Tricresyl phosphate (EHC 110, 1990)

INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

ENVIRONMENTAL HEALTH CRITERIA 110

TRICRESYL 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

World Health Orgnization
Geneva, 1990

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chemicals.

WHO Library Cataloguing in Publication Data

Tricresyl phosphate.

(Environmental health criteria ; 110)

1.Tritolyl phosphates - adverse effects 2.Tritolyl phosphates -
toxicity I.Series

ISBN 92 4 157110 1 (NLM Classification: QV 627)
ISSN 0250-863X

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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR TRICRESYL 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
2.1.1. Tricresyl phosphate
2.1.2. Tri- o-cresyl phosphate
2.1.3. Tri- m-cresyl phosphate
2.1.4. Tri- p-cresyl phosphate
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 procedures
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 levels and processes
3.1.1. Accidental release
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
4.2.1. Fish
4.2.2. Plants

5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

5.1. Environmental levels
5.1.1. Air
5.1.2. Water
5.1.3. Soil
5.1.4. Sediment

5.2. General population exposure
5.2.1. Drinking-water
5.2.2. Fish
5.2.3. Human tissues
5.3. Occupational exposure

6. EFFECTS ON ORGANISMS IN THE ENVIRONMENT

6.1. Unicellular algae
6.2. Aquatic organisms
6.3. Insects
6.4. Plants

7. KINETICS AND METABOLISM

7.1. Absorption
7.2. Distribution
7.3. Metabolic transformation
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
8.4. Teratogenicity
8.5. Reproduction
8.6. Mutagenicity and carcinogenicity
8.7. Neurotoxicity
8.7.1. Experimental neuropathology
8.7.2. Neurochemistry
8.7.3. Interspecies sensitivity and variability to OPIDN
8.7.4. Neurophysiology

9. EFFECTS ON HUMANS

9.1. Historical background
9.2. Occupational exposure
9.3. Clinical features
9.4. Prognosis
9.5. Neurophysiological investigations
9.6. Pathological investigations
9.7. Laboratory investigations
9.8. Treatment

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

REFERENCES

RESUME

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

RECOMMANDATIONS

RESUMEN

EVALUACION DE LOS RIESGOS PARA LA SALUD HUMANA Y DE LOS EFECTOS EN EL
MEDIO AMBIENTE

RECOMENDACIONES

WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR TRICRESYL 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 Organiz-
ation, 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 TRICRESYL PHOSPHATE

A WHO Task Group meeting on Environmental Health
Criteria for Tricresyl 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 partici-
pants 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 tricresyl 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

ACh acetylcholine
AChE acetylcholinesterase
BCF bioconcentration factor
CNS central nervous system
FPD flame photometric detector
GC gas chromatography
GLC gas liquid chromatography
GPC gel permeation chromatography
IC₅₀ inhibition concentration, median
LC₅₀ lethal concentration, median
MS mass spectrometry
NOEL no-observed-effect level
NPD nitrogen-phosphorus sensitive detector
NTE neurotoxic esterase
OPIDN organophosphate-induced delayed neuropathy
2-PAM
chloride pralidoxine (2-pyridine aldoxime methyl) chloride
PVC polyvinyl chloride
TAP triaryl phosphate
TBP tributyl phosphate
TCP tricresyl phosphate
TLC thin-layer chromatography
TMCP tri- m-cresyl phosphate
TOCP tri- o-cresyl phosphate
TPCP tri- p-cresyl phosphate
TPP triphenyl phosphate

1. SUMMARY

1.1 Identity, physical and chemical properties, analytical methods

Tricresyl phosphate (TCP) is a non-flammable, non-
explosive, colourless, viscous liquid. Its partition coef-
ficient between octanol and water (log P_ow) is 5.1. It
is easily hydrolysed in an alkaline medium to produce
dicresyl phosphate and cresol, but it is stable in neutral
and acidic media at normal temperatures.

The analytical method of choice is gas chromatography
with a nitrogen-phosphorus sensitive detector or a flame
photometric detector. The detection limit in a water
sample is approximately 1 ng/litre. TCP is easily ex-
tracted from aqueous solution with various organic sol-
vents. Florisil column chromatography is usually used for
clean-up, but it is difficult to separate TCP from lipids
by this method. Other clean-up methods (GPC, activated
charcoal chromatography and Sep-pak C-18) have been rec-
ommended for the purpose. Analytical reagents are often
contaminated with traces of TCP because of its widespread
use. Therefore, care must be taken in order to obtain
reliable data in trace analysis of TCP.

1.2 Sources of human and environmental exposure

TCP is usually produced by the reaction of cresols
with phosphorus oxychloride. There are two industrial
sources of cresols: "cresylic acid" obtained as a residue
from coke ovens and petroleum refining; and "synthetic
cresols" prepared from cymene via oxidation and degrad-
ation. As a result, TCP is a mixture of various triaryl
phosphates.

TCP is used as a plasticizer in vinyl plastics, as a
flame-retardant, as an additive to extreme pressure lubri-
cants, and as a non-flammable fluid in hydraulic systems.

1.3 Environmental transport, distribution, and transformation

The release of TCP to the environment derives mainly
from end-point use, little release occurring during
production. The total release to the environment in the
USA was estimated at 32 800 tonnes in 1977.

Because of its low water solubility and high adsorp-
tion to particulates, TCP is rapidly adsorbed onto river
or lake sediment and soil. Its biodegradation in the
aquatic environment is rapid, being almost complete in
river water within 5 days. The ortho isomer is degraded
slightly faster than the meta or para isomers. TCP is
readily biodegraded in sewage sludge with a half-life of
7.5 h, the degradation within 24 h being up to 99%.
Abiotic degradation is slower with a half-life of 96 days.

Bioconcentration factors (BCF) of 165-2768 were
measured for several fish species in the laboratory using
radiolabelled TCP. The radioactivity was lost rapidly on
cessation of exposure, depuration half-lives ranging
between 25.8 and 90 h.

1.4 Environmental levels and human exposure

TCP has been measured in air at concentrations up to
70 ng/m³ in Japan but reached a maximum of only 2 ng/m³
at a production site in the USA. Workplace air in the USA
contained less than 0.8 mg/m³ at a lubrication oil bar-
rel-filling operation and 0.15 mg/m³ (total phosphates)
in an automobile zinc die-casting plant. Concentrations
of TCP measured in drinking-water in Canada were low (0.4
to 4.3 ng/litre) and TCP was undetectable in well-water.
Levels in river and lake waters are frequently consider-
ably higher. However, this is due to the presence of sus-
pended sediment to which TCP is strongly adsorbed.

Concentrations in sediment are higher with up to 1300
ng/g in river sediment and 2160 ng/g in marine sediment.

Levels in soil and vegetation measured within the
perimeter of production plants were elevated.

Residues in fish and shellfish of up to 40 ng/g have
been reported but the majority of sampled animals con-
tained no detectable residues.

1.5 Effects on organisms in the environment

The primary productivity of cultures of freshwater
green algae was reduced to 50% by tri- o-cresyl phosphate
(TOCP) at 1.5 to 4.2 ng/litre, depending on the species,
whereas the meta and para isomers were less toxic. There
are limited data on the acute toxicity of TCP to aquatic
invertebrates: the 48-h LC₅₀ for Daphnia is 5.6 ng/litre;
the 24-h LC₅₀ for nematodes is 400 ng/litre; the 2-week
NOEL for Daphnia (mortality, growth, reproduction) is 0.1
mg/litre. The 96-h LC₅₀ values for three fish species
were between 4.0 and 8700 mg/litre. Rainbow trout showed
approximately 30% mortality after a 4-month exposure to
0.9 ng/litre IMOL S-140 (2% tri- o-cresyl phosphate,
TOCP) and minor effects within 14 days.

The exposure levels used in these experiments were
much greater than likely water concentrations in the en-
vironment and, in most cases, greatly exceed the solu-
bility of the compounds.

1.6 Kinetics and metabolism

The absorption, distribution, metabolism, and elimin-
ation of organophosphates are critical to the delayed
neuropathic effects of these compounds.

Dermal absorption of TOCP in humans appears to be at
least an order of magnitude faster than that in dogs.
Significant dermal absorption also appears to occur in
cats. Oral absorption of the compound has been reported
in rabbits. There is no direct information on absorption
via the inhalation route.

In cat studies, absorbed TOCP was widely distributed
throughout the body, the highest concentration being found
in the sciatic nerve, a target tissue. Other tissues with
high concentration of TOCP and its metabolites were the
liver, kidney, and gall bladder.

TOCP is metabolized via three pathways. The first is
the hydroxylation of one or more of the methyl groups, and
the second is dearylation of the o-cresyl groups. The
third is further oxidation of the hydroxymethyl to alde-
hyde and carboxylic acid. The hydroxylation step is criti-
cal because the hydroxymethyl TOCP is cyclized to form
saligenin cyclic o-tolyl phosphate, the relatively
unstable neurotoxic metabolite.

TOCP and its metabolites are eliminated via the urine
and faeces, together with small amounts in the expired
air.

1.7 Effects on experimental animals and in vitro test systems

Of the three isomers of TCP, TOCP is by far the most
toxic in acute and short-term exposure. It is the only
isomer that produces delayed neurotoxicity.

There is wide interspecies variability for the various
toxic end-points (e.g., acute lethality, delayed neurotox-
icity) of TOCP exposure, the chicken being one of the most
sensitive species.

Organophosphate-induced delayed neuropathy (OPIDN) has
been produced with both single and repeated exposure
regimes in a wide range of experimental species and it is
classified as a "dying-back neuropathy". Degenerative
changes occur in the distal axon and extends with time
towards the cell body.

Clinical signs are paralysis of the hindlegs after a
characteristic delay of 2-3 weeks after exposure. A single
oral dose of 50-500 mg TOCP/kg induced delayed neuropathy
in chickens, whereas doses of 840 mg/kg or more were
necessary to produce spinal cord degeneration in Long-
Evans rats. The metabolite saligenin cyclic o-tolyl phos-
phate is the active neurotoxic agents. Species sensitivity
is inversely correlated with rate of further metabolism.

Inhibition of "neurotoxic esterase" is thought to be
the biochemical lesion leading to OPIDN; inhibition by

more than 65% shortly after exposure to TOCP presages sub-
sequent neuropathy. Factors other than metabolism (e.g.,
route of exposure, age, sex, strain) influence variability
in response to TOCP neurotoxicity. A clear no-observed-
effect level for delayed neuropathy is not apparent from
the data available.

