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

         The International Programme on Chemical Safety (IPCS) is a
    joint venture of the United Nations Environment Programme, the
    International Labour Organisation, and the World Health
    Organization. The main objective of the IPCS is to carry out and
    disseminate evaluations of the effects of chemicals on human health
    and the quality of the environment. Supporting activities include
    the development of epidemiological, experimental laboratory, and
    risk-assessment methods that could produce internationally
    comparable results, and the development of manpower in the field of
    toxicology. Other activities carried out by the IPCS include the
    development of know-how for coping with chemical accidents,
    coordination of laboratory testing and epidemiological studies, and
    promotion of research on the mechanisms of the biological action of

    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

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

    (c) World Health Organization 1990

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

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

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



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                                         


    2.1. 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                           


    3.1. Production levels and processes                           
         3.1.1. Accidental release                                  
    3.2. Uses                                                      


    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                                             


    5.1. 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                                                 


    8.1. 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                                                 


    10.1. 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                                                





MEDIO AMBIENTE                      



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, 

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


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

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


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

    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). 


    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.


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
  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


1.1   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 Pow)   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 

    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 

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 

    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.


2.1  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, 

    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 
Colour                    colourless                colourless       colourless       colourless     

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

Melting or                -33b                      11a              25.6a            77-78a         
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;     1.1955a          1.150a           1.237a        
(density)                 1.165c 

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

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

Flash point (°C)          257c 

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/mold

Solubility in water       0.36e; 0.34 ± 0.04f                                         0.074g

Octanol-water partition   5.11e 
coefficient (log Pow)     5.12h 
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  Pow)   is approximately 

    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 phosphatesa
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-

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
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   
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       

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.
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   
                charcoal column      
                concentrated sulfuric
                acid extraction and  
                Florisil column      

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       
Table 4.  (contd.)

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

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-  

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 


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 1984a.   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 acidsa 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 

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 
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 
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)



     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 

     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 

     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 

    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, 

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., 

    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 

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 
(Pow)   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.)  methoda  (K1/K2)      ration      (k1,    (k2 x      half-life
                                                      (mg/litre)  h-1)    103,h-1)   (hr)     

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



     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
Shikoku (Japan)       1976  atmosphere              26.7-70.3 ng/m3        (3/19)       Yasuda 
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
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 

    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, 

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).



     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-

     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        TCPa    40-100   20    stat                           96-h LC50    8700      Dawson et 
silverside               mm                                                                   al. (1977)
( Menidia  
 beryllina )

Bluegill         TCPa    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
Guppy            TCPa                   stat
( Poecilia                                                              96-h LC50    4.0       Adema et 
 reticulata )                                            mortality,     96-h NOEL    1.0       al. (1983)b

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

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

Flagfish         TCPa                                   egg-larval     6-week       0.01      Adema et 
( Jordanella                                             development,   NOEL                   al. (1983)b
 floridae  )                                             mortality, 

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)

                 TCPa    0.23 g   12    flow-    44                    96-h LC50    0.26      Mayer & 
                         0.50 g         through                                     0.40      Ellersieck

Waterflea        TCPa                   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

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           Effecta       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 LD7     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.



     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, 

    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 lung and brain.  At 
the lower dose level, about 28% of the dose was eliminated 
via  the  bile within  24 h.  The expiratory  excretion as 
14CO2 over 3 days  amounted to  18%  of the radioactivity, 
which  was reduced to 3%  when the rats were  treated with 
neomycin.  The  authors  suggested that  the enterohepatic 
circulation  and  intestinal microflora  play an important 
role in the degradation of TPCP biliary metabolites.



     Of  the three isomers of TCP, TOCP is by far the most toxic 
 and is the only isomer that produces delayed neuropathy. 

     A  wide  animal  interspecies variability  exists  for  the 
 various  end-points  (e.g., lethality,  neuropathology, ataxia, 
 enzyme inhibition) of TOCP exposure, the chicken being  one  of 
 the  most sensitive species to delayed neuropathy (i.e. OPIDN). 

     Species  sensitivity to the lethal effects of TOCP adminis-
 tration is highly variable, chickens and cats being more sensi-
 tive than rats and mice. A single oral dose of  50-500 mg  TOCP 
 per kg induced delayed neuropathy in chickens, whereas doses of 
 840 mg/kg  or more were necessary to produce spinal cord degen-
 eration in Long-Evans rats. 

     No effects were reported in skin and eye irritation studies 
 on rabbits.  

     Reproduction  studies on 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.   However, no reproductive  effects were seen  in  a 
 study  with  TPCP. A  clear  no-observed-effect level  for  the 
 reproductive  effects of TOCP  was not apparent  from the  data 
 available.   A study in  rats, using oral  doses that  produced 
 maternal toxicity, failed to show any teratogenicity. 

     Little or no information is available on  mutagenicity  and 

     Delayed neuropathy 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". 
 "Neurotoxic esterase" is thought to be the biochemical target 
 of  OPIDN  and its  inhibition by more  than 65% shortly  after 
 exposure to TOCP presages subsequent neuropathy.  Factors other 
 than  metabolism (e.g., route  of exposure, age,  sex, species, 
 strain) influence variability in sensitivity to OPIDN. 

     Electrophysiology  studies have been performed  in cats and 
 chickens exposed to TOCP. 

     In the chicken, single exposures below 58 mg/kg  or  short-
 term  (i.e. 90-day exposure) daily  doses of less than  5 mg/kg 
 appear  to be no-observed-effect levels for delayed neuropathy. 

8.1  Single exposure

    The  acute  toxicity of  TCP  to different  species is 
summarized in Table 13.

Table 13.  LD50 values for TCP and its isomers
Compounds       Route   Species  LD50      Reference
                of               (mg/kg)
Tricresyl       oral    rat      5190      Marhold (1972)
phosphate       oral    rat      >4640     Stauffer (1988)a
(mixed          oral    rat      >15 800   Johannsen (1977)
isomers)        oral    mouse    3900      Izmerov (1982)
                oral    chicken  >10 000   Johannsen et al. (1977)
                dermal  rabbit   >7900     Johannsen et al. (1977)
                dermal  cat      1500      Abou-Donia et al. (1980)
Tri- o- cresyl   oral    rat      8400      Johannsen et al. (1977) 
phosphate       oral    rat      1160      Veronesi et al. (1984a)
                oral    rabbit   3700      Johannsen et al. (1977)
                oral    chicken  500       Kimmerle & Loeser (1974)
                oral    chicken  100-200   Smith et al. (1932)
Tri- p- cresyl   oral    rabbit   >3000      Smith et al. (1932)
phosphate               chicken  >1000      Smith et al. (1932)
Tri- m- cresyl   oral    rabbit   >3000      Smith et al. (1932)
phosphate       oral    chicken  >2000      Smith et al. (1932)
a  Personal communication to the IPCS from Stauffer Chem. Co. (1988) 
   entitled: Test procedures and data summaries for t-butyl phenyl 
   diphenyl phosphate, tricresyl phosphate, trixylenyl phosphate, 
   mixed triaryl phosphate and isopropyl phenyl diphenyl.
    The  acute  symptoms  of intoxication  are  typical of 
organophosphorus  poisoning.   The  most  toxic   compound 
appears to be TOCP; the acute toxicity of TCP  depends  on 
the relative proportions of the different isomers.

    The  chicken, guinea-pig, and rabbit are the most sen-
sitive  species, death occurring  at an oral  dose of  100 
mg/kg  (Smith et al., 1932);  rats and mice are  the least 
sensitive species.

    Sheep  given oral doses  (100, 200, or  400 mg/kg)  of 
TOCP  exhibited acute intoxication characterized  by diar-
rhoea,  dehydration, metabolic acidosis, and  death within 
6 days.   Pigs dosed with  100 to 1600 mg  TOCP/kg  showed 
minimal  signs of acute intoxication, but developed severe 
signs  of  delayed neuropathy  approximately 15 days after 
administration (Wilson et al., 1982).

8.2  Short-term exposure

    Saito  et al. (1974) conducted a 3-month study in rats 
with TCP consisting of 60-65% TMCP and 35-40%  TPCP.   The 
compound  was suspended in  water with 5%  gum arabic  and 

given orally to SD rats at 30, 100, 300, or 1000 mg/kg per 
day.   Histopathological  examination revealed  no notable 
changes  associated  with  the compound.   Based  on those 
observations,  the authors concluded  that TCP was  of low 
short-term toxicity.

    Oishi  et al. (1982) reported  that Wistar rats fed  a 
pellet  diet containing a mixture of TCP isomers at a con-
centration  of 5 g/kg diet for 9 weeks developed increases 
in  absolute  and  relative liver  weights. Haematological 
examination  revealed  no  notable changes,  but,  in  the 
plasma,  total  protein, urea,  cholesterol and glutamate-
pyruvate transaminase were significantly increased. Slight 
liver  histopathology included cytoplasmic  vacuolization, 
increase  in the number of binucleated cells, and enlarge-
ment of cell size.

    Chapin et al. (1988) exposed male and female CD-1 mice 
to  diets containing 0, 0.437,  0.875, 1.75, 3.5, or  7.0% 
TCP  (a mixture  of ortho,  meta, and  para  isomers)  for 
14 days.  No clinical signs of toxicity were  observed  in 
the  animals at doses  up to 0.875%.   All animals in  the 
groups  given 1.75, 3.5,  or 7.0% exhibited  piloerection, 
tremors,  and diarrhoea, and  were lethargic before  death 
during the 14-day exposure.

8.3  Skin and eye irritation

    No published information is available.

8.4  Teratogenicity

    Mele  &  Jensh  (1977) reported  that no abnormalities 
were  found in fetuses  from pregnant Wistar  rats treated 
with 500 or 750 mg TOCP/kg of on the 18th and 19th days of 
gestation.  This study was primarily  designed to investi-
gate  the effects of prenatal treatment with TOCP on post-
natal behaviour.  As such, it cannot be regarded as a true 
teratogenicity study.

    Tocco  et al. (1987) tested the teratogenicity of TOCP 
in Long-Evans rats treated with 87.5, 175,  and  350 mg/kg 
per  day throughout organogenesis from gestation days 6 to 
18.  No maternal deaths or toxicity were observed  at  the 
low or medium dose levels. Maternal lethality in the high-
dose  group was higher  than that in  the control  groups. 
Numerous  soft  tissue  and  skeletal  malformations  were 
observed  in  both  control and  TOCP-treated  groups, but 
there  were no significant differences in the frequency of 
malformations between the treated and control animals.

8.5  Reproduction

    In  studies by Somkuti et al. (1987a), TOCP was tested 
for effects on the male reproductive tract in male Fisher-
344  rats.  Animals were dosed  daily for 63 days at  dose 
levels  ranging from 10  to 100 mg/kg per  day.   Vehicle-
treated  animals served as  controls. As judged  by  enzy-
matic,  hormonal,  and  sperm motility,  density, and mor-
phology  investigations, the minimum effective (threshold) 
dose  for  observable testicular  toxicity was 10-25 mg/kg 
per day.  The data suggested that TOCP interfered directly 
with  spermatogenic processes and  sperm motility and  not 
via  androgenic  mechanisms or  decreased vitamin E avail-
ability.   Testicular  pathological  changes were  seen at 
doses above 25 mg/kg per day and included  the  following: 
PAS-positive  droplets, immature germ cells,  and multinu-
cleate giant cells in the lumen.  TPCP produced a decrease 
in sperm density but no other testicular effects at a dose 
level of 100 mg/kg per day.

    To  study the time course of the TOCP-induced testicu-
lar lesion in F-344 rats, the onset of possible changes in 
sperm  numbers and production, serum hormones, and various 
enzyme  activities  was followed.   Rats were administered 
TOCP  daily (150 mg/kg) for periods of 3, 7, 10, 14, or 21 
days,  while  vehicle-treated animals  served as controls. 
Both  sperm  motility and  the number of  sperm per mg  of 
cauda  epididymis were lower in treated animals by day 10. 
The ratio of testicular to body weight  was  significantly 
decreased only those rats treated for 21 days.  Testicular 
neurotoxic  esterase  and nonspecific  esterase activities 
were also inhibited, while beta-glucuronidase activity was 
not affected. Luteinizing and follicle-stimulating hormone 
levels  were normal, as  were both serum  and interstitial 
fluid  testosterone  concentrations.   Sertoli cell  fluid 
secretion,  as  measured  by testis  weight increase after 
efferent  duct  ligation,  showed no  significant changes. 
Other  organs  (spleen,  liver,  kidney,  pancreas,  small 
intestine,  and adrenal and pituitary  glands) revealed no 
overt signs of pathology as observed by  light  microscopy 
in animals treated for 21 days. A separate group  of  ani-
mals  was  treated  for 21 days  and subsequently examined 
after 98 days of observation (two cycles of the rat semin-
iferous  epithelium).   Normal  spermatogenesis  did   not 
return,  indicating that the toxicity  was irreversible at 
the dose used.  The effects noted in these studies further 
define  the testicular lesion  produced by TOCP,  and show 
that a dose level 150 mg/kg per day for  21 days  produces 
irreversible testicular toxicity (Somkuti et al., 1987b).

    The  testicular effects of TOCP have also been studied 
in  the  rooster,  100 mg/kg per  day  being  administered 
orally  to ten adult  leghorn roosters for  18 consecutive 
days.   By  days 7-10  of the  study,  TOCP-treated  birds 
exhibited  limb paralysis characteristic of  OPIDN. Enzyme 

analyses  at  the end  of  the study  revealed significant 
inhibition  of neurotoxic esterase (NTE)  activity in both 
brain  and testis and a  slight decrease in brain  acetyl-
cholinesterase  (AChE) activity.  Sperm motility was shown 
to  be  greatly  decreased.   In  addition,  sections   of 
formalin-fixed,  methacrylate-embedded  testes from  TOCP-
treated  birds  showed vacuolation  and disorganization in 
the  seminiferous  epithelium.   The marginal  body weight 
decrease  (17%) in treated  animals was not  considered to 
contribute  to  the  testicular toxicity  induced  by TOCP 
(Somkuti et al., 1987c).

    TCP  (isomer mixture not  known) was tested  in  sperm 
morphology   and  vaginal  cytology   examination  (SMVCE) 
studies  in groups of  25 male and female  Fisher-344 rats 
and  25 male and female Swiss CD-1 mice.  Treatment lasted 
for 13 weeks at dose levels of 1700, 3300,  or  6600 mg/kg 
diet  or 50, 100, 200,  400, or 800 mg/kg body  weight via 
gavage in the rats, and 500, 1000, or 2100 mg/kg  diet  or 
50,  100, or 200 mg/kg body weight via gavage in the mice. 
Effects  were seen in treated animals, but no details were 
given (Morrissey et al., 1988a). In a follow-up continuous 
breeding reproduction study in Swiss CD-1 mice,  male  and 
female fertility was reduced (Morrissey et al., 1988b).

    Carlton   et  al.  (1987)  examined  the  reproductive 
effects of TCP (mixed isomers; < 9% TOCP). Male Long-Evans 
rats received 0, 100, or 200 mg/kg and females received 0, 
200,  or 400 mg/kg in  corn oil by  gavage.  The  low-dose 
males  were mated with low-dose females, and the high-dose 
males with high-dose females. Males were dosed for 56 days 
and females for 14 days prior to breeding  and  throughout 
the  breeding period, gestation, and lactation. Sperm con-
centration,   motility,  and  progressive   movement  were 
decreased  in the high-dose males,  and there was a  dose-
dependent  increase  in  abnormal  sperm  morphology.  The 
number  of  females  delivering live  young  was  severely 
reduced  by TCP exposure.   Litter size and  pup viability 
were decreased in the high-dose group, but pup body weight 
and   developmental  landmarks  were  unaffected   by  TCP 
exposure. Histological changes were observed in the testes 
and epididymides of treated males (i.e. necrosis, degener-
ation, early sperm granulomas in seminiferous tubules, and 
epididymal  hypospermia)  and  in the  ovaries  of treated 
females  (i.e. diffuse vacuolar cytoplasmic  alteration of 
interstitial  cells and increased numbers of follicles and 
corpora lutea).

    In a continuous breeding study, Chapin et  al.  (1988) 
fed Swiss CD-1 mice a diet containing TCP (mixed  o-,  m-, 
p-isomers)  at a level of  0, 0.5, 1, or  2 g/kg diet over 
98 days.   Although the fertility index was not changed in 
the  high-dose  groups, the  number  of litters  per  pair 
decreased  in a dose-dependent fashion, and the proportion 
of  pups born alive  and their weight  were  significantly 

decreased.   Histopathological examination of the parental 
generation   revealed  dose-related  seminiferous   tubule 
atrophy and decreased testis and epididymal weights in the 
high-dose  males, but the female reproductive tract showed 
no  histopathological  changes.  A  crossover mating trial 
revealed  impaired  fertility  in both  males  and females 
exposed to 2 g/kg diet.

8.6  Mutagenicity and carcinogenicity

    Haworth  et al. (1983) reported a negative result with 
TCP  (substitution  pattern  not known)  in the Salmonella 
mutagenicity test.

8.7  Neurotoxicity

8.7.1  Experimental neuropathology

    TOCP first gained notoriety as the culpable neurotoxic 
agent  of  the  "Ginger  Jake"  epidemic  (Jeter,  1930; 
Goodale  & Humphreys, 1931; Vonderahe,  1931).  Since then 
several experimental studies have modelled TOCP neuropathy 
in various species.

    Smith  & Lillie (1931)  produced delayed paralysis  in 
various   animals,  including  dogs,  monkeys,  cats,  and 
chickens.  These animal models were used to  describe  the 
functional  and morphological features of TOCP neuropathy. 
After  a delay period  of 2-3 weeks following  exposure to 
single  or  multiple  doses,  paralysis  of  the  hindlegs 
developed in these species in response to the TOCP. Neuro-
pathologically,  degeneration  was confined  to the spinal 
cord  and  peripheral  nerve fibres.   These  changes were 
essentially  similar  to  the lesions  reported  in  human 
victims of the "Ginger Jake" epidemic.

    The  delayed neuropathy associated with TOCP and other 
organophosphorous compounds has been termed OPIDN.

