface water

         As a part of the German Monitoring Programme, water from the
    River Weser was examined for concentrations and loads of various
    chemicals including plasticizers. Several samples were taken at
    various points over 35 km of the river. The average concentration of
    TEHP over 10 sampling points did not exceed 10 ng/litre at any time.
    On one day in 1987 peak values of 290 ng/litre were measured,
    indicating direct emissions (Bohlen et al., 1989).

         Water samples from estuaries of the German rivers Elbe, Weser and
    Ems were analysed from 1977 to 1983. TEHP could be identified only in
    water samples from the estuary of the River Elbe, where concentrations
    were in the range of 1-5 ng/litre (Weber & Ernst, 1983). In a second
    series of water samples from the estuaries of the Elbe and Weser
    (taken in 1983-1985) concentrations of approximately 90 to 7500 ng
    TEHP/litre were measured (Ernst, 1988).

         The concentration of TEHP in Rhine water at Dusseldorf was
    usually below 20 ng/litre. The maximum concentration found was
    50 ng/litre (ARW, 1987).

         Ishikawa et al. (1985) could not detect TEHP at 16 river sampling
    sites or nine seawater sampling sites around Kitakyushu, Japan. The
    limit of determination was 20 ng/litre.

         TEHP was found in water of the Yodo River (Osaka area) at
    concentrations of 80-2000 ng/litre, with a mean value of 100 ng/litre.
    The detection limit was 80 ng/litre (Fukushima et al., 1986). In river
    water of the Osaka City area, Kawai et al. (1985) detected 15-84
    ng/litre (determination limit not reported).

         No TEHP could be detected in 63 water samples from 21 locations
    throughout Japan (with a limit of determination of 10 ng/litre)
    collected during the period 1974-1981 (Environmental Agency Japan,
    1983, 1987).

    B5.1.3  Drinking-water

         In drinking-water samples collected during October 1978 from two
    Eastern Ontario (Canada) water treatment plants, TEHP was detected at
    a concentration of 0.3 ng/litre in water from one plant (LeBel et al.,
    1981).

    B5.1.4  Effluents

         In a study of organic pollutants from influent and effluent of
    the Gothenburg regional sewage plant (Sweden) during the period 1989
    to 1991, TEHP was not detected (limit of detection unknown) (Paxeus et
    al., 1992). Effluent from water treatment plants into the River Weser,
    Germany, contained up to 144 ng TEHP/litre (Bohlen et al., 1989).

         In a study of leachate from Osaka North Port (Japan) sea-based
    solid waste disposal site and surrounding seawater, no TEHP was
    detected (Kawagoshi & Fukunaga, 1994).

    B5.1.5  Sediment

         An environmental monitoring programme was carried out during the
    period 1974-1981. Bottom deposit samples were collected at 21 sites
    all over Japan. In 43 out of 63 of the samples, levels of 2-7 µg/kg
    were found. The limit of determination was 1-5 µg/kg (Environmental
    Agency Japan, 1983).

         In one river sediment and five sea sediment samples, Ishikawa et
    al. (1985) could not detect TEHP. The limit of determination was
    10 µg/kg.

    B5.1.6  Food

         Total-diet studies of the US Food and Drug Administration were
    reported by Gartrell et al. (1986b). Baskets of 120 food items
    representing a typical 14-day diet for infants, young children and
    adults were collected from October 1980 to March 1982 from retail
    markets throughout the USA. Foods were classified into various groups.
    TEHP was found in the oil and fat food group of the diet used by young
    children. The average concentration in this food group was 38.5 µg/kg,
    and the average daily intake was calculated to be 0.385 µg/day.

         In follow-up reports, Gunderson (1988, 1995a,b) presented data
    for various groups of age (Table 6).

         In adult total diet samples, collected during October 1980 to
    March 1982, TEHP was found only in the meat, fish and poultry food
    group at an average concentration of 6.7 µg/kg; the average daily
    intake was calculated to be 1.73 µg/day. All the other food groups,
    i.e., dairy products, grain and cereals, potatoes, leafy vegetables,
    legume vegetables, root vegetables, fruits, oils and fats, sugar and
    adjuncts and beverages (including water), were free of TEHP (Gartrell
    et al., 1986a).

         The daily intakes of TEHP with adult food for 1978, 1979, 1980
    and 1981/1982 were nd, nd, nd and 0.025 µg/kg body weight per day,
    respectively (Gartrell et al., 1986a).

         In a similar study on ready-to-eat food sampled during 1982-1991,
    TEHP was found in 22 out of 230 food items. Raw sweet cherries
    contained the highest concentration (505 µg/kg) (Kan-Do Office and
    Pesticide Team, 1995).

        Table 6.  Mean daily intake (µg/kg body weight per day) of TEHP according to age and gender
                                                                                                                                

               6-11 months   2 years         14-16 years old              25-30 years old                 60-65 years old
               old           old           females      males          females        males            females      males
                                                                                                                                

    1982-84    0.0272        0.071         0.0249       0.0317         0.024          0.0282           0.0232       0.0264

    1984-86    0.0018        0.015         0.011        0.0101         0.0392         0.0385           0.0444       0.0471

    1986-91    0.0015        0.0051        0.0029       0.0033         0.0039         0.0055           0.0033       0.0037
                                                                                                                                
        


    B6.  KINETICS AND METABOLISM IN LABORATORY ANIMALS

         In an inhalation study, nine male rats received a single, 
    head-only exposure of 20 min to an aerosol of [32P]-TEHP. The 
    animals were killed after the following post-exposure intervals: 5 
    min, 30 min; 1, 4, 17, 18, 24, 48 and 70 h. Exposure concentrations 
    were 0.72 and 0.91 mg/litre. TEHP and/or its metabolites were 
    distributed into the lungs (13% of total radioactivity after 5 min), 
    stomach contents (64% after first hour), brain and liver (9 and 16%, 
    respectively, after 30 min). Spleen, kidney, bone, muscle and fat 
    retained less than 2% of the radioactivity at any time. Faecal 
    excretion was high but urinary excretion was relatively low. 
    Chromatographic analysis of urine and faeces showed TEHP was partly 
    biotransformed but the nature of the metabolites was not mentioned
    (MacFarland & Punte, 1966).

         Kluwe et al. (1985) assumed, although no confirmatory data are
    available, that TEHP is hydrolysed to 2-ethylhexanol and
    di(2-ethylhexyl) phosphate. This may be analogous to other compounds
    containing 2-ethylhexyl ester groups, which could be readily
    hydrolysed to the corresponding mono- or di-ester and 2-ethylhexanol.
    

    B7.  EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

    B7.1  Single exposure

         The LD50 values for TEHP are summarized in Table 7.

        Table 7.  Acute toxicity of TEHP
                                                                                  

    Route      Species     LD50                        Reference
                                                                                  

    Oral       rat         37.08 g/kg body weight      Smyth & Carpenter (1948)

    Oral       rat         >10.0 g/kg body weight      Bayer (1958)

    Oral       rat         >36.8 g/kg body weight      MacFarland & Punte (1966)

    Oral       rabbit      46.0 g/kg body weight       MacFarland & Punte (1966)
                                                                                  
    
         From Table 7, it can be concluded that TEHP has low acute
    toxicity by the oral and dermal routes.

         Acute inhalation toxicity of TEHP has been investigated in Wistar
    rats and Hartley guinea-pigs. Groups of 10 animals of each species
    (sex not stated) were used. Rats were exposed to air concentrations of
    287 to 460 mg/m3 for 30 to 210 min without any mortality in any
    group. Guinea-pigs were exposed to air concentration of 287 to 460
    mg/m3 for 30 to 180 min, with some mortality in each group, varying
    from 30% (at 450 mg/m3 for 30 min, 298 mg/m3 for 60 min, and 460
    mg/m3 for 60 min) to 80% (at 287 mg/m3 for 120 min). The mass median
    diameter for the TEHP aerosol was 1.5 µm (MacFarland & Punte, 1966).

    B7.2  Repeated exposure

    B7.2.1  Oral

         Feeding doses of 110-1550 mg TEHP/kg body weight per day to rats
    in their diet for 30 days revealed a NOEL of 430 mg/kg body weight. At
    1550 mg/kg body weight, weight loss was observed (Smyth & Carpenter,
    1948).

         In a 2-week dose range-finding study, groups of five male and
    five female F 344/N rats and five male and five female B6C3F1 mice
    were administered 0, 375, 750, 1500, 3000 or 6000 mg TEHP/kg body
    weight in corn oil by gavage for 14 consecutive days. No animals died.
    There was no effect on body weight gain in mice. The final mean body
    weights of male rats that received 1500-6000 mg/kg body weight and
    female rats that received 3000-6000 mg/kg body weight were lower than
    those of the vehicle controls (US NTP, 1984).

         Groups of 10 Fisher-344 rats of each sex received 0, 250, 500,
    1000, 2000 or 4000 mg TEHP/kg body weight by gavage in corn oil on 5
    days/week for 13 weeks and groups of 10 mice of each sex were
    administered 0, 500, 1000, 2000, 4000 or 8000 mg/kg body weight. The
    animals were examined twice daily and body weights were recorded
    weekly. Postmortem and histopathological examinations were performed
    on all animals except those excessively autolysed or cannibalized. No
    deaths, toxic effects or induced histological alteration were
    attributed to TEHP administration at any of these treatment dosage
    levels other than a slight to moderate suppression in body weight gain
    (US NTP, 1984; Kluwe et al., 1985). The suppression of body weight
    gain at the highest dose in male and female rats was 5%; in male and
    female mice the suppression of weight gain at the highest dose was 7%
    and 5%, respectively. The Task Group did not consider these minimal
    changes biologically significant. Hence, the NOAEL in rats was 2860
    mg/kg body weight per day and in mice 5710 mg/kg body weight per day.

         Results of a 2-year study on rats and mice are given in
    section B7.6.

         Two cats were administered 1.0 ml (926 mg) TEHP/kg body weight
    per day by gavage 5 days/week for 4 weeks. During the treatment and
    the recovery periods there were no signs of intoxication. Measurements
    of erythrocyte cholinesterase activity during the test period revealed
    no inhibitory effects (Bayer, 1958).

    B7.2.2  Dermal

         A daily dose of 0.1 ml (93 mg) undiluted TEHP was applied 5 days
    a week to the clipped intact skin of six male rabbits (2-3 kg). Four
    animals received ten applications and the remaining two animals 20
    applications. No evidence of systemic intoxication was seen based on
    gross necropsies and on the fact that animals, with one exception,
    gained weight throughout the study (MacFarland & Punte, 1966).

    B7.2.3  Inhalation

         In a 3-month inhalation study, three test groups and a control
    group, each consisting of equal numbers of males and females and
    comprising 20 guinea-pigs, two dogs and two rhesus monkeys, were
    exposed whole body for 6 h/day, 5 days/week for a total of 60
    exposures (MacFarland & Punte, 1966). Three concentrations of TEHP
    aerosol were tested; controls received the same air-flow but without
    TEHP. The mean concentrations and standard deviations received by the
    three test groups over the 12-week period were: low-dose, 10.8 ± 6.0
    mg/m3; mid-dose, 24.4 ± 16.8 mg/m3; high-dose, 85.0 ± 33.3 mg/m3.
    The median particle size was 4.4 µm with a geometric standard
    deviation of 3.0.

         No mortality and a normal increase in body weight was observed in
    dogs and monkeys. There were no treatment-related alterations in a
    limited range of biochemical and haematological parameters and organs
    function test. Activities of plasma and erythrocyte cholinesterases
    were unaffected. While the lungs of monkeys were normal, the lungs of
    dogs showed mild, chronic parenchymal inflammatory changes. In an
    evaluation of effects on trained behaviour, no effects were detected
    in the performance of monkeys in a visual discrimination test; the
    performance of dogs trained in conditional avoidance deteriorated as
    the exposure concentration increased. The guinea-pig portion of the
    study was invalidated due to the high mortality from intercurrent
    respiratory infections.

         The 3-month inhalation study was repeated with guinea-pigs. Two
    groups of 20 male guinea-pigs were exposed to two concentrations of
    TEHP. A third group acted as control and inhaled uncontaminated air in
    the exposure chamber. Tetracycline was administered prophylactically
    in the drinking-water throughout the study. The mean concentrations
    and standard deviations for the two test groups were: low dose, 1.6 ±
    0.8 mg/m3; high-dose, 9.6 ± 1/5 mg/m3. Exposures were for 6 h/day, 5
    days/week for a total of 60 exposures. The mean particle size was 3.8
    µm with a geometric standard deviation of 1.7.

         The high-dose guinea-pigs showed a significantly increased body
    weight in comparison with the controls. Plasma and erythrocyte
    cholinesterase activities were unaffected in terminal blood samples.
    Both test groups exhibited a lower kidney-to-body weight ratio than
    the controls. Histopathological alterations in the lung, liver and
    kidneys were not related to the treatment. Sections of the spinal cord
    and sciatic nerve, stained to demonstrate the myelin sheaths, showed
    no pathological changes (MacFarland & Punte, 1966).

    B7.3  Skin and eye irritation; sensitization

         No irritation was seen after exposure to TEHP by a saturated
    cotton swab placed on the inside of the ears of rabbits for 24 h
    (Kimmerle, 1958).

         TEHP was tested in three albino rabbits according to OECD 404
    test guideline. Well-defined erythema, slight to moderate oedema,
    crust formation and desquamation were observed. TEHP produced a
    primary irritation index of 4.2/8.0 and was classified as a moderate
    irritant to rabbit skin. No corrosive effects were observed (Guest,
    1993b).

         A single dose of 250 mg undiluted TEHP applied to the clipped
    skin of rabbits produced moderate erythema, which persisted for a week
    (MacFarland & Punte, 1966). Repeated applications of 0.1 ml on 5
    days/week (10 or 20 applications) produced moderate erythema after the
    first application. With further applications a spreading zone of
    erythema developed with desquamation, leatheriness and some fissuring
    with haemorrhages. At the end of the observation period, thickening
    and severe hyperkeratosis of the skin was apparent.

         TEHP was non-irritating when tested in the eyes of three albino
    rabbits according to OECD 405 Test Guideline (Guest, 1993a).

         TEHP was instilled into the conjunctival sac of one eye of each
    of two rabbits at dose levels of 0.01 to 0.5 ml. Doses up to 0.05 ml
    produced slight conjunctivitis, while doses of 0.1 and 0.5 ml produced
    moderate conjunctivitis which cleared up in 24 h (MacFarland & Punte,
    1966).

    B7.4  Reproductive toxicity, embryo toxicity and teratogenicity

         No data on the reproductive toxicity of TEHP are available.

    B7.5  Mutagenicity

         TEHP was shown to be non-genotoxic in a range of mutagenicity
    assays.

    B7.5.1  In vitro assays

         TEHP was tested for mutagenicity in a  Salmonella/microsome
    assay using strains TA1535, TA1537, TA98 and TA100 in the presence and
    absence of S9 derived from livers of Aroclor 1254-treated
    Sprague-Dawley rats. Results were negative (Zeiger et al., 1985).

         In a mouse lymphoma assay, concentrations of TEHP of up to and
    exceeding the apparent solubility limit of 62.5 µl/litre produced no
    gene mutations. The assay was carried out in the presence and absence
    of S9 from livers of Aroclor 1254-treated male F-344 rats (Myhr &
    Caspary, 1991).

         An  in vitro cytogenetic assay in Chinese hamster ovary (CHO)
    cells was carried out using concentrations of TEHP up to 251 µg/ml in
    the presence and absence of S9 derived from livers of Aroclor
    1254-treated Sprague-Dawley rats. There was no evidence of induction
    of chromosome damage (Ivett et al., 1989).

         An  in vitro sister-chromatid exchange (SCE) assay was carried
    out in CHO cells in the presence and absence of S9 derived from livers
    of Aroclor 1254-treated Sprague-Dawley rats. Concentrations of up to
    251 µg/ml were used, but at 16.7 µg/ml and above there was severe cell
    cycle delay, which limited the number of cells available for analysis.
    TEHP did not increase the number of SCEs (Ivett et al., 1989).

    B7.5.2  In vivo assays

         A mouse bone marrow micronucleus assay was carried out in male
    B6C3F1 mice, which were given intraperitoneal TEHP injections of 500,
    1000 or 2000 mg/kg body weight on three consecutive days. Bone marrow
    was harvested at 24 h after the last dose, and was examined for
    micronucleus-containing polychromatic erythrocytes (MN-PCEs). A
    statistically significant  (P < 0.001) dose-related increase in the
    number of MN-PCEs was detected in the bone marrow from treated mice.

    The assay was repeated in two further experiments using doses of 1500
    and 2000 mg/kg body weight in one and 2000 and 3000 mg/kg body weight
    in the other. No increase in the number of bone marrow MN-PCEs was
    detected in either of these experiments. It is concluded that the
    initial result was an artefact and that TEHP is not mutagenic in this
    assay (Shelby et al., 1993).

         An  in vivo cytogenetic assay was carried out in male B6C3F1
    mice, which were given a single intraperitoneal injection of TEHP
    (dose not stated). Bone marrow was harvested for analysis at 17 and 36
    h post-dosing and metaphase cells were examined for chromosomal
    aberrations. The number of chromosomal aberrations was not elevated in
    TEHP-treated mice (Shelby & Witt, 1995).

         In an  in vivo liver unscheduled DNA synthesis (UDS) assay, male
    B6C3F1 mice were given TEHP doses of 1000 or 2000 mg/kg body weight
    by gavage. Mice were killed at 24, 39 and 48 h post-dosing and liver
    preparations were made. There was no evidence of increased UDS in
    hepatocytes from TEHP-treated mice (Miyagawa et al., 1995).

    B7.6  Carcinogenicity

         In a US NTP (1984) study, TEHP was administered in corn oil (10
    ml/kg body weight) by gavage 5 days/week for 103 weeks to groups of 50
    male and 50 female F-344/N rats and B6C3F1 mice. The doses
    administered were:

                                                                                         
                          Fischer-344 rats                     B6C3F1 mice

    Dose             Male            Female                Male          Female
                                                                                     

    Control          Vehicle         Vehicle               Vehicle       Vehicle

    Low dose         2000 mg/kg      1000 mg/kg            500 mg/kg     500 mg/kg

    High dose        4000 mg/kg      2000 mg/kg            1000 mg/kg    1000 mg/kg
                                                                                     
    
         The animals were observed twice daily and body weight was
    measured weekly for the first 13 weeks and once every 4 weeks
    thereafter. Clinical examinations were performed once every 4 weeks.
    Necropsies and histopathological examinations were performed on all
    animals, but organ weight changes were not reported.

         No compound-related clinical toxicity was observed in either sex
    of either species. Decrease in body weight, compared with controls,
    was limited to male rats at the low dose (11.5%) and the high dose
    (15.8%). The decreased body weight did not affect survival.

         In male rats the incidence of phaeochromocytomas of the adrenal
    gland increased with dose and two (4%) were malignant in the high-dose
    group. The incidence of adrenal phaeochromocytomas in male rats was:
    control 2/50 (4%), low-dose 9/50 (18%) and high-dose 12/50 (24%). In
    two previous gavage studies in the same laboratory, the incidence of
    phaeochromocytomas in control male rats was 24 and 26%.

         In female mice the incidence of hepatocellular carcinomas was:
    control 0/48 (0%), low dose 4/50 (8%) and high dose 7/50 (14%). The
    incidence of hepatocellular carcinomas showed a dose-related increase
    and the incidence at the high-dose level was statistically
    significant.

         The results of these 2-year gavage studies in rats and mice were
    interpreted by NTP as showing some evidence of carcinogenicity in
    female mice based on the increase in hepatocellular carcinomas and
    equivocal evidence of carcinogenicity in male rats based on the
    increased incidence of phaeochromocytomas (US NTP, 1984; Kluwe et al.,
    1985)

         In this same study (US NTP, 1984), TEHP caused a dose-related
    increase in the incidence of follicular cell hyperplasia of the
    thyroid in male and female B6C3F1 mice. The incidence of hyperplasia
    was: in males, control 0/49 (0%), low dose 12/48 (25%) and high dose
    24/47 (51%); in females, control 1/44 (2%), low dose 13/47 (28%) and
    high dose 12/46 (26%). There was no dose-related increase in thyroid
    tumours. The LOAEL for thyroid hyperplasia was 357 mg/kg body weight
    per day; a NOAEL was not established.