Reproduction studies in rats and mice receiving
repeated oral exposure to TOCP showed histopathological
damage in the testes and ovaries, morphological changes in
sperm, decreased fertility in both sexes, and decreased
litter size and viability. A clear no-effect level for the
reproductive effects of TOCP was not apparent from the
data available. A teratogenicity study in rats, using
oral doses producing maternal toxicity, yielded negative
results.

Little information is available on mutagenicity and
none on carcinogenicity.

1.8 Effects on humans

Accidental ingestion is the main cause of intoxi-
cation. Since the end of the nineteenth century, numerous
cases of poisoning due to contamination of drink, food,
or drugs have been reported. Occupational exposure is
principally via dermal absorption or inhalation, and some
cases of poisoning have been reported. Ingestion of prep-
arations contaminated by TOCP may be followed by gastro-
intestinal symptoms (nausea, vomiting, and diarrhoea),
although in some cases polyneuropathy is the first evi-
dence of poisoning. The neurological symptoms are charac-
teristically delayed. The initial symptoms are pain and
paraesthesia in the lower extremities. A mild impairment
of cutaneous sensations and sometimes an impairment of
vibratory sense may be present. In most cases the muscle
weakness progresses rapidly to a striking paralysis of the
lower extremities with or without an involvement of the
upper extremities. Severe cases show pyramidal signs.
Fatalities are rare, but recovery from the neurological
signs and symptoms can be extremely slow and extend over a
number of months or years. Histopathological findings
show axonal degeneration. Routine laboratory examinations
show no abnormal findings, but an increase of protein con-
centration in the cerebrospinal fluid may be seen. First
aid should reduce exposure by inducing vomiting immedi-
ately after ingestion, providing the patient is conscious.
The cardinal long-term therapy is physical rehabilitation
and no specific antidote is known. There is considerable
variation between individuals both in response to TCP and
recovery from the toxic effects. Severe symptoms have
been reported following the ingestion of 0.15 g of TCP,
while other individuals failed to show any toxic effect
after ingesting 1-2 g. Some patients show complete
recovery, whereas others retain marked effects for a
considerable period.

2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

2.1 Identity

2.1.1 Tricresyl phosphate (commercial product: mixture of isomers)

Chemical structure:

Molecular formula: C₂₁H₂₁O₄P

Relative molecular mass: 368.4

CAS chemical name: phosphoric acid, tritolyl ester

CAS registry number: 1330-78-5

RTECS registry number: TD0175000

Synonyms: tricresylphosphate, tricresyl phos-
phate, TCP, tritolyl phosphate, tri-
methylphenyl phosphate

Trade name: Kronitex-TCP^(R), Santicizer 140^(R),
Pliabrac 521^(R), Phosflex 179^(R),
Disflamoll TKP^(R), Lindol^(R),
Kolflex 5050^(R), PX.917^(R),
Celluflex 179C^(R),

Manufacturers and suppliers (Modern Plastics Encyclopedia,
1975):

Albright & Wilson Ltd., Ashland Chemical Co., Bayer AG,
Celanese Co., East Coast Chemicals Co., F.M.C. Corp.,
Harwick Chemical Corp., Kolker Chemical Co., McKesson
Chemical Co., Mobay Chemical Co., Pittsburgh Chemical
Co., Rhone-Poulenc Co., Sobin Chemical Co., Stauffer
Chemical Co., Daihachi Chemical Ind. Co. Ltd., Kyowa
Hakko Kogyo Co. Ltd., Hodogaya Chemical Co. Ltd.,
Mitsubishi Gas Chemical Co. Inc., Kurogane Kasei Co.
Ltd., Kashima Ind. Co.

2.1.2 Tri- o-cresyl phosphate

Chemical structure:

CAS chemical name: phosphoric acid, tri- o-tolyl ester

CAS registry number: 78-30-8

RTECS registry number: TD0350000

Synonyms: tri- o-cresyl phosphate, tri- o-
cresylphosphate, phosphoric acid
tris(2-methylphenyl) ester, o-TCP,
TOCP, TOTP, tri- o-tolyl phosphate,
tri-2-tolyl phosphate, tri-2-methyl-
phenyl phosphate

2.1.3 Tri- m-cresyl phosphate

Chemical structure:

CAS chemical name: phosphoric acid, tri- m-tolyl ester

CAS registry number: 563-04-2

Synonyms: tri- m-cresylphosphate, phosphoric
acid tris(3-methylphenyl) ester,
m-TCP, tri- m-tolyl phosphate,
tri-3-tolyl phosphate, tri-3-methyl-
phenyl phosphate

2.1.4 Tri- p-cresyl phosphate

Chemical structure:

CAS chemical name: phosphoric acid, tri- p-tolyl ester

CAS registry number: 78-32-0

Synonyms: tri- p-cresylphosphate, phosphoric
acid tris(4-methylphenyl) ester,
p-TCP, tri- p-tolyl phosphate,
tri-4-tolyl phosphate, tri-4-methyl-
phenyl phosphate

2.2 Physical and chemical properties

The physical properties of tricresyl phosphate (TCP)
are listed in Table 1.

Table 1. Physical properties of tricresyl phosphate and isomers
________________________________________________________________________________________________________
Physical properties Tricresyl phosphate Tri- o- cresyl Tri- m- cresyl Tri- p- cresyl
(mixtures of isomers) phosphate phosphate phosphate
_________________________________________________________________________________________________________
Physical state liquid liquid half-solid crystalline
solid
Colour colourless colourless colourless colourless

Odour very slightly very slightly very slightly very slightly
aromatic aromatic aromatic aromatic

Melting or -33^b 11^a 25.6^a 77-78^a
freezing point (°C)

Boiling point or 241-255 (4 mmHg)^b
range (°C) 190-200 (0.5-10 mmHg)^c 410 (760 mmHg)^a 260 (15 mmHg)^a 244 (3.5 mmHg)^a

Specific gravity 1.160-1.175 (25 °C)^b; 1.1955^a 1.150^a 1.237^a
(density) 1.165^c

Refractive index 1.553-1.556 (25 °C)^b; 1.5575^a 1.5575^a
1.556 (20 °)^c

Viscosity (cSt) 60 (25 °C), 4.0 (100 °C)^c

Flash point (°C) 257^c

Vapour pressure (mmHg) 1 x 10^-4 (20 °C)^c 10 (265 °C)^a

Henry's Law constant 1.1-2.8 x 10^-6 atm-m³/mol^d

Solubility in water 0.36^e; 0.34 ± 0.04^f 0.074^g
(mg/litre)

Octanol-water partition 5.11^e
coefficient (log P_ow) 5.12^h
________________________________________________________________________________________________________
^a Hine et al. (1981).
^b Modern Plastics Encyclopedia (1975).
^c Lefaux (1972).
^d Boethling & Cooper (1985).
^e Saeger et al. (1979).
^f Ofstad & Sletten (1985).
^g Hollifield (1979).
^h Kenmotsu (1980b).

TCP is non-flammable and non-explosive. When the para
isomer was heated at 370 °C with air for 30 min, 99% of
the compound was recovered. The main volatile products
obtained were water, carbon dioxide, toluene, and cresols
(Paciorek et al., 1978). No data on pyrolysis or combus-
tion of TCP at higher temperatures are available (at about
600 °C, triphenyl phosphate begins to decompose, yielding
some aromatic hydrocarbons, some oxygenated aromatic com-
pounds, and phosphoric oxides). Its partition coefficient
between octanol and water (log P_ow) is approximately
5.11-5.12.

Hydrolysis of TCP is thought to proceed in an anal-
ogous manner to triphenyl phosphate. It hydrolyses rapidly
in an alkaline solution. Despite a lack of data, neutral
or acidic hydrolysis of TCP, by analogy to TPP, is assumed
to be very slow. The hydrolysis rate constants and half-
lives reported are summarized in Table 2. Formation of
dicresyl phosphate during alkaline hydrolysis would be
expected, but no data are available (Wolfe, 1980).
Table 2. Hydrolysis rate constant (2nd order, K₂) and half-lives in
aqueous solution
________________________________________________________________________________
Temper- Rate
Compound Solution ature pH constant Half- Reference
(°C) (M^-1.sec^-1) life
________________________________________________________________________________

Tri- p-cresyl Water 27 alkaline 2.5 x 10^-1 Wolfe (1980)
phosphate 0.2N NaOH/ 22 13 1.66 h Muir et al.
acetone (1983)
(1 : 1)

Tri- m-cresyl 0.1N NaOH/ 22 13 1.31 h Muir et al.
phosphate acetone (1983)
(1 : 1)
________________________________________________________________________________

The photolysis of TAPs in ethanol yielded the corre-
sponding monoaryl phosphate and diphenyl derivatives
(Finnegan, 1972). The results are summarized in Table 3.

2.3 Conversion factor

Tricresyl phosphate 1 ppm = 15.07 mg/m³ air

Table 3. Photolysis of symmetrical triaryl phosphates^a
________________________________________________________________________
Starting Resulting compounds Recovered Quantum yield
compound ---------------------- ester (%) for biaryl
Ar-Ar (%) ArOPO₃H₂(%) formation
________________________________________________________________________
Phenyl 2 48 6 x 10^-4
p-Tolyl 35-51 2-10 13-20 190 x 10^-4
p-t-butylphenyl 51 55 24 44 x 10^-4
Mesityl 4 7 7 not determined
________________________________________________________________________
^a From: Finnegan & Matson (1972).
The esters were irradiated, at a concentration of 0.02 mol/litre
ethanol, using a 450W Hanovia arc lamp, for 5 h.

2.4 Analytical methods

Analytical methods for determining TCP in air, water,
sediment, fish, biological tissues, and edible oils are
summarized in Table 4. The method of choice is gas chro-
matography (GC) with a nitrogen-phosphorus sensitive de-
tector (GC/NPD) or a flame photometric detector (GC/FPD).
The detection limit in water samples is at the ng/litre
level. Using GC, TCP and other trialkyl/aryl phosphates,
such as triphenyl phosphate (TPP), trioctyl phosphate, and
trixylenyl phosphate, can be simultaneously determined.
High-performance liquid chromatography (HPLC) and thin-
layer chromatography (TLC) are sometimes used for deter-
mining TCP, but these are not widely applicable.

It should be noted that the behaviour of TCP in ana-
lytical processes and in its environmental distribution is
similar to that of other TAPs, lipids, and phthalic acid
esters, owing to analogous physical and chemical proper-
ties.

