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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY






    ENVIRONMENTAL HEALTH CRITERIA 209




    FLAME RETARDANTS: TRIS(CHLOROPROPYL)
    PHOSPHATE AND TRIS(2-CHLOROETHYL)
    PHOSPHATE



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

    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, 1998

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    WHO Library Cataloguing in Publication Data

    Flame retardants : tris(chloropropyl) phosphate and
    tris(2-chloroethyl) phosphate.

         (Environmental health criteria ; 209)

         1.Phosphoric acid esters - toxicity
         2.Phosphoric acid esters - adverse effects
         3.Flame retardants - toxicity
         4.Flame retardants - adverse effects
         5.Environmental exposure
         I.International Programme on Chemical Safety
         II.Series

         ISBN 92 4 157209 4               (NLM Classification: QD 181.P1)
         ISSN 0250-863X

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    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR FLAME RETARDANTS: TRIS(CHLOROPROPYL)
    PHOSPHATE AND TRIS(2-CHLOROETHYL) PHOSPHATE

    PREAMBLE

    ABBREVIATIONS

    TRIS(CHLOROPROPYL) PHOSPHATE

    1. SUMMARY

         1.1. Tris(1-chloro-2-propyl) phosphate (TCPP)
         1.2. Tris(1,3-dichloro-2-propyl) phosphate (TDCPP)

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

         2.1. Tris(1-chloro-2-propyl) phosphate (TCPP)
              2.1.1. Identity
              2.1.2. Physical and chemical properties
         2.2. Tris(1,3-dichloro-2-propyl) phosphate (TDCPP)
              2.2.1. Identity
              2.2.2. Physical and chemical properties
         2.3. Conversion factors
         2.4. Analytical methods

    3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         3.1. Natural occurrence
         3.2. Anthropogenic sources
              3.2.1. Production and processes
              3.2.2. Release in the environment
              3.2.3. Uses
                        3.2.3.1   TCPP
                        3.2.3.2   TDCPP

    4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

         4.1. Transport and distribution between media
         4.2. Transformation
              4.2.1. Abiotic
              4.2.2. Biotic
              4.2.3. Degradation
              4.2.4. Bioaccumulation

    5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         5.1. Environmental levels
              5.1.1. Air
              5.1.2. Water
              5.1.3. Sediment
              5.1.4. Biota
              5.1.5. Food
         5.2. General population exposure
              5.2.1. Adipose tissue
              5.2.2. Biological fluids

    6. KINETICS AND METABOLISM IN LABORATORY ANIMALS

         6.1. TCPP
         6.2. TDCPP

    7. EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

         7.1. Single exposure
              7.1.1. TCPP
              7.1.2. TDCPP
         7.2. Short-term exposure
              7.2.1. TCPP
              7.2.2. TDCPP
         7.3. Long-term exposure
              7.3.1. TCPP
              7.3.2. TDCPP
         7.4. Skin and eye irritation or sensitization
              7.4.1. TCPP
                        7.4.1.1   Skin irritation
                        7.4.1.2   Eye irritation
                        7.4.1.3   Sensitization
              7.4.2. TDCPP
                        7.4.2.1   Skin irritation
                        7.4.2.2   Eye irritation
                        7.4.2.3   Sensitization
         7.5. Reproductive toxicity, embryotoxicity and teratogenicity
              7.5.1. TCPP
              7.5.2. TDCPP
         7.6. Mutagenicity and related end-points
              7.6.1. TCPP
              7.6.2. TDCPP
         7.7. Carcinogenicity
              7.7.1. TCPP
              7.7.2. TDCPP
         7.8. Other studies
              7.8.1. Immunotoxicity
                        7.8.1.1   TCPP
                        7.8.1.2   TDCPP
              7.8.2. Neurotoxicity
                        7.8.2.1   TCPP
                        7.8.2.2   TDCPP

    8. EFFECTS ON HUMANS

         8.1. TCPP
         8.2. TDCPP

    9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         9.1. Microorganisms
         9.2. Aquatic organisms
              9.2.1. Algae
              9.2.2. Invertebrates
              9.2.3. Fish
         9.3. Terrestrial organisms

    10. EVALUATION

         10.1. TCPP
         10.2. TDCPP


    11. FURTHER RESEARCH

    TRIS(2-CHLOROETHYL) PHOSPHATE

    A1.  SUMMARY

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

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

    A3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         A3.1 Natural occurrence
         A3.2 Anthropogenic sources
              A3.2.1    Production and processes
              A3.2.2    Uses

    A4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

         A4.1 Transport and distribution between media
         A4.2 Transformation
              A4.2.1    Abiotic
              A4.2.2    Biotic
         A4.3 Bioaccumulation

    A5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         A5.1 Environmental levels
              A5.1.1    Air
              A5.1.2    Water
                        A5.1.2.1  Surface water
                        A5.1.2.2  Drinking-water
                        A5.1.2.3  Effluents
                        A5.1.2.4  Leachates
         A5.2 Sediment
         A5.3 Biota and food
              A5.3.1    Biota
              A5.3.2    Food

    A6.  KINETICS AND METABOLISM IN LABORATORY ANIMALS

         A6.1 Mice
         A6.2 Rats

    A7.  EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

         A7.1 Single exposure
         A7.2 Short-term exposure
              A7.2.1    Mice
              A7.2.2    Rats
         A7.3 Long-term exposure
              A7.3.1    Mice
              A7.3.2    Rats
         A7.4 Skin and eye irritation or sensitization
              A7.4.1    Skin irritation
              A7.4.2    Eye irritation
              A7.4.3    Sensitization
         A7.5 Reproductive toxicity, embryotoxicity and teratogenicity
              A7.5.1    Developmental toxicity
              A7.5.2    Fertility
         A7.6 Mutagenicity and related end-points
              A7.6.1     In vitro studies
              A7.6.2     In vivo studies
         A7.7 Carcinogenicity
              A7.7.1    Oral
                        A7.7.1.1  Mice
                        A7.7.1.2  Rats
              A7.7.2    Dermal
                        A7.7.2.1  Mice
         A7.8 Other special studies
              A7.8.1    Neurotoxicity

    A8.  EFFECTS ON HUMANS

    A9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         A9.1 Microorganisms
         A9.2 Aquatic organisms
              A9.2.1    Algae
              A9.2.2    Invertebrates
              A9.2.3    Fish

    A10. EVALUATION

    A11. FURTHER RESEARCH

    A12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         REFERENCES

         RÉSUMÉ

         RESUMEN
    

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    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR FLAME RETARDANTS:
    TRIS(CHLOROPROPYL) PHOSPHATE AND TRIS(2-CHLOROETHYL) PHOSPHATE

     Members

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

    Mr R. Cary, Health and Safety Executive, Toxicology Unit, Bootle,
    Merseyside, United Kingdom

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

    Mr D. Renshaw, Department of Health, London, United Kingdom
     (Chairman)

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

    Dr J. Wagstaff, US Food and Drug Administration, Center for Food
    Safety and Applied Nutrition, Washington, DC, USA

     Observers

    Dr R. Henrich, AKZO NOBEL, Dobbs Ferry, New York, USA

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

    Mr M. Papez, European Flame Retardants Association (EFRA), c/o
    European Chemical Industry Council (CEFIC), Brussels, Belgium

    Mr D. Thornton, Courtaulds Chemicals, Spondon, Derby, United Kingdom

     Secretariat

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

    Dr P.G. Jenkins, International Programme on Chemical Safety, World
    Health Organization, Geneva, Switzerland

    ENVIRONMENTAL HEALTH CRITERIA FOR FLAME RETARDANTS: TRIS(CHLOROPROPYL)
    PHOSPHATE AND TRIS(2-CHLOROETHYL) PHOSPHATE

         A WHO Task Group on Environmental Health Criteria for Flame
    Retardants: Tris(chloropropyl) phosphate and Tris(2-chloroethyl)
    phosphate met at the offices of the Health and Safety Executive (HSE),
    London, United Kingdom from 9 to 13 March 1998. Drs B. Woodard (HSE)
    and P. Brantom (British Industrial Biological Research Association)
    opened the meeting and welcomed the participants on behalf of the
    organizing institutes. Dr M. Baril, IPCS, welcomed the participants on
    behalf of Dr M. Mercier, Director of the IPCS and the three
    cooperating organizations (UNEP/ILO/WHO). The Task Group reviewed and
    revised the draft 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 monographs.

         Dr P.G. Jenkins (IPCS Central Unit, Geneva) and Dr M. Baril (IPCS
    technical adviser, 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

    BaP       benzo (a)pyrene
    BCF       bioconcentration factor
    CA        chromosome aberration
    ECD       electron capture detection
    FPD       flame photometric detection
    GC        gas chromatography
    ip        intraperitoneal
    LOEC      lowest-observed-effect concentration
    LOEL      lowest-observed-effect level
    MS        mass spectrometry
    NADPH     reduced nicotinamide adenine dinucleotide phosphate
    NCI       negative ion chemical ionization
    ND        not detectable
    NOEC      no-observed-effect concentration
    NOEL      no-observed-effect level
    NPD       nitrogen phosphorus detection
    NTE       neurotoxic esterase
    OECD      Organisation for Economic Co-operation and Development
    PB        phenobarbital
    PCB       polychlorinated biphenyl
    SC        subcutaneous
    SCE       sister chromatid exchange
    TCEP      tris(2-chloroethyl) phosphate 
    TCPP      tris(1-chloro-2-propyl) phosphate
    TDCPP     tris(1,3-dichloro-2-propyl) phosphate
    TOCP      tris- ortho-cresyl phosphate

    TRIS(CHLOROPROPYL) PHOSPHATE

    Tris(1-chloro-2-propyl) phosphate
    Tris(1,3-dichloro-2-propyl) phosphate

    1.  SUMMARY

    1.1  Tris(1-chloro-2-propyl) phosphate (TCPP)

         Tris(1-chloro-2-propyl) phosphate (TCPP) is a colourless liquid
    used as a flame retardant, mainly in polyurethane foams. It is not
    volatile. Its solubility in water is 1.6 g/litre, it is soluble in
    most organic solvents, and it has a log octanol/water partition
    coefficient of 2.59.

         Analysis is by gas chromatography/mass spectrometry (GC/MS).
    Concentration of TCPP from water prior to analysis can be achieved
    using XAD resin, followed by extraction with various organic solvents.

         TCPP is manufactured from propylene oxide and phosphorus
    oxychloride. Annual worldwide demand exceeded 40 000 tonnes in 1997.

         TCPP is not readily biodegraded in sewage sludge inocula. It is
    rapidly metabolized in fish.

         Traces of TCPP have been detected in industrial and domestic
    effluents but not in surface waters. It has not been detected in
    surveys of sediments. Traces of TCPP have been detected in raw
    peaches, raw pears and fish.

         No data are available on the kinetics and metabolism of TCPP in
    mammals.

         TCPP is of low to moderate acute toxicity by the oral (LD50 in
    rats = 1017-4200 mg/kg body weight), dermal (LD50 in rats and rabbits
    is > 5000 mg/kg body weight) and inhalation routes (LC50 in rats is
    > 4.6 mg/litre).

         Rabbit eye and skin irritancy studies have indicated that TCPP is
    either non-irritant or mildly irritant. A skin sensitization study
    showed that TCPP has no sensitizing properties.

         The reproductive toxicity, immunotoxicity and carcinogenic
    potential of TCPP have not been investigated. The results of  in 
     vitro  and  in vivo mutagenicity studies investigating an
    appropriate range of end-points indicate that TCPP is not genotoxic.

         TCPP has been investigated for potential delayed neurotoxicity in
    hens. There was no evidence of delayed neurotoxicity when two oral
    doses (each of 13 230 mg/kg body weight) were given 3 weeks apart.

         No studies of the effects of TCPP on humans are available.

         Toxicity values for organisms in the environment are available,
    LC50 values ranging from 3.6 to 180 mg/litre. The no-observed-effect
    concentrations for algae, daphnids and fish are 6, 32 and 9.8
    mg/litre, respectively.

    1.2  Tris(1,3-dichloro-2-propyl) phosphate (TDCPP)

         Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is a viscous
    colourless liquid used as a flame retardant in a range of plastic
    foams, resins and latexes. It is not volatile. Its solubility in water
    is 0.1 g/litre, it is soluble in most organic solvents, and it has a
    log octanol/water partition coefficient of 3.8.

         Analysis is by GC/MS. Concentration of TDCPP from water prior to
    analysis can be achieved using XAD resin, followed by extraction with
    various organic solvents.

         TDCPP is manufactured from epichlorohydrin and phosphorus
    oxychloride. The commercial product is predominantly TDCPP with trace
    amounts of tris (2,3-dichloropropyl) phosphate. Annual worldwide
    demand was 8000 tonnes in 1997.

         TDCPP is not readily degraded in sewage sludge inocula.

         Studies have demonstrated limited degradation of TDCPP in natural
    waters. It is rapidly metabolized by fish.

         Bioconcentration factors are low (3-107). The half-life of
    elimination in killifish is 1.65 h.

         Traces of TDCPP have been detected in sewage effluent, river
    water, seawater, drinking-water, sediment and in fish. TDCPP has been
    found in some samples of human adipose tissue.

         Kinetic studies in rats using 14C-labelled TDCPP showed the
    radiolabel to be distributed throughout the body following oral or
    dermal administration. The major metabolite of TDCPP identified in the
    urine of rats was bis(1,3-dichloro-2-propyl) phosphate. Elimination of
    the radiolabel was primarily in faeces and urine, with a small amount
    in expired air as CO2.

         TDCPP is of low to moderate acute toxicity by the oral route
    (LD50 in rats = 2830 mg/kg body weight) and of low acute toxicity by
    the dermal route (dermal LD50 in rats is > 2000 mg/kg body weight).

         In a 3-month study in mice, an exposure of approximately 1800
    mg/kg body weight per day caused death within one month. The
    no-observed-effect level (NOEL) for the study was 15.3 mg/kg body
    weight per day; the lowest-observed level (LOEL) for increased liver
    weight was 62 mg/kg body weight per day.

         The sensitization potential of TDCPP has not been investigated.

         The potential for TDCPP to affect human male reproductive ability
    is unclear in view of testicular toxicity in rats but a lack of effect
    on male reproductive performance in rabbits. The possible effect on
    female reproduction has not been investigated.

         A teratology study on rats showed fetotoxicity at an oral dose of
    400 mg/kg body weight per day; there was maternal toxicity at doses of
    100 and 400 mg/kg body weight per day. No teratogenicity was seen.

         Overall, the mutagenicity data show that TDCPP is not genotoxic
     in vivo.

         The carcinogenicity of TDCPP has been investigated in a single
    2-year feeding study. It was carcinogenic (increased occurrence of
    liver carcinomas) at all exposure levels that were tested (5-80 mg/kg
    body weight per day) in both male and female rats. Kidney, testicular
    and brain tumours were also found. In addition, there were
    non-neoplastic adverse effects in bone marrow, spleen, testis, liver
    and kidney. The effects in the kidney and testis occurred at all
    exposure levels. Only animals in the highest dose and control groups
    were evaluated for effects in the bone marrow and spleen. It was
    impossible, therefore, to determine whether there was a dose-response
    relationship for these effects in these organs.

         TDCPP exposure produced some indications of immunotoxicity in
    mice but only at high doses.

         Limited human studies following occupational exposure are
    available but they add little to the knowledge of the safety aspects
    of TDCPP.

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

    2.1  Tris(1-chloro-2-propyl) phosphate (TCPP)

    2.1.1  Identity

    Chemical formula:        C9H18Cl3O4P


    Chemical structure:

    CHEMICAL STRUCTURE 1


    Relative molecular mass: 327.55

    CAS name:                tris(2-chloroisopropyl) phosphate

    CAS registry number:     13674-84-5

    Synonyms:                2-propanol, 1-chlorophosphate (3:1);
                             1-chloro-2-propyl phosphate (1:3);
                             tris(1-chloromethylethyl) phosphate;
                             tris(2-chloroisopropyl) phosphate;
                             tris(ß-chloropropyl) phosphate;
                             phosphoric acid, tris(2-chloro-1-methyl
                             ethyl) ester

    Trade names:             Fyrol PCF; Amgard TMCP; Antiblaze 80;
                             Levagard PP; Tolgard TMCP; TCPP

    Common names:            TCPP; TMCP; TCIP

    2.1.2  Physical and chemical properties

    Physical state:          clear, colourless liquid

    Melting point:           -42°C

    Boiling point:           235-248°C

    Flash point:             218°C (Cleveland open cup method)

    Vapour pressure:         <2 mmHg at 25°C

    Viscosity:               61 cP at 25°C

    Specific gravity:        1.29 at 25°C

    Solubility in water:     1.6 g/litre at 20°C

    Stability:               Hydrolyses slowly under alkaline or acidic
                             conditions

     n-Octanol/water partition
    coefficient (log Pow):   2.59

    References: ECB (1995); Akzo (1995)

    2.2  Tris(1,3-dichloro-2-propyl) phosphate (TDCPP)


    2.2.1  Identity

    Chemical formula:        C9H15Cl6O4P

    Relative molecular mass: 430.91

    CAS name:                tris(1,3-dichloroisopropyl) phosphate

    CAS registry number:     13674-87-8

    Synonyms:                1,3-dichloro-2-propanol phosphate;
                             2-propanol, 1,3-dichloro-, phosphate;
                             phosphoric acid tris(1,3-dichloro-2- propyl)
                             ester; tris(1-chloromethyl-2-chloroethyl)
                             phosphate; tris(1,3-dichloroisopropyl)
                             phosphate; tris(1,3-dichloro-2-propyl)
                             phosphate; tris [2-chloro-1-(chloromethyl)
                             ethyl] phosphate

    Trade names:             CRP; Firemaster T33P; Fyrol FR 2; PF 38; PF
                             38/3; Apex Flame Proof Emulsion 197 and 212;
                             Antiblaze 195; Amgard; TDCP

    Common names:            TDCPP; TDCP

         There is some confusion concerning TDCPP isomers. The commercial
    product has predominantly branched substituent propyl groups in the
    "iso" orientation joined via the centre carbon. The alternate isomer,
    i.e. tris(2,3-dichloro-1-propyl) phosphate (CAS registry number
    78-43-3), exists only as a trace in the former because of steric
    hindrance from chlorine substitution on adjacent carbon atoms.
    Commercial production via reaction of phosphorus oxychloride and
    epichlorohydrin can, therefore, only produce the major species:

    i.e.