    B7.7  Special studies

    B7.7.1  Neurotoxicity

         MacFarland & Punte (1966) tested TEHP for its neurotoxic
    potential. Four groups of female chickens, each weighing 1.5-2.0 kg,
    received a single dose of test material into the crops as follows:

        Group        Number of chickens       Test material      Dose
                                                                         

    1            4                        Saline             1.5 ml/kg
    2            8                        TOCP               500 mg/kg
    3            8                        TEHP               500 mg/kg
    4            8                        TEHP               2500 mg/kg
                                                                         
             After receiving a single dose of the test material the animals
    were kept under observation for 4 weeks and then killed. Body weights
    were recorded weekly and changes in appearance and behaviour noted
    daily. Gross necropsy was performed on all chickens. Sections of
    brain, three levels of the spinal cord and the sciatic nerve were
    examined microscopically.

         In the tri- ortho-cresyl phosphate (TOCP) group used as positive
    control, weight loss become apparent by the end of the first week and
    signs of ataxia and muscular weakness were evident by the 12th day.

         These signs increased in intensity, so that the chickens were
    prostate by the end of the study. The microscopic examination of the
    nerve tissue sections confirmed that TOCP was producing
    demyelinization. The chickens in the saline and TEHP groups appeared
    normal and maintained or gained weight throughout the study. There
    were no macroscopic signs of neurotoxicity and microscopically no
    demyelinization was observed.

         No evidence of systemic intoxication or, in particular,
    neurotoxicity was seen in chickens dosed with a single dose of up to
    2.500 mg TEHP/kg body weight (MacFarland & Punte, 1966).

         Single hens were administered a single dose of 0.25, 0.5 or
    1.0 g/kg body weight by gavage. The animals were kept under
    observation for 2 months and examined for neurotoxicity twice weekly.
    No abnormalities in behaviour were detected. A single intramuscular
    injection of 0.25, 0.5 or 1.0 g TEHP/kg body weight to single chicken
    again induced no signs of intoxication (Kimmerle, 1958).

         In 3-month inhalation studies (see section B7.2.3) with 
    guinea-pigs, dogs and rhesus monkeys, determination of plasma and 
    erythrocyte cholinesterase activity and histological examination of 
    sections of tissue including spinal cord and sciatic nerve did not 
    reveal any abnormalities. In dogs and rhesus monkeys, the 
    cholinesterase were measured after 4, 8 and 12 weeks of exposure to 
    10.8, 26.4 or 85 mg TEHP/m3, but in guinea-pigs measurements were 
    made after 12 weeks of exposure to 1.6 or 9.6 mg/m3
    (MacFarland & Punte, 1966).

         In two cats receiving 28 doses of 1.0 ml TEHP/kg body weight by
    gavage (see section 7.2.1) no signs of neurotoxicity and no inhibition
    in the erythrocyte cholinesterase activity was found (Bayer, 1958).
    

    B8.  EFFECTS ON HUMANS

         No irritant effects were seen after 24 h of exposure to a 
    TEHP-saturated cotton swab placed on the skin of the forearm of six
    volunteers. A piece (2 cm2) of PVC plastic containing 40% TEHP was
    placed on the arm of 8 volunteers for 72 h. Slight redness but no
    irritation was observed (Kimmerle, 1958).

         No other data are available concerning the effect of TEHP on
    humans.
    

    B9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

    B9.1  Laboratory experiments

    B9.1.1  Microorganisms

         A bacterial growth inhibition test, carried out according to ISO
    8192 indicated an IC50 for TEHP greater than 100 mg/litre (Bayer,
    1982b).

    B9.1.2  Aquatic organisms

    B9.1.2.1  Vertebrates

         A 96-h exposure of zebra fish  (Brachydanio rerio) under static
    conditions to TEHP (100 mg/litre) produced no deaths (Bayer, 1989).

    B9.1.3  Terrestrial organisms

         No data on the toxicity of TEHP to terrestrial organisms are
    available.
    

    PART C

    TETRAKIS(HYDROXYMETHYL) PHOSPHONIUM SALTS

    C.  SUMMARY AND EVALUATION

    C1.  Tetrakis(hydroxymethyl) phosphonium salts

    C1.1  Summary

         Tetrakis(hydroxymethyl) phosphonium salts represent the major
    class of chemicals used as a flame retardant for cotton, cellulose and
    cellulose-blend fabrics. There is low migration from fabrics treated
    with tetrakis(hydroxymethyl) phosphonium chloride (THPC)-urea. The
    sulfate salt (THPS) is mainly used as a biocide. Combined world
    production is estimated to be >3000 tonnes for THP salts and around
    3000 tonnes for the THPC-urea condensate.

         Photodegradation and hydrolysis of THP salts are significant
    abiotic degradation pathways in the environment. THPS binds poorly to
    environmental particulates and is, therefore, mobile. THPS degrades
    rapidly under both aerobic and anaerobic conditions. Trihydroxymethyl
    phosphine oxide (THPO) and bishydroxymethyl phosphonic acid (BMPA)
    have been identified as breakdown products.

         Since no monitoring has been reported, no estimates can be made
    of exposure to humans or organisms in the environment.

         The acute oral toxicity of THPC and THPS is moderate; dermal
    toxicity is low.

         In short-term (up to 28 days) studies in rats and mice, the main
    toxic effect for both THPC and THPS is decreased body weight. The
    NOAEL for both chemicals in both species is approximately 8 mg/kg body
    weight per day. In longer-term studies (13 weeks), the main target
    organ for toxicity is the liver. The NOAEL for this effect ranged from
    3 to 7 mg/kg body weight per day for both salts in both species.
    Carcinogenicity bioassays on THPC also showed effects on the liver,
    but a NOAEL was not established. The LOAEL was approximately 3 mg/kg
    body weight per day for both species. In a carcinogenicity bioassay on
    THPS in mice, the NOAEL for focal hyperplasia in the adrenal medulla
    was 3.6 mg/kg body weight per day; in rats the LOAEL for mortality was
    3.6 mg/kg body weight per day.

         THPS did not cause skin irritation when administered as a single
    dose to rabbits. However repeated dermal exposure of rats resulted in
    severe skin reaction. THPC-urea was corrosive. THPS was identified as
    severe eye irritant in rabbits.

         THPS and THPC-urea cause skin sensitization guinea-pigs
    (Magnusson & Kilman Maximization test).

         THPS and THPC-urea did not cause developmental toxicity in orally
    dosed experimental animals.

         THPC and THPS have mutagenic potential  in vitro, but THPS is
    not mutagenic  in vivo (no  in vivo mutagenicity data are available
    for THPC). Limited mutagenicity data for THPC-urea suggest that it is
    not mutagenic  in vivo. THPO is non-genotoxic. There is no convincing
    evidence to suggest that fabrics treated with THP salts are mutagenic.
    Available information indicates that there is no genotoxic hazard to
    humans.

         THPC and THPS were not carcinogenic in rats and mice in 2-year
    bioassays. Dermal studies have shown that THP salts are promoters of
    skin cancer but not initiators.

         THPS and THPO did not inhibit acetylchlolinesterase activity  in
     vitro, suggesting a lack of neurotoxic hazard for humans.

         THPC-urea-treated fabric did not cause skin irritation in humans.

         For THPS, reported acute toxicity values for algae are less than
    1 mg/litre, with one no-observed-effect concentration (NOEC) of
    0.06 mg/litre. The acute NOEC for the water flea is 10 mg/litre.
    Reported acute toxicity values for marine invertebrates range from 1.6
    to 340 mg/litre.

         Fish 96-h LC50 values range from 72 to 119 mg/litre, with NOEC
    values in the range of 18 to 41 mg/litre. An acute avian LD50 of 311
    mg/kg body weight and dietary LC50 values of 1300 and 2400 mg/kg diet
    have been reported.

    C1.2  Evaluation

         No exposure information is available for either humans or
    organisms in the environment. Therefore no quantitative risk
    assessment could be made.
    

    C2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL
         METHODS

    C2.1  Identity

         Tetrakis(hydroxymethyl) phosphonium salts (THP salts) have the
    following general chemical structure :

    CHEMICAL STRUCTURE 3

         The commercially relevant salts of THP are the sulfate (THPS) and
    the chloride (THPC). In addition, tetrakis(hydroxymethyl) phosphonium
    chloride-urea condensate is the major commercially available flame
    retardant product.

         In the past other salts and salt-urea condensates have been used;
    their names and CAS numbers are listed in IARC (1990).

    C2.1.1  Tetrakis(hydroxymethyl) phosphonium chloride (THPC)

    Chemical formula:         C4H12O4PCl

    Chemical structure:

    CHEMICAL STRUCTURE 4

    Chemical name:            Phosphonium, tetrakis(hydroxymethyl)
                              chloride

    Relative molecular mass:  190.56

    CAS registry number:      124-64-1

    CAS name:                 Phosphonium tetrakis(hydroxymethyl)
                              chloride

    IUPAC name:               Tetrakis(hydroxymethyl) phosphonium
                              chloride

    Trade names:              Tolcide PC800; Tolcide THPC; Retardol C

    Synonyms:                 Tetrahydroxymethyl phosphonium chloride
                              Tetramethylol phosphonium chloride

    C2.1.2  Tetrakis(hydroxymethyl) phosphonium sulfate (THPS)

    Chemical formula:         C8H24O8P204S

    Chemical structure:

    CHEMICAL STRUCTURE 5

    Chemical name:            Phosphonium, tetrakis(hydroxymethyl)
                              sulfate

    Relative molecular mass:  406.28

    CAS registry number:      55566-30-8

    CAS name:                 Phosphonium, tetrakis(hydroxymethyl)
                              sulfate (2:1)

    IUPAC name:               bis[tetrakis(hydroxymethyl) phosphonium]
                              sulfate (salt)

    Trade names:              Tolcide PS75; Tolcide THPS, Retardol S

    Synonyms:                 Octakis(hydroxymethyl) phosphonium sulfate

    C2.1.3  Tetrakis(hydroxymethyl) phosphonium chloride-urea condensate
            (THPC-urea)

    Chemical formula:         [C4H12O4P.CH4N2O.Cl]x

    Chemical name:            Tetrakis(hydroxymethyl) phosphonium
                              chloride-urea copolymer

    Chemical structure:

    CHEMICAL STRUCTURE 6

    Relative molecular mass:  300 for the repeat unit shown above

    CAS registry number:      27104-30-9

    CAS name:                 Phosphonium, tetrakis(hydroxymethyl)-
                              chloride, polymer with urea

    Trade names:              Proban CC; Retardol AC
                              Proban 210 is no longer produced.

    C2.2  Physical and chemical properties

         Physical and chemical properties are given in Table 8.

    C2.2.1  Technical products

         THPC and THPS are marketed in concentrated aqueous solutions at
    approximately 80 and 75% (by weight), respectively (Albright & Wilson,
    personal communication to IPCS). Typically THPS is marketed with less
    then 1% of formaldehyde content (Albright & Wilson, personal
    communication to IPCS). In the past values ranging from 3.79% at pH
    0.4 to 14.1% at pH > 5.0 have been reported (Loewengart & Van Duuren,
    1977; Ulsamer et al., 1980). Tetrakis(hydroxymethyl) phosphonium
    acetate/phosphate (THPA/P) was previously available in the USA as a
    clear, nearly colourless solution with a pH of approximately 5,
    containing 10% active phosphorus (Hooper et al., 1976).

    C2.3  Conversion factors

    THPC      1 ppm = 7.76 mg/m3
              1 mg/m3 = 0.128 ppm

    THPS      1 ppm = 16.61 mg/m3
              1 mg/m3 = 0.0602 ppm

    C2.4  Analytical methods

         A standard method for THPS and THPC determination is by iodine
    titration. However, this not substance specific and is therefore
    subject to interference by many other chemicals that may be present in
    the sample to be analysed. The method involves dilution in water
    containing an aliquot of a saturated solution of disodium hydrogen
    orthophosphate. A solution of polystyrene sulfonic acid is then added
    followed by a few drops of a starch indicator. Titration against a
    previously standardized iodine solution is then carried out (Albright
    & Wilson, personal communication to IPCS).

         The most accurate analytical technique for the quantitative
    substance-specific determination of THP salts is currently ion
    chromatography. In this method the sample is chromatographed using an
    Ionpac CS5 column with a CG5 guard column. The mobile phase is
    hydrochloric acid (0.1 mol/litre) at 1 ml/min. The ion chromatography
    separates the THP salt from any free formaldehyde, which is largely
    retained. The THP salt is then detected using a visible wavelength

    detector at 425 nm following a post-column reaction with an
    acetylacetone reagent containing acetic acid, ammonium acetate and
    acetyl acetone. The reagent breaks down the THP salt to form free
    formaldehyde, which forms a cyclic coloured complex. Free formaldehyde
    also reacts but two separate and distinct peaks are seen on the
    chromatogram.

        Table 8.  Physical and chemical properties of THP salts
                                                                                                                           
       Parameter                           THPS                                     THPC                  THPC-urea copolymer

                                 100%                     75%                      80-85%
                                                                                                                            

    Appearance             Soft waxy solid         Colourless liquid            Clear straw-coloured     Straw-coloured liquid
                                                                                liquid

    Odour                  Resembles               Resembles aldehyde           Pungent                  Pungent
                           aldehyde

    Boiling point (°C)                             108.5                        115

    Melting point (°C)     54.2-81.5                                                                     -21

    Flash point                                                                 >100

    Vapour pressure        <2.6 × 10-4 Pascal      26.7 mmHg at 25°C
                           at 20°C

    Viscosity                                      38 cStp at 25°C                                       0.27 Pa.s at 29°C

    pH                                             3.19 (0.01 M solution)       < 2                      5

    Stability              21°C -- stable for      21°C -- stable for 14 days   Stable under normal      Stable under normal
                           14 days                                              conditions               conditions
                           54°C -- stable for      54°C -- stable for 14 days
                           14 days

    Table 8.  (continued)
                                                                                                                           
       Parameter                           THPS                                     THPC                  THPC-urea copolymer

                                 100%                     75%                      80-85%
                                                                                                                            
    Decomposition                                  Oxides of sulfur, phosphorus Oxides of phosphorus;    Oxides of phosphorus;
    products                                       and carbon;  phosphine       chlorine, ammonia        chlorine, ammonia

    Relative density       1.53                    1.39                         1.34                     1.31

    Solubility             Infinitely soluble in   Completely soluble           Completely soluble       Miscible with water
                           water

    Log n-octanol/water                            -9.8 (calculated)
    partition coefficient
                                                                                                                            

    From: Cowlyn (1991a,b); Antony (1993); Barth (1994); Willis (1995)
        


    C3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURES

    C3.1  Natural occurrence

         These compounds are not known to occur as natural products.

    C3.2  Anthropogenic sources

    C3.2.1  Production levels and processes

         THP salts have been produced for commercial use since the 1950s.
    The first of these, THPC, was introduced in 1953.

         THP salts are synthesized in high yields through the reaction of
    formaldehyde with phosphine and the corresponding acid in an enclosed
    process (Weil, 1980; Hawley, 1981).

              PH3 + HCl + 4CH2O --> [(HOCH2)4P]Cl

         The resulting products exist in an equilibrium with THP+, which
    is highly pH dependent. Increasing the pH shifts this equilibrium to
    the right with the resultant production of formaldehyde, i.e., one of
    the methylol groups from the THP salt becomes hydrolysed.

         Currently there is one major producer of these salts and
    THPC-urea condensates in the United Kingdom and some production
    potential in the USA. Combined worldwide production of THP salts is
    greater than 3000 tonnes; the urea-condensate production is around
    3000 tonnes annually of which 40% is consumed in the USA (Albright &
    Wilson, personal communication to IPCS).

    C3.2.2  Uses

         THPC-based products represent the major class of chemicals used
    as flame retardants for cotton, cellulose and cellulose-blend fabrics.
    Until 1976, THPC was the major THP salt used as a flame retardant. In
    addition, THPS and some mixed salts were commercially available.

         THPC-based flame retardants have been found to be more reactive
    and efficient as flame retardants when compared with similar 
    THPS-based products (Albright & Wilson, personal communication to 
    IPCS). Nowadays, the THPC-urea condensates dominant the market for 
    flame retardant treatment of cellulose and cellulose-blend fabrics 
    where durability to laundering and dry cleaning is required.

         It has been suggested that bis(chloromethyl) ether (BCME) may be
    formed during the manufacture of THPC and thus may present an
    occupational hazard (Loewengart & Van Duuren, 1977). However, an
    extensive airborne monitoring survey coupled with chemical analysis
    (using mass spectroscopy) conducted at the United Kingdom
    manufacturing site during 1975 did not detect the presence of BCME at
    the minimum level of analytical detection of 2.35 µg/m3 (0.5 ppb).
    These results were later independently confirmed in a separate survey
    carried out by the United Kingdom Factory Inspectorate (personal
    communication by R. Williams, HM Inspector of Factories, United
    Kingdom Health and Safety Executive to Albright & Wilson, 1975).

         The results of the two occupational hygiene surveys are supported
    by a study in 1974 in which kinetic measurements in aqueous media
    (manufacture is via an aqueous route) showed that BCME undergoes rapid
    hydrolysis with a half-life of approximately 10-40 seconds at ambient
    temperature (Tou et al.,1974). BCME, if formed, would therefore exist
    as a transient species in aqueous media containing formaldehyde and
    hydrochloric acid, or other acid chlorides.

         The major application of THPS now is as a biocide in a variety of
    preservative applications which include leather, textile, paper and
    photographic films, as well as industrial water treatment and offshore
    oil production processes.
    

    C4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

    C4.1  Transport and distribution between media

         A field study was conducted on the use of THPS as a biocide in
    the water of an industrial cooling tower. THPS was added to produce an
    initial concentration of approximately 100 mg/litre and lithium
    chloride was added simultaneously as a marker for determination of
    dilution volumes in the tower and associated drainage systems.
    Analysis of THPS was by HPLC. The half-life of lithium (and therefore
    of THPS by dilution) was calculated to be 3 days. THPS levels were
    found to decrease more rapidly than simple dilution would have
    suggested, indicating hydrolysis; actual concentrations in the Rhyne,
    the drainage channel of the cooling tower, were <0.5 mg/litre
    (Heaton, 1991).

         Adsorption of radiolabelled THPS was studied using agricultural
    sand, silt loam, sandy loam, pond sediment and marine sediment; the
    percentage of organic carbon in the tested soil/sediments ranged from
    0.17 to 1.1%. Estimated Koc values ranged from 72 to 266 (mean
    153 ± 69.2), indicating medium-to-high mobility for the compound
    (Heim, 1998).

    C4.2  Transformation

    C4.2.1  Biodegradation

         Inherent biodegradability of THPS was assessed using the OECD
    302B guideline; >20% degradation occurred within a 28-day period
    (Douglas & Pell, 1985).

         Aquatic aerobic degradation of THPS was assessed in a soil/water
    system under US EPA Guidelines. The soil was dosed with THPS at
    1 µg/g. The compound was metabolized with 60% of applied radioactivity
    appearing as CO2 within 7 days. Major metabolites were
    trihydroxymethyl phosphine oxide (THPO) and bishydroxymethyl
    phosphonic acid (BMPA), which were both found in the water; neither
    degradate reached a concentration of 10% of the applied dose (Gorman,
    1996). A comparable study at the same initial concentration of THPS
    but under anaerobic conditions also showed 60% degradation within 30
    days, and the same breakdown products were identified (Gorman, 1997).

         Natural seawater was dosed with THPS to an initial concentration
    of 4.16 mg/litre. Biodegradation (measured as oxygen demand) reached
    17.7% after 28 days. A parallel toxicity test showed that the
    substance was inhibitory to bacteria at the concentration used in the
    test (McWilliam, 1994).