2.4.1 Extraction and concentration

TCP is easily extracted from aqueous solution with
methylene chloride, hexane, or benzene (Kenmotsu et al.,
1980a; Muir et al., 1981). Low levels of TCP in water can
be successfully concentrated on an Amberlite XAD-2 resin
column (Lebel et al., 1981; Lebel & Williams, 1983). TCP
has been extracted from sediment with various polar sol-
vents, such as aqueous methanol (Muir et al., 1980, 1981),
acetonitrile (Kenmotsu et al., 1980a), or acetone
(Ishikawa et al., 1985). The extraction method established
by the US Association of Official Analytical Chemists
(AOAC) for organochlorine and organophosphorus pesticides
is also applicable for the extraction of TCP from fat-
containing foods and fish (Lombardo & Egry, 1979). Hexane
(Lombardo & Egry, 1979), methanol (Muir et al., 1980,
1981; Muir & Grift, 1983), acetonitrile and methylene
chloride (Kenmotsu et al., 1979), and acetone-hexane
(Lebel & Williams, 1983) have been used for the extraction

of TCP from fish or adipose tissue. Workplace airborne
samples can be collected on Millipore^(R) filters and the
particulate TCP analysed (US NIOSH, 1977, 1979, 1982).
Vapour phase and particulate TCP in the atmosphere have
been simultaneously collected on glycerol-coated
Florisil^(R) columns and 96% of the TCP recovered (Yasuda,
1980). The Midwest Research Institute (MRI/USA) has used
high-volume air filter pads and activated carbon filters
to sample ambient air (MRI, 1979).

2.4.2 Clean-up procedures

Florisil column chromatography has been used routinely
for clean-up of TCP (Lombardo & Egry, 1979; Kenmotsu et
al., 1980a; Lebel & Williams, 1983). The separation of TCP
from tributyl phosphate (TBP) and parathion is possible by
this procedure but is more difficult than for other TAPs
such as trixylenyl phosphate (Kenmotsu et al., 1981b;
Lebel & Williams, 1983). Sulfur-containing compounds,
which often exist in sediment samples and interfere with
the analysis of TCP by GC/FPD, can easily be separated by
elution with hexane from Florisil columns (Kenmotsu et
al., 1980a). Partitioning between acetonitrile and pet-
roleum ether is useful to separate TCP from fish fat
(Lombardo & Egry, 1979; Kenmotsu et al., 1980a). Since
the polarity of TCP is similar to that of lipids in bio-
logical tissues, it is difficult to separate TCP from
lipids by Florisil column chromatography. Gel permeation
chromatography (GPC) is useful in this case (Muir et al.,
1981), the elution volume varying according to the
type of phosphate ester, i.e. trialkyl-, triaryl-, or
tri(haloalkyl) phosphates (Lebel & Williams, 1983). Acti-
vated charcoal column chromatography (Kenmotsu et al.,
1980a), alumina column chromatography (Muir et al., 1980,
1981), and C-18 bonded silica cartridge (Sep-pak C-18)
(Muir et al., 1980; Muir & Grift, 1983) have also been
used to separate TCP from co-extracting compounds in vari-
ous samples.

Table 4. Methods for the determination of TCP and TPP
________________________________________________________________________________________________________
Sample type Sampling method Analytical Limit of Applicability Reference
extraction/clean-up method detection
________________________________________________________________________________________________________
Workplace collect with Millipore GC/FPD 1 µg per TCP and TPP US NIOSH (1982)
air filter, extract with sample
ethanol

Environmental trap with glycerol- GC/FPD 1 ng/m³ simultaneous Yasuda (1980)
air Florisil column, eluate method for
with methanol, add trialkyl/aryl
water, and extract with phosphates
hexane

Air collect by aspiration TLC 5 ng/plate TCP and TPP Druyan (1975)
through ethanol,
hydrolyse with NaOH; the
resultant phenols are
reacted with
p-O₂NC₆H₄N₂⁺ and
separated with silica
gel plate

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

River or sea extract with GC/NPD 0.02 µg/litre simultaneous Kenmotsu et al.
water methylene chloride GC/FPD (TPP) method for (1980a, 1981b,
or benzene GC/MS 0.05 µg/litre trialkyl/aryl 1982b)
(TCP) phosphates Muir et
al. (1981)
Ishikawa et
al. (1985)

Farm pond reflux with methanol- GC/NPD 1 ng/g simultaneous Muir et al.
sediment water (9+1) or method for (1980, 1981)
methylene chloride- triaryl
methanol (1+1), phosphates
clean-up by acid
alumina column
chromatography

Table 4. (contd.)
________________________________________________________________________________________________________

Sample type Sampling method Analytical Limit of Applicability Reference
extraction/clean-up method detection
________________________________________________________________________________________________________

River or sea extract with GC/FPD 5 ng/g simultaneous Kenmotsu et al.
sediment acetonitrile or GC/MS method for (1980a, 1981b,
acetone, clean-up by trialkyl/aryl 1982a, 1982b,
charcoal or Florisil phosphates 1983)
column chromatography Ishikawa et al.
(1985)

Fish extract with hexane GC/NPD 1 ng/g simultaneous Muir et al.
or methanol, clean-up GC/MS method for (1980, 1981,
by gel permeation triaryl 1983)
column chromatography phosphates
and acid alumina
column chromatograpy

Fish extract with GC/FPD 5 ng/g simultaneous Kenmotsu et
acetonitrile and GC/MS method for al. (1980a)
methylene chloride, trialkyl/aryl
clean-up by phosphates
acetonitrile-hexane
partitioning,
charcoal column
chromatography,
concentrated sulfuric
acid extraction and
Florisil column
chromatography

Human adipose extract with benzene GC/NPD 1 ng/g simultaneous Lebel & Williams
tissues or acetone-hexane (15 GC/FPD method for (1983)
+ 85), clean-up by GC/MS trialkyl/aryl
gel permeation phosphates
chromatography and
Florisil column
chromatography
Table 4. (contd.)
________________________________________________________________________________________________________

Plasma extract with ethyl HPLC 50 ng/injection TCP and its Nomeir &
ether, filter with (254 nm) metabolites Abou-Donia
0.45-µm nylon filter (1983)

Edible oils extract with ethanol, colori- 0.01% simple method Vaswani et
hydrolyse with NaOH; metric for TCP al. (1983)
the resultant cresol determination
is coupled with 2,6-
dichlorobenzoquinone

Edible oils separate with silica TLC simple method Bhattacharyya
gel G thin-layer (UV) for TCP et al.(1974)
plate; spray determination
rhodamine B solution
________________________________________________________________________________________________________

2.4.3 Gas chromatography and mass spectrometry

To identify TCP in environmental samples by packed
column GLC, it is useful to compare retention times using
two types of liquid phase with different polarities. As a
low polarity liquid phase, 10% OV-1 (Kenmotsu et al.,
1980a), 3% SE-30 (Ramsey & Lee, 1980), 3% OV-17 (Lebel et
al., 1981), 3% OV-101 (Deo & Howard, 1978), SP-2100 (Muir
et al., 1980), and 5% DC-200 (Daft, 1982) have been used,
while 1% QF-1 (Bloom, 1973), 5% FFAP and 5% Thermon-3000
(Kenmotsu et al., 1980a), and 2% DEGS (Daft, 1982) have
been used as a higher polarity liquid phase.

TCP is often accompanied by other TAPs in environmen-
tal samples, which show multiple peaks in GC and occasion-
ally have the same retention indices as that of TCP
(Ramsey & Lee, 1980; Kenmotsu et al., 1982b). Therefore,
capillary GLC or GC-mass spectrometry (GC/MS) is preferred
(Lebel et al., 1981; Lebel & Williams, 1983; Kenmotsu et
al., 1983; Ofstad & Sletten, 1985). In electron impact
mass spectrometry, TCP gives a high intensity molecular
ion, as do other TAPs (Deo & Howard, 1978; Wightman &
Malaiyandi, 1983; Kenmotsu et al., 1982b). A selected ion
monitoring (SIM) technique is also useful for trace analy-
sis of TCP in environmental samples (Ishikawa et al.,
1985), but care must be taken to select suitable fragment
ions in order to avoid interference by other TAPs.

The phenolic components of TCP are confirmed by alka-
line hydrolysis, followed by GLC analysis of the resulting
phenols (Murray, 1975; Sugden et al., 1980).

2.4.4 Contamination of analytical reagents

The widespread use of TCP in plastics and hydraulic
fluids can cause contamination of analytical reagents.
Traces of TCP have been found in rubber O-rings and rubber
seals used in a Corning water supply system (Lebel et al.,
1981), Super Q water (Williams & Lebel, 1981), and aceto-
nitrile, methylene chloride, and hexane (Daft, 1982).
Trialkyl phosphates have also been found in cyclohexane
(Bowers et al., 1981), hexane (Hudec et al., 1981), and
analytical grade filters (Daft, 1982). Therefore, care
must be taken to avoid contamination of analytical re-
agents in order to obtain accurate data in trace analysis
of TCP.

2.4.5 Other analytical methods

A rapid colorimetric method has been developed for the
determination of TCP in edible oil (Vaswani et al., 1983),
but no information about the interference with other TAPs
is available. Silica gel TLC has been used for deter-
mining TCP in edible oil (Bhattacharyya et al., 1974;

Krishnamurthy et al., 1985). Reversed phase TLC has also
been used (Renberg et al., 1980). However, separating TAPs
from each other by TLC is not sufficient (Bloom, 1973).
HPLC with a C-18 bonded column has been used for deter-
mining TCP in plasma, while size exclusion HPLC has been
used in the case of machine oil (Majors & Johnson, 1978).
An ultraviolet spectrometric detector is usually used in
HPLC, but it is not specific for TAPs. Tittarelli &
Mascherpa (1981) described a highly specific HPLC detec-
tor for TAPs using a graphite furnace atomic absorption
spectrometer.

3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

3.1 Production levels and processes

Tricresyl phosphate does not occur naturally in the
environment. Figures concerning the total world production
are not available. In Japan, 33 000 tonnes were produced
in 1984^a. In the USA, approximately 54 000 tonnes of TAP
including 10 400 tonnes of TCP were produced in 1977
(Boethling & Cooper, 1985). About 800-1000 tonnes TCP per
year is now produced in China.