    CHEMICAL STRUCTURE 2


         It is therefore assumed that all referenced studies were
    conducted on commercial samples (CAS registry number 13674-87-4).

    2.2.2  Physical and chemical properties

    Physical state:          viscous liquid

    Boiling point:           236-237°C at 5 mmHg
                             (decomposes at > 200°C at 4 mmHg)

    Specific gravity:        1.52 at 25°C

    Solubility:              0.1 g/litre (30°C) in water;
                             soluble in most organic solvents

    Flash point:             252°C (Cleveland open cup method)

    Stability:               resistant to chlorination in aqueous
                             solution; it has an extremely low rate of
                             hydrolysis and resists attack by bases

    Viscosity:               1800 cP (25°C)

     n-Octanol/water partition
    coefficient (log Pow):   3.8

    Vapour pressure:         0.01 mmHg at 30°C

    References: Hollifield (1979); Sasaki et al. (1981); Windholz (1983);
    Chemical Information Systems (1988); Ishikawa & Baba (1988); Akzo
    (1997b)

    2.3  Conversion factors

    TCPP
         1 ppm = 0.0746 mg/m3
         1 mg/m3 = 13.39 ppm

    TDCPP
         1 ppm = 0.0567 mg/m3
         1 mg/m3 = 17.62 ppm

    2.4  Analytical methods

         Gas chromatography and mass spectrometry (GC/MS) with a
    nitrogen-phosphorus detector (GC/NPD) is used to detect
    tris(chloropropyl) phosphates in drinking-water and adipose tissue.
    Water samples are prepared as follows: absorption on a XAD resin
    cartridge, extraction with methylene chloride or elution with
    acetone/hexane, drying over anhydrous sodium sulfate and concentration
    and determination by GC/MS (LeBel et al., 1981; Benoit & LeBel, 1986).
    LeBel et al. (1987) used large-volume resin sampling cartridges to
    obtain sufficient organic extracts from water for analysis. Recovery
    at 10 ng TDCPP/litre fortification was 96.8%.

         The limit of determination for tris(chloropropyl) phosphates in
    human adipose tissue is < 1 ng/g (LeBel & Williams, 1983). The
    recovery of TDCPP from human adipose tissue fortified with TDCPP was
    92.1 to 111.4% in a concentration range of 2.5-25 µg/kg with benzene
    extraction (LeBel & Williams, 1983).

         Gas chromatography with negative chemical ionization mass
    spectrometry (GC/NCIMS) has been used to identify TDCPP in human blood
    samples (Sellström & Jansson, 1987).

         TDCPP can be analysed in food by GC/NPD (Draft, 1982).

    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1  Natural occurrence

         Neither TCPP nor TDCPP occur as natural products.

    3.2  Anthropogenic sources

    3.2.1  Production and processes

         TCPP production and use has continued to grow at an average of 4%
    per year since the mid-1960s when it was first commercialized. Its
    growth has been a reflection of polyurethane tonnage growth compounded
    by legislative advances and the fact that TCPP has replaced some other
    flame retardants, e.g., tris(chloroethyl) phosphate (TCEP).

         All commercial TCPP is produced by the reaction of phosphorus
    oxychloride with propylene oxide followed by purification.

         All commercial TDCPP is produced by reaction of phosphorus
    oxychloride with epichlorohydrin.

         In 1997, global TCPP demand reached over 40 000 tonnes per year;
    global TDCPP demand was estimated at 8000 tonnes per year and growing.

    3.2.2  Release in the environment

         The environmental fate of TCPP is unknown; entry into and
    transport through the aquatic media, however, appear to be the most
    likely sources of contamination. TCPP fire retardants could
    potentially reach the environment from waste streams generated: (a) in
    manufacturing plants; (b) where they are added to fabrics and
    plastics; and (c) from the final product during its use, disposal or
    recycling. Their transport to the environment could also occur by
    atmospheric emissions, by leaching or with the movement of treated
    fabrics or plastic products (US EPA, 1976).

         Ahrens et al. (1979) determined the rate of release of TDCPP as a
    function of the number of launderings of children's polyester
    sleepwear. They observed that about 37% of the flame retardant was
    lost after 20 washings, most of which was lost by the tenth wash.
    Prepolymers containing polyethyleneimine with TDCPP impart flame
    retardancy to cotton fabrics but do not withstand persistent
    laundering (Bertoniere & Rowland, 1977).

         TDCPP may undergo thermal oxidative degradation in air at 370°C.
    The major chlorinated C3 species (97% volatiles) are
    1,3-dichloropropene and 1,2,3-trichloropropane and acrolein.
    Hydrochloric acid is also produced.

    3.2.3  Uses

    3.2.3.1  TCPP

         The vast majority of TCPP is used in rigid polyurethane foams. It
    is also used in flexible polyurethane foams for furniture and its
    upholstery, principally in the United Kingdom and Ireland.

         TCPP is added at various points in the polyurethane supply chain:
    to final foam producers; to "system houses" who pre-blend and
    formulate ready-made systems; and to base polyol producers who may use
    it to reduce polyol viscosity/mobility.

         The use in rigid polyurethane foams may be further sub-divided
    into blocks and spray systems for building insulation and for
    refrigerator casings. Very small use of TCPP also exists in textile
    back-coating formulations and in certain coatings.

    3.2.3.2  TDCPP

         TDCPP is added as a flame retardant to: (a) polyurethane foam
    (both rigid and flexible); (b) other plastics and resins; and (c)
    acrylic latexes for back coating and binding of non-woven fabrics
    (Weil, 1980; US EPA, 1988).

         Incorporation of TDCPP into polyurea coatings for application to
    wool has produced flame-resistant, machine-washable and
    shrink-resistant material (Fincher et al., 1973).

         TDCPP was formerly used as a flame retardant for children's and
    infant's clothing.

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

    4.1  Transport and distribution between media

         No data are available regarding transport and distribution of
    TCPP or TDCPP between different media.

    4.2  Transformation

    4.2.1  Abiotic

         TCPP hydrolyses slowly under both acidic and alkaline conditions
    (Akzo, 1997a).

    4.2.2  Biotic

         TCPP is not readily biodegradable in sewage sludge inocula.
    Following inoculation at 20 mg/litre in a MITI test, 14% was degraded
    in 28 days (MITI, 1992). After inoculation at 100 mg/litre in a test
    under OECD Guideline 3OI C, there was no degradation within 28 days
    (Bayer AG, 1990, unpublished data). Using Amgard TMCP, TCPP was
    assessed for inherent biodegradability under OECD Guideline 302C.
    Calculated degradation (from oxygen uptake) was 21% after 28 days
    (SafePharm, 1996a). In the same test, Amgard TDCP (TDCPP), showed no
    degradation within 28 days (SafePharm, 1996b).

    4.2.3  Degradation

         Hattori et al. (1981) studied the degradation of TDCPP in
    environmental water during 1979-1980. Using the molybdenum blue
    colorimetric method, the increase of phosphate ions was analysed in Oh
    River and Neya River water and seawater from Osaka Bay. According to
    measurements made at 7 and 14 days, the degradation was 12.5 and
    18.5%, respectively, when 20 mg TDCPP/litre was added to water from
    the Oh River, 0 and 5.4%, respectively, when 1 mg/litre was added to
    water from the Neya River, 0 and 22% respectively in seawater from
    Osaka Bay (Tomagashima), and 0% in seawater from Osaka Bay (Senboku).

         The percentage degradation of TDCPP in water in the presence of
    killifish  (Orzyias latipes) or goldfish  (Carassius auratus) was
    monitored by Sasaki et al. (1981). Initial concentration and fish
    numbers per unit volume were not reported. More than 90% of the TDCPP
    degradation with killifish, and approximately 70% with goldfish,
    occurred within 100 h; the half-lives being 31 h for killifish and 42
    h for goldfish.

    4.2.4  Bioaccumulation

         Bioaccumulation of TDCPP was studied in both static and
    continuous-flow tests using killifish  (Oryzias latipes). In static
    tests, bioconcentration factors (BCFs) ranged from 47 to 107 following

    exposure to TDCPP at 0.3-1.2 mg/litre for 96 h. In continuous-flow
    systems, BCFs ranged from 31 to 59 following exposure to 0.04-0.4
    mg/litre over 3 to 32 days. The half-life of elimination was 1.65 h
    following transfer to clean water after exposure in the
    continuous-flow system (Sasaki et al., 1982). Static BCFs for goldfish
     (Carassius auratus) ranged from 3 to 5 for TDCPP (Sasaki et al.,
    1981).

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1  Environmental levels

    5.1.1  Air

         TCPP and TDCPP concentrations of 0.0053 and 0.0047 µg/m3,
    respectively, were measured in the ambient air of Kitakyushu, Japan,
    in 1983 (Haraguchi et al., 1985).

    5.1.2  Water

         In 1975 and 1978 more than 100 samples of river water were
    analysed in Japan for the presence of TDCPP. In 1975 0/100 and in 1978
    0/114 samples contained the substance. The limit of determination in
    1975 was 0.02-0.25 and in 1978 it was 0.001-0.5 µg/litre
    (Environmental Agency Japan, 1983, 1987).

         In a survey conducted in 1980, 25 samples of river water and
    seawater were collected near Kitakyushu City, Japan, and analysed for
    TDCPP. All samples contained this phosphate at concentrations of
    0.023-0.136 µg/litre (limit of determination, 0.01 µg/litre) (Ishikawa
    et al., 1985a).

         Twenty-four samples of water were collected and analysed for the
    presence of TDCPP in Japan in 1984. None of the samples contained
    either TDCPP (limit of determination 0.25-1 µg/litre) or TCPP (limit
    of determination 0.05-1 µg/litre) (Environmental Agency Japan, 1987;
    personal communication from the Japanese Ministry of Health and
    Welfare to the IPCS, July 1993).

         TDCPP has been identified in raw river water and drinking-water
    extracted from Japanese rivers (Takahashi & Morita, 1988). A study of
    river water samples collected at Isojima in the Yodo river basin in
    1984 led to the conclusion that urban run-off was not a source of
    river water pollution in that area (Fukushima et al., 1986). Fukushima
    et al. (1992) determined the trend of TCPP and TDCPP levels in the
    basin from 1976 to 1990. There was a peak in the polluted area of
    TDCPP in 1987 where the concentration reached 0.9 µg/litre and one in
    a less polluted area in 1988 where it was 0.6 µg/litre.

         Industrial and domestic effluents in Kitakyushu, Japan, contained
    detectable levels of TDCPP (limit of determination, 0.03 µg/litre).
    The concentration ranged from not detectable (ND) to 0.1 µg/litre at 3
    food factories, ND to 0.6 µg/litre at 7 chemical factories, ND to 0.29
    µg/litre at 5 steel factories, ND to 0.59 µg/litre at 6 other
    industrial sites and ND to 0.18 µg/litre at 3 metal processing plants,
    0.28 to 1.4 µg/litre in 5 sewage treatment plant effluents (influents
    0.33 to 1.6 µg/litre) and ND to 0.56 µg/litre in 5 domestic effluents.
    It was concluded by the authors that the water pollution in the area
    was due to a combination of pollution sources of low concentrations
    (Ishikawa et al., 1985b). TCPP was detected at 0.06 µg/litre only in

    one of the "other industrial sites" and was not detected in other
    industrial effluents. TCPP was found at only one of the sewage
    treatment plants (at 0.98 µg/litre in the influent and 0.32 µg/litre
    in the effluent).

         TDCPP was detected at concentrations ranging from trace to 0.22
    µg/litre in water from water treatment plants in Japan (Takahashi &
    Morita, 1988).

         In 1979 a survey of drinking-water from treatment plants
    throughout Canada was carried out. Samples were taken approximately 3
    months apart in August/September and again in November/ December.
    TDCPP was found at levels ranging from 0.0003 to 0.023 µg/litre in the
    drinking-water supply of 15 Canadian cities. It was not detected in
    drinking-water from 14 other cities (Williams & LeBel, 1981).

         The concentration of TDCPP in drinking-water samples (one sample
    at each station) collected in 1980 from 12 Canadian Great Lakes
    municipalities ranged up to 0.0157 µg/litre during January and from
    0.0001 to 0.0046 µg/litre during August (Williams et al., 1982).
    Drinking-water samples (two samples of each station) collected from
    six Eastern Ontario water treatment plants, in the period June-October
    1978, contained 0.0002 to 0.0018 µg/litre (LeBel et al., 1981).

         In a survey of organic effluent pollutants from three Swedish
    waste water treatment plants, Paxéus (1996) found TDCPP at
    concentrations of < 0.5 to 3 µg/litre.

    5.1.3  Sediment

         In 1975, 100 samples and, in 1978, 114 samples of sediment were
    analysed for the presence of TDCPP in Japan. No TDCPP was found (limit
    of determination in 1975 was 0.002-0.05 and, in 1978, 0.0001-0.06
    mg/kg) (Environmental Agency Japan, 1983, 1987).

         In a survey in 1980, four out of six samples of sediment
    collected from a river and the sea near Kitakyushu City, Japan,
    contained TDCPP at concentrations of 9-17 µg/kg (limit of
    determination, 5 µg/kg) (Ishikawa et al., 1985a).

         Twenty-four samples of sediment were collected and analysed for
    the presence of TDCPP and TCPP in Japan in 1984. None of the samples
    contained TDCPP (limit of determination, 0.03-0.06 mg/kg) or TCPP
    (limit of determination, 0.011-0.05 mg/kg) (Environmental Agency
    Japan, 1987; personal communication from the Japanese Ministry of
    Health and Welfare to the IPCS, July 1993).

    5.1.4  Biota

         In 1975 and in 1978 samples of Japanese fish were analysed for
    the presence of TDCPP. In 1975, 7/94 samples contained TDCPP at
    concentrations of 0.015-0.025 mg/kg and in 1978 0/93 samples contained

    TDCPP (limit of determination, 0.001-0.03 mg/kg) (Environmental Agency
    Japan, 1983, 1987).

    5.1.5  Food

         In a market-basket survey of 234 food items conducted over a
    10-year period between 1982 and 1991, TCPP was found 3 times. Residues
    found in raw peach and raw pear were 0.009 mg/kg (limits of detection
    unspecified) (Kan-Do Office and Pesticides Team, 1995).

    5.2  General population exposure

    5.2.1  Adipose tissue

         In a series of studies (LeBel & Williams, 1983, 1986; LeBel et
    al., 1989), TDCPP was detected in human adipose tissue. In initial
    studies, concentrations ranged from not detectable (< 0.001 µg/kg) to
    257 µg/kg. In later studies, samples from 4 out of 6 cities showed no
    detectable TDCPP, whilst in the other two concentrations ranged up to
    32 µg/kg.

    5.2.2  Biological fluids

         Using NCI mass spectrometry with a limit of detection of 0.01 µg,
    Hudec et al. (1981) found TDCPP in the seminal fluid of 34 out of 123
    student donors. The TDCPP concentrations ranged from 5 to 50 µg/litre.

    6.  KINETICS AND METABOLISM IN LABORATORY ANIMALS

    6.1  TCPP

         No data are available on the kinetics or metabolism of TCPP.

    6.2  TDCPP

         The only data available derive from studies in rats.

         Groups of 2-8 male Sprague-Dawley rats received an unstated
    amount of 14C-TDCPP by intravenous injection (Lynn et al., 1981). The
    position of the radiolabel was not specified. Urine, faeces and
    expired air were collected for 24-h periods over 5 days; bile and
    plasma samples were collected over 24 h only. Total radiolabel and
    tissue concentrations of TDCPP were assessed in most major organs at 5
    min, 30 min, 8 h, 24 h and 5 days after injection. The major
    metabolite isolated from urine, faeces and bile was
    1,3-dichloro-2-propyl phosphate (BDCP); in addition
    1,3-dichloro-2-propanol and a dimethyl derivative of BDCP were
    identified in urine. There was also substantial elimination of 14CO2
    via exhaled air. The tissue distribution studies indicated
    distribution of the parent compound and the major metabolite
    (1,3-dichloro-2-propyl phosphate) throughout the body. On completion
    of 5 days collection, approximately 96% of the administered
    radiolabelled material had been recovered in the urine, faeces or
    exhaled air.

         Similar results were reported following dermal application of 0.9
    mg/kg and oral administrations of up to 22 mg/kg (Nomeir et al., 1981;
    Minegishi et al., 1988).

         Following the intraperitoneal administration of 14C-TDCPP to
    male Sprague-Dawley rats, urine collected over 24 h contained a major
    metabolite, bis(1,3-dichloro-2-propyl) phosphate (BDCPP) (Lynn et al.
    1981). In rats receiving intravenous injection, 54% of the radiolabel
    was excreted in the urine after 5 days; 62% of the urinary label was
    BDCPP (Lynn et al., 1980,1981).

         Nomeir et al. (1981) studied the metabolism of 14C-TDCPP in
    rats. Labelled TDCPP was distributed rapidly throughout the body
    following either oral or dermal administration or intravenous
    injection. Elimination of TDCPP was primarily in the bile, faeces and
    urine, but some was expired as C02. About 80% of the dose was
    eliminated within 24 h, but traces of radioactivity were found in most
    tissues 10 days following exposure.

         In a similar study, Minegishi et al. (1988), using male Wistar
    rats, showed, after 168 h of an oral administration of 21.5 mg/kg in
    olive oil, a recovery of 43.2% in the urine, 39.2% in the faeces and
    16.2% in the expired air.

         Six hours after intravenous administration of 14C-TDCPP (40.7
    mg/kg) to CD-1 mice, binding of TDCPP-derived radioactivity was
    detected in isolated RNA, DNA and protein from liver, kidney and
    muscle. The maximum levels in RNA, DNA and protein were 28, 8.3 and 57
    nmoles/kg, respectively (Morales & Matthews, 1980).

         TDCPP was rapidly metabolized  in vitro by an NADPH- dependent
    microsomal mixed-function oxidase system and glutathione
    S-transferases from rat liver to BDCPP, 1,3-dichloro-2-propanol,
    3-chloro-1,2-propanediol, and one metabolite which was probably a
    glutathione conjugate (Nomeir et al., 1981; Sasaki et al., 1984).

