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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 112





    TRI- n -BUTYL 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

    First draft prepared by Dr. A. Nakamura,
    National Institute for Hygienic Sciences, Japan

    World Health Orgnization
    Geneva, 1991


         The International Programme on Chemical Safety (IPCS) is a
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    WHO Library Cataloguing in Publication Data

    Tri- n -butyl phosphate.

        (Environmental health criteria ; 112)

        1.Phosphoric acid esters - adverse effects
        2.Phosphoric acid esters - toxicity 
        I.Series

        ISBN 92 4 157112 8        (NLM Classification: QV 627)
        ISSN 0250-863X

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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR TRI- n -BUTYL PHOSPHATE

 1. SUMMARY

    1.1. Identity, physical and chemical properties, analytical methods
    1.2. Sources of human and environmental exposure
    1.3. Environmental transport, distribution, and transformation
    1.4. Environmental levels and human exposure
    1.5. Effects on organisms in the environment
    1.6. Kinetics and metabolism
    1.7. Effects on experimental animals and  in vitro  test systems
    1.8. Effects on humans

 2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

    2.1. Identity
    2.2. Physical and chemical properties
    2.3. Conversion factor
    2.4. Analytical methods
        2.4.1. Extraction and concentration
        2.4.2. Clean-up procedure
        2.4.3. Gas chromatography and mass spectrometry
        2.4.4. Contamination of analytical reagents
        2.4.5. Other analytical methods

 3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1. Production and processes
    3.2. Uses

 4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    4.1. Transport and transformation in the environment
        4.1.1. Release to the environment
        4.1.2. Fate in water and sediment
        4.1.3. Biodegradation
        4.1.4. Water treatment
    4.2. Bioaccumulation and biomagnification

 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. Fish, shellfish, and birds
    5.2. General population exposure
        5.2.1. Food
        5.2.2. Drinking-water
        5.2.3. Human tissues
    5.3. Occupational exposure

 6. EFFECTS ON ORGANISMS IN THE ENVIRONMENT

    6.1. Unicellular algae, protozoa, and bacteria
    6.2. Aquatic organisms
    6.3. Plants
    6.4. Arachnids

 7. KINETICS AND METABOLISM

    7.1. Absorption
    7.2. Distribution
    7.3. Metabolism
    7.4. Excretion

 8. EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO  TEST SYSTEMS

    8.1. Single exposure
    8.2. Short-term exposure
    8.3. Skin and eye irritation; skin sensitization
    8.4. Teratogenicity
    8.5. Mutagenicity and carcinogenicity
    8.6. Neurotoxicity

 9. EFFECTS ON HUMANS

10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT

    10.1. Evaluation of human health risks
         10.1.1. Exposure levels
         10.1.2. Toxic effects
    10.2. Evaluation of effects on the environment
         10.2.1. Exposure levels
         10.2.2. Toxic effects

11. RECOMMENDATIONS

    11.1. Recommendations for further research

REFERENCES

RESUME

EVALUATION DES RISQUES POUR LA SANTE HUMAINE ET DES EFFETS SUR 
L'ENVIRONNEMENT

RECOMMANDATIONS

WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR TRI- n -BUTYL 
PHOSPHATE

 Members

Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood Experimental
   Station, Abbots Ripton, Huntingdon, Cambridgeshire, England  (Chairman)

Dr S.  Fairhurst,  Medical  Division,  Health  and  Safety Executive,
   Bootle,  Merseyside,   England  (Joint Rapporteur)

Ms N. Kanoh, Division of Information  on Chemical Safety, National
   Institute  of Hygienic  Sciences, Setagaya-ku,  Tokyo, Japan

Dr A.  Nakamura,  Division  of Medical  Devices,  National Institute of
   Hygienic  Sciences, Setagaya-ku,  Tokyo, Japan

Dr M.  Tasheva,  Department  of Toxicology,  Institute  of Hygiene and
   Occupational Health, Sofia, Bulgaria

Dr B. Veronesi, Neurotoxicology Division, US Environmental Protection
   Agency,  Research  Triangle   Park,  North Carolina, USA

Mr W.D.  Wagner,  Division  of Standards  Development and Technology
   Transfer, National Institute for  Occupational Safety and Health,
   Cincinnati, Ohio, USA

Dr R.  Wallentowicz, Exposure Assessment  Application Branch, US
   Environmental Protection Agency, Washington, DC, USA  (Joint Rapporteur)

Dr Shen-Zhi  Zhang,  Beijing Municipal  Centre for Hygiene and Epidemic
   Control, Beijing, China

 Observers

Dr M.  Beth, Berufsgenossenschaft der Chemischen Industrie (BG Chemie),
   Heidelberg, Federal Republic of Germany

Dr R.  Kleinstück, Bayer AG, Leverkusen,  Federal Republic of Germany

 Secretariat

Dr M. Gilbert, International Programme on Chemical Safety, Division of
   Environmental Health, World Health Organization, Switzerland  (Secretary)

NOTE TO READERS OF THE CRITERIA DOCUMENTS


    Every  effort has been  made to present  information in the  criteria
documents as accurately  as possible without unduly delaying their
publication.  In the interest of all users  of  the  environmental health
criteria  documents, readers  are  kindly  requested to  communicate any
errors that may have occurred to the Manager of the International
Programme  on Chemical Safety, World  Health Organization, Geneva,
Switzerland, in order that they may be included in corrigenda, which will
appear in subsequent volumes.



                                *   *    *



    A  detailed  data  profile and  a  legal  file  can  be obtained  from
the International  Register of Potentially Toxic  Chemicals,  Palais  des
Nations,  1211  Geneva  10, Switzerland (Telephone No. 7988400 or
7985850).

ENVIRONMENTAL HEALTH CRITERIA FOR TRI- n -BUTYL PHOSPHATE


    A WHO Task Group meeting on Environmental Health Criteria for Tri- n -
butyl Phosphate was held at the British Industrial  Biological
Research  Association   (BIBRA), Carshalton, United Kingdom, from 9 to 13
October 1989.  Dr S.D.  Gangolli, Director, BIBRA, welcomed the
participants on behalf of the host institution and Dr M. Gilbert opened
the  meeting on behalf  of the three  cooperating organizations  of the
IPCS (ILO,  UNEP, WHO).   The  Task  Group reviewed  and revised the draft
criteria document and made an  evaluation  of  the risks  for  human
health and  the environment from exposure to tri- n -butyl phosphate.

    The first draft of this document was prepared by Dr A. Nakamura, National
Institute for Hygienic Sciences, Japan. Dr  M. Gilbert and  Dr P.G.
Jenkins,  both members of  the IPCS  Central  Unit,  were  responsible
for  the  overall scientific content and editing, respectively.

ABBREVIATIONS

BCF  bioconcentration factor

BUN  blood urea nitrogen

EC   effective concentration

FPD  flame photometric detector

GC   gas chromatography

GPC  gel permeation chromatography

HPLC  high performance liquid chromatography

LC   lethal concentration

LD   lethal dose

MS   mass spectrometry

NADPH  reduced nicotinamide adenine dinucleotide phosphate

NPD  nitrogen-phosphorus sensitive detector

OPIDN  organophosphate-induced delayed neuropathy

TAP  trialkyl/aryl phosphate

TBP  tri- n -butyl phosphate

TCP  tricresyl phosphate

TLC  thin-layer chromatography

TPP  triphenyl phosphate

1.  SUMMARY
    
1.1.  Identity, physical and chemical properties, analytical methods

    Tri- n -butyl  phosphate (TBP) is a non-flammable, non-explosive,
colourless, odourless liquid.  However,  it is thermally unstable and
begins to decompose at temperatures below its boiling point.  By analogy
with the known chemical properties of trimethyl phosphate, TBP is
thought  to hydrolyse  readily in either acidic,  neutral, or alkaline
solutions.   It behaves as  a weak alkylating  agent.  The partition
coefficient  between  octanol  and  water  (log Pow) is 3.99-4.01.

    The  analytical method of choice is gas-liquid chromatography  with  a
nitrogen-phosphorus sensitive  or flame photometric  detector.   The
detection limit  in water is about  50 ng/litre.  Contamination of
analytical reagents with  TBP  has  been frequently  reported; therefore,
care must  be taken in order  to obtain reliable data  in trace analysis
of TBP.

1.2.  Sources of human and environmental exposure

    TBP is manufactured by the reaction of  n - butanol  with phosphorus
oxychloride. It is used as a solvent for cellulose  esters,  lacquers,
and  natural  gums, as  a primary plasticizer  in  the  manufacture of
plastics  and  vinyl resins,  as  a metal  extractant, as a  base stock in
the formulation  of fire-resistant aircraft  hydraulic fluids, and as an
antifoaming agent.  During the past  few  years, the  utilization of TBP
as an extractant  in the  dissolution  process  in conventional  nuclear
fuel reprocessing has increased considerably.

    Exposure of the general population through normal use can be regarded as
minimal.

1.3.  Environmental transport, distribution, and transformation

    When used as an extraction reagent, solvent, or anti-foaming  agent, 
TBP is  continuously lost to  the air  and aquatic environment. The
biodegradation of TBP is moderate or slow depending on the ratio of TBP
to  active  biomass. It  involves  stepwise enzymatic  hydrolysis to
orthophosphate and  n -butanol,  which undergoes further degradation.
The  concentration of  TBP in  water is  not decreased  by standard
techniques for drinking-water treatment.

    Bioconcentration   factors  (BCF)  measured   for  two species of fish
(killifish and goldfish) range from  6  to 49. The depuration half-life
was 1.25 h.

1.4.  Environmental levels and human exposure

    TBP has been found frequently in air, water, sediment, and  aquatic
organisms, but levels  in environment samples are  low.  Higher
concentrations of TBP have been detected in air, water, and fish samples
collected near paper manufacturing  plants in Japan: 13.4 ng/m3   in air;
25 200 ng per  litre in river water; 111 ng/g in fish organs.  Total diet-
studies  in the United  Kingdom and the  USA indicate average daily TBP
intakes of approximately  0.02-0.08 µg per kg body weight per day.

1.5.  Effects on organisms in the environment

    The inhibitory concentrations (EC0, EC50, EC100) of TBP for the
multiplication of unicellular algae, protozoa, and bacteria have been
estimated to  lie within the range  of 3.2-100 mg/litre.  The acute
toxicity fish (LC50) ranges from 4.2 to 11.8 mg/litre. TBP increases the
drying rate of plant leaves, which results in rapid and complete inhi-
bition of leaf respiration.

1.6.  Kinetics and metabolism

    In experimental animals, oral or intraperitoneally injected TBP is
readily transformed by the liver,  and  presumably by the kidney, to yield
hydroxylated  products  as butyl moieties. TBP is excreted mainly as
dibutyl hydrogen phosphate,  butyl  dihydrogen  phosphate, and  butyl
bis-(3-hydroxybutyl) phosphate. Alkyl moieties hydroxylated as alkyl
chains are removed and excreted partly as  n -acetylalkyl cysteine and
partly as carbon dioxide.

1.7.  Effects on experimental animals and in vitro test systems

    Oral LD50 values for TBP in mice and rats have been reported to range
from about 1 to 3 g/kg, indicating relatively low acute toxicity.

    In  subchronic toxicity studies with TBP, dose-dependent depression of
body weight gain and increases in liver, kidney,  and testis weights were
reported.  The results of the subchronic studies indicate that the kidney
may  be  a target organ of TBP.

    Primary skin irritation caused by TBP in albino rabbits may be as
serious as that caused by morpholine.

    TBP  is reported to  be slightly teratogenic  at  high dose levels. The
mutagenicity of TBP has been inadequately investigated.  Negative results
have been reported in bacterial  tests and in a recessive lethal mutation
test with  Drosophila melanogaster. 

    There  are  no adequate  data  to assess  the carcinogenicity  of TBP,
and the effects on reproduction have not been investigated.