    Cavanagh  (1964)  showed  that, in  cats and chickens, 
degeneration affected the long fibres in the  spinal  cord 
and  peripheral nerves; moreover, in  cats, fibre diameter 
seemed  to  be  important  in  determining  the  onset and 
severity  of the peripheral nerve lesions.  He categorized 
this  delayed neuropathy as  a "dying-back".  Thus,  the 
lesions of the ascending tracts are seen in  the  cervical 
region,  especially in the dorsal columns (i.e. fasciculus 
gracilis), while those of the descending tracts  are  seen 
in  the  thoracic and  lumbosacral  regions of  the spinal 
cord. He also showed that the peripheral and central nerve 
lesions were the result of axonal degeneration and did not 
reflect  primary demyelination.  The affected  nerve axons 
degenerate  in a "dying-back"  fashion towards the  cell 
body, i.e. axonal degeneration begins at the  most  distal 
portion of the axon and proceeds towards the cell body.

    Prineas   (1969)  described  axons   with  accumulated 
tubulovesicular  membranes  within myelinated  motor nerve 
terminals  in the foot  muscles of cats  dosed with  TOCP. 
Similar  early axoplasmic changes have been noted in TOCP-
treated  chickens (Bischoff, 1967, 1970;  Spoerri & Glees, 
1979, 1980).

    At  the ultrastructural level,  the nerve endings  are 
characterized  by a marked proliferation and distension of 
vesicular  elements  of  the endoplasmic  reticulum  and a 
coinciding  disintegration of the filamentous  and tubular 
organelles (Bischoff, 1977).  Bischoff also noted that the 
presynaptic nerve terminals and  boutons terminaux appeared 
particularly sensitive in TOCP intoxication.

    OPIDN has also been produced in rats dosed  with  TOCP 
(Veronesi,  1984).  The pathological changes  developed in 
the  absence of discernable ataxia after a 2-week exposure 
to acute  and multiple oral doses of TOCP (>840 mg/kg). In 
the rat, dorsal column degeneration of the  cervical  cord 
and  a  selective  vulnerability of  large diameter tibial 
branches  supported  a  "dying-back" neuropathy,  as  in 
other species.

    OPIDN  has  also  been described  in  European ferrets 
( Mustela   putorius furo)  administered  a single oral  or 
dermal dose of 250, 500, or 1000 mg TOCP/kg  body  weight. 
Five  animals per group were sacrificed 48 h after dosing, 
the others being observed for another 54 days. All ferrets 
dosed  dermally  with  1000 mg/kg  developed  neurological 
signs  ranging from ataxia  to partial paralysis.   Dermal 
doses  of 250 and  500 mg/kg produced variable  degrees of 
hind  limb  weakness and  ataxia.   Of the  animals  dosed 
orally,  only those treated with  1000 mg/kg showed neuro-
logical  signs, which did not progress beyond mild ataxia. 
Slight  axonal degeneration was noted  in the dorsolateral 
part of the lateral funicilus and in the  fasciculus  gra-
cilis of spinal cords in ferrets receiving a  dermal  dose 
of  1000 mg/kg.  Whole brain neurotoxic  esterase activity 
was  maximally inhibited (46%)  at this dose  level.   The 
study  demonstrated that in the ferret dermal exposure was 
more effective than oral exposure at the same  dose  level 
(Stumpf et al., 1989).

8.7.2  Neurochemistry

    Johnson  (1969) found that  approximately 6% of  brain 
esterases  are  not affected  by non-neuropathic compounds 
but  are  specifically inhibited,  irreversibly, by neuro-
pathic ones, such as TOCP.  Johnson used the term "neuro-
toxic esterase" (NTE) and proposed that NTE is  the  pri-
mary  target of the organophosphorus  esters causing OPIDN 
(Johnson,  1975a,b). There appears  to be a  strong corre-
lation  in the chicken  between NTE inhibition  above  70% 

shortly  after  exposure  and subsequent  neuropathy for a 
large   number   of  tested   organophosphorous  compounds 
(Johnson, 1974).

    Padilla  & Veronesi (1985) demonstrated  the relevance 
of NTE to the rodent model of OPIDN by exposing Long-Evans 
rats  to  single doses  of TOCP ranging  from 290 to  3480 
mg/kg.  High NTE inhibition in the spinal cord  (>72%) and 
the  brain  (> 66%) produced  severe spinal cord damage in 
over 90% of exposed rats, indicating that  NTE  depression 
could  predict  OPIDN damage  in  rats acutely  exposed to 

    Concerning  the  role  of lipids  in  TOCP neuropathy, 
Morazain & Rosenberg (1970) showed that there was  a  rise 
of  25-50% in the cholesterol  level in the sciatic  nerve 
and a 50% decrease in its triglyceride content in chickens 
orally  dosed with 1 ml TOCP/kg.  Phospholipids, diglycer-
ides,  cholesterol esters, proteolipids, and  tissue phos-
pholipases  were  not  affected  by  TOCP.   The  possible 
involvement  of lipids in  the production of  TOCP-induced 
delayed neuropathy has not yet been resolved.

    Other  toxic effects have been  demonstrated.  Brown & 
Sharma  (1975)  found  that neural  membrane  ATPases were 
inhibited  by  organophosphates.   Cohen &  Murphy  (1970) 
reported  that  TOCP  potentiates  the  anticholinesterase 
action  of malathion by 29-fold in mice, 17-fold in quail, 
and 11-fold in sunfish.

8.7.3  Interspecies sensitivity and variability to OPIDN

    Certain  animal species (e.g.,  cats, dogs, cows,  and 
chickens)  are  susceptible  to  OPIDN-related  paralysis, 
whereas  others (e.g., rats and mice) are less susceptible 
to  the ataxia but  very susceptible to  the  pathological 
changes.   Species susceptibility to delayed neurotoxicity 
induced by TOCP shows an inverse correlation with the rate 
of  metabolic conversion to the neurotoxic metabolite (see 
section 7).  Because of its high susceptibility to ataxia, 
the adult chicken has been used as an  experimental  model 
to study OPIDN.

    TOCP  is  metabolized  to the  more  potent neurotoxic 
agent,  saligenin cyclic  o-tolyl  phosphate, which  is at 
least  five  times more  neurotoxic  than TOCP  after oral 
administration to chickens: a metabolite level of 40 mg/kg 
caused  ataxia  equivalent  to that  resulting from 200 mg 
TOCP/kg (Bleiberg & Johnson, 1965).

    It has been shown that a single oral dose of  TOCP  in 
the range of 58 to 580 mg/kg (i.e. 0.05-0.5 ml/kg) induces 
mild  to severe paralysis  in the hen ( Gallus  domesticus) 
(Cavanagh, 1954; Hine et al., 1956).

    Johannsen  et al. (1977) showed that chickens adminis-
tered cumulative doses of TCP (60 000 mg/kg) or TOCP (1500 
mg/kg)  developed  both  the ataxic  and neuropathological 
symptoms of OPIDN.

    In  90-day  studies  in hens,  obvious  functional and 
morphological  neuropathological  changes  were  found  at 
daily  oral dose levels of 5 to 20 mg TOCP/kg body weight, 
but not at lower dosages (Smith et al., 1932;  Prentice  & 
Majeed, 1983; Roberts et al., 1983).

    In  a subchronic feeding study, Haggerty et al. (1986) 
exposed  rats  to  TCP (isomeric  substitution pattern not 
known)  for 13 weeks at dose levels of 0, 900, 1700, 3300, 
6600,  or  13 000 mg/kg. Decreased  hindlimb grip strength 
was  observed in male rats  (at 13 000 mg/kg), but not  in 
female  rats.  In mice exposed to 0, 250, 500, 1000, 2100, 
or  4200 mg/kg, decrements in both fore- and hindlimb grip 
strength  were  observed  in  males  (at  4200 mg/kg)  and 
females  (at 2100 and  4200 mg/kg).  A reduction  of  body 
weight was seen both in rats and mice at the  two  highest 
dose   levels.   Preliminary  histopathological  diagnosis 
indicated  demyelination  and  axonal degeneration  of the 
sciatic nerve in male and female mice only.

    Freeman  et al. (1988) tested the neurotoxicity of TCP 
(substitution pattern not known) to F-344 rats in a short-
term study. After 13 weeks of dosing with TCP in the feed, 
hindlimb grip strength decreased in male rats at  300  and 
600 mg/kg,  but not in female  rats.  Serum cholinesterase 
was  reduced  at  300 and  600 mg/kg  in  both  males  and 
females.   All effects observed with 600 mg/kg were appar-
ently reversible during the recovery period.

    In  a 13-week short-term  feeding study, Irwin  et al. 
(1987)  exposed F-344 rats to TCP (0, 75, 150, 300, or 600 
mg/kg;  substitution pattern not known), while B6C3F1 mice 
receive  0,  60, 125,  or  250 mg/kg.  After  13 weeks  of 
dosing,  forelimb grip strength  was unaffected by  TCP in 
both mice and rats.  Hindlimb grip strength  decreased  in 
male rats (at 300 and 600 mg/kg) but not in  female  rats. 
In  mice,  decrements  in  hindlimb  grip  strength   were 
observed  in males (250 mg/kg)  and females (125  and  250 
mg/kg).  Serum cholinesterase levels showed  a dose-depen-
dent reduction in both rats and mice. TCP had no effect on 
food  consumption in either species.  All groups exhibited 
normal body weight values.

    Factors  such as age,  sex, and strain  figure  promi-
nently  in the  expression of  OPIDN. The  young  of  most 
species are non-susceptible to TOCP-induced delayed neuro-
pathy (Johnson & Barnes, 1970), which could be due to poor 
absorption  of TOCP.  However, recent experiments (Olson & 
Bursian, 1988) have suggested that factors (e.g., route of 
administration) other than absorption are more critical to 
this lack of susceptibility.

    Strain  differences in the  susceptibility of rats  to 
TOCP-delayed neuropathy have been reported. Although OPIDN 
can  be readily produced in  Long-Evans and Sprague-Dawley 
rats  after acute  oral doses of >  840 mg/kg (Veronesi  & 
Abou-Donia,  1982; Veronesi, 1984), repeated doses of TOCP 
(10-100 mg/kg) failed to produce neuropathy in Fischer-344 
rats (Somkuti et al., 1988). Variations in TOCP inhibition 
of  brain AChE and  NTE have also  been reported in  these 
three strains (Carrington & Abou-Donia, 1988).

8.7.4  Neurophysiology

    Robertson  et  al. (1987)  investigated electrophysio-
logical  changes in the  adult hen following  single  oral 
doses  of 30 or 750 mg  TOCP/kg.  At the higher  dose, the 
birds  demonstrated  clinical  signs of  toxicity  12 days 
after  dosing  that  included  gait  abnormalities,  which 
became  progressively more severe and in some cases led to 
complete  ataxia.   Lymphocyte  NTE was  inhibited by more 
than  70%. The lower  dose produced no  clinical signs  of 
toxicity  and  only  54% lymphocyte  NTE  inhibition. Both 
treated  groups  displayed  significant  action  potential 
disruption  in  both the  tibial  and sciatic  nerves that 
resulted  in decreased refractoriness in the tibial nerve, 
increased   refractoriness  in  the  sciatic   nerve,  and 
elevated strength duration threshold for both nerves.

    Electrophysiological changes have been investigated in 
cats  following single dermal  doses ranging from  250  to 
2000 mg TOCP/kg and 90-day dermal administration of  1  to 
100 mg/kg  (Abou-Donia et al.,  1986). In contrast  to the 
hen,  the clinical signs  of TOCP neurotoxicity  appear in 
the cat 21-26 days before the electrophysiological effects 
on  the gastrocnemius muscle.   Recovery of the  cat  from 
delayed  neurotoxicity symptoms was more  marked than that 
of the hen.  No effects on peripheral  nerve  transmission 
or  on neuromuscular junction functioning were seen in the 



     There  have been many  reported cases of  human  poisoning, 
 mostly  from accidental or irresponsible contamination of food-
 stuffs.   Occupational poisoning, usually resulting from dermal 
 exposure, has also been reported.  The ortho isomer of  TCP  is 
 the responsible toxic agent. 

    Though   short-term  symptoms  of  ingestion  might  involve 
 vomiting,  abdominal  pain,  and diarrhoea,  characteristically 
 delayed,  longer-term  symptoms  are  neurological,  frequently 
 leading to paralysis and pyramidal signs (spasticity, etc.). 

     There is considerable variation in the sensitivity of indi-
 viduals to TOCP; severe symptoms were reported with a TOCP dose 
 of  0.15 g in one individual, while others were unaffected by 1 
 to  2 g.  There is also  considerable variation in the  rate of 
 recovery  from  poisoning, some  patients recovering completely 
 and  others still severely  affected years later,  after appar-
 ently similar exposure. 

     First-aid treatment involves the induction  of  vomiting or 
 pumping  of the stomach.  The patient should be hospitalized as 
 soon as possible. Atropine or 2-PAM may be used as an effective 
 antidotal  treatment against cholinergic  symptoms.  Long-term, 
 antispastic drugs may be useful, though physical rehabilitation 
 is the cardinal therapy. 

9.1  Historical background

    Of  the tricresyl phosphate isomers,  the ortho (TOCP) 
is by far the most toxic and alone gives rise to the major 
neurotoxicity  in man.  It is considered that the toxicity 
of the commercial products depends on the concentration of 
the ortho isomer, but the mixed  o-cresyl  esters in these 
products are also toxic and contribute to  the  neurotoxic 

    It is well known that TOCP produces delayed effects on 
the central and peripheral nervous systems. TOCP poisoning 
has  occurred throughout the  world (Inoue et  al., 1988); 
the major outbreaks are indicated in Table 14.

Table 14.  Major outbreaks of TOCP poisoning
Year        Place       Number      Vehicles of TOCP  Reference
                        of cases
1898       France       6           phospho-creosote  Lorot (1899)

1900-1928  Europe       43          phospho-creosote  Roger & Recordier 
                                    (15% TOCP)        (1934)

1930-1931  USA          50 000      ginger extract    Morgan (1982)

1931       Europe       several     Apiol pill        Susser & Stein 
                        hundred                       (1957)

1938       South Africa 68          cooking oil       Sampson (1942)

1940       Switzerland  80          cooking oil       Walthard (1945)

1941-1945  Germany      more than   cooking oil       Mertens (1948)

1945       England      17          cooking oil       Hotston (1946)

1955       South Africa 11          water or solvent  Susser & Stein 

1957       Morocco      about       cooking oil       Smith & Spalding 
                        10 000                        (1959)

1960       India        58          solid food        Vora et al. (1962)

1962       India        more than   flour             Chaudhuri (1965)

1967       Fiji         56          flour             Sorokin (1969)

1980       Romania      12          alcohol           Vasilescu & Florescu 

1981       Sri Lanka    more than   cooking oil       Senanayake & 
                        20          (0.56%)           Jeyaratnam (1981)

    In 1899, Lorot initially reported six cases  of  poly-
neuropathy  out  of  41 cases  of  pulmonary  tuberculosis 
treated with phospho-creosote. Later it was shown that the 
phospho-creosote contained 15% TOCP. In the next 30 years, 
43 additional  cases caused by  the drug were  reported in 
various  parts of continental  Europe (Roger &  Recordier, 

    In  the  spring of  1930,  in mid-western  and  south-
western  USA,  an  outbreak of  paralysis characterized by 
bilateral  foot- and wrist-drop appeared suddenly (Burley, 

1930; Merritt & Moor, 1930). Ultimately 50 000 people were 
poisoned  by  a  popular  substitute  for  alcohol  called 
"Ginger Jake" (Morgan, 1982). Smith et al. (1930) proved 
that  the adulterated beverage contained about 2% TOCP and 
that this caused the paralysis.

    In  1931, several hundred women  in Europe (especially 
in  Germany, The Netherlands, Yugoslavia, and France) were 
poisoned by the TOCP contained in Apiol pills and taken as 
an abortifacient (Roger & Recordier, 1934; Susser & Stein, 
1957).   The TOCP was presumably included as an additional 
stimulus to abortion (Ter Braak & Carrillo, 1932).

    An  outbreak  involving 11 people  occurred in Durban, 
South  Africa, in 1955  (Susser & Stein,  1957). From  the 
epidemiological  survey  it  was suggested  that water, as 
well as solvents, may have been a vehicle for the TOCP.

    In 1959, about 10 000 Moroccan people were intoxicated 
by  TOCP: jet  engine oil  had been  illegally mixed  into 
their  cooking  oil  (Smith &  Spalding, 1959; Svennilson, 
1960). Accidental poisoning by TOCP contamination of solid 
food occurred in 1960 in Bombay, India,  where  58 victims 
were recorded (Vora et al., 1962).

    During  the  period  April-June, 1962,  more  than 400 
cases  of  paralysis occurred  in  the Malda  district  in 
India. The cause of this disease proved to be the consump-
tion of flour contaminated with TOCP (Chaudhuri, 1965).

    In 1967, similar poisoning was recorded in Fiji, where 
56 people showed neuropathy (Sorokin, 1969). The cause was 
stated  to be contamination  of dry sharps  flour by  TOCP 
through the sacking material.

    Vasilescu  &  Florescu  (1980) in  Romania reported 12 
patients with toxic neuropathy following accidental inges-
tion of alcohol contaminated by TOCP.

    An  outbreak of acute polyneuropathy  in over 20 young 
females occurred in Sri Lanka during 1977-1978 (Senanayake 
&  Jeyaratnam,  1981).  The  cause  of the  neuropathy was 
traced  to TCP found as a contaminant in a special cooking 
oil (gingili oil).  Contamination probably occurred during 
transport  of the oil  in containers previously  used  for 
storing mineral oils.

9.2  Occupational exposure

    Gartner  &  Elsaesser (1943)  reported  the case  of a 
worker  who  developed  pyramidal signs  after exposure to 
TOCP  for two years in  a German chemical plant.   In this 
case,  percutaneous  absorption  was considered  to be the 
main route of exposure.

    In  1944,  three  cases of  toxic polyneuropathy among 
workers  who had worked for six to eight months in a plant 
manufacturing TCP in England were reported (Hunter et al., 
1944).  Skin penetration and inhalation were thought to be 
the main causes of the occupational poisoning.

    Parnitzke  (1946)  reported  a case  of TOCP poisoning 
after  3 years of exposure  in a German  plant and  stated 
that TOCP had been absorbed through the skin  and  presum-
ably the gastrointestinal tract.