TCP is usually produced by the reaction of cresols
with phosphorus oxychloride. One of the industrial sources
of cresols is the so-called cresylic acid or tar acid,
which is a mixture of isomers of cresol and varying
amounts of xylenols, phenol, and other high-boiling phe-
nolic fractions obtained as a residue from coke ovens and
petroleum refining (Duke, 1978). Another source is
"synthetic cresol", prepared from cymene via oxidation
and catalytic degradation (Association of the Plasticizer
Industry of Japan, 1976), and this has been used for pro-
duction of TCP in Japan since 1971. The composition of
some cresylic acids and synthetic cresol is shown in
Table 5.

TCP derived from these alkylphenols is, therefore, a
complex mixture of various TAPs, i.e. tri- o-cresyl phos-
phate, tri- m-cresyl phosphate, tri- p-cresyl phosphate,
di- m-cresyl- p-cresyl phosphate, di- p-cresyl- m-cresyl phos-
phate, etc. The very toxic tri- o-cresyl phosphate
(TOCP) is usually excluded as much as possible. In some
cases, commercial tricresyl phosphate (TCP) has been
reported to contain a small amount of TPP (Daft, 1982;
Ofstad & Sletten, 1985).

The most noteworthy trend in aryl phosphate manufac-
ture and use in the USA has been the replacement of tri-
phenyl, tricresyl, and trixylenyl phosphates derived from
petroleum-based feedstocks by aryl phosphates derived from
synthetic precursors. The production of cresyl diphenyl
phosphate, a petroleum-based aryl phosphate, was discon-
tinued in 1979 in the USA. The mixed trialkyl/aryl phos-
phates are replacing TPP and TCP as a plasticizer, whereas
the synthetic TAPs are replacing TCP and trixylenyl phos-
phate in functional fluids (Boethling & Cooper, 1985).

______________
^a Personal communication from the Association of the
Plasticizer Industry of Japan, 1985.

Table 5. Composition of some commercial cresylic acids^a and
"synthetic cresol"^b
______________________________________________________________
Composition (%)
Boiling Cresylic Acids Synthetic
Constituents point Sample Sample Sample Cresol
(°C) A B C
______________________________________________________________
o- cresol 191.0 3 0 0 0.1%
2,6-Xylenol 201.0 6 6 0
m- Cresol 202.2 42 43 47 \
p- Cresol 202.3 30 31 34 /99%
o- Ethylphenol 204.5 3 3 0
2,4-/2,5-Xylenol 211.5 16 17 19
______________________________________________________________
^a From: Bondy et al. (1960).
^b From: Association of the Plasticizer Industry of Japan
(1976).

3.1.1 Accidental release

Liquid TCP and hydraulic fluid and lubricant oil con-
taining phosphate esters are transported by tank trucks,
rail cars, and to a lesser extent in barrels (US NIOSH,
1979). Occasionally, empty barrels (or drums) previously
containing hydraulic fluid or lubricant oil have been
reused to store or to transport edible oil (or water), and
this has resulted in poisoning of humans and cattle
(Susser & Stein, 1957; Smith & Spalding, 1959; Chaudhuri,
1965; Nicholson, 1974; Senanayake, 1981). Another case of
poisoning involved flour contaminated with oil from a leak
during shipping (Sorokin, 1969).

In a report by Beck et al. (1977), accidental spillage
of TAPs intended for use in pipeline pumping stations oc-
curred and resulted in poisoning of cattle. Effluent from
an evaporation pond overflowed onto the pasture during
spring run-off. Sampling showed concentrations of TAPs
from 0.304% to 3.44% by weight in soil, grass, and water
near the plant. Thirty days later TAPs were still present
in the evaporation pond but not in the soil samples
(Chemical and Geological Laboratories Ltd., 1971).

Beck et al. (1977) described in his report: "Mass
poisonings are possible because large quantities of tri-
aryl phosphate are used as lubricants and coolants in jet
engines in pipeline compressor stations. If an emergency
arises as much as 1200 gallons of this material can be
expelled into the atmosphere within 20 seconds. The con-
struction of pipelines over thousands of miles, with
manned or unmanned compressors every 100 miles, consti-
tutes an environmental hazard to both domestic livestock
and wildlife."; and "Natural leaching of the ground by
weather conditions probably removed the poison from the
soil, but repeated spills of large quantities of a stable
compound could contaminate ground water supplies".

3.2 Uses

TCP is used as a plasticizer in vinyl plastic manufac-
ture, as a flame-retardant, a solvent for nitrocellulose,
in cellulosic molding compositions, as an additive to
extreme pressure lubricants, and as a non-flammable fluid
in hydraulic systems (Windholz, 1983). The main market for
PVC-based products plasticized with organic phosphate
esters is in the manufacture of automobile and other motor
vehicle interiors in the USA (Lapp, 1976). In Japan, ap-
proximately 2500 tonnes of TCP was used in 1984 as a plas-
ticizer in PVC film for agricultural use, 400 tonnes as
non-flammable plasticizer in floor and wall covering, and
100 tonnes for miscellaneous purposes (Association of the
Plasticizer Industry of Japan, 1985).

The fastest growing use of organic phosphate esters is
in the manufacture of fire-resistant hydraulic fluids and
lubricants in the USA (Lapp, 1976). The two types of
organic phosphate hydraulic fluids being manufactured are
phosphate ester oil blends and "pure synthetics". The
phosphate ester oil blends contain between 30% and 50%
organic phosphate esters in addition to petroleum oil and
coupling agents; the "pure synthetics" contain a mixture
of organic phosphate esters. For example, a typical syn-
thetic organic phosphate fluid contains TCP, trixylenyl
phosphate, and other TAPs. The compositions of several
commercial synthetic organic phosphate fluids are listed
in Table 6. Organic phosphate ester lubricant additives
are usually of three general types: extreme pressure
agents, anti-wear agents, and stick-slip moderators. The
first two types are used in systems with some type of
gears and account for over 80% of all organic phosphate
lubricant additives. These agents are also used in cut-
ting oils, machine oils, transmission fluids, and cooling
lubricants (Lapp, 1976).

In Japan, approximately 300 tonnes of TCP was used for
lubricant additives in 1985 (Association of the Plasti-
cizer Industry of Japan, 1985), and approximately 1320
tonnes of TAPs was used in 1976 in Ontario, Canada (Muir
et al., 1980).

There are other minor uses of TCP: additives in making
synthetic leather (Franchini et al., 1978), shoes (Pegum,
1966), and polyvinyl acetate products (Anon., 1986); sol-
vent for acrylate lacquers and varnishes (Anon., 1986); in
non-smudge carbon paper (Hjorth, 1962; Pegum, 1966).

Table 6. Composition of various commercial organophosphorus hydraulic fluids and lubricants
________________________________________________________________________________________________________
Component (%)
________________________________________________________
Name TPP TCP Others Producer Reference
________________________________________________________________________________________________________
IMOL S-140 1 2 (ortho) Tris(dimethylphenyl)- (18) Imperial Oil Ltd. Lockhart
42 (meta) Tris(ethylphenyl)- (6) et al.
31 (para) Tris(trimethylphenyl)- (1975)
and unknown (1)

Pydraul 50E 36 nonylphenyl diphenyl phosphate (40) Monsanto Co. Nevins &
cumylphenyl diphenyl phosphate (22) Johnson
(1978)
Pydraul 115E 7 nonylphenyl diphenyl phosphate (29)
cumylphenyl diphenyl phosphate (62)

Pydraul 50E 18.4 nonylphenyl diphenyl (52.8) Monsanto Co. Deo &
cumylphenyl diphenyl (24.0) Howard
(1978)
Kronitex TCP 20.7 (meta) dicresyl xylenyl (9.2) FMC Corp. Deo &
38.8 (di- Howard
meta, para) (1978)
30.4 (di-
para, meta)

Santicizer- 14.7 19.4 m-cresyl diphenyl (18.6) Monsanto Co. Deo &
140 CDP p-cresyl diphenyl (14.4) Howard
phenyl dicresyl (29.4) (1978)

Fyrquel GT 19.2 m-cresyl diphenyl (2.1) Stauffer Chem. Co. Deo &
phenyl dicresyl (3.2) Howard
dicresyl xylenyl (36.2) (1978)
di(C₃-phenyl) xylenyl (37.1)

Phosflex 41-P 11.9 40.8 m-cresyl diphenyl (2.1) Stauffer Chem. Co. Deo &
trixylenyl (9.4) Howard
(C₃-phenyl)₃ (28.7) (1978)
________________________________________________________________________________________________________

________________________________________________________________________________________________________
Component (%)
_______________________________________________________

Name TPP TCP Others Producer Reference
________________________________________________________________________________________________________
Fyrquel 220 phosphates derived from Imperial Oil Ltd. Pickard et
phenol (2.6); o-cresol (0.5); m- and al. (1975)
p-cresol (13.6); 2-ethylphenol (0.6)
2,4- and 2.5-xylenol (22.3); mixed
xylenol (49.2); 3,4-xylenol (8.6);
6-9 phenolics (1.3); 2,4,6-trimethyl
phenol (1.4)

Kronitex 100 18 diphenyl 2-isopropylphenyl (27) FMC Corp. Nobile et
diphenyl 4-isopropylphenyl (11) al. (1980)
tris(2-isopropylphenyl) (11)
phenyl di-(2-isopropylphenyl) (7)
phenyl di-(4-isopropylphenyl) (5)

Kronitex 50 33 diphenyl 2-isopropylphenyl (21) FMC Corp. Nobile et
diphenyl 4-isopropylphenyl (12) al. (1980)
tris(2-isopropylphenyl) (8)
phenyl di-(2-isopropylphenyl) (6)
phenyl di-(4-isopropylphenyl) (2)
________________________________________________________________________________________________________

4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

Summary

The majority of TCP release to the environment is accounted
for by end-point use rather than production. Total release to
the environment in the USA was estimated at 32 800 tonnes in
1977.

TCP released into water is readily adsorbed on to sediment
particles, and little or none remains in solution.

TCP is readily biodegraded in sewage sludge with a half-
life of 7.5 h, the degradation within 24 h being up to 99%. TCP
is almost completely degraded within 5 days in river water. The
ortho isomer is degraded slightly faster than the meta or para
isomers. Abiotic degradation is slower with a half-life of 96
days.

TCP has, because of its physico-chemical properties, a high
potential for bioaccumulation. Laboratory studies of continuous
exposure to high concentrations (which are environmentally
unrealistic) of radiolabelled TCP have shown high bioconcen-
tration factors (BCF). However, these studies failed to show
that the isotope was still associated with the original com-
pound. Taking into account the ready biodegradability of TCP,
these data should be viewed as probable overestimates, and it
is suggested that little bioaccumulation would occur with
environmentally realistic TCP exposure.