    The ability of TBP to produce delayed neuropathy has been inadequately
investigated.  Effects  seen following oral administration of a high dose
(0.42 ml/kg per day for 14 days) suggested delayed neuropathy, but no
axonal  degeneration was seen and no definite conclusions  could  be
drawn.   This same high  dose (0.42 ml/kg per day for 14 days) caused a
significant reduction in conduction velocity  of the caudal nerve and
morphological alteration of unmyelinated fibres in rats.  These results
indicate that TBP has a neurotoxic effect on the peripheral nerve.

1.8.  Effects on humans

    In an  in vitro  study, TBP has been reported to have a slight
inhibitory effect on human plasma cholinesterase.

    There are no case reports of delayed neurotoxicity, as has  been
observed  in cases  of tri- o -cresyl   phosphate poisoning.



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

Chemical Structure:

                      O
                      ||
H3C -- (CH2)3 -- O -- P -- O -- (CH2)3 -- CH3
                      |
                      O
                      |
                    (CH2)3
                      |
                     CH3

Molecular formula: C12H27O4P

Relative molecular mass:  266.3

CAS chemical name: Phosphoric acid, tributyl ester

CAS registry number: 126-73-8

RTECS registry number: TC7700000

Synonyms:  TBP; tri- n -butyl phosphate; phosphoric acid, tri- n -butyl ester

Trade name:  Phosflex 4(R); Skydrol LD-4(R);
             Celluphos 4(R); Disphamol 1 TBP(R)

Manufacturers and suppliers (Modern Plastics Encyclopedia, 1975; Parker,
1980; Laham et al., 1984): 
    Albright & Wilson Ltd.;  A & K Petroleum Ind.  Ltd. (Laham et al., 
    1984);  Ashland Chemical Co.; Bayer AG; Commercial Solvent Corp.; 
    East Coast Chemicals Co.;  FMC Corporation; McKesson Chemical Co.; 
    Mobay Chemical Co.; Mobil Chemical Co.; Monsanto Chemical Co.; 
    Rhone-Poulenc Co.; Protex (SA) Stauffer Chemical Co.; Tenneco 
    Organics Daihachi Chemical Ind. Co.; Nippon Chemical Ind. Co. Ltd. 

2.2.  Physical and chemical properties

    The physical properties of tri- n -butyl phosphate (TBP) are listed in
Table 1.

Table 1.  Physical properties of tri- n -butyl phosphate
-----------------------------------------------------------------
Physical state             colourless, odourless liquid                     
Melting point (°C)         -80a                                             
Boiling point (°C)         289 (with decomp.)b,d; 177-178 
                           (3.6 kPa)b,d; 150 (1.33 kPa)b 
Flash point (°C)           193b; 166a; 146d                                 
Relative density           0.973-0.983 (25 °C)b; 0.978 (20 °C)a             
Refractive index           1.4226 (25 °C)b; 1.4215 (25 °C)d                 
Viscosity (cSt)            3.5-12.2b; 3.7a                                  
Surface tension            29 dynes/cm (20 °C)                              
Vapour pressure            66.7 kPa (200 °C)a; 973 Pa (150 °C)a             
                           133 Pa (100 °C)c; 9 Pa (25 °C)                   
Solubility in              miscible with organic solvents                   
  organic solvents
Solubility in              1012 (4 °C)e; 0.422 (25 °C)e;                    
  water (mg/litre)         2.85 x 10-4 (50 °C)e                             

Octanol-water partition    4.00f; 3.99g; 4.01h                              
coefficient  (log Pow)
-----------------------------------------------------------------
a  Laham et al. (1984)
b  Modern Plastics Encyclopedia (1975)
c  Parker (1980)
d  Windholz (1983)
e  Higgins et al. (1959)
f  Saeger et al. (1979)
g  Sasaki et al. (1981)
h  Kenmotsu et al. (1980b)

    TBP  is non-flammable and non-explosive.   However, it is thermally
unstable and begins to decompose  at  temperatures  below its boiling
point (Paciorex et  al.,  1978; Bruneau et al., 1981).  The weak bond of
the  molecule  is the  C-O bond, and its  primary splitting leads to
butene and  phosphoric  acid (Bruneau  et  al., 1981).   With  an excess
of oxygen, complete  combustion to carbon  dioxide and water occurs at
about 700 °C (Bruneau et al., 1981).

    Despite a lack of data, TBP is thought to hydrolyse readily in either
acidic, neutral,  or alkaline solution, based  on  the  known  chemical
properties  of  trimethyl phosphate (Barnard et al., 1961).

2.3.  Conversion factor

    Tributyl phosphate 1 ppm = 10.89 mg/m3

2.4.  Analytical methods

    Analytical  methods for determining TBP in air, water, sediment,  fish,
and biological tissues  are summarized in Table 2. The methods of choice
are gas chromatography (GC) equipped  with  a  nitrogen-phosphorus
sensitive  detector (GC/NPD)  or flame photometric detector  (GC/FPD), and
gas chromatography  plus mass spectrometry (GC/MS). The detection limit
in water by GC/NPD or GC/FPD  is  approximately 50 ng/litre.   TBP  and
other  trialkyl/aryl   phosphates (TAPs),  e.g.,  triphenyl phosphate

(TPP), trioctyl phosphate,  and  tricresyl  phosphate  (TCP),  can  be
simultaneously  determined by  GC.  Thin-layer  chromatography (TLC)  is
sometimes used  for determining TBP but is  not widely applicable.

2.4.1.   Extraction and concentration

    TBP  is  easily  extracted from  aqueous solution with methylene
chloride  or  benzene (Kenmotsu  et al., 1980a; Kurosaki et al., 1983;
Ishikawa et al., 1985).  Low levels of TBP in water are successfully
concentrated on Amberlite XAD-2  resin  (Lebel  et  al.,  1979,  1981),
XAD-4 resin (Hutchins  et al., 1983),  or a mixed  resin of XAD-4  and
XAD-8 (Rossum & Webb, 1978).  The purge-trap  method  with charcoal filter
for ng/litre levels of TBP was reported by Grob  & Grob (1974), but  the
percentage recovery was  not calculated.

    TBP may be extracted from sediment with polar solvents such as
acetonitrile (Kenmotsu et al., 1980a)  or  acetone (Ishikawa et al.,
1985).

    Acetonitrile  and methylene chloride (Kenmotsu et al., 1980a) or
acetone-hexane  (Lebel &  Williams, 1983; EAJ, 1984)  have been used for
extracting TBP  from  fish  or adipose  tissues.   Gas-phase  and 
particulate  TBP in the atmosphere have been simultaneously collected on 
glycerol-coated Florisil(R) columns (Yasuda, 1980). 

    An octadecyl column has been used for  extracting  and concentrating  TBP
in blood plasma preparations (Pfeiffer, 1988). The sample was passed
through the column from which TBP was eluted with chloroform. The recovery
of 50 µg  per litre was more than 90% of the TBP added to the column.


Table 2.  Methods for the determination of TBP
---------------------------------------------------------------------------------------------------------
Sample type     Sampling method;      Analytical  Limit of    Comment              Reference
                extraction/clean-up     methoda   detection
---------------------------------------------------------------------------------------------------------
Environmental   trap with glycerol-     GC/FPD    1 ng/m3     simultaneous method  Yasuda (1980)
  air           Florisil column,                              for trialkyl/aryl
                elute with methanol,                          phosphates
                add water, and                         
                extract with hexane

Workplace air   automatic continuous    air       0.12 mg/m3  For air monitoring   Parker (1980)
                air monitor             monitor      
                using flame            
                photometric detector

Drinking-water  adsorb with XAD-2       GC/NPD    1 ng/litre  method for low       Lebel et al.
                resin, elute with       GC/MS                 level trialkyl/aryl  (1979, 1981)
                acetone-hexane                                phosphates

River, sea and  extract with            GC/NPD    50 ng/litre simultaneous method  Kenmotsu et al.
drinking-water  methylene chloride      GC/FPD                for trialkyl/aryl    (1980a, 1981, 1982)
                or benzene              GC/MS                 phosphates           Ishikawa et al. (1985)

Waste water     extract with            TLC       2.5 mg/                          Komlev et al. (1979)
                chloroform and                    litre
                separate with          
                silica gel plate

River and sea   extract with            GC/FPD    1 ng/g      simultaneous method  Kenmotsu et al. (1980a,
sediment        acetonitrile or         GC/MS                 for trialkyl/aryl    1981, 1982)
                acetone, clean up                             phosphates           Ishikawa et al. (1985)
                with charcoal or       
                Florisil column  
                chromatography   

Table 2.  (contd.)
---------------------------------------------------------------------------------------------------------
Sample type     Sampling method;      Analytical  Limit of    Comment              Reference
                extraction/clean-up     methoda   detection
---------------------------------------------------------------------------------------------------------

Fish            extract with            GC/FPD    1 ng/g      simultaneous method  Kenmotsu et al. (1980a)
                acetonitrile and        GC/MS                 for trialkyl/aryl
                methylene chloride,                           phosphates
                clean up with                          
                acetonitrile-                          
                hexane partitioning,                   
                charcoal column        
                chromatography,     
                concentrated        
                sulfuric  acid      
                extraction, and     
                Florisil sulfuric   
                column              
                chromatography      

Fish            extract with acetone    GC/FPD    10 ng/g     simultaneous method  EAJ (1977, 1978a,b)
                and hexane,             GC/NPD                for organochlorine
                clean up with                                 pesticides
                acetonitrile-hexane                    
                partitioning and       
                Florisil column     
                chromatography      

Human adipose   extract with benzene    GC/NPD    1 ng/g      simultaneous method  Lebel & Williams (1983)
  tissues       or acetone-             GC/FPD                for trialkyl/aryl
                hexane (15 + 85),       GC/MS                 phosphates
                clean up with                          
                gel permeation      
                chromatography      
                and Florisil column 
                chromatography      
---------------------------------------------------------------------------------------------------------
a  NPD = nitrogen-phosphorous selective detector   FPD = flame photometric detector   
   GC = gas chromatography   TLC = thin-layer chromatography
   MS   = mass spectrometry
2.4.2.   Clean-up procedure

    Florisil  column  chromatography  has  been  used  for clean-up
(Kenmotsu, et al., 1980a; Lebel & Williams, 1983; EAJ, 1984).  This method
allows the separation of TBP from other  phosphate esters, e.g.,  TPP, and
from organophosphorus pesticides, e.g., parathion. Sulfur-containing
compounds, which often exist in sediment samples  and  interfere with the
analysis of TBP by GC/FPD, are easily separated by elution with hexane
from the Florisil column.  Re-extraction with sulfuric acid from the
hexane layer  is  a useful  technique to avoid interference by sulfur-
containing  compounds (Kenmotsu et  al., 1980a).  However,  it is
difficult to separate TBP from lipids by  Florisil  column chromatography
because of their similar  polarities (Kenmotsu et al., 1980a).  In such
cases,  gel  permeation chromatography  (GPC) is useful (where  the
elution volume varies  depending  on the  type  of phosphate  ester, i.e.
trialkyl,  triaryl, or tri(haloalkyl) phosphates) (Lebel & Williams,
1983).   Partitioning between  acetonitrile and petroleum ether is an
effective way of separating TBP from adipose  tissue (Kenmotsu et al.,
1980a; EAJ, 1984).  Activated charcoal column chromatography has also been
used to separate TBP from  co-extractives  of sediment samples (Kenmotsu
et al., 1980a)

2.4.3.   Gas chromatography and mass spectrometry

    To identify TBP in environmental samples by packed column  GLC, a
comparison of each retention time using two types  of liquid phase of
different polarity is desirable. As a low polarity liquid phase, 3% or 10%
OV-1  (Kenmotsu et  al.,  1980a;  Ramsey &  Lee,  1980),   2% or  3% SE-30
(Ramsey  & Lee, 1980; EAJ, 1984), 2% or 3% OV-17 (Lebel et al.,  1981;
EAJ, 1984),  3% or 7%  OV-101 (Sasaki et  al., 1981;  Lebel et al., 1981),
SP-2100 (Rossum & Webb, 1978), 2%  OV-225 (Yasuda, 1980), 2% DC-200 (EAJ,
1984), and  2% OV-17  plus 2% PZ-179  (Ishikawa et al., 1985) have  been
used.  For the higher polarity liquid phase, 1% or 2% QF- 1 (Bloom,  1973;
Kurosaki  et al.,  1983), 5%  FFAP, and  5% Thermon-3000 (Kenmotsu  et 
al., 1980a,  1982)  have been used.   When a non-polar liquid phase is 
used in  packed column  GC,  the  reproducibility of  the phosphate ester
chromatogram  is often poor.   High loading of  the liquid phase generally
gives a good reproducibility (Kenmotsu et al., 1980a; Nakamura et al.,
1980).