    Since  1958, a high prevalence of polyneuropathy among 
shoe factory workers has been reported in Italy. The cause 
has  been  attributed to  TCP  (Cavalleri &  Cosi,  1978). 
Although  this is possible, this cause-effect relationship 
has not so far been based on unquestionable evidence. This 
polyneuropathy  might  have  various aetiological  factors 
(including  n-hexane)   or be produced by a combination of 
them (Leveque, 1983).

9.3  Clinical features

    Goldstein  et  al. (1988)  reported  a case  of severe 
intoxication  in a 4-year-old child following ingestion of 
a  lubricant  containing  TCP  (substitution  pattern  not 
known).  The clinical findings were acute gastrointestinal 
symptoms,  delayed  cholinergic  crisis, and  neurological 

    The  severity  of  signs and  symptoms after poisoning 
with  TOCP seems  not always  to be  proportional  to  the 
dosage  (Staehelin, 1941).  In  a Swiss Army  outbreak  of 
poisoning  among  more  than 80 young  men, toxic symptoms 
appeared  in once case  after eating food  containing only 
0.15 g  TOCP. Severe neurological disturbance developed in 
three  men from the intake of 0.5 to 0.7 g, whereas in two 
other  cases  the intake  of 1.5-2 g did  not lead to  any 
symptoms.   This leads to  the conclusion that  individual 
susceptibility varies greatly (Staehelin, 1941).

    In general, the signs and symptoms of  TOCP  poisoning 
are   distinctive,   whereas  the   symptomatology  varies 
somewhat  according to whether  a single relatively  large 
dose or small cumulative doses are taken.  In  the  former 
case,  the initial symptoms are  gastrointestinal, ranging 
from  slight  to  severe nausea  and  vomiting,  sometimes 
accompanied  by abdominal pain and diarrhoea.  Among these 
symptoms, vomiting is most frequently observed (Staehelin, 
1941).  These symptoms are usually transient, lasting from 
a few hours to a few days (Walthard, 1945; Susser & Stein, 

    In  cases  of chronic  low  level exposure,  the above 
symptoms  may not be  present and the  major symptoms  are 
neurological  (Parnitzke, 1946).  The clinical features of 

acute exposure to TOCP were described by Staehelin (1941). 
A  latent  period of  3-28 days  is observed  after  acute 
exposure,  and clear "delayed neurotoxicity" then gradu-
ally appears. The initial neurological symptoms are sharp, 
cramp-like  pains  in the  calves,  and some  numbness and 
tingling in the feet and sometimes the hands. Within a few 
hours or a day or two at most, these pains are followed by 
increasing  weakness  of the  lower  limbs, and  soon  the 
patient  becomes unsteady and then unable to maintain bal-
ance.   The cramp-like pains may  cease with the onset  of 
weakness, or persist for some days. One or two weeks after 
the onset in the lower limbs and while paralysis may still 
be  progressing, the weakness spreads to the hands.  While 
some patients show complete wrist drop and total  loss  of 
power  in the  hands, sometimes  with weakness  up to  the 
elbows,  the  predominant  neurological abnormalities  are 
observed in the lower limbs. Bilateral foot drop with com-
plete  loss  of  power from  the  ankle  down is  a common 
finding.   Depending on the severity of the affection, the 
patient  may have weakness in the knees, less at the hips, 
and, only in the most severe cases, weakness of the trunk. 
About  three weeks or more after the onset of paralysis, a 
most striking and rapid wasting may be observed. While the 
small muscles of the feet, calves, the  anterior  tibials, 
and  the thighs do not  escape this wasting, in  so far as 
they  are involved  in the  disease, the  change  is  most 
obvious in the small muscles.

    In the initial stage, the ankle jerks are  absent  and 
knee  reflexes  may  be normal  or occasionally depressed. 
Plantar reflexes are unobtainable.  Mild cases do not show 
any upper motor neuron signs.  On the other hand,  in  the 
more severe cases, even at the early stage, knee jerks may 
be  exaggerated, presaging the development  of upper motor 
neuron involvement.  In general, upper motor neuron signs, 
e.g.,  pyramidal signs, gradually become  evident at about 
the third week or later. Knee jerks become exaggerated and 
so  also  may the  biceps,  triceps, and  supinator  jerks 
(Cavanagh,  1964).  A finger flexor reflex appears for the 
first  time or increases (Susser  & Stein, 1957).  As  the 
pyramidal tract lesion becomes evident, involuntary flexor 
withdrawal  of  the  whole limbs  follows  gentle  plantar 
stimulation.   Babinski responses are observed much later. 
Muscle  tonus of the limbs gradually increases.  In severe 
cases, the signs of upper motor involvement  are  delayed, 
probably masked by the gross flaccid muscle weakness.

    Several  authors state emphatically that  sensory dis-
turbances  do not occur.  Sampson  (1942) reported sensory 
disturbances  although these were  admittedly unobtrusive, 
in  contrast to motor  dysfunction. Reports of  muscle and 
peripheral  nerve tenderness are fairly  frequent.  If the 
sensory  disturbances are observed, there  is hypoesthesia 
with  loss of pin-prick and temperature sense; the ability 

to  detect vibration is sometimes  affected distally.  The 
sensory  disturbances vary in extent from merely the soles 
of the feet to the whole of the limbs.

    Usually  cranial nerves are not involved.  In general, 
mental  signs are rare,  but transient euphoria  and  con-
fusion  have  been observed  in  the early  stage (Schwab, 

9.4  Prognosis

    Following  exposure,  muscle weakness  progresses over 
several  weeks,  sometimes  even months.   Sensory changes 
often  begin to regress during  the early weeks, the  rap-
idity  depending on  the severity  of the  case, and  then 
muscle strength gradually returns in patients who are only 
mildly  affected.  Improvement begins  with the return  of 
sensation,  then muscle strength in the hands, and eventu-
ally strength in the lower limbs.  In cases  of  pyramidal 
signs,   recovery  is  generally  poor.    Zeligs  (1938), 
reporting  eight  years  after the  1930  mid-western  and 
south-western  USA outbreak, surveyed  the records of  316 
patients.   He was able to  follow up 60 patients, all  of 
whom were disabled and still in institutions. Aring (1942) 
examined  more than 100 patients in the 10 years following 
this  outbreak  and they  appeared  still to  be affected. 
Morgan & Penovich (1978) followed up 11 survivors  in  the 
47 years  after the same outbreak;  the principal findings 
were  the  spasticity and  abnormal  reflexes of  an upper 
motor neuron syndrome.

    Of  the 80 patients in  the 1940 Swiss  army accident, 
14 were quite well after five years, 15 were totally inca-
pacitated, and 38 showed spasticity (Walthard 1945).

    In the 1938 Durban outbreak, all the  patients  showed 
some  symptoms  of the  disease  18 years later  (Susser & 
Stein, 1957).  The mildest case had slight weakness at the 
ankle,  while the most  severely affected had  foot  drop, 
muscle  atrophy,  and  pyramidal signs  (spasticity, ankle 
clonus, and positive Babinski sign).

    The residual signs and symptoms are mainly confined to 
the lower limbs. They consist of weakness and muscle atro-
phy of varying degrees in the feet and the  small  muscles 
of  the hand.  Disability  is principally related  to  the 
pyramidal  signs  with  resultant spasticity  of the lower 

9.5  Neurophysiological investigations

    There  have been very few electrophysiological studies 
on  human TOCP poisoning.   Svennilson (1960) reported  an 
electromyographic study on 65 patients in the 1959 Morocco 

poisoning.   These cases showed varying  degrees of dener-
vation and polyphasic abnormal potentials in the paralysed 
muscles. The clinically healthy proximal groups of muscles 
also  showed marked polyphasic  action potentials but  not 

    Vasilescu  & Florescu (1980) reported detailed studies 
on  12 patients from the  1980 accident in  Romania.  They 
observed >  50%  decrease  in the  muscle evoked potential 
amplitude,  fibrillation potentials in the same muscles at 
rest, and decreased motor nerve conduction velocity.

    In  neurophysiological studies by Senanayake (1981) in 
Sri  Lanka, the main  findings were widespread  neurotoxic 
patterns and prolongation of terminal latencies with rela-
tively  mild slowing of motor nerve conduction velocities. 
These  studies confirmed the  evidence of axonal  degener-

9.6  Pathological investigations

    Numerous pathological studies have been made on biopsy 
or autopsy samples since the Jamaica ginger  accidents  in 
1930.   In 1930, Goldfain described  some changes observed 
in  the peripheral nerves and spinal cord, quoting Jeter's 
autopsy   report.   Histopathological  investigations   by 
Goodale  &  Humphreys  (1931)  indicated  degeneration  of 
myelin  sheaths and axis cylinders in the radial, sciatic, 
and tibial nerves in all cases examined.  Vonderahe (1931) 
found  marked  degenerative  changes in  the anterior horn 
cells,  characterized  by swelling,  central chromatolysis 
(disappearance  of the Nissl substance), excentric nuclei, 
and shrinking of the cells.  The pathological studies also 
revealed  degeneration in the  radial and anterior  tibial 
nerves,  and degenerative changes  in the anterior  roots. 
There  were no pathological signs of inflammation. Accord-
ing to Smith & Lillie (1931), the paralysis due to Jamaica 
ginger  was  essentially  a  degeneration  of  the  myelin 
sheaths of the peripheral nerves, with a  variable  amount 
of   relatively  moderate  central   degenerative  changes 
affecting  the anterior horn  cells throughout the  spinal 
cord, but more often in the lumber and  cervical  regions. 
In the 1938 Durban (South Africa) epidemic, Sampson (1942) 
also reported that degeneration of the anterior horn cells 
occurred  in  some  instances and  that  peripheral nerves 
showed  axonal degeneration. Aring (1942) described degen-
eration  in  the posterior  and  lateral columns  in later 
investigations  of survivors of the outbreak, thereby con-
firming  the origin of some of the spinal symptoms.  It is 
noteworthy  that the latter  changes were evident  in  the 
lumbar region, while the dorsal column changes,  in  which 
only  the fasciculus gracilis was  involved, concerned the 
cervical region.

    Muscle  biopsy  studies  of  patients  from  the  1959 
Moroccan  poisoning  showed  a moderate  degree  of muscle 
atrophy  and a slight increase of the muscle fibre nuclei. 
Spherical axonal swelling and terminal knobs were noted as 
a  sign  of  peripheral  nerve  degeneration  in   muscles 
(Svennilson,  1960).  Similar changes  were also noted  in 
the  poisoning  cases reported  in  Malda, India,  in 1962 
(Chaudhuri  et al., 1962). These effects on muscle suggest 

9.7  Laboratory investigations

    Little  information has been obtained  from laboratory 
examinations  of exposed humans.  There  is no significant 
change  in the urine or blood (Sampson, 1942; Senanayake & 
Jeyaratnam, 1981), but the cerebrospinal fluid may show an 
increase  in protein concentration, with  or without pleo-
cytosis  (Sampson,  1942;  Mertens, 1948;  Susser & Stein, 

    Vora  et  al.  (1962)  measured  blood  cholinesterase 
levels in patients admitted to hospitals during  the  1960 
Bombay poisoning and demonstrated that plasma cholinester-
ase was increased one month after exposure.  The  erythro-
cyte  cholinesterase  level  was  considerably  diminished 
(50%) quite early after the onset of symptoms. Both plasma 
and  erythrocyte  cholinesterase  activities  returned  to 
normal within about 3 months.

    In  a  factory manufacturing  TAP,  about half  of the 
workers  examined showed significant decreases  in pseudo-
cholinesterase  (cholinesterase other than AChE), and many 
of  them had minor signs  and symptoms (Tabershaw et  al., 

    Morgan  & Hughes (1981) also investigated cholinester-
ase activity in workers in a plant manufacturing TAP plas-
ticizers. They found that plasma cholinesterase estimation 
in  workers exposed to TAP  compounds cannot be used  as a 
sensitive  barometer of organic phosphate absorption; thus 
routine  regular estimations serve no useful purpose.  Its 
value  is chiefly as a screening method at the pre-employ-
ment  medical examination to exclude personnel at risk, as 
a  baseline  in the  event of massive  exposure, and as  a 
means of diagnosis in cases of CNS disease  that  simulate 
TAP poisoning.

9.8  Treatment

    In  the event of  skin contact with  TCP, contaminated 
clothing should be rapidly removed and affected body areas 
copiously  irrigated with water.  The ingestion of food or 
drink contaminated with TOCP should be treated by inducing 
vomiting,  unless the patient is unconscious.  Atropine or 

pralidoxine (2-PAM) chloride may be required to counteract 
cholinergic effects. No specific antidote is available.

    Medical therapy should begin as soon as possible, even 
though  the results of  medical therapeutic measures  have 
been disappointing. B-complex vitamins and corticosteroids 
may  protect  nervous  tissue against  further involvement 
(Geoffroy et al., 1960).  The cardinal therapy is physical 
rehabilitation.   Administration of anti-spastic drugs may 
be required.


10.1  Evaluation of human health risks

    Human  poisoning involving the accidental ingestion of 
tri- o-cresyl   phosphate (TOCP) or  occupational exposure 
of workers has frequently been reported.  The likely route 
of  occupational  exposure  is cutaneous  absorption.  The 
neurotoxic  symptoms involve initial inhibition of cholin-
esterases  and subsequent delayed neuropathy characterized 
by severe paralysis.

    Because of considerable variation among individuals in 
sensitivity  to TOCP, it  is not possible  to establish  a 
safe  level of exposure.  Symptoms have been reported from 
the  ingestion of 0.15 g of an isomeric mixture with a low 
proportion  of  TOCP; the  minimum  effective dose  of the 
ortho  isomer is, therefore, much lower than this.  Animal 
studies  show considerable variation among  species in the 
response  to TOCP, and  humans appear to  be  particularly 

    Irritant and allergic dermatitis have been reported.

    Both  the pure ortho isomer and isomeric mixtures con-
taining  TOCP are, therefore, considered  major hazards to 
human health.

    There is no safe level for ingestion.  Exposure to the 
compound  through dermal contact  or inhalation should  be 

10.1.1  Exposure levels

    Exposure  of the general population to tricresyl phos-
phate (TCP) through various environmental media, including 
drinking-water,  can be regarded as minimal.  TCP has been 
detected  at relatively higher concentrations in urban air 
than  in air collected  at production sites,  although the 
levels  are usually low.   TCP was not  detected in  human 
adipose tissue samples in a survey conducted in  the  USA. 
There have been many cases of accidental  human  poisoning 
through  the ingestion of medicines,  food, flour, cooking 
oil,  and beverages contaminated  with hydraulic fluid  or 
lubricant  oil  containing  TCP produced  from  "cresylic 
acid". The toxic symptoms can be observed after ingestion 
of only 0.15 g of tri- o-cresyl  phosphate, a component of 
TCP  from  cresylic  acid.  The  contamination has usually 
happened  when empty barrels or drums, previously used for 
hydraulic  fluid  or  lubricating oil  storage,  have been 

10.1.2  Toxic effects

    Accidental human exposure to a single large  dose  re-
sults  in gastrointestinal disturbance varying from slight 
to  severe nausea and  vomiting, accompanied by  abdominal 
pain and diarrhoea. In the case of exposure to small cumu-
lative doses, "delayed neurotoxicity" gradually proceeds 
after  a latent period of  3-28 days.  In most cases,  the 
muscle weakness changes rapidly to a striking paralysis of 
the  lower limbs, with  or without an  involvement of  the 
hands.  In severe cases, pyramidal  signs gradually become 
evident.  Some  neurophysiological studies  indicate wide-
spread  neurotoxic  patterns and  prolongation of terminal 
latencies  with relatively small decreases  of motor nerve 
conduction  velocities.   This  confirms the  evidence  of 
axonal degeneration, which is the main feature observed in 
pathological investigations.

    The  neurotoxic metabolite of TCP  has been identified 
as  saligenin cyclic  o-tolyl  phosphate, which is derived 
from  o-hydroxymethyl  metabolites. Thus, it seems that at 
least one  o-tolyl group among the three phenolic moieties 
of TCP is necessary to induce neurotoxic effects. TCP pro-
duced from synthetic cresol, which contains less than 0.1% 
of  o-cresol, is therefore not neurotoxic.

    Subchronic  animal  studies  on TCP  derived from syn-
thetic  cresol indicate that  the target organs  are liver 
and  kidney,  but this  was not confirmed  in the case  of 
human  intoxication.   No  adequate data  are available on 
mutagenicity  and  carcinogenicity.   TCP is  not toxic to 
chick embryos.

10.2  Evaluation of effects on the environment

    The measurement of environmental concentrations of TCP 
in  water has shown only low levels of contamination. This 
reflects  the low water solubility and ready degradability 
of  the compound.   Since the  acute toxicity  of  TCP  to 
aquatic  organisms is  also low,  it is  unlikely that  it 
poses a threat to such organisms.

    As a consequence of the physico-chemical properties of 
TCP,  there is a high potential for bioaccumulation.  How-
ever, this does not occur in practice, owing to  low  con-
centrations of TOCP in the environment and  living  organ-
isms and to its rapid degradation.

    TCP  bound to sediment accumulates in the environment, 
and  levels measured in river, estuarine, and marine sedi-
ments have been high. Since there is no information either 
on the bioavailability of these residues to  burrowing  or 
bottom-living  organisms or on  their hazards, the  possi-
bility of effects on such species cannot be discounted.

    TCP  spillage leads to  hazard for the  local environ-

10.2.1  Exposure levels

    TCP  is found in  air, surface water,  soil, sediment, 
and  aquatic organisms near heavily  industrialized areas, 
although concentrations are usually low. Owing to the high 
biodegradation rate of TCP in aqueous environment,  it  is 
not considered to affect aquatic organisms adversely.  One 
report  showed  an  extremely high  concentration of total 
triaryl  phosphate (26.55 g/kg) in a  soil sample obtained 
from a production plant yard. This suggests the  need  for 
land waste disposal.

10.2.2  Toxic effects

    Freshwater  algae are relatively sensitive to TCP, the 
50%  growth inhibitory concentration  ranging from 1.5  to 
5.0 mg/litre.   Among fish species,  the rainbow trout  is 
adversely  affected by TCP concentrations below 1 mg/litre 
(0.3-0.9 mg/litre),  with  sign of  chronic poisoning, but 
the  tidewater silverside is more resistant (LC50 is  8700 
mg/litre). TCP does not inhibit cholinesterase activity in 
fish  or frogs, but it has a synergistic effect on organo-
phosphorus insecticide activity.