4.1 Transport and transformation in the environment

4.1.1 Release to the environment

Total losses of aryl phosphates to the environment in
the USA from production in 1977 were estimated as 2585
tonnes, the main source being land disposal of manufactur-
ing wastes (2540 tonnes). Releases from end-product use
(32 800 tonnes in the USA in 1977) are estimated to be
much greater than from production. The amount of volatil-
ization and leaching from plastic items was 16 300 tonnes
and that of leakage of hydraulic fluids and lubricants
13 400 tonnes (Boethling & Cooper, 1985). One major hy-
draulic fluid manufacturer estimated that as much as 80%
of the annual consumption of aryl phosphate hydraulic
fluids is used to make up for leakage (MRI, 1979).

No data are available on the release to the atmosphere
of TCP from production processes. However, open, high-tem-
perature processes such as roll milling, calendering, and
extrusion of plasticized polymers may result in signifi-
cant gaseous emissions of aryl phosphates (Boethling &
Cooper, 1985).

Yasuda (1980) detected significant levels of TCP in
urban air and in the atmosphere over coastal waters near
industrialized areas. Details are described in section
5.1.1.

The results of a study by the US Environmental Protec-
tion Agency (MRI, 1979) showed that TCP can evaporate from
automotive upholstery fabric and condense on the interior
surface of a relatively cool window.

The emission of TCP from waste incineration plants may
also be a pathway to the atmosphere. In a study by Vick et
al. (1978), TCP was not detected in vapour samples taken
before and after the dust collectors of incinerators.

4.1.2 Fate in water and sediment

The solubility of TCP in water is low (Table 1). Moni-
toring studies have shown trialkyl/triaryl phosphates to
be present in water and sediment sampled near major indus-
trialized areas (Konasewich et al., 1978; Sheldon & Hites,
1978, 1979; Mayer et al., 1981; Williams & Lebel, 1981;
Williams et al., 1982; Ishikawa et al., 1985; Fukushima &
Kawai, 1986). However, TCP was only occasionally detected
in water samples, whereas TPP was often detected (Mayer et
al., 1981; Williams & Lebel, 1981; Williams et al., 1982;
Ishikawa et al., 1985). The total concentrations of
Pydraul (Table 6) components in river (0.24 µg/litre) and
lake sediments (570 µg/kg) in the USA revealed a water-
sediment difference of more than 3 orders of magnitude
(Mayer et al., 1981). Equilibrium of TCP with the bottom
sediment in a shallow (0.5-m depth) pond would be expected
to be reached rapidly, as in the case of TPP (Muir et al.,
1982). The adsorption coefficient of TCP on marine sedi-
ment was found to be 420 (Kenmotsu et al., 1980b).

It is apparent from the following data that TCP is
rapidly adsorbed onto river sediment: the level of total
aryl phosphate in the sediment of the Kanawha River (USA)
was 229 mg/kg at the FMC plant outfall but only 4.4 mg/kg
13 km downstream (Boethling & Cooper, 1985).

Wagemann et al. (1974) and Wagemann (1975) reported
that a commercial synthetic lubricating oil, IMOL S-140
(Table 6), degraded in sterilized river water under lab-
oratory fluorescent light and under sunlight at 25 °C, and
that the first order rate constant and half-life were,
respectively, 9 x 10^-3 days^-1 and 96 days (Wagemann,
1975).

4.1.3 Biodegradation

River die-away studies by Saeger et al. (1979) on nine
phosphate esters demonstrated that these esters, exposed
to the natural microbial population of the river, under-
went primary biodegradation at moderate to rapid rates. A

200-µg portion of TCP was completely degraded within 4
days in 200 ml of Mississippi River (USA) water at room
temperature. Hattori et al. (1981) also investigated the
degradation of TCP in Neya and Oh River water (Osaka,
Japan). After a lag period of 1-2 days, the TCP (1 mg per
litre) was almost completely degraded within 5 days under
non-sterilized conditions, whereas no degradation in heat-
sterilized water occurred during 15 days. In clear non-
sterilized sea water, however, the degradation was very
slow. Saeger et al. (1979) also found that in sterile
river water there was no significant evidence of non-
biological degradation or loss. Among the isomers of TCP,
the ortho isomer degraded in river water slightly faster
than the meta isomer and both isomers degraded faster than
the para isomer, which degraded about as fast as TPP
(Howard & Deo, 1979).

Primary biodegradation rates from semicontinuous acti-
vated sludge (SCAS) studies (US Soap and Detergent Assoc.,
1965; Mausner et al.,1969) showed generally the same trend
in degradation rates as river die-away studies. At a 24-h
feed level of 3-13 mg/litre, TCP showed 99% degradation.

The ultimate biodegradability of TCP was measured by
Saeger et al. (1979) using the apparatus and procedure
developed by Thompson & Duthie (1968) and modified by
Sturm (1973). At 26.4 mg TCP/litre, the carbon dioxide
evolution reached 82% of its theoretical value.

For alkyl-aryl and triaryl phosphates, increasing the
number and size of substituent groups on the phenyl mol-
ecule decreases the biodegradability (Saeger et al.,
1979).

The degradation pathway for TCP most probably involves
stepwise enzymatic hydrolysis to orthophosphate and
phenolic moieties (Barrett et al., 1969; Pickard et al.,
1975). The phenol would then be expected to undergo
further degradation. Dagley & Patel (1957) demonstrated
that p-cresol is oxidized to p-hydroxybenzoic acid by a
species of Pseudomonas. Ku & Alvarez (1982) studied the
biodegradation of [¹⁴C]-tri- p-cresyl phosphate in a
laboratory model sewage treatment system, and, in 24-h
experiments, found that 70-80% of the TCP (added at
1 mg/litre) was degraded, with a half-life of 7.5 h. The
major metabolite extracted with ethyl ether from the
aqueous phase was identified as p-hydroxybenzoic acid by
thin-layer chromatography and gas chromatography-mass
spectrometry, while two other radioactive spots remained
unidentified.

4.1.4 Water treatment

Data from FMC Corporation (USA) show that TCP (6.23
mg/litre) in waste water was reduced to 0.23 mg/litre in
the effluent water by biological treatment, whereas the
aryl phosphates with higher relative molecular mass (>452)
(and, therefore, more highly substituted) were not easily
removed (Boethling & Cooper, 1985). Fukushima & Kawai
(1986) reported that TCP (0.186-9.31 µg/litre) in raw
water was reduced to 0.078 µg/litre or less in treated
water by conventional waste water treatment. Filtration of
effluent samples through 1-µm pore size filters resulted
in a further removal of 93% of total aryl phosphates,
again demonstrating the adsorptive behavior of these com-
pounds (Boethling & Cooper, 1985).

4.2 Bioaccumulation and biomagnification

4.2.1 Fish

Data on the bioconcentration and depuration of TCP are
given in Table 7. None of the exposures were considered to
be representative of realistic environmental levels. More-
over the bioconcentration factor (BCF) measured in the
laboratory must be considered as a bioaccumulation poten-
tial rather than an absolute bioaccumulation factor (Veith
et al., 1979).

Several equations have been used in attempts to
predict the BCF of organic chemicals in various fish
strains using the octanol-water partition coefficient
(P_ow) or water solubility values (Neely et al., 1974; Lu
& Metcalf, 1975; Kanazawa, 1978; Veith et al., 1979;
Sasaki et al., 1982).

The clearance of tri- m-cresyl phosphate has been
shown to be biphasic, with higher rates of clearance in
the first 6 days after transfer to clean water, especially
for rainbow trout. The clearance rate constants for rain-
bow trout were about 50% more than those for fathead
minnows (Muir et al., 1983).

4.2.2 Plants

The uptake and translocation of tri- p-cresyl phos-
phate by soybean plants has been studied by Casterline et
al. (1985), the initial concentration in soil being 10 mg
per kg. Approximately 70% of the compound had disappeared
from the soil within 90 days (when the plants were har-
vested). At that time, the amount per plant was 34 µg
(0.17% of the applied TCP). Of this total plant content,
74% was found in the stem, 24% in the leaves, and 2% in
the pods. The seeds contained no detectable tri- p-
cresyl phosphate.

Table 7. Bioaccumulation and clearance of tricresyl phosphate by fish
________________________________________________________________________________________________________
Flow/ Analy- Exposure Uptake Clearance Depura-
Species Com- stat tical BCF concent- rate rate tion Reference
pound (temp.) method^a (K₁/K₂) ration (k₁, (k₂ x half-life
(mg/litre) h^-1) 10³,h^-1) (hr)
________________________________________________________________________________________________________

Rainbow para stat TR 2768 ± 641^b 0.005-0.05 9.6-13.3 72.2 Muir
trout isomer (10°C) TR 1420 ± 42^c 14.0 et al.
( Salmo TR 1466 ± 138^d 17.0 (1983)
gairdneri ) HER 770 ± 24^c 65.4
meta TR 1162 ± 313^b 11.5-24.2 30.3
isomer TR 784 ± 82^c 18.5
TR 1102 ± 137^d 21.2
HER 310 ± 52^c 25.8
Fathead para stat TR 2199 ± 227^b 0.005-0.05 7.0-9.6 90.0 Muir
minnows isomer (10°C) TR 928 ± 78^c 4.9 et al.
( Pimephales TR 588 ± 129^d 9.6 (1983)
promelas ) HER 709 ± 76^c 73.7
meta TR 1653 ± 232^b 8.5-14.7 59.2
isomer TR 596 ± 103^c 7.9
TR 385 ± 92^d 8.7
HER 62 ± 3^c 53.3
commer- flow GC- 165 0.0316 Veith et
cial (25°C) FPD al. (1979)

Bluegill TCP
( Leptomis para TR 1589 Sitthich-
macrochirus ) isomer aikasem
(1978)
________________________________________________________________________________________________________
^a GC-FPD = gas chromatography (flame photometric detector) after suitable extraction;
TR = total radioactivity; HER = hexane-extractable radioactivity.
^b BCF was calculated by the "initial rate method".
^c The static test method was used (Zitko, 1980).
^d k₁ and k₂ were derived by non-linear regression calculation.

5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

Summary

TCP has been measured in the atmosphere in Japan at concen-
trations up to 70 ng/m³ but only reached 2 ng/m³ at a pro-
duction site in the USA. Workplace air in the USA contained
less than 0.8 mg/m³ at a lubrication oil barrel-filling oper-
ation and 0.15 mg/m³ (total phosphates) in an automobile zinc
die-casting plant. The concentrations of TCP measured in
drinking-water in Canada were low (0.4 to 4.3 ng/litre), and
TCP was undetectable in well-water. Levels in river and lake
water are frequently considerably higher. However, this is due
to the presence of suspended sediment to which TCP is strongly
adsorbed. Concentrations up to 1300 µg/kg in river sediment
and 2160 µg/kg in marine sediment have been measured.