    Capillary  column  GC  has  also  been  used  for  the identification
and determination of TBP  in environmental samples.  Lebel et al. (1981)
and Hutchins et  al.  (1983) used  SP-2100  fused  silica capillary
column (25 m long; 0.22 mm internal diameter) for the determination of TBP
in water  samples.  A wide-bore capillary  glass column (25 m long)
coated with  OV-101 was  used by  Rogers  &  Mahood (1982).

    Lebel  &  Williams  (1983) used  GC-MS for identifying TBP.   The
selected ion monitoring (SIM) technique is also useful  for the
quantification of low TBP levels (Lebel et al.,  1981;  Lebel  &
Williams,  1983;  Ishikawa  et al., 1985).

2.4.4.   Contamination of analytical reagents

    The  widespread use of TBP  in the plastics and  paper industries may
cause contamination of analytical reagents. Traces  of TBP have been
found in cyclohexane (Bowers  et al.,  1981;  Karasek  et al.,  1981),
methylene  chloride (Lebel  et  al.,  1981), activated  charcoal,  and
Avicel (crystalline  cellulose) (Kenmotsu et al.,  1980a). Therefore,
care must be taken in order to obtain reliable data in trace analysis of
TBP.

2.4.5.   Other analytical methods

    TLC has been used for determining TBP.   Bloom  (1973) reported good
separation of TBP by coupling TLC  with  GC. Komlev  et al. (1979)
described an analytical  method for TBP  in  waste  water and  air  using
TLC.  Tittarelli  & Mascherpa (1981) described a highly specific HPLC 
detector for  TAPs using  a  graphite  furnace  atomic  absorption 
spectrometer.  In general, TLC and HPLC have not  been  as widely  used as 
GC.  Parker (1980) described the automatic monitoring of air using a flame 
photometric detector. 


           
3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

3.1.  Productions and processes

    TBP does not occur naturally in the environment. Figures  concerning
total world production are not available. In  Japan, 230 tonnes were
produced  in 1984a,  and 45 tonnes were produced in the USA in 1982
(Schultz  et  al., 1984).   The estimated 1985 worldwide  production
capacity was 2720-4080 tonnes per year (US EPA, 1987a).

    TBP is prepared by the reaction of phosphorus oxychloride with 
 n -butanol (Windholz, 1983).

3.2.  Uses

    TBP is  used  as  a  solvent  for  cellulose  esters, lacquers,  and
natural gums,  as a primary  plasticizer in the  manufacture of plastics
and  vinyl resins, and as  an antifoam agent (Sandmeyer & Kirwin, 1981;
Windholz, 1983). In recent years, there has been a considerable increase
in the use of TBP as an extractant in the dissolution process in
conventional  nuclear  fuel processing  (Parker, 1980; Laham  et al.,
1984; Schultz  et al.,  1984) and  in  the preparation  of  purified
phosphoric  acid (wet phosphoric acid  method)  (Davister & Peeterbroeck,
1982).  Some 40% to 60% of all TBP consumed (probably in the USA)  is
used as  a  base stock  in  the formulation  of  fire-resistant aircraft
hydraulic fluids (US EPA, 1985).  In  Japan,  140 tonnes was used in 1984
as an antifoaming agent (mainly in paper manufacturing plants), 40 tonnes
as a metal extractant,  and 50 tonnes for miscellaneous purposesa.    TBP
is also used as a constituent of cotton defoliants, which act by producing
leaf scorching (Harris & May-Brown, 1976).



________________________
a Personal communication to IPCS from the Association of the Plasticizer
  Industry of Japan (1985)

4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

 Summary 

     TBP  has  been found  widely  in environmental  media (air, water,
 sediment, and biological  tissues) but usually  at  low concentrations.
 Sources  of  TBP in  the  environment include leakage  from  sites  of
 production  and  use  (e.g., aircraft hydraulic  fluids) and release from
 plastics or other products. No  figures on the  amounts released into  the
 environment  are available.

     Once  in the environment, it  appears that the majority  of TBP  finds
 its way  to sediments.  Biodegradation  in water  is dependent on water
 quality (1 mg/litre was degraded in  7  days in River Mississippi water).
 Little or no  degradation  occurs in sterile river water or natural sea
 water.   The  degradation pathway most probably involves stepwise
 enzymatic hydrolysis.

     In  drinking-water  treatment,  TBP levels  do not decrease unless
 powdered activated carbon is used, when  very  effective adsorption
 occurs (90-100% at a TBP concentration of 0.1 g per litre).

     The  bioaccumulation  potential  for TBP  in  killifish and goldfish 
 is low, the bioconcentration factor ranging from 6 to 49.  Depuration is
 rapid (half-life, 1.25 h).

     There is no information on the fate of TBP in air, but this does not
 appear to be an area of concern.  In  addition,  there are no data on
 transport to ground water.                                         

4.1.  Transport and transformation in the environment

4.1.1.   Release to the environment

    A major potential pathway  of entry of  TBP into  the environment is by
leakage from sites of production or use, and leaching from plastics
disposed in landfill  sites  or aquatic environments.  TBP has been found
widely in air, water, sediment, fish, and several biota, but usually
at low concentrations.

    Extraction reagents and solvents are continuously lost from  solvent
extraction processes and  may be transferred to  aquatic environments.
Ashbrook (1973),  Ritcey et al. (1974),  and Ashbrook et  al. (1979)
estimated  the losses from  solvent  extraction  plants.  When  recycled
acid is used  in the dissolution process in a conventional nuclear fuel
reprocessing plant, TBP and its phosphate derivatives build  up to a level
where low concentrations of  organo-phosphate  vapour  are  released  to
the  off-gas  stream (Parker,  1980).  However, no data on TBP levels in
air at these plants are available.

    TBP  used in antifoaming agents may be lost from manufacturing  plants
into the environment,  but the resultant amounts in the environment have
not been  measured.   High concentrations  of TBP have  been detected in
river water (7.61-25.2 µg/litre),  fish (4.2-111.0 ng/g), and air over the
sea (13.4 ng/m3)  sampled near  Kawanoe City, Japan, where  there are
many  paper manufacturing sites  (Yasuda, 1980; Tatsukawa et al., 1975)
(Table 5).

4.1.2.   Fate in water and sediment

    The  solubility of TBP  in water is  considerably less than 1 g/litre
at ambient temperatures (Table 1). Monitoring  studies have shown that it
is widely present in water and sediment (Suffet et al., 1980; Hattori et
al.,  1981; Williams & Lebel, 1981; Shinohara et al.,  1981;  Williams et
al., 1982; Ellis et al., 1982; Kurosaki et al., 1983). The  difference  in
TBP concentrations  between water and sediment was estimated to be about 3
orders  of  magnitude (river water, 20-110 ng/litre; river sediment, 8-130
ng/g; sea water, 6-150 ng/litre; sea sediment, 2-240 ng/g) (EAJ, 1978a,b).
The concentration factor of TBP on marine sediment was reported to be 4.3
(Kenmotsu et al., 1980b).

4.1.3.   Biodegradation

    The biodegradation of TBP in river water is slower than that of
triphenyl phosphate and may depend to a considerable  extent on water
quality.  Hattori et al. (1981) reported that 1 mg/litre completely
disappeared in 6 days in  Oh River water, Osaka, Japan, after a two-day
lag period.  However, at an initial TBP concentration of 20 mg per  litre,
only 21.9% was  biodegraded in Oh River  water after 14 days (Hattori et
al., 1981). In Neya River water, Osaka, Japan, degradation started at 6
days and  was  complete  after 9 days. In River Mississippi water (St.
Louis waterfront,  USA), degradation of TBP (1 mg/litre) started after  2
days and  was complete within  7 days (Saeger  et al., 1979).  No
degradation was observed in sterile river water  (Saeger et al., 1979; 
Hattori et al., 1981)  or in clear non-sterile sea water after 15 days
(Hattori et al., 1981).   Primary biodegradation rates  from
semicontinuous activated  sludge studies (US  Soap and Detergent  Assoc.,
1965;  Mausner  et al.,  1969)  generally showed  the same trend in
degradation rates as river die-away studies.  TBP degradation  was 96%
complete  at a 3-mg  per litre,  24-h feed  level, but only 56%  (± 21%)
at a  13-mg/litre, 24-h feed  level (Saeger et al., 1979). The ultimate
biodegradability  of the phosphate esters was measured by Saeger et al.
(1979) using the apparatus and procedure developed by Thompson  & Duthie
(1968)  and modified by  Sturm  (1973). Two  widely different results were
obtained for the degradation  TBP (20 mg/litre): 3.3% and 90.8% of the
theoretical carbon dioxide evolution were measured in  two  experiments.
Such differences are probably due to variations in the composite seed used
in the two tests.  A difference in the  ratio of TBP to  active biomass
may have  resulted in inhibition  in  the  first case  but  not  in  the
second (Saeger, et al., 1979).

    The  degradation pathway for TBP  most likely involves stepwise
enzymatic  hydrolysis to  orthophosphate and alcohol moieties (Pickard,
et al., 1975).  The alcohol would then be expected to undergo further
degradation.

4.1.4.   Water treatment

    Fukushima and Kawai (1986) reported that 0.105-21.2 µg TBP/litre
(geometric mean: 0.543 µg/litre) in untreated water was  reduced  to
0.018-3.80 µg/litre  (geometric  mean: 0.156 µg/litre) by conventional
waste water treatment.

    Piet et al. (1981) investigated the behaviour  of  organic compounds in
dune infiltration: no change of concentration of TBP was observed.
Sheldon & Hites  (1979)  reported  that a TBP level of 400 ng/litre was
not decreased by  standard techniques  for  drinking-water treatment.

However, TBP is effectively adsorbed to powdered activated carbon  (90-
100% at a  TBP concentration of  0.1 g/litre). The  adsorption coefficient
(Freundlich equation) obtained from  an experiment using 0.01 to 10 mg
TBP/litre at 25 °C was 190 (Ishikawa et al., 1985).

4.2.  Bioaccumulation and biomagnification

    Data reported on the bioaccumulation and depuration of TBP  in killifish
and goldfish  are given in Table  3.  No data  for other fish species  are
available.  Calculations of  bioconcentration factors (BCF) for  other
species have been  made  on  the basis  of  physico-chemical properties
(Sasaki et al., 1981, 1982). However, these must  be  considered  less
reliable  than  the  low  values  actually measured in killifish and
goldfish.