    When tri-substituted cresols are used in the synthesis 
and  manufacture of other compounds, the purified meta and 
para isomers should be used in order to avoid the acciden-
tal synthesis of ortho-substituted products.


Delayed neurotoxicity of a single dermal administration of o-ethyl 
o-4-nitro-phenyl phenylphosphonothioate and tri-o-cresyl phosphate 
to cats.   Toxicol. Lett.,  1 (Special issue): 141. 

(1986)  Electromyographic, neuropathologic and functional 
correlates in the cat as the result of tri-o-cresyl phosphate 
delayed neurotoxicity.  Toxicol. appl. Pharmacol.,  83(1): 126-141. 

Consecutive system of tests for assessment of the effects of 
chemical agents in the aquatic environment. In:  Pesticide 
 chemistry-Human welfare and the environment.  Proceedings of the 
 Fifth International Congress on Pesticide Chemistry,Kyoto, Japan, 
 29 August - 4 September, 1982,  Oxford, New York, Pergamon Press, 
Vol. 3, pp. 537-544. 

ALDRIDGE, W.N. (1954) Tricresyl phosphates and cholinesterase. 
 Biochem. J.,  56: 185-189. 

ALDRIDGE, W.N. & BARNES, J.M. (1961) Neurotoxic and biochemical 
properties of some triaryl phosphates.  Biochem. Pharmacol.,  6: 

ANONYMOUS (1986)  Handbook of commodity chemicals,  Tokyo, Kagaku-

ARING, C.D.  (1942) The systemic nervous affinity of triorthocresyl 
phosphate (Jamaica ginger palsy).  Brain,  65: 34-47. 

 the plasticizer TCP, tricresyl phosphate,  Tokyo, Association of 
the Plasticizer Industry of Japan. 

TUREMAN, J.R. (1959) Toxicology of a triaryl phosphate Oil. III. 
Human exposure in operational use aboard ship.  Am Med. Assoc. Arch. 
 ind. Hyg.,  20: 258-261. 

WELCH, V.A. (1961)  The reactions of organic phosphates. Part V. 
The hydrolysis of triphenyl and trimethyl phosphates.  J. Chem. Soc. 
 (B),  1961: 2670-2676. 

B., VERNON, C.A., & WELCH, V.A. (1966) Reactions of organic 
phosphates. Part VI. The hydrolysis of aryl phosphates.   J. Chem. 
 Soc. (B),  1966: 227-235. 

BARRETT, H., BUTLER, R., & WILSON, I.B. (1969) Evidence for a 
phosphoryl-enzyme intermediate in alkaline phosphatase catalyzed 
reactions.  Biochemistry,  8: 1042-1047. 

BECK, B.E., WOOD, C.D., & WHENHAM, G.R. (1977) Triaryl phosphate 
poisoning in cattle.  Vet. Pathol.,  14: 128-137. 

BELL, J.D. & RUSVINE, J.R. (1967) Synergism of organophosphates in 
 Musca domestica and  Chrysomya putoria. Entomol. exp. appl.,  10: 

S.K. (1974) Detection and estimation of tricresyl phosphate in 
mustard oil.  Forensic Sci.,  3: 263-270. 

BISCHOFF, A. (1967) The ultrastructure of tri-ortho-cresyl 
phosphate poisoning. I. Studies on myelin and axonal alterations in 
the sciatic nerve.  Acta neuropathol.,  9: 158-174. 

BISCHOFF, A.  (1970) The ultrastructure of tri-ortho-cresyl 
phosphate poisoning in the chicken. II. Studies on spinal cord 
alterations.  Acta neuropathol., 15: 142-155. 

BISCHOFF, A. (1977) Tri-ortho-cresyl phosphate neurotoxicity. In: 
Roisin, L., Shiraki, H., & Grcevic, N., ed.  Neurotoxicology, New 
York, Raven Press, pp. 431-441. 

BLEIBERG, M.J. & JOHNSON, H. (1965) Effects of certain 
metabolically active drugs and oximes on tri- o-cresyl phosphate 
toxicity.  Toxicol. appl. Pharmacol.,  7: 227-235. 

BLOOM, P.J. (1973) Application des chromatographies sur couche 
mince et gaz-liquide à l'analyse qualitative et quantitative des 
esters des acides phosphorique et phosphoreux.  J. Chromatogr.,  
75: 261-269. 

BOETHLING, R.S. & COOPER, J.C. (1985) Environmental fate and 
effects of triaryl and tri-alkyl/aryl phosphate esters.  Residue 
 Rev.,  94: 49-99. 

BONDY, H.F., FIELD, E.J., WORDEN, A.N., & HUGHES, J.P.W. A study of 
the acute toxicity of the tri-aryl phosphates used as plasticizers. 
(1960)  Br.   J. ind. Med.,  17: 190-200. 

KARASEK, F.W. (1981) Trace impurities in solvents commonly used for 
gas chromatographic analysis of environmental samples.  J. 
 Chromatogr.,  206: 279-288. 

BROWN H.R. & SHARMA, R.P. (1975) Inhibition of neural membrane 
adenosine-triphosphatases by organophosphates.  Toxicol. appl. 
 Pharmacol.,  33: 140. 

BURLEY, B.T. (1930) The 1930 type of polyneuritis.  New Engl. J. 
 Med.,  202: 1139-1142. 

CARLTON, B.D., HASARAN, A.H., MEZZA, L.E., & SMITH, M.K. (1987)  
Examination of the reproductive effects of tricresyl phosphate 
administered to Long-Evans rats.  Toxicology,  46: 321-328. 

CARRINGTON, C.D. & ABOU-DONIA, M.B. (1988) Variation between three 
strains  of rat: inhibition of neurotoxic esterase and 
acetylcholinesterase by tri-o-cresyl phosphate.  J. Toxicol. 
 environ. Health,  25(3): 259-268. 

CASIDA,  J.E. (1961) Specificity of substituted phenyl phosphorus 
compounds for esterase inhibition in mice.  Biochem. Pharmacol.,  5: 

CASIDA, J.E., ETO, M., & BARON R.L. (1961) Biological activity of a 
tri-o-cresyl phosphate metabolite.  Nature (Lond.),  191: 1396-1397. 

CASTERLINE, J.L., Jr., KU, Y., & BARNETT, N.M. (1985) Uptake of 
tri-p-cresyl phosphate in soybean plants.  Bull. environ. Contam. 
 Toxicol.,  35: 209-212. 

CAVALLERI, A. & COSI, V. (1978) Polyneuritis incidence in shoe 
factory workers: Case report and etiological considerations.  Arch. 
 environ. Health, 33: 192-197. 

CAVANAGH, J.B.(1954) The toxic effects of tri-ortho-cresyl 
phosphate on the nervous system. An experimental study in hens.  J. 
 Neurol. Neurosurg.   Psychiatry,  17: 163-172. 

CAVANAGH, J.B. (1964) The significance of the "dying back" process 
in experimental and human neurological disease.  Int. Rev. exp. 
 Pathol.,  3: 219-267. 

CHAPIN, R.E., GEORGE, J.D., & LAMB, J.C., IV (1988) Reproductive 
toxicity of tricresyl phosphate in a continuous breeding protocol 
in Swiss (CD-1) mice.  Fundam. appl. Toxicol.,  10: 344-354. 

CHAUDHURI, R.N. (1965) Paralytic disease caused by consumption of 
flour contaminated with tricresyl phosphate.  Trans. R. Soc. Trop. 
 Med. Hyg., 59: 98-102. 

ADHYA, R.N., MITRA, N.K., SAHA, T.K., & MITRA, P. (1962) Recent 
outbreak of a paralytic disease in Malda, West Bengal.  Bull. 
 Calcutta Sch. Trop. Med.,  10: 141-152. 

Chemical and Geological Laboratories (Laboratory report No. E71-

CLAYTON, G.D. & CLAYTON, F.E., ed. (1981)  Patty's industrial 
 hygiene and toxicology,  New York, Wiley-Interscience, Vol. 2A, 
pp. 2362-2363. 

COHEN, S.D. & MURPHY, S.D. (1970) Comparative potentiation of 
malathion by triorthotolyl phosphate in four classes of 
vertebrates.  Toxicol. appl. Pharmacol.,  16: 701-708.

DAFT, J.L. (1982) Identification of aryl/alkyl phosphate residues 
in foods.  Bull. environ. Contam. Toxicol.,  29: 221-227. 

DAGLEY, S. & PATEL, M.D. (1957) Oxidation of p-cresol and related 
compounds by a  Pseudomonas. Biochem. J.,  66: 227-233. 

DAVISON, A.N. (1953) The cholinesterases of the central nervous 
system after the administration of organo-phosphorus compounds. 
 Brit. J. Pharmacol.,  8: 212-216. 

The acute toxicity of 47 industrial chemicals to fresh and salt 
water fishes.  J. hazard. Mater.,  1: 303-318. 

DEO, P.G. & HOWARD, P.H. (1978) Combined gas-liquid chromatographic 
mass spectrometric analysis of some commercial aryl phosphate oils. 
 J. Assoc. Off. Anal. Chem.,  61: 266-271. 

DRUYAN, E.A. (1975) [Separation and determination of tricresyl 
phosphate, triphenyl phosphate, phenol,  o-, m-, and  p-cresol by 
thin-layer chromatography.]  Gig. i Sanit. , 10: 62-65 (in Russian). 

DUKE, A.J. (1978) The significance of isomerism and complexity of 
composition on the performance of triaryl phosphate plasticisers in 
PVC.  Chimia,  32: 457-463. 

EAJ (1977) [ Environmental monitoring of chemicals ], Tokyo, 
Environment Agency Japan, pp. 212-214 (Environmental Survey Report 
Series, No. 3) (in Japanese). 

EAJ (1979) [ Chemicals in the environment], Tokyo, Environment 
Agency Japan, pp. 61, 78, 92, 93 (Office of Health Studies Report 
Series, No. 5) (in Japanese). 

EAJ (1981) [ Environmental monitoring of chemicals: Environmental 
 Survey Report of 1978, 1979 F.Y. ], Tokyo, Environment Agency 
Japan, pp. 116-117 (in Japanese). 

LISK, D.J. (1977) Further toxicologic studies with commercial and 
candidate flame retardant chemicals. Part II.  Bull. environ. 
 Contam. Toxicol., 17: 720-726. 

ETO, M., CASHIDA, J.E., & ETO, T. (1962) Hydroxylation and 
cyclization reactions involved in the metabolism of tri- o-cresyl 
phosphate.  Biochem. Pharmacol.,  11: 337-352. 

ETO, M., OSHIMA, Y., & CASHIDA, J.E. (1967) Plasma albumin as a 
catalyst in cyclization of diaryl-o-(a-hydroxy)tolyl phosphates. 
 Biochem. Pharmacol., 16: 295-308. 

Fungitoxicity and insecticide synergism of monothioquinol phosphate 
esters and related compounds.  Botyu Kagaku,  40: 110-117. 

FINNEGAN, R.A. & MATSON, J.A. (1972) Irradiation of triaryl 
phosphate esters. A new photochemical coupling reaction.  J. Am. 
 Chem. Soc.,  94: 4780-4782. 

G., GATTI, R., JUVARRA, G., & PALLA, G. (1978) Studies on the 
etiology of the experimental neuropathy from industrial adhesives 
(glues).  Experientia (Basel),  34: 250-252. 

PETERS, A.C. (1988) Reversibility and tolerance to tricresyl 
phosphate-induced neurotoxic effects in F344 rats.  Toxicologist,  
8: 76. 

FUKUSHIMA, M. & KAWAI, S. (1986) [Present status and transition of 
selected organophosphoric acid triesters in the water area of Osaka 
city.]  Seitai Kagaku,  8: 13-24 (in Japanese). 

GARTNER, W. & ELSAESSER, K.H. (1943) [Commercial ortho-
tricresylphosphate poisoning.]  Arch. Gewerbepathol. Gewerbehyg.,  
12: 1-9 (in German). 

Myèlopoly-néurites tri-crésyl phosphatées. Toxi-épidémie marocaine 
de septembre-octobre 1959.  World Neurol.,  1: 294-315. 

GOLDFAIN, E. (1930) Jamaica ginger multiple neuritis.  J. Oklahoma 
 State Med. Assoc.,  23: 191-193. 

GOLDSTEIN, D.A., MCGUIGAN, M.A., & RIPLEY, B.D. (1988) Acute 
tricresyl phosphate intoxication in childhood.  Hum. Toxicol.,  7: 

GOODALE, R.H. & HUMPHREYS, M.B. (1931) Jamaica ginger paralysis. 
Autopsy observations.  J. Am. Med. Assoc.,  96: 14-16. 

GROSS, E. & GROSSE, A. (1932) [A contribution to the toxicology of 
ortho-tricresylphosphates.]  Arch. exp. Pathol. Pharmakol.,  168: 
473-514 (in German). 

A.C., & IRWIN, R. (1986) Effects of subchronic exposure to 
tricresyl phosphate in F344 rats and B6C3F1 mice: behavioural and 
morphological correlates.  Toxicologist,  6: 218. 

[Environmental fate of organic phosphate esters.]  Shuishitu Odaku 
 Kenkyu,  4: 137-141 (in Japanese). 

(1983) Salmonella mutagenicity test results for 250 chemicals. 
 Environ. Mutagen.,  Suppl. 1:  3-142. 

ANDERSON, H.H. (1956) The neurotoxicity and anticholinesterase 
properties of some substituted phenyl phosphates.  J. Pharmacol. 
 exp. Ther.,  116: 227-236. 

G.T. (1981) In: Clayton, G.D. & Clayton, F.E., ed.  Patty's 
 industrial hygiene and toxicology,  3rd revised ed., New York, 
Wiley-Interscience, Vol. 2A, pp. 2362-2363. 

HJORTH, N. (1962) Contact dermatitis from cellulose acetate film. 
Cross-sensitization between tricresylphosphate (TCP) and 
triphenylphosphate (TPP).  Contact dermatitis,  2: 86-100. 

HODGE, H.C. & STERNER, J.H. (1943) The skin absorption of 
triorthocresyl phosphate as shown by radioactive phosphorus.  J. 
 Pharmacol. exp. Ther., 79: 225-234. 

HOLLIFIELD, H.C. (1979) Rapid nephelometric estimate of water 
solubility of highly insoluble organic chemicals of environmental 
interest.  Bull. environ. Contam. Toxicol.,  23: 579-586. 

HOTSTON, R.D. (1946) Outbreak of polyneuritis due to orthotricresyl 
phosphate poisoning.  Lancet,  1: 207. 

HOWARD, P.H. & DEO, P.G. (1979) Degradation of aryl phosphates in 
aquatic environments.  Bull. environ. Contam. Toxicol.,  22: 337-344. 

HUDEC, T., THEAN, J., KUEHL, D., & DOUDHERTY, R.C. (1981) Tris(di-
chloropropyl)phosphate, a mutagenic flame retardant: Frequent 
occurrence in human seminal plasma.  Science,  211: 951-952. 

HUNTER, D., PERRY, K.M.A., & EVANS, R.B. (1944) Toxic polyneuritis 
arising during the manufacture of tricresyl phosphate.  Br. J. ind. 
 Med.,  1: 227-231. 

INDEN, T. & TACHIBANA, S. (1975) [Damage of crops by gases from the 
plastic materials under covering conditions.]  Bull. Fac. Agric. Mie 
 Univ.,  1975: 1-10 (in Japanese). 

Triorthocresyl phosphate poisoning: A review of human cases. 
 Sangyo-Ika-Daigaku-Zasshi, 10(4): 433-442. 

(1987) Effects of chronic exposure to tricresyl phosphate in F344 
rats and B6C3F1 mice: behavioural and biochemical correlates.  Soc. 
 Neurosci. Abstr.,  13: 90. 

ISHIKAWA, S., TAKETOMI, M., & SHINOHARA, R. (1985) Determination of 
trialkyl and triaryl phosphates in environmental samples.  Water 
 Res.,  19: 119-125. 

IZMEROV, N.F., SANOTSKY, I.V., & SIDOROV, K.K. (1982)  Toxicometric 
 parameters of industrial toxic chemicals under single exposure, 
Moscow, Centre of International Projects, GKNT, p. 114. 

JETER, H. (1930) Autopsy report of a case of so-called "Jake 
Paralysis".  J. Am. Med. Assoc.,  95: 112-113. 

RADUE, R.W., & GRAHAM, P.R. (1977) Evaluation of delayed 
neurotoxicity and dose-response relationships of phosphate esters 
in the adult hen.  Toxicol. appl. Pharmacol.,  41: 291-304. 

JOHNSON, M.K. (1969) Delayed neurotoxic action of some 
organophosphorus compounds.  Br. med. Bull.,  25: 231-235. 

JOHNSON, M.K. (1974) The primary biochemical lesion leading to the 
delayed neurotoxicity of some organophosphorus esters.  J. 
 Neurochem.,  23: 785-789. 

JOHNSON, M.K. (1975a) Organophosphorus esters causing neurotoxic 
effects. Mechanism of action and structure/activity studies.  Arch. 
 Toxicol.,  34: 259-288. 

JOHNSON, M.K. (1975b) The delayed neuropathy caused by some 
organophosphorus esters: mechanism and challenge.  CRC Crit. Rev. 
 Toxicol.,  3: 289-316. 

JOHNSON, M.K. & BARNES, J.M. (1970) The sensitivity of chicks to 
the delayed neurotoxic effects of some organophosphorous compounds. 
 Biochem. Pharmacol.,  19: 3045. 

KANAZAWA, J. (1978) Studies on formulation and residue analysis of 
pesticides.  J. pestic. Sci.,  3: 185-193. 

KAWAI, S., FUKUSHIMA, M., ODA, K., & UNO, G. (1978) [Water 
pollution caused by organophosphorus compounds.]  Kankyo Gijyutsu, 
7: 668-675 (in Japanese). 

environ-mental survey of chemicals. XI. Analytical methods of 
organic phosphoric acid triesters.]  Okayama-ken Kankyo Hoken Senta 
 Nempo,  3: 175-191 (in Japanese). 