    C4.2.2  Abiotic degradation

         Laboratory studies using UV light showed that THPS photodegrades
    to THPO when at low concentrations in aqueous solution. Conversion to
    THPO was almost complete at concentrations up to about 20 mg/litre
    within 2 h. Conversion also took place in synthetic seawater.

    Photodegradation was pH-dependent, with greater conversion at
    environmentally relevant pH. Exposure to natural sunlight showed high
    levels (not stated) of conversion over a 3-month period (Lloyd, 1994).

         Hydrolysis of THPS is pH-dependent; half-lives for the compound
    at 25°C were 131, 72 and 7 days at pH 5, 7 and 9, respectively
    (O'Connor, 1992).

    C4.3  Migration from textiles

         A method is available for the determination of the fixation
    efficiency of the THPC-urea copolymer in terms of the percentage
    phosphorus applied and fixed during the flame retardant treatment of
    various textiles. A fixation efficiency of greater than 90% is common
    for the PROBANR process (Albright & Wilson, personal communication
    to IPCS). The THPC-urea copolymer is chemically converted to a 
    water-insoluble polymer of high relative molecular mass during the 
    textile processing, first by exposure to ammonia in an enclosed 
    chamber and then by an oxidation process involving hydrogen peroxide. 
    This latter process converts any phosphorus to the inert pentavalent 
    form. At the same time the hydrogen peroxide will convert any unfixed 
    THPC-urea copolymer to tetrakis(hydroxymethyl) phosphine hydroxide 
    (THPOH), which is subsequently removed from the fabric during the 
    final washing-off steps.

         Wetting the treated fabric with water, beverages, liquid foods or
    urine does not release the flame retardant polymer. The lack of water
    solubility and the physical entrapment of the polymer inside the
    fibres (which make up the treated fabric) make the polymer resistant
    to removal by cleaning materials that a consumer might normally employ
    to clean these flame-retardant-treated articles.

         Industrial work clothing treated with THPC-urea condensate flame
    retardants have been shown to be flame resistant after 50-100 washings
    or dry cleanings, demonstrating the durability of the polymer to
    leaching and washing (Albright & Wilson, personal communication to
    IPCS).

         Appendix A lists flammability standards met regularly by products
    treated with THPC-urea condensates.
    

    C5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         Approximately 20 workers are currently potentially exposed during
    production of THP salts and THPC-urea condensate in the United Kingdom
    (Albright & Wilson, personal communication to IPCS). No data on levels
    of exposure are available.
    

    C6.  KINETICS AND METABOLISM IN LABORATORY ANIMALS

         A metabolism study on rats has been conducted using
    14C-radiolabelled THPS. THPS was not found in rat urine. However,
    three metabolites were present, identified as trihydroxymethyl
    phosphine oxide, bishydroxymethylphosphonic acid and possibly a
    formaldehyde adduct of the trihydroxy compound (Dr P. Martin, Albright
    & Wilson, personal communication to IPCS).
    

    C7.  EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

    C7.1  Single exposure

    C7.1.1  Oral

         Acute oral toxicity results are given in Table 9.

        Table 9.  Oral LD50 values for THPC, THPS and THPC-urea condensate in
    mice and rats (mg/kg body weight) a
                                                                               

    Species      Sex              THPCb         THPSc            THPC-urea
                                                                               

    Mice         female           280           200 (none died)  400 (all died)

    Rats         male             282

    Rats         both sexes       575                            962

    Rats         male             185           333

    Rats         female           161           248
                                                                               

    a   From Ulsamer et al. (1980); US NTP (1987); Tuffnell (1991);
        Guest (1994a)
    b   75% solution in water
    c   72% solution in water
    
         In THPC-treated rats that survived, reddish fluids around the
    nostrils and laboured breathing were observed. All mice were lethargic
    and had a rough coat. With THPS no signs of intoxication were noted
    (Ulsamer et al., 1980; US NTP, 1987).

    C7.1.2  Dermal

         The dermal LD50 value in albino rabbits was greater than 4084 mg
    THPC/kg body weight after a 24-h exposure. Erythema and oedema of the
    integumentary system were observed (US NTP, 1987).

         No deaths occurred when rats were treated dermally with THPS or
    THPC-urea at 2000 mg/kg body weight (Liggett & Allen, 1989; Snell,
    1994).

    C7.1.3  Inhalation

         The LC50 4-h value for THPS was 5.5 mg/litre in rats exposed to
    respirable aerosol (nose only) (McDonald & Anderson, 1989).

    C7.2  Repeated exposure

    C7.2.1  Oral

    C7.2.1.1  THPC

         Groups of five 6-week-old, F-344/N rats of each sex were
    administered 0, 9.4, 18.8, 37.5, 75 or 150 mg THPC (as a 75% aqueous
    solution) per kg body weight in deionized water by gavage for 14 days.
    At the two highest dose levels an increased mortality was observed. At
    75 mg/kg the mortality for males was 20%, and at 150 mg/kg all males
    and females died. The body weight gain of the male animals
    administered 18.8 and 37.5 mg/kg was decreased, respectively, by 7 and
    11%. This effect was also found in the females administered 75 mg/kg
    (27%). Rats with 150 mg/kg had yellow to tan or mottled red livers. No
    histopathology was carried out (US NTP, 1987).

         Groups of ten 4-week-old F-344/N rats of each sex were gavaged 5
    days/week for 13 weeks with 0, 3.75, 7.5, 15, 30 or 60 mg THPC (as a
    75% aqueous solution) per kg. All males and 5/10 females that received
    60 mg/kg died. The final mean body weight of males that received 30
    mg/kg was 89% of vehicle controls. The final mean body weight of
    females that received 60 mg/kg was 80% of vehicle controls.

         At the highest dose level, clinical signs of toxicity included
    rough coat, hunched back, diarrhoea, lethargy, paresis and
    hyperextension of back legs. Periportal hepatocellular necrosis was
    observed in 9/10 males and 7/10 females that received 15 mg/kg, all
    males and females that received 30 mg/kg, and 7/10 males and 8/10
    females that received 60 mg/kg.

         Periportal cytoplasmic vacuolization was observed in 8/10 males
    that received 7.5 mg/kg, 9/10 males and 8/10 females that received
    15 mg/kg, and all rats that received 30 or 60 mg/kg. Degeneration of
    the axons was found in 2/10 females that received 60 mg/kg. The NOAEL
    for this study was 2.7 mg/kg body weight per day; the LOAEL was 5.4
    mg/kg body weight per day (US NTP, 1987).

         Groups of five 5-week-old B6C3F1 mice of each sex were
    administered 0, 18.8, 37.5, 75, 150 or 300 mg THPC (as a 75% aqueous
    solution) per kg body weight by gavage for 14 consecutive days. At the
    highest dose level all mice died. At 150 mg/kg, body weight was
    depressed by 18% in males and 20% in females compared to control mice.
    No clinical sign of toxicity were observed in animals surviving to the
    end of the study. No compound-related effects were observed at
    necropsy (US NTP, 1987).

         Groups of ten 4-week-old B6C3F1 mice of each sex were
    administered by gavage 0, 1.5, 4.5, 15, 45 or 135 mg/kg body weight
    5 days/week for 13 weeks. Seven of 10 males and 6/20 females that
    received 135 mg/kg died. The final mean body weight for mice that
    received 135 mg/kg was 8% lower than that of the controls for males
    and 19% lower for females. Paresis of the hind legs and loss of
    coordination were observed in all males and 9/10 females that received
    135 mg/kg. Mice in this group also had marked axonal degeneration,

    characterized by swollen axon sheaths, missing fragmented axons and
    some proliferation of neurolemmal cells in the sciatic nerve, dorsal
    roots of the caudal spinal nerves and tracts of the spinal cord
    particularly in the dorsal column of the lumbar cord. Intracytoplasmic
    vacuoles were seen in periportal hepatocytes of all mice in the 15, 45
    and 135 mg/kg groups. The NOAEL for this study was 3.2 mg/kg body
    weight per day; the LOAEL was 10.7 mg/kg body weight per day (US NTP,
    1987).

    C7.2.1.2  THPS

         Group of 12 male ICR Swiss mice were administered daily by gavage
    THPS in saline (2, 10 or 50 mg/kg body weight) for 14 days. In the
    high-dose group 75% of the animals died (Connor et al., 1980).

         Groups of five, 5-week-old, B6C3F1 mice of each sex were
    administered 0, 12.5, 25, 50, 100 or 200 mg THPS (obtained as a 72%
    aqueous solution) per kg body weight by gavage for 14 consecutive
    days. Mice of the two highest dose groups had increased mortality at
    100 mg/kg (20% male, 40% female) and at 200 mg/kg (80% male, 100%
    female). At 25 mg/kg or more there was a decrease in body weight gain.
    The animals given 100 or 200 mg/kg had laboured breathing and rough
    coat and female mice of these groups also showed loss of movement in
    their hind legs (US NTP, 1987).

         Groups of 10, 5- to 6-week-old B6C3F1 mice of each sex were
    administered 0, 5, 10, 20, 40 or 60 mg THPS (obtained from a 72%
    aqueous solution) per kg body weight by gavage on 5 days/week for 13
    weeks. One of 10 females that received 60 mg/kg and 2/10 males and
    1/10 females that received 40 mg/kg died. The final mean body weights
    of mice that received 20, 40 or 60 mg/kg were 4%, 7% or 11%,
    respectively, lower than those of the controls for males and 3%, 5%
    and 11% lower for females. Periportal vacuolar degeneration occurred
    in all male and female mice that received 60 mg/kg, all males and 9/10
    females that received 40 mg/kg, and 8/10 male mice that received 20
    mg/kg. The NOAEL for this study was 7.1 mg/kg body weight per day, and
    the LOAEL was 14.3 mg/kg body weight per day (US NTP, 1987).

         Groups of five, 4-week-old, F-344/N rats of each sex were
    administered 0, 12.5, 25, 50, 100 or 200 mg THPS (obtained as a 72%
    aqueous solution) per kg body weight by gavage for 14 consecutive
    days. All rats given 100 or 200 mg/kg died. Animals that received 25
    or 50 mg/kg gained less weight than controls by 11% and 21%,
    respectively, in males and 1% and 7% in females. The animals given the
    two highest dose levels showed tremors, and one animal had partial
    loss of movement of the hind legs. At necropsy no abnormalities were
    seen (US NTP, 1987).

         In an oral 28-day study, Charles River derived CD rats (five
    females and five males/group) were given by gavage 6, 30 or 60 mg THPS
    (75% obtain as aqueous solution) per kg body weight daily. At the
    highest dose level, one male rat died on day 20, one female rat on day
    21 and the remaining rats on day 22. Post-dose salivation, emaciation,
    hypoactivity, hunched posture, noisy breathing, urogenital staining

    and ptosis were seen only in the 60 mg/kg group. There was severe
    weight loss during week 3 (body weight 52% for male and 74% for female
    relative to controls at the end of week 3). The NOEL was considered to
    be 6 mg/kg body weight per day (Hill, 1989).

         Groups of ten, 5- to 6-week-old F-344/N rats of each sex were
    administered 0, 5, 10, 20, 40 or 60 mg THPS (obtained from a 72%
    aqueous solution) per kg body weight by gavage 5 days/week for
    13 weeks. Three of the male rats that received 60 mg/kg died. Final
    mean body weights were 5%, 15% and 22% lower than those of the
    controls for males that received 20, 40 or 60 mg/kg and 9%, 12% and
    19% lower for females that received 20, 40 or 60 mg/kg. Vacuolar
    degeneration of hepatocytes occurred in all males receiving 10 mg/kg
    or more, in all females receiving 40 or 60 mg/kg, and in 5/10 females
    receiving 20 mg/kg. Lymphoid depletion in the spleen was seen in three
    males in the 60 mg/kg group. Bone marrow hypoplasia was diagnosed in
    3/10 male and 4/10 female rats in the 60 mg/kg groups. The NOAEL in
    this study was 3.6 mg/kg body weight per day; the LOAEL was 7.1 mg/kg
    body weight per day (US NTP, 1987).

         Groups of 10 Charles River derived CD rats of each sex received
    0, 1, 5 or 10 mg THPS (75% aqueous solution) per kg body weight per
    day by gavage daily for 13 weeks. One female rat from the 5 mg/kg
    group died on day 14, one female from the 1 mg/kg group on day 53 and
    another on day 81. No clinical signs or changes in body weight were
    attributed to THPS administration at any dose level other than mean
    plasma ALAT and ASAT levels being twice control values for males of
    the highest dose group. Histopathology showed moderate to marked
    cytoplasmic vacuolation of periportal hepatocytes in all male rats and
    moderate vacuolation in one female rat of the highest dose group. The
    NOEL for this study was 1 mg/kg body weight per day (Hill & Newman,
    1990).

    C7.2.2  Dermal

         Application of 125, 350, 700 or 1000 mg THPS/kg body weight on
    chemically depilated back skin of groups of 12 male ICR mice daily for
    up to 14 days caused reduced body weight, paralysed back muscles at
    700 mg/kg body weight or more, and some superficial necrosis at all
    doses (Connor et al., 1980). Similar effects were reported in mice by
    Afansa'eva & Evseenko (1971).

         Both THPC and THPS were toxic when applied dermally for long
    periods on the skin. Rats and rabbits were dosed daily for 20 days
    with 15%, 20% or 30% aqueous solutions of THPC. Severe skin lesions
    occurred and all rats in the highest dose group died after 9 days of
    application (Aoyama, 1975).

         In a study by Wragg et al. (1996), trihydroxymethyl phosphine
    oxide was administered by dermal application to three groups, each of
    five male and five female Sprague-Dawley CD rats, for up to 28
    consecutive days at dose levels of 0, 300, 650 and 1000 mg/kg body
    weight per day. There were no deaths or clinical abnormalities
    attributable to the test material. Body weight gain and food

    consumption were similar in treated groups and controls. Females
    treated with 1000 mg/kg showed an increase in plasma total protein and
    a reduction in albumin/globulin ratio compared to controls. Males
    treated with 1000 mg/kg and both males and females in the remaining
    treatment groups showed no toxicologically significant changes in
    these parameters. Both males and females dosed at 1000 mg/kg showed
    cortical hypertrophy of the adrenal glands. Adverse dermal reactions
    (scabs sometimes accompanied by scar tissue) were seen at all dose
    levels. The incidence of these adverse dermal reactions gradually
    increased during the second half of the treatment period amongst males
    (but not females) dosed at 1000 mg/kg, and by day 28 all five males
    showed dermal abnormalities. A NOAEL for dermal reactions was not
    established. The NOAEL for systemic toxicity was determined to be 650
    mg/kg body weight per day (Wragg et al., 1996).

    C7.3  Long-term exposure

    C7.3.1  THPC

         Groups of 50 F-344/N rats of each sex (7 weeks of age) were
    administered 0, 3.75 or 7.5 mg THPC (obtained from a 75% aqueous
    solution) per kg body weight by gavage on 5 days/week for 103 weeks.
    The mean body weights of different groups were comparable. Clinical
    signs noted were rough hair coat and diarrhoea. The survival of 
    high-dose female rats was significantly lower than that of controls 
    after week 70  (P = 0.013). A dose-related increase in the 
    incidence of hepatocellular lesions, primarily cytoplasmic 
    vacuolization, was found (males: controls 0%, low-dose 18% and 
    high-dose 47%; females: controls 6%, low-dose 22% and high-dose 50%).
    The LOAEL for this study was 2.7 mg/kg body weight per day; a NOAEL
    was not established (US NTP, 1987).

         Groups of 50 male B6C3F1 mice (8 weeks of age) were administered
    0, 7.5 or 15 mg THPC (obtained from a 75% aqueous solution) per kg
    body weight, and groups of 50 female B6C3F1 mice received 0, 15 or 30
    mg/kg body weight by gavage 5 days/week for 103 weeks. No clear
    difference between control and treated groups concerning body weight
    gain and mortality was observed. Compound-related clinical signs
    consisted of rough hair coat and diarrhoea. No signs of neurotoxicity
    were observed. There was a dose-related increase in the incidence of
    hepatocellular cytoplasmic vacuolization (males: controls 0%, low-dose
    80%, and high-dose 88%; females: controls 0%, low-dose 84%, and 
    high-dose 96%). Follicular cell hyperplasia of the thyroid gland was
    observed in the high-dose females (22% versus 6% in controls). The
    LOAEL for this study was 5.4 mg/kg body weight per day; a NOAEL was
    not established (US NTP, 1987).

    C7.3.2  THPS

         Groups of 49 or 50 F-344/N rats of each sex were administered 0,
    5 or 10 mg THPS (obtained from a 72% aqueous solution) per kg body
    weight by gavage 5 days/week for 104 weeks. Mean body weights of the
    different groups were comparable. Clinical signs were rough hair coat

    and diarrhoea. The survival of both the male low-dose (after week 102)
    and high-dose (after week 67) animals was significantly lower
     (P = 0.036 and 0.006, respectively). The effect level for mortality
    in this study was 3.6 mg/kg body weight per day, the lowest dose
    tested (US NTP, 1987).

         Groups of 50 B6C3F1 mice of each sex (7 weeks of age) were
    administered 0, 5 or 10 mg THPS (obtained from a 72% aqueous solution)
    per kg body weight by gavage 5 days/week for 104 weeks. Mean body
    weight and survival of control and treated groups were comparable.
    Clinical signs were limited to rough hair coat and diarrhoea. 
    Non-neoplastic lesions seen were focal hyperplasia of the adrenal 
    medulla, but the numbers were statistically unrelated to dose 
    (controls 3/49, low-dose 5/48, high-dose 10/49). The NOAEL for this 
    study was 3.6 mg/kg body weight per day; the LOAEL was 7.1 mg/kg body 
    weight per day (US NTP, 1987).

    C7.4  Skin and eye irritation; sensitization

    C7.4.1  Skin irritation

    C7.4.1.1  THPS

         When 0.5 ml of THPS (75%) was applied to the skin of six New
    Zealand white rabbits for a period of 4 h (OECD 404), no dermal
    irritation was observed (Liggett, 1989a).

         In a dermal study, daily doses of 25, 250 or 500 mg THPS (75%
    aqueous solution) were applied to the shaved neck skin of ten (five
    females, five males) Charles River derived CD rats. The treatment had
    to be terminated and animals killed after 6 days due to the nature and
    severity of the skin reaction observed at the application site (Hill,
    1989).

    C7.4.1.2  THPC-urea

         A single 4-h semi-occluded application of THPC-urea to the intact
    skin of six rabbits produced corrosive effects at two skin sites and
    slight-to-well-defined erythema and very slight to slight oedema at
    the other four treated skin sites (Snell, 1994).

    C7.4.2  Eye irritation

         In a test for eye irritation (OECD 405), an aliquot of 0.1 ml
    THPS (75%) was introduced to one eye of a New Zealand rabbit. Opacity
    was observed 24 h after application and lasted at least for 24 h. Red
    coloration of the conjunctiva accompanied by considerable swelling was
    observed. On the basis of these effects, THPS (75%) is considered to
    be a severe eye irritant (Liggett, 1989b).

    C7.4.3  Skin sensitization

    C7.4.3.1  THPS

         THPS (75%) was assessed for skin sensitization using the
    Magnusson & Kligman Maximisation test (OECD 406). Fourteen out of 20
    animals challenged with the test substance were sensitized (Guest,
    1994b). These data clearly demonstrate a sensitization potential for
    THPS (75%).

    C7.4.3.2  THPC-urea

         When THPC-urea was tested for skin sensitization potential using
    the guinea-pig Magnusson & Kligman Maximisation test, 53% of the
    animals were sensitized (Tufnell, 1992).

    C7.5  Reproductive toxicity, embryotoxicity and teratogenicity

    C7.5.1  THPS

         Three groups of 16 New Zealand white rabbits were administered
    (OECD 414) by gavage THPS (75%) at 6, 18 and 60 mg/kg body weight per
    day from day 7 to 19 of gestation. All animals were kill on day 21. At
    60 mg/kg mean body weight gain was significantly lower than that of
    controls, showing maternal toxicity. Treatment at 60 mg/kg resulted in
    increase incidence (42/120) of fetuses with eye malformation and some
    with additional hydrocephaly or limb/phalangeal reduction defects. An
    increase incidence of specific skeleton variation was also observed.
    No adverse effects were noticed in the two lower-dose group (Barker,
    1991a).

