Tributyl phosphate (EHC 112, 1991)

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

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coordination of laboratory testing and epidemiological studies, and
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chemicals.

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 P_ow) 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) -80^a
Boiling point (°C) 289 (with decomp.)^b,d; 177-178
(3.6 kPa)^b,d; 150 (1.33 kPa)^b
Flash point (°C) 193^b; 166^a; 146^d
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) 3.5-12.2^b; 3.7^a
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 4.00^f; 3.99^g; 4.01^h
coefficient (log P_ow)
-----------------------------------------------------------------
^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 method^a 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 method^a 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 1984^a, 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 purposes^a. 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
factor^a (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 Concentration^a 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 Concentration^a 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 Japan^a
------------------------------------------------------------------------
Year Animal/species^b Location^c Concent- Number of
ration^d 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- Habitat^a 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 218^b 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 11.4^a Dave
(Brachydanio (7.3-8.5) et al.,
retio) 1981

Embryo-larva; 25 8.3 stat- 100 Egg: turning 10-d LC₀ 13.5^a 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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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 P_ow) 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)