KENMOTSU, K., MATSUNAGA, K., & ISHIDA, T. (1980a) [Multiresidue 
determination of phosphoric acid triesters in fish, sea sediment 
and sea water.]  J. Food Hyg. Soc. Jpn.,  21: 18-31 (in Japanese). 

KENMOTSU, K., MATSUNAGA, K., & ISHIDA, T. (1980b) [Studies on the 
mechanisms of biological activities of various environmental 
pollutants. V. Environmental fate of organic phosphoric acid 
triesters.]  Okayama-ken Kankyo Hoken Senta Nempo,  4: 103-110 (in 

KENMOTSU, K., MATSUNAGA, K., & ISHIDA, T. (1981a) [Studies on the 
biological toxicity of several pollutants in environments.] 
 Okayama-ken Kankyo Hoken Senta Nempo,  5: 167-175 (in Japanese). 

KENMOTSU, K., MATSUNAGA, K., SAITO, N., & OGINO, Y. (1981b) [An 
environmental survey of chemicals. XVII. Multiresidue determination 
of organic phosphate esters in environment samples.]  Okayama-ken 
 Kankyo Hoken Senta Nempo,  5: 145-156 (in Japanese). 

(1982a) [An environmental survey of chemicals. XIX. Determination 
of organophosphoric acid triesters (2).]  Okayama-ken Kankyo Hoken 
 Senta Nempo, 6: 126-132 (in Japanese). 

(1982b) [Studies on the biological toxicity of several pollutants 
in environments. VII. GC/MS Spectrometric determination of 
organophosphoric acid triesters in sediment.]  Okayama-ken Kankyo 
 Hoken Senta Nempo,  6: 142-152 (in Japanese). 

(1983) [An environmental survey of chemicals. XXII. GC/MS 
spectrometric determination of organophosphoric acid triesters in 
sediment (2).]  Okayama-ken Kankyo Hoken Senta Nempo, 7: 143-149 (in 

KIMMERLE, G. & LOESER, E. (1974) Delayed neurotoxicity of 
organophosphorus compounds and copper concentration in the serum of 
hens.  Environ. Qual. Saf., 3: 174-178. 

KONASEWICH, D., TRAVERSY, W., & ZAR, H. (1978) Status report on 
organic and heavy metal contaminants in the Lakes Erie, Michigan, 
Huron and Superior basins.  Great Lakes Water Qual. Bd. 

Detection of tricresyl phosphates and determination of tri-o-cresyl 
phosphate in edible oils.  J. Assoc. Off. Anal. Chem., 68(6): 

KU, Y. & ALVAREZ, G.H. (1982) Biodegradation of (14C) tri- p-cresyl 
phosphate in a laboratory activated-sludge system.  Appl. environ.  
 Microbiol.,  43: 619-622. 

KUREBAYASHI, H., TANAKA, A., & YAMAHA, T. (1985) Metabolism and 
dispo-sition of the flame retardant plasticizer, tri-p-cresyl 
phosphate, in the rat.  Toxicol. appl. Pharmacol.,  77: 395-404. 

LAPP, T.W. (1976)  Study on chemical substances from information 
 concerning the manufacture, distribution, use, disposal, 
 alternatives, and magnitude of exposure to the environment and 
 man: Task 1 - The manufacture and use of selected aryl and alkyl 
 phosphate esters, Springfield, Virginia, National Technical 
Information Service, 129 pp (EPA contract No. 68-01-2687) (NTIS PB-

LEBEL, G.L. & WILLIAMS, D.T. (1983) Determination of organic 
phosphate triesters in human adipose tissue.  J. Assoc. Off. Anal. 
 Chem., 66: 691-699. 

Isolation and concentration of organophosphorus pesticides from 
drinking water at the ng/L level, using macroreticular resin.  J. 
 Assoc. Off. Anal. Chem.,  62: 241-249. 

LEBEL, G.L., WILLIAMS, D.T., & BENOIT, F.M. (1981) Gas 
chromatographic determination of trialkyl/aryl phosphates in 
drinking water, following isolation using macroreticular resin.  J. 
 Assoc. Off. Anal.  Chem.,  64: 991-998.

LEFAUX, R. (1968)  Practical toxicology of plastics, London, Iliffe 
Books Ltd, p. 580. 

LEFAUX, R. (1972) Industrial toxicology. Phosphoric esters. In: 
 Practical toxicology of plastics, London, Iliffe Books Ltd, pp. 

LEVEQUE, J. (1983) Tricresyl phosphates. In:  Encyclopaedia of 
 occupational health safety, 3rd ed., Geneva, International Labour 
Office, Vol. 2, pp. 2216-2218. 

D. (1975) Chronic toxicity of a synthetic tri-aryl phosphate oil to 
fish.  Environ. Physiol. Biochem., 5: 361-369. 

LOMBARDO, P. & EGRY, I.J. (1979) Identification and gas-liquid 
chromatographic determination of aryl phosphate residues in 
environmental samples.  J. Assoc. Off. Anal. Chem.,  62: 47-51. 

LOROT, C. (1899) Les combinations de la créosote dans le traitement 
de la tuberculose pulmonaire, Paris (Thèse de Paris No. 25). 

LU, P.-Y. & METCALF, R.L. (1975) Environmental fate and 
biodegradability of benzene derivatives as studied in a model 
aquatic ecosystem.  Environ. Health Perspect., 10: 269-284. 

MAJORS, R.E. & JOHNSON, E.L. ( 1978) High-performance exclusion 
chromatography of low-molecular-weight additives.  J. Chromatogr., 
167: 17-30. 

MARHOLD, J.V. (1972)  Collection of results of toxicological 
 assessments of compounds and formulations tested at the Department 
 of Toxicology, Research Institute for Organic Syntheses, Prague, 
Institute for Management Training in the Chemical Industry. 

J.E. (1969) The status of biodegradability testing of nonionic 
surfactants.  J. Am. Oil Chem. Soc., 46: 432-440. 

MAYER, F.L. & ELLERSIECK, M.R. (1986)  Manual of acute toxicity: 
 Interpretation and data base for 410 chemicals and 66 species of 
 freshwater animals, Springfield, Virginia, National Technical 
Information Service. 

P.M., & SAEGER, V.W. (1981) Phosphate ester hydraulic fluids: An 
aquatic environmental assessment of Pydrauls 50E and 115E. In: 
Branson R. & Dickson, K.L., ed.  Aquatic Toxicology and Hazard 
 Assessment: Fourth Conference,  Philadelphia, American Society for 
Testing and Materials, pp. 103-123 (ASTM STP 737). 

MELE, J.M. & JENSH, R.P. (1977) Teratogenic effects of orally 
administered tri-o-cresyl phosphate on Wistar albino rats. 
 Teratology, 15: 32A. 

MERRITT, H.H. & MOOR, M. (1930) Peripheral neuritis associated with 
ginger extract ingestion.  New Engl. J. Med., 203: 4-12. 

MERTENS, H.G. (1948) [Clinical aspects of tri-orthocrésyl phosphate 
poisoning (including a report on several cases of poisoning in an 
Igelit factory).]  Arch. Psychiatr. Nervenkr., 179: 458-482 
(in German). 

MRI (1979)  Assessment of the need for limitation on triaryl and 
 trialkyl/aryl phosphates. Draft final report, Kansas City, Midwest 
Research Institute (EPA Contract 68-01-4313).

MODERN PLASTICS ENCYCLOPEDIA (1975) International Advertising 
Supplement 52(10A), p 697, New York, McGraw-Hill Inc. 

MORAZAIN, R. & ROSENBERG, P. (1970) Lipid changes in tri-o-cresyl-
phosphate-induced neuropathy.  Toxicol. appl. Pharmacol., 16: 461-474. 

MORGAN, A.A. & HUGHES, J.P.W. (1981) An investigation into the 
value of cholinesterase estimations of workers in a plant 
manufacturing tri-aryl phosphate plasticizers.  J. Soc. Occup. Med., 
31: 69-75. 

MORGAN, J.P. (1982) The Jamaica Ginger Paralysis.  J. Am. Med. 
 Assoc., 248: 1864-1867. 

MORGAN, J.P. & PENOVICH, P. (1978) Jamaica Ginger Paralysis. Forty-
seven-year follow-up.  Arch. Neurol., 35: 530-532. 

J.L., & MORRIS, R.W. (1988a) Evaluation of rodent sperm, vaginal 
cytology, and reproductive organ weight data from National 
Toxicology Program 13-week study.  Fundam. appl. Toxicol., 11: 

J.L., & MORRIS, R.W. (1988b) Association of sperm, vaginal 
cytology, and reproductive organ weight data with results of 
continuous breeding reproductive studies in Swiss CD-1 mice. 
 Fundam. appl. Toxicol., 11: 359-371. 

MUIR, D.C.G. (1984) Phosphate esters. In: Hutzinger, O., ed.  The 
 handbook of environmental chemistry, Berlin, Heidelberg, New York, 
Tokyo, Springer-Verlag, Vol. 3, Part C, pp. 41-66. 

MUIR, D.C.G. & GRIFT, N.P. (1983) Extraction and cleanup procedures 
for determination of diarylphosphates in fish, sediment, and water 
samples.  J. Assoc. Anal. Off. Chem., 66: 684-690. 

MUIR, D.C.G., GRIFT, N.P., & SOLOMON, J. (1980) Determination of 
several triarylphosphates in fish and sediment samples.  Can. Plains 
 Proc., 9: 1-12. 

MUIR, D.C.G., GRIFT, N.P., & SOLOMON, J. (1981) Extraction and 
cleanup of fish, sediment, and water for determination of triaryl 
phosphates by gas-liquid chromatography.  J. Assoc. Off. Anal. 
 Chem., 64: 79-84. 

MUIR, D.C.G., GRIFT, N.P., & LOCKHART, W.L. (1982) Comparison of 
laboratory and field results for prediction of the environmental 
behavior of phosphate esters.  Environ. Technol. Chem., 1: 113-119. 

MUIR, D.C.G., YARECHEWSKI, A.L., & GRIFT, N.P. (1983) Environmental 
dynamics of phosphate esters. III. Comparison of the 
bioconcentration of four triaryl phosphates by fish.  Chemosphere, 
12: 155-166. 

MURRAY, D.A.J. (1975) Analysis of tri-aryl phosphate esters and the 
determination of IMOL S-140 in fish tissue and water samples by gas 
chromatography.  J. Fish Res. Board Can., 32: 457-460. 

(1955) Metabolism of triaryl phosphates in rodents.  Nature (Lond.), 
176: 259-260. 

NEELY, W.B., BRANSON, D.R., & BLAU, G.E. (1974) Partition 
coefficient to measure the bioconcentration potential of organic 
chemicals in fish.  Environ. Sci. Technol., 8: 1113-1115. 

NEVINS, M.J. & JOHNSON, W.W. (1978) Acute toxicity of phosphate 
ester mixtures to invertebrates and fish.  Bull. environ. Contam. 
 Toxicol., 19: 250-256. 

NICHOLSON, S.S. (1974) Bovine posterior paralysis due to 
organophosphate poisoning.  J. Am. Vet. Med. Assoc., 165: 280-281. 

NOBILE, E.R., PAGE, S.W., & LOMBARDO, P. (1980) Characterization of 
four commercial flame retardant aryl phosphates.  Bull. environ. 
 Contam. Toxicol., 25: 755-761.

NOMEIR, A.A. & ABOU-DONIA, M.B. (1983) High-performance liquid 
chromato-graphic analysis on radial compression column of the 
neurotoxic tri-o-cresyl phosphate and metabolites.  Anal. Biochem., 
135: 296-303. 

NOMEIR, A.A. & ABOU-DONIA, M.B. (1984) Disposition of (14C)tri-o-
cresyl phosphate and its metabolites in various tissues of the male 
cat following a single dermal application.  Drug Metab. Disp., 12
(6): 705-711. 

NOMEIR, A.A. & ABOU-DONIA, M.B. (1986a) Studies on the metabolism 
of the neurotoxic tri-o-cresyl phosphate synthesis and 
identification by infrared, proton nuclear magnetic resonance and 
mass spectrometry of five of its metabolites.  Toxicology, 38: 1-13. 

NOMEIR, A.A. & ABOU-DONIA, M.B. (1986b) Studies on the metabolism 
of the neurotoxic tri- o-cresyl phosphate, distribution, excretion, 
and metabolism in male cats after a single, dermal application. 
 Toxicology, 38: 15-33. 

OECD (1981)  OECD guidelines for testing of chemicals. Section 2: 
 Effects on biotic systems, Paris, Organization for Economic 
Cooperation and Development, Publications Office. 

OFSTAD, E.B. & SLETTEN, T. (1985) Composition and water solubility 
determination of a commercial tricresylphosphate.  Sci. total 
 Environ., 43: 233-241. 

OISHI, H., OISHI, S., & HIRAGA, K. (1982) Toxicity of several 
phosphoric acid esters in rats.  Toxicol. Lett., 13: 29-34. 

OLSON, B.A. & BURSIAN, S.J. (1988) Effect of route of 
administration on the development of organophosphate-induced 
delayed neurotoxicity in 4-week-old chicks.  J. Toxicol. environ. 
 Health, 23(4): 499-505. 

CHRISTOS, T., & HARTSTEIN, A.M. (1978) Thermal oxidative 
degradation studies of phosphate esters.  Am. Ind. Hyg. Assoc. J., 
39: 633-639. 

PADILLA, S. & VERONESI, B. (1985) The relationship between 
neurological damage and neurotoxic esterase inhibition in rats 
acutely exposed to tri-ortho-cresyl phosphate.  Toxicol. appl. 
 Pharmacol., 78(1): 78-87. 

PARNITZKE, K.H. (1946) [On the recent accumulation of ortho-
tricresylphosphate poisoning (sources and clinical course).]  Dtsch. 
 Gesundheitswes., 1: 666-670 (in German). 

PEGUM, J.S. (1966) Contact dermatitis from plastics containing tri-
aryl phosphates.  Br. J. Dermatol., 78: 626-631. 

PENMAN, D.R & OSBORNE, G.O. (1976) Trialkyl phosphates and related 
compounds as antifertility agents of the twospotted spider mite.  J. 
 econ. Entomol., 69(2): 266-268. 

Utilization of triaryl phosphates by a mixed bacterial population. 
 Can. J. Microbiol., 21: 140-145. 

PLAPP, F.W., Jr & TONG, H.H.C. (1966) Synergism of malathion and 
parathion against resistant insects: Phosphorus esters with 
synergistic properties.  J. econ. Entomol., 59(1): 11-15. 

PRENTICE, D.E. & MAJEED, S.K. (1983) A subchronic study (90 days) 
using multiple dose levels of tri-ortho-cresyl phosphate (TOCP): 
some neuropathological observations in the domestic hen. 
 Neurotoxicology, 4(2): 277-282. 

PRINEAS, J.S. (1969) The pathogenesis of dying-back 
polyneuropathies. Part I. An ultrastructural study of experimental 
tri-ortho-cresyl phosphate intoxication in the cat.  J. Neuropathol. 
 exp. Neurol., 28: 571-597. 

Environmental degradation of the insect growth regulator 
methoprene. V. Metabolism by house-flies and mosquitoes.  Pestic. 
 Biochem. Physiol., 5: 233-241. 

RAMSEY, J.D. & LEE, T.D. (1980) Gas-liquid chromatographic 
retention indices of 296 non-drug substances on SE-30 or OV-1 
likely to be encountered in toxicological analyses.  J. Chromatogr., 
184: 185-206. 

RENBERG, L., SUNDSTROM, G., & SUNDH-NYGARD, K. (1980) Partition 
coefficients of organic chemicals derived from reversed phase thin 
layer chromatography. Evaluation of methods and application on 
phosphate esters, polychlorinated paraffins and some PCB-
substitutes.  Chemosphere, 9: 683-691. 

ROBERTS, N.L., FAIRLEY, C., & PHILLIPS, C. (1983) Measurements and 
evaluation of clinical signs following use of the hen as the animal 
model for screening acute delayed and subchronic neurotoxicity 
studies.  Neurotoxicology, 4(2): 263-270. 

ANDERSON, R.J. (1987) Electrophysiologic changes following 
treatment with organophosphorus-induced delayed neuropathy-
producing agents in the adult hen.  Toxicol. appl. Pharmacol., 87: 

ROGER, H. & RECORDIER, M. (1934) Les polynéurites 
phosphocréosotiques (phosphate de créosote, ginger paralysis, 
apiol).  Ann. Med., 35: 44-63. 

& TUCKER, E.S. (1979) Environmental fate of selected phosphate 
esters.  Environ. Sci. Technol., 13: 840-844. 

Y. (1974) [Subacute toxicity of tricresylphosphate (TCP) in rats.] 
 Pharmacometrics, 8: 107-118 (in Japanese). 

SAMPSON, B.F. (1942) The strange Durban epidemic of 1937.  S. Afr. 
 med. J., 16: 1-9. 

Bioconcentration and excretion of phosphoric acid triesters by 
Killifish  (Oryzeas latipes). Bull. environ. Contam. Toxicol., 28: 

SCHWAB, H. (1948) [Psychic disturbance by triorthocresylphosphate 
poisoning.]  Dtsch. Med. Wochenschr., 73: 124-125 (in German).

SENANAYAKE, N. (1981) Tri-cresyl phosphate neuropathy in Sri Lanka: 
a clinical and neurophysiological study with a three year follow 
up.  J. Neurol. Neurosurg. Psychiatry, 44: 775-780. 

SENANAYAKE, N. & JEYARATNAM, J. (1981) Toxic polyneuropathy due to 
gingili oil contaminated with tri-cresyl phosphate affecting 
adolescent girls in Sri Lanka.  Lancet, 10 January: 88-89. 

SHARMA, R.P. & WATANABE, P.G. (1974) Time related disposition of 
tri-o-tolyl phosphate (TOTP) and metabolites in chicken.  Pharmacol. 
 Res. Commun., 6(5): 475-484. 

SHELDON, L.S. & HITES, R.A. (1978) Organic compounds in the 
Delaware River.  Environ. Sci. Technol., 12: 1188-1194. 

SHELDON, L.S. & HITES, R.A. (1979) Sources and movement of organic 
chemicals in the Delaware River.  Environ. Sci. Technol., 13: 574-579. 