Table 3.  Bioaccumulation and clearance of TBP by fish
----------------------------------------------------------------------
Species     Temp. Flow/ Bioconcen-  Exposure   Depuration
            (°C)  stat  tration     conc.      half life   Reference
                        factora     (mg/litre) (h)
----------------------------------------------------------------------
Killifish   25    stat  11-49       0.2-0.06               Sasaki et  
 (Oryzias          flow  16-27       0.84-0.1   1.25        al. (1982)
  latipes)   25    stat  30-35       3-4                    Sasaki et 
                                                           al. (1981)
Goldfish    25    stat  6-11        3-4                    Sasaki et 
 (Carassius                                                 al. (1982)
 auratus) 
----------------------------------------------------------------------
a   Determined by GC-FPD

5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

 Summary 

     TBP has been found frequently in environmental samples (air,  water,
 sediment, and  fish) but usually  at low  levels. Measured  ambient air
 concentrations range  from non-detectable to 41.4 ng/m3 ;   the higher
 levels occurring near manufacturing sites.   Surface water levels up  to
 25 200 ng/litre have  been reported,  but  no  groundwater sampling  data
 are  available. Levels in sediment range from 1 to 350 ng/g.

     TBP levels in biological samples, including fish and shellfish, of
 up to 111 ng/g have been measured.  It  has  also been detected in bird
 populations.

     Human adipose tissues obtained from the autopsy of individuals
 with no known occupational exposure to  TBP  showed one positive sample
 (9.0 ng TBP/g) out of 16.

     Exposure  of the general  population can occur  by  several routes,
 including the ingestion of contaminated drinking-water (levels up to 29.5
 ng/litre),  fish and shellfish,  and  other foodstuffs.   US FDA  total-
 diet  studies  have  found  average intake  levels of 38.9, 27.7, and 2.7-
 6.2 ng/kg body weight per day for infants, toddlers, and adults,
 respectively.

     Occupational  exposure can occur in several industries, and especially
 where aircraft maintenance workers handle hydraulic fluids.  Exposure
 during the synthesis of TBP and  in  plastics production  is unlikely if
 protective measures are  taken  and because   the  various  processes
 have  been  automated  to  a considerable extent.

    Although  production amounts are lower  than for other triaryl/alkyl
phosphates, TBP has been found frequently in environmental samples (water,
sediment, and fish), whereas other triaryl/alkyl phosphates occur more
rarely. However, the  measured concentrations are  usually low.  These
are listed in Tables 4-6.


Table 4.  Concentration of TBP in air, water, and fish sampled in Northern Shikoku, Japan
---------------------------------------------------------------------------------------------------------
   Location                       Date            Sample            Concentrationa    Reference
---------------------------------------------------------------------------------------------------------
Hiuchi-Nada area 
   Hiuchi-Nada Sea                1977, July      air               13.4 ng/m3        Yasuda (1980)
   (along Kannonji-Kawanoe)

   Other sampling areas           1977, June      air               2.3-3.5 ng/m3     
   on Seto Inland Sea                                               (3/3)

   Kinsei River (Kawanoe City)    1974, July      water             7610 ng/litre     Tatsukawa et 
                                        Nov.                        24 100 ng/litre   al. (1975)
                                        Dec.                        25 200 ng/litre

   Kawanoe Harbour                1974, Dec.      flatfish muscle,  19.3 ng/g
                                                  goby viscera      111.0 ng/g

   Hatoba Harbour                 1974            goby viscera,     4.3 ng/g
                                                  goby muscle       4.2 ng/g
Dogo Plain, Ozu Basin area 
   Omoto River, Kutani            1974            water             ND-187 ng/litre   Tatsukawa et 
   River, etc.                                                      (4/10)            al. (1975)

   Kawauchi Town                  1976, July 1    air               3.1 ng/m3         Yasuda (1980)
                                        Sep. 16                     9.3 ng/m3
                                        Sep. 17                     6.1 ng/m3
                                        Sep. 19                     41.4 ng/m3
                                        Sep. 20                     25.7 ng/m3
                                        Sep. 22                     27.5 ng/m3
                                        Nov. 18                     ND

   Other locations                1976, July-Nov. air               ND-6.4 ng/m3 
                                                                    (10/12)
---------------------------------------------------------------------------------------------------------
a  Figures in parentheses indicate number of samples (detected/analysed);  ND = not detected.

Table 5.  Concentration of TBP in water, sediment, and fish at various locations
---------------------------------------------------------------------------------------------------------
Year     Location                   Sample                   Concentrationa     Number of    Reference
                                                                                samples
                                                                                (detected/
                                                                                analysed)
---------------------------------------------------------------------------------------------------------
1973     Zurich (Switzerland)       lake water               54-82 ng/litre        2/2       Grob & Grob 
                                    ground water             10 ng/litre           1/1       (1974)
                                    tap water                14 ng/litre           1/1

1975     Japan (Various locations)  river and sea water      20-710 ng/litre       16/100    EAJ (1977)
                                    river and sea sediment   1-350 ng/g            34/100
                                    fish                     3-26 ng/g             31/94

1977     Japan (Various locations)  river and sea water      6-580 ng/litre        39/117    EAJ (1978a,b)
                                    river and sea sediment   1.9-240 ng/g          48/117
                                    fish                     1.1-9.3 ng/g          27/85

1976     Osaka (Japan)              river water              20-4500 ng/litre      12/13     Kawai et al. 
                                                                                             (1978)
1978     Eastern Ontario (Canada)   drinking-water           0.6-11.8 ng/litre     12/12     Lebel et al. 
                                                                                             (1981)
1978     Tokyo (Japan)              river water              60-2100 ng/litre      12/12     Wakabayashi 
                                    sea water                50-870 ng/g           2/3       (1980)
                                    river sediment           0.9-7.7 ng/g          13/15
                                    sea sediment             1.7-2.6 ng/g          3/3

1979     Canada (Various locations) drinking-water           0.2-62.0 ng/litre     57/60     Williams & 
                                                                                             Lebel (1981)
1979     River Nitelva (Norway)     river water              100-900 ng/litre      3/7       Schou & Krane 
                                                                                             (1981)
1980     Seto Inland Sea (Japan)    fish and shell fish      ND (2 ng/g)           0/41      Kenmotsu et 
                                                                                             al. (1981)
1980     Great Lakes (Canada)       drinking-water           0.8-29.5 ng/litre     24/24     Williams et 
                                                                                             al. (1982)
1980     Kitakyushu City (Japan)    river water              5-36 ng/litre         8/16      Ishikawa et 
                                    sea water                ND (5 ng/litre)       0/9       al. (1985)
                                    sea sediment             ND (2 ng/g)           0/6

1982     Niigata City (Japan)       river water              140 ng/litre          1/1       Kurosaki et 
                                                                                             al. (1983)
not      USA                        city water               ND (50-500 ng/litre)  2/10      Muir (1984)
reported
---------------------------------------------------------------------------------------------------------
a  ND = not detected; figures in parentheses indicate the limit of detection.
Table 6.  Monitoring of TBP in wildlife performed by the Environmental 
Agency of Japana
------------------------------------------------------------------------
Year   Animal/speciesb      Locationc           Concent-     Number of 
                                                rationd      samples
                                                (ng/g)       (detected/
                                                             analysed)
------------------------------------------------------------------------

1980   Fish                 various locations   ND           0/50
       Shellfish            various locations   ND           0/15

1981   Fish
        Greenling           Yamada Bay          20           5/5
        Sea bass            Osaka Bay           Trace        5/5
        Other fish          various locations   ND           0/35

       Shellfish
        Common mussel       Yamada Bay          10-20        5/5
        Other shellfish     various locations   ND           0/15

       Birds
        Gray starling       Morioka             50-170       7/7

1982   Fish
        Sea bass            Seto Inland Sea     10-20        2/5
        Other fish          various locations   ND           0/45

       Shellfish                                ND           0/20

       Birds
        Gray starling       Morioka             20-30        3/5
        Black-tailed gull   Tokyo Bay           ND           0/4

1983   Fish                 various locations   ND           0/50

       Shellfish            various locations   ND           0/20

       Birds
        Gray starling       Morioka             30-250       5/5
        Black-tailed gull   Tokyo Bay           ND           0/5
------------------------------------------------------------------------
a  From : EAJ (1981, 1982, 1983, 1984)
b  Monitoring species     - Fish : chum salmon; angry rockfish; 
                            greenling; Pacific saury; cod; sea bass; dace
                          - Shellfish : common mussel, Asiatic mussel
                          - Bird : gray starling, black-tailed gull
c  Monitoring locations : off the coast of Kushiro; off the coast of 
                          Nemuro (Hokkaido); Yamada Bay (Iwate);
                          off the coast of Joban (Ibaraki); off the coast 
                          of Tohoku (Yamagata); Tokyo Bay; Osaka Bay;
                          off the coast of Sanin (Tottori); Lake Biwa 
                          (Shiga); Miura Peninsula (Kanagawa);
                          Noto Peninsula (Ishikawa); Naruto (Tokushima)
d  ND = not detected; detection limit = 10 ng/g

5.1.  Environmental levels

5.1.1.   Air

    Yasuda (1980) investigated the distribution of various organic phosphorus
compounds in the  atmosphere above the Dogo  Plain and Ozu  Basin
agricultural areas  of  Western Shikoku  and  above the  Eastern  Seto
Inland  Sea,  Japan (Table 4). TBP concentrations were usually less than
10 ng per m3, but higher concentrations (13.4-41.4 ng/m3) were oc-
casionally  found. These higher atmospheric concentrations of  TBP are
probably due  to fumes  liberated from  paper manufacturing plants located
around Kawanoe City. However, the  source of these  higher concentrations
has  not  been clearly  identified.  TBP has  also been detected  in  the
atmosphere  in Okayama City,  Japan, but the  levels  were less than 1
ng/m3 (Kenmotsu et al., 1981).

5.1.2.   Water

    TBP has been widely detected in river, lake,  and  sea water  in Europe,
Japan, Canada, and the USA (Tables 4 and 5).

    Tatsukawa  et al. (1975) measured  the distribution of five  phosphate
esters in river  water in the Seto  Inland Sea area of Japan and found 10
to several hundred  ng  per litre. Higher TBP concentrations (7600 to 25
200 ng/litre) were detected in Kinsei River, Kawanoe City,  Japan.   The
authors  suggested that these high concentrations were the result of
effluent from paper manufacturing plants.

5.1.3.   Sediment

    Despite  low sediment adsorption coefficients, TBP has frequently  been
detected  in sediment  samples  in Japan (EAJ,  1978a,b; Wakabayashi,
1980; Rogers  & Mahood, 1982; Ishikawa et al., 1985). The concentrations
ranged  from  1 to 350 ng/g.

5.1.4.   Fish, shellfish, and birds

    Although  bioconcentration  factors  are low  (section 4.2), significant
concentrations of TBP (ranging from 1 to
30 ng/g)  have been found frequently in fish and shellfish (Tables  4-6).
Tatsukawa et  al. (1975) reported  a  high concentration (111 ng/g) in the
organs of goby  caught  in Kawanoe harbour at the entrance to the Kinsei
River, Japan (Table 4).  Although no clear evidence was available, this
may  have  been due  to  pollution by  paper manufacturing plants located
around Kawanoe City. Rogers & Mahood (1982) also found TBP in fish caught
downstream from  pulp  mills and  a sewage plant  outfall, but the
concentrations were not reported.

    Reports  of  wildlife monitoring  by the Environmental Agency  of  Japan
(EAJ,  1982,  1983, 1984)  indicated TBP levels of 20-250 ng/g in birds
(Gray starlings).

5.2.  General population exposure

5.2.1.   Food

    The presence of TBP in infant and  toddler  total-diet samples  and in
adult diet samples was studied by Gartrell et  al.  (1986a,b).  These
samples  were collected between October 1980 and March 1982 during a
survey made  for  the US  Food and Drug Administration  (FDA).  Gunderson
(1988) also investigated the presence of TBP in samples collected between
April 1982 and April  1984 during FDA total  diet studies.   TBP was only
found  in approximately 2% of  the samples,  corresponding to average
daily  intakes of 38.9, 27.7, and 2.7-6.2 ng/kg body weight per day  for
infants, toddlers, and adults, respectively.