Elevated TOCP levels in soil and vegetation have been found
within the perimeter of production plants.

Residues of TOCP in fish and shellfish up to 40 µg/kg have
been reported but the majority of animals sampled contained no
detectable amounts.

5.1 Environmental levels

TCP has been found in air, water, soil, sediment, and
aquatic organisms. However, the levels of TCP in environ-
mental samples are low (Table 8), except in soil and sedi-
ment collected in heavily industrialized areas (Table 9).

5.1.1 Air

Yasuda (1980) measured the distribution of various
organic phosphorus compounds in the atmosphere over the
eastern Seto Inland Sea, Japan. Near the heavily industri-
alized cities (Fukuyama, Akashi, Osaka), 11.5-21.4 ng
TCP/m³ was detected. Yasuda (1980) also measured levels
of phosphate esters in the atmosphere above the Dogo Plain
and the Ozu Basin agricultural area of Western Shikoku.
TCP was detected only in the urban air of Matsuyama, where
the level was 26.7-70.3 ng/m³. TCP levels of 0.01-2 ng/m³
in air collected at production sites in the USA have been
reported (MRI, 1979).

Table 8. Concentration of TCP in environmental air, water, sediment, and fish at various locations
______________________________________________________________________________________________________
Locations Year Sample Concentration Number of Reference
samples
(detected/
analysed)
______________________________________________________________________________________________________
Shikoku (Japan) 1976 atmosphere 26.7-70.3 ng/m³ (3/19) Yasuda
(1980)
Eastern Seto 1977 atmosphere 11.5-21.4 ng/m³ (3/4)
Inland Sea (Japan)

Japan (various 1975 river and sea water ND (50-1500 ng/litre)^a (0/100) EAJ (1977)
locations) river and sea sediment 150 ng/g (1/100)
fish ND (20-250 ng/g)^a (0/100

Japan (various 1978 river and sea water ND (50-2500 ng/litre)^a (0/114) EAJ (1979)
locations) river and sea sediment 1060-2160 ng/g (3/114)
fish ND (0.25-150 ng/g)^a (0/98)

Osaka (Japan) 1976 river water 100-9500 ng/litre (11/13) Kawai et
al. (1978)
Eastern Ontario 1978 drinking-water 0.3 ng/litre (1/12) Lebel et
water treatment al. (1981)
plant (Canada)

Tokyo (Japan) 1978 river water ND (50 µg/litre)^a (0/12) Wakabayashi
sea water ND (50 µg/litre)^a (0/3) (1980)
river sediment 7-370 ng/g (9/10)
sea sediment 4 ng/g (1/3)

Canada (various 1979 drinking-water 0.7-4.3 ng/litre (7/60) Williams &
locations) Lebel (1981)

Great Lake 1980 drinking-water 0.4-1.8 ng/litre (5/12) Williams et
(Canada) al. (1982)

Kitakyushu 1980 river water 67-259 ng/litre (3/16) Ishikawa et
City (Japan) sea water ND (20 ng/litre)^a (0/9) al. (1985)
sea sediment ND (10 ng/g)^a (0/6)

Seto Inland 1980 fish and shell fish 1-19 ng/g (4/41) Kenmotsu et
Sea (Japan) al. (1981a)
_____________________________________________________________________________________________________
^a Range of detection limits due to analytical methods used; ND = not detected.

Table 9. Concentration of TCP detected near the producers and users of trialkyl/aryl phosphates
_____________________________________________________________________________________________
Locations Year Sample Concentration Number of Reference
samples
(detected/
analysed)
_____________________________________________________________________________________________
Near TAPs manufacturing fish 2-5 ng/g Muir (1984)
plants (USA)

Columbia River (USA) fish (sturgeon) 40 ng/g Lombardo &
Egry (1979)

Kanawha River (USA) 1978 river water 20 000 ng/litre Boethling &
Cooper (1985)

FMC Corp., Nitro, MV 1979 air (HV)^a 2 ng/m³ Boethling &
(USA) Cooper (1985)

Stauffer Chemical Co., 1979 air (HV)^a 0.01-0.05 ng/m³ (2/4) Boethling &
Gallipolis Ferry, MV vegetation 1000-20 000 ng/g (4/4) Cooper (1985)
(USA) soil 1000-4000 ng/g (4/4)

FMC Corp. Plant (USA) 1980 waste water 6.23 mg/litre Boethling &
effluent water 0.23 mg/litre Cooper (1985)

Baltimore Harbour 1983 sediment 400-600 ng/g (2/3) Boethling &
(USA) Cooper (1985)

Detroit River, mouth 1983 sediment 230-1300 ng/g (2/2) Boethling &
(USA) Cooper (1985)
_____________________________________________________________________________________________
^a HV = High volume filter pad (air sampler).

5.1.2 Water

Although there have been many monitoring studies for
TAPs in water, TCP has not often been detected in natural
water. Where present, it is only at low levels. According
to the annual reports of the Environment Agency of Japan,
TCP has not been detected in river or sea water at any
sampling points. Due to the variety of analytical methods
and procedures used, the detection limits varied between
5 and 2500 ng/litre between different laboratories (EAJ,
1977; 1979; 1981). Kawai et al. (1978) detected TCP at
100-9500 ng/litre in river water sampled in Osaka (Japan),
and found that the concentration of TCP in river water
tended to parallel the concentration of suspended solid.
Ishikawa et al. (1985) detected TCP levels of 67-259
ng/litre in 3 out of 16 samples of river water in
Kitakyushu City (Japan), but not in sea water. Both cities
are located in the most heavily industrialized areas of
Japan.

Relatively high concentrations of TAPs have frequently
been detected in river water sampled near producer or user
sites: 20 µg TCP/litre was detected in the Kanawha River
(USA) 8 miles downstream from the plant outfall (Boethling
& Cooper, 1985).

5.1.3 Soil

There has been only one report of TCP in soil (from
Stauffer Chemical Co. at Gallipolis Ferry (USA)), the
level being 1.0-4.0 mg/kg (Boethling & Cooper, 1985). The
high concentration of total TAPs (26 550 mg/kg) in this
sample was thought to reflect product accumulation in the
area, which was subject to frequent spills.

5.1.4 Sediment

Because of the high sediment adsorption coefficient,
higher levels of TCP have frequently been detected in
sediment than in water. TCP was detected at 400-600 ng/g
in sediment in Baltimore harbour (USA) and at 230-1300
ng/g in the Detroit River (USA) (Boethling & Cooper,
1985). According to the annual reports of the Environment
Agency of Japan, a level of 150 ng/g was found (Mitaki
River, Japan) in one out of 100 sediment samples in 1975,
whereas 1060-2160 ng/g (Doukai Bay, Japan) was found in 3
out of 114 samples in 1978 (EAJ, 1977; 1979; 1981).
Wakabayashi (1980) detected 7-370 ng/g in nine out of ten
river sediment samples, and 4 ng/g in one out of three sea
sediment samples in Tokyo.

5.2 General population exposure

5.2.1 Drinking-water

TCP levels in drinking-water are very low. Lebel et
al. (1981) analysed TAPs in drinking-water sampled from
eastern Ontario water treatment plants and found TCP (at
0.3 ng/litre) in only one out of 12 samples. In an
extended survey of drinking-water conducted in Canada
(Williams & Lebel, 1981), TCP was detected at 0.7-4.3
ng/litre in 7 out of 60 samples of treated potable water
obtained at the treatment plants of 29 municipalities.

In a study by Williams et al. (1982), TCP was detected
in river and lake water but not in well-water. TCP was
also found, at concentrations of 0.4 to 1.8 ng/litre, in 5
out of 12 samples of drinking-water obtained from 12 water
treatment plants located around the Great Lakes (USA).

In general, the TCP concentration in drinking-water is
lower (by factors of 10^-2 to 10^-3) than that in river
water. This is due to the efficient removal of TCP at
water treatment plants by infiltration using activated
carbon with a high adsorption coefficient.

5.2.2 Fish

Lombardo & Egry (1979) found a TCP concentration of
40 ng/g in sturgeon caught in the Columbia River (USA),
where many metal-processing plants were located upstream
from the sampling point. Muir (1984) found 2-5 ng/g in
fish caught near TAP manufacturing plants. According to
the annual reports of the Environment Agency of Japan, TCP
was not detected in fish caught at any sampling points
(EAJ, 1977; 1979; 1981). The analytical detection limits
varied from 0.25 to 250 ng/g. Kenmotsu et al. (1981a)
found 1-19 ng/g in 4 out of 41 samples of fish and shell-
fish collected in the Seto Inland Sea, Japan.

5.2.3 Human tissues

There has been only one report of TAPs in human adi-
pose tissues (Lebel & Williams, 1983). Although there was
no history of TCP exposure in these patients, tris(1,3-
dichloroisopropyl) phosphate and tributoxyethyl phosphate
were detected at levels of 0.5-110 ng/g and 4.0-26.8 ng/g,
respectively.

5.3 Occupational exposure

The National Institute for Occupational Safety and
Health, USA (US NIOSH) has monitored workplace air, and
found that air samples collected near barrel-filling
operations where lubricating oil was produced by blending
TCP contained less than 0.8 mg TAP/m³ (US NIOSH, 1979).

Air collected near the zinc die-casting machine in auto-
mobile manufacturing contained a total phosphate ester
level of 0.15 mg/m³ (US NIOSH, 1980). Airborne TOCP
resulting from the production of heavy-duty radiators has
been investigated by NIOSH, but the concentration was
below the limit of detection (US NIOSH, 1982). Triaryl
phosphates (at approximately 0.1 ppm) were detected in the
air of the aircraft elevator machinery spaces on the
carrier USS Leyte (CVS-32) where a triaryl phosphate oil
was used as a hydraulic fluid (Baldridge et al., 1959).