         Charles River CD rats (24 animals per group) were administered by
    gavage THPS (75%) at 15, 30 and 60 mg/kg body weight per day from day
    6 to 15. All animals were killed on day 21. Treatment at 60 mg/kg
    reduced significantly body weight gain from day 12 of gestation
    onwards, indicating maternal toxicity. No treatment-related effects
    were observed in dams at the low-dose level. At the high-dose level,
    the incidence of fetuses showing extra thoraco-lumbar ribs was
    significantly higher than for controls. At 30 mg/kg only minor signs
    of maternal toxicity were observed (Barker, 1991b).

         From these studies a NOAEL of 18 mg/kg body weight per day based
    on maternal toxicity could be derived. No developmental effects were
    observed in the absence of maternal toxicity.

    C7.5.2  THPC-urea

         Dose levels of 10, 30 and 100 mg THPC-urea/kg body weight per day
    were administered to groups of 16 rabbits from day 7 to 19 of
    gestation. All animals were killed on day 29. At the high-dose level,
    an initial mean weight loss was followed by significantly reduced
    weight gain over the treatment period. Treatment did not affect the
    incidence of fetuses showing external, visceral or skeletal
    malformations or variations (Barker, 1992).

    C7.6  Mutagenicity and related end-points

    C7.6.1  THPC-urea

    C7.6.1.1  In vitro studies

         An  in vitro cytogenetic assay was performed with THPC-urea
    using human lymphocytes. Harvest times of 16 and 40 h were used for
    cells incubated in the presence of S9 from induced rat liver, and
    times of 20 and 44 h were used when S9 was absent. In one experiment,
    THPC-urea had no effect on the number of aberrant cells at
    concentrations up to 40 mg/ml, but, in a repeat experiment, increased
    numbers of aberrant cells were seen at 20 and 40 mg/ml. The reason for
    the difference in results between the two experiments is not clear
    (Durward, 1995; Bailey, 1995).

    C7.6.1.2  In vivo studies

         No mutagenicity of THPC-urea was evident in a mouse micronucleus
    test in which oral doses of 212.5, 425 and 850 mg/kg body weight were
    administered (Durward, 1996).

    C7.6.2  THPC

          Salmonella microsomal assays have shown uniformly negative
    results for THPC (Table 10).

         THPC produced chromosomal aberrations in Chinese hamster ovary
    (CHO) cells in the absence of metabolic activation, but the results
    were equivocal when it was tested in the presence of S9 from livers of
    Sprague-Dawley rats treated with Aroclor 1254 (US NTP, 1987; Loveday
    et al., 1989). THPC induced chromosomal aberrations in Chinese hamster
    DON-6 cells in the absence of metabolic activation (Sasaki et al.,
    1980).

         THPC induced sister-chromatid exchange (SCE) in CHO cells when
    incubated in the absence of metabolic activation (US NTP, 1987;
    Loveday et al., 1989).

        Table 10.  Mutagenicity tests with  Salmonella typhimurium
                                                                                                                         

    Strain                             Dose             Metabolic activation                    Reference
                                       (µg/plate)
                                                                                                                         

    TA100, TA1535, TA1537, TA98        0.33-33          none, S9 rat liver (male),              US NTP (1987)a
                                                        S9 Syrian hamster liver (male)

    TA98, TA100, TA1535, TA1537        10-1000          none, S9 liver (Aroclor 1254, rat)      MacGregor et al. (1980)

    TA98, TA100, TA1535, TA1537        10-300           none, S9 liver (Aroclor 1254, rat)      MacGregor et al. (1980)

    TA98, TA100, TA1535, TA1537        Up to 10 000     none, S9 liver (Aroclor 1254, rat)      Zeiger et al. (1987)

    TA98, TA100                        not know         none, S9                                Kawachi et al. (1980b)b
                                                                                                                         

    a  THPC gave positive results in a mouse lymphoma assay in the absence of metabolic activation (US NTP, 1987).
    b  Kawachi et al. (1980b) found positive results with THPC in the  Bacillus subtilis rec assay with and without
       metabolic activation.
    

    C7.6.3  THPS

         THPS produced no mutagenicity when tested in the  Salmonella
    microsome assay using strains TA98, TA100, TA1535, TA1537 and 
    TA1538 in the presence and absence of S9 from the livers of
    Aroclor-1254-treated rats (Dillon & Riach, 1990). Leachate from
    THPS-treated paper also showed no mutagenicity when tested with
    strains TA98, TA100, TA102, TA1535 and TA1537 in the presence and
    absence of S9 from Aroclor-1254-treated rats (Ballentyne, 1996b).

         When tested in the mouse lymphoma assay, THPS caused mutations
    both in the presence and absence of S9 from Aroclor-treated rats
    (Riach, 1996). US NTP (1987) also reported positive results for THPS
    in the mouse lymphoma assay in the absence of S9.

         High levels of structural chromosomal aberrations were detected
    at metaphase in CHO cells treated with THPS in the presence or absence
    of S9 from liver of Aroclor-treated rats (Leddy, 1990). Anaphase
    analysis of THPS-treated CHO cells also showed that chromosomal
    aberrations were produced along with abnormal spindles (Coutino,
    1979).

         The results of an  in vitro assay for unscheduled DNA synthesis
    in a primary culture of rat hepatocytes were negative (Downey et al.,
    1990; Riach, 1994).

         Bone marrow from THPS-treated mice was analysed for
    micronucleated polychromatic erythrocytes (MN-PCEs) and for metaphase
    cells showing chromosomal aberrations. There was no effect on the
    number of MN-PCEs nor on the number of chromosomal aberrations (Connor
    et al., 1980).

         The  in vivo mutagenicity of dermal doses of THPS was
    investigated in Swiss (ICR) mice using a similar protocol to that of
    the previous study. Dermal doses of 125, 350, 700 and 1000 mg/kg body
    weight per day were used. Urine from treated mice was not mutagenic in
    the  Salmonella microsome assay. Analysis of bone marrow from treated
    mice showed a slight increase in the number of polyploid cells at the
    highest dose level, but otherwise there was no indication of
    mutagenicity (Connor et al., 1980).

         In a dominant lethal assay in Swiss (ICR) mice, males were dosed
    with up to 1000 mg/kg body weight. There was no evidence to suggest
    that THPS produced dominant lethal mutations (personal communication
    by M. Legator to Hooker Chemicals and Plastics Corp., 1977).

         In a dominant lethal study in rats, gavage doses of 5, 10 or 15
    mg/kg body weight per day were given to males for 10 weeks. After
    mating, investigation of the pregnant females indicated no dominant
    lethal mutations (Clode, 1996).

    C7.6.4  THPO

         THPO is a metabolite and breakdown product of THP salts. It was
    not mutagenic in  Salmonella typhimurium strains TA98, TA100, TA1535
    and TA1537 or in  Escherichia coli strain WP2  uvra when tested in
    the presence and absence of S9 from livers of Aroclor-1254-treated
    rats (Ballentyne, 1996a).

         THPO was not mutagenic in the mouse lymphoma assay in either the
    presence or absence of liver S9 from Aroclor-1254-treated rats
    (Fellows, 1996). It did not produce chromosomal aberrations in CHO
    cells cultured in either the presence or absence of S9 (Marshall,
    1996).

    C7.6.5  Treated fabrics

         Groups of 12 male ICR mice received 0 (no fabric), 2500 mg
    untreated fabric per kg diet or 250, 1250 or 2500 mg THPS-treated
    fabric per kg diet for 5 successive days. Femurs were collected for
    analyse of bone marrow for MN-PCEs and chromosomal aberrations. All
    tests were negative (Connor et al., 1980).

    C7.7  Carcinogenicity

    C7.7.1  Oral studies

    C7.7.1.1  Mice

         In a 103-week study of THPC (75%) in mice (see section C7.3.1),
    there was no evidence of carcinogenicity (US NTP, 1987).

         In a 104 week study of THPS (72%) in mice(see section C7.3.2),
    there was no evidence of carcinogenicity (US NTP, 1987).

    C7.7.1.2  Rats

         In a 103 week study for THPC (75%) in rat (see section C7.3.1),
    there was no evidence of carcinogenicity (US NTP, 1987).

         In a 104 week study for THPS (72%) in rat (see section C7.3.2),
    there was no evidence of carcinogenicity (US NTP, 1987).

    C7.7.2  Dermal studies: Initiation and promotion

         A group of 60 female ICR/Ha Swiss mice, 6-8 weeks of age,
    received skin applications of THPC (2 mg/mouse) in acetone three times
    a week for 71 weeks. The control group received acetone only. There
    was no significant increase in tumours (papillary tumours of the lung
    and papillomas of the forestomach) in the animals treated with THPC
    (Van Duuren et al., 1978).

         Groups of 20 female ICR/Ha Swiss mice, 6-8 weeks of age, received
    skin applications of THPC (2 mg/mouse) or Pyroset TKP
    (acetate/phosphate mixture of THP) (7 mg/mouse) in dimethyl sulfoxide

    three times a week for 57 weeks to examine the initiating, promoting
    and complete carcinogenic potential in skin carcinogenesis bioassays.
    Both chemicals were active as tumour promoters using a single
    application of 7,12-dimethylbenz[ a]anthracene (DMBA) (20 µg in 0.1
    ml acetone) as initiator. Neither chemical was active as a tumour
    initiator or complete carcinogen (Loewengart & van Duuren, 1977).

    C7.8  Special studies

         THPS and THPO did not inhibit acetyl cholinesterase when tested
     in vitro using malathion (a known inhibitor of cholinesterase) as a
    positive control (Thompson, 1997a,b).
    

    C8.  EFFECTS ON HUMANS

         Fabric treated with THPC-urea condensate was tested on human
    volunteers in a 48-h skin patch test. The treated fabric was not
    irritant to exposed human skin (Jackson, 1982).
    

    C9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

    C9.1  Laboratory experiments

    C9.1.1  Aquatic organisms

         THPS showed an EC50 for growth inhibition of the marine
    microalga  Skeletonema costatum of 0.16 mg/litre over 72 h (Hushagen
    & McWilliam, 1994). For the freshwater green alga  Selenastrum
     capricornutum, EC50 values of 0.652 mg/litre (based on growth rate)
    and 0.204 mg/litre (based on biomass) were determined. The NOEC for
    both end-points was 0.063 mg/litre. The test was conducted under OECD
    Guideline 201 (Jenkins, 1991c).

         The 48-h LC50, based on immobilization and using nominal
    concentrations, for THPS in the water flea  (Daphnia magna) was
    determined to be 19.4 mg/litre, with a NOEC of 10.4 mg/litre. The test
    was conducted under US EPA/OECD Guideline 202 (Jenkins, 1989).
    Concerning estuarine/marine invertebrates, the 96-h LC50 for the
    mysid shrimp  (Mysidopsis bahia) is 7.3 mg/litre (NOEC 3.5 mg/litre)
    (Boeri et al., 1995a), the 96-h LC50 for the brown shrimp  (Crangon
     crangon) is 340 mg/litre (Douglas & Pell, 1986), and the 48-h LC50
    for the brine shrimp  (Acartia tonsa) is 0.6 mg/litre (Torp &
    McWilliam, 1994). The 96-h EC50 for shell deposition in juvenile
    Eastern oysters  (Crassostrea virginica) was reported to be
    1.6 mg/litre, with a NOEC of 0.67 mg/litre for THPS in a test
    following US EPA guidelines (Boeri et al., 1995c). The 10-day LC50
    for THPS was determined for the sediment-dwelling amphipod  Corophium
     volutator to be 2174 mg/kg dry sediment weight (Roddie, 1994).

         The 96-h LC50, based on nominal concentrations of THPS, for the
    rainbow trout  (Oncorhynchus mykiss) was determined to be 119
    mg/litre with a NOEC of 18.1 mg/litre in a test conducted according to
    OECD Guideline 203 (Jenkins, 1991a). A test conducted under US
    EPA/OECD Guideline 203 determined the 96-h LC50 for THPS in bluegill
    sunfish  (Lepomis macrochirus) to be 93 mg/litre, with a NOEC of 22.7
    mg/litre (Jenkins, 1991b). The 96-h LC50 for the marine sheepshead
    minnow  (Cyprinodon variegatus) was determined to be 72 mg/litre,
    with a NOEC of 41 mg/litre using US EPA guidelines (Boeri et al.,
    1995b). For juvenile plaice  (Pleuronecta platessa), the 96-h LC50
    was 86 mg/litre (Douglas & Handley, 1989).

    C9.1.2  Terrestrial organisms

         The acute oral LD50 for young adult mallard ducks  (Anas
     platyrynchus) was 311 mg/kg body weight (Roberts & Phillips, 1988a).
    Dietary LC50 values for the mallard duck and bobwhite quail
     (Colinus virginianus) were 1313 and 2414 mg/kg diet, respectively
    (Roberts & Fairley, 1988; Roberts & Phillips, 1988b).
    

    C10.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         The International Agency for Research on Cancer evaluated the
    carcinogenicity of tetrakis(hydroxymethyl) phosphonium salts in 1989
    (IARC, 1990) and concluded:

    a)   There is  inadequate evidence for the carcinogenicity of
         tetrakis(hydroxymethyl) phosphonium salts in experimental
         animals.

    b)   No data were available from studies in humans on the
         carcinogenicity of tetrakis(hydroxymethyl) phosphonium salts.

    c)   Tetrakis(hydroxymethyl) phosphonium salts  are not classifiable
          as to their carcinogenicity to humans (Group 3).
    

    REFERENCES

    Adachi K, Mitsuhashi M, & Ohkuni N (1984) Pesticides and trialkyl
    phosphates in tap water (Jpn.) Hyogo-ken Eisei Kenkyusho Kenkyu
    Hokoku, 19: 1-6 (Abstract).

    Afansa'eva LV & Evseenko NS (1971) Hygiene evaluation of fire-proof
    textiles processed with an organophosphorus impregnant based on
    tetrahydroxymethyl phosphonium chloride. Hyg Sanit , 36(3): 450-453.

    Anderson GD, Elvin AT, & Lalka D (1984) Estimation of
    tris(2-butoxyethyl) phosphate in biological fluids: Novel intersubject
    variability in recovery from human serum. J Pharm Sci, 73(12):
    1791-1793.

    Antony C (1993) THPS 75% viscosity (Study sponsored by Albright &
    Wilson). Whippany, New Jersey, Case Consulting Laboratories Inc.

    Aoyama M (1975) Effect of anti-flame treating agents on the skin.
    Nagoya Med J, 20: 11-19.

    Arias P (1992) Brominated diphenyloxides as flame retardants: Bromine
    based chemicals (Unpublished report to the OECD).

    Armstrong JA & Yule WN (1978) The distribution of aerially-applied
    spray deposits in spruce trees. Can Entomol , 110: 1259-1267.

    ARW (1987) [Annual report 1987.] Düsseldorf, Working Group
    Rhine-Waterworks, p 86 (in German).

    Ashby J & Tennant RW (1988) Chemical structure,  Salmonella
    mutagenicity and extent of carcinogenicity as indicators of genotoxic
    carcinogens among 222 chemicals tested in rodents by the US NCI/NTP.
    Mutat Res, 204: 17-115.

    Bailey IA (1995) Proban CC:  in vitro cytogenetic assay review (Study
    sponsored by Albright & Wilson). Cheshire, United Kingdom, Zeneca Ltd,
    Central Toxicology Laboratory (Report No. CTL/B/31).

    Ballentyne M (1996a) Trishydroxymethyl phosphine oxide: Reverse
    mutation in five histidine-requiring strains of  Salmonella
     typhimurium. Harrogate, United Kingdom, Corning Hazleton (Europe)
    (Unpublished report No. 254/47-1052).

    Ballentyne M (1996b) THPS paper leachate PLO1: Reverse mutation in
    four histidine-requiring strains of  Salmonella typhimurium and one
    tryptophan-requiring strain of  Escherichia coli. Harrogate, United
    Kingdom, Corning Hazleton (Europe) (Unpublished report No.
    254/45-1052).

    Barker L (1991a) THPS: Oral (gavage) teratology study in the rabbit
    (Study sponsored by Albright & Wilson). Harrogate, United Kingdom,
    Corning Hazleton (Europe) (Unpublished report No. 6380-254/19).

    Barker L (1991b) THPS: Oral (gavage) teratology study in the rat
    (Study sponsored by Albright & Wilson). Harrogate, United Kingdom,
    Corning Hazleton (Europe) (Unpublished report No. 6358-254/23).

    Barker L (1992) Proban CC: Oral (gavage) teratology study in the
    rabbit (Study sponsored by Albright & Wilson). Harrogate, United
    Kingdom, Corning Hazleton (Europe) (Unpublished report No.
    6742-254/26).

    Barth T (1994) Bioaccumulation OECD 117 partition coefficient
     n-octanol/water (HPLC)- tolcide PS75 (Study sponsored by Albright &
    Wilson). Bergen, Norway, Terra Miljö-Laboratories A/S.

    Bayer (1958) [Toxicological testing of the softener
    tri-2-ethylhexylphosphate (TOF).] Leverkusen, Germany, Bayer AG,
    Institute of Toxicology (Unpublished report) (in German).

    Bayer (1989) [Phosphoric acid, bis(2-ethylhexyl)ester ecotoxicological
    data -- Fish toxicity: Basic data set for existing chemicals above
    1000 t/year.] Leverkusen, Germany, Bayer AG (in German).

    Bayer (1982a) [Biological degradation of tris(2-ethylhexyl)phosphate.]
    Leverkusen, Germany, Bayer AG, Institute for Environmental Analysis
    and Assessment (Unpublished report) (in German).

    Bayer (1982b) [Bacterial test on chemicals, ETAD 3002/ISO8192.]
    Leverkusen, Germany, Bayer AG, Institute for Environmental Analysis
    and Assessment (Unpublished report) (in German).

    Boeri RL, Magazu JP, & Ward TJ (1995a) Acute toxicity of tetrakis
    (hydroxymethyl) phosphonium sulphate (THPS) to the Mysid  (Mysidopsis
     bahia), under flow-through conditions (Study No. 41238). Columbia,
    Missouri, ABC Laboratories Inc. (Unpublished report).

    Boeri RL, Magazu JP, & Ward TJ (1995b) Acute toxicity of
    tetrakis(hydroxymethyl) phosphonium sulphate (THPS) to the sheepshead
    minnow,  (Cyprinodon variegatus), under flow-through conditions
    (Study No. 41239). Columbia, Missouri, ABC Laboratories Inc.
    (Unpublished report).

    Boeri RL, Magazu JP, & Ward TJ (1995c) Acute flow-through mollusc
    shell deposition test with tetrakis(hydroxymethyl) phosphonium
    sulphate (THPS) (Study No. 41240). Columbia, Missouri, ABC
    Laboratories Inc. (Unpublished report).

    Bohlen H, Hicke K, Stobel A-O, Zierott M, & Thiemann W (1989) [The
    contamination of the lower part of the Weser River by organochlorine
    and organophosphorus compounds I.] Vom Wasser, 72: 185-197 (in
    German).

    BUA (1996) [German Chemical Society-Advisory Committee on Existing
    Chemicals of Environmental Relevance (BUA): Di(2-ethylhexyl)
    phosphate, tri(2-ethylhexyl) phosphate.] Stuttgart, Germany, S. Hirzel
    (BUA Report 172) (in German).

    Carrington CD, Lapadula DM, Othman M, Farr C, Nair RS, Johanssen F, &
    Abou-Donia M (1990) Assessment of the delayed neurotoxicity of
    tributyl phosphate, tributoxyethyl phosphate and dibutylphenyl
    phosphate. Toxicol Ind Health, 6(3/4): 415-423.

    Clode SA (1996) THPS: Oral (gavage) dominant lethal study in the rat.
    Harrogate, United Kingdom, Corning Hazleton (Europe) (Unpublished
    report No. 254/43-1050l).

    Connor T, Meyne J, & Legator M (1980) The mutagenic evaluation of
    tetrakis(hydroxymethyl) phosphonium sulfate using a combined testing
    protocol approach. J Environ Pathol Toxicol, 1: 145-158.