    Gilbert  et  al. (1986)  analysed composite total-diet samples
(representative  of  15 different  commodity food types encompassing an
average adult diet for each of eight regions  in the United Kingdom) for
the presence of trialkyl  and triaryl phosphates.   Of the food  groups,
offal, other animal products, and nuts consistently contained the highest
levels, but the proportion of individual compounds in  the different food
groups  varied.  Trioctyl phosphate was  the major component in  the
carcass meat, offal,  and poultry  groups, and there were significant
amounts of TBP and  TPP.   Total phosphate  intake  was estimated  to  be
between 0.08 and 0.16 mg per person per day.

5.2.2.   Drinking-water

    TBP  has  been  monitored in  drinking-water in Canada (Suffet  et al.,
1980; Lebel  et al.,  1981;  Williams  & Lebel,  1981;  Williams et  al.,
1982), and  the  concentrations ranged from 0.2 to 29.5 ng/litre.

5.2.3.   Human tissues

    Lebel  & Williams (1983) analysed  phosphate esters in human adipose
tissue and detected TBP (9.0 ng/g) in one of 16  autopsy samples from
humans with no known occupational exposure to TBP.  In a similar study
carried out by the US EPA (1986), a trace amount of TBP was detected in
one  of 46 samples.

5.3.  Occupational exposure

    In its 1981-1983 National Occupational Exposure Survey (NOES), the
National Institute for Occupational Safety and Health  (NIOSH), USA,
estimated  that 12 111 workers  in 6 industries  and 13 occupations were
potentially exposed to TBP.  Not included in this survey were workers
involved in aircraft  maintenance.   Due to  manipulation of hydraulic
fluids containing TBP, these workers represent the largest population
occupationally exposed.  In 1988, the Tributyl Phosphate  Task  Force
(TBPTF) of  the  Synthetic Organic Chemical  Manufacturers Association
(SOCMA) estimated that approximately 45 000 aircraft workers, the greatest
number of  workers potentially exposed  to TBP, are  exposed once per
week for 30 min to 2 h to hydraulic fluids containing TBP (US EPA, 1987b,
1989).

6.  EFFECTS ON ORGANISMS IN THE ENVIRONMENT

 Summary 

     TBP is moderately toxic to aquatic organisms, the 96-h LC50  being
 2.2 mg/litre for Daphnia and 4.2-11.4 mg/litre for fish  in static tests.
 No data on non-target plants are available, but since the compound is
 used in  desiccant  defoliants, some  damage to plants adjacent  to
 treated areas could  be expected. 

6.1.  Unicellular algae, protozoa, and bacteria

    Toxicity data of TBP for protozoa, algae, and bacteria are  given  in
Table 7.  The inhibitory concentrations (EC0, EC50, EC100)   of
TBP for the multiplication of unicellular  algae, protozoa, and bacteria
have been estimated to lie within the range of 3.2-100 mg/litre.

6.2.  Aquatic organisms

    Data  on the toxicity of TBP for aquatic organisms are given in 
Table 8.

    There  is little difference in sensitivity between the few species of
fish that have been studied;  96-h LC50 values range  from 4.2 to  11.8
mg/litre.  It seems  that embryo-larval stages are less sensitive than
post-natal stages of the  fish life-cycle, but  since the test  conditions
used were not identical this has not been fully  confirmed.  A series of
tests carried out at different temperatures with rainbow trout suggested
that toxicity increases with increasing temperature (Dave et al., 1979).
    
    In  studies by Dave & Lidman (1978), rainbow trout did not show any
obvious effects at water concentrations below 5.6 mg TBP/litre but behaved
very calmly when trapped in a hand-net at a concentration of 1 mg/litre
(all concentrations  are  nominal value).  At  10 mg/litre, the fish
started  showing  severe  balance disturbances,  which included  highly 
atypical  movements like  darting, coiling swimming, and  backward 
somersaults, but  they recovered after 24-72 h at this concentration.  
On the  other  hand, the  balance disturbances persisted  until the end  
of the experiment at a concentration of 11.5 mg/litre. At 13.5 mg per litre, 
the fish were immobilized, lying on their sides at the bottom of the water, 
and some of them died. 


Table 7.  Toxicity of TBP to protozoa, unicellular algae, and bacteria
---------------------------------------------------------------------------------------------------------
Organism    Species          Temper- Habitata  Exposure  Concent-  Effect                 Reference
                             ature                       ration    
                             (°C)                        (mg/litre)
---------------------------------------------------------------------------------------------------------
Protozoa     Entosiphon       25      F         3 days    14        Inhibition of cell     Bringmann (1975, 
              sulcatum                                              multiplication: EC0    1978); 
                                                                                          Bringmann & 
                                                                                          Kühn (1977a, 
                                                                                          1981)
             Uronema          25      F         20 h      21        Inhibition of cell     Bringmann & 
              parduczi                                              multiplication: EC0    Kühn (1980, 
                                                                                          1981)
             Chilomonas       20      F         2 days    42        Inhibition of cell     Bringmann & 
              paramacecium                                          multiplication: EC0    Kühn (1980, 
                                                                                          1981)
Cyano-       Microcystis      27      F         8 days    4.1       Inhibition of cell     Bringmann 
bacterium     aeruginosa                                            multiplication: EC0    (1975)            
(blue-green
alga)                                                                                                              
                                                                                                                   
Green alga   Chlorella        25      F         2 days    10 - 50   Inhibition of cell     Dave et al. 
               emersonii                                            multiplication: EC50   (1979)

Green alga   Scendesmus       27      F         7 days    3.2       Inhibition of cell     Bringmann 
              quadricaudata                                         multiplication: EC0    (1975); 
                                                                                          Bringmann & 
                                                                                          Kühn (1979)
Algae       13 algal         20      F         14 days   50        Inhibition of cell     Blanck et al. 
             species                                               multiplication: EC100  (1984)

Bacteria     Thiobacillus     35      S         0-90 min  218b      Inhibition of oxygen   Torma & 
              ferroxidans                                           uptake; 64% of control Itzkovitch 
                                                                                          (1976)

             Pseudomonas      25      S         16 h      >100     Inhibition of cell     Bringmann & 
              putida                                                multiplication: EC0    Kühn (1977a); 
                                                                                          Bringmann & 
                                                                                          Kühn (1979, 
                                                                                          1980)
---------------------------------------------------------------------------------------------------------
a  F = fresh water;  s = sediment
b  Total organic carbon content

Table 8.  Toxicity of TBP for aquatic organisms
---------------------------------------------------------------------------------------------------------
Organisms     Age/size        Temp.   pH       Stat/    Hard-  Endpoint        Effect     Concent- Refer-
                              (°C)             renewal  ness   or                         ration   ence
                                                        (mg/   criteria used              (mg/
                                                        litre)                            litre)
---------------------------------------------------------------------------------------------------------
Rainbow       Fry; 0.15 g     5       7.0      stat     45                     96-h LC50  9.4      Dave 
trout         Fry; 0.15 g     10      7.0      stat     45                     96-h LC50  11.8     et al., 
 (Salmo        Fry; 0.15 g     15      7.0      stat     45                     96-h LC50  8.2      1979
 gairdneri)    Fry; 0.15 g     20      7.0      stat     45                     96-h LC50  4.2      
                   20 g       15(±1)  8.5      stat     43.4                   96-h LC50  5-9      Dave & 
                                                                                                   Lidman, 
                                                                                                   1978
                                    (7.0-9.4)
              Embryo-larva;   8(±1)   8.3      stat-    100    Egg: turning    50-d LC0   8        Dave 
               2 weeks before                  renewal         white to                            et al., 
               hatching                                        yellowish;                          1981
                                                               larva: no  
                                                               response to
                                                               mechanical 
                                                               stimulation



Killifish     0.1 - 0.2 g     25               stat                            96-h LC50  9.6      Sasaki 
 (Oryzias                                                                                           et al., 
 latipes)                                                                                           1981

Goldfish      0.8 - 2.8 g     25               stat                            96-h LC50  8.8      Sasaki 
 (Carassius                                                                                         et al., 
 auratus)                                                                                           1981

Table 8. (contd.)
---------------------------------------------------------------------------------------------------------
Organisms     Age/size        Temp.   pH       Stat/    Hard-  Endpoint        Effect     Concent- Refer-
                              (°C)             renewal  ness   or                         ration   ence
                                                        (mg/   criteria used              (mg/
                                                        litre)                            litre)
---------------------------------------------------------------------------------------------------------

Zebra fish    0.25 g          25      8.3      stat     100                    96-h LC50  11.4a    Dave 
 (Brachydanio                        (7.3-8.5)                                                      et al., 
 retio)                                                                                             1981

              Embryo-larva;   25      8.3      stat-    100    Egg: turning    10-d LC0   13.5a    Dave 
               5 h after                       renewal         opaque;                             et al., 
               fertilization                                   larva: no                           1981
                                                               response to
                                                               mechanical 
                                                               stimulation


Goldenorfe    5-7 cm,         20(±1)  7 - 8    stat     269                    48-h LC50  7.6      Juhnke 
 (Leuciscus    1.5(±0.3g)                       (±54)                                               & Lüde-
                                                                                                   mann,
                                                                                                   1978
 idusmelanotus)                                                                                     
Waterflea     <24 h           20      8.0      stat     200    Immobilization  24-h EC50  30       Bring-
 (Daphnia                                                                                (25-36)    mann        
                                                                                                   & Kühn,
                                                                                                   1982   
 magna)        24 h            20-22   7.6-7.7  stat     286                    24-h LC50  33       Bring-
                                                                                                   mann &      
                                                                                                   Kühn,
                                                                                                   1977
                                                                                                    
Fathead       1.20 g          17.0    7.4      stat     44                     96-h LC50  1-10     Mayer & 
minnow                                                                                             Eller-
 (Pimephales                                                                                        sieck,
 promelas)                                                                                          1986
            
---------------------------------------------------------------------------------------------------------
a  Nominal value
6.3.  Plants

    TBP  is used as  a constituent of  cotton  defoliants, producing  leaf
scorching,  and  is  associated  with  an increase in the rate of leaf
drying (Harris  &  May-Brown, 1976).   Kennedy et al. (1955) reported that
TBP increases the  drying rate of  lucerne, resulting in  excessive leaf
loss.

    TBP  applied by  spraying as  an emulsion  (at a  rate equivalent  to
0.25%  of freshly  harvested  leaf/weight) doubled  the drying rate of
ryegrass leaves.  Leaf respiration  stopped and did not resume in the
subsequent 4 days (Harris  & May-Brown, 1976).  TBP has been shown to
damage the leaf surface and help herbicides penetrate bean leaves (Babiker
& Dancan, 1975; Turner, 1972).

    There  is no information on the effects of TBP on non-target  plants,
even at concentrations designed to produce desiccation of crop plants.

6.4.  Arachnids

    No mortality was observed among two-spotted spider mites   (Tetranychus
 urticae) fed TBP at a concentration of 2 g/kg (Penman & Osborne, 1976).

7.  KINETICS AND METABOLISM

 Summary 

     TBP is readily absorbed (greater than 50%) from  the  gastrointestinal
 tract  in rats. Some  absorption of TBP  through the skin  also occurs,
 although the extent of dermal absorption  is  difficult to quantify from
 the data available. No information  is  available on the absorption of
 TBP following inhalation,  and  there is  no satisfactory information on
 the distribution of TBP  or its metabolites following absorption.  The
 metabolism of TBP is characterized  by  oxidation  of the  butyl
 moieties. Oxidized butyl  groups are removed  as glutathione conjugates
 and  subsequently excreted as N-acetyl cysteine derivatives. TBP metab-
 olites  are  excreted  predominantly  in  the  urine,  although smaller
 amounts also appear in the faeces and expired air. 