6. EFFECTS ON ORGANISMS IN THE ENVIRONMENT

Summary

The primary productivity of cultures of freshwater green
algae was reduced to 50% by TOCP at levels of 1.5 to 4.2 mg per
litre, depending on the species. The meta and para isomers were
less toxic. There are few data on the acute toxicity of TCP to
aquatic invertebrates: a 48-h LC₅₀ for Daphnia of 5.6 mg per
litre, a 24-h LC₅₀ for a nematode of 400 mg/litre, and a
2-week NOEL for Daphnia (mortality, growth, reproduction) of
0.1 mg/litre. The 96-h LC₅₀ values for three fish species
varied between 4.0 and 8700 mg TCP/litre. Rainbow trout showed
approximately 30% mortality after a 4-month exposure to IMOL
S-140 (2% TOCP) at 0.9 mg/litre and minor effects within 14
days. The exposure levels used in these studies were much
higher than likely water concentrations in the environment and,
in most cases, greatly exceeded the solubility of the compounds.

There is no information on the bioavailability or toxicity
to burrowing or bottom-living organisms of TCP bound to sedi-
ment.

There is an indication that crop plants can be affected by
TOCP released from plastic coverings, but there is no infor-
mation concerning the effects on wild plant species.

6.1 Unicellular algae

Data on the toxicity of TCP compounds to unicellular
algae are given in Table 10.

The toxicity of TCP compounds to freshwater algae
depends on their chemical structure. Substitution of the
hydrogen by a methyl group in the benzene ring decreases
the toxicity (Wong & Chau, 1984). Of the TCP isomers, the
ortho isomer was the most toxic for the primary pro-
ductivity of Ankistradesmus falcatus, followed by the
meta and para isomers (Wong & Chau, 1984).

6.2 Aquatic organisms

Data on the toxicity of TCP to aquatic organisms are
presented in Table 11.

Table 10. Toxicity of TCP to freshwater unicellular algae
________________________________________________________________________________________________________
Organism Isomer Temper- Species Effect Concent- Reference
ature ration
(°C) (mg/litre)
________________________________________________________________________________________________________

Alga ortho 20 Ankistrodesmus falcatus 24-h IC₅₀ for primary 2.5 Wong & Chau
meta 20 var. acicularis productivity >5.0 (1984)
para 20 >5.0

Green alga ortho 20 Scenedesmus 24-h IC₅₀ for primary 4.2 Wong & Chau
meta 20 quadricaudata productivity >5.0 (1984)
para 20 >5.0

Lake Ontario ortho 20 24-h IC₅₀ for primary 1.7 Wong & Chau
phytoplankton meta 20 productivity 4.1 (1984)
para 20 >5.0

Green alga Scenedesmus 4-day EC₅₀ 1.5 Adema et al.
pannonicus (1983)^a

________________________________________________________________________________________________________
^a Tests were performed according to or in line with standardized procedures (OECD, 1981).
EC₅₀: 50% effective concentration; IC₅₀: 50% inhibition concentration.

Table 11. Toxicity of TCP to aquatic organisms
________________________________________________________________________________________________________
Organisms Chem- Size/ Temp. Flow/ Hard- End-point Parameter Concent- Reference
icals weight (°C) stat ness or criteria ration
(mg/ (mg/
litre) litre)
________________________________________________________________________________________________________
Tidewater TCP^a 40-100 20 stat 96-h LC₅₀ 8700 Dawson et
silverside mm al. (1977)
( Menidia
beryllina )

Bluegill TCP^a 35-75 23 55 96-h LC₅₀ 7000 Dawson et
( Lepomis mm al. (1977)
macrochirus ) 0.60 g 12 flow- 44 96-h LC₅₀ 0.26 Mayer &
through 314 0.061 Ellersieck
(1986)
Guppy TCP^a stat
( Poecilia 96-h LC₅₀ 4.0 Adema et
reticulata ) mortality, 96-h NOEL 1.0 al. (1983)^b
swimming
behaviour,
colour

mortality, 4-week 1.0 Adema et
growth, NOEL al. (1983)^b
swimming
behaviour

IMOL stat mortality, 24-h NOEL > 57 Wagemann
S-140 visible (1975)
effects

Flagfish TCP^a egg-larval 6-week 0.01 Adema et
( Jordanella development, NOEL al. (1983)^b
floridae ) mortality,
growth,
swimming
behaviour,
colour
________________________________________________________________________________________________________

Table 11. (contd.)
________________________________________________________________________________________________________
Organisms Chem- Size/ Temp. Flow/ Hard- End-point Parameter Concent- Reference
icals weight (°C) stat ness or criteria ration
(mg/ (mg/
litre) litre)
________________________________________________________________________________________________________
Rainbow trout IMOL flow- ate less, condition 0.9 Wagemann
( Salmo S-140 through less active after 8 (1975)
gairdneri ) days

ceased condition 0.9 Wagemann
surface after 14 (1975)
feeding days

mortality condition 0.9 Wagemann
(5/16) after 4 (1975)
months

TCP^a 0.23 g 12 flow- 44 96-h LC₅₀ 0.26 Mayer &
0.50 g through 0.40 Ellersieck
(1986)

Waterflea TCP^a flow- mortality 48-h LC₅₀ 5.6 Adema et
( Daphnia through al. (1983)^b
magna ) mortality, 2-week NOEL 0.1 Adema et
reproduction, al. (1983)^b
growth

Channel catfish 1.30 g 12 flow- 44 96-h LC₅₀ 0.80 Mayer &
( Ictalurus through Ellersieck
punctatus ) (1986)

Yellow perch 0.79 g 292
________________________________________________________________________________________________________
^a No descriptions of isomeric compositions were given in the references.
^b Tests were performed according to or in line with standardized procedures (OECD, 1981).
Measurement of the acute toxicity (96-h LC₅₀) of TCP
to fish range from 8700 mg/litre in tidewater silversides
(Dawson et al., 1977) to 4 mg/litre in guppies (Adema et
al., 1983). The composition of the materials that were
used in these experiments was not given.

Tests on guppies showed that a saturated solution of
IMOL S-140 (see Table 6) in water (14 mg/litre) was not
acutely toxic (96-h exposure), but exposures of 4 months
or more at concentrations of 0.3-0.9 mg/litre caused symp-
toms of chronic poisoning in rainbow trout. Initially only
feeding habits and behaviour changed, but later swimming
ability was impaired, and the fish eventually died
(Wagemann et al., 1974; Wagemann, 1975). Fatty tissue
turned a blue-grey colour, the liver enlargened, and the
activities of lactate dehydrogenase (LDH) and glutamic-
oxaloacetic transaminase (GOT) increased (Wagemann et al.,
1974; Wagemann, 1975; Lockhart et al., 1975).

Phosflex 179-C (TOCP) slightly inhibited the acetyl-
cholinesterase activity of an electric ray (Torpedo
electroplax) but did not interfere with binding of
acetylcholine to its receptor (Eldefrawi et al., 1977).

Fish or frogs that received IMOL S-140 or TOCP did not
show, under the test conditions, significant reduction of
brain cholinesterase activity (Lockhart et al., 1975). A
similar observation was made by Cohen & Murphy (1970) on
mice and quail.

6.3 Insects

The toxicity of TCP to insects is presented in Table
12. Most of these data were obtained in the course of
studies on the synergism of TCP or TPP with organophos-
phorus insecticides or juvenile insect hormone mimics.

6.4 Plants

The effects of gaseous TCP on crops covered with vinyl
film have been investigated. TCP emitted from the film
caused a certain amount of leaf shrinking (Inden &
Tachibana, 1975).

The active metabolite of TOCP, saligenin cyclic o-
tolyl phosphate, caused decreased germination of kidney
beans and wheat (Eto et al., 1962).

Table 12. Toxicity of TCP to insects
____________________________________________________________________________________________________
Species TCP Application Age Effect^a Concentration Reference
isomer method
____________________________________________________________________________________________________

Mosquito larva ortho in water early 4th 5-day LD₁₃ 0.1 mg/litre Quinstad et
( Aedes aegypti) instar [± 19] al. (1975)
(LD₂[± 3]
in control)

Mosquito larva in water 4th instar 5-day LD_{7 0.1 mg/litre Quinstad et}
( Culex pipiens [± 7] al. (1975)
quinquefasciatus) (LD₅[± 5]
in control)

Mosquito larva in water 4-h instar 24-h LC₅₀ > 1 mg/litre Plapp & Tong
( Culex tarsalis) (1966)

Housefly larva topical 3rd instar 7-day LD₁₂ 0.1 mg/g Quinstad et
( Musca domestica) treatment [± 6] al. (1975)
(LD₈[± 10]
in control)

Housefly contact 2-5 days old 24-h LD₅₀ > 1 mg/jar Plapp & Tong
( Musca domestica) method (1966)

Housefly meta contact 2-5 days old 24-h LD₅₀ > 1 mg/jar Plapp & Tong
( Musca domestica) method (1966)

Mosquito larva in water 4th instar 24-h LD₅₀ > 1 mg/litre Plapp & Tong
( Culex tarsaris) (1966)

Housefly para contact 2-5 days old 24-h LD₅₀ > 1 mg/jar Plapp & Tong
( Musca domestica) method (1966)

Mosquito larva in water 4th instar 24-h LD₅₀ > 1 mg/litre Plapp & Tong
( Culex tarsaris) (1966)
____________________________________________________________________________________________________
a Values in square brackets are standard deviations.

7. KINETICS AND METABOLISM

Summary

The absorption, distribution, metabolism, and elimination
of organophosphates are critical to the delayed neuropathic
effects of these compounds. In addition, other factors (e.g.,
route of administration, sex, age, strain) affect their meta-
bolic fate and subsequent neurotoxic expression. Variability in
these factors may underline the interspecies variation in the
sensitivity to TOCP-induced delayed neuropathy (i.e. OPIDN).
This correlation has been demonstrated with other OPIDN com-
pounds, but relevant studies on TOCP itself are limited.

Dermal absorption of TOCP in humans appears to be at least
an order of magnitude faster than in dogs. Significant dermal
absorption also appears to occur in cats. Oral absorption of
the compound has been reported in rabbits. There is no direct
information on absorption via the inhalation route.

In cat studies, absorbed TOCP was widely distributed
throughout the body, the highest concentration being found in
the sciatic nerve, a target tissue. Other tissues with high
concentrations of TOCP and its metabolites are the liver, kid-
ney, and gall bladder.

TOCP is metabolized via three pathways. The first is the
hydroxylation of one or more of the methyl groups, and the sec-
ond is dearylation of the o-cresyl groups. The third is further
oxidation of the hydroxymethyl to aldehyde and carboxylic acid.
The hydroxylation step is critical because the hydroxymethyl
TOCP is cyclized to form saligenin cyclic o-tolyl phosphate,
the relatively unstable neurotoxic metabolite.