    Coutino R (1979) Analysis of anaphase in cell culture: An adequate
    test system for the distinction between compounds which selectively
    alter the chromosome structure or the mitotic apparatus. Environ
    Health Perspect, 31: 131-136.

    Cowlyn TC (1991a) THPS: Determination of physical-chemical properties
    (Study sponsored by Albright & Wilson). Eye, United Kingdom, Life
    Science Research Limited

    Cowlyn TC (1991b) THPS-75: Determination of physical-chemical
    properties (Study sponsored by Albright & Wilson). Eye, United
    Kingdom, Life Science Research Limited.

    Dillon DM & Riach CG (1990) THPS-75, batch No 88/22: Testing for
    mutagenic activity with  Salmonella typhimurium TA1535, TA1537,
    TA1538, TA98 and TA100 (Project No.740423). Falls Church, Virginia,
    Inveresk Research International.

    Douglas MT & Handley JW (1989) The acute toxicity of DP435 to juvenile
    plaice  (Pleuronectes platessa) (Study sponsored by Albright &
    Wilson). Huntingdon, United Kingdom, Huntingdon Research Centre
    Limited (Unpublished report No. A&W 491/881590).

    Douglas MT & Pell IB (1985) Assessment of inherent biodegradability of
    DP 435 (Study sponsored by Albright & Wilson). Huntingdon, United
    Kingdom, Huntingdon Research Centre Limited (Report No.
    A&W457(C)/85679).

    Douglas MT & Pell IB (1986) The acute toxicity of DP435 to Brown
    shrimp  (Crangon crangon) (Study sponsored by Albright & Wilson).
    Huntingdon, United Kingdom, Huntingdon Research Centre Limited
    (Unpublished report No. A&W 470(b)/8677).

    Downey E, Riach CG, & Mohammed R (1990)
    Tetrakishydroxymethylphosphonium sulphate: assessment of genotoxicity
    in an unscheduled DNA synthesis assay using adult rat hepatocyte
    primary culture (Project No. 741343). Falls Church, Virginia, Inveresk
    Research International (Unpublished Report No. 6230).

    Durward R (1995) Proban CC: Chromosomal aberration test in human
    lymphocytes  in vitro (SPL project No. 071/346, sponsored by Albright
    & Wilson). Derby, United Kingdom, Safepharm Laboratories Ltd.

    Durward R (1996) Proban CC: Micronucleus test in the mouse (SPL
    project No. 071/372, sponsored by Albright & Wilson). Derby, United
    Kingdom, Safepharm Laboratories Ltd.

    ECETOC (1992a) Tris(2-ethylhexyl) phosphate (CAS No. 78-42-2);
    Bis(2-ethylhexyl) phosphate (CAS No. 298-07-7); and Mono(2-ethylhexyl)
    phosphate (CAS No. 12645-31-7). Brussels, European Chemical Industry
    Ecology and Toxicology Centre (Joint Assessment of Commodity Chemicals
    No. 20).

    ECETOC (1992b) Tris(2-butoxylethyl) phosphate. Brussels, European
    Chemical Industry Ecology and Toxicology Centre ( Joint Assessment of
    Commodity Chemicals No. 21).

    Eldefrawi AT, Mansour NA, Brattsten LB, Ahrens VD, & Lisk DJ (1977)
    Further toxicologic studies with commercial and candidate flame
    retardant chemicals: Part II. Bull Environ Contam Toxicol, 17(6):
    720-726.

    Environmental Agency Japan (1983) Environmental monitoring of
    chemicals: Environmental survey report of FYs 1980 and 1981. Tokyo,
    Environmental Agency, Department of Environmental Health, Office of
    Health Studies..

    Environmental Agency Japan (1987) Chemicals in the environment: Report
    on environmental survey and wildlife monitoring of chemicals in FYs
    1984 and 1985. Tokyo, Environmental Agency, Department of
    Environmental Health, Office of Health Studies.

    Environmental Agency Japan (1978) Environmental monitoring of
    chemicals: Environmental survey report of 1977 FY. Tokyo,
    Environmental Agency, Department of Environmental Health, Office of
    Health Studies.

    Ernst W (1988) [Evaluation of contaminants of low degradability in
    estuaries.] Biotechnology, 129(3): 60-63 (in German).

    Fellow SM (1996) Tris hydroxymethyl phosphine oxide (THPO); mutation
    at the thymidine kinase (tk) locus of mouse lymphoma L517BY cells
    using the microtitre fluctuation technique (Study sponsored by
    Albright & Wilson). Harrogate, United Kingdom, Corning Hazleton
    (Europe). 

    FMC (1990) Material safety data sheet on KP-140: Tributoxyethyl
    phosphate. Princeton, New Jersey, FMC Corporation.

    FMC (1998) Material safety data sheet: Reomol TOP. Princeton, New
    Jersey, FMC Corporation (Rev. 1).

    Freeman C (1991a) KP-140: Non-definitive primary skin irritation study
    in rabbits (Study No. I91-1206). Princeton, New Jersey, FMC
    Corporation, Toxicology Laboratory

    Freeman C (1991b) KP-140: Non-definitive acute oral toxicity study in
    rats (Study No. I91-1207). Princeton, New Jersey, FMC Corporation,
    Toxicology Laboratory.

    Freeman C (1991c) KP-140: Non-definitive primary eye irritation study
    in rabbits (Study No. 191-1205). Princeton, New Jersey, FMC
    Corporation, Toxicology Laboratory.

    Frimmel FH, Millington DS, & Christman RF (1987) [Quantification of
    organic compounds in charcoal extracts using gas chromatography/mass
    spectrometry.] Fresenius Z Anal Chem, 327: 149-153 (in German).

    Fukushima M & Kawai S (1986) Present status and fate of selected
    organophosphoric acid triesters in the water area of Osaka City.
    Seitai Kagaku, 8(4): 13-24.

    Fukushima M, Kawai S, Chimaki S, & Morioka T (1986) Urban runoff as a
    source of selected chemicals to river waters: An observation at
    Isojima sampling station in the Yodo River Basin. Health Environ Sci,
    49: 11-20.

    Fukushima M, Kawai S, & Yamaguchi Y (1992) Behavior of
    organophosphoric acid triesters in Japanese riverine and coastal
    environment. Water Sci Technol, 25(11): 271-278.

    Gabriel KL (1980a) Primary eye irritation study -- rabbits (Project
    No. 80-1907A). Philadelphia, Pennsylvania, Bioresearch Inc.

    Gabriel KL (1980b) Primary skin irritation study -- rabbits (Project
    No. 80-1907A). Philadelphia, Pennsylvania, Bioresearch Inc.

    Gabriel KL (1980c) Acute dermal toxicity -- rabbits (Project No.
    80-1907A). Philadelphia, Pennsylvania, Bioresearch Inc.

    Gartrell MJ, Craun JC, Podrebarac DS, & Gunderson EL (1986a)
    Pesticides, selected elements and other chemicals in infant and adult
    total diet samples: October 1980-March 1982. J Assoc Off Anal Chem,
    69: 146-161.

    Gartrell MJ, Craun JC, Podrebarac DS, & Gunderson EL (1986b) Chemical
    contaminants monitoring: Pesticides, selected elements and other
    chemicals in infant and toddler total diet samples, October 1980-March
    1982. J Assoc Off Anal Chem, 69: 123-145.

    Gorman M (1996) Aerobic aquatic metabolism of
    14C-tetrakishydroxylmethyl phosphonium sulphate (THPS): Final report
    (Study Sponsored by Albright & Wilson). Columbia, Missouri, ABC
    Laboratories Inc. (Unpublished report No. 40054).

    Gorman M (1997) Anaerobic aquatic metabolism of
    14C-tetrakishydroxylmethyl phosphonium sulphate (THPS): Final report
    (Study sponsored by Albright & Wilson). Columbia, Missouri, ABC
    Laboratories Inc. (Unpublished report No. 40055).

    Guest RL (1993a) Amgard TOF: Acute eye irritation test in the rabbit
    (Project No. 71/200, sponsored by Albright & Wilson). Derby, United
    Kingdom, Safepharm Laboratories Ltd.

    Guest RL (1993b) Amgard TOF: Acute dermal irritation test in the
    rabbit (Project No. 71/199, sponsored by Albright & Wilson). Derby,
    United Kingdom, Safepharm Laboratories Ltd.

    Guest RL (1994a) Tolcide THPS 75 %: Acute oral toxicity test in the
    rat (Study sponsored by Albright & Wilson). Derby, United Kingdom,
    Safepharm Laboratories Ltd (Unpublished report).

    Guest RL (1994b) Tolcide THPS 75 %: Magnusson & Kligman maximisation
    study in the guinea pig (Project No. 71/288). Derby, United Kingdom,
    Safepharm Laboratories Ltd (Unpublished report).

    Gunderson EL (1988) Dietary intakes of pesticides, selected elements
    and other chemicals: FDA total diet study, April 1982-April 1984. J
    Assoc Off Anal Chem, 71(6): 1200-1209.

    Gunderson EL (1995a) Dietary intakes of pesticides, selected elements
    and other chemicals: FDA total diet study, June 1984-April 1986. J
    Assoc Off Anal Chem, 78(4): 910-921.

    Gunderson EL (1995b) Dietary intakes of pesticides, selected elements
    and other chemicals: FDA total diet study, July 1986-April 1991. J
    Assoc Off Anal Chem, 78(6): 1353-1363.

    Haseman JK, Crawford DD, Huff JE, Boorman GA, & McConnell EE (1984)
    Results from 86 two-year carcinogenicity studies conducted by the
    National Toxicology Program. J Toxicol Environ Health, 14: 621-639.

    Hattori Y, Ishitani H, Kuge Y, & Nakamoto M (1981) Environmental fate
    of organic phosphate esters. Suishitsu Odaku Kenkyu, 4(3): 137-141.

    Hawley GG (1981) Condensed chemical dictionary, 12th ed. New York, Van
    Nostrand Reinhold, p 1133.

    Heaton PE (1991) Determination of the environment fate of THPS in
    water treatment applications. Oldbury, United Kingdom, Albright &
    Wilson UK Ltd, Biocides Group (Unpublished report No. BTSP-4A).

    Heim LC (1998) Soil/sediment adsorption-desorption of
    14C-tetrakishydroxymethyl phosphonium sulphate (THPS) (Study
    sponsored by Albright & Wilson). Columbia, Missouri, Analytical
    Bio-Chemistry (ABC) Laboratories, Inc. (Final report No. 40053).

    Hill RE (1989) DP435: 28 day dose range finding study in the rat 
    -- Sub-acute dermal study in the rat. Toxicol Laboratories Limited
    (Unpublished report No. ALW/7/89).

    Hill RE & Newman AJ (1990) DP435: 13 week oral (gavage) toxicity study
    in the rat -- Oral 90-day studies. Toxicol Laboratories Limited
    (Unpublished report No. ALW/4/90).

    Hinckley DA, Bidleman TF, Foreman WT, & Tuschall JR (1990)
    Determination of vapor pressures for nonpolar and semipolar organic
    compounds from gas chromatographic retention data. J Chem Eng Data,
    35: 232-237.

    Hoechst (1987) [Safety data sheet on tributoxyethyl phosphate, TBEP.]
    Frankfurt, Germany, Hoechst AG (in German).

    Hoechst (1989) [TBEP: Assessment of acute aerosol inhalation toxicity
    in male and female SPF-Wistar rats, 4 hours LC50.] Frankfurt,
    Germany, Hoechst AG, Pharma-Research Toxicology and Pathology (in
    German).

    Hooper G, Nakajima WN, & Herbes WF (1976) The use of various
    phosphonium salts for flame retardancy by the ammonium cure technique.
    In: Bhatnagar VM ed. Fire retardants: Proceedings of the International
    Symposium on Flammability and Fire Retardants, Montreal, Canada, 22-23
    May 1975. Westport, Connecticut, Technomic Publishing Co., pp 98-114.

    Hushagen H & McWilliam P (1994) Tolcide PS75 (THPS): Marine algal
    growth inhibition test with  Skeletonema costatum. Bergen, Norway,
    Terra Miljö-Laboratories A/S (Unpublished report No.
    60090.aw\tm.001\skelet

    IARC (1990) Some flame retardants and textile chemicals, and exposures
    in the textile manufacturing industry. Lyon, International Agency for
    Research on Cancer, pp 95-107 (IARC Monographs on the Evaluation of
    Carcinogenic Risks to Humans, Volume 48).

    IPCS (1998) Concise international chemical assessment document No. 10:
    2-Butoxyethanol. Geneva, World Health Organization, International
    Programme on Chemical Safety, 29 pp. 

    Ishikawa S, Taketomi M, & Shinohara R (1985) Determination of trialkyl
    and triaryl phosphates in environmental samples. Water Res, 19(1):
    119-125.

    Ivett JL, Brown BM, Rodgers C, Anderson BE, Resnick MA, & Zeiger E
    (1989) Chromosomal aberrations and sister chromatid exchange test in
    Chinese hamster ovary cells  in vitro: IV. Results with 15 chemicals.
    Environ Mol. Mutagen, 14: 165-187.

    Jackson JR (1982) Study to determine the primary irritancy of
    untreated fabric. Proban 210 treated fabric, Proban NX treated fabric,
    laundered Proban NX treated fabric in human volunteers. Oldbury,
    United Kingdom, Albright & Wilson UK Ltd.

    Jenkins WR (1989) THPS: Acute toxicity to  Daphnia magna (Study
    sponsored by Albright & Wilson). Eye, United Kingdom, Life Science
    Research Limited (Unpublished report No. 90/AWL007/0471).

    Jenkins WR (1991a) Acute toxicity to Rainbow trout (Study sponsored by
    Albright & Wilson). Eye, United Kingdom, Life Science Research Limited
    (Unpublished report No. 90/AWL006/0470).

    Jenkins WR (1991b) THPS -- Acute toxicity to Bluegill Sunfish (Study
    sponsored by Albright & Wilson). Eye, United Kingdom, Life Science
    Research Limited (Unpublished report No. 90/AWL005/0469).

    Jenkins WR (1991c) THPS -- Determination of its EC50 to  Selenastrum
     capricornutum under non-axenic conditions (Study sponsored by
    Albright & Wilson). Eye, United Kingdom, Life Science Research Limited
    (Unpublished report No. 90/AWL009/0473).

    KAN-DO Office and Pesticides Team (1995) Accumulated pesticide and
    industrial chemical finding from a ten-year study of ready-to-eat
    foods. J Assoc Off Anal Chem, 78(3): 614-631.

    Kawachi T, Komatsu T, Kada T, Ishidate M, Sasaki M, Sugiyama T, &
    Tazima Y (1980a) Results of recent studies on the relevance of various
    short-term screening tests in Japan: The predictive value of
    short-term screening tests in carcinogenicity evaluation. Appl Methods
    Oncol, 3: 253-267.

    Kawachi T, Yahagi T, Kada T, Tazima T, Ishidate M, Sasaki M, &
    Sugiyama T (1980b) Cooperative programme on short-term assays for
    carcinogenicity in Japan. In: Montesano R, Bartsch H, & Tomatis L ed.
    Molecular and cellular aspects of carcinogen screening tests, pp
    323-330 (IARC Scientific Publications No. 27).

    Kawagoshi Y & Fukunaga I  (1994) Levels and features of
    organophosphoric acid triesters at Osaka North Port Sea-Based solid
    waste disposal site. J Environ Chem, 4(4): 797-804.

    Kawagoshi Y & Fukunaga I (1995) Organophosphoric acid triesters in
    leachate from solid waste disposal site. Kankyo Kagaku, 5: 390-391.

    Kawai S, Fukushima M, Kitano M, & Morishita H (1985) Degradation of
    organophosphoric acid triesters by the bacteria in the river water of
    Osaka City. Annu Rep Osaka City Inst Public Health Environ Sci, 48:
    175-183.

    Kawai S, Fukushima M, Kitano M, Takayuki N, & Morishita H (1986)
    Degradation of organophosphoric acid triesters by the bacteria in the
    river water -- (ii) Properties of TBP (tributyl phosphate) degrading
    bacteria and their enzymes. Annu Rep Osaka City Inst Public Health
    Environ Sci , 49: 160-166.

    Keith LH & Walters DB (1985) Compendium of safety data sheet for
    research and industrial chemicals. New York, VCH Publishers Inc., part
    III, pp 1630-1631.

    Keith LH & Walters DB (1987) Compendium of safety data sheets for
    research and industrial chemicals. New York, VCH Publishers Inc., part
    IV, p 856.

    Kimmerle G (1958) [Softener tri-2-ethylhexylphosphate (TOF).]
    Leverkusen, Germany, Bayer AG, Laboratory of Toxicology and Pathology
    (Unpublished report No. 1764) (in German).

    Kluwe WM, Huff JE, Matthews HB, Irwin R, & Haseman JK (1985)
    Comparative chronic toxicities and carcinogenic potentials of 
    2-ethylhexyl containing compounds in rats and mice. Carcinogenesis,
    6(11): 1577-1583.

    Komsta E, Secours VE, Chu I, Valli VE, Morris R, Harrison J,
    Baranowski E, & Villeneuve DC (1989) Short-term toxicity of nine
    industrials chemicals. Bull Environ Contamin Toxicol, 43: 87-94. 

    Krzymien M (1981) Sample collection and field analysis of
    tris(2-ethylhexyl) phosphate used in a study of pesticide spray drift.
    J Chromatogr, 204: 453-459.

    Laham S, Long G, Schrader K, & Szabo J (1984a) Induction of electro
    physiological and morphological changes in Sprague-Dawley rats fed
    tributoxyethyl phosphate. J Appl Toxicol, 4(1): 42-48.

    Laham S, Szabo J, & Long G (1984b) Short-term neurotoxicity studies on
    tributoxyethyl phosphate orally administered to Sprague-Dawley rats.
    Chemosphere, 13(7): 801-812.

    Laham S, Long GW, & Broxup BR (1985a) Subchronic oral toxicity of
    tributoxyethyl phosphate in the Sprague-Dawley rat. Arch Environ
    Health, 40(1): 12-17.

    Laham S, Szabo J, Long G, & Schrader K (1985b) Dose-response toxicity
    studies on tributoxyethyl phosphate orally administered to
    Sprague-Dawley rats. Am Ind Hyg Assoc J, 46(8): 442-448.

    Lebel GL & Williams DT (1983a) Problems in collection of
    representative samples for determination of tributoxyethyl phosphate
    in potable water. J Assoc Off Anal Chem, 66(1): 202-203.

    Lebel GL & Williams DT (1983b) Determination of organic phosphate
    triesters in human adipose tissue. J Assoc Off Anal Chem, 66(1):
    691-699.

    Lebel GL & Williams DT (1986) Levels of triaryl/alkyl phosphates in
    human adipose tissue from eastern Ontario. Bull Environ Contam
    Toxicol, 37: 41-46.

    Lebel GL, Williams DT, & Benoit FM (1981) Gas chromatographic
    determination of trialkyl/aryl phosphates in drinking water, following
    isolation using macroreticular resin. J Assoc Off Anal Chem, 64(4):
    991-998.

    Lebel GL, Williams DT, & Benoit FM (1987) Use of large volume resin
    cartridges for the determination of organic contaminants in drinking
    water derived from the Great Lakes. Adv Chem Ser, 214: 309-325.

    Lebel GL ,Williams DT, & Berard D (1989) Triaryl/alkyl phosphate
    residues in human adipose autopsy samples from six Ontario
    municipalities. Bull Environ Contam Toxicol, 43: 225-230.

    Leddy IA (1990) THPS-75: Chromosal aberrations assay with Chinese
    hamster ovary cells  in  vitro (Project No.740444). Falls Church,
    Virginia, Inveresk Research International (Unpublished report No.
    6144).

    Lenga RE (1993) The Sigma-Aldrich library of chemical safety data.
    Buchs, Switzerland, Sigma-Aldrich, pp 1117-1118.

    Leo A (1989) CLOGP-3.54 MedChem software 1989. Claremont, California,
    Daylight Chemical Information Systems.