7.1.  Absorption

    No information is available on the absorption  of  TBP following
inhalation.   Substantial  absorption from  the gastrointestinal  tract
occurred  in rats  given a single oral  dose of  TBP (Suzuki  et al.,
1984a,b; Khalturin  & Andryushkeeva, 1986).  Suzuki et al. (1984b)
reported that more  than 50% of an  orally administered dose of  TBP was
absorbed within 24 h.  Dermal absorption of TBP  has  been demonstrated in
pigs, and there was little  difference  in the  rate  of skin  penetration
between regions  with  or without   hair  follicles  (Schanker,  1971).
 In   vitro investigations  on isolated human skin showed that TBP has a
high penetrating capacity.  The average maximum steady-state rate of
penetration through isolated human  skin  is 6.7 x 10-4 µmol/cm2 per min
(Marzulli et al., 1965).

    In  a study by  Sasaki et al.  (1985), TBP was  poorly absorbed in
goldfish but readily absorbed in killifish.

7.2.  Distribution

    Little information is available on the distribution of TBP and its
metabolites. Following single or repeated oral dosing in rats, TBP was
detected in  the  gastrointestinal tract, blood, and liver (Khalturin &
Andryushkeeva, 1986).

7.3.  Metabolism

    The  metabolic transformation of TBP  has been studied in  male rats
following  oral or intraperitoneal  administration  of 14C-labelled  TBP
(Suzuki et  al., 1984a,b). The  first stage in the  metabolic process
appeared to  be oxidation,  catalysed by cytochrome  P-450-dependent mono-
oxygenase, at the  w  or  w -1 position on the butyl chains. The hydroxy
groups generated at the  w   and  w -1 positions were further oxidized to
produce  carboxylic  acids and ketones,  respectively (Suzuki et al.,
1984b).  Following these oxidations, the oxidized alkyl moieties were
removed as glutathione conjugates,  which were then excreted as  N -acetyl
cysteine derivatives (Suzuki et al., 1984a). It has been reported that TBP
is also metabolized in  rodents  to butyl- n -cysteine   (Jones, 1970).

However, the presence of butyl- n -cysteine  was refuted by Suzuki et al.
(1984a). In  the urine, the major phosphorus-containing metabolites are
dibutyl  hydrogen  phosphate, butyl  dihydrogen phosphate, and butyl
bis(3-hydroxybutyl)  phosphate as well as small amounts of the following
phosphates: dibutyl 3-hyroxy-butyl, butyl 2-hydroxybutyl hydrogen,  butyl
3-hydroxybutyl hydrogen, butyl 3-carboxypropyl hydrogen,  3-carboxypropyl 
dibutyl, butyl 3-carboxypropyl 3-hydroxybutyl, butyl bis (3-carboxypropyl), 
and 3-hydroxybutyl dihydrogen (Suzuki et al., 1984b). 

    The  rate of metabolism of  TBP and the nature  of the metabolites
produced were determined in  in vitro  tests on rat liver homogenate.  It
was found that rat liver microsomal enzymes rapidly metabolized TBP in
the  presence  of NADPH (within 30 min), but only slight metabolic
breakdown (11%)  occurred in the absence of added NADPH.  Dibutyl(3-
hydroxybutyl)  phosphate was obtained  as a metabolite  in the first stage
of the test.  The extended incubation time in the second stage of the test
yielded two further metabolites,  butyl  di(3-hydroxybutyl)  phosphate
and  dibutyl hydrogen  phosphate, which were produced  from the primary
metabolite  dibutyl(3-hydroxybutyl)  phosphate (Sasaki  et al.,  1984).
The degradation of TBP to these three metabolites has also been observed
in  in vitro  studies on goldfish and killifish (Sasaki et al., 1985).

7.4.  Excretion

    In  studies by Suzuki et al. (1984b), male Wistar rats (weighing 
180-210 g) were given  a single oral or  intraperitoneal  dose of 14 
mg  14C-labelled TBP per kg  body weight.  Urine and faeces were 
collected separately. Within  24 h of oral administration, 50% of the  
radioactivity  was eliminated in  the urine, 10%  in the  exhaled air, 
and 6% in the faeces; the total elimination  after  5 days  was 82%. 
Following intraperitoneal injection, 70% of the  radioactivity  was 
eliminated  in the urine, 7%  by exhalation, and 4% in the  faeces 
within 24 h;  the total elimination after 5 days was 90%. 

8.  EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO  TEST SYSTEMS

 Summary 

     Acute  toxicity  studies suggest  that  the chicken is the least
 sensitive species to TBP, rats and mice being more sensitive.   A single
 injection of TBP produces clinical symptoms of mild anaesthesia, weakness,
 and respiratory failure.

     Some  short-term toxicity studies showed that TBP depresses body  weight.
 However,  other short-term  studies  showed  no depression of body weight
 but histological evidence of degenerative  changes in the seminiferous
 tubules.  Further short-term studies  indicated diffuse hyperplasia  of
 the urinary  bladder epithelium.

     Mild to  severe  skin irritation, inducing  erythema  and oedema, has
 been reported together with mild  irritation  after instillation of TBP
 into the conjunctival sac of rabbits.

     In  mutagenicity studies, equivocal results have been  obtained in the
 Ames test in the presence or absence of metabolic activation.  However,
 Escherichia coli tests, Salmonella microsome  tests, and recessive lethal
 mutation tests in Drosophila melanogaster all indicate that TBP is non-
 mutagenic.

     TBP produces only mild plasma cholinesterase depression in rats.
 Short-term exposure results in the depression of caudal nerve  conduction
 velocity and equivocal  morphological changes in the Schwann cells of
 peripheral nerves.

     Chicken dosed with high levels of TBP showed no evidence of ataxia  or
 nerve and  brain histopathology. These  data  demonstrate  that  TBP does
 not produce delayed  neuropathy  (i.e. OPIDN) in the chicken. 

8.1.  Single exposure

    The acute lethality data for TBP are presented in Table 9.

    Vandekar (1957) observed that a single injection of 80 or 100 mg TBP/kg
in female rats produced clinical symptoms of  mild anaesthesia, pronounced
weakness, incoordination, and respiratory failure 1-2 h later.

Table 9.  Acute lethality date for TBP
----------------------------------------------------------------------
Species  Route of           LD50/LC50         Reference
         administration     values
----------------------------------------------------------------------
Rat      oral               1400 mg/kg        Johannsen et al. (1977)
         oral               1390-1530 mg/kg   Mitomo et al. (1980)
         oral               1552 mg/kg        Bayer AG (1986)
         oral               1600-3200 mg/kg   Eastman Kodak (1986)
         oral               3000 mg/kg        Dave & Lidman (1978)
         6-h inhalation     1359 mg/m3        Eller (1937)
         intraperitoneal    800-1600 mg/kg    Eastman Kodak (1986)
         intravenous        100 mg/kg         Vandekar (1957)

Mouse    oral               900-1240 mg/kg    Mitomo et al. (1980)
         oral               400-800 mg/kg     Eastman Kodak (1986)
         intraperitoneal    100-200 mg/kg     Eastman Kodak (1986)
         subcutaneous       3000 mg/kg        Eller (1937)

Rabbit   dermal             > 3100 mg/kg      Johannsen et al. (1977)

Cat      4-5-h inhalation   2500 mg/m3        Eller (1937)

Chicken  oral               1800 mg/kg        Johannsen et al. (1977)
----------------------------------------------------------------------

    Mitomo  et al. (1980) reported  acute toxicity studies on TBP. The 
oral LD50 values  for ddY mice and Wistar rats were 1240 mg/kg (male 
mice), 900 mg/kg (female mice), 1390 mg/kg (male rats), and 1530 mg/kg 
(female rats). 

8.2.  Short-term exposure

    In  a  short-term toxicity  study  with TCP  and  TBP, Wistar rats 
were fed pelleted diet containing a mixture of TBP and TCP at a 
concentration of 5000 mg/kg for  9  weeks (Oishi  et al., 1982).   The 
body weights  of TBP-treated rats  were significantly lower than those 
of the controls. Oishi  and  his  co-workers  also  reported  a  short-
term toxicity study with TBP in which Wistar male rats were fed diets  
containing 0, 5000 or 10 000 mg TBP/kg for 10 weeks (Oishi  et al., 
1980).  The body weights and food consumption of the treated groups were 
significantly  lower  than those  of the controls.  The relative weights 
of the brain and  kidneys in  the high-dose  group  were significantly 
higher  although  the absolute  weights were significantly lower  than 
those of the  control rats. Total protein  and cholesterol in the high-
dose group and blood urea nitrogen (BUN) in both TBP-treated groups were 
significantly higher than those in the controls. Cholinesterase 
activities were not  inhibited.  The blood coagulation time of the 
treated groups was significantly prolonged. 

    Laham et al. (1984) reported the results of  a  short-term  toxicity 
study in which Sprague-Dawley rats were administered TBP by gavage at 
doses of 0.14  and  0.42 ml/kg for  14 days.  No  overt signs of  
toxicity were  observed throughout  the study.  There were  no 

significant differences in body weight between the test groups and 
their respective controls,  but  absolute  and  relative  liver weights  
were significantly  increased in  the  high-dose group (both sexes). 
Histopathological examination revealed a  low incidence of degenerative 
changes in the seminiferous tubules of the high-dose group. 

    In a follow-up 18-week study, Laham et al. (1985) administered  TBP
by gavage  once a day  (5 days/week)  to Sprague-Dawley rats (12 rats of
each sex per group).  Low-dose  animals  received  200 mg/kg per  day
throughout the study.   High-dose animals received 300 mg/kg  per day for
the  first 6 weeks and 350 mg/kg per day for the remaining 12  weeks.
Histopathological examination  of tissues revealed that all treated rats
developed diffuse hyperplasia of  the urinary bladder epithelium.
Similar changes were not found in the control animals.  No testicular
changes were observed in the high-dose rats.

    When Sprague-Dawley rats were fed diets containing TBP at  levels of 
0, 8, 40, 200,  1000, or 5000 mg/kg  for 90 days,  clinical chemistry 
changes included increased serum gamma-glutamyl  transpeptidase levels 
in both sexes given 5000 mg/kg  (Cascieri  et  al., 1985).   Both 
absolute and relative  liver weights were  increased in both  sexes  at 
this dose. Histopathological studies indicated TBP-induced transitional  
cell hyperplasia in  the urinary bladder  of males given 1000 or 5000 
mg/kg and females  given  5000 mg per kg. 

    Mitomo  et al. (1980) reported  that seven consecutive daily  oral 
intubations of TBP  at doses of 140  or 200 mg per  kg in Wistar rats 
resulted in marked increases in the relative weights of the liver and 
kidneys,  increased  BUN values, and tubular degeneration. The daily 
administration of  130 or 460 mg  TBP/kg to rats  for one month  caused 
a marked depression of body weight gain and  mortalities  of 20  and 
40%, respectively.  Three-month feeding studies at TBP doses of 0, 500, 
2000, or 10 000 mg/kg in ddY mice and SD  rats produced dose-dependent 
depression of body weight gain accompanied by increases in liver, 
kidney, and testes weights and a decrease in uterine weight.   Increased  
BUN values were found in the high-dose groups of both rats and mice. 

8.3.  Skin and eye irritation and skin sensitization

    Smyth  & Carpenter (1944) observed  primary skin irritation  effects
following a single  0.01 ml application of TBP to the clipped belly of
albino rabbits.

    A single dermal application of 500 mg TBP to  the  intact  or abraded
skin of six rabbits produced severe irritation, inducing erythema and
oedema in all the  animals.  The instillation of 100 mg TBP in the
conjunctival sac of rabbits gave rise to mild irritation, which was noted
1, 2, 3, and 7 days  following the application (FMC  Corporation, 1985a).

    A  test on the  irritating and corrosive  potential of TBP,  conducted
according  to  the  OECD  Guidelines  for Testing of Chemicals, No. 404
and 405 (OECD, 1981), showed that  TBP  was slightly  irritating  to
rabbit  skin  (4-h exposure) and to rabbit eyes (Bayer AG, 1986).