    7.  EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

    7.1  Single exposure

    7.1.1  TCPP

         Acute oral LD50 values for TCPP in rat have been reported in a
    series of studies, as presented in Table 1, and range between 931 and
    4200 mg/kg body weight for males and 707 and 2500 mg/kg body weight
    for females.

         LC50 values for inhalation exposure to TCPP administered as an
    aerosol to rats are given in Table 2.

         Dermal LD50 values for the rat and for the rabbit are above 2000
    mg/kg body weight (Gordon, 1980; Smithey, 1981c; Cuthbert, 1989f).

    7.1.2  TDCPP

         Slc/ddY mice (10 male, 10 female per group) were given a single
    oral intubation of TDCPP in olive oil and were observed for 14 days.
    There were 7 dose groups and a control group for males and 6 dose
    groups and a control group for females. The dose range was 2210-3500
    mg/kg for males and 1890-2780 mg/kg for females. Clinical signs
    included ataxia, hyperactivity and convulsion (incidence not
    reported). LD50 values for male and female mice were 2670 mg/kg
    (range 2520-2830) and 2250 mg/kg (range 2120-2390 mg/kg), respectively
    (Kamata et al., 1989).

         In two different studies using male and female Sprague-Dawley
    rats, Cuthbert (1989a,b) investigated the oral and dermal LD50 of
    TDCPP. In the oral study, clinical signs noted 1-5 days after dosing
    included hypokinesia, piloerection, soiled coats, ataxia,
    chromodacryorrhoea, rhinorrhoea and salivation. In the dermal study,
    no death occurred and no clinical signs were noted 24 h after
    administration. In both cases the LD50 was evaluated as greater than
    2000 mg/kg.

         When Anderson (1990b) administered a TDCPP-containing aerosol to
    groups of 5 male and female Sprague-Dawley rats, the LC50 was greater
    than 5220 mg/m3.

    7.2  Short-term exposure

    7.2.1  TCPP

         Groups of rats fed ad libitum for 14 days at levels of 4200,
    6600, 10 600 and 16 600 mg/kg diet presented minimal evidence of
    toxicity. No treatment-related changes were seen in haematology,
    clinical chemistry or cholinesterases activity. Increased relative and
    absolute liver weights were reported without concomitant
    histopathological change (Stauffer, 1980).

    7.2.2  TDCPP

         No histological effects were observed in the liver, kidneys or
    gonads of rats given daily doses of 250 mg/kg per day for 10 days
    (Ulsamer et al., 1980).

    7.3  Long-term exposure

    7.3.1  TCPP

         No data on TCPP are available.


    
    Table 1.  Oral LD50 values for TCPP in rats
                                                                                                                                  

    Straina                  LD50 (mg/kg body weight)                Clinical signs                               Reference
                             Male          Female
                                                                                                                                  
    Sprague-Dawley           4200          2800             "depression", tremors, lacrimation,              Stauffer, 1979
                                                            salivation, convulsion                           

    Sprague-Dawley           2710          -                "depression" and tremors at                      Stauffer, 1972
                                                            dosage > 1000 mg/kg                             

    Sprague-Dawley           2000          1260             "depression" and intermittent muscle             Stauffer, 1970
                                                            spasm at 464 mg/kg; salivation ataxia
                                                            and spasmodic jumping at high dose               

    Sprague-Dawley           931           -                "depression" hunched posture, decreased          Safepharm (undated/a)
                                                            respiratory rate, increased salivation,
                                                            laboured respiration                   

    Sprague-Dawley           1310          -                hunched posture, decreased respiratory           Safepharm (undated/c)
                                                            rate, signs of lethargy, ataxia, laboured
                                                            respiration                           

    Sprague-Dawley           -             980              ataxia, hunched posture, decreased               Safepharm (undated/d)
                                                            respiratory rate, lethargy, laboured
                                                            respiration                       

    Sprague-Dawley           -             1548             ataxia, hunched posture, lethargy,               Safepharm (undated/e)
                                                            piloerection, decreased respiratory rate,
                                                            laboured respiration             

    NS                       -             1011             piloerection, hunched posture, waddling          Huntingdon Life
                                                            gait, lethargy, respiratory distress,            Sciences, 1997b
                                                            increased salivation, clonic convulsions

    NS                       -             707              hunched posture, waddling gait, lethargy,        Huntingdon Life
                                                            respiratory distress, increased salivation       Sciences, 1997a


    Table 1.  (Continued)
                                                                                                                                  

    Straina                  LD50 (mg/kg body weight)                Clinical signs                               Reference
                             Male          Female
                                                                                                                                  
    NS                       1546          1017             increased or reduced activity; oral, nasal,      Mehsl, 1980
                                                            perional and ocular discharge, hunching,
                                                            rough coat, aggression, diarrhoea, anorexia
                                                            and sporadic twisting                      

    NS                       1824          1101             reduced activity, oral/nasal discharge,          Anon, 1981a
                                                            convulsion, emaciation, prostration              

    NS                       1750          1150                             -                                Bayer AG, 1990
                                                                                                             (unpublished data)

    NS                       1419b                                                                           Stauffer, 1978
                                                                                                             (Report No. T6539)

    NS                       >2000b,c                      After 1-3 days, reduced activity,                 Cuthbert, 1989d
                                                            piloerection and ataxia                          
                                                                                                                                  

    a    NS = not specified
    b    Separate values for males and females not given
    c    10 animals (5 of each sex)

    Table 2.  LC50 values for TCPP administered as aerosol to rats

                                                                                                                               

    Duration         LC50 (mg/litre)                Remarksa                                             Reference
    (h)
                                                                                                                               

    1                > 17.8                         10 animals (5 of each sex), whole                    Mehlman & Smart, 1981
                                                    body exposure; clinical signs:
                                                    decreased activity, partially closed
                                                    eyes, swollen eye lids, lacrimation                  

    4                > 4.6                          clinical signs: mild lethargy and matted fur         Stauffer, 1979

    4                > 7.9                          10 animals (5 of each sex)                           Anderson, 1990a

    4                approximately 5 (female)       whole body exposure (one exposure                    Mehlman & Singer, 1981
                     > 5 (male)                     level only; 0/5 male; 3/5 female);                  
                                                    clinical signs: decreased activity, increased
                                                    salivation
                                                                                                                               

    a  There were no deaths in the first three studies but three females out of five died in the study of
       Mehlman & Singer (1981)

    

    7.3.2  TDCPP

         Slc/ddY mice (12 male, 12 female per group) were administered
    diets containing 0, 100, 400, 1300, 4200 or 13 300 mg/kg diet for 3
    months. The daily intake of TDCPP reported by the authors was 0, 13,
    47, 171, 576 or 1792 mg/kg body weight per day for males and 0, 15,
    62, 214, 598 or 1973 mg/kg body weight per day for females. The
    animals in the highest exposure groups showed emaciation, rough hair
    and tremor (incidence not reported) and all animals died within one
    month. Haemoglobin concentration was decreased in males and females by
    13% and 11%, respectively, in the group treated with 4200 mg/kg diet.

         There was a progressive increase in serum alkaline phosphatase
    and serum alanine aminotransferase activities with increasing
    exposure, but the change was not statistically significant after 3
    months. There was also an increase in relative liver weight in males
    (statistically significant in the 1300 and 4200 mg/kg groups where the
    increases were 32% and 51%, respectively) and females (statistically
    significant in the 400, 1300 and 4200 mg/kg groups, where the
    increases were 16%, 29% and 51%, respectively). There was also an
    increase in relative kidney weight in males (statistically significant
    in the 4200 mg/kg group where the increase was 39%) and females
    (statistically significant in the 1300 and 4200 mg/kg groups where the
    increases were 34% and 40%, respectively). A slight necrosis was
    reported in the liver of two females of the 4200 mg/kg group. In this
    study the NOEL for the increase in relative liver weight in males was
    47 mg/kg body weight per day and in females 15 mg/kg body weight per
    day; the LOEL in males was 171 mg/kg body weight per day and in
    females 62 mg/kg body weight per day (Kamata et al., 1989).

    7.4  Skin and eye irritation or sensitization

    7.4.1  TCPP

    7.4.1.1  Skin irritation

         TCPP was investigated in New Zealand white rabbits for dermal
    irritation. Two reports classified TCPP as mild or slightly irritant
    to rabbit skin (Cuthbert, 1989e; Safepharm, 1979c).

         In a study conducted under OECD Test Guideline 404, 0.5 ml TCPP
    was applied to the skin of three New Zealand white rabbits under a
    semi-occlusive dressing for 4 h (Liggett & McRae, 1991a). Slight
    erythema (grade 1) was noted in one animal on day 1 only. Thereafter,
    there were no signs of skin irritation.

         In two different studies, 0.5 ml of TCPP was applied to two test
    sites, one abraded and one intact skin of the back of six New Zealand
    white rabbits under an occlusive binder for 24 h. Using the technique
    of Draize test, sites were scored for irritancy at 24 and 72 h after
    application. In both case the test material was classified as not
    irritant (Smithey, 1980b, 1981b).

    7.4.1.2  Eye irritation

         In a study conducted under OECD Test Guideline 405, 0.1 ml TCPP
    was instilled into one eye of each of three New Zealand white rabbits
    (Liggett & McRae, 1991b). Slight conjunctival redness (grade 1) was
    seen in each animal on day 1 only. Thereafter, there were no signs of
    eye irritation.

         Three older studies conducted under different guidelines using
    albinos or New Zealand white rabbits reported no signs of eye
    irritation (Safepharm, 1979b; Smithey, 1980a, 1981a). In a limited
    study, Cuthbert & Jackson (1990b) reported that TCPP was slightly
    irritant, but the effect was quickly reversible in New Zealand white
    rabbits.

    7.4.1.3  Sensitization

         TCPP was examined using the Magnuson and Kligman method for
    possible contact sensitization potential in guinea-pigs. TCPP produced
    no skin sensitization(Safepharm, 1979a).

    7.4.2  TDCPP

    7.4.2.1  Skin irritation

         The acute dermal irritation potential of TDCPP was investigated
    in three New Zealand white rabbits. Well defined (score 2) erythema
    was recorded in 2 animals 1 h after patch removal. The third animal
    showed very slight erythema at 1 h. By 48 h all treated sites were
    normal. TDCPP was classified as irritant to rabbit skin (Cuthbert,
    1989c).

    7.4.2.2  Eye irritation

         New Zealand white rabbits were used to evaluate the eye
    irritation potential of TDCPP. Slight conjunctival redness and slight
    discharge were noted 1 h after instillation. By 24 h after
    instillation, all treated eyes were normal. It was concluded that
    TDCPP was slightly irritant to the rabbit eye (Cuthbert & Jackson,
    1990a).

    7.4.2.3  Sensitization

         No data on the skin sensitization potential of TCPP are
    available.

    7.5  Reproductive toxicity, embryotoxicity and teratogenicity

    7.5.1  TCPP

         No studies concerning the possible reproductive toxicity,
    embryotoxicity or teratogenicity of TCPP have been reported.

    7.5.2  TDCPP

         Female Wistar rats (15-24 per group) were given 25, 50, 100, 200
    or 400 mg/kg body weight by oral intubation on days 7 to 15 of
    gestation. In the 400 mg/kg group, there was severe maternal toxicity;
    maternal body weight gain and food consumption were markedly
    suppressed and 11 out of 15 dams died. Clinical signs in dams at 400
    mg/kg included piloerection, salivation and haematuria. Fetal death
    was markedly increased at 400 mg/kg. In the 200 mg/kg group there was
    a statistically significant increase in relative kidney weight (15%
    increase) in dams. No effects on dams were seen at lower exposures.
    There was no evidence of an increased number of fetal deaths, of
    abnormal fetal development, or of malformation at an exposure of 200
    mg/kg or less. In this study the NOEL and LOEL for maternal toxicity
    were 100 mg/kg and 200 mg/kg body weight per day, respectively, and
    the NOEL and LOEL for fetotoxicity were 200 mg/kg and 400 mg/kg body
    weight per day, respectively (Tanaka et al., 1981).

         In a fertility study, male rabbits were given oral gavage TDCPP
    doses of 2, 20 or 200 mg/kg body weight per day for 12 weeks. The
    treatment did not affect mating behaviour, fertility, sperm quality or
    sperm quantity. Kidney and liver weight were increased at 200 mg/kg
    body weight per day, but it was reported that no histopathological
    lesions were seen in kidneys, liver, pituitaries, testes or epididymes
    (Wilczynski et al., 1983).

    7.6  Mutagenicity and related end-points

    7.6.1  TCPP

         There was no clear evidence from a battery of assays for
    mutagenicity and related effects to suggest that TCPP was genotoxic
    (Tables 3 and 4).

         TCPP produced no gene mutations in strains TA1535, TA1537,
    TA1538, TA97, TA98 and TA100 in any of six Salmonella/microsome plate
    assays and one  Escherichia coli (Stauffer, 1978c; Nakamura et al.,
    1979; Anon, 1980; Zeiger et al., 1992; Mehlman et al., 1980; Parmar,
    1977; Kouri & Parmar, 1977) nor in a yeast gene mutation assay
    (Stauffer, 1978c) in either the presence or absence of metabolic
    activation. One mouse lymphoma assay gave equivocal results (Anon,
    1981b), but a second mouse lymphoma assay was negative in the presence
    and absence of metabolic activation (Stauffer, 1978a). An  in vitro 
    assay for unscheduled DNA synthesis (UDS) in a primary culture of rat
    hepatocytes gave a negative result (Bayer, 1991, Report No. 20393),
    whereas the results of  in vitro UDS assays in WI-38 cells (Stauffer,
    1978b) were equivocal in the presence and absence of metabolic
    activation. Two out of three cell transformation assays in BALB/3T3
    cells gave negative results in the absence of metabolic activation
    (Stauffer, 1978b, 1980, Report No. T10182), whereas the third was
    equivocal (Stauffer, 1978, Report No. T6357).

         TCPP caused no chromosomal damage in bone marrow in three  in 
     vivo cytogenetic assays using oral or subcutaneous administration to
    rats (Stauffer, 1978, Report No. T6539) and intraperitoneal
    administration to mice (Bayer, 1991, Report No. 20029).

    7.6.2  TDCPP

         TDCPP has been tested for mutagenic effects  in vitro and  in 
     vivo (Tables 5 and 6).

         TDCPP has been investigated several times in bacterial gene
    mutation studies using the  Salmonella/microsome mutation test.
    Mortelmans et al. (1986) reported the findings of four tests performed
    in three different laboratories which tested TDCPP using strains
    TA100, TA1535, TA98, TA97 (2 labs) and TA1537 (2 labs) in the presence
    and absence of metabolic activation by S9 from Aroclor 1254 activated
    livers of rats and hamsters. There was no evidence of mutagenicity in
    the absence of S9, but all three laboratories obtained some positive
    results in the presence of S9. Positives were reported in at least
    some of the laboratories for strains TA97, TA100 and TA1535 with both
    hamster and rat S9. All three laboratories reported positive findings
    in TA100. Two other studies (Gold et al., 1978; Sœderlund et al.,
    1985) also found a mutagenic response in TA100 in the presence of
    metabolic activation. Brusick et al. (1980) found no mutagenicity in
    strains TA1535 or G46 in the presence or absence of S9, but obtained
    different results in TA100 depending upon the source of the S9 used in
    the assay: mutagenic activity was seen when they used S9 from rat
    liver activated with Aroclor 1254 or phenobarbital but not with S9
    from human liver or from mouse liver activated with Aroclor 1254 or
    phenobarbital. Taken as a whole, the results of bacterial tests show
    TDCPP to have mutagenic potential.

         No mutagenic activity was noted in strains TA98, TA100, TA1535 or
    TA1537 when they were incubated with untreated or
    beta-glucuronidase-treated urine from TDCPP-treated mice (Brusick et
    al., 1980). The CD1 mice had been given oral doses of 0.05, 0.17 or
    0.5 ml/kg body weight per day, and urine was collected on the fourth
    day of treatment. It was unclear from the report of the study whether
    or not the urine samples had been tested for mutagenicity in the
    presence of any metabolizing system.

         TDCPP did not induce gene mutations in the mouse lymphoma assay
    either in the absence or presence of various exogenous metabolic
    systems (S9 from rat or mouse liver induced with either Aroclor 1254
    or phenobarbital) when tested up to a concentration causing a 50%
    reduction in cell growth (Brusick et al., 1980).