    Lerche J & Morch J (1973) Qualitative and quantitative gas
    chromatographic determination of plasticizers in polyvinyl chloride.
    Arch Pharm OG Chem, 1: 25-30.

    Liggett MP (1989a) Irritant effects on rabbit skin of THPS (Study
    sponsored by Albright & Wilson). Peterborough, United Kingdom,
    Huntingdon Research Center Limited (Unpublished report No.89361D/A&W
    498/SE).

    Liggett MP (1989b) Irritant effects on rabbit eye of THPS (Study
    sponsored by Albright & Wilson). Peterborough, United Kingdom,
    Huntingdon Research Center Limited (Unpublished report No. 89447D/A&W
    499/SE).

    Liggett MP & Allen SA (1989) Acute dermal toxicity to rats of THPS
    (Study sponsored by Albright & Wilson). Peterborough, United Kingdom,
    Huntingdon Research Center Limited.

    Lloyd GR (1994) UV degradation of THPS. Oldbury, United Kingdom,
    Albright & Wilson UK Ltd, Specialities Technical Laboratory.

    Loewengart G & Van Duuren BL (1977) Evaluation of chemical flame
    retardants for carcinogenic potential. J Toxicol Environ Health, 2:
    539-546.

    Loveday KS, Lugo MH, Resnick MA, Anderson BE, & Zeiger E (1989)
    Chromosome aberration and sister chromatid exchange tests in Chinese
    hamster ovary cells  in vitro: II. Results with 20 chemicals. Environ
    Mol Mutagen, 13: 60-94.

    McDonald P & Anderson BT (1989) THPS acute inhalation toxicity study
    in rats (Study sponsored by Albright & Wilson). Tranent, Edinburgh,
    United Kingdom, Inveresk Research International.

    MacFarland HN & Punte CL (1966) Toxicological studies on
    tri-(2-ethylhexyl)-phosphate. Arch Environ Health, 13: 13-20.

    MacGregor JT, Diamond MJ, Mazzeno LW Jr, & Friedman M (1980)
    Mutagenicity tests of fabric-finishing agents in  Salmonella
     typhimurium : Fiber-reactive wool dyes and cotton flame retardants.
    Environ Mutagen, 2: 405-418.

    MacKeller DG (1978) Kp-140 tris(butoxyethyl) phosphate mutagenicity
    screening test salmonella microsomal assay (Ames test). Princeton, New
    Jersey, FMC Corporation (Report No. ICG/T-78-006).

    McWilliam P (1994) Tolcide PS355A: Biodegradability in seawater 
    -- Closed bottle test (Study sponsored by Albright & Wilson). Bergen,
    Norway, Terra Miljö-Laboratories A/S (Unpublished report No.
    60090.aw\tm.002\biodeg).

    Marshall R (1996) Trishydroxymethyl phosphine oxide: Induction of
    chromosome aberrations in cultured chinese hamster ovary (CHO) cells.
    Harrogate, United Kingdom, Corning Hazelton (Europe) (Unpublished
    report No. 254/44-1052).

    Mead C & Handley JW (1998) Assessment of ready biodegradability CO2
    evolution test (modified sturm test) of Amgard TBEP (Project No.
    071/607). Derby, United Kingdom, Safepharm Laboratories Ltd.

    Miyagawa M, Takasawa H, Sugiyama A, Inoue Y, Murata T, Uno Y, &
    Yoshikawa K (1995) The  in vivo-in vitro replicative DNA synthesis
    (RDS) test with hepatocytes prepared from male B6C3F1 mice as an early
    prediction assay for putative nongenotoxic (Ames-negative) mouse
    hepatocarcinogens. Mutat Res, 343: 157-183.

    Monsanto (1976) Biodegradability of phosphate esters: Analytical
    chemistry -- Special study AC-75-55-9. St Louis, Missouri, Monsanto
    Industrial Chemicals, Applied Sciences.

    Monsanto (1984a) Summary sheet: t-Butoxyethyl phosphate  (Daphnia
     magna). St Louis, Missouri, Monsanto Industrial Chemicals,
    Environmental Sciences Toxicity.

    Monsanto (1984b) Acute toxicity of TBEP to fathead minnow
     (Pimephales promelas). Wareham, Massachusetts, Springborn Bionomics
    Inc. (Unpublished report No. SB 89-9160, prepared for Monsanto
    Industrial Chemicals, Environmental Sciences Toxicity, St Louis,
    Missouri).

    Monsanto (1984c) Tributoxyethyl phosphate: Acute toxicity/irritation
    studies. St Louis, Missouri, Monsanto, Department of Medicine and
    Environmental Health (Unpublished report No. BD-84-038).

    Monsanto (1984d) Tributoxyethyl phosphate microbial (AMES)
    mutagenicity. St Louis, Missouri, Monsanto, Department of Medicine and
    Environmental Health (Unpublished report No. SR-84-143).

    Monsanto (1984e) Repeat human insult patch test of tributoxyethyl
    phosphate. St Louis, Missouri, Monsanto, Department of Medicine and
    Environmental Health (Unpublished report No. SH-84-002).

    Monsanto (1985a) Four-week feeding study of tributoxyethyl phosphate
    in male and female Sprague-Dawley rats. St Louis, Missouri, Monsanto,
    Department of Medicine and Environmental Health (Unpublished report
    No. ML-84-093).

    Monsanto (1985b) Twenty-one-day dermal toxicity study in rabbits with
    tributoxyethyl phosphate. St Louis, Missouri, Monsanto, Department of
    Medicine and Environmental Health (Unpublished report No. BD-84-130).

    Monsanto (1985c) CHO/HGPRT mammalian cell forward gene mutation assay
    with tributoxyethyl phosphate. St Louis, Missouri, Monsanto,
    Department of Medicine and Environmental Health (Unpublished report
    No. PK-84-408).

    Monsanto (1985d) Range-finding teratology study in rats with
    tributoxyethyl phosphate. St Louis, Missouri, Monsanto, Department of
    Medicine and Environmental Health (Unpublished report No. IR-84-224).

    Monsanto (1985e) Teratology study in rats with tributoxyethyl
    phosphate. St Louis, Missouri, Monsanto, Department of Medicine and
    Environmental Health (Unpublished report No. IR-84-225).

    Monsanto (1986) Neurotoxicity studies of tributoxyethyl phosphate in
    chickens. St Louis, Missouri, Monsanto, Department of Medicine and
    Environmental Health (Unpublished report No. DU-84-358).

    Monsanto (1987a) Eighteen-week feeding study of tributoxyethyl
    phosphate with Sprague-Dawley rats. St Louis, Missouri, Monsanto,
    Department of Medicine and Health Sciences (Unpublished report No.
    ML-84-437 [EHL No. 84108]).

    Monsanto (1987b) Peripheral nerve conduction after an eighteen-week
    feeding exposure to tributoxyethyl phosphate in rats. St Louis,
    Missouri, Monsanto, Department of Medicine and Health Sciences
    (Unpublished report No. ML-84-435 [EHL No. 84110]).

    Mount E (1991) KP-140 non-definitive acute inhalation toxicity study
    in rats (Study No. 191-1208). Princeton, New Jersey, FMC Corporation,
    Toxicology Laboratory.

    Myhr BC & Caspary WJ (1991) Chemical mutagenesis at the thymidine
    kinase locus in L5178Y mouse lymphoma cells: Results for 31 coded
    compounds in the National Toxicology Program. Environ Mol Mutagen, 18:
    51-83.

    Nakashima H, Matsunaga I, & Miyano N (1993) Determination of tris
    (2-butoxyethyl) phosphate in textiles and household wax products by
    capillary gas chromatography. Jpn J Toxicol Environ Health, 39(6):
    549-553.

    O'Conner J (1992) THPS: Determination of hydrolysis as a function of
    pH. Eye, United Kingdom, Life Science Research Limited (LSR report No.
    91/AWL/015/0737, prepared for Albright & Wilson, International
    Technical Center, Oldbury, United Kingdom).

    Paxéus N, Robinson P, & Balmér P (1992) Study of organic pollutants in
    municipal wastewater in Göteborg, Sweden. Water Sci Technol, 25(11):
    249-256.

    Piegorsch WW & Hoel DG (1988) Exploring relationships between
    mutagenic and carcinogenic potencies. Mutat Res, 196: 161-175.

    Riach CG (1994) THPS-75%: Assessment of genotoxicity in an unscheduled
    DNA synthesis assay using adult rat hepatocyte primary cultures
    -- Supplemental information to report MRID No. 4222363-17. Falls
    Church, Virginia, Inveresk Research International (Unpublished
    report).

    Riach CG (1996) THPS mouse lymphoma mutation assay (Project No.
    756936). Falls Church, Virginia, Inveresk Research International
    (Unpublished report No. 12110).

    Rivera J, Ventura F, Caixach J, de Torres M, & Figueras A (1987)
    GC/MS, HPLC and FAB mass spectrometric analysis of organic pollutants
    in Barcelona's water supply. J Environ Chem, 29: 15.

    Roberts NL & Fairley C (1988) The dietary toxicity (LC50) of DP 435
    to the mallard duck. Huntingdon, United Kingdom, Huntingdon Research
    Center Limited (Unpublished report No. A&W 473/87982).

    Roberts NL & Phillips C (1988a) The dietary toxicity (LC50) of DP 435
    to the Bobwhite quail. Huntingdon, United Kingdom, Huntingdon Research
    Center Limited (Unpublished report No. A&W 474/871332).

    Roberts NL & Phillips C (1988b) The acute oral toxicity (LD50) of DP
    435 to the mallard duck. Huntingdon, United Kingdom, Huntingdon
    Research Center Limited (Unpublished report No. A&W 475/87999).

    Roddie B (1994) Assessment of the sediment-phase toxicity of Tolcide
    PS 75 to the sediment-dwelling amphipod  Coronium volutator.
    Edinburgh, United Kingdom, Environment & Resource Technology Limited
    (Unpublished report No. ERT 94/005/V1).

    Saeger VW, Hicks O, Kaley RG, Michael PR, Mieure JP, & Tucker ES
    (1979) Environmental fate of selected phosphate esters. Environ Sci
    Technol, 13(7): 840-844.

    Saitoh M, Umemura T, Kawasaki Y, Momma J, Matsushima Y, Matsumoto M,
    Eshita N, Isama K, & Kaniwa M (1994) Subchronic toxicity study of
    tributoxyethyl phosphate in Wistar rats. Eiser Shikensko Hokoku, 112:
    27-39.

    Sasaki M, Sugimura K, Yoshida MA, & Abe S (1980) Cytogenic effects of
    60 chemicals on cultured human and Chinese hamster cells. Senshokutai,
    20: 574-584.

    Shelby MD & Witt KL (1995) Comparison of results from mouse bone
    marrow chromosome aberration and micro nucleus tests. Environ Mol
    Mutagen, 25: 302-313.

    Shelby MD, Erexson GL, Hook GJ, & Tice RR (1993) Evaluation of a three
    exposure mouse bone marrow micronucleus protocol: Results with 49
    chemicals. Environ Mol Mutagen, 21: 160-179.

    Sheldon LS & Hites RA (1978) Organic compounds in the Delaware River.
    Environ Sci Technol, 12(10): 1188-1194.

    Smyth HF & Carpenter CP (1948) Further experience with the range
    finding test in the industrial toxicology laboratory. J Ind Hyg
    Toxicol, 30(1): 63-68.

    Snell K (1994) Proban CC: Acute dermal irritation test in the rabbit
    (Project No. 71/344, sponsored by Albright & Wilson). Derby, United
    Kingdom, Safepharm Laboratories Ltd. 

    Thompson PW (1997a) THPS cholinesterase inhibition test (Project No.
    071/506, sponsored by Albright & Wilson). Derby, United Kingdom,
    Safepharm Laboratories Ltd.

    Thompson PW (1997b) THPO cholinesterase inhibition test (Project No.
    071/507, sponsored by Albright & Wilson). Derby, United Kingdom,
    Safepharm Laboratories Ltd.

    Torp UM & McWilliam P (1994) Tolcide PS75: Determination of acute
    lethal toxicity to  Acartia  tonsa. Bergen, Norway, Terra
    Miljö-Laboratories A/S (Unpublished report No.
    60090.aw\tm.001\acartia).

    Tou JC, Westover LB, & Sonnabend LF (1974) Kinetic studies of
    bis(chloromethyl)ether hydrolysis by mass spectrometry. J Phys Chem,
    78(11): 1096-1098.

    Tremain SP & Bartlett AJ (1994) Amgard TBEP determination of hazardous
    physico-chemical properties (Project No. 583/014, sponsored by
    Albright & Wilson). Derby, United Kingdom, Safepharm Laboratories Ltd.

    Tsuda M, Saito M, Umemura T, Kawasaki Y, Momma J, Matsushima Y,
    Matsumoto M, Isama K, Kawiwa M, & Kurokawa Y (1993) A 14-week oral
    toxicity study of tributoxyethyl phosphate (TBEP) in rats. J Toxicol
    Sci, 18(4): 421, 429.

    Tsuji S, Tonogai Y, Ito Y, & Kanoh S (1986) The influence of rearing
    temperatures on the toxicity of various environmental pollutants for
    killifish  (Oryzias latipes). Eisei Kagaku, 32(1): 46-53.

    Tuffnell PP (1991) Proban CC: Acute oral toxicity test in the rat
    (Study sponsored by Albright & Wilson). Derby, United Kingdom,
    Safepharm Laboratories Ltd.

    Tuffnell PP (1992) Proban CC: Magnusson & Kligman maximisation study
    in the guinea pig (Project No. 71/127, sponsored by Albright &
    Wilson). Derby, United Kingdom, Safepharm Laboratories Ltd. 

    Ulsamer AG, Osterberg RE, & McLaughlin J Jr (1980) Flame-retardant
    chemicals in textiles. Clin Toxicol, 17(1): 101-131.

    US NTP (1984) Toxicology and carcinogenesis studies of
    tris(2-ethylhexyl)phosphate (CAS No. 78-42-2) in F344/N rats and
    B6C3F1 mice (gavage studies). Research Triangle Park, North Carolina,
    US Department of Health and Human Services, National Toxicology
    Program (Technical Report Series No. 274; NIH Publication No.
    84-2530).

    US NTP (1987) Toxicology and carcinogenesis studies of
    tetrakis(hydroxymethyl) phosphonium sulfate (THPS) (CAS No.
    55566-30-8) an tetrakis(hydroxymethyl) phosphonium chloride (THPC)
    (CAS No. 124-64-1) in F344/N rats and B6C3F1 mice (gavage studies).
    Research Triangle Park, North Carolina, US Department of Health and
    Human Services, National Toxicology Program (Technical Report Series
    No. 29; NIH Publication No. 87-2552).

    Van Duuren B, Loewengart G, Seidman I, Smith A, & Melchionne S (1978)
    Mouse skin carcinogenicity tests of the flame retardants
    tris(2,3-dibromopropyl) phosphate, tetrakis(hydroxymethyl) phosphonium
    chloride, and polyvinylbromide. Cancer Res, 38: 3236-3240.

    Watts CD & Moore K (1988) Fate and transport of organic compounds in
    rivers. In: Angeletti G & Bjorseth A ed. Organic micropollutants in
    the aquatic environment: Proceedings of the 5th European Symposium,
    Rome, 20-22 October 1987. Boston, Massachusetts, Kluwer Academic
    Publishers, pp 154-169 (Water Pollution Research Reports Series, No.
    4; EUR 11350).

    Weber K & Ernst W (1983) [Presence and fluctuation of organic
    environmental chemicals in German estuaries.] Vom Wasser, 61: 111-123
    (in German).

    Weil ED (1980) Kirk-Othmer encyclopedia of chemical technology. New
    York, John Wiley and Sons, vol 10, pp 488-489.

    Weschler CJ (1984) Indoor-outdoor relationships for nonpolar
    constituents of aerosol particles. Environ Sci Technol, 18(9):
    648-652.

    Weschler CJ (1980) Characterization of selected organic compounds in
    size-fractionated indoor aerosols. Environ Sci Technol, 14(4):
    428-431.

    Weschler CJ & Fong KL (1986) Characterization of organics species
    associated with indoor aerosol particles. Environ Int, 12: 93-97.

    Weschler CJ & Shields HC (1986) The accumulation of "Additives" in
    office air -- Proceedings of the 79th Annual Meeting of the Air
    Pollution Control Association, Minneapolis, 22-27 June 1986.
    Pittsburgh, Pennsylvania, Air Pollution Control Association.

    Wetton PM & Handley JW (1998) Acute toxicity to Rainbow trout (Project
    No. 071/608R, sponsored by Albright & Wilson). Derby, United Kingdom,
    Safepharm Laboratories Ltd. 

    Williams DT, Nestmann ER, Lebel GL, Benoit FM, Otson R, & Lee EGH
    (1982) Determination of mutagenic potential and organic contaminants
    of Great Lakes drinking water. Chemosphere, 11(3): 263-276.

    Willis CV (1995) Tolcide PS75 final report. Physical and chemical
    characteristics of Tolcide PS75: vapor pressure (Study sponsored by
    Albright & Wilson). Whippany, New Jersey, Case Consulting Laboratories
    Inc.

    Wragg MS, Thomas ON, & Brooks PN (1996) Twenty-eight day subacute
    dermal toxicity study in the rat (Sponsored by Albright & Wilson).
    Derby, United Kingdom, SafePharm Laboratories Ltd. Derby UK.

    Yasuda H (1980) Concentration of organic phosphorus pesticides in the
    atmosphere above the Dogo and Ozun Basin. J Chem Soc Jpn, 4: 645-653.

    Zeiger E, Anderson B, Haworth S, Lawlor T, Mortelmans K, & Speck W
    (1987) Salmonella mutagenicity test: III. Results from the testing of
    255 chemicals. Environ Mutagen, 9(suppl 9): 1-110.

    Zeiger E, Haworth S, Mortelmans K, & Speck W (1985) Mutagenicity
    testing of di(2-ethylhexyl)phthalate and related chemicals in
     Salmonella. Environ Mutagen, 7: 213-232.
    

    Appendix A

    Flammability standards met by products treated by THPC-urea
    condensates a

        Items                                   Flammability standards
                                                                                       

    Protective clothing           ASTM F-1506
                                  ASTM F-955
                                  NFPA 1975
                                  NFPA 1977
                                  EN 533 : 1977 Index 3 after 50 washes at 75°C
                                  EN 531 : 1995 para. 6.2.2 after 50 washes at 75°C
                                  EN 470-1 : 1995 para. 6.1 after 50 washes at 75°C
                                  EN 470-1 : para. 6.2
                                  EN 531 : 1995 para. 6.3
                                  EN 531 : 1995 para. 6.4
                                  EN 531 : 1995 para. 6.6

    Sheeting, blankets and        Ingnition sources 0, 1 and 5.
    BS 7175 counterpanes          When tested on top of and below the test
                                  fabric, after 200 washes at 74°C (BS 5651 HLPN).
                                  BS 5815 : Part 3 : 1991

    Curtains and drapes           NFPA 701
                                  BS 5867 : 1980 Part 2 Type B after 200 washes
                                  at 74°C (BS 5651 HLPN).

    Mattress ticking and          Ignition sources 0, 1 and 5 when tested
    BS 7175 mattresses            on top of and below the test fabric, after 3
                                  washes at 74°C
                                  BS 597-1 : 1995 (fabric tested in combination
                                  with a non-fire-retardant polyurethane foam block).
                                  BS 597-2 : 1995 (fabric tested in combination with a
                                  non-fire-retardant polyurethane foam block).

    Sleepwear                     DOC FF 3-71
                                  BS 5722 : 1984 when testing in accordance with
                                  BS 5438 : 1976 Test 2.
                                  BS 5722 : 1991 Level 1.