    Skin  sensitization testing in human is inadequate (US EPA, 1987b, 1989).
Although results suggest that TBP does not  elicit any sensitization
reaction in humans, the poor protocols used prevent any pertinent
assessment.

8.4.  Teratogenicity

    Roger et al. (1969) reported that TBP was slightly teratogenic in
chickens at high levels.

8.5.  Mutagenicity and carcinogenicity

    Hanna & Dyer (1975) reported that TBP was not mutagenic in recessive
lethal mutation tests using  Drosophila melanogaster.    However, Gafieva
& Chudin (1986) reported that TBP was mutagenic in the Ames test with 
Salmonella typhimurium TA 1535 and TA 1538 at concentrations of 500 and
1000 µg/plate both with and without metabolic activation.  No mutagenicity
was noted at lower concentrations (less than 100 µg/plate).

    The mutagenicity  of TBP was also evaluated in S. typhimurium strains TA
98, TA 100, TA 1535 and TA 1538 (Ames Test) both in the  presence and
absence of  added metabolic  activation  by  Aroclor-induced  rat liver S9
fraction.  TBP, diluted with  DMSO, was tested  at concentrations up to
100 µl/plate  using the plate incorporation technique.  TBP did not
produce a positive response in any strain  with  metabolic  activation.
Strains  TA 1535, TA 1537,  and TA 1538, without metabolic activation,
produced twice the number of revertants per plate compared  to  the
solvent control (DMSO) for at least three of the five test concentrations,
but  no  dose-response  relationship  was observed (US EPA, 1978).

    Tests on  Escherichia coli  strains WP2, WP2 uvr  A, CM561, CM571, 
CM611, WP67, and  WP12 showed no  mutagenic effect after  48  or 72 h  of
incubation at  37°C (Hanna &  Dyer, 1975).

    TBP  was tested for mutagenic effects in a Salmonella/microsome test,
both with and without S9 mix (metabolizing system),  at doses of  up to
12.5 mg/plate  using four  S. typhimurium  LT2 mutants (histidine-
auxotrophic strains TA 1535,  TA 100,  TA 1537  and  TA 98).  Doses  of
up   to 120 µg/plate  produced no bacteriotoxic effects. Bacterial counts
remained unchanged.  At high  concentrations there was marked strain-
specific bacterial toxicity so that only the  range up to 500 µg/plate
could be evaluated.  There were  no  indications that  TBP  had any
mutagenic effect (Bayer AG, 1985).

    The testing of TBP at doses of 97 to  97 000 µg  per plate, both with
and without a metabolizing  system  (S9 mix), on S. typhimurium  strains
TA 98, TA 100,  TA 1537, and  TA 1538 confirmed the lack of mutagenic
activity (FMC Corporation, 1985b).

    No data are available on the carcinogenicity of TBP.

8.6.  Neurotoxicity

    Sabine & Hayes (1952) showed that both  technical  and reagent  grades
of  TBP possess  very weak cholinesterase activity  and  that  very large

doses produce cholinergic symptoms   in  vivo.    They concluded that
although TBP was capable  of  producing  cholinergic  symptoms,  the
doses required  were  so large  that  the "risk  of  accidental
absorption of acutely toxic amounts is negligible.  If the dosages  for
rats are  roughly  applicable to  humans, it would  be necessary for the
development of symptoms that a human  ingest  a dose  in the order  of 100
ml  or receive several millilitres parenterally".  Sabine & Hayes (1952)
found  that  TBP  induced  sleepiness  and  coma  in  male Sprague-Dawley
rats when it  was orally and  parenterally administered.

    Laham et al. (1983) reported the effects of TBP on the peripheral
nervous system of Sprague-Dawley rats.  In male rats fed TBP by gavage for
14 consecutive days (0.42 ml/kg per day) a small but significant reduction
of caudal nerve conduction velocity, accompanied by morphological changes
in the sciatic  nerve, was  found.  Electron microscopic examination  of
sciatic nerve sections showed a retraction of Schwann cell processes in
unmyelinated fibres, which may be interpreted as an early response to
chemical insult.  No axonal degeneration was observed in these animals.
Laham et al. (1984) also investigated subacute oral toxicity  of TBP in
Sprague-Dawley rats and observed no overt signs of neurotoxicity (ataxia,
convulsion, loss of righting reflex, etc.).

    Johannsen et al. (1977) administered TBP orally to adult chickens at a
cumulative dosage of  3680 mg/kg.  No dysfunctional changes were noted
during the period from 24 to 42 days following exposure.  Formalin-fixed
brain, sciatic nerve, and spinal cord samples examined 42 days after
exposure showed no pathology.

9.  EFFECTS ON HUMANS

    Although there are no case reports of delayed neurotoxicity  resulting
from TBP exposure,  workers exposed to 15 mg TBP/m3  air have complained
of nausea and headaches (ACGIH, 1986).

    TBP has  a  high  capacity  for  skin  penetration (Marzulli  et  al.,
1965)  and has been  shown to have  an irritant effect on the skin and
mucous membranes in humans (Stauffer,  1984).  It also  appears to have
an irritant effect on the eye and respiratory tract.

    In an  in vitro  study, Sabine & Hayes (1952) found that TBP  had  a
slight  inhibitory  effect  on  human  plasma cholinesterase.

10.  EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT

10.1.  Evaluation of human health effects

    There have been no reports that TBP has effects on occupationally
exposed humans other than  headache, nausea, and symptoms of skin, eye,
and mucous membrane irritation. No cases of poisoning among the general
population have been reported.

    There is no indication from animal studies of a neuro-toxic effect
comparable to organophosphate-induced delayed neuropathy (OPIDN).
Systemic toxicity in humans following acute exposure is likely to be low.

    From  in vitro  test results, TBP is not considered to be mutagenic.

    TBP is absorbed through the skin and so dermal exposure should be
minimized.

    The likelihood of long-term effects in occupationally exposed humans is
small.

10.1.1.   Exposure levels

    The general population may be exposed to  TBP  through various
environmental  media,  including  drinking-water. However,  the
concentrations of TBP  measured in drinking-water  by  the  USA
Environmental  Protection  Agency were extremely  low and similar low
levels were found in Japan, Canada, and Switzerland.  Analyses in the USA
of human adipose  tissue revealed trace amounts  of TBP in a  small number
of samples.  There are insufficient data to evaluate the  significance of
general population exposure to TBP.

    Workers involved in aircraft maintenance are potentially the most highly
exposed population because of manipulation of hydraulic fluids containing
TBP.

10.1.2.   Toxic effects

    Tributyl phosphate may enter the body by dermal penetration and by
ingestion.  However, the data available do not permit a useful comparison
of the dermal and oral pharmacokinetics.

    The available information does not  permit an assessment of the risk
presented by TBP as a potential carcinogen, neurotoxic agent, or dermal
sensitizer.  Observations relating to hyperplasia of urinary  bladder
epithelium in rats,  neurotoxicity signs (ataxia, incoordination, weak-
ness, respiratory failure) in rats, and sensitization of guinea-pigs  are
considered inadequate to  evaluate the hazardous  potential of TBP  for
human health.   No tumour development has been observed in rats. TBP does
not  produce delayed neurotoxic effects in hens.  No adequate data are
available on the effects of TBP on reproduction (function of gonads,
fertility, parturition, growth and development of offspring).

10.2.  Evaluation of effects on the environment

    Although, on the basis of physico-chemical properties, TBP has a high
potential for bioaccumulation, measurements in laboratory experiments show
that this is  not  realized in  practice.  Residues in biota sampled from
the environment  are  generally  low, though  measurable  residues in
birds  suggest that  some transfer  in the  food chain  is possible.
Toxicity data are limited but suggest moderate toxicity  to aquatic
organisms.  This information tends to support the view that TBP presents
little risk  to  organisms in the environment since measured
concentrations in surface waters are generally low.

10.2.1.   Exposure levels

    TBP  has been found widely in surface water, sediment, and ground
water, but normally only at low concentrations. The  biodegradation of
TBP  in water is  substantial under aerobic  conditions but proceeds only
at a slow rate below certain concentrations.  It is possible that a  low 
level equilibrium is reached in the environment between continuous release
and removal.  The lack of data on the rate of TBP hydrolysis does not
permit a reliable  assessment of the  persistence of TBP in the
environment.  Consequently, the potential hazard of the substance cannot
be evaluated.  More  data are  required on  the rate  of TBP  hydrolysis,
which, when used with the available information  on  the biodegradability,
will  facilitate the  assessment of its persistence  and consequently the
environmental risk posed by its manufacture, use, and disposal.

10.2.2.   Toxic effects

    The sensitivity of aquatic organisms to TBP  has  been determined in
static tests.  However, the biodegradability and  relative  hydrophobicity
suggest that flow-through testing would provide more reliable data because
of more constant  exposure.   The available information indicates moderate
toxicity of TBP to algae, daphnids, and rainbow trout.  TBP causes damage
to terrestrial plants by increasing leaf drying rates, which results in
excessive leaf loss.   No information is  available on uptake  and
translocation.

11.  RECOMMENDATIONS

11.1.  Recommendations for further research

    There is a need for further studies on skin sensitization,
teratogenicity  and reproductive  toxicity, and on the pharmacokinetics of
different exposure routes.

    Further testing for mutagenic potency is required. Initial  in vitro 
tests on mammalian cell cultures should, if  necessary, be followed by  in
 vivo  testing.  Depending on  the outcome of  these mutagenicity tests,  a
carcinogenicity study may be required.

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SUZUKI,  T.,  SASAKI,  K., TAKEDA,  M.,  &  UCHIYAMA, M.  (1984b)
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RESUME

1. Identité, propriétés physiques et chimiques, méthodes  d'analyse

    Le phosphate de tri- n -butyle  (TBP) est un liquide ininflammable,
inexplosible, incolore et  inodore. Toute-fois, il est instable à  la
chaleur  et commence  à se décomposer  à  des  températures inférieures  à
son point d'ébullition.   Par analogie avec les propriétés chimiques du
phosphate de triméthyle, il devrait subir une hydrolyse rapide  en milieu
acide neutre ou alcalin.  C'est un agent faiblement  alkylant.   Son
coefficient de  partage entre l'octanol et l'eau (log de Pow) est de 3,99-
4,01.

    Pour  l'analyse, la méthode choix  est la chromatographie  gaz-liquide,
avec détection au moyen d'un dispositif sensible à l'azote/phosphore ou
par photométrie de flamme. Les  réactifs pour analyse sont fréquemment
contaminés par du  TBP;  aussi, faut-il  veiller à ce  problème lorsqu'on
s'efforce  d'obtenir des données fiables  sur la recherche de traces de
TBP.

2. Sources d'exposition humaine et environnementale

    Le phosphate de tri- n -butyle est produit par réaction du 
 n -butanol sur l'oxychlorure de phosphore.  On l'utilise  comme solvant 
des esters cellulosiques,  des vernis  et des gommes naturelles et comme
plastifiant pour différentes  matières  plastiques,  notamment les résines
vinyliques.   On l'utilise également pour l'extraction des métaux,  comme
base  dans  la  préparation  des  liquides hydrauliques  ininflammables
destinés à  l'aéronautique et comme  agent antimousse.  Au  cours des
dernières  années, l'usage  du TBP comme solvant d'extraction dans le
procédé par  dissolution utilisé pour  le retraitement du  combustible
nucléaire, s'est beaucoup développé.

    On peut considérer qu'en  utilisation normale, la population  dans son
ensemble n'encourt qu'une exposition minime.

3. Transport, distribution et transformation dans l'environnement

    Lorsqu'on  l'utilise  comme  réactif,  comme   solvant d'extraction  ou
comme agent antimousse,  le TBP s'échappe continuellement   dans
l'atmosphère  et  dans  le  milieu aquatique.   Sa  biodégradation  est
moyennement  lente  à lente  selon  sa  proportion  par  rapport  à  la
biomasse active.    Elle  comporte  une  hydrolyse  enzymatique  en
plusieurs étapes conduisant à un orthophosphate et au  n -butanol, lequel
est dégradé à son tour.   Les  techniques ordinaires  de  traitement  de
l'eau  de  consommation  ne réduisent pas sa teneur en phosphate de
tributyle.