TOCP and its metabolites are eliminated via the urine and
faeces, together with small amounts in the expired air.

7.1 Absorption

TOCP absorption has been studied in a variety of
species using oral or dermal administration. No infor-
mation is available on absorption following inhalation.

Gross & Grosse (1932) reported that TOCP given orally
(0.1 g/kg in olive oil) was absorbed by rabbits.

Hodge & Sterner (1943) demonstrated poor absorption of
³²P-labelled TOCP in a dog after administration of a
single dermal dose of 200 mg/kg. The rate of transfer
(dose: 2-4 mg [³²P]-TOCP/kg) through intact human palm
skin appeared to be about 100 times faster than that
through the abdominal skin of the dog. This was based on
urinary excretion and surface area considerations.

Another species, the cat, showed even greater absorp-
tion. When [¹⁴C]-TOCP (50 mg/kg) was dermally applied to
adult male cats, the disappearance of radioactivity from
the application site was bi-exponential. In the first
phase, 73% of the TOCP disappeared within 12 h, while the
second phase half-life was 2 days (Nomeir & Abou-Donia,
1984; 1986b).

Studies by Kurebayashi et al. (1985) indicated incom-
plete absorption of tri- p-cresyl phosphate (TPCP) from
the intestine of rats after a single oral dose of [methyl-
¹⁴C]-TPCP (7.8 or 89.6 mg/kg) in 1.5 ml of dimethyl
sulfoxide. Much of the radioactivity was recovered in the
faeces, predominantly in the form of unchanged TCP.

7.2 Distribution

After a single oral dose of [³²P]-TOCP (770 mg/kg)
to chickens, the total radioactivity in liver increased
consistently throughout 72 h. The levels of radioactivity
in the plasma were consistently lower than those in liver;
at 24 h the plasma levels were 5% of those in liver. The
radioactivity was predominantly associated with TOCP
metabolites in liver but with unmetabolized TOCP in blood
(Sharma & Watanabe, 1974).

Following a single dose of [³²P]-TOCP (200 mg/kg) to
the abdominal skin of the dog, the radioactivity in the
blood within 24 h was equivalent to an average value of
80 µg/litre and was distributed throughout the visceral
organs, muscle, brain, and bone. The levels of radioac-
tivity in tissues were in the following descending order:

liver > blood > kidney > lung > muscle or spinal
cord > brain or sciatic nerve (Hodge & Sterner, 1943).

In cats given a single dermal dose of 50 mg [¹⁴C]-
TOCP/kg, the chemical was absorbed from the skin and sub-
sequently distributed throughout the body. TOCP reached
its highest concentration in plasma at 12 h, and its
metabolites attained their maximum concentration between
24-48 h. The relative residence values of unmetabolized
TOCP in various tissues, relative to the plasma, were:
brain, 0.09; spinal cord, 0.18; sciatic nerve, 2.1; liver,
0.44; kidney, 0.55; lung, 1.27. Parent TOCP was the pre-
dominant compound in the brain, spinal cord, and sciatic
nerve, while the metabolites o- hydroxybenzoic acid and
di- o-cresyl phosphate were predominant in the liver,
kidney, and lung (Nomeir & Abou-Donia, 1984). In contrast,
when measuring total radioactivity sampled 1-10 days post
exposure, highest levels were found in the bile, gall
bladder, urinary bladder, kidney, and liver, with only low
levels in the spinal cord and brain (Nomeir & Abou-Donia,
1986b).

Gross & Grosse (1932) reported that most of the cresol
ester was recovered from the liver (5%) and intestine
(67%) within 2 h after an intravenous injection (0.5 g/kg)
of TOCP into rabbits.

At 24, 72, and 168 h after oral administration of
[¹⁴C]-TPCP to rats, the concentrations of radioactivity
in adipose tissue, liver, and kidney were higher than
those in other tissues (Kurebayashi et al., 1985).

7.3 Metabolic transformation

TOCP is metabolized in rats, rabbits, mice, and
chickens to form a neurotoxic esterase inhibitor (Davison,
1953; Aldridge, 1954; Aldridge & Barnes, 1961; Casida,
1961). In rats injected intraperitoneally with TOCP, this
esterase inhibitor was located mainly in the intestine and
liver (Myers et al., 1955). The neurotoxic metabolite was
isolated from the intestine and liver of rats following
TOCP administration and was identified as saligenin cyclic
o-tolyl phosphate [2-( o-cresyl)-4H-1:3:2-benzodioxaphos-
phoran-2-one] (M-1); M2 and M3 in Fig. 1 are also possible
metabolites (Casida et al., 1961; Eto et al., 1962). The
saligenin cyclic o-tolyl phosphate was also found in
chickens (Eto et al., 1962; Sharma & Watanabe, 1974) and
in cats (Taylor & Buttar, 1967; Nomeir & Abou-Donia, 1984;
1986a,b). Although quantitative data are not available,
indirect evidence suggests that cats metabolize this
neurotoxic compound more efficiently than chickens
(Taylor & Buttar, 1967). Two intermediate metabolites,
di-( o-cresyl) mono- o-hydroxymethylphenyl phosphate
[mono-hydroxymethyl TOCP] and di-( o-hydroxymethylphenyl)
mono- o-cresyl phosphate, [di-hydroxymethyl TOCP],
transform to saligenin cyclic o-tolyl phosphate (Eto
et al., 1962; 1967), which is relatively unstable and is
rapidly hydrolysed to inactive metabolic products.

TOCP is metabolized via three essential pathways. The
first is the hydroxylation of one or more of the methyl
groups to hydroxymethyl, which is responsible for the for-
mation of mono- and di-hydroxymethyl TOCP and o-hydroxy-
benzyl alcohol. This reaction is known to be catalysed by
the microsomal mixed-function oxidase system (Eto et al.,
1967). The hydroxymethyl TOCP is cyclized to form sal-
igenin cyclic o-tolyl phosphate with spontaneous release
of o-cresol, this being catalysed by the reaction of
plasma albumin or other components (Eto et al., 1967). The
cyclic phosphate metabolite is relatively unstable and is
rapidly hydrolysed to inactive metabolic products (Eto et
al., 1967). The second pathway is the dearylation of one
or more of the o-cresyl groups of TOCP, resulting in the
formation of o-cresol, di- o-cresyl phosphate, o-cresyl
phosphate, and phosphoric acid. The third pathway is
further oxidation of hydroxymethyl to aldehyde and car-
boxylic acid. These oxidation reactions are most likely to
be mediated by alcohol and aldehyde dehydrogenases.

Studies with [³²P]-TOCP in rats have shown that
hydrolysis leads to the rapid excretion in the urine of
diaryl phosphates, monoaryl phosphates, and phosphoric
acid (Casida et al., 1961).

Nomeir & Abou-Donia (1984; 1986a,b) clearly identified
the metabolites of TOCP in male cats. Mono- and di-
hydroxymethyl TOCPs and saligenin cyclic- o-tolyl phos-
phates were present in most tissues, but their concen-
trations were low compared with those of other metab-
olites. The major metabolite of TOCP in the liver, kidney,
lung, and urine of cats was o-hydroxybenzoic acid; di-
o-cresyl phosphate, o-cresyl phosphate, o-cresol,
o-hydroxy-benzyl alcohol, and o-hydroxybenzaldehyde
were also identified. However,the brain, spinal cord,
sciatic nerve, and faeces contained predominantly
unchanged TOCP.

Johnson (1975a) compared the metabolic pathways of the
three isomers of TCP. The main observations, which con-
cerned several organophosphorus esters, were as follows:

(i) Provided that the o-alkyl group has at least one
hydrogen on the alpha-carbon atom, cyclic derivatives
can be obtained that are often highly neurotoxic.

(ii) At the para position, a substituent requires two
hydrogen atoms on the alpha-carbon atom in order to
produce a neurotoxic metabolite inhibiting NTE.

(iii) Substituents at the meta position may be metab-
olized but do not yield inhibitory products.

The major urinary metabolites of TPCP in rats were
p- hydroxybenzoic acid, di- p- cresyl phosphate, and
p- cresyl p- carboxyphenyl phosphate. Mono- (or di-) p-
cresyl di- (or mono-) p- carboxyphenyl phosphate was
identified as the intermediate metabolite in the bile
(Kurebayashi et al., 1985).

7.4 Excretion

After a single oral dose of [³²P]-TOCP (770 mg/kg)
to hens, 26.5% of the total radioactivity was eliminated
in the combined urinary-faecal excreta over 72 h, mostly
as TOCP (Sharma & Watanabe, 1974).

After a single dose of [¹⁴C]-TOCP (50 mg/kg) to male
cats, approximately 28% of the applied dose was excreted
in the urine and 20% via the bile into the faeces within
10 days (Nomeir & Abou-Donia, 1986b). After this exposure,
the disappearance of TOCP and its metabolites from the
plasma followed monoexponential kinetics. The apparent
half-lives of TOCP and its metabolites (in days) in the
plasma were: TOCP, 1.20; saligenin cyclic- o- tolyl phos-
phate, 2.47; di- o- cresyl phosphate, 4.50; o- cresyl
phosphate, 4.30; o- cresol, 2.65; o- hydroxybenzyl
alcohol, 14.0; o- hydroxy-benzaldehyde, 5.70; o-
hydroxybenzoic acid, 6.00; monohydroxymethyl TOCP, 2.20.
The apparent half-lives of TOCP and its metabolites
reflected the rates of all processes involving the

conversion, clearance, and/or redistribution of these
metabolites (Nomeir & Abou-Donia, 1984).

Elimination via the bile has been demonstrated after
intravenous injection into rabbits (Gross & Grosse, 1932)
and intraperitoneal injection into rats (Myers et al.,
1955). Smith et al. (1932) measured the urinary phenol
excretion in cats given subcutaneous doses of 0.4 to 1.0
ml TOCP/kg. Little if any increase in the urinary phenol
excretion was found either before or after the onset of
paralysis of the hindlimbs.

After a single oral dose (500 mg/kg) of tri- m-cresyl
phosphate (TMCP) or TPCP to rabbits, 92% of TMCP and 95%
of TPCP was eliminated in the faeces within 4 days (Gross
& Grosse, 1932). After a single oral dose of [methyl-
¹⁴C]-TPCP (7.8 or 89.6 mg/kg), about 90% or 76%,
respectively, of the radioactivity was eliminated in the
urine and faeces within 24 h (Kurebayashi et al., 1985).
The apparent half-lives of the radioactivity in tissues
ranged from 14 h for blood to 26 h for