    Upholstery                    BS 5852 part 1 Ignition sources 0 (smouldering
                                  cigarette) and 1 (simulated match) after a 30-min
                                  water soak, BS 5651 amended.
                                  EN 1021-1 : 1994 (fabric tested in combination with
                                  a non-fire-retardant polyurethane foam block).
                                  EN 1021-2 : 1994 (fabric tested in combination with
                                  a non-fire-retardant polyurethane foam block).
                                                                                      

    a  From: Dr P. Martin, Albright & Wilson, personal communication to IPCS
    
    

    RÉSUMÉ, EVALUATION ET RECOMMANDATIONS

    1.  Phosphate de tris(2-butoxyéthyle) (TBEP)

    1.1  Résumé

         Le phosphate de tris(butoxyéthyle) ou TBEP est utilisé pour la
    confection d'encaustiques destinés à l'entretien des sols ou encore
    comme plastifiant dans les caoutchoucs et les matières plastiques. On
    ne connaît pas le volume de la production annuelle mondiale, mais on
    pense qu'il est de l'ordre de 5000 à 6000 tonnes.

         La présence du TBEP dans l'environnement résulte exclusivement de
    l'activité humaine. Sa répartition dans l'environnement a été étudiée
    dans certains pays industrialisés. On a trouvé une concentration
    inférieure à 300 ng/litre dans les eaux de surface et comprise entre
    100 et 1000 µg/kg dans les matières particulaires. Aucune des 167
    analyses effectuées n'a permis d'en mettre en évidence dans les
    poissons. Une unique étude en a décelé sa présence dans l'air
    extérieur (< 200 ng/m3). Le dosage du TBEP dans l'air de bureaux a
    donné une concentration de 25 ng/m3 tout au plus. Le TBEP est associé
    aux matières particulaires et la source en est dans ce cas les
    encaustiques que l'on applique sur le sol. On l'a décelé à des
    concentrations de l'ordre du µg/kg dans les tissus adipeux humains.
    D'après des études basées sur le panier de la ménagère, la dose
    journalière ingérée serait de moins de 0,02 µg/kg de poids corporel
    pour diverses tranches d'âge. On en a également signalé la présence
    dans l'eau de boisson à des concentrations pouvant atteindre 270
    µg/litre. Elle est due, semble-t-il, à la migration du produit contenu
    dans les joints de caoutchouc de l'installation sanitaire.

         On estime que le TBEP est facilement biodégradable. Des mesures
    effectuées dans des stations d'épuration des eaux d'égout et des
    dosages pratiqués en semi-continu au laboratoire sur des boues de même
    provenance montrent que le TBEP s'élimine en grande partie (> 80 %).
    Dans les cours d'eau et les eaux littorales, le TBEP est totalement
    décomposé. On a fait état d'une demi-vie d'environ 50 jours dans les
    eaux estuarielles, la décomposition étant minime dans l'eau de mer non
    adaptée.

         Le composé présente une faible toxicité aiguë pour les mammifères
    et son pouvoir irritant est également faible.

         Plusieurs études subchroniques sur des animaux de laboratoire
    montrent que la toxicité du TBEP s'exerce au niveau du foie qui en est
    l'organe cible. Une étude sur des rats Sprague-Dawley incite à penser
    que le TBEP pourrait provoquer une myocardite focale. Des effets
    neurologiques ont été observés chez le rat après ingestion d'une seule
    dose, mais ils n'apparaissent pas systématiquement. Lorsqu'on
    l'administre répétitivement à forte dose à des rats par gavage, le
    TBEP réduit la vitesse de conduction nerveuse et augmente la durée de
    la période réfractaire. Après administration à des poules, on n'a pas
    constaté de neurotoxicité retardée, mais il y avait par contre
    inhibition de la cholinestérase cérébrale et plasmatique.

         Une étude de 18 semaines au cours desquelles des rats ont reçu
    des doses répétées de TBEP a permis de fixer à 15 mg.kg-1j-1 pc la
    dose sans effet observable (NOEL) sur le foie, la dose la plus faible
    produisant un effet observable (LOEL) étant de 150 mg.kg-1.j-1 pc.

         Ni la toxicité à long terme ni le pouvoir cancérogène de ce
    composé n'ont été étudiés.

         Les tests de mutation génique effectués sur des cellules
    mammaliennes et sur des bactéries n'ont donné que des résultats
    négatifs mais il n'existe aucun compte rendu de recherche de lésions
    chromosomiques.

         Une étude effectuée sur des rats n'a révélé aucun effet
    tératogène. Il n'existe pas de publication faisant état d'autres
    effets toxiques sur la reproduction.

         Les tests de sensibilisation effectués sur des sujets humains par
    apposition d'un timbre cutané ne font ressortir aucune sensibilisation
    mais seulement une légère irritation.

         Le TBEP est modérément toxique pour les organismes aquatiques. La
    CL50 à 48 h pour  Daphnia magna est de 75 mg/litre et la CL50 à 96 h
    se situe entre 16 et 24 mg/litre pour les poissons.

    1.2  Evaluation

         L'exposition sur les lieux de travail se produit
    vraisemblablement au niveau de la peau pendant la fabrication ou
    l'utilisation d'encaustiques pour sols (exposition accidentelle). Le
    composé est absorbé par voie percutanée chez l'animal de laboratoire,
    mais on ne possède aucune information sur sa cinétique ou son
    métabolisme. On ne peut donc pas évaluer quantitativement l'exposition
    par cette voie, mais on peut penser qu'elle doit être faible. Les
    mesures montrent que l'exposition par la voie respiratoire dans un
    bureau est au plus égale à 25 ng/m3.

         L'exposition de la population générale s'opère principalement par
    la voie alimentaire, (du fait que le TBEP est présent comme
    plastifiant dans les plastiques utilisés pour l'emballage des produits
    alimentaires) et par la consommation d'eau de boisson contaminée par
    le TBEP contenu dans les joints de caoutchouc synthétique de la
    plomberie. Elle est cependant très faible dans les deux cas (estimée à
    moins de 0,2 µg par kg pc et par jour avec une concentration dans
    l'eau de boisson inférieure à 270 µg/litre).

         Compte tenu de la valeur de la NOEL tirée des études sur l'animal
    (15 mg.kg-1.j-1, valeur obtenue après administration répétée du
    composé par voie orale), on peut considérer que le risque est très
    faible pour la population générale. On estime qu'il est également très
    faible sur les lieux de travail, encore qu'il ne soit pas possible
    d'en donner une évaluation chiffrée.

         Dans l'environnement, on peut déduire de la faible volatilité, du
    fort coefficient d'adsorption et de sa solubilité modérée dans l'eau,
    que le TBEP va se répartir entre les différents types de matières
    particulaires. Les quelques mesures dont on dispose confirment cette
    hypothèse. Sa décomposition dans les différents compartiments de
    l'environnement devrait être rapide. On ne dispose d'aucune donnée sur
    ces produits de décomposition ; le reste phosphate libéré au cours de
    ce processus ne devrait pas sensiblement augmenter la concentration
    globale des nutriments présents dans l'environnement. La Fig. 1 donne
    la valeur de la concentration relevée dans les eaux de surface en
    fonction de la toxicité aiguë observée. Il y a plusieurs ordres de
    grandeur entre la concentration la plus élevée mesurée et la plus
    faible de la toxicité observée, d'où une marge de sécurité élevée et
    donc un faible risque pour les organismes aquatiques. On n'est pas en
    mesure d'évaluer l'importance du risque pour les organismes
    terrestres.

    FIGURE 4

    1.3  Recommandations

         Pour procéder à une évaluation scientifique complète de ce
    composé, il faudrait identifier et étudier chacun de ses métabolites
    chez des mammifères, étant donné le profil toxicologique d'un des
    métabolites possibles, le 2-butoxyéthanol.

    2.  Phosphate de tris (2-éthylhexyle) (TEHP)

    2.1  Résumé

         Le phosphate de tris (2-éthylhexyle) ou THEP, se présente sous la
    forme d'un liquide incolore et ininflammable, dont la solubilité dans
    l'eau et la tension de vapeur sont faibles et qui est utilisé comme
    retardateur de flammes et comme plastifiant dans le PVC et l'acétate
    de cellulose ou encore comme solvant. On le prépare à partir de
    l'oxychlorure de phosphore et du 2-éthyléthanol. On ne connaît pas les
    chiffres actuels de production dans le monde. En Allemagne, la
    production annuelle est actuellement d'environ 1000 tonnes.

         On n'a pas décelé la présence de TEHP dans l'air extérieur ; à
    l'intérieur des bâtiments, sa concentration dans l'air est inférieure
    à 10 ng/m3. Dans les cours d'eau, la concentration peut atteindre
    7500 ng/litre et dans les matières particulaires, 2 à 70 ng/g. On en a
    trouvé 0,3 ng/litre dans un seul et unique échantillon d'eau de
    boisson. D'après des études sur le panier de la ménagère, la dose
    ingérée journalière pour diverses tranches d'âge serait inférieure à
    0,05 µg/kg pc.

         Le TEHP est rapidement décomposé dans les eaux naturelles, mais
    des essais en laboratoire portant sur des boues activées ont donné des
    résultats équivoques. Il ne subit pas de décomposition abiotique
    importante.

         Le TEHP présente une faible toxicité aiguë pour les mammifères,
    la DL50 par voie orale étant > 10 000 mg/kg pc pour le rat.

         Le TEHP irrite la peau mais il n'est pas irritant pour l'oeil.
    Des applications répétées de TEHP sur la peau de lapins à raison de
    0,1 ml (93 mg) n'ont produit aucun signe d'intoxication générale.

         Des études au cours desquelles des rats et des souris ont reçu
    pendant 13 semaines du TEHP par gavage n'ont pas permis d'observer
    d'effets toxiques importants. Pour les rats, la dose sans effet nocif
    observable (NOAEL) était égale à 2860 mg/kg pc et pour les souris, à
    5710 mg/kg pc, soit les deux plus fortes doses utilisées chez chaque
    espèce.

         Lors d'une étude de 3 mois au cours de laquelle on a fait inhaler
    du TEHP à des chiens à des doses allant jusqu'à 85,0 mg/m3, on a
    observé de légères altérations inflammatoires chroniques au niveau des
    poumons et constaté que le réflexe conditionné d'évitement
    s'affaiblissait parallèlement à l'augmentation des doses.

         Il n'existe pas d'étude consacrée à la toxicité génésique du
    TEHP.

         Le composé a donné des résultats négatifs dans plusieurs tests de
    mutagénicité  in vitro et  in vivo.

         On a étudié la toxicité chronique et le pouvoir cancérogène du
    TEHP sur des rats et des souris. La NOAEL relative à la toxicité
    chronique était de 2857 mg.kg-1.j-1 pour les rats mâles et de 1428
    mg.kg-1.j-1 pour les femelles. Chez les souris mâles et femelles, la
    dose la plus faible produisant un effet nocif observable (LOAEL) était
    de 357 mg.kg-1.j-1, le critère retenu étant une hyperplasie des
    cellules folliculaires de la thyroïde. On n'a pas établi de NOAEL pour
    les souris. Les auteurs de ces études concluent que le composé
    présente un certain pouvoir cancérogène, compte tenu de l'augmentation
    des carcinomes hépatocellulaires qui a été observée chez les souris
    femelles, cette cancérogénicité étant plus équivoque pour les rats
    mâles chez qui a été relevée une augmentation de l'incidence des
    phéochromocytomes surrénaliens aux deux doses administrées. Malgré
    l'augmentation de l'incidence des phéochromocytomes aux deux doses
    chez les rats mâles et de celle des carcinomes hépatocellulaires chez
    les souris soumises à la plus forte dose, on estime qu'il n'y a pas
    lieu de considérer que le TEHP comporte un risque cancérogène
    important pour l'Homme. En effet, chez le rat l'incidence
    « naturelle » des phéochromocytomes est variable. Ainsi, dans deux
    études toxicologiques effectuées antérieurement par le National
    Toxicology Programme (NTP ) on a observé des phéochromocytomes dont
    l'incidence était égale à celle constatée dans l'étude précédente.
    Pour ce qui est de l'autre type de tumeur observé, à savoir le
    carcinome hépatocellulaire chez les souris femelles soumises à la dose
    la plus forte, le fait que son incidence soit faible, qu'elle ne se
    soit manifestée que dans un seul sexe et chez une seule espèce, qu'on
    n'ait pas de preuve d'une quelconque activité génotoxique et que
    l'Homme ne soit guère exposé au TEHP, rend improbable la possibilité
    d'un risque cancérogène notable pour l'Homme.

         Des études sur la neurotoxicité du TEHP ont été effectuées sur
    plusieurs espèces. Le composé ne provoque aucune modification dans
    l'activité de la cholinestérase plasmatique ou érythrocytaire. On n'a
    pas connaissance d'études sur la neurotoxicité retardée du TEHP.

         Une étude sur des volontaires humains n'a pas révélé d'irritation
    cutanée.

         Les quelques données disponibles montrent que le composé présente
    une faible toxicité aiguë pour les organismes aquatiques. Pour les
    bactéries, la CI50 à 96 h est supérieure à 100 mg/litre et pour un
    poisson comme le danio  (Brachydanio rerio), elle dépasse également
    cette valeur, qui correspond d'ailleurs à la limite de solubilité du
    TEHP dans l'eau.

    2.2  Evaluation

         L'exposition au TEHP se produit vraisemblablement par voie
    cutanée au cours de la préparation du composé (exposition
    accidentelle) ou par suite de l'utilisation de produits qui en
    contiennent. Le TEHP est absorbé par voie percutanée chez l'animal de
    laboratoire mais on dispose d'aucune donnée sur sa cinétique ou son
    métabolisme après absorption par cette voie. On ne peut donc pas
    évaluer quantitativement ce type d'exposition, mais on peut penser
    qu'elle est faible. La mesure de l'exposition par inhalation de l'air
    des bureaux a donné une valeur au plus égale à 10 ng/m3.

         L'exposition de la population générale se produit principalement
    par la consommation de nourriture et d'eau de boisson. Quelle que soit
    la source, cette exposition est très faible (l'exposition par voie
    alimentaire est estimée à moins de 0,05 µg.kg-1.j-1 ; une seule et
    unique mesure effectuée sur de l'eau de boisson a donné 0,3 ng/litre).

         Si l'on se base sur la LOAEL de 357 mg.kg-1.j-1 obtenue chez la
    souris avec comme critère une hyperplasie de la thyroïde, le risque
    est très faible à l'échelon de la population générale. On estime que
    le risque est également très faible sur les lieux de travail, encore
    qu'il ne soit pas possible d'en donner une évaluation quantitative.

         On estime que le TEHP n'est pas cancérogène pour l'Homme.

         Dans l'environnement, on peut déduire de la faible volatilité, du
    fort coefficient d'adsorption et de sa solubilité modérée dans l'eau,
    que le TEHP va se répartir entre les différents types de matières
    particulaires. Les mesures dont on dispose sont cependant trop peu
    nombreuses pour le confirmer. On peut s'attendre à une décomposition
    dans l'environnement, mais les données de laboratoire relatives à la
    décomposition du TEHP dans les boues d'égout sont ambiguës. On ne
    dispose d'aucune donnée sur ses produits de décomposition ; le reste
    phosphate libéré au cours de ce processus ne devrait pas sensiblement
    augmenter la concentration globale des nutriments. La Fig. 2 donne la
    valeur de la concentration relevée dans divers compartiments du milieu
    en fonction de la toxicité aiguë relevée (aucun effet toxique observé
    à la limite de solubilité dans l'eau). Il y a plusieurs ordres de
    grandeur entre la concentration la plus élevée mesurée et la plus
    faible valeur de la toxicité observée, d'où une marge de sécurité
    élevée et donc un faible risque pour les organismes aquatiques. On
    n'est pas en mesure d'évaluer l'importance du risque pour les
    organismes terrestres.

    2.3  Recommandations

         Pour procéder à une évaluation scientifique complète de ce
    composé, il faudrait identifier et étudier chacun de ses métabolites
    chez des mammifères, étant donné le profil toxicologique d'un des
    métabolites possibles, le 2-éthylhexanol.

         La toxicité génésique doit être étudiée, notamment en ce qui
    concerne d'éventuels effets sur le développement.

    3.  Sels de tétrakis(hydroxyméthyl) phosphonium

    3.1  Résumé

         Les sels de tétrakis(hydroxyméthyl)phosphonium (THP) constituent
    un groupe important de composés utilisés comme retardateurs de flammes
    pour le coton, la cellulose et les toiles constituées de mélanges de
    cellulose. On constate que la migration du chlorure de
    tétrakis(hydroxyméthyl)phosphonium (THPC) à partir des tissus traités
    par le condensat de ce composé avec l'urée reste faible. Le sulfate de
    THP (THPS) est surtout utilisé comme produit biocide. On estime que la
    production mondiale est de moins de 3000 tonnes par an pour les sels
    de THP et d'environ 3000 tonnes pour le condensat chlorure de tétrakis
    (hydroxyméthyl)phosphonium-urée.

         La photodécomposition et l'hydrolyse des sels de THP constituent
    des voies de dégradation abiotiques importantes dans l'environnement.
    Le sulfate de THP ne se fixe guère sur les matières particulaires et
    il est donc mobile. Le THPS se décompose rapidement en aérobiose comme
    en anaérobiose. On a constaté la présence d'oxyde de
    trihydroxyméthylphosphine (THPO) et d'acide
    bishydroxyméthylphosphonique ou BMPA dans les produits de
    décomposition.

         Comme il ne semble pas y avoir de surveillance de ces composés,
    on ne peut pas évaluer l'exposition de l'Homme ni celle des autres
    êtres vivants dans leur milieu naturel.

         Le THPC et le THPS présentent une toxicité aiguë modérée par voie
    orale ; au niveau cutané, leur toxicité est faible.

         Des études à court terme (jusqu'à 28 jours) effectuées sur des
    rats et des souris ont montré que le principal effet toxique du THPC
    et du THPS était une réduction du poids corporel. Chez les deux
    espèces, la NOAEL est d'environ 8 mg.kg-1.j-1. Des études plus
    longues (13 semaines) montrent que le principal organe cible est le
    foie. La NOAEL relative à cet effet varie de 3 à 7 mg.kg-1.j-1 pour

    les deux sels chez les deux espèces. Les tests biologiques de
    cancérogénicité effectués sur le THPC ont également montré que ces
    effets se produisaient au niveau du foie, mais on n'a pas établi de
    NOAEL. Chez les deux espèces, la LOAEL était d'environ 3 mg.kg-1.j-1.
    Lors d'une étude de cancérogénicité portant sur le THPS et effectuée
    sur des souris, on a évalué à 3,6 mg.kg-1.j-1 la NOAEL pour une
    hyperplasie médullo-surrénalienne focale; chez les rats, la LOAEL pour
    la mortalité avait la même valeur.

         Administré en dose unique à des lapins, le THPS n'a pas provoqué
    d'irritation cutanée. Cependant, l'exposition répétée de rats à ce
    composé par la voie cutanée a entraîné une sérieuse réaction à ce
    niveau. Le condensat THPC-urée s'est révélé corrosif. Chez le lapin,
    le THPS irrite fortement la muqueuse oculaire.

    FIGURE 5

         Le THPS et le condensat THPC-urée provoquent une sensibilisation
    cutanée chez le cobaye (test de sensibilisation maximale de Magnusson
    & Kilman).

         Ni le THPS ni le condensat THPC-urée n'ont eu d'effets toxiques
    sur le développement lorsqu'ils étaient administrés par voie orale à
    des animaux de laboratoire.

         Le THPC et le THPS manifestent une activité mutagène  in vitro,
    mais celle-ci disparaît  in vivo dans le cas du THPS (on ne dispose
    pas de données sur l'activité mutagène du THPC  in vivo). Les
    résultats limités dont on dispose au sujet du condensat THPC-urée
    incitent à penser qu'il n'est pas mutagène  in vivo. Le THPO n'est
    pas génotoxique. Rien n'indique de façon probante que les tissus
    traités par des sels de THP puissent avoir des effets mutagènes. Les
    données disponibles montrent qu'il n'y a pas de risque de génotoxicité
    pour l'Homme.

         Le THPS et le THPC ne sont pas révélés cancérogènes chez le rat
    ou la souris lors d'études biologiques d'une durée de deux ans. Les
    tests cutanés montrent que les sels de THP agissent comme promoteurs
    dans le processus de cancérisation, mais pas comme initiateurs.

         Le THPS et le THPO n'inhibent pas l'activité cholinesterasique in
    vitro, ce qui indique qu'ils ne sont pas neurotoxiques pour l'Homme.