    Les  facteurs  de  bioconcentration mesurés  chez deux espèces  de
poissons  (un cyprinodontidé  et  le  poisson rouge) vont de 6 à 49.  La
demi-vie d'élimination  est  de 1,25 heure chez ces poissons.

4. Niveaux dans l'environnement et exposition humaine

    On  trouve fréquemment du  TBP dans l'air,  l'eau, les sédiments  et les
organismes aquatiques  mais les prélèvements effectués n'en contiennent
que de faibles quantités. On en a trouvé de plus fortes concentrations
dans  l'air, l'eau  et les poissons  prélevés à proximité  d'usines  de
pâte  à papier au Japon: 13,4 ng/m3 dans  l'air, 25 200 ng par  litre dans
l'eau de rivière et 111 ng/gramme dans les organes pisciaires. Des études
de ration totale effectuées au  Royaume-Uni et aux  Etats-Unis indiquent
que  l'apport alimentaire  moyen quotidien de  TBP est d'environ  0,02 à
0,08 µg/kg de poids corporel.

5. Effets sur les êtres vivants dans leur milieu naturel

    On  estime que la concentration inhibant la multiplication des algues
unicellulaires, des protozoaires et des bactéries  (CE0,  CE50,  CE100),
se  situe  dans les limites de 3,2 à 100 mg/litre.  La toxicité aiguë pour
les poissons (CL50)  varie de 4,2 à 11,8 mg/litre.    Le  TBP augmente  la
vitesse  de  dessèchement  des  feuilles, entraînant  une  inhibition
rapide  et  complète  de  la respiration foliaire.

6. Cinétique et métabolisme

    Administré  par voie  orale  ou injecté par voie intrapéritonéale  à des
animaux de laboratoire, le TBP est rapidement transformé par le foie et
peut-être  aussi  par le rein en produits d'hydroxylation au niveau  des
restes butyliques.   Le TBP  est principalement  excrété sous la forme
d'hydrogénophosphate  de dibutyle, de dihydrogéno-phosphate de butyle et
de phosphate de butyle et  de bis-hydroxy-3  butyle.   Les  restes alkyles
hydroxylés  sont éliminés et excrétés sous forme de  n -acétylalkyl
cystéine et de gaz carbonique.

7. Effets sur les animaux d'expérience et les systèmes d'épreuve  in vitro 

    Les valeurs de la DL50 par  voie orale chez la souris et le rat seraient
d'environ 1 à 3 g/kg ce qui indique une toxicité aiguë relativement
faible.

    Des  études  de  toxicité  subchronique  ont permis d'observer une
réduction du gain de poids liée à  la  dose ainsi qu'une augmentation du
poids du foie, des  reins  et des  testicules.  Le rein  semble être
l'organe  cible  du phosphate de tri- n -butyle.

    L'irritation  cutanée  provoquée  par le  TBP chez des lapins albinos
paraît aussi sévère qu'avec la morpholine.

    Le TBP serait légèrement  tératogène à fortes  doses. Quant  à son
pouvoir mutagène, il n'a pas été suffisamment étudié. Des résultats
négatifs ont été signalés à la suite d'épreuves  sur  bactéries  ainsi
qu'après  une épreuve de mutation létale récessive sur  Drosophila
melanogaster.

    Il n'existe  pas  de données  suffisantes  permettant l'évaluation  du
pouvoir cancérogène du  TBP et on n'en  a pas étudié les effets  sur la
fonction de reproduction.

    L'aptitude  du TBP à produire une neuropathie retardée n'a  pas  été
suffisamment étudiée.   Certes,  les effets observés  après administration
orale d'une dose importante (0,42 ml/kg/jour  pendant  14 jours)  font
songer  à  une neuropathie  retardée, mais aucune dégénérescence  n'a été
relevée   au  niveau  de   axones  et  aucune   conclusion définitive  ne
peut donc être  tirée de ces études.   A la même  dose (0,42 ml/kg/jour 
pendant 14 jours) on a observé une  réduction sensible de  la  vitesse de  
conduction au niveau  du nerf caudal et une altération morphologique des 
fibres  non  myélinisées  chez  le  rat. Ces   résultats montrent  que le 
TBP  exerce des effets  neurotoxiques sur les nerfs périphériques. 

8. Effets sur l'homme

    Lors d'une étude  in vitro,   on a relevé  que le  TBP avait  un  léger
effet inhibiteur  sur  la cholinestérase plasmatique.

    On  n'a  signalé  aucun cas  de neurotoxicité retardée comme  cela est
arrivé  lors d'intoxications par  le phosphate de tricrésyle.


EVALUATION DES RISQUES POUR LA SANTE HUMAINE ET DES EFFETS SUR 
L'ENVIRONNEMENT

1. Evaluation des risques pour la santé humaine

    A part des maux de tête, des nausées et des symptômes d'irritation  au
niveau  de la  peau,  des  yeux  et  des muqueuses,  on n'a pas signalé
d'effets chez des personnes exposées de par leur profession.  Aucun cas
d'intoxication n'a été signalé dans la population générale.

    Rien  n'indique, compte tenu des résultats obtenus sur l'animal, que le
TBP ait des effets neurotoxiques comparables à la neuropathie retardée
que produisent les composés organophosphorés. Il est probable que la
toxicité aiguë du TBP est faible pour l'homme.

    Les résultats d'épreuves  in vitro  indiquent que le TBP n'est pas 
mutagène.

    Le  TBP est absorbé  par voie cutanée,  aussi  faut-il éviter toute
exposition de l'épiderme.

    Des  effets  à  long  terme  dus  à   une   exposition professionnelle
sont peu probables.

1.1 Niveaux d'exposition

    Il y  a probablement  un  risque d'exposition  de  la population
générale au TBP par l'intermédiaire des divers compartiments de
l'environnement et notamment par l'eau de consommation.   Toutefois les
concentrations  de phosphate de  tributyle  mesurées  dans  de  l'eau  de
boisson  par l'Agence  de Protection de l'Environnement  des Etats-Unis se
sont  révélées extrêmement  faibles  et l'on  a trouvé également  des
valeurs très basses au Canada et en Suisse. Des  analyses  effectuées  aux
Etats-Unis  sur  des tissus adipeux  humains ont révélé la  présence de
traces de  TBP dans  un  petit  nombre  d'échantillons.   Cependant,  les
données  sont insuffisantes pour qu'on puisse se faire une idée  du degré
d'exposition  de la population  générale au TBP.

    Les  personnes  qui  travaillent  à  l'entretien  des aéronefs  sont
les plus exposées  au TBP  car elles  sont amenées  à  manipuler  des
liquides  hydrauliques  qui  en contiennent.

 1.2 Effets toxiques

    Le  phosphate  de  tributyle  peut  pénétrer  dans l'organisme  par 
voie percutanée  ou  par  ingestion. Toutefois,  les données disponibles 
ne permettent pas  de comparer  utilement la pharmacocinétique de ces deux
voies de pénétration.

    A la lumière des  données disponibles, il  n'est  pas possible 
d'évaluer le risque que constitue la TBP en tant qu'agent cancérogène,
neurotoxique  ou   sensibilisant potentiel.   Les observations qui  font
état d'une  hyperplasie de l'épithélium vésical chez le rat, de  signes de
neurotoxicité  (ataxie,  incoordination,  faiblesse, défaillance
respiratoire)  chez  ce même  animal et d'une sensibilisation   chez  les

cobayes,  ne  paraissent  pas suffisantes  pour qu'on puisse  procéder à
une  évaluation réelle  du  risque  pour la  santé  humaine.   On n'a  pas
observé de tumeur chez les rats.  Chez les poulets, le TBP ne produit pas
d'effets neurotoxiques retardés.  En ce qui concerne  la  fonction  de
reproduction,  les  données disponibles  ne sont pas  suffisantes (qu'il
s'agisse  des gonades, de la fécondité, de la parturition ainsi  que  de
la croissance et du développement des poussins).

2. Evaluation des effets sur l'environnement

    Compte tenu de ses propriétés physicochimiques, le TBP présente  une
forte tendance à la bioaccumulation mais les mesures  effectuées au
laboratoire montrent qu'il n'en est rien dans la pratique.  Les résidus
présents dans la faune sauvage  sont généralement faibles encore  que la
présence de résidus dosables chez certains oiseaux fasse  songer  à une
possibilité de transfert  par la chaîne  alimentaire. Les  données
toxicologiques sont  limitées mais indiquent une  toxicité  moyenne  pour
les  organismes  aquatiques. Toutes  ces  données  tendent à  confirmer
l'opinion selon laquelle  le  TBP n'est  guère  dangereux pour  les  êtres
vivants   dans  leur  milieu  naturel,  du  fait  que  les concentrations
mesurées  dans  les eaux  de  surface sont généralement faibles.

2.1 Niveaux d'exposition

    On trouve du TBP un peu partout dans les  eaux  superficielles, les
sédiments et les eaux souterraines mais en principe  sa concentration est
faible.  Dans l'eau, le TBP subit une biodégradation aérobie appréciable
mais celle-ci est  plutôt lente en-dessous de  certaines concentrations.
Il  est possible qu'il  s'établisse un équilibre  à faible concentration
dans  le  milieu naturel  entre l'apport et l'élimination  du TBP.
L'absence de données concernant la vitesse  d'hydrolyse  du TBP  ne
permet pas  d'évaluer de façon   fiable   la   persistance  de   ce
produit  dans l'environnement.  On ne peut donc pas déterminer le danger
potentiel  que  constitue  cette substance.   Il  faudrait avoir
davantage de données sur la vitesse d'hydrolyse, ce qui,  compte tenu de
ce que l'on sait de la biodégrabilité du TBP, faciliterait l'évaluation de
sa persistance et par voie  de  conséquence,  le  risque  qu'il  constitue
pour l'environnement   du  fait  de   sa  production,  de   son
utilisation et de son rejet.

2.2 Effets toxiques

    Des  épreuves  statiques  ont  pebmis   d'évaluer  la sensibilité  des
organismes aquatiques au  TBP.  Toutefois ce produit étant biodégradable
et relativement hydrophobe, il  serait  bon d'effectuer  des  essais dans
un  courant d'eau,  ce  qui  permettrait d'obtenir  des  données  plus
fiables  en raison de  la meilleure constance  de  l'exposition.   Les
données disponibles indiquent que le TBP est modérément  toxique pour les
algues, les daphnies  et  la truite  arc-en-ciel.   Il est dangereux
pour les plantes terrestres  car il accroît  la vitesse de  dessication
des feuilles ce qui entraîne une défoliation excessive.  On ne dispose
d'aucune donnée sur  la fixation du  phosphate de tributyle ni sur sa
translocation.


RECOMMANDATIONS

    Il  est nécessaire de  poursuivre les travaux  sur  la sensibilisation
cutanée  par  le  phosphate  de    tri- n -butyle, sur sa tératogénicité et
sur sa toxicité  pour  la fonction  de  reproduction,  ainsi que  sur  sa
pharmacocinétique selon différentes voies d'exposition.

    Il est également nécessaire de  poursuivre l'étude du pouvoir  mutagène.
Les  épreuves  in vitro  initiales  sur cultures  de  cellules mammaliennes
devront si nécessaire être  suivies d'épreuves  in vivo.  Selon les
résultats de ces  épreuves  de  mutagénicité,  il pourra s'avérer
nécessaire d'effectuer une étude de cancérogénicité.



    See Also:
       Toxicological Abbreviations
       Tributyl phosphate (ICSC)
       Tributyl phosphate (SIDS)