Tri-o-cresyl Phosphate

Tricresyl phosphates are available as the o-isomer (TOCP), the m-isomer (TMCP), and p-isomer (TPCP). The ortho-isomer is the most toxic of the three; the meta-and para-isomers are relatively inactive. The commercial product may contain the ortho-isomer as a contaminant unless special precautions are taken during manufacture. Pure tri-para-cresyl phosphate is a solid, and ortho-and meta-are liquids (see below). The tri-o-cresyl phosphate will be discussed here as the specific example of these compounds because it is the most toxic of the tricresyl phosphates and specifically regulated by OSHA. TOCP is a colorless to pale yellow, odorless liquid or solid (below 52/F/11℃).

Tri-o-cresyl phosphate is a colorless to pale yellow, odorless to faint aromatic-like liquid, and it is a solid below the 25.6 °C melting point. It is sparingly soluble in water, but is slightly soluble in ethanol and very soluble in ethyl ether (Budavari, 1996). The vapor pressure of TOCP is 0.00002mm Hg at room temperature, but is 10mm Hg at 265 °C (Bisesi, 1994). It decomposes slightly upon boiling (bp 410 °C) (Budavari, 1996).

TOCP finds wide applications in several areas. It is used as a flame retardant; as a plasticizer; as a waterproofing agent; as a synthetic lubricant; as an additive in gasoline to control preignition; and in hot extrusion molding, hydraulic fluid, and solvent mixture for resins..

Tri-o-cresyl phosphate is used widely as a gasoline additive, plasticizer, fire retardant, solvent, extreme pressure additive, intermediate in pharmaceutical manufacturing, water-proofing agent, heat exchange medium, and as a lead scavenger in gasoline.

As plasticizer in lacquers and varnishes.

Prepared from cresol and phosphorus oxychloride, phosphoric acid, or phosphorus pentachloride. The grades of cresol commonly used are the isomeric (o-, m-, /p-), and meta-para mixtures from coal tar and cresylic acid from petroleum. Purification of the product is based on the intended use; the commercial product is generally obtained as a mixture. A 'refined grade' of tricresyl phosphate is prepared by vacuum distillation, or alternatively by washing with 2% NaOH and water (Lowenheim and Moran 1975).

Toxic by ingestion and skin absorption. The oisomer is highly toxic. TLV: 0.1 mg/m3 (skin); not classifiable as a Human Carcinogen.

Non-industrial:
During the prohibition era in the United States in the 1920s and 1930s, Jamaican ginger extract was used as an additive to beverages for popular consumption. An outbreak of polyneuritis, an estimated 20,000 to 30,000 cases, led to the discovery that the ginger extract, used because of its alcohol content, was contaminated with TOCP, leading to the polyneuritis. This syndrome thus came to be known as 'jake', 'ginger jake', and 'jake leg' (Baron 1981; Morgan 1982). The discovery of the polyneuritis associated with tri-o-cresyl phosphate led to much research on this compound (Lillie and Smith 1932; Smith and Elvove 1930; Smith and Lillie 1931; Smith et al 1930, 1932) and related materials, particularly the organophosphorus insecticides, in which polyneuritis was associated with a delayed neuropathy characterized by degeneration of axons with subsequent secondary degeneration of myelin (Abou-Donia 1981). Man may very well be the most sensitive species.
The best known and most studied incidences of poisoning by TOCP, therefore, are associated with the contamination of Jamaican ginger extract with 0.5 to 3% tri-o-cresyl phosphate during the 1930s in the United States (Abou-Donia 1981; Baron 1981; Calabrese 1971; Morgan 1982; Morgan and Penovich 1978). However, other cases of poisoning have been reported in connection with the use of contaminated cooking oil in Japan (Yuasa et al 1970) and Morocco (Smith and Spalding 1959), gingili oil in Sri Lanka (Senanayake and Jeyaratnam 1981), and in other situations as summarized by Morgan (1982).
Industrial:
Cases of poisoning associated with the use of TOCP have been reported in workers in the shoe industries of Italy (Capellini et al 1968; Cosi et al 1973; Desantis 1979; Faggi et al 1971) and Spain (Bermejillo 1971a,b). The glues and adhesives used, apparently contaminated with TOCP, are associated with symptoms characteristic of TOCP poisoning. However, Morgan (1981) suggests caution in assigning causation in such situations because of the possibility of the presence of other chemicals which may cause similar symptomology.