        Table 3.  Mutagenicity and related end-points for TCPP in vitro
                                                                                                                                    
    Test system                             Concentration            Activation          Resulta        Reference
                                                                     +S9      -S9                       
                                                                                                                                    
    Bacterial gene mutation assays

    Salmonella typhimurium
    TA100, TA1535                           0.3-10 µmol/plate        +        +          -              Nakamura et al., 1979

    Salmonella typhimurium
    TA97, TA98, TA100, TA1535, TA1537       3.3-1000 µg/plate        +        +          -              Zeiger et al., 1992

    Salmonella typhimurium
    TA98, TA100, TA1535, TA1537, TA1538     0.001-5 µl/plate         +        +          -              Stauffer, 1978c

    Salmonella typhimurium
    TA98, TA100, TA1535, TA1537, TA1538     0.03-1 µl/plate          +        +          -              Anon, 1980

    Salmonella typhimurium
    TA98, TA100, TA1535, TA1537, TA1538     0.03-0.33 µl/plate       +        +          -              Mehlman et al., 1980

    Salmonella typhimurium
    TA98, TA100, TA1535, TA1537, TA1538     1-50 µl/plate            +        +          -              Parmar, 1977

    Escherichia coli
    Pol A+, Pol A-                          2-20 µl/plate            +        +          -              Kouri & Parmar, 1977

    Yeast gene mutation assay

    Saccharomyces cerevisiae                0.001-5 µl/plate         +        +          -              Stauffer, 1978c
    L5178Y TK+/-                            0.08-0.48 µl/ml          +        +          -              Stauffer, 1978c
    L5178Y TK+/-                            0.006-0.028 µl/ml        +        +          ±              Anon, 1981b
                                                                                             
    Unscheduled DNA synthesis
    Human diploid WI-38 cells               0.1-5 µl/ml              +        +          ±              Stauffer, 1978b
                                                                                             
    Table 3.  (Continued)
                                                                                                                                    
    Test system                             Concentration            Activation          Resulta        Reference
                                                                     +S9      -S9                       
                                                                                                                                    
    Human diploid WI-38 cells               0.1-100 µl/ml            +        -          ±              Stauffer, 1978b
    Rat liver primary cells                 12.5-200 µg/ml           +        -          -              Bayer, 1991
                                                                                                        (Report No. 20393)
    Cell transformation assays
    BALB/3T3 cells                          0.00125-0.02 µl/ml       -        +          ±              Stauffer, 1978
                                                                                                        (Report No. T6357)
    BALB/3T3 cells                          0.00125-0.02 µl/ml       -        +          -              Stauffer, 1978b
    BALB/3T3 cells                          0.00015-3 µl/ml          -        +          -              Stauffer, 1980
                                                                                                        (Report No. T10182)
                                                                                                                                    
    a     ±     = equivocal result
         

    Table 4.  In vivo mutagenicity assays for TCPP

                                                                                                                               

    Species               Route of administration   Dose                       Result                        Reference
                                                                                                                               

    Cytogenetic assays

    Rat                   oral                      0.011, 0.04 and            no chromosomal                Stauffer, 1978
                                                    0.11 ml/kg body weight     aberrations                  (Report No. T6539)

    Rat                   subcutaneous              0.011, 0.04 and            no chromosomal                Stauffer, 1978
                                                    0.11 ml/kg body weight     aberrations                   (Report No. T6539)
                                                    on 5 consecutive days
                                                                                          

    Mouse                 intraperitoneal           350 mg/kg body weight      "no clastogenic effects"      Bayer, 1991
                                                                                                             (Report No. 20029)

                                                                                                                               



    Table 5. Mutagenicity and related end-points for TDCPP in vitro

                                                                                                           

    Test system                          Concentration               Result         Reference
                                                                                                           

    Bacterial tests

    S. typhimurium
    TA100, TA1535, G46                   10200 µg/plate             +              Brusick et al., 1980

    S. typhimurium
    TA97, TA98, TA100, TA1535, TA1537    10 to 10 000 µg/plate      +              Mortelmans et al., 1986

    S. typhimurium
    TA100                                50-1000 µg/plate           +              Soderlund et al., 1985

    S. typhimurium
    TA100                                50-250 µg/plate            +              Gold et al., 1978

    Mouse lymphoma assay
    L5178Y cells                         up to 0.07 µl/ml           -              Brusick et al., 1980

    SCE assay
    L5178Y cells                         0.005-0.07 µl/ml           ?              Brusick et al., 1980

    Chromosomal aberration assays
    L5178Y cells                         0.01-0.1 µl/ml             +              Brusick et al., 1980
    CHL cells                            ?                          +              Kawachi et al., 1980;
                                                                                   Ishidate et al., 1981
    Human fibroblasts                    ?                          -              Kawachi et al., 1980;
                                                                                   Ishidate et al., 1981

    Cell transformation
    BALB/3T3 cells                       up to 0.312 µl/ml          -              Brusick et al., 1980

                                                                                                           


    Table 6. In vivo mutagenicity of TDCPP

                                                                                                              

    Test systema                       Dose                     Result              Reference
                                                                                                              

    Insect assay
    SLRL mutations in Drosophila       2.5 and 25% in feed      -                   Brusick & Jagannath, 1977;
                                                                                    Brusick et al., 1980
    Mammalian bone marrow assays
    SCE & CA in CD1 mice               0.05-0.5 ml/kg           -                   Brusick et al., 1980
                                       body weight              
    Micronuclei in mice                2000 mg/kg body weight   -                   Thomas & Collier, 1985

                                                                                                              

    a   SLRL = sex-linked recessive lethal
        SCE = sister-chromatid exchange
        CA = chromosome aberration

    

         TDCPP was also tested for  in vitro chromosome effects, i.e.
    chromosomal aberrations (CA) and sister chromatid exchanges (SCE),
    using mouse lymphoma (L5178Y) cells at concentrations up to those
    causing a 50% reduction in growth rate (Brusick et al., 1980). Tests
    were performed in the absence and presence of various exogenous
    metabolic systems (S9 from mouse liver induced with either Aroclor
    1254 or phenobarbital). The results for SCEs were equivocal, whereas
    those for CAs showed increased numbers of chromosomal aberrations
    (excluding gaps) with both metabolic activation systems. Induction of
    SCEs was reported in a separate study by Gold et al., 1978. Incomplete
    reports of  in vitro cytogenetic studies claimed that TDCPP caused
    chromosomal aberrations in CHL cells but not in human fibroblasts
    (Kawachi et al., 1980; Ishidate et al., 1981).

         TDCPP did not induce primary DNA damage as measured indirectly as
    unscheduled DNA synthesis in a primary culture of rat hepatocytes
    (Williams et al., 1989).  In vivo covalent binding studies in CD1
    mice have revealed that TDCPP and/or its metabolites can bind to
    cellular DNA from the liver and kidney (Morales & Matthews, 1980).
    Section 6.2 includes other details of this study.

         TDCPP did not induce sex-linked recessive lethal mutations in
     Drosophila melanogaster (Brusick et al., 1980).

         TDCPP did not induce SCEs or CAs in bone marrow cells of CD1 mice
    (sex not reported) following either a single oral gavage dose of 0.05,
    0.17 or 0.5 ml TDCPP/kg body weight (using bone marrow harvest times
    of 6, 24 and 48 h post-dosing) or 5 consecutive daily oral exposures
    at the same dose levels with a harvest time of 6 h after the last dose
    (Brusick et al., 1980).

         TDCPP did not induce micronuclei in polychromatic erythrocytes in
    the bone marrow of either sex of mice (strain not reported) that had
    been given a single dose of 2000 mg TDCPP/kg body weight by an
    unspecified route of administration (Thomas & Collier, 1985). The
    ratio of normochromatic erythrocytes to polychromatic erythrocytes was
    not elevated at any of the sampling times (24, 48 and 72 h
    post-dosing), but, as there was systemic toxicity seen in the treated
    mice, the TDCPP must have entered the blood circulation and thus the
    bone marrow cells must have been exposed to TDCPP and/or its
    metabolites.

         TDCPP did not induce morphological cell transformations in
    BALB/3T3 cells in two independent tests in the absence of any
    metabolic activation (Brusick et al., 1980).

    7.7  Carcinogenicity

    7.7.1  TCPP

         No data on the carcinogenic potential of TCPP are available.

    7.7.2  TDCPP

         Groups of 50 male and 50 female Sprague-Dawley rats received
    approximately 0, 5, 20 and 80 mg TDCPP/kg per day by dietary
    administration for 2 years (Aulette & Hogan, 1981). An additional 10
    animals per group were killed after 1 year for interim investigations.
    Examinations included body weight gain and food consumption,
    haematology, clinical chemistry, urinalysis, ophthalmoscopy, organ
    weights and extensive macroscopic and microscopic investigations.

         Increased mortality was reported in males at 80 mg/kg per day.
    Reduced body weight gain was noted in males and females at 80 mg/kg
    per day (approximately 20% lower than control), although food
    consumption was unaffected. Ophthalmoscopy revealed sacculations on
    the retinal arterioles in one male at 20 mg/kg per day and four males
    and four females at 80 mg/kg per day at 80 or 104 weeks. Red blood
    cell values were reduced amongst males and females at 80 mg/kg per
    day. In addition, there was a slight decrease in plasma cholinesterase
    activity in females at 80 mg/kg per day, although erythrocyte
    cholinesterase was unaffected.

         Increased liver, kidney and thyroid weights were reported at 12
    and 24 months at the highest dose in both males and females.
    Microscopic pathology changes were observed in liver, kidneys, testes
    (and associated tissues), bone marrow, spleen and parathyroids. In the
    liver, a slight increase in the occurrence of local hepatocellular
    alterations was noted in males and females at 80 mg/kg per day (males,
    29/46 compared to 20/45 in controls; females, 35/50 compared to 15/49
    in controls). In addition, there was a slight increase in the
    incidence of dilated sinusoids in the liver at this exposure level
    (males, 12/46 compared to 4/55; females, 18/50 compared to 7/49). In
    the kidneys, an increased occurrence of hyperplasia in the convoluted
    tubules was observed in all groups of treated males and females
    (males, 2/45, 10/49, 28/48, 24/46; females 0/49, 1/48, 3/48, 22/50).
    In addition, there was an increase in the occurrence of chronic
    nephropathy in males and females at 80 mg/kg per day (males, 39/46
    compared to 25/45; females, 25/50 compared to 7/49). In the
    seminiferous tubules there was a slight increase in the occurrence of
    germinal epithelial atrophy and oligospermia (30/43, 29/48, 42/47,
    44/45); eosinophilic material in the tubular lumen (2/43, 4/48, 12/47,
    11/45); sperm stasis (5/43, 5/45, 11/47, 14/45); periarteritis nodosa
    (5/43, 10/48, 19/47, 14/45). Seminal vesicle atrophy and decreased
    secretory products were reported in all treated groups. In the
    epididymides males given 80 mg/kg per day had an increased incidence
    of oligospermia and degenerated seminal products.

         An increased incidence of bone marrow erythroid/myeloid
    hyperplasia was recorded in males and females at 80 mg/kg (males,
    21/42 compared to 12/40 in controls; females, 18/44 compared to
    13/41). However, no samples were taken from other treated groups.

         An increased incidence of spleen erythroid/myeloid metaplasia was
    seen in males and females at 80 mg/kg per day (males, 10/45 compared
    to 12/45 in controls; females, 33/50 compared to 30/49). Again there
    were insufficient tissue samples taken from other treatment groups to
    draw firm conclusions about the dose-response relationship. Similarly,
    there was an increased occurrence of parathyroid hyperplasia in males
    and females at 80 mg/kg per day (males, 12/31 compared to 1/21;
    females, 9/25 compared to 6/26). Insufficient samples were taken from
    other treated groups to determine the dose-response relationship.

         Neoplastic changes were observed in the liver, kidneys, testes,
    brain, thyroid and adrenals. In liver, the occurrence of benign
    neoplastic nodules was 2/45, 7/48, 1/48, 13/46 in males and 1/49,
    1/47, 4/46, 8/50 in females; the incidence of carcinoma was 1/45,
    2/48, 3/48, 7/46 in males and 0/49, 2/47, 2/46, 4/50 in females. In
    the kidneys the incidence of renal cortical tumours (benign and/or
    malignant) was 1/45, 3/49, 9/48, 32/46 in males and 0/49, 1/48, 8/48,
    49/50 in females. The incidence of benign testicular interstitial
    tumours was 7/43, 8/48, 23/47 and 36/45. A slight increase in the
    incidence of brain astrocytomas was observed in males receiving 80
    mg/kg per day (4/46 compared to 0/44 in controls) and a single
    oligodendroglioma was observed amongst males and females given 80
    mg/kg per day.

         The occurrence of thyroid adenomas was increased amongst females
    at 80 mg/kg per day (5/49 compared to 1/42 in controls). In addition,
    a slight increase in the occurrence of parafollicular cell adenomas
    was noted in males and females at 80 mg/kg per day (males, 3/41
    compared to 0/40; females, 4/49 compared to 2/42). The occurrence of
    adrenal cortical adenomas was increased only in females at 80 mg/kg
    per day (19/49 compared to 8/48 in controls).

         It was concluded that TDCPP is carcinogenic at all exposure
    levels that were tested in both sexes of rats based on the increased
    occurrence of liver carcinomas. Kidney, testicular and brain tumours
    were also found. In addition, there were non-neoplastic adverse
    effects in bone marrow, spleen, testis, liver and kidney. Effects in
    the kidney and testis occurred at all exposure levels. Only the
    animals in the highest dose and control groups were evaluated for
    effects in the bone marrow and spleen. It was impossible, therefore,
    to determine the dose-response relationship for these effects.

    7.8  Other studies

    7.8.1  Immunotoxicity

    7.8.1.1  TCPP

         No data on the immunotoxic potential of TCPP are available.

    7.8.1.2   TDCPP

         The effects of TDCPP on immunological functions and host
    susceptibility to infectious agents were examined following exposure
    in adult mice. Groups of 7-10 B6C3F1 mice received 0, 0.25, 2.5 or 25
    mg/kg per day by subcutaneous injection for 4 days. Immunological
    tests included bone marrow cellularity and colony formation,
    lymphoproliferative responses to mitogens, delayed hypersensitivity
    and serum IgG, IgM, and IgA concentrations. Other end-points examined
    included clinical signs of toxicity, haematology, clinical chemistry,
    body weight, and the weight of thymus, spleen and liver. There were no
    clinical signs of toxicity, no significant effects on body weight,
    organ weight, and no abnormal histopathology.

         TDCPP treatment induced minimal changes in immune functions and
    host susceptibility only at the highest dose tested. This was
    indicated by decreased (P < 0.05) lymphoproliferative responses to
    mitogens and increased tumour takes following tumour cell challenge,
    where there was an increase (P < 0.05) in the number of animals with
    tumours (8/10 versus 5/10 in control) but no change in the latency
    period (Luster et al., 1981).

    7.8.2  Neurotoxicity

    7.8.2.1  TCPP

         The neurotoxic potential of TCPP in adult white Leghorn hens was
    evaluated by Sprague et al. (1981). A group of 18 hens received an
    initial oral dose of 13.23 g TCPP/kg body weight followed by the same
    treatment 3 weeks later. The animals were sacrificed 3 weeks after the
    second dose. Loss of body weight, transient reduction in food
    consumption and one death were reported for the treated animals. Egg
    production ceased shortly after the first dose and there was severe
    loss of feathers. No behavioural or histological evidence for delayed
    neurotoxicity was seen.

    7.8.2.2  TDCPP

         Chickens exposed orally to TDCPP at doses of 0.6, 1.2, 2.4 or 4.8
    g/kg body weight per day for 5 days exhibited leg and wing weakness at
    doses of 1.2 g/kg or more and 100% mortality at 4.8 g/kg body weight,
    while lower dose levels caused leg and wing weakness (Ulsamer et al.,
    1980).

         White Leghorn hens, 12 months old, were orally exposed to 420 mg
    TDCPP/kg body weight per day for five consecutive days as specified in
    the procedure outlined in Navy MIL-H-19457B (SHIPS) protocol. After 21
    days of observation there were no signs of neurotoxicity, whereas
    TOCP, used as positive control, induced inability to walk,
    hypertension, ataxia and prostration (Bullock & Kamienski, 1972).

    8.  EFFECTS ON HUMANS

    8.1  TCPP

         No data concerning the effects of TCPP on humans are available.

    8.2  TDCPP

         A retrospective cohort study examined mortality in 289 workers
    employed in the manufacture of TDCPP. The cohort included all male
    workers employed for 3 months or more in a manufacturing plant in the
    USA during 1956-1977. The subjects were followed up until 1980.
    Overall mortality in the subjects was 75% of the normal expected for
    the male population in the USA. Three cases of cancer of the lung were
    identified (0.8 cases expected), but all three decedents were moderate
    to heavy smokers. Air samples were not taken at the time of exposure
    but breathing zone samples were taken from other area/job
    classifications in 1981 and all contained less than 0.4 µg/m3 (7 ppb)
    of TDCPP. The slight increase in the number of people with lung cancer
    was not statistically significant and its association with TDCPP
    exposure remains unclear due to the small size of this study, the
    absence of evidence of exposure to TDCPP, the effect of possible mixed
    exposure to other chemicals and other confounding factors including
    smoking history (Stauffer, 1983b).

         During 1981 workers at a TDCPP manufacturing plant in the USA had
    their health assessed in physical examinations. The health reports of
    93 potentially exposed workers from the factory were compared with the
    health reports of 31 non-exposed workers who were matched for age,
    alcohol consumption and smoking habits. The two groups of workers were
    comparable with regard to chest X-ray results. Exposed workers had a
    2-fold increase in the prevalence of "abnormal" electrocardiograms,
    but fewer exposed workers had a history of heart disease. There were
    no significant differences in any of the clinical chemistry parameters
    investigated. The prevalence of minor respiratory disease was slightly
    increased in exposed workers. The results of the study did not reveal
    any significantly increased morbidity in workers exposed to TDCPP
    (Stauffer, 1983a).

    9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

    9.1  Microorganisms

         The LC50 for bacteria from sewage sludge was reported to be
    > 10 000 mg/litre for TDCPP (Akzo, 1997b). No data were identified
    for TCPP.

    9.2  Aquatic organisms

    9.2.1  Algae

         The EC50 for growth has been reported to be 47 mg TCPP/litre for
    the green alga  Selenastrum capricornutum (Akzo, 1997c). The
    corresponding EC50 in the same alga for TDCPP was 12 mg/litre (Akzo,
    1997b). Exposure of the alga  Scenedesmus subspicatus to TDCPP
    (Amgard TDCP) at 10 mg/litre for 72 h had no effect on growth or
    biomass (SafePharm, 1994).

    9.2.2  Invertebrates

         The 48-h LC50 for  Daphnia was reported to be 131 mg/litre
    (measured concentration corresponding to 209 mg/litre nominal
    concentration) for TCPP as Antiblaze 80 under static conditions
    (Mobil, 1985a). A lower-observed-effect concentration (LOEC) (based on
    nominal concentrations) of 33.5 mg/litre was determined on the basis
    of behavioural observations.

         A 21-day reproduction test using  Daphnia magna showed a
    no-observed-effect concentration (NOEC) of 32 mg/litre for TCPP based
    on adult mortality. No reproductive effects were seen at lower
    concentrations (SafePharm, undated/b).

         A 48-h LC50 of 4.6 mg/litre for  Daphnia magna was reported
    using TDCPP (Amgard TDCP), together with a NOEC of 1.8 mg/litre
    (SafePharm, 1993a).

    9.2.3  Fish

         The 96-h LC50 for the fathead minnow  (Pimephales promelas) was
    51 mg/litre (based on measured concentrations; equivalent to 98
    mg/litre nominal concentration) under static conditions. The
    corresponding LC50 for bluegill sunfish  (Lepomis macrochirus) was
    180 mg/litre. The NOEC for both species was estimated to be 9.8
    mg/litre for TCPP as Antiblaze 80 (Mobil 1985b,c).