         Les tissus traités par le condensat THPC-urée ne provoquent pas
    d'irritation cutanée chez l'Homme.

         Dans le cas du THPS, la valeur de la concentration entraînant des
    effets toxiques aigus pour les algues est de l'ordre de 1 mg/litre,
    avec une concentration sans effet observable (NOEC) de 0,06 mg/litre.
    En ce qui concerne la daphnie, la valeur de la NOEC relative aux
    effets aigus est de 10 mg/litre. Chez les invertébrés marins, les
    valeurs correspondant à des effets toxiques aigus oscillent entre 1,6
    et 340 mg/litre.

         Chez les poissons, la valeur de la CL50 à 96 h va de 72 à 119
    mg/litre, avec une NOEC comprise entre 18 et 41 mg/litre. Pour les
    oiseaux, on donne pour la DL50 une valeur de 311 mg/litre (effets
    aigus). Dans le cas de la toxicité par ingestion, on a retenu, pour la
    CL50, une valeur comprise entre 1300 et 2400 mg/kg de nourriture.

    3.2  Evaluation

         On ne dispose d'aucune information sur l'exposition de l'Homme ou
    des autres êtres vivants dans leur milieu naturel. Dans ces
    conditions, il n'est pas possible de donner une estimation
    quantitative du risque.
    

    RESUMEN, EVALUACION Y RECOMENDACIONES

    1.  Tris(2-butoxietil)fosfato (TBEP)

    1.1  Resumen

         El tris(2-butoxietil)fosfato (TBEP) se utiliza en ceras para el
    suelo y como plastificante del caucho y del plástico. No se dispone de
    datos sobre el volumen de producción mundial, pero se calcula que es
    del orden de 5000 a 6000 toneladas.

         El TBEP se encuentra en el medio ambiente sólo como consecuencia
    de la actividad humana. Se ha investigado en determinados países
    industrializados su distribución en la naturaleza. Se comprobó que la
    concentración en las aguas superficiales era inferior a 300 ng/litro,
    mientras que en los sedimentos oscilaba entre 100 y 1000 ìg/kg. No se
    detectó TBEP en ninguno de los 167 análisis realizados en peces. Se ha
    detectado en un estudio único en el aire exterior (<200 ng/m3). La
    medición del TBEP en el aire de espacios cerrados de oficina puso de
    manifiesto concentraciones de 25 ng/m3 o inferiores. El TBEP se
    asocia a partículas y se considera que la fuente es la aplicación de
    cera al suelo. Se ha detectado a niveles del orden de ìg/kg en el
    tejido adiposo humano. La ingesta diaria con los alimentos notificada
    a partir de estudios de la cesta de la compra, para una gama de grupos
    de edad, fue <0,02 ìg/kg de peso corporal al día. Se han notificado
    concentraciones en el agua de bebida de hasta 270 ìg/litro,
    estimándose que procede de la migración desde las juntas de caucho de
    las tuberías.

         Se considera que el TBEP es fácilmente biodegradable. Las
    mediciones en depuradoras de aguas residuales y las pruebas
    semicontinuas de laboratorio de los lodos cloacales han indicado una
    eliminación sustancial de TBEP (>80%). En aguas fluviales y costeras,
    el TBEP se degradó completamente. Se notificó que la semivida en el
    agua de los estuarios era de unos 50 días y que había poca degradación
    en el agua marina no adaptada.

         La toxicidad aguda sistémica en mamíferos y el potencial de
    irritación son bajos.

         En varios estudios subcrónicos en animales de laboratorio se ha
    comprobado que el hígado es el órgano destinatario de la toxicidad del
    TBEP. Los resultados de un estudio en ratas Sprague-Dawley macho
    parecen indicar que el TBEP podría causar miocarditis focal. Los
    efectos neurotóxicos en ratas tras dosis únicas de TBEP no son
    uniformes. La administración repetida de dosis elevadas de TBEP a
    ratas mediante sonda produjo una disminución de la velocidad de
    conducción nerviosa y un aumento del período de refracción. No produjo
    neurotoxicidad retardada en gallinas, pero inhibió las colinesterasas
    del cerebro y del plasma.

         Tomando como base un estudio de dosis repetidas de 18 semanas en
    ratas, se notificó una concentración sin efectos observados (NOEL) en
    el hígado de 15 mg/kg de peso corporal al día, mientras que la
    concentración más baja con efectos observados (LOEL), fue de 150 mg/kg
    de peso corporal al día.

         No se han estudiado la toxicidad y la carcinogenicidad del TBEP a
    largo plazo.

         Las pruebas de mutación genética en bacterias y células de
    mamíferos dieron resultados negativos, pero no se han notificado
    pruebas sobre los daños cromosómicos.

         En un estudio realizado en ratas no se observó teratogenicidad.
    No se han notificado otros aspectos de toxicidad reproductiva.

         En una prueba epicutánea (con parche) repetida para estudiar los
    efectos del TBEP en la piel humana se vio que no se producía
    sensibilización y que la irritación era mínima.

         La toxicidad del TBEP para los organismos acuáticos es moderada.
    La CL50 a las 48 horas en  Daphnia magna es de 75 mg/litro y los
    valores de la CL50 a las 96 horas en peces oscilan entre 16 y
    24 mg/litro.

    1.2  Evaluación

         Es probable que se produzca exposición ocupacional al TBEP por
    vía cutánea durante la fabricación (exposición occidental) y a partir
    de las ceras del suelo. El compuesto se absorbe por vía cutánea en
    animales de experimentación, pero no se dispone de información sobre
    su cinética y metabolismo. Por consiguiente, no se puede cuantificar
    la exposición cutánea, pero es previsible que sea baja. La exposición
    por inhalación medida en el entorno de oficina ha sido de 25 ng/m3 o
    inferior.

         La exposición de la población general se produce fundamentalmente
    a través de los alimentos (debido al uso de TBEP como plastificante en
    los plásticos de envasado) y del agua de bebida (contaminada por
    lixiviación del caucho sintético utilizado en las arandelas de las
    cañerías). La exposición a partir de ambas fuentes es muy baja
    (estimada en <0,2 ìg/kg de peso corporal al día a partir de los
    alimentos y concentraciones en el agua de bebida de <270 ìg/litro).

         Teniendo en cuenta la NOEL notificada a partir de estudios en
    animales de 15 mg/kg de peso corporal al día obtenida en un estudio de
    administración oral con dosis repetidas, el riesgo para la población
    general es muy bajo. El riesgo para las personas expuestas en el
    trabajo se considera también muy bajo, aunque no se puede cuantificar.

         En el medio ambiente, se supone que el TBEP (dada su baja
    volatilidad, su elevado coeficiente de adsorción y su solubilidad
    moderada en agua) se reparte en los sedimentos. Los escasos datos
    medidos así lo confirman. La degradación en los compartimentos del
    medio ambiente se supone que es rápida. No se dispone de información

    sobre los productos de su degradación; no parece que el fosfato
    liberado durante la degradación contribuya de manera significativa a
    la concentración de nutrientes del medio ambiente. La Fig. 1 es una
    representación gráfica de las concentraciones en el medio ambiente
    medidas en aguas superficiales frente a los valores notificados de
    toxicidad aguda. El margen de inocuidad entre las concentraciones más
    altas y los valores de toxicidad más bajos notificados es de varios
    órdenes de magnitud, lo que indica un riesgo bajo para los organismos
    del medio ambiente acuático. No se puede hacer una evaluación del
    riesgo para el compartimento terrestre.

    1.3  Recomendaciones

         Para una evaluación científica completa del compuesto, sería
    necesaria la identificación y evaluación de los metabolitos en los
    mamíferos, dado el perfil toxicológico de uno de los metabolitos
    propuestos, el 2-butoxietanol.

    2.  Tris(2-etilhexil)fosfato (TEHP)

         El tris(2-etilhexil)fosfato (TEHP) es un líquido incoloro no
    inflamable, poco soluble en agua y de presión de vapor muy baja, que
    se utiliza como pirorretardante y plastificante para el PVC y el
    acetato de celulosa, y como disolvente. Se produce a partir del
    oxicloruro de fósforo y el 2-etilhexanol. No se dispone de cifras para
    la producción mundial actual. En Alemania se producen actualmente unas
    1000 toneladas.

    FIGURE 6


         No se ha detectado TEHP en el aire exterior; se ha encontrado en
    el aire de espacios cerrados en concentraciones de menos de 10 ng/m3,
    en aguas fluviales en concentraciones de hasta 7500 ng/litro y en
    sedimentos de 2-70 ng/g. Se detectó TEHP en una sola muestra de agua
    de bebida en una concentración de 0,3 ng/litro. La ingesta diaria
    notificada en los alimentos a partir de estudios de la cesta de la
    compra, para una gama de grupos de edad, fue inferior a 0,05 ìg/kg de
    peso corporal al día.

         El TEHP se degrada rápidamente en las aguas naturales, pero las
    pruebas de laboratorio con lodos activados dieron resultados
    equívocos. No hay una degradación abiótica significativa.

         El TEHP tiene una toxicidad aguda baja para los mamíferos, siendo
    la DL50 por vía oral >10 000 mg/kg de peso corporal en ratas.

         El TEHP es irritante cutáneo, pero no ocular. La aplicación
    repetida de 0,1 ml (93 mg) de TEHP a la piel de conejos no produjo
    signos de intoxicación sistémica.

         En estudios de administración con sonda durante 13 semanas a
    ratas y ratones no aparecieron efectos tóxicos significativos. La
    concentración sin efectos adversos observados (NOAEL) en ratas fue de
    2860 mg/kg de peso corporal al día y en ratones de 5710 mg/kg de peso
    corporal al día, la dosis más elevada probada en ambas especies.

         En un estudio de inhalación de tres meses con concentraciones de
    hasta 85 mg de TEHP/m3 se observaron cambios inflamatorios crónicos
    leves en los pulmones de perros y los resultados de rechazo
    condicionado empeoraron en relación con la concentración administrada.

         No se dispuso de estudios sobre toxicidad reproductiva.

         El TEHP dio resultados negativos en varias pruebas de
    mutagenicidad  in vivo e  in vitro. 

         Se realizaron pruebas de toxicidad crónica y carcinogenicidad del
    TEHP en ratas y ratones. La NOAEL para la toxicidad crónica en ratas
    macho fue de 2857 mg/kg de peso corporal al día y en ratas hembras de
    1428 mg/kg de peso corporal al día. La concentración más baja con
    efectos adversos observados (LOAEL) en ratones machos y hembras para
    la hiperplasia de las células foliculares del tiroides fue de 357
    mg/kg de peso corporal al día. No se estableció una NOAEL en ratones.
    Los autores llegaron a la conclusión de que había algunas pruebas de
    carcinogenicidad basadas en una mayor incidencia de carcinomas
    hepatocelulares en ratones hembra con un nivel de dosificación alto y
    pruebas equívocas de carcinogenicidad basadas en la mayor incidencia
    de feocromocitomas suprarrenales en ratas macho en ambos grupos de
    dosis. Aunque se produjo un aumento de feocromocitomas suprarrenales
    en ambos grupos de dosis de ratas macho y de carcinomas
    hepatocelulares en ratones hembra del grupo de dosificación alta, no
    se considera que estos resultados indiquen que el TEHP presenta un

    riesgo carcinogénico significativo para el ser humano. Los
    feocromocitomas muestran una incidencia de base variable en ratas. La
    incidencia de estos tumores en dos biovaloraciones anteriores del
    Programa Nacional de Toxicología fue igual a la observada en la
    biovaloración del TEHP. Solamente hubo otro resultado neoplásico
    significativo, consistente en carcinomas hepatocelulares, en el grupo
    de ratones hembra de dosificación alta. Teniendo en cuenta la baja
    incidencia de este tumor, su presencia en un solo sexo de una especie,
    la falta de pruebas de toxicidad genética y la baja exposición del ser
    humano al TEHP, no es probable que este producto cree un riesgo
    carcinogénico significativo para el ser humano.

         Se han realizado estudios de neurotoxicidad en varias especies.
    El TEHP no produce ninguna alteración de la actividad de la
    colinesterasa del plasma o los glóbulos rojos. No se han notificado
    estudios sobre neurotoxicidad retardada.

         En un estudio realizado en voluntarios humanos, no se notificó
    irritación cutánea.

         Los escasos datos disponibles indican una toxicidad aguda baja
    del TEHP en el medio acuático. La CL50 para bacterias es superior a
    100 mg/litro y la CL50 a las 96 horas para el pez  Brachydanio rerio
    es superior a 100 mg/litro, que es el límite de la solubilidad del
    TEHP en agua.

    2.2  Evaluación

         Es probable que se produzca exposición ocupacional al TEHP por
    vía cutánea durante la fabricación (exposición occidental) y por el
    uso de algunos productos. El compuesto se absorbe por vía cutánea en
    los animales de experimentación, pero no se dispone de información
    sobre su cinética o metabolismo en esta vía. Por consiguiente, no se
    puede cuantificar la exposición cutánea, pero es previsible que sea
    baja. La exposición por inhalación medida en el entorno de oficina es
    de 10 ng/m3 o menor.

         La exposición de la población general se produce fundamentalmente
    a través de los alimentos y el agua de bebida. La exposición a partir
    de ambas fuentes es muy baja (estimada en <0,05 ìg/kg de peso
    corporal día a partir de los alimentos; una concentración única medida
    en el agua de bebida fue de 0,3 ng/litro).

         Teniendo cuenta la LOAEL notificada para la hiperplasia tiroidea
    de 357 mg/kg de peso corporal día en ratones, el riesgo para la
    población general es muy bajo. El riesgo para las personas expuestas
    en el trabajo se considera también muy bajo, aunque no se puede
    cuantificar.

         El TEHP no parece ser carcinogénico para el ser humano.

         En el medio ambiente, se supone que el TEHP (dada su baja
    volatilidad, su elevado coeficiente de adsorción y su solubilidad baja
    en agua) se repartirá en los sedimentos. Los datos medidos son
    demasiado escasos para confirmarlo. Se prevé su degradación en los
    compartimentos del medio ambiente, aunque los datos de laboratorio
    sobre la degradación en lodos cloacales son equívocos. No se dispone
    de información sobre los productos de la degradación; no parece que el
    fosfato liberado durante su degradación contribuya de manera
    significativa a la concentración de nutrientes del medio ambiente. La
    Fig. 2 es una representación gráfica de las concentraciones en el
    medio ambiente medidas en sus compartimentos frente a los valores
    notificados de toxicidad aguda (éstos indican que no tiene efectos
    tóxicos en el límite de solubilidad en el agua). El margen de
    inocuidad entre las concentraciones más altas y los valores de
    toxicidad más bajos notificados es de varios órdenes de magnitud, lo
    que indica un riesgo bajo para los organismos del medio ambiente
    acuático. No se puede hacer una evaluación del riesgo para el
    compartimento terrestre.

    2.3  Recomendaciones

         Para una evaluación científica completa del compuesto, sería
    necesaria la identificación y evaluación de los metabolitos en los
    mamíferos, dado el perfil toxicológico de uno de los metabolitos
    propuestos, el 2-etilhexanol.

         Es necesario investigar la toxicidad reproductiva, en particular
    los posibles efectos en el desarrollo.

    FIGURE 7

    3.  Sales de tetrakis(hidroximetil)fosfonio

    3.1  Resumen

         Las sales de tetrakis(hidroximetil)fosfonio representan la clase
    principal de productos químicos utilizados como pirorretardantes en el
    algodón, la celulosa y los tejidos con celulosa. Hay una migración
    baja a partir de los tejidos tratados con cloruro de
    tetrakis(hidroximetil)fosfonio (THPC)-urea. La sal sulfatada (THPS) se
    utiliza fundamentalmente como biocida. La producción mundial combinada
    se estima que es >3000 toneladas para las sales de THP y de unas 3000
    toneladas para el condensado de THPC-urea.

         La fotodegradación y la hidrólisis de las sales de THP son vías
    importantes de degradación abiótica en el medio ambiente. El THPS se
    une débilmente a las partículas del medio ambiente, por lo que es
    móvil. Se degrada rápidamente tanto en condiciones aerobias como
    anaerobias. Se han identificado como productos de su degradación el
    óxido de trihidroximetilfosfuro (THPO) y el ácido
    bihidroximetilfosfónico (BMPA).

         Puesto que no se ha notificado ninguna vigilancia, no se pueden
    hacer estimaciones de la exposición del ser humano o de los organismos
    en el medio ambiente.

         La toxicidad aguda por vía oral del THPC y el THPS es moderada;
    la toxicidad cutánea es baja.

         En estudios breves (hasta 28 días) en ratas y ratones, el
    principal efecto tóxico tanto del THPC como del THPS es la disminución
    del peso corporal. La NOAEL para ambos productos químicos en las dos
    especies es de unos 8 mg/kg de peso corporal al día. En estudios más
    prolongados (13 semanas), el principal órgano destinatario de la
    toxicidad es el hígado. La NOAEL para este efecto  osciló entre 3 y 7
    mg/kg de peso corporal al día para ambas sales en las dos especies.
    Las biovaloraciones de la carcinogenicidad del THPC también pusieron
    de manifiesto efectos en el hígado, pero no se estableció una NOAEL.
    La LOAEL fue de unos 3 mg/kg de peso corporal al día para ambas
    especies. En una biovaloración de la carcinogenicidad del THPS en
    ratones, la NOAEL para la hiperplasia focal en la médula suprarrenal
    fue de 3,6 mg/kg de peso corporal al día; en ratas, la LOAEL para la
    mortalidad fue de 3,6 mg/kg de peso corporal al día.

         El THPS administrado en dosis única a conejos no provocó
    irritación cutánea. Sin embargo, la exposición cutánea repetida en
    ratas produjo una reacción grave en la piel. El THPC-urea fue
    corrosivo. Se comprobó que el THPS ocasionaba una irritación grave de
    los ojos en conejos.

         El THPS y el THPC-urea producen sensibilización cutánea en
    cobayas (prueba de maximización de Magnusson y Kilman).

         En animales de experimentación tratados por vía oral, el THPS y
    el THPC-urea no produjeron toxicidad en el desarrollo.

         El THPC y el THPS tienen potencial mutagénico  in vitro, pero el
    THPS no es mutagénico  in vivo (no hay datos de mutagenicidad  in
    vivo para el THPC). Los limitados datos de mutagenicidad para el
    THPC-urea parecen indicar que no es mutagénico  in vivo. El THPO no
    es genotóxico. No hay pruebas convincentes que indiquen que las telas
    tratadas con sales de THP sean mutagénicas. La información disponible
    pone de manifiesto que no hay peligro genotóxico para el ser humano.

         El THPC y el THPS no fueron carcinogénicos en ratas y ratones en
    biovaloraciones de dos años. En estudios cutáneos se ha observado que
    las sales son promotoras de cáncer cutáneo, pero no iniciadoras.

         El THPS y el THPO no inhibieron la actividad de la
    acetilcolinesterasa  in vivo, lo que parece indicar una ausencia de
    peligro neurotóxico para el ser humano.

         Las telas tratadas con THPC-urea no produjeron irritación cutánea
    en el ser humano.

         Para el THPS, los valores de toxicidad aguda notificados en algas
    son inferiores a 1 mg/litro, con una concentración sin efectos
    observados (NOEC) de 0,06 mg/litro. La NOEC para la pulga de agua es
    de 10 mg/litro. Los valores de toxicidad aguda notificados para los
    invertebrados marinos oscilan entre 1,6 y 340 mg/litro.

         Los valores de la DL50 a las 96 horas para los peces van de 72 a
    119 mg/litro, con valores de la NOEC entre 18 y 41 mg/litro. Se ha
    notificado una DL50 aguda para las aves de 311 mg/kg de peso corporal
    y valores de la CL50 de 1 300 y 2 400 mg/kg de alimentos.

    3.2  Evaluación

         No se dispone de información sobre la exposición para el ser
    humano ni para los organismos del medio ambiente. Por consiguiente, no
    se pudo realizar una evaluación cuantitativa del riesgo.
    


See Also:
        Flame retardants: A general introduction (EHC 192, 1997)