TOCP is a highly poisonous compound. Its toxicity is greater than that of the meta- or para-isomer. The toxic routes are inhalation, ingestion, and absorption through the skin; and the symptoms varied with the species and the route of admission.
Ingestion of 40–60 mL of the liquid can be fatal to humans. An oral dose of 6–7 mg/kg has produced serious paralysis in humans (Patty 1949). The toxic symptoms from oral intake can be gastrointestinal pain, diarrhea, weakness, muscle pain, kidney damage, and paralysis. The target organs are the gastrointestinal tract, kidney, central nervous system, and neuromuscular system.
LD50 value, oral (rabbits): 100 mg/kg
Somkuti et al. (1987) reported testicular toxicity of TOCP in adult leghorn roosters. Birds dosed with 100 mg/kg/day exhibited limb paralysis in 7–10 days. Such symptoms are characteristics of delayed neurotoxicity caused by organophosphorus compounds. Analysis at the termination of 18 days indicated a significant inhibition of neurotoxic esterase activity in both brain and testes, and a decrease in sperm motility and brain acetylcholinesterase activity.
TOCP caused adverse reproductive effects in mice, such as increased maternal mortality and a decreased number of viable litters. An LD50 value of 515 mg/kg/day is reported
(Environmental Health Research and Testing 1987)..

Noncumbustible solid; vapor pressure 0.02 torr at 150°C (302°F); fire retardant.

1. As additive to extreme pressure lubricants.
2. As a non-flammable fluid in hydraulic systems.
3. As plasticizer in lacquers and varnishes.
4. As plasticizer in vinyl plastics manufacture.
5. As flame retardant.
6. As lead scavenger in gasoline.
7. As solvent for nitrocellulose, in cellulosic molding compositions.

Poison by subcutaneous, intramuscular, intravenous, and intraperitoneal routes. Moderately toxic by ingestion. Most of the cases of tri-o-cresyl phosphate poisoning have followed its ingestion. In 1930, some 15,000 persons were affected in the United States, and of these, 10 died. The responsible material was found to be an alcoholic drink known as Jamaica ginger, or "jake." This beverage had been adulterated with about 2% of tri-o-cresyl phosphate. The affected persons developed a polyneuritis, which progressed, in many cases, with degeneration of the peripheral motor nerves, the anterior horn cells, and the pyramidal tracts. Sensory changes were absent. Since 1930 there have been several other outbreaks of poisoning following ingestion of the material. Tri-ocresyl phosphate is more toxic than the mform, and much more so than tri-p-cresyl phosphate or triphenyl phosphate. Experimental reproductive effects. flame. Can react with oxidizing materials. To fight fire, use CO2, dry chemical. When heated to decomposition it emits highly toxic fumes of POx. See also PHOSPHATES. Combustible when exposed to heat or

Tricresyl phosphate is used as an additive in hydraulic fluids; as a plasticizer; pigment dispersant; flame retardant; as a plasticizer for chlorinated rubber; vinyl plastics; polystyrene, polyacrylic, and polymethacrylic esters; as an adjuvant in milling of pigment pastes; as a solvent and as a binder in nitrocellulose and various natural resins, and as an additive to synthetic lubricants and gasoline. It is also used in the recovery of phenol in coke-oven wastewaters.

Biological. A commercial mixture containing tricresyl phosphates was completely degraded by indigenous microbes in Mississippi River water to carbon dioxide. After 4 wk, 82.1% of the theoretical carbon dioxide had evolved (Saeger et al., 1979).
Chemical/Physical. Tri-o-cresyl phosphate hydrolyzed rapidly in Lake Ontario water, presumably to di-o-cresyl phosphate (Howard and Doe, 1979). When an aqueous solution containing a mixture of isomers (0.1 mg/L) and chlorine (3 to 1,000 mg/L) was stirred in the dark at 20 °C for 24 h, the benzene ring was substituted with one to three chlorine atoms (Ishikawa and Baba, 1988).
Decomposes at temperatures greater than 424 °C (Dobry and Keller, 1957).

The skin penetrating ability of a series of phosphorus esters, including tri-o-cresyl phosphate, was studied by Marzulli et al (1965). They found a relationship between the solubility of the compounds studied in benzene and water, the molecular weight, and the volatility and their skin-penetrating capacity. Tri-ocresyl phosphate was one of the least penetrating of the compounds studied in