         The 96-h LC50 for rainbow trout  (Oncorhynchus mykiss) was 1.1
    mg/litre for TDCPP (Amgard TDCP) and the NOEC 0.56 mg/litre
    (SafePharm, 1993b). One out of 6 goldfish  (Carassius auratus) died
    after exposure to TDCPP at 1 mg/litre for 168 h and all fish died
    after exposure to 5 mg/litre (Eldefrawi et al., 1977). The 96-h LC50

    values for killifish  (Oryzias latipes) and goldfish
     (Carassius auratus) were reported to be 3.6 and 5.1 mg/litre,
    respectively, for a static exposure system. Killifish exposed to 3.5
    mg/litre for 24 h showed spinal deformities (Sasaki et al., 1981).

    9.3  Terrestrial organisms

         An acute toxicity test in artificial soil on TDCPP (Amgard TDCP)
    conducted according to OECD Guideline 207 on the earthworm
     Eisenia foetida gave an LC50 value after 14 h of 130 mg/kg soil and
    a NOEC of 100 mg/kg soil (SafePharm, 1996c). The corresponding values

    for TCPP (Amgard TMCP) were a 14-h LC50 of 97 mg/kg and a NOEC of 32
    mg/kg soil (SafePharm, 1996d).

    10.  EVALUATION

    10.1  TCPP

         Residues of TCPP are found infrequently and at low concentration
    in food items. TCPP has not been found in drinking-water. The low
    volatility of TCPP precludes significant exposure from air. Exposure
    to TCPP from these sources will not present an acute hazard to the
    general population. Although toxicological data from long-term studies
    are limited, because of low exposure to TCPP the risk of adverse
    health effects to the general population is negligible.

         TCPP has been tested at three trophic levels for acute exposure
    and two trophic levels for chronic exposure of organisms relevant to
    the environment. The lowest reported chronic NOEC is more than 3
    orders of magnitude higher than the highest reported concentration in
    sewage effluent (Fig. 1). There will be no adverse effects on the
    environment from the use of TCPP.

    10.2  TDCPP

         TDCPP has been tested at three trophic levels for acute exposure
    and two trophic levels for chronic exposure of organisms relevant to
    the environment. The lowest reported chronic NOEC is more than 3
    orders of magnitude higher than the highest reported concentration in
    sewage effluent and surface waters (Fig. 2). There will be no adverse
    effects on the environment from the use of TDCPP.

         Residues of TDCPP are found infrequently and at low concentration
    in food items and drinking-water. The low volatility of TDCPP
    precludes significant exposure from air. Exposure to TDCPP from these
    sources will not present an acute hazard to the general population.
    TDCPP was genotoxic in bacterial tests and in some  in vitro 
    mammalian cell tests. However, it has not been sufficiently tested for
    mutagenicity  in vivo. TDCPP has been found to be carcinogenic in
    rats. The mechanism of carcinogenicity has not be elucidated. The
    exposure level leading to the residues found in humans is unknown.
    Insufficient information, therefore, is available to estimate
    accurately human risk. However, because of the low exposure, the risk
    is expected to be low.


    FIGURE 2



    FIGURE 3


    11.  FURTHER RESEARCH

         Further investigations of the tumorigenicity of TDCPP and the
    mechanisms underlying it are needed.


    TRIS(2-CHLOROETHYL) PHOSPHATE

    A1.  SUMMARY

         Tris(2-chloroethyl) phosphate (TCEP) is a colourless to pale
    yellow liquid, which is used as a flame retardant mainly in the
    production of liquid unsaturated polyester resins. It is also used in
    textile back-coating formulations, PVC compounds, cellulose ester
    compounds and coatings. It is not volatile and its solubility in water
    is 8 g/litre. It is soluble in most organic solvents. Its log
    octanol/water partition coefficient is 1.7.

         Analysis is by GC/MS. Concentration of TCEP from water prior to
    analysis can be achieved using XAD resin or activated charcoal,
    followed by extraction with various organic solvents.

         TCEP is manufactured from phosphorus oxychloride and ethylene
    oxide. Production and use of TCEP has been in decline since the 1980s.
    Annual worldwide demand was less than 4000 tonnes in 1997.

         TCEP is not readily biodegradable. Bioconcentration factors are
    low and the half-life of elimination in fish is 0.7 h.

         Traces of TCEP have been detected in river water, seawater,
    drinking-water, sediment, biota (fish and shellfish) and in a few
    samples of various foods.

         In rats, oral doses of TCEP are absorbed and distributed around
    the body to various organs, particularly the liver and kidney, but
    also the brain. Metabolites in rats and mice include
    bis(2-chloroethyl) carboxymethyl phosphate; bis(2-chloroethyl)
    hydrogen phosphate; and bis(2-chloroethyl)-2-hydroxyethyl phosphate
    glucuronide. Excretion is rapid, nearly complete and mainly via the
    urine.

         TCEP is of low to moderate acute oral toxicity (oral LD50 in the
    rat = 1150 mg/kg body weight).

         In repeat dose studies, TCEP caused adverse effects on the brain
    (hippocampal lesions in rats), liver and kidneys. The NOEL was 22
    mg/kg body weight per day and the LOEL 44 mg/kg body weight per day
    for increased weights of liver and kidneys in rats.

         TCEP is non-irritant to skin and eyes, but has not been tested
    for sensitization potential.

         TCEP is not teratogenic. It adversely affects the fertility of
    male rats and mice.

         No conclusions can be drawn about the mutagenicity of TCEP as
     in vitro  test results were inconsistent and an  in vivo bone
    marrow micronucleus test gave equivocal results.

         TCEP causes benign and malignant tumours at various organ sites
    in rats and mice.

         A very high oral dose of TCEP caused some inhibition of plasma
    cholinesterase and brain neuropathy target esterase in hens, but did
    not cause delayed neurotoxicity. In rats, a high dose of TCEP caused
    convulsions, brain lesions and impaired performance in a water maze.

         The LC50/EC50 values for organisms in the environment range from
    90 to 5000 mg/litre.

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

    A2.1  Identity

    Chemical formula:        C6H12Cl3O4P

    Chemical structure:

    CHEMICAL STRUCTURE 3

    Relative molecular mass: 285.49

    CAS name:                tris(2-chloroethyl) phosphate

    CAS registry number:     115-96-8

    IUPAC name:              phosphoric acid, tris(2-chloroethyl) ester

    Synonyms:                phosphoric acid, tris(2-chloroethyl) ester;
                             tris(beta chloroethyl) phosphate;
                             tris(chloroethyl) phosphate;
                             tris(2-chloroethyl) phosphate; 
                             tris(2-chloroethyl) orthophosphate;
                             2-chloroethanol phosphate (3:1); ethanol, 
                             2-chlorophosphate (3:1)

    Trade names:             Celanese Celluflex CEF; Celluflex CEF;
                             Disflamoll TCA; Fyrol CEF; Fyrol CF; Genomoll
                             P; Niax 3CF; Niax Flame retardant 3
                             (nospaa)CF; Hosta flam UP 810; Amgard TCEP;
                             Tolgard TCEP; Antiblaze TCEP; Levagard EP;
                             Nuogard TCEP

    Common name:             TCEP

    A2.2  Physical and chemical properties

         TCEP is a clear, colourless to pale yellow liquid with a slight
    odour.

    Boiling point:           351°C (at 760 mmHg)

    Specific gravity:        1.425 at 20°C

    Solubility:              slightly soluble in water (8 g/litre at
                             20°C); soluble in aliphatic hydrocarbons,
                             polar organic solvents such as alcohols,
                             esters, ketones, and in aromatic hydrocarbons
                             and chlorinated hydrocarbons

    Vapour pressure:         < 10 mmHg at 25°C

    Flash point:             202°C (Pensky Martin closed cup)

    Stability:               Rapid decomposition occurs above 220°C;
                             stable to short-term exposure at 150°C.
                             The products of thermal decomposition are
                             carbon monoxide, hydrogen chloride,
                             2-chloroethane and dichloroethane.
                             Hydrolytic stability decreases with
                             increasing temperature and pressure or
                             extreme pH.

    Refractive index:        1.4721 at 20°C

    Viscosity:               34 cP at 25°C

    Henry's law constant:    3.29 × 10-6

     n-Octanol/water 
    partition coefficient 
    (log Pow):             1.7

    A2.3  Conversion factors

         1 mg/m3 = 11.68 ppm
         1 ppm = 0.0856 mg/m3

    A2.4  Analytical methods

         Selected methods for the analysis of TCEP are presented in Table
    7.


    
    Table 7.  Methods for the analysis of tris(2-chloroethyl) phosphate

                                                                                                                            
    Sample matrix       Sample preparation                     Assay procedurea     Limit of         References
                                                                                    detection
                                                                                                                            
    Air                 Sample on glass-fibre filter           GC/NPD               0.04-0.1 ng      Haraguchi et al. (1985)
                        or XAD-7 resin;
                        prefractionate on
                        silica gel column

    Water               Extract with dichloromethane;          GC/MS                10 ng/litre      Ishikawa et al. (1985a);
                        dry (anhydrous sodium sulfate);                                              Ishikawa & Baba (1988)
                        concentrate                                                                  

                        Extract with dichloromethane           GC/FPD               2 ng/litre       Burchill et al. (1983)

    Drinking-water      Adsorb on XAD resin cartridge;         GC/NPD               0.3 ng/litreb    LeBel et al. (1981)
                        extract with dichloromethane;
                        dry (anhydrous sodium sulfate);
                        concentrate                            

                        Adsorb on XAD resin cartridge;         GC/MS and GC/NPD     0.1 ng/litre     LeBel et al. (1987)
                        elute with acetone/ hexane; dry
                        (anhydrous sodium sulfate);
                        concentrate; extract (dichloromethane)


    Sediment            Extract with acetone; filter; add      GC/MS                5 ng/g           Ishikawa et al. (1985a)
                        filtrate to purified water, extract
                        with dichloromethane; dry (anhydrous
                        sodium sulfate); concentrate           

    Table 7.  Methods for the analysis of tris(2-chloroethyl) phosphate

                                                                                                                            
    Sample matrix       Sample preparation                     Assay procedurea     Limit of         References
                                                                                    detection
                                                                                                                            
    Seawater, fish,
    sea sediment        Extract with acetonitrile and          GC/MS                1-5 ng/g         Kenmotsu et al. (1980b)
                        dichloromethane; adsorb; extract
                        on activated charcoal column;                               (fish)
                        extract with sulfuric acid; wash
                        with sodium hydroxide; purify by
                        Florisil chromatography                GC/FPD

                                                                                                                            

    a    GC/NPD = gas chromatography/nitrogen phosphorus detection;
         GC/MS = gas chromatography/ mass spectrometry;
         GC/FPD = gas chromatography/flame photometric detection.

    b    By direct fortification, in the concentration range of 1 up to 100 ng/litre, a recovery of 90% was obtained.

    

    A3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    A3.1  Natural occurrence

         TCEP is not a natural product.

    A3.2  Anthropogenic sources

    A3.2.1  Production and processes

         TCEP production and use has been in rapid decline since the 1980s
    as its historic use in rigid and flexible polyurethane foams and
    systems has been substituted by other flame retardants.

         Global TCEP consumption peaked at over 9000 tonnes in 1989 but
    had declined to below 4000 tonnes by 1997.

         All commercial TCEP has been produced by the reaction of
    phosphorus oxychloride with ethylene oxide followed by subsequent
    purification (personal communication by EFRA to IPCS, 1998).

    A3.2.2  Uses

         Historically TCEP was used in polyurethane foams and systems,
    mainly for rigid foam but with minor use in flexible polyurethane.

         TCEP is currently mainly used in the production of liquid
    unsaturated polyester resins. It is also used in textile back-coating
    formulations, PVC compounds, cellulose ester compounds and coatings.

         TCEP is not recommended by producers for use as a flame retardant
    additive for use in textiles nor for use in block polyurethane foams
    because of the probability of its decomposition (personal
    communication by EFRA to IPCS, 1998).

    A4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

    A4.1  Transport and distribution between media

         The Henry's law constant has been estimated to be 3.29 × 10-6,
    indicating very slow volatilization from surface waters. Estimates for
    Koc range from 34 to 141, indicating low adsorption to soil or
    aquatic sediment and, therefore, high mobility of TCEP. It can be
    assumed that TCEP released to the environment would, therefore, be
    predominantly in the water compartment (National Medical Library,
    1998).

    A4.2  Transformation

    A4.2.1  Abiotic

         TCEP hydrolyses slowly in water. Hydrolysis increases with
    temperature and at the extremes of the pH range (personal
    communication by Courtaulds to IPCS).

    A4.2.2  Biotic

         TCEP has been evaluated as "inherently biodegradable" in tests
    conducted aerobically under OECD guidelines (ECB, 1995).

         There was virtually no uptake of TCEP into killifish
     (Oryzias latipes) or goldfish  (Carassius auratus) over a 100-h
    period and, consequently, little metabolism of the compound (Sasaki et
    al., 1981).

    A4.3  Bioaccumulation

         Bioconcentration factors (BCF) of 1.4-2.2 were measured for
    killifish  (Oryzias latipes) exposed to TCEP concentrations of
    0.3-8.5 mg/litre for 96 h. BCF values for the same species, exposed
    for 5 or 11 days to concentrations of 12.7 or 2.3 mg/litre,
    respectively, in continuous-flow systems, were 1.1 and 1.3,
    respectively. The half-life for elimination in clean water following
    continuous-flow exposure was 0.7 h (Sasaki et al., 1982).

         Goldfish  (Carassius auratus) exposed to TCEP at 4 mg/litre for
    96 h under static conditions showed a BCF of 0.9 (Sasaki et al.,
    1981).

    A5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    A5.1  Environmental levels

    A5.1.1  Air

         No data on the levels of TCEP in air are available.

    A5.1.2  Water

    A5.1.2.1  Surface water

         Water samples were analysed in 1975 and 1978 in Japan for TCEP.
    In 1975, 8/40 water samples contained 0.1-0.34 µg TCEP/litre (limit of
    determination, 0.013-0.1 µg/litre). In 1978 the values were 0.09
    µg/litre (limit of determination, 0.01-1 µg/litre) for 3/114 water
    samples (Environmental Agency Japan, 1983, 1987).

         A 1980 survey around Kitakyushu, Japan, identified TCEP in 14/16
    samples at levels in the range of 0.017-0.347 µg/litre in river water
    and in 9/9 samples (0.014-0.060 µg/litre) of seawater (limit of
    detection 10 ng/litre) (Ishikawa et al., 1985a). TCEP was also
    detected in river water and sewage sludge from the Okayama area
    (Kenmochi et al., 1981).

         In Canadian rivers at 13 sites, TCEP was found at a mean
    concentration of 0.0087 µg/litre. Water from the Great Lakes contained
    TCEP at a mean concentration of 0.0017 µg/litre at 10 Canadian sites
    (US EPA, 1988).

         TCEP was detected in water from the River Rhine at Lobith in the
    Netherlands at 1 µg/litre in 1979 (Zoeteman, 1980) and at levels from
    0.16 to 0.35 µg/litre in 1986 (Brauch & Kühn, 1988). The compound was
    also found in the Dutch river Waal in 1974 (Meijers & van der Leer,
    1976). In Italy, Galassi (1991) reported concentration ranging from
    < 10 up to 293 ng/litre at one river station (River Po) and two
    marine stations in the Adriatic Sea in sample collected at three
    periods in 1988. Barcelo et al. (1990) identified TCEP in a Spanish
    river (Llobregat) in May and June 1988 at concentrations of 0.4 and
    0.3 µg/litre, respectively.

         TCEP was detected at levels of up to 5.5 µg/litre in raw water
    samples from the River Trent, United Kingdom, in 1979-1980 (Burchill
    et al., 1983).

    A5.1.2.2  Drinking-water

         In a study of drinking-water from surface supplies in Northern
    Italy, Galassi et al. (1989) found TCEP at concentrations between 0.01
    µg/litre and 0.04 µg/litre.

         TCEP has also been identified in drinking-water from Canada;
    0.0003-0.0092 µg/litre in six eastern Ontario treatment plants in 1978
    (LeBel et al., 1981); 0.0002-0.052 µg/litre in 22 of 29 municipalities
    in 1979 (Williams & LeBel, 1981); 0.0003-0.0138 µg/litre in 11 of 12
    Great Lakes municipalities in 1980 (Williams et al., 1982); and
    0.003-0.0096 µg/litre in 1982 and 1983 in four out of five Great Lakes
    areas (LeBel et al., 1987).

         Drinking-water was collected at six Great Lakes water treatment
    plants from Eastern Ontario, Canada and analysed for TCEP. From each
    plant two samples were taken. The concentrations ranged from 0.6 to
    3.7 ng/litre as determined by GC/MS; determination by GC/NPD showed
    concentrations of 3.0 up to 9.6 ng/litre (LeBel et al., 1987).

         In the USA, 15 pooled drinking-water samples contained an average
    of 0.0026 µg/litre (US EPA, 1988).

         Drinking-water was collected in Japan over a period of 1 year and
    a mean concentration of 0.0174 (range 0.002-0.060) µg/litre was found
    (Adachi et al., 1984) (no details).

         In a survey of infant and toddler dietary intake conducted in the
    USA from October 1978 to September 1979, 1 sample of drinking-water
    containing 0.3 µg TCEP/litre was identified (Gartrell et al., 1985a).

    A5.1.2.3  Effluents

         Industrial and domestic wastewater effluents in Kitakyushu,
    Japan, contained detectable levels of TCEP (limit of determination,
    0.03 µg/litre). Concentrations were not detectable (ND) to 0.087
    µg/litre at 3 food factories, 0.043-0.74 µg/litre at 8 chemical
    factories, ND to 14.0 µg/litre at 5 steel factories, ND to 11.0
    µg/litre at 6 other industrial sites, and 0.5-1.2 µg/litre in effluent
    (0.54 to 1.2 in influent) at 5 sewage treatment plants. Concentrations
    in river water samples ranged from ND to 0.35 µg/litre (limit of
    determination 0.01 µg/litre) (Ishikawa et al., 1985b).

    A5.1.2.4  Leachates

         Oman & Hynning (1993) using GC-MS (detection limit 1-10 µ/litre)
    showed the presence of TCEP in one sample of a municipal landfill
    leachate.