SITTHICHAIKASEM, S. (1978)  Some toxicological effects of phosphate 
 esters on rainbow trout and bluegill, Iowa State University (Ph. D. 

SMITH, H.V. & SPALDING, J.M.K. (1959) Outbreak of paralysis in 
Morocco due to ortho-cresyl phosphate poisoning.  Lancet, 2: 

SMITH, M.I. & LILLIE, R.D. (1931) The histopathology of 
triorthocresyl phosphate poisoning.  Arch. Neurol Psychiatry, 26: 

SMITH, M.I., ELVOVE, E., & FRAZIER, W.H. (1930) The pharmacological 
action of certain phenol esters, with special reference to the 
etiolgy of so-called ginger paralysis.  Public Health Rep., 45: 

SMITH, M.I., ENGEL, E.W., & STOHLMAN, F.F. (1932) Further studies 
on the pharmacology of certain phenol esters with special reference 
to the relation of chemical constitution and physiologic action. 
 Natl. Inst. Health Bull., 160: 1-53. 

ABOU-DONIA, M.B. (1987a) Reproductive tract lesions resulting from 
subchronic administration (63 days) of tri-o-cresyl phosphate in 
male rats.  Toxicol. appl. Pharmacol., 89: 49-63. 

ABOU-DONIA, M.B. (1987b) Time course of the tri-o-cresyl phosphate-
induced testicular lesion in F-344 rats: enzymatic, hormonal, and 
sperm parameter studies.  Toxicol. appl. Pharmacol., 89: 64-72. 

(1987c) Testicular toxicity following oral administration of tri-o-
cresyl phosphate (TOCP) in roosters.  Toxicol. Lett., 37: 279-290. 

LAPADULA, D.M., & ABOU-DONIA, M.B. (1988) Lack of delayed 
neurotoxic effect after tri-ortho-cresyl phosphate treatment in 
male Fischer-344 rats: bio-chemical, neurobehavioural, and 
neuropathological studies.  Fundam. appl. Toxicol., 10: 199-205. 

SOROKIN, M. (1969) Orthocresyl phosphate neuropathy: Report of an 
outbreak in Fiji.  Med. J. Aust., 1: 506-508. 

SPOERRI, P.E. & GLEES, P. (1979) Ultrastructural reactions of 
spinal ganglia to tri-ortho-cresyl phosphate: Effects of 
neurotoxicity.  Cell Tissue Res., 199: 409-414. 

SPOERRI, P.E. & GLEES, P. (1980) Ultrastructural changes in neurons 
and neuroglia of the avian telencephalon (Hyperstriatum 
Accessorium) following tri-ortho-cresyl phosphate intoxication. 
 Cell Tissue Res., 206: 203-210. 

STAEHELIN, R. (1941) [On the triorthocresylphosphate poisonings.] 
 Schweiz. Med. Wochenschr., 71: 1-5 (in German). 

Delayed neurotoxic effects of tri-o-tolyl phosphate in the European 
ferret.  J. Toxicol. environ. Health, 26: 61-73. 

STURM, R.N. (1973) Biodegradability of nonionic surfactants: 
Screening test for predicting rate and ultimate biodegradation.  J. 
 Am. Oil Chem. Soc., 50: 159-167.

Characterization of delayed neurotoxic triaryl phosphates by 
analysis of trifluoroacetylated phenolic moieties.  Environ. Sci. 
 Technol., 14(12): 1498-1501. 

SUSSER, M. & STEIN, Z. (1957) An outbreak of tri-ortho-cresyl 
phosphate (TOCP) poisoning in Durban.  Br. J. ind. Med., 14: 

SVENNILSON, E. (1960) Studies of triorthocresyl phosphate 
neuropathy, Morocco 1960.  Acta psychiatr. Scand., 150(Suppl): 

TABERSHAW, I.R., KLEINFELD, M., & FEINER, B. (1957) Manufacture of 
tricresyl phosphate and other alkyl phenyl phosphates: An 
industrial hygiene study.  Am. Med. Assoc. Arch. ind. Health, 15: 

TAYLOR, J.D. & BUTTAR, H.S. (1967) Evidence for the presence of 2-
(o-cresyl)-4 H-1:3:2-benzodioxaphosphoran-2-one in cat intestine 
following tri-o-cresyl phosphate administration.  Toxicol. appl. 
 Pharmacol., 11: 529-537. 

TER BRAAK, J.W.G. & CARRILLO, R. (1932) [Polyneuritis after usage 
of an abortifacient (tri-ortho-cresyl-phosphate-poisoning).]  Dtsch. 
 Z. Nervenheilkd., 125: 86-116 (in German). 

THOMPSON, J.E. & DUTHIE, J.R. (1968) The biodegradability and 
treatability of NTA.  J. Water Pollut. Control Fed., 40: 306-319. 

TITTARELLI, P. & MASCHERPA, A. (1981) Liquid chromatography with 
graphite furnace atomic absorption spectrophotometric detector for 
speciation of organophosphorus compounds.  Anal. Chem., 53: 1466-1469. 

TOCCO, D.R., RANDALL, J.L., YORK, R.G., & SMITH, M.K. (1987) 
Evaluation of the teratogenic effects of tri-ortho-cresyl phosphate 
in the Long-Evans hooded rat.  Fundam. appl. Toxicol., 8(3): 291-297. 

US NIOSH (1977)  NIOSH manual of analytical methods, 2nd ed., 
Cincinnati, Ohio, National Institute for Occupational Safety and 
Health, Vol. 3, P & CAM, pp. S/209-S/210 (DHEW (NIOSH) Publication 
No. 7-157C). 

US NIOSH (1979)  Industrial hygiene walk-through survey report on 
 organophosphorus exposures at Chevron Chemical, Belle Chase, 
 Louisiana, Cincinnati, Ohio, National Institute for Occupational 
Safety and Health (NTIS PB-82-216268. 

US NIOSH (1980)  Industrial hygiene walk-through survey report on 
 organophosphorus exposures at Rochester products division, 
 General Motors Corp., 1000 Lexington Avenue, Rochester, New York, 
Cincinnati, Ohio, National Institute for Occupational Safety and 
Health (PB82-104530, NTIS). 

US NIOSH (1982)  Industrial hygiene walk-through survey report on 
 organophosphorous exposures at Chevron Chemical, Belle Chase, 
 Louisiana, Cincinnati, Ohio, National Institute for Occupational 
Safety and Health, Division of Surveillance, Hazard Evaluations and 
Field Studies (Report No. IWA-89.10). 

US SOAP AND DETERGENT ASSOCIATION (1965) A procedure and standards 
for the determination of the biodegradability of alkyl benzene 
sulfonate and linear alkylate sulfonate (Report of the Subcommittee 
on Biodegradation Test Methods).  J. Am. Oil Chem. Soc., 42: 986-993. 

VASILESCU, C. & FLORESCU, A. (1980) Clinical and 
electrophysiological study of neuropathy after organophosphorus 
compound poisoning.  Arch. Toxicol., 43: 305-315. 

VASWANI, M., MAHAJAN, P.M., SETIA, R.C., & BHIDE, N.K. (1983) A 
simple colorimetric method for estimation of tricresyl phosphate in 
edible oils.  J. Oil Technol. Assoc. India, 15(1): 12-13. 

VEITH, G.D., DEFOE, D.L., & BERGSTEDT, B.V. (1979) Measuring and 
estimating the bioconcentration factor of chemicals in fish.  J. 
 Fish Res. Board Can., 36: 1040-1048. 

VERONESI, B. (1984) A rodent-model of organophosphorus-induced 
delayed neuropathy: distribution of central (spinal cord) and 
peripheral nerve damage.  Neuropathol. appl. Neurobiol., 10(6): 

VERONESI, B. & ABOU-DONIA, M.B. (1982) Central and peripheral 
neuropathology induced in rats by tri-o-cresyl phosphate (TOCP). 
 Vet. hum. Toxicol., 24: 3 (abstract). 

VERONESI, B., NEWLAND, D., & INMAN, A. (1984) The effect of 
metabolic interference on rodent-sensitivity to tri-ortho-cresyl 
phosphate.  Toxicologist, 4: 55. 

(1978) Organic emissions from combustion of combination coal/refuse 
to produce electricity.  Chemosphere, 7: 893-902. 

VONDERAHE, A.R. (1931) Pathologic changes in paralysis caused by 
drinking Jamaica Ginger.  Arch. Neurol. Psychiatry, 25: 29-43. 

C.G.S., FONDEKAR, R.B., & PRABHAKARAN, K. (1962) Toxic polyneuritis 
in Bombay due to ortho-cresyl-phosphate poisoning.  J. Neurol. 
 Neurosurg. Psychiatry, 25: 234-242. 

WAGEMANN, R. (1975) Some environmental and toxicological aspects of 
a tri-aryl phosphate synthetic oil.  Verh. Int. Ver. Limnol., 19: 

WAGEMANN, R., GRAHAM, R., & LOCKHART, W.L. (1974)  Studies on 
 chemical degradation and fish toxicity of a synthetic tri-aryl 
 phosphate lubrication oil, IMOL S-140. Ottawa, Environment Canada, 
Fisheries and Marine Service, (Technical Report, No. 486). 

WAKABAYASHI, A. (1980) [Environmental pollution caused by 
organophosphoric fire-proofing plasticizers.]  Annu. Rep. Tokyo 
 Metrop. Res. Inst. Environ. Prot., 11: 110-113 (in Japanese). 

WALTHARD, K.M. (1945) Aperçu des résultats obtenus lors des 
derniers examens des malades intoxiqués en 1940 par le phosphate 
triorthocrésilique.  Schweiz. Arch. Neurol. Psychiatry, 58: 189-194. 

WIGHTMAN, R.H. & MALAIYANDI, M. (1983) Physical properties of some 
synthetic trialkyl/aryl phosphate commonly found in environmental 
samples.  Environ. Sci. Technol., 17: 256-261. 

WILLIAMS, D.T. & LEBEL, G.L. (1981) A national survey of 
tri(haloalkyl)-, trialkyl-, and triarylphosphates in Canadian 
drinking water.  Bull. environ. Contam. Toxicol., 27: 450-457. 

R. (1982) Determination of mutagenic potential and organic 
contaminants of Great Lakes drinking water.  Chemosphere, 11: 263-276. 

WILSON, R.D., ROWE, L.D., LOVERING, S.L., & WITZEL, D.A. (1982) 
Acute toxicity of tri-ortho-cresyl phosphate in sheep and swine. 
 Am. J. vet. Res., 43(11): 1954-1957. 

WINDHOLZ, M., ed. (1983)  The Merck index, 10th ed., Rahway, New 
Jersey, Merck and Co., Inc. 

WOLFE, N.L. (1980) Organophosphate and organophosphorothionate 
esters: Application of linear free energy relationships to estimate 
hydrolysis rate constants for use in environmental fate assessment. 
 Chemosphere, 9: 571-579. 

WONG, P.T.S. & CHAU, Y.K. (1984) Structure-toxicity of triaryl 
phosphates in freshwater algae.  Sci. total Environ., 32(2): 157-165. 

YASUDA, H. (1980) [Concentration of organic phosphorus pesticides 
in the atmosphere above the Dogo plain and Ozu basin.]  J. Chem. 
 Soc. Jpn, 1980(4): 645-653 (in Japanese). 

ZELIGS, M.A. (1938) Upper motor neuron sequelae in "Jake" paralysis 
: A clinical follow up study.  J. nerv. ment. Dis., 87: 464-470. 

ZITKO, V. (1980) Proceedings of the 6th Annual Aquatic Toxicity 
Workshop.  Can. Tech. Rep. fish aquat. Sci., 575: 234-265. 

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

    Le  phosphate  de  tricrésyle  (TCP)  est  un  liquide 
visqueux,  ininflammable,  inexplosible et  incolore.  Son 
coefficient  de partage entre  l'octanol et l'eau  (log de 
Pow)    est  égal à  5,1.   Il s'hydrolyse  facilement  en 
milieu alcalin pour donner du phosphate de dicrésyle, mais 
il  est stable  en milieu  neutre ou  acide à  température 

    Du point de vue analytique, la méthode de choix est la 
chromatographie  en  phase  gazeuse avec  détection par un 
dispositif sensible à l'azote/phosphore ou par photométrie 
de flamme.  La limite de détection dans  les  échantillons 
aqueux  est d'environ 1 mg/litre. Le TCP s'extrait facile-
ment  des solutions aqueuses  au moyen de  divers solvants 
organiques.  Pour la purification, on  emploie habituelle-
ment  une colonne chromatographique  de Florisil, mais  il 
est  difficile de  séparer le  TCP des  lipides par  cette 
méthode.  D'autres  méthodes  de purification  ont été re-
commandées  à cette fin (chromatographie en phase gazeuse, 
chromatographie sur charbon activé ou Sep-pack C-18).  Les 
réactifs  analytiques  sont  souvent  contaminés  par  des 
traces de TCP en raison de la très large utilisation faite 
de ce produit. Aussi faut-il prendre certaines précautions 
si l'on veut que l'analyse des traces de TCP soit fiable.

2.  Sources d'exposition humaine et environnementale

    Le  TCP est généralement produit par réaction des cré-
sols sur l'oxychlorure de phosphore. Il y a  deux  sources 
de  production  industrielle de  crésols: l'"acide crésy-
lique",  résidu  des  fours à  coke  et  du raffinage  du 
pétrole,  et les "crésols de synthèse" préparés par oxy-
dation  et dégradation  du cymène.   Le TCP  est  donc  un 
mélange de divers phosphates de triaryle.

    Le  TCP  est  utilisé comme  plastifiant  des matières 
plastiques  vinyliques, comme retardateur  d'inflammation, 
comme additif pour les lubrifiants à très  haute  pression 
et  comme liquide ininflammable dans  les systèmes hydrau-

3.  Transport, distribution et transformation dans l'environnement

    La  libération  de  TCP dans  l'environnement  est peu 
importante  au cours de la production et se produit essen-
tiellement  lors de l'utilisation  finale du produit.   On 
estime  qu'en 1977, 32 800 tonnes  en ont été  libérées au 
total dans l'atmosphère aux Etats-Unis.

    En  raison de sa faible solubilité dans l'eau et de sa 
forte  adsorption aux particules, le TCP s'adsorbe rapide-
ment  aux sédiments des rivières et des lacs et aux parti-
cules  du  sol.  Il  est  rapidement biodégradé  en milieu 
aquatique,  sa  décomposition étant  pratiquement complète 
dans les cours d'eau en l'espace de cinq jours.  L'isomère 
ortho se décompose légèrement plus vite que  les  isomères 
méta et para.  Le TCP est facilement biodégradé  dans  les 
boues d'égouts, avec une demi-vie de 7,5 heures, la dégra-
dation  atteignant 99% en l'espace de 24 heures. La dégra-
dation  abiotique est plus lente,  puisque dans ce cas  la 
demi-vie est de 96 jours.

    Des  facteurs de bioconcentration de  165-2768 ont été 
mesurés en laboratoire sur plusieurs espèces de poissons à 
l'aide de TCP radio-marqué.  La radioactivité a rapidement 
disparu  après cessation de  l'exposition, la demi-vie  de 
dépuration allant de 25,8 à 90 heures.

4.  Niveaux dans l'environnement et exposition humaine

    On a relevé dans l'air des concentration de TCP allant 
jusqu'à  70 ng/m3   au Japon, les concentrations maximales 
dans  une  unité  de production  des Etats-Unis d'Amérique 
n'étant  que de 2 ng/m3.    Dans un atelier de remplissage 
de fûts d'huile lubrifiante, aux Etats-Unis d'Amérique, on 
a  constaté que l'air ne contenait que 0,8 mg/m3   de TCP, 
la  concentration ne dépassant  pas 0,15 mg/m3   en  phos-
phates  totaux, dans une  unité de moulage  de zinc  d'une 
usine  d'automobiles.   Les  concentrations mesurées  dans 
l'eau de boisson au Canada se sont révélées faibles (0,4 à 
4,3 ng/litre)  et le TCP n'a pas pu être décelé dans l'eau 
des  puits.  Dans les  rivières et les  lacs, les  concen-
trations sont souvent beaucoup plus élevées.  Toutefois on 
peut attribuer cet état de choses à la présence  de  sédi-
ments en suspension auxquels le TCP est fortement adsorbé.

    Les  concentrations  sédimentaires  sont plus  élevées 
puisqu'elles peuvent atteindre 1300 ng/g dans le sédiments 
de cours d'eau et 2160 ng/g par les sédiments marins.

    Des  concentrations élevées ont  été mesurées dans  le 
sol et la végétation aux alentours d'unités de production.

    On  a fait état  de résidus dans  des poissons et  des 
fruits de mer allant jusqu'à 49 ng/g, mais la majorité des 
échantillons n'en contenaient pas de quantités décelables.

5.  Effets sur les êtres vivants dans leur milieu naturel

    On  a révélé une réduction  de 50% de la  productivité 
des cultures d'algues vertes d'eau douce, en  présence  de 
concentrations  de  phosphate  de  tri- o-crésyle   (TOCP) 
allant  de 1,5 à 4,2 ng/litre, selon les espèces, les iso-
mères méta et para étant moins toxiques. On ne dispose que 

de données limitées sur la toxicité aiguë du TCP vis-à-vis 
des  invertébrés aquatiques: la CL50   à 48 heures pour la 
daphnie est de 5,6 ng/litre; la CL50 à  24 heures pour les 
nématodes est de 400 ng/litre; la dose sans  effet  obser-
vable à 2 semaines pour la daphnie (mortalité, croissance, 
reproduction)  est de 0,1 mg/litre.  Pour trois espèces de 
poissons, les valeurs de la CL50 à  96 heures se situaient 
entre  4,0 et 8700 mg/litre.  Chez des truites arc-en-ciel 
on a constaté une mortalité d'environ 30% après exposition 
de  quatre mois à 0,9 ng/litre de IMOL S-140 (phosphate de 
tri- o-crésyle    à 2%) et des  effets plus légers sur  une 
période de 14 jours.

    Les  niveaux d'exposition au cours  de ces expériences 
étaient  beaucoup plus élevés que  les concentrations sus-
ceptibles  d'être  rencontrées  dans le  milieu naturel et 
dans   la  plupart  des  cas,  les  valeurs  étaient  très 
supérieures à la solubilité des composés.