         TCEP was identified at a mean concentration of 0.57 µg/litre in
    two monitoring wells adjacent to a municipal wastewater infiltration
    system at Fort Devens (near Boston), Massachusetts, USA (Bedient et
    al., 1983).

    A5.2  Sediment

         Sediment samples were analysed for TCEP in 1975 and 1978 in
    Japan. In 1975, 1/20 sediment samples contained 0.07 mg/kg (limit of
    determination, 0.025 mg/kg). In 1978, 114 sediment samples did not
    contain TCEP (limit of determination, 0.001-0.05 mg/kg) (Environmental
    Agency Japan, 1983, 1987).

         A survey conducted in Japan in 1977 and 1978 did not detect TCEP
    in 99 samples of sediment from rivers, estuaries or the sea. In 1980,
    however, 5/6 samples taken around Kitakyushu showed TCEP at
    concentrations of 0.013-0.028 µg/kg sediment (limit of detection 5
    ng/kg) (Ishikawa et al., 1985a).

    A5.3  Biota and food

    A5.3.1  Biota

         Fish samples collected in Japan in 1975 and 1978 were analysed.
    In 1975 20 fish samples did not contain TCEP (limit of determination
    0.025 mg/kg), but in 1978 9/93 fish samples contained 0.005-0.14 mg/kg
    (limit of determination 0.001-0.05 mg/kg) (Environmental Agency Japan,
    1983, 1987).

         TCEP was found at levels ranging between < 0.005 and 0.019 mg/kg
    in fish and shellfish sampled in the Okayama area (Kenmochi et al.,
    1981).

    A5.3.2  Food

         When fruit and fruit juices were sampled for TCEP from ten cities
    in the USA in 1979, one contained 0.002 mg/kg (Gartrell et al.,
    1985a,b). In oil and fat from toddler foods sampled from 1980 to 1982
    in 13 different US cities, TCEP was found in one sample at a
    concentration of 0.0385 mg/kg. Over the same period, samples of meat,
    fish and poultry for adult consumption were collected in 27 different
    US cities. TCEP was found in one sample at a concentration of 0.0067
    mg/kg (Gartrell et al., 1986).

         The daily intake of TCEP by infants and toddlers in 1978, 1979,
    1980 and 1981/1982 was ND, 0.016, 0.004 and ND µg/kg body weight for
    infants and ND, 0.009, ND and 0.028 µg/kg body weight for toddlers
    (Gartrell et al., 1986).

         In another survey of infant and toddler diets over the period
    October 1979 to September 1980, TCEP was found in 1 sample of
    composite fruit and fruit juice at a concentration of 0.2 µg/litre. It
    was not detected in other foods tested (Gartrell et al., 1985b).

    A6.  KINETICS AND METABOLISM IN LABORATORY ANIMALS

    A6.1  Mice

         In a study on male B6C3F1 mice, more than 70% of an oral dose of
    175 mg 14C-labelled TCEP/kg body weight was excreted in urine within
    8 h. Identified urinary metabolites of TCEP in mice were
    bis(2-chloroethyl) carboxymethyl phosphate, bis(2-chloroethyl)
    hydrogen phosphate and bis(2-chloroethyl) 2-hydroxyethyl phosphate
    glucuronide (Burka et al., 1991).

    A6.2  Rats

         Male and female Fischer-344 rats were gavaged with 14C-labelled
    TCEP at 0, 175, 350 or 700 mg/kg body weight. Plasma concentrations of
    TCEP and its metabolites in rats dosed at 175 mg/kg peaked by 30 min.
    Concentrations were higher in females at the peak but by 4 h there
    were no sex differences. TCEP concentrations in the hippocampus, the
    site of the major lesions, were no higher than in other brain tissues
    and there were no sex differences (Herr et al., 1991).

         Minegishi et al. (1988) studied the distribution and excretion of
    14C-labelled TCEP in 5-week-old male Wistar rats orally dosed with 50
    µmol/kg body weight. The label was concentrated by various tissues,
    especially the liver and kidney, during the first 6 h following
    administration and then rapidly decreased. Most of the label was
    excreted by 24 h and by 168 h less than 1% remained in tissues. Urine
    accounted for 96%, faeces for 6%, and expired air for 2% of the label.
    Rapid urinary excretion was confirmed by Burka et al. (1991), who
    found 40% of the label in urine within 8 h after a dose of 175 mg 14C
    TCEP/kg body weight in male and female rats. They identified the same
    urinary metabolites as those listed above for mice.

         Chapman et al. (1991) found that the hepatic microsomal fraction
    from male rats, but not female rats, metabolized TCEP. Liver slices
    and blood plasma, however, of both sexes metabolized the compound,
    demonstrating that at least part of the metabolism is extramicrosomal.
    Liver slices and microsomes from both male and female humans
    metabolized TCEP, but plasma and whole blood did not.

         Urinary elimination of TCEP in rats was not increased by 9 daily
    doses of 175 mg/kg, indicating that TCEP is not capable of inducing
    its own metabolism (Burka et al., 1991).

    A7.  EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

    A7.1  Single exposure

         The acute oral LD50 for TCEP was 1.23 g/kg body weight following
    a 30-day observation period in rats. An oral LD50 of 0.5 g/kg body
    weight was found in a second study with male rats. Treated rats died
    within 24 h and showed spasmodic contractions and acute depressions.
    The LD50 values for female rats were reported to be 0.79, 0.50 and
    0.43 g/kg body weight with three different lots of the chemical
    (Ulsamer et al., 1980). Smyth et al. (1951) reported an LD50 of 1.41
    g/kg body weight in rats.

         In a study conducted according to OECD Test Guidelines 401,
    groups of 5 male and 5 female Sprague-Dawley rats received 800, 1000
    or 1260 mg/kg body weight by oral gavage. One female receiving 1000
    mg/kg died on day 2 and 4/5 males and 4/5 females receiving 1260 mg/kg
    body weight died by day 4. The LD50 was calculated to be 1150 mg/kg
    body weight. Clinical signs of toxicity included piloerection and
    increased salivation amongst all animals; hunched posture, abnormal
    gait, lethargy, laboured respiration, ptosis and pale extremities were
    observed amongst all animals receiving 1000 and 1260 mg/kg body
    weight. No clinical signs of toxicity were observed in surviving
    animals from day 4 onwards. No microscopic pathology abnormalities
    were seen amongst decedent animals or those killed on completion of
    the 14-day observation period (Kynoch & Denton, 1990)

         In an earlier study conducted at the same location, male and
    female CD rats (5 animals per group) received 2.5, 3.2, 4.0 and 5.0
    g/kg body weight by oral gavage. Signs of reaction to treatment
    observed in all animals within one half-hour of dosing were
    piloerection, hunched posture, abnormal gait and increased salivation.
    The calculated LD50 was 3.6 g/kg body weight for males and females
    combined (Gardner, 1987).

    A7.2  Short-term exposure

    A7.2.1  Mice

         Groups of five B6C3F1 mice of each sex were gavaged with 0, 44,
    88, 175, 350 or 700 mg TCEP/kg body weight in corn oil 5 days/week for
    2 weeks. Mice given 350 and 700 mg/kg exhibited ataxia and convulsive
    movements during the first 3 days of dosing. No changes of body weight
    gain, absolute and relative organ weight or histopathological
    abnormalities were observed (US NTP, 1990; Matthews et al., 1990).

    A7.2.2  Rats

         A 30-day feeding study, in which up to 0.5% of TCEP was given in
    the diet to male and female rats, resulted in no adverse effects on
    growth, appearance and behaviour, liver and kidney weights or changes
    in pathological examinations of survivors (Ulsamer et al., 1980).

         Groups of five rats of each sex of the strain F-344/N were
    administered by gavage 0, 22, 44, 88, 175 or 350 mg TCEP/kg body
    weight 5 days/week for 2 weeks. No difference in body weight gain was
    found in the treated animals versus controls. The mean absolute and
    relative kidney weights of the males given 175 and 350 mg/kg body
    weight were increased (10% and 12%, respectively). Liver weights of
    the high-dose females were also significantly increased (17%). Serum
    cholinesterase activity was not reduced in males, but was decreased by
    18% and 20% in female at 175 and 350 mg/kg body weight. No gross or
    histopathological abnormalities were found (US NTP, 1990; Matthews et
    al., 1990).

    A7.3  Long-term exposure

    A7.3.1  Mice

         Groups of 10 male and 10 female B6C3F1 mice (9-10 weeks old)
    were administered by gavage 0, 44, 88, 175, 350 or 700 TCEP mg/kg body
    weight in corn oil 5 days/week for 16 weeks. During week 4, the two
    highest doses were incorrectly prepared and administered for the first
    3 days of this week. The mice of the two highest dose levels received
    double the target levels. No difference in body weight gain or serum
    cholinesterase activity was found between the treated groups and the
    control group. The absolute liver weights were significantly increased
    (P <0.01) in females receiving 175, 375 and 700 mg/kg body weight
    (14%, 20% and 13%, respectively) and in males receiving 700 mg/kg
    (5%). The liver-to-body weight ratios, however, were not increased.
    Male mice in the 175, 350 and 700 mg/kg body weight groups had
    significantly (P <0.01) reduced absolute kidney weights (5%, 10%
    and 20%, respectively). The kidney-to-body weight ratio, however, was
    not affected. No gross abnormalities were observed, but epithelial
    cells with enlarged nuclei (mild cytomegaly and karyomegaly) were
    observed in the renal tubules in all animals given 700 mg/kg body
    weight. The lesions were observed primarily in the proximal convoluted
    tubules of the inner cortex and outer strip of the outer medulla and
    to a lesser extent in the straight portion of the loops of Henle in
    the medulla (US NTP, 1990; Matthews et al., 1990).

    A7.3.2  Rats

         Groups of 10 male and 10 female F-344/N rats (8-9 weeks old) were
    administered 0, 22, 44, 88, 175 or 350 TCEP mg/kg body weight in corn
    oil by gavage, 5 days/week for 16 weeks (females) and 18 weeks
    (males). The animals with the two highest dose levels received a
    double dose for 3 days in week 4. Consequently two females of each
    dose level died and a few other animals showed signs of intoxication;
    ataxia, excessive salivation, gasping and convulsions. During the
    16-week exposure additional animals died in these two groups; the
    deaths of one male of the 175 mg/kg body weight group and 4 males and
    3 females of the 350 mg/kg body weight group were attributed to
    chemical toxicity. Body weight was comparable with the controls. The
    relative liver and kidney weights were significantly (P < 0.01)
    increased in the high-dose males and in females receiving 44 to 350

    mg/kg body weight. In males given 350 mg/kg per day the increases in
    relative liver and kidney weights were 22% and 26%, respectively. In
    females the increases in relative liver weight were 13%, 13%, 19% and
    50% in the 44, 88, 175 and 350 mg/kg body weight groups, respectively;
    the increases in relative kidney weight were 8%, 11%, 11% and 22% in
    the 44, 88, 175 and 350 mg/kg groups, respectively.

         Cholinesterase activity determined in serum at necropsy was 75%
    and 59% of the control value at 175 and 350 mg/kg body weight,
    respectively, in female rats, but was not reduced in males. No gross
    lesions were observed, but necrosis of neurons, mainly of the
    dorsomedial portion of the pyramidal row of the hippocampus, was
    observed in 10/10 females and 2/10 males of the 350 mg/kg group and in
    8/10 females of the 175 mg/kg group. Mineral deposits were present in
    the affected areas of the brain. In the high-dose females, neuronal
    necrosis was seen in the thalamus. Based on the increases in relative
    liver and kidney weights in females, the NOEL in this study was 22
    mg/kg per day and the LOEL 44 mg/kg per day (US NTP, 1990; Matthews et
    al., 1990)

    A7.4  Skin and eye irritation or sensitization

    A7.4.1  Skin irritation

         In a study conducted according to modern protocol standards, 0.5
    ml TCEP was applied to the skin of three New Zealand white rabbits
    under a semi-occlusive dressing for 4 h. Slight erythema (grade 1) was
    observed in each animal on day 1 only. Thereafter there were no signs
    of skin irritation (Liggett & McRae, 1991c).

    A7.4.2  Eye irritation

         In a study conducted according to modern protocol standards, 0.1
    ml TCEP was instilled into the eye of each of 3 New Zealand white
    rabbits (Liggett & McRae, 1991d). Slight conjunctival redness (grade
    1) was observed in each animal on day 1 and in one animal on day 2.
    Thereafter, there were no signs of eye irritation.

    A7.4.3  Sensitization

         No data on the possible sensitizing effects of TCEP are
    available.

    A7.5  Reproductive toxicity, embryotoxicity and teratogenicity

    A7.5.1  Developmental toxicity

         Development toxicity was tested by the Chernoff/Kavlock
    preliminary development toxicity test by treating pregnant CD-1 mice
    on gestation days 6-15 at an overtly maternally toxic dose of TCEP.
    The dose used was 940 mg/kg per day. The depression in maternal body

    weight gain was 12%. There were no significant adverse effects on
    maternal mortality, pup survival rate, litter size, weight gain of
    pups, or birth weight of pups (Hardin, 1987; Hardin et al., 1987).

         Wistar rats were given by gavage 50, 100 or 200 mg TCEP/kg body
    weight suspended in olive oil on days 7-15 of gestation. No change in
    maternal body weight gain, food consumption or general appearance was
    found in the low- and mid-dose groups. In the high-dose group,
    maternal food consumption was markedly suppressed; piloerection and
    general weakness occurred and 7/30 dams died. On day 20 of gestation,
    no increase in fetal death or malformations attributable to treatment
    were observed in any group. There was some increase (not statistically
    significant) in the incidence of supernumerary cervical and lumbar
    ribs in the high-dose group (this end-point is considered a variation
    not a malformation). Postnatal examination revealed normal development
    in the offspring of all groups; no abnormalities on morphological
    examination or in functional behaviour tests (open field, water maze,
    rota rod, inclined plane test, pain reflex or Preyer's reflex) were
    found (Kawashima et al., 1983a,b).

    A7.5.2  Fertility

         In a study in B6C3F1 mice, animals were dosed by gavage at dose
    levels of 44, 175 and 700 mg/kg body weight for 13 weeks. In the
    males, no effects were noted regarding body weight, absolute and
    relative cauda weights, relative epididymis weight, motility or sperm
    concentration. The absolute epididymis weight and absolute and
    relative testes weights were decreased and an increase in the number
    of sperm with abnormal morphology were noted. In the females, no
    increase in estrous cycle length was noted in any of the treatment
    groups (Morrissey et al., 1988).

         TCEP was tested for its effects on fertility and reproduction in
    Swiss CD-1 mice according to a continuous breeding protocol. Animals
    were exposed via gavage to doses of 175, 350 and 700 mg/kg body
    weight. Males and females (F0 generation) were exposed daily for 7
    days pre-cohabitation and 98 days cohabitation periods. In the F0
    generation, TCEP decreased the number of litters per pair and the
    number of live pups per litter. Both sexes were affected, but the
    males were relatively more sensitive. All sperm end-points
    (concentration, motility and percentage of abnormal sperm) were
    adversely affected. Due to poor fertility in the 700 mg/kg body weight
    per day group, only one F0 pair delivered a litter. None of these
    pups survived to postnatal day 4. The data indicated reduced fertility
    due to TCEP exposure at doses of 175 mg/kg body weight or more (Gulati
    et al., 1991).

         In a study on F-344 rats, animals were dosed by gavage at levels
    of 22, 88 and 175 mg/kg body weight for 13 weeks. In the males no
    effects were noted on body weight, absolute and relative cauda
    weights, absolute and relative epididymal weights, absolute and
    relative testes weights, sperm concentration, and number of abnormal

 

    sperm. However, sperm motility was reduced. In the females, no
    increase in estrous cycle length was noted in any of the treatment
    groups (Morrissey et al., 1988).

         In an inhalation study using whole body exposure, male rats
    (strain and group size not specified) were continuously exposed to 0.5
    or 1.5 mg TCEP/m3 for 4 months. Testicular toxicity was seen at both
    dose levels, with most severe effects at the highest dose. There were
    decreased sperm counts, decreased sperm mortility and abnormal sperm
    morphology. Histology of the testes showed an increased number of
    spermatogonia but decreased numbers of sperm in the later stages of
    development. When the treated males were mated, there was decreased
    fertility at the 1.5 mg/m3 dose, with increased pre- and
    post-implantation loss, and litter sizes were decreased (Shepel'skaya
    & Dyshinevich, 1981).

    A7.6  Mutagenicity and related end-points

    A7.6.1  In vitro studies

         TCEP was found not to be mutagenic in  Salmonella typhimurium 
    strains TA1535, TA1537, TA1538, TA98 and TA100 at dose levels up to 5
    mg/plate, both with and without metabolic activation with Aroclor
    1254-induced rat liver S9 (Simmon et al., 1977).

         Negative results were obtained when TCEP was tested at doses of
    3.3, 10, 33, 100 and 333 µg/plate in liquid pre-incubation assays
    employing  Salmonella typhimurium TA1535, TA1537, TA98 and TA100,
    both with and without a metabolic system from Aroclor 1254-induced rat
    liver or Syrian hamster liver S9 (Haworth et al., 1983).

         In contrast, TCEP at dose levels of 285, 755, 2850 and 8550
    µg/plate produced a dose-related increase in mutations (with a maximum
    7.6-fold increase of revertants over the control at 2850 µg/plate) in
     Salmonella typhimurium TA1535 in the presence but not in the absence
    of metabolic system from Kanechlor 500-induced Wistar rat liver S9.
    The same doses produced a dose-related increase in mutations in TA100
    with a maximum 1.8-fold increase in revertants at 2850 µg/plate
    (Nakamura et al., 1979).

         TCEP (5 to 1600 µg/ml) was tested for CA and SCE in Chinese
    hamster ovary cells both with and without an exogenous metabolism
    system from liver of Sprague-Dawley rats induced by Aroclor 1254. TCEP
    did not induce CAs. The results of the SCE test were regarded as
    equivocal because a positive response was seen only in one trial with
    S9 fraction at 500 and 1600 µg/ml but was not observed in a repeated
    trial under the same conditions (Galloway et al., 1987).

         The frequency of 6-thioguanine-resistant mutants using V79 cells
    without S9 was determined at 0, 500, 1000 and 2000 µg/ml. TCEP did not
    significantly increase the number of 6-thioguanine-resistant mutants
    (Sala et al., 1982).

         TCEP was tested for SCEs in V79 cells in two separate experiments
    at concentration levels of 343, 490, 700 and 1000 µg/ml (exp. I) and
    2000 and 3000 (exp. II). In the first experiment, a statistical
    increase in the number of SCEs was noted at 700 and 1000 µg/ml with S9
    (3-methylcholanthrene-induced rat liver) and at 700 µg/ml without S9
    (1000 µg/ml was not tested without S9). In the second experiment, TCEP
    was only tested without S9 and was positive at both concentrations
    tested. However, the 3000 µg/ml concentration caused cytotoxicity
    (Sala et al., 1982).

         In the presence of S9 from livers of Wistar rats induced with
    methylcholanthrene, TCEP at 900 and 1500 µg/ml gave a negative result
    in a transformation assay using C3H10T1/2 cells.

         A high level of transformation of Syrian hamster embryo cells was
    observed with TCEP at concentrations of 400 and 500 µg/ml. The two
    highest dose concentrations (600 and 800 µg/ml) were toxic and no
    transformation was seen at these concentrations (Sala et al., 1982).

         TCEP caused a dose-related (343-1000 µg/ml) increase in the
    incidence of sister chromatid exchange in the Chinese hamster V79 cell
    line, but doses from 500 to 2000 µg/ml did not induce mutations at the
    HPRT locus in the same cell line (Sala et al., 1982).

    A7.6.2  In vivo studies

         TCEP was administered intraperitoneally at dose levels of 63.5,
    125, 250 mg/kg body weight to groups of male and female Chinese
    hamsters. There was no clear dose-dependent increase in the number of
    micronuclei isolated from bone marrow cells. However, in some of the
    dose groups an approximate doubling in the number of micronuclei was
    noted (females at 62.5 and 125 mg/kg body weight, and males at 250
    mg/kg body weight) (Sala et al., 1982).

         TCEP gave a negative response in the w/w+ bioassay for somatic
    cell damage in  Drosophila melanogaster (Vogel & Nivard, 1993).

    A7.7  Carcinogenicity

    A7.7.1  Oral

    A7.7.1.1  Mice

         Groups of 50 male and 50 female Slc:ddy mice received
    approximately 0, 12, 60, 300 or 1500 mg/kg body weight per day by
    dietary administration (assuming 30 g body weight and 3 g/day food
    consumption) for 18 months (Takada et al., 1989). Distension of the
    abdomen was noted in males receiving 1500 mg/kg per day from week 65.
    Reduced survival was noted in males and females receiving 1500 mg/kg
    per day (approximately 40% survival compared to around 65% survival in
    controls). A marked reduction in body weight gain was noted in males
    and females receiving 1500 mg/kg per day (approximately 60% lower than

    the control value). Other groups were not adversely affected, and
    there were no changes in food consumption. There were no significant
    changes in haematological parameters recorded at termination.
    Histologically, hyperplasia, hypertrophy and karyomegaly were observed
    in the kidney of all treated animals although the incidence and
    severity of effects in the kidneys was unclear. In addition, cysts of
    the kidneys, necrosis and interstitial fibrosis were reported only
    amongst animals given 1500 mg/kg per day, although no further details
    were available. An increased incidence of renal adenomas was noted in
    males (0/50, 0/49, 0/49, 2/49, 9/50) and females (0/49, 0/49, 0/50,
    0/49, 2/50). In addition, there was an increased incidence of renal
    carcinomas in males (2/50, 0/49, 2/49, 3/47, 32/50) and females (1/50
    at 1500 mg/kg per day and zero in all other groups). In the liver,
    there was an increased incidence of adenomas in males and females
    (3/50, 4/49, 3/49, 10/47, 16/50 in males, and 2/50 in females at 1500
    mg/kg per day with zero in all other groups). In addition, there was a
    slight, but not dose-related, increase in the incidence of liver
    carcinomas in males (1/50, 1/49, 4/49, 2/47, 3/50). A slight increase
    in the incidence of forestomach papillomas and carcinomas was reported
    in treated males and females.

         Groups of 60 males and 60 females B6C3F1 mice received 0, 175 or
    350 mg/kg 5 days/week by gavage for 103 weeks (US NTP, 1990). An
    interim sacrifice was performed on groups of 10 males and 10 females.
    At 66 weeks, there were no effects seen on body weight gain,
    haematology or clinical chemistry. At 103 weeks there were no adverse
    effects on survival or body weight gain. Non-neoplastic lesions were
    seen in the kidney; karyomegaly in the proximal convoluted tubules
    (2/50, 16/50 and 39/50 in males and 0/50, 5/49 and 44/50 in females).
    In the liver, an increased incidence of eosinophilic foci was observed
    in males (0/50, 3/50, 8/50). Neoplastic lesions in the kidney were
    observed: adenoma, 1/50, 0/50 and 1/50 in males and 0/50, 1/49 and
    0/50 in females; adenocarcinoma, 0/50, 0/50 and 1/50 in males. In the
    liver of males an increased incidence of adenomas was seen: 20/50,
    18/50 and 28/50. In addition, there was a slight increase in the
    incidence of Harderian gland adenomas in females.

    A7.7.1.2  Rats

         Groups of 60 males and 60 females F-344 rats received 0, 44 or 88
    mg/kg 5 days/week by gavage for 103 weeks (US NTP, 1990). An interim
    sacrifice was performed on groups of 10 males and 10 females. At 66
    weeks, there were no adverse effects seen on body weight gain or
    haematology. There were unquantified decreases in serum alkaline
    phosphatase and alanine aminotransferase in females receiving 88 mg/kg
    per day. Slight increases in liver and kidney weights were recorded in
    males at 88 mg/kg per day (14% and 20%, respectively, greater than
    controls). Also observed at this time point were renal tubule adenomas
    in one male receiving 88 mg/kg per day and local necrosis and
    accumulation of inflammatory cells in the cerebrum and thalamus of the
    brains of 3/10 females given 88 mg/kg per day.

         At 103 weeks there were no adverse effects on body weight gain
    and no clinical signs of toxicity. Reduced survival was noted in males
    and females at 88 mg/kg per day (males 51% survival compared to 78% in
    controls; females 37% compared to 66% in controls). No organ weight
    data were presented for this time point. Non-neoplastic findings in
    the kidneys were hyperplasia: 0/50, 2/50 and 24/50 in males and 0/50,
    3/50, 16/50 in females.

         A marked increase in the incidence of degenerative lesions of the
    brain stem and cerebrum (thalamus, hypothalamus and basal ganglia)
    (such as gliosis, haemorrhage, necrosis and mineralization) was noted
    at 88 mg/kg per day (occurring in approximately 40% of females at 88
    mg/kg per day compared to 2% of controls).

         Neoplastic lesions were observed in the kidney; the frequency of
    adenomas was 1/50, 5/50 and 24/50 in males and 0/50, 2/50, 5/50 in
    females. In the brain, benign granular cell tumours were observed in
    3/50 males at 88 mg/kg per day only. There were no treatment-related
    increases in the incidence of tumours in the brain of females. A
    slight increase in the incidence of thyroid follicular adenomas was
    noted in males (1/50, 2/48, 3/50), and of carcinomas in males and
    females (0/50, 0/48, 2/50 in males; 0/50, 2/50, 3/50 in females).

         There were increased occurrences of mononuclear cell leukaemia in
    males (5/50, 14/50, 13/50) and in females (14/50, 16/50, 20/50). These
    occurrences, however, were within the range of historical controls
    (2-44%).

    A7.7.2  Dermal

    A7.7.2.1  Mice

         There was no significant increase in tumours in female Slc/ddy
    mice whose shaved skin was treated twice weekly for 79 weeks with
    ethanol solutions containing 5% or 50% of TCEP. However, the amount of
    the solution applied to skin was not reported (Takada et al., 1991).

         An  in vivo short-term skin test for sebaceous gland suppression
    and the induction of epidermal hyperplasia was carried out. Groups of
    25 Swiss mice (45 days of age) received dorsal applications on days 1,
    3 and 5 of TCEP at 0, 31.9, 53.2 and 74.5 mg (total dose applied in
    three applications). Benzo (a)pyrene was used as positive control.
    TCEP did not suppress the sebaceous gland and did not induce
    hyperplasia (Sala et al., 1982).

         Groups of Swiss mice were used to test TCEP for skin initiation
    and/or promoter activity. TCEP showed no significant complete
    carcinogenic, initiating or promoter activity on mouse skin (Sala et
    al., 1982). A working group of IARC (1990) noted that the promoting
    activity and complete carcinogenicity of TCEP in the Sala et al.
    (1982) study could not be evaluated because of the lack of control.

    A7.8  Other special studies

    A7.8.1  Neurotoxicity

         The neurotoxicity effects of TCEP were evaluated in adult (12-14
    months old) White Leghorn hens given 14 200 mg/kg body weight of the
    chemical in corn oil followed 3 weeks later by a second dose. Four out
    of 18 treated hens died within 6 weeks of the first dose. Egg
    production ceased, body weights fell and feather loss began shortly
    after the first treatment. No microscopic changes in brain, spinal
    cord or sciatic nerve were found after the treatment. In a separate
    group of hens, the activities of brain neuropathy target esterase and
    plasma cholinesterase were determined 24 h after the first dose of
    TCEP. Plasma cholinesterase activity was inhibited by 87% and brain
    neuropathy target esterase by 30%. No delayed neurotoxicity was
    observed (Sprague et al., 1981).

         White Leghorn hens (12 months old) were orally exposed to 420 mg
    TECP/kg body weight per day for 5 consecutive days. After 21 days of
    observation there was no signs of neurotoxicity as compared with TDCP
    (positive control) which induced an inability to walk, hypertension,
    ataxia and prostration (Bullock & Kamienski, 1972).

         Female Fischer-344 rats gavaged with 275 mg TCEP/kg body weight
    convulsed within 60-90 min and had extensive loss of CA1 hippocampal
    pyramidal cells when examined after 7 days. When convulsions were
    controlled, the histological lesions were diminished, indicating
    possibly that the lesions were due to convulsions and not directly due
    to TCEP. In a second study, rats gavaged with 275 mg/kg TCEP body
    weight had impaired acquisition of a reference memory task in a water
    maze when trained and tested starting 3 weeks following exposure,
    suggesting long-term impairment of some brain functions (Tilson et
    al., 1990).

    A8.  EFFECTS ON HUMANS

         No data concerning the effects of TCEP on humans are available.

    A9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

    A9.1  Microorganisms

         The toxicity of TCEP to aerobic bacteria  (Pseudomonas putida) 
    and anaerobic bacterial cultures from sewage sludge is very low with
    LC50 values in excess of 5000 mg/litre (Bayer, 1986) and 1000
    mg/litre (Hoechst, 1985), respectively.

    A9.2  Aquatic organisms

    A9.2.1  Algae

         The EC50 for growth of  Tetrahymena pyriformis was reported to
    be 126 mg/litre (Yoshioka et al., 1986)

    A9.2.2  Invertebrates

         Yoshioka et al. (1986) reported an LC50 of 1000 mg/litre for a
    daphnid  (Moina macropoda) and an LC50 of 158 mg/litre for a
    flatworm  (Dugesia japonica).

    A9.2.3  Fish

         Sasaki et al. (1981) reported 96-h LC50 values for killifish
     (Oryzias latipes) and goldfish  (Carassius auratus) of 210 and 90
    mg/litre, respectively. Killifish exposed to TCEP at 200 mg/litre for
    72 h showed spinal deformities. Yoshioka et al. (1986) reported an
    LC50 for the killifish  (Oryzias latipes) of 251 mg/litre.

         Unpublished studies gave the following acute toxicity values for
    fish: 48-h LC50 for killifish  (Oryzias latipes) of 300 mg/litre
    (MITI, 1992); and 96-h LC50 for rainbow trout
     (Oncorhynchus mykiss) of 249 mg/litre (NOEC, 50 mg/litre) (Akzo,
    1990).

    A10.  EVALUATION

         Traces of TCEP have been found in food items and drinking-water.
    The low volatility of TCEP precludes significant exposure from air.
    Exposure to TCEP from these sources will not present an acute hazard
    to the general population. The genetic toxicity data are ambiguous.
    TCEP has been found to be carcinogenic in rats and mice. The mechanism
    of carcinogenicity has not been elucidated. However, because of the
    low exposure, the risk of adverse health effects from TCEP to the
    general population is expected to be very low.

         TCEP has been tested at three trophic levels for acute and two
    trophic levels for chronic exposure of organisms relevant to the
    environment. The lowest reported chronic NOEC is more than 3 orders of
    magnitude higher than the highest reported concentration in sewage
    effluent and surface waters (Fig. 3). There will be no adverse effects
    on the environment from the use of TCEP.

    FIGURE 4



    A11.  FURTHER RESEARCH

         Further investigations of the mechanisms underlying the
    tumorigenicity of TCEP are needed.

    A12.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         The International Agency for Research on Cancer evaluated
    tris(2-chloroethyl) phosphate in 1989 and concluded:

    a)   "There is inadequate evidence for the carcinogenicity of
         tris(2-chloroethyl) phosphate in experimental animals.

    b)   No data were available from studies in humans on the
         carcinogenicity of tris(2-chloroethyl) phosphate.

    c)   Tris(2-chloroethyl) phosphate is not classifiable as to its
         carcinogenicity to humans" (Group 3) (IARC, 1990).

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    RÉSUMÉ

    1.  Le phosphate de tris(1-chloro-2-propyle) (TCPP)

         Le phosphate de tris(1-chloro-2-propyle) ou TCPP se présente sous
    la forme d'un liquide incolore. On l'utilise comme retardateur de
    flamme, principalement dans les mousses de polyuréthanne. Il n'est pas
    volatil. Sa solubilité dans l'eau est de 1,6 g/litre; il est soluble
    dans la plupart des solvants organiques et son coefficient de partage
    entre l'octanol et l'eau (log Kow) est égal à 2,59.

         L'analyse s'effectue par chromatographie en phase gazeuse couplée
    à la spectrométrie de masse. Pour doser le TCPP présent dans l'eau, on
    commence par le concentrer sur résine XAD puis on procède à une
    extraction avec divers solvants organiques.

         Le TCCP est produit à partir de l'époxypropane et de
    l'oxychlorure de phosphore. La demande mondiale a dépassé 40 000
    tonnes en 1997.

         Le TCPP est difficilement biodégradé dans les inoculums de boues
    d'égout. Les poissons le métabolisent rapidement.

         On a décelé des traces de TCPP dans des effluents industriels et
    domestiques, à l'exclusion des eaux superficielles. Les contrôles
    effectués sur des sédiments n'en n'ont pas décelé la présence. Il a
    été mis en évidence à l'état de traces dans des pêches et des poires
    crues ainsi que dans du poisson.

         On ne dispose d'aucune donnée sur sa cinétique ni sur son
    métabolisme chez les mammifères.

         La toxicité aigüe du TCPP se révèle faible à modérée après
    ingestion (DL50 pour le rat= 1017 à 4200 mg/kg de poids corporel),
    contact cutané (DL50 pour le rat et le lapin > 5000 mg/kg de poids
    corporel) ou inhalation (CL50 pour le rat > 4,6 mg/litre).

         Des études sur le pouvoir irritant du TCPP pour la muqueuse
    oculaire et l'épiderme effectuées sur des lapins ont montré que ce
    composé n'est pas irritant ou tout au plus légèrement irritant. Une
    étude de sensibilisation cutanée a montré que le TCPP n'avait aucune
    action sensibilisatrice.

         On n'a pas étudié la toxicité génésique et immunologique du TCPP
    ni sa cancérogénicité. Les résultats des études de mutagénicité  in 
     vitro et  in vivo, portant sur un ensemble approprié de points
    d'aboutissement, indiquent que le composé n'est pas génotoxique.

         La neurotoxicité retardée du TCPP a été étudiée sur des poules.
    L'ingestion de deux doses de composé (égales chacune à 13 320 mg/kg
    p.c.) à 3 semaines d'intervalle n'a pas fait apparaître de signes de
    neurotoxicité retardée.

         Il n'existe pas d'étude consacrée aux effet du TCPP sur l'homme.

         En ce qui concerne la toxicité du TCPP pour les êtres vivants
    dans leur milieu naturel, on a relevé, pour la CL50, des valeurs
    allant de 3,6 à 180 mg/litre. La concentration sans effet observable
    pour les algues, les daphnies et les poissons est respectivement égale
    à 6, 32 et 9,8 mg/litre.

    2.  Le phosphate de tris(1,3-dichloro-2-propyle) (TDCPP)

         Le phosphate de tris(1,3-dichloro-2-propyle) ou TDCPP se présente
    sous la forme d'un liquide incolore de consistance visqueuse. Il est
    utilisé comme retardateur de flamme dans diverses mousses plastiques,
    résines et latex. Il n'est pas volatil. Sa solubilité dans l'eau est
    de 0,1 g/litre et il est soluble dans la plupart des solvants
    organiques. Son coefficient de partage entre l'octanol et l'eau (log
    Kow) est de 3,8.

         L'analyse s'effectue par chromatographie en phase gazeuse couplée
    à la spectrométrie de masse. Pour doser le TDCPP présent dans l'eau,
    on commence par le concentrer sur résine XAD et on procède ensuite à
    une extraction au moyen de divers solvants organiques.

         Le TDCPP est produit à partir de l'épichlorhydrine et de
    l'oxychlorure de phosphore. Le produit commercial est constitué
    principalement de TDCPP avec des traces de phosphate de
    tris(2,3-dichloropropyle). La demande mondiale a été de 8000 tonnes en
    1997.

         Le TDCPP est difficilement biodégradé dans les inoculums de boues
    d'égout.

         Selon certaines études, la décomposition du TDCPP est limitée
    dans les eaux naturelles. Les poissons le métabolisent rapidement.

         La valeur du facteur de bioconcentration est faible (de 3 à 107).
    Sa demi-vie d'élimination est égale à 1,65 h chez les cyprinodontes.

         Des traces de TDCPP ont été mises en évidence dans des effluents
    d'égouts, des cours d'eau, dans la mer, dans de l'eau destinée à la
    boisson, des sédiments et des poissons. On en a également trouvé dans
    certains échantillons de tissus adipeux humains.