6.  Cinétique et métabolisme

    L'absorption,  la  distribution,  le  métabolisme   et 
l'élimination  des organophosphorés jouent un  rôle déter-
minant  dans les effets neuropathologiques retardés de ces 

    Chez  l'homme, l'absorption percutanée du  TOCP semble 
être  au moins dix fois plus rapide que chez le chien.  On 
observe également une importante absorption par cette voie 
chez  le chat.  L'absorption par voie orale a été observée 
chez  le lapin.  On ne  possède aucune donnée de  première 
main sur l'absorption par la voie respiratoire.

    Chez  le chat, on  a constaté qu'après  absorption, le 
TOCP  se répartissait largement dans l'ensemble de l'orga-
nisme,  la concentration la plus élevée se situant dans le 
nerf sciatique, qui constitue un tissu cible.   De  fortes 
concentrations  de TOCP ou  de ses métabolites  se rencon-
traient  également au niveau du  foie, des reins et  de la 
vésicule bilaire.

    La  métabolisation  du  TOCP  s'effectue  selon  trois 
voies.   La première consiste dans l'hydroxylation d'un ou 
plusieurs  groupes  méthyles  et la  seconde  comporte  la 
désarylation  des  groupements  orthocrésyles.   Dans   la 
troisième,  il y a encore oxydation du groupement hydroxy-
méthyle  en aldéhyde et en  acide carboxylique. L'hydroxy-
lation  constitue  une  étape déterminante,  car  le  TOCP 
hydroxyméthylé   est  cyclisé  pour  former  du  phosphate 
cyclique  d' o-tolyle   et  de  saligénol,  un  métabolite 
neurotoxique relativement instable.

    Le  TOCP  et ses  métabolites  sont éliminés  dans les 
urines  et  les matières  fécales  ainsi que,  en  petites 
quantités, dans l'air expiré.

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

    Des trois isomères du TCP, le TOCP est de  loin  celui 
qui  présente la toxicité  aiguë la plus  forte et qui  se 
révèle  également  le  plus toxique  en  cas  d'exposition 
brève.   Il  est le  seul  à déterminer  une neurotoxicité 

    Les   différents  paramètres  toxicologiques   varient 
beaucoup  selon l'espèce (qu'il s'agisse par exemple de la 
mortalité  aiguë  ou  de la  neurotoxicité  retardée).  Le 
poulet est l'une des espèces les plus sensibles.

    On  a pu obtenir chez des espèces d'animaux de labora-
toire très variées une neuropathie retardée induite par un 
organophosphoré  (NRIOP) tant à la  suite d'une exposition 
unique  qu'à  la  suite d'expositions  répétées. Il s'agit 
d'une  neuropathie  qui  se traduit  par  des  altérations 
dégénératives au niveau de la partie distale de l'axone et 
qui s'étend peu à peu à l'ensemble du neurone.

    Elle  se manifeste cliniquement par  une paralysie des 
pattes  postérieures après une période de latence caracté-
ristique  de deux à  trois semaines suivant  l'exposition. 
Une  dose orale unique de 50 à 500 mg de TOCP/kg a produit 
une  neuropathie retardée chez  des poulets, des  doses de 
840 mg/kg ou davantage étant nécessaires pour produire une 
dégénérescence de la moëlle épinière chez des  rats  Long-
Evans.  C'est l'un des métabolites du TOCP,  le  phosphate 
cyclique  d' o-tolyle   et  de  saligénol,  qui  constitue 
l'agent  neurotoxique  actif.  La  sensibilité des espèces 
varie  en  sens inverse  de  la vitesse  de métabolisation 

    On  pense que la lésion  biochimique qui conduit à  la 
neuropathie  consiste  dans  l'inhibition de  l'"estérase 
neurotoxique". Un taux d'inhibition de plus de 65% peu de 
temps après une exposition au TOCP fait présager l'appari-
tion ultérieure d'une neuropathie.  La variabilité dans la 
réponse  neurotoxique  dépend également  d'autres facteurs 
(par  exemple  la voie  d'exposition,  l'âge, le  sexe, la 
souche).   Les  données  disponibles ne  permettent pas de 
définir  clairement une dose sans effet observé pour cette 

    Les  études de reproduction effectuées sur des rats et 
des souris qui recevaient des doses répétées de  TOCP  par 
voie  orale, ont révélé la présence de lésions histopatho-
logiques au niveau des testicules et des ovaires, de modi-
fications  dans  la morphologie  des spermatozoïdes, d'une 
moindre  fécondité  chez les  deux  sexes ainsi  que d'une 
diminution de la taille des portées et de la viabilité des 
ratons  et des souriceaux.  Les  données disponibles n'ont 
pas permis de déterminer la dose sans effet pour  ce  type 

d'anomalies  imputables au TOCP. Une  étude de tératogéni-
cité  effectuée  sur  des  rats,  avec  des  doses  orales 
toxiques   pour   la  mère,  n'a pas  donné  de  résultats 

    On  n'a guère de données sur la mutagénicité et aucune 
sur la cancérogénicité de cette substance.
8.  Effets sur l'homme

    L'ingestion accidentelle constitue la cause principale 
d'intoxication.   Depuis la fin du dix-neuvième siècle, de 
nombreux  cas  d'intoxication  dus à  la  contamination de 
boissons,  de denrées alimentaires ou  de produits pharma-
ceutiques  ont été signalés.  L'exposition professionnelle 
tient essentiellement à une absorption percutanée ou à une 
inhalation et certains cas d'intoxication de ce  type  ont 
été signalés.  L'ingestion de préparations contaminées par 
du  TOCP  peut  produire des  symptômes digestifs (nausée, 
vomissements  et diarrhées), encore que dans certains cas, 
c'est  la polyneuropathie qui  constitue le premier  signe 
d'intoxication.   Les symptômes neurologiques  sont carac-
térisés par une période de latence. Les premiers symptômes 
consistent  en douleurs et paresthésie  aux extrémités des 
membres  inférieurs.  Il y a  une légère diminution de  la 
sensibilité  cutanée et quelques fois réduction de la sen-
sibilité vibratoire. Dans la plupart des cas, la faiblesse 
musculaire   évolue  rapidement  vers  une  paralysie  des 
extrémités  inférieures avec ou sans extension aux membres 
supérieurs.   Dans les cas graves, apparaissent des signes 
d'atteinte  pyramidale.  Les cas  mortels sont rares  mais 
les symptômes neurologiques peuvent être très lents à dis-
paraître et la guérison peut prendre des mois,  voire  des 
années.  L'examen histopathologique révèle  une dégénéres-
cence  des axones.  Les examens  classiques de laboratoire 
ne  révèlent  pas  d'anomalies  si  ce  n'est  parfois une 
augmentation de la teneur en protéines du liquide céphalo-
rachidien.    Les  premiers  soins  consistent  à  réduire 
l'exposition  en  faisant  vomir immédiatement  le malade, 
dans la mesure où celui-ci est encore conscient.   A  plus 
long  terme, le traitement consiste essentiellement en une 
réadaptation  physique  car  on ne  connaît pas d'antidote 
spécifique.   La réaction au phosphate de tricrésyle varie 
considérablement d'un individu à l'autre de même  que  les 
possibilités  de guérison à  la suite d'une  intoxication. 
On a signalé l'apparition de symptômes graves après inges-
tion  de 0,15 g de TCP, alors que chez d'autres personnes, 
l'ingestion  de quantités atteignant  1 à 2 g  n'a produit 
aucun effet toxique. Certains malades guérissent complète-
ment  alors que d'autres présentent des séquelles marquées 
pendant de très longues périodes.


1.  Evaluation des risques pour la santé humaine

    On  a souvent signalé  des cas d'intoxication  humaine 
par  suite  d'une  ingestion accidentelle  de phosphate de 
tri- o-crésyle   ou par suite d'une exposition profession-
nelle.   Les  symptômes  neurotoxiques correspondent  tout 
d'abord  à l'inhibition de  la cholinestérase puis  à  une 
neuropathie   retardée  caractérisée  par   une  paralysie 

    Etant  donné  les  variations considérables  de sensi-
bilité  selon  les individus,  il  n'est pas  possible  de 
déterminer quel est le seuil de sécurité.   Des  symptômes 
ont  été signalés après  ingestion de 0,15 g  d'un mélange 
d'isomères  contenant  une  faible proportion  de TOCP; la 
dose  minimale efficace d'isomères ortho est donc beaucoup 
plus  faible encore. L'expérimentation animale fait égale-
ment  ressortir de très  importantes variations selon  les 
espèces  pour  ce  qui concerne  la  réaction  au TOCP  et 
l'homme semble être particulièrement sensible.

    Des  cas  de  dermatite d'irritation  et de dermatites 
allergiques ont été rapportés.

    On  peut donc considérer  que l'isomère ortho  et  les 
mélanges  d'isomères  qui  en contiennent  constituent  un 
risque de première importance pour la santé humaine.

    Aucune dose n'est sans danger si elle est ingérée.  Il 
convient  de  réduire  au minimum  l'exposition cutanée ou 

1.1  Niveaux d'exposition

    On  peut considérer comme minimale  l'exposition de la 
population   générale  au  phosphate  de   tricrésyle  par 
l'intermédiaire   des   divers  compartiments   du  milieu 
ambiant, notamment l'eau de consommation. On a  décelé  du 
phosphate  de tricrésyle à des  concentrations plus fortes 
dans  l'air urbain que  dans l'air prélevé  au niveau  des 
sites  de  production,  encore  que  ces  valeurs   soient 
généralement  faibles.   Lors d'une  enquête effectuée aux 
Etats-Unis  d'Amérique on n'a pas  décelé de TCP dans  des 
échantillons  de  tissu  adipeux humain.  Il  y  a  eu  de 
nombreux  cas  d'intoxication  humaine accidentelle  dus à 
l'ingestion  de  médicaments,  de nourriture,  de  farine, 
d'huile  de  cuisine et  de  boissons contaminés  par  des 
fluides  hydrauliques  ou des  lubrifiants  à base  de TCP 
produits  à  partir  d'acide  crésylique.   Des  symptômes 
toxiques  peuvent s'observer après  ingestion de doses  ne 
dépassant pas 0,15 g de TOCP, substance qui  est  présente 
dans  le TCP produit  à partir de  l'acide crésylique.  La 

contamination   se   produit   généralement  lors   de  la 
réutilisation  de fûts ou  de tonneaux vides  qui  avaient 
contenu un liquide hydraulique ou de l'huile lubrifiante.

1.2  Effets toxiques

    L'absorption  accidentelle  d'une forte  dose entraîne 
chez l'homme des troubles digestifs, à savoir  une  nausée 
d'intensité  variable,  pouvant  aller jusqu'aux  vomisse-
ments,  accompagnée  de  douleurs abdominales  et de diar-
rhées.  En cas d'exposition à de faibles  doses  cumulées, 
une  "neuropathie  retardée" s'installe  progressivement 
après  une période de  latence de 3 à  28 jours.  Dans  la 
plupart  des cas, la faiblesse  musculaire fait rapidement 
place  à  une paralysie  des  membres inférieurs  qui peut 
parfois s'étendre aux mains.  Dans les cas graves, on voit 
peu  à  peu  appraître des  signes  d'atteinte pyramidale. 
Certaines  études neurophysiologiques révèlent l'existence 
d'une neurotoxicité généralisée avec prolongation du temps 
de  latence terminale et réduction  relativement faible de 
la  vitesse de conduction  des nerfs moteurs.  Ces consta-
tations  confirment la dégénérescence  axonale qui est  la 
principale caractéristique relevée lors des examens histo-

    Le métabolite neurotoxique du TCP a été identifié;  il 
s'agit du phosphate cyclique de  o-tolyle   et de saligénol 
qui provient lui-même des   métabolites  o-hydroxyméthylés. 
Il  semble donc que la  présence d'au moins un  groupement 
 o-tolyle  soit nécessaire parmi  les trois restes  phéno-
liques  du  TCP  pour qu'apparaissent  des  effets  neuro-
toxiques.   Le TCP produit à partir du crésol de synthèse, 
qui contient moins de 0,1% d'orthocrésol, n'est  donc  pas 

    Les   résultats  d'études  de   toxicité  subchronique 
effectuées sur des animaux d'expérience avec du  TCP  pré-
paré  à partir  de crésol  de synthèse,  montrent que  les 
organes cibles sont le foie et le rein;   toutefois  cette 
observation  n'a pas été  confirmée chez l'homme.   On  ne 
dispose  pas de données suffisantes sur la mutagénicité et 
la cancérogénicité du TCP.  On sait néanmoins que  le  TCP 
n'est pas toxique pour l'embryon de poulet.

2.  Evaluation des effets sur l'environnement

    Le  dosage du TCP  dans l'eau montre  que la  contami-
nation est faible.  Cet état de choses tient à  la  faible 
solubilité  dans l'eau du TCP et à l'aisance avec laquelle 
il se décompose.  Etant donnée la faible toxicité aiguë du 
TCP  pour les organismes  aquatiques, il est  peu probable 
qu'il constitue une menace pour ces organismes.

    Du  fait de ses propriétés physico-chimiques, le TCP a 
une forte tendance à la bioaccumulation.  Toutefois celle-
ci  ne  se produit  pas dans la  pratique en raison  de la 
faible  concentration du TOCP dans  l'environnement et les 
êtres  vivants  et  de  la  dégradation  rapide  de  cette 

    Les   TCP   fixés  aux   sédiments  s'accumulent  dans 
l'environnement  et  on  en a  relevé  des  concentrations 
élevées  dans les sédiments des  cours d'eau et des  estu-
aires  ainsi que dans les  sédiments marins.  Du fait  que 
l'on ne possède aucune information sur la biodisponibilité 
de  ces  résidus pour  les  organismes fouisseurs  ou ben-
thiques, ni sur les dangers qu'ils pourraient représenter, 
on  ne  peut  écarter  à  priori  la  possibilité d'effets 

    Il faut également mentionner la possibilité de risques 
localisés  pour l'environnement dus à un déversement acci-
dentel de TCP.

2.1  Niveaux d'exposition

    Les TCP sont présents dans l'air, dans les eaux super-
ficielles,  dans le sol,  les sédiments et  les organismes 
aquatiques,  à  proximité des  zones très industrialisées, 
encore  que  leurs  concentrations y  soient  généralement 
faibles.  En raison de la vitesse élevée de biodégradation 
de  ces substances  en milieu  aqueux, il  ne  semble  pas 
qu'elles  puissent avoir des  effets nocifs sur  la  faune 
aquatique. Il a été fait état d'une concentration extrême-
ment  élevée en phosphates totaux de triaryle (25,55 g/kg) 
dans  un  échantillon  de sol  provenant d'une plantation. 
Cette  observation montre qu'il est nécessaire de procéder 
à l'enfouissement des déchets.

2.2  Effets toxiques

    Les algues d'eau douce sont relativement sensibles aux 
TCP,  la concentration inhibant  à 50% la  croissance com-
prise entre 1,5 et 5,0 ml/litre.  En ce qui  concerne  les 
poissons,   des   concentrations  de   TCP  inférieures  à 
1 mg/litre   (0,3-0,9 mg/litre)   provoquent  des   signes 
d'intoxication  chronique chez la truite arc-en-ciel, mais 
 Menidia    notata est  plus  résistant  (CL50     de  8700 
mg/litre).  Les TCP n'inhibent pas  l'activité cholinesté-
rasique  des poissons ou  des grenouilles mais  ils poten-
tialisent l'effet des insecticides organophosphorés.


    Lorsqu'on  utilise des crésols tri-substitués  pour la 
synthèse  et  la  préparation d'autres  composés,  il  est 
préférable  d'utiliser des isomères para  et méta purifiés 
afin  d'éviter  toute  synthèse  accidentelle  de  dérivés 


1.  Identidad, propiedades físicas y químicas, y métodos analíticos

    El fosfato de tricresilo (FTC) es un líquido ininflam-
able, no explosivo, incoloro y viscoso.  Su coeficiente de 
partición  entre el octanol  y el agua  (log Pow)   es  de 
5,1. Se hidroliza con facilidad en un medio alcalino dando 
fosfato de dicresilo y cresol, pero es estable  en  medios 
neutros y ácidos a temperaturas normales.

    El método analítico de elección es la cromatografía de 
gases con un detector sensible al nitrógeno-fósforo  o  un 
detector  fotométrico de llama.  El límite de detección en 
una  muestra de agua es de 1 ng/litro aproximadamente.  El 
FTC  se extrae con facilidad de las soluciones acuosas con 
distintos disolventes orgánicos.  Se utiliza habitualmente 
para la extracción la cromatografía en columna  de  flori-
sil,  pero es difícil  separar el FTC  de los lípidos  con 
este  método.  Se han recomendado para esa finalidad otros 
métodos  de extracción (GPC, cromatografía en carbón vege-
tal  activado y Sep-pak  C-18).  Los reactivos  analíticos 
están contaminados a menudo con cantidades infinitesimales 
de FTC debido a su amplio uso. Por consiguiente, la obten-
ción de datos fiables en el análisis de cantidades infini-
tesimales de FTC requiere un procedimiento cuidadoso.

2.  Fuentes de exposición humana y ambiental

    El  FTC  se  produce  habitualmente  por  reacción  de 
cresoles  con oxicloruro de fósforo.   Existen dos fuentes 
industriales de cresoles: el "ácido cresílico", obtenido 
como residuo de los hornos de carbón de coque y del refino 
del  petróleo; y los "cresoles sintéticos", preparados a 
partir del cimeno por oxidación y degradación. Como resul-
tado,  el FTC es una  mezcla de varios fosfatos  triaríli-

    El  FTC se utiliza como plastificante en los plásticos 
vinílicos,  y  también como  pirorretardante, aditivo para 
lubricantes  de presión extrema y  líquido ininflamable en 
los sistemas hidráulicos.

3.  Transporte, distribución y transformación en el medio ambiente

    El  paso de FTC al  medio ambiente se debe  principal-
mente a su uso final, pues la liberación en el curso de la 
fabricación  es escasa.  En  1977 se calculó  que el  paso 
total al medio ambiente en los Estados Unidos  de  América 
fue de 32 800 toneladas.

    Debido  a su escasa  hidrosolubilidad y a  su  elevada 
adsorción  por  los materiales  en  partículas, el  FTC se 
absorbe con rapidez en los sedimentos de ríos o lagos y en 
el  suelo.  Su  biodegradación  en  el  medio  acuático es 

rápida, quedando casi terminada en el agua de río en cinco 
días. El isómero orto se degrada con una  rapidez  ligera-
mente mayor que los isómeros meta o para. El FTC se biode-
grada  con facilidad en  el fango de  los alcantarillados, 
presentando  una semivida de 7,5 horas;  la degradación en 
24 horas alcanza el 99%.  La degradación abiótica  es  más 
lenta, dando una semivida de 96 días.

    Se  midieron los factores de  bioconcentración de 165-
2768  en varias especies de peces en el laboratorio utili-
zando  FTC  radiomarcado.   La  radiactividad  desapareció 
rápidamente al cesar la exposición, observándose semividas 
de depuración comprendidas entre 25,8 y 90 horas.

4.  Niveles medioambientales y exposición humana

    En el Japón se han medido concentraciones atmosféricas 
de FTC de hasta 70 ng/m3,   pero alcanzaron un  máximo  de 
sólo  2 ng/m3   en una  instalación de fabricación  de los 
Estados Unidos de América. En este país, el aire del medio 
laboral  contenía  menos de  0,8 mg/m3    en una  nave  de 
llenado  de barriles de aceite  lubricante  y   0,15 mg/m3 
(fosfatos  totales) en una  planta de troquelado  de  zinc 
para  automóviles.  En el  Canadá, las concentraciones  de 
FTC  medidas  en  el agua  potable  fueron  bajas  (0,4  a 
4,3 ng/litro)  y  el  producto resultó  indetectable en el 
agua de pozo.  Las concentraciones observadas en las aguas 
de  ríos  y  lagos  son  con  frecuencia   apreciablemente 
mayores. Sin embargo, ello se debe a la presencia de sedi-
mentos en suspensión en los que queda  fuertemente  absor-
bido el FTC.

    Las concentraciones en los sedimentos son altas en los 
ríos  y en el mar,  habiéndose observado valores de  hasta 
1300 ng/g y 2160 ng/g, respectivamente.

    Se observaron concentraciones altas en el suelo  y  la 
vegetación  en los alrededores de  instalaciones de fabri-

    Se  han señalado restos en  peces y mariscos de  hasta 
40 ng/g, pero la mayor parte de los animales examinados no 
contenían residuos apreciables.

5.  Efectos sobre los seres vivos del medio ambiente

    La  productividad primaria de cultivos de algas verdes 
de agua dulce quedó reducida en el 50% mediante la adición 
de  fosfato  de  tri- o-cresilo  a  razón  de  1,5  a  4,2 
ng/litro,  según las especies,  mientras que los  isómeros 
meta y para resultaban menos tóxicos.  Son  limitados  los 
datos  referentes a la  toxicidad aguda del  FTC para  los 
invertebrados acuáticos: la CL50 en  48 horas para Daphnia 
es de 5,6 ng/litro y la CL50 en  24 horas para los nemato-
dos es de 400 ng/litro; la concentración NOEL (mortalidad, 

crecimiento,  reproducción) en dos semanas para Daphnia es 
de 0,1 mg/litro.  Los valores de CL50   en  96 horas  para 
tres  especies de peces se hallaban comprendidos entre 4,0 
y 8700 mg/litro. La trucha irisada presentó una mortalidad 
del  30%  aproximadamente  después de  una  exposición  de 
cuatro meses a una concentración de 0,9 ng/litro  de  IMOL 
S-140 (fosfato de tri- o-cresilo  al 2%) y efectos menores 
en un periodo de 14 días.

    Los  niveles de exposición utilizados  en esos experi-
mentos  fueron mucho mayores  que las concentraciones  que 
probablemente  pueden  hallarse en  el  agua en  el  medio 
ambiente y, en la mayoría de los casos, excedían  en  gran 
manera a la solubilidad de los productos.

6.  Cinética y metabolismo

    La  absorción, distribución, metabolismo y eliminación 
de  los  organofosfatos  son  elementos  críticos  en  los 
efectos neuropáticos tardíos de estos productos.

    La  absorción cutánea del FTOC en el hombre parece ser 
por lo menos de un orden de magnitud más rápida que en los 
perros.  También se observa una absorción cutánea signifi-
cativa en el gato. En el conejo se ha señalado  la  absor-
ción  oral del producto.  No hay información directa sobre 
la absorción por inhalación.

    En estudios efectuados en gatos se observó que el FTOC 
absorbido se distribuye ampliamente por todo el organismo, 
hallándose  la máxima concentración en  el nervio ciático, 
que  es el tejido diana. Otros órganos en los que se encu-
entran  altas concentraciones de FTOC y de sus metabolitos 
son el hígado, los riñones y la vesícula biliar.

    El metabolismo del FTOC sigue tres vías.   La  primera 
es  la hidroxidación de  uno o más  grupos metílicos y  la 
segunda  es la desarilación de los grupos  o-cresilo.    La 
tercera  vía es la  oxidación ulterior del  grupo hidroxi-
metilo para dar aldehído y ácido carboxílico.  La etapa de 
hidroxilación  es decisiva porque el  FTOC hidroximetílico 
forma  un  producto  cíclico,  el  fosfato  cíclico  de  o-
tolilo saligenina,  metabolito  neurotóxico  relativamente

    El  FOTC y sus metabolitos se eliminan por la orina en 
las  heces,  junto  con  pequeñas  cantidades  en  el aire 

7.  Efectos en los animales de experimentación y en sistemas de
prueba  in vitro 

    Entre los tres isómeros del FTC, el FOTC es  con  gran 
diferencia  el más tóxico en la exposición aguda y a corto 
plazo.   Es  el  único isómero  que produce neurotoxicidad 

    Existe  una amplia variabilidad  entre especies en  lo 
que respecta a los distintos puntos finales  tóxicos  (por 
ejemplo,  letalidad  aguda,  neurotoxicidad tardía)  de la 
exposición  al FOTC, siendo el  pollo una de las  especies 
más sensibles.

    Se ha producido neuropatía tardía inducida por organo-
fosfatos  mediante la exposición  única y repetida  en una 
amplia gama de animales de experimentación; este trastorno 
se  clasifica  como una  "neuropatía  de muerte  sobre el 
dorso".   Se producen lesiones  degenerativas en el  axón 
distal,  que se extienden con el tiempo hacia el cuerpo de 
la célula.

    Los signos clínicos consisten en la parálisis  de  las 
patas  traseras después de un  intervalo característico de 
2-3  semanas a partir  de la exposición.   Una sola  dosis 
oral  de 50-500 mg de FOTC/kg produjo la neuropatía tardía 
en  pollos, mientras que se necesitaron dosis de 840 mg/kg 
o más para producir la degeneración de la  médula  espinal 
en  ratas  Long-Evans.   El metabolito  fosfato cíclico de 
o-tolilo   saligenina es el agente neurotóxico activo.  La 
sensibilidad  de  las especies  guarda correlación inversa 
con la tasa de metabolismo ulterior.

    Se  cree que  la inhibición  de la  "esterasa  de  la 
neurotoxicidad"  es la lesión bioquímica que conduce a la 
neuropatía  tardía  inducida por  organofosfatos; la inhi-
bición  de más del  65% poco después  de la exposición  al 
FOTC permite prever una neuropatía ulterior. En  la  vari-
abilidad  de  la  respuesta neurotóxica  al  FOTC influyen 
factores  distintos del metabolismo (por  ejemplo, vías de 
exposición, edad, sexo, estirpe). Los datos disponibles no 
permiten  establecer un nivel neto  sin efectos observados 
para la neuropatía tardía.

    Los  estudios de reproducción en ratas y ratones some-
tidos  a una exposición  oral repetida al  FOTC  mostraron 
lesiones histopatológicas de los testículos y los ovarios, 
alteraciones  morfológicas del esperma, disminución  de la 
fecundidad  en  ambos  sexos,  y  descenso  del  tamaño  y 
viabilidad de las crías. Los datos disponibles no permiten 
establecer  un nivel neto sin efectos en lo que respecta a 
la acción del FOTC sobre la reproducción.  Un  estudio  de 
teratogenicidad  en  ratas,  utilizando dosis  orales  que 
producían toxicidad materna, dio resultados negativos.

    Se  dispone de escasa  información sobre la  mutageni-
cidad y de ninguna sobre la cancerogenicidad.

8.  Efectos en la especie humana

    La  ingestión  accidental  es la  principal  causa  de 
intoxicación.   Desde fines del siglo XIX se han observado 

numerosos casos de intoxicación por contaminación de bebi-
das,  alimentos o medicamentos.  La exposición profesional 
se  produce principalmente por  absorción cutánea o  inha-
lación,  habiéndose registrado algunos casos  de envenena-
miento.   La ingestión de preparaciones que contienen FOTC 
puede  ir seguida de síntomas gastrointestinales (náuseas, 
vómitos  y diarrea), aunque en algunos casos la polineuro-
patía  es el primer  signo de intoxicación.   Los síntomas 
neurológicos  suelen ser tardíos.  Los  síntomas iniciales 
consisten  en  dolor  y  parestesia  de  las  extremidades 
inferiores.   Puede observarse una alteración  moderada de 
las  sensaciones cutáneas  y a  veces del  sentido  de  la 
vibración.   En  la mayoría  de  los casos,  la  debilidad 
muscular  evoluciona  rápidamente  hasta dar  una  marcada 
parálisis de las extremidades inferiores, con o sin parti-
cipación  de las superiores.  En los casos graves aparecen 
signos  piramidales.  Son raras  las defunciones, pero  la 
recuperación  de los síntomas y  signos neurológicos puede 
ser  extremadamente lenta y durar varios meses o años.  El 
examen  histopatológico  muestra la  presencia de degener-
ación del axón.  Los análisis corrientes de laboratorio no 
muestran   hallazgos  anormales,  pero  cabe  observar  un 
aumento de la concentración de las proteínas en el líquido 
cefalorraquídeo.   Los  primeros auxilios  consisten en la 
reducción de la exposición provocando el vómito inmediata-
mente  después de la  ingestión, siempre que  el  paciente 
esté consciente.  El tratamiento fundamental a largo plazo 
consiste  en  la  rehabilitación física,  no  conociéndose 
ningún  antídoto específico.  Existen  grandes variaciones 
entre las personas en la respuesta al FTC y en la recuper-
ación después de producirse los efectos tóxicos.   Se  han 
registrado  síntomas  graves  después de  la  ingestión de 
0,15 g  de FTC, mientras que otras personas no presentaron 
efecto  tóxico alguno después  de ingerir 1-2 g.   Ciertos 
enfermos  se  recuperan  por completo,  mientras que otros 
conservan efectos marcados durante un periodo apreciable.


1.  Evaluación de los riesgos para la salud humana

    Se   han  registrado  con   frecuencia  intoxicaciones 
humanas por ingestión  accidental de  fosfato  de   tri- o-
cresilo  (FTOC) o por exposición  laboral de trabajadores. 
La vía probable de la exposición laboral es  la  absorción 
cutánea.  Entre los síntomas neurotóxicos figuran la inhi-
bición  inicial  de  las colinesterasas  y  la  neuropatía 
tardía ulterior caracterizada por parálisis grave.

    Debido  a  la  considerable variación  existente en la 
sensibilidad  de las personas  al FTOC, no  puede estable-
cerse  un nivel de exposición sin riesgo.  Se han señalado 
síntomas por ingestión de 0,15 g de una mezcla de isómeros 
con baja proporción de FTOC; así pues, la  dosis  efectiva 
mínima  del  ortoisómero  es muy  inferior.   Los estudios 
efectuados  en animales muestran considerables variaciones 
entre  especies en la  respuesta al FTOC,  y las  personas 
parecen ser especialmente sensibles.

    Se  han  señalado  casos  de  dermatitis  irritante  y 

    En  consecuencia, tanto el  ortoisómero puro como  las 
mezclas  de  isómeros  que contienen  FTOC  se  consideran 
riesgos importantes para la salud humana.

    No existe un nivel inocuo de ingestión.  La exposición 
al  producto  por  contacto  cutáneo  o  inhalación   debe 
reducirse al mínimo.

1.1  Niveles de exposición

    Puede  considerarse mínima la exposición  de la pobla-
ción general al fosfato de tricresilo (FTC)  por  conducto 
de  distintos  medios  ambientales, incluida  el  agua  de 
beber.  Se han observado concentraciones  de FTC relativa-
mente  más altas en el aire urbano que en el aire recogido 
en  los emplazamientos de fabricación,  aunque los niveles 
suelen  ser bajos.  En un estudio efectuado en los Estados 
Unidos  de  América no  se detectó el  FTC en muestras  de 
tejido  adiposo humano.  Se han  observado numerosos casos 
de  intoxicación humana accidental por  ingestión de medi-
camentos, alimentos tales como harina y aceite de cocinar, 
y  bebidas  contaminados  con líquido  hidráulico o aceite 
lubricante  que  contenían  FTC  producido  a  partir  del 
"ácido  cresílico".  Pueden observarse  síntomas tóxicos 
después  de la ingestión de sólo 0,15 g de fosfato de tri-
 o-cresilo,   componente del FTC obtenido a partir de ácido 
cresílico.  El origen habitual de la contaminación ha con-
sistido en la reutilización de barriles o  bidones  vacíos 
utilizados  previamente para contener líquido hidráulico o 
aceite lubricante.

1.2  Efectos tóxicos

    La  exposición humana accidental a una sola dosis alta 
ocasiona  trastornos gastrointestinales que varían  de las 
náuseas  ligeras a las intensas con vómitos, dolor abdomi-
nal  y diarrea.  En  el caso de  la exposición a  pequeñas 
dosis  acumuladas, aparece progresivamente la "neurotoxi-
cidad tardía" después de un periodo latente de 3-28 días. 
En  la mayor  parte de  los casos,  la debilidad  muscular 
pasa  rápidamente a ser una  marcada parálisis de las  ex-
tremidades  inferiores, con o sin afectación de las manos. 
En   los  casos  graves  aparecen  progresivamente  signos 
piramidales.   Algunos estudios neurofisiológicos muestran 
fenómenos  extendidos de neurotoxicidad y  prolongación de 
las  latencias  terminales, con  disminución relativamente 
pequeña  de  la velocidad  de  conducción de  los  nervios 
motores.   Ello  confirma  los signos  de degeneración del 
axón,  que es la característica principal observada en los 
exámenes histopatológicos.

    Se  ha identificado el metabolito  neurotóxico del FTC 
como el fosfato cíclico de  o-tolilo  saligenina, derivado 
de  los metabolitos  o-hidroximetílicos.   Parece pues que 
los  efectos neurotóxicos exigen la presencia por lo menos 
de  un grupo  o-tolilo  entre las tres porciones fenólicas 
del  FTC.  Ello  significa que  no es  neurotóxico el  FTC 
producido a partir de cresol sintético, que contiene menos 
del 0,1% de  o-cresol.

    Los  estudios  de  toxicidad subcrónica  efectuados en 
animales con FTC obtenido de cresol sintético muestran que 
los  órganos diana son el  hígado y los riñones,  pero esa 
observación  no se ha confirmado  en los casos de  intoxi-
cación humana.  No se dispone de datos apropiados sobre la 
mutagenicidad  y la cancerogenicidad.  El FTC no es tóxico 
para los embriones de pollo.

2.  Evaluación de los efectos en el medio ambiente

    La medición de las concentraciones de FTC en  el  agua 
ambiental  ha mostrado que  existen sólo niveles  bajos de 
contaminación.   Ese  hecho  refleja la  escasa hidrosolu-
bilidad  y la fácil degradabilidad del producto.  Dado que 
la  toxicidad aguda del  FTC para los  seres acuáticos  es 
también  baja,  es  improbable que  represente una amenaza 
para ellos.

    Debido   a  las  propiedades  fisicoquímicas  del  FTC 
existen   altas  posibilidades  de   bioacumulación.   Sin 
embargo, ello no se produce en la práctica porque las con-
centraciones  de FOTC en el medio ambiente y en los organ-
ismos vivos son bajas y porque los productos  se  degradan 
con rapidez.

    El  FTC fijado  por los  sedimentos se  acumula en  el 
medio ambiente, habiéndose medido concentraciones altas en 
los  sedimentos de ríos, estuarios  y mares.  Dado que  se 
carece  de información sobre la  biodisponibilidad de esos 
residuos para los seres vivos que se hallan en madrigueras 
o en el fondo o sobre sus riesgos, no puede descartarse la 
posibilidad de que aparezcan efectos en tales especies.

    La  fuga de FTC suscita riesgos para el medio ambiente 

2.1  Niveles de exposición

    El FTC se halla en el aire, las aguas  de  superficie, 
el suelo, los sedimentos y los seres vivos acuáticos cerca 
de  las  zonas  muy industrializadas,  aunque  en  concen-
traciones habitualmente bajas.  Debido a la alta  tasa  de 
biodegradación del FTC en el medio acuoso, no se considera 
que afecta adversamente a los seres vivos acuáticos. En un 
estudio  se encontró una concentración extremadamente alta 
de   fosfatos  triarílicos  totales  (26,55 g/kg)  en  una 
muestra  de suelo obtenida  en el patio  de una planta  de 
producción.   Ello  sugiere  la necesidad  de eliminar los 
residuos por relleno de terrenos.

2.2  Efectos tóxicos

    Las algas de agua dulce son relativamente sensibles al 
FTC, cuya concentración inhibidora del 50% del crecimiento 
es de 1,5 a 5,0 mg/litro.  Entre las especies de peces, la 
trucha irisada sufre el efecto de concentraciones  de  FTC 
inferiores  a 1 mg/litro (0,3-0,9 mg/litro), con signos de 
intoxicación  crónica, pero el pez argentado de las mareas 
es  más resistente (CL50    de 8700 mg/litro).  El  FTC no 
inhibe la actividad colinesterásica seca de peces y ranas, 
pero   tiene   un   efecto  sinérgico   con  la  actividad 
insecticida de los órganos fosforados.


    Cuando  se  utilizan  cresoles  trisustituidos  en  la 
síntesis  y fabricación de  otros productos, es  necesario 
emplear  isómeros meta y  para purificados para  evitar la 
síntesis accidental de productos orto-sustituidos.

    See Also:
       Toxicological Abbreviations