         Les études cinétiques effectuées sur des rats à l'aide de TDCPP
    marqué au carbone-14 montrent que le produit marqué se répartit dans
    l'ensemble de l'organisme après administration par voie buccale ou
    percutanée. Le principal métabolite du TDCPP identifié dans l'urine
    des rats était le phosphate de bis(1,3-dichloro-2-propyle).
    L'élimination du marqueur radioactif s'est effectuée principalement
    dans les matière fécales et les urines, une petite fraction étant
    également rejetée dans l'air expiré sous forme de CO2.

         La toxicité aiguë du TDCPP est faible à modérée par la voie
    buccale (DL50 chez le rat = 2830 mg/kg p.c.); elle est faible par la
    voie percutanée (DL50 par voie percutanée chez le rat >2000 mg/kg
    p.c.).

         Lors d'une étude de 3 mois sur des souris, une exposition
    correspondant à une dose journalière d'environ 1800 mg/ kg p.c. a été
    fatale aux animaux en l'espace d'un mois. La dose sans effet
    observable (NOEL) était de 15,3 mg/kg p.c. par jour. La dose la plus
    faible provoquant un effet observable (LOEL)- en l'espèce, une
    augmentation du poids du foie- était de 62 mg/kg p.c. par jour.

         Le pouvoir sensibilisateur du TDCPP n'a pas été étudié.

         On ne peut pas dire avec certitude si le TDCPP est susceptible
    d'affecter la fonction de reproduction masculine car on a observé un
    effet toxique sur le testicule du rat mais aucun effet de ce genre sur
    le lapin mâle. Les éventuels effets qu'il pourrait avoir sur la
    fonction génitale femelle n'ont pas été étudiés.

         Une étude tératologique effectuée sur des rats a montré que le
    TDCPP était fétotoxique par voie buccale à la dose journalière de 400
    mg/kg p.c.; le composé était toxique pour les rattes gravides aux
    doses journalières de 100 et 400 mg/ kg p.c. Aucun signe de
    tératogénicité n'a été relevé.

         Globalement, les données de mutagénicité montrent que le TDCPP
    n'est pas génotoxique  in vivo.

         Une unique étude d'alimentation portant sur deux ans a été
    consacrée à la cancérogénicité du TDCPP. Le composé s'est
    effectivement révélé cancérogène pour le rat (augmentation de la
    fréquence des cancers du foie) à toutes les doses administrées (5-80
    mg/kg p.c. par jour), tant chez les mâles que chez les femelles. On a
    également constaté la présence de tumeurs des reins, des testicules et
    de l'encéphale ainsi que des lésions non malignes au niveau de la
    moelle osseuse, de la rate, des testicules, du foie et des reins. Les
    lésions rénales et testiculaires étaient présentes à toutes les doses.
    En revanche les effets sur la moelle osseuse et la rate n'ont été
    étudiés que dans le groupe témoin et chez les animaux soumis aux doses
    les plus fortes. Dans ces conditions, il était impossible de
    déterminer s'il existait une relation dose-effet au niveau de ces
    organes.

         Il semblerait également que le TDCPP ait une certaine
    immunotoxicité chez la souris, mais uniquement à forte dose.

         On dispose des résultats d'études limitées effectuées sur l'homme
    à l'occasion d'expositions professionnelles au TDCPP, mais ils
    n'apportent pas grand chose à la connaissance du degré de sécurité
    qu'offre ce composé.

    3.  Le phosphate de tris(2-chloéthyle) (TCEP)

         Le phosphate de tris(2-chloréthyle) se présente sous la forme
    d'un liquide jaune pâle que l'on utilise comme retardateur de flamme,
    surtout dans la production de résines polyesters liquides insaturées.
    On l'utilise aussi dans les enduits destinés à certains textiles, le
    PVC ainsi que les matériaux et enduits à base d'esters cellulosiques.
    Il n'est pas volatil et sa solubilité dans l'eau est de 8 g/litre. Il
    est soluble dans la plupart des solvants organiques. Son coefficient
    de partage entre l'octanol et l'eau (log Kow) est égal à 1,7.

         L'analyse s'effectue par chromatographie en phase gazeuse couplée
    à la spectrométrie de masse. Pour doser le TCEP présent dans l'eau, on
    peut commencer par le concentrer sur résine XAD ou charbon actif, puis
    l'extraire au moyen de divers solvants organiques.

         Le TCEP est produit à partir de l'époxyéthane et de l'oxychlorure
    de phosphore. Depuis les années 1980, la production et l'usage de ce
    composé sont en déclin. En 1997, la demande mondiale de TCEP a été
    inférieure à 4000 tonnes.

         Le TCEP n'est pas aisément biodégradable. Le facteur de
    bioconcentration est faible, et la demi-vie d'élimination est de 0,7 h
    chez les poissons.

         Des traces de TCEP ont été décelées dans des cours d'eau, dans la
    mer, dans de l'eau destinée à la boisson, dans divers biotes (poissons
    et invertébrés aquatiques) ainsi que dans certaines denrées
    alimentaires.

         Chez le rat, le TCEP administré par ingestion se répartit dans
    les divers organes, en particulier dans le foie et les reins, mais
    aussi dans l'encéphale. Chez le rat et la souris, on a relevé la
    présence, entre autres, des métabolites suivants: phosphate de
    carboxyméthyle et de bis(2-chloréthyle), hydrogénophosphate de
    bis(2-chloréthyle) et glucuronide du phosphate de
    bis(2-chloréthyl)-2-hydroxyéthyle. L'excrétion est rapide,
    pratiquement complète et s'effectue principalement par la voie
    urinaire.

         La toxicité aiguë du TCEP par voie buccale est faible à modérée
    (DL50 par voie buccale = 1150 mg/kg p.c. chez le rat).

         Lors d'études comportant des doses réitérées, le TCEP a provoqué
    des effets indésirables sur l'encéphale (lésions de l'hippocampe chez
    le rat), le foie et les reins. La dose sans effet observable (NOEL)
    était égale à 22 mg/kg p.c. par jour et la dose la plus faible
    produisant un effet (LOEL), à 44 mg/kg p.c. par jour, l'effet pris en
    compte étant l'augmentation du poids du foie et du rein chez le rat.

         Le TCEP n'est irritant ni pour la peau ni pour les yeux, mais son
    pouvoir sensibilisateur n'a pas été étudié.

         Le TCEP n'est pas tératogène. En revanche, il a un effet négatif
    sur la fécondité des rats et des souris mâles.

         Il n'est pas possible de se prononcer sur le pouvoir mutagène du
    TCEP car les épreuves  in vitro n'ont pas donné de résultats
    cohérents; par ailleurs, les résultats du test des micronoyaux sur la
    moelle osseuse sont douteux.

         Chez le rat et la souris, le TCEP provoque l'apparition de
    tumeurs bénignes et malignes de localisations diverses.

         Une dose très élevée administrée par la voie buccale a entraîné
    une certaine inhibition de la cholinestérase plasmatique et de
    l'estérase cérébrale neuropathogénique chez la poule, sans toutefois
    manifester une neurotoxicité retardée. Chez le rat, une forte dose de
    TCEP a provoqué des convulsions, des lésions cérébrales et une
    diminution des performances en labyrinthe.

         Pour les êtres vivants dans leur milieu naturel, on trouve des
    valeurs de la CL50 et de la CE50 qui vont de 90 à 5000 mg/litre.

    RESUMEN

    1.  Tris(1-cloro-2-propil) fosfato (TCPP)

         El tris(1-cloro-2-propil) fosfato (TCPP) es un líquido incoloro
    que se utiliza como pirorretardante, principalmente en espumas de
    poliuretano. No es volátil. Su solubilidad en agua es de 1,6 g/litro,
    es soluble en la mayor parte de los disolventes orgánicos y tiene un
    coeficiente de reparto octanol/agua de 2,59.

         El análisis se realiza mediante cromatografía de
    gases/espectrometría de masas (CG/EM). La concentración de TCPP a
    partir del agua antes del análisis se puede conseguir mediante el uso
    de resina XAD, seguido de la extracción con diversos disolventes
    orgánicos.

         El TCPP se fabrica a partir del óxido de propileno y el
    oxicloruro de fósforo. La demanda anual en todo el mundo superó en
    1997 las 40 000 toneladas.

         El TCPP no es fácilmente degradable en inóculos de fangos
    cloacales. Se metaboliza rápidamente en los peces.

         Se han detectado trazas de TCPP en efluentes industriales y
    domésticos, pero no en las aguas superficiales. No se ha observado en
    análisis de sedimentos. Se han encontrado trazas en melocotones
    crudos, peras crudas y pescado.

         No se dispone de datos sobre la cinética y metabolismo del TCPP
    en los mamíferos.

         Su toxicidad aguda es de baja a moderada por vía oral (DL50 en
    ratas = 1017-4200 mg/kg de peso corporal), cutánea (DL50 en ratas y
    conejos es > 5000 mg/kg de peso corporal) y por inhalación (DL50 en
    ratas > 4,6 mg/litro).

         En estudios de irritación ocular y cutánea realizados en conejos
    se ha puesto de manifiesto que el TCPP tiene una capacidad irritante
    nula o leve. En estudios de sensibilización cutánea se ha demostrado
    que no tiene propiedades de sensibilización.

         No se ha investigado la toxicidad reproductiva, la
    inmunotoxicidad y el potencial carcinogénico del TCPP. Los resultados
    de los estudios de mutagenicidad  in vivo e  in vitro realizados
    para investigar una gama apropiada de efectos finales indican que no
    es genotóxico.

         Se ha investigado su potencial de neurotoxicidad retardada en las
    gallinas. No se encontraron pruebas de dicho efecto en un estudio
    realizado con dos dosis orales (de 13 230 mg/kg de peso corporal cada
    una) administradas a una distancia de tres semanas.

         No se dispone de estudios de los efectos del TCPP en el ser
    humano.

         Se conocen valores de toxicidad para organismos del medio
    ambiente, oscilando los correspondientes a la CL50 entre 3,6 y 180
    mg/litro. Las concentraciones sin efectos observados para las algas,
    los dáfnidos y los peces son de 6, 32 y 9,8 mg/litro, respectivamente.

    2.  Tris(1,3-dicloro-2-propil) fosfato TDCPP

         El Tris(1,3-dicloro-2-propil) fosfato (TDCPP) es un líquido
    incoloro viscoso que se utiliza como pirorretardante en diversas
    espumas de plástico, resinas y látex. No es volátil. Su solubilidad en
    agua es de 0,1 g/litro, es soluble en la mayor parte de los
    disolventes orgánicos y el logaritmo del coeficiente de reparto
    octanol/agua es de 3,8.

         Se analiza mediante CG/EM. La concentración de TDCPP a partir del
    agua antes del análisis se puede conseguir mediante el uso de resina
    XAD, seguido de la extracción con diversos disolventes orgánicos.

         El TDCPP se fabrica a partir de la epiclorohidrina y el
    oxicloruro de fósforo. El producto comercial consiste fundamentalmente
    en TDCPP con cantidades traza de tris(2,3-dicloropropil) fosfato. La
    demanda total en todo el mundo fue en 1997 de 8000 toneladas.

         El TDCPP no se degrada fácilmente en inóculos de fangos
    cloacales.

         En diversos estudios se ha puesto de manifiesto una degradación
    limitada del TDCPP en las aguas naturales. Los peces lo metabolizan
    con rapidez.

         Los factores de bioconcentración son bajos (3-107). La semivida
    de eliminación en peces del género  Phundulus es de 1,65 h.

         Se han detectado trazas de TDCPP en aguas residuales, fluviales,
    marinas y potable, y en sedimentos y en los peces. Se ha encontrado
    asimismo en algunas muestras de tejido adiposo humano.

         Los estudios cinéticos en ratas utilizando TDCPP marcado con 14C
    mostraron que, tras la administración oral o cutánea, el marcador
    radiactivo se distribuía por todo el cuerpo. El metabolito principal
    del TDCPP identificado en la orina de ratas fue el
    bis(1,3-dicloro-2-propil) fosfato. La eliminación del marcador
    radiactivo se produjo fundamentalmente por las heces y la orina, con
    una pequeña cantidad en el aire expirado como CO2.

         La toxicidad aguda del TDCPP es de baja a moderada por vía oral
    (DL50 en ratas = 2830 mg/kg de peso corporal) y baja por vía cutánea
    (DL50 cutánea en ratas > 2000 mg/kg de peso corporal).

         En un estudio de tres meses realizado en ratones, la exposición a
    unos 1800 mg/kg de peso corporal al día provocó la muerte en el plazo
    de un mes. La concentración sin efectos observados (NOEL) del estudio
    fue de 15,3 mg/kg de peso corporal al día; la concentración más baja
    observada (LOEL) para el aumento de peso del hígado fue de 62 mg/kg de
    peso corporal al día.

         No se ha investigado su potencial de sensibilización.

         No está claro si puede afectar a la capacidad reproductiva
    masculina en el ser humano, habida cuenta de su toxicidad testicular
    en las ratas y de la falta de efectos en el rendimiento reproductivo
    de los conejos machos. No se han investigado los posibles efectos en
    la reproducción de las hembras.

         En un estudio teratológico en ratas se observó fetotoxicidad a
    una dosis oral de 400 mg/kg de peso corporal al día. No se observaron
    efectos teratogénicos.

         En conjunto, los datos de mutagenicidad demuestran que el TDCPP
    no es genotóxico  in vivo.

         La carcinogenicidad del TDCPP se ha investigado en un estudio
    único de alimentación de dos años de duración. Fue carcinogénico
    (aumento de la frecuencia de carcinomas hepáticos) en todas las
    concentraciones utilizadas en las pruebas (5-80 mg/kg de peso corporal
    al día) en ratas tanto machos como hembras. Se detectaron asimismo
    tumores renales, testiculares y cerebrales. Además, se observaron
    efectos adversos no neoplásicos en la médula ósea, el bazo, los
    testículos, el hígado y el riñón. Los efectos en el riñón y los
    testículos aparecieron con todas las concentraciones. Los efectos en
    la médula ósea y el bazo sólo se evaluaron en los animales sometidos a
    las dosis más altas y los grupos testigo. Por consiguiente, fue
    imposible determinar si había una relación dosis-respuesta para estos
    efectos en dichos órganos.

         La exposición al TDCPP produjo algunos signos de inmunotoxicidad
    en ratones, pero sólo en dosis elevadas.

         Se dispone de estudios humanos limitados tras la exposición
    ocupacional, pero añaden poca información a lo que se conoce acerca de
    los aspectos de la inocuidad del TDCPP.

    3.  Tris(2-cloroetil) fosfato (TCEP)

         El tris(2-cloroetil) fosfato (TCEP) es un líquido entre incoloro
    y amarillo pálido que se utiliza como pirorretardante, principalmente
    en la producción de resinas líquidas de poliésteres insaturados. Se
    usa también en formulaciones de revestimientos de refuerzo de
    textiles, compuestos de PVC, compuestos de ésteres de celulosa y
    revestimientos. No es volátil y su solubilidad en agua es de 8
    g/litro. Es soluble en la mayor parte de los disolventes orgánicos. El
    logaritmo del coeficiente de reparto octanol/agua es de 1,7.

         El análisis se realiza mediante CG/EM. La concentración de TCEP a
    partir del agua antes del análisis se puede conseguir mediante el uso
    de resina XAD o carbón activado, seguido de la extracción con diversos
    disolventes orgánicos.

         El TCEP se fabrica a partir del oxicloruro de fósforo y el óxido
    de etileno. La producción y uso de este producto ha ido disminuyendo
    desde los años ochenta. La demanda anual en todo el mundo fue en 1997
    inferior a 4000 toneladas.

         El TCEP no es fácilmente biodegradable. Los factores de
    biodegradación son bajos, y la semivida de eliminación en los peces es
    de 0,7 h.

         Se han detectado trazas de TCEP en aguas fluviales, marinas y
    potable, en sedimentos, en la biota (peces y moluscos) y en algunas
    muestras de diversos alimentos.

         En las ratas, las dosis orales de TCEP se absorben y distribuyen
    por todo el cuerpo hasta alcanzar diversos órganos, en particular el
    hígado y el riñón, pero también el cerebro. Entre los metabolitos
    detectados en ratas y ratones figuran el bis(3-cloroetil) carboximetil
    fosfato; el bis(2-cloroetil) bifosfato y el
    bis(2-cloroetil)-2-hidroxietil fostato glucurónido. La excreción es
    rápida, casi completa y fundamentalmente por la orina.

         El TCEP tiene una toxicidad aguda por vía oral entre baja y
    moderada (DL50 en la rata=1150 mg/kg de peso corporal).

         En estudios de dosis repetidas, el TCEP produjo efectos adversos
    en el cerebro (lesiones del hipocampo en ratas), el hígado y los
    riñones. La NOEL fue de 22 mg/kg de peso corporal al día y la LOEL de
    44 mg/kg de peso corporal al día para el aumento de peso del hígado y
    el riñón en ratas.

         No es irritante de la piel ni de los ojos, pero no se han
    realizado pruebas para estudiar una posible sensibilización.

         El TCEP no es teratogénico. Afecta negativamente a la fecundidad
    de ratas y ratones machos.

         No se pueden sacar conclusiones acerca de la mutagenicidad del
    TCEP, puesto que los resultados de las pruebas  in vitro no fueron
    uniformes y una prueba del micronúcleo de médula ósea  in vivo dio
    resultados equívocos.

         El TCEP provoca tumores benignos y malignos en diversos puntos de
    los órganos de las ratas y los ratones.

         Una dosis oral muy alta de TCEP provocó una cierta inhibición de
    la colinesterasa del plasma y neuropatía cerebral a través de la
    esterasa en las gallinas, pero no produjo neurotoxicidad retardada. En
    ratas, una dosis elevada de TCEP causó convulsiones, lesiones

    cerebrales y alteraciones del comportamiento en un laberinto de agua.

         Los valores de la CL50/CE50 para organismos del medio ambiente
    oscilan entre 90 y 5000 mg/litro.
    



    See Also:
       Toxicological Abbreviations
       Flame retardants (EHC 192, 1997)
       Flame retardants (EHC 218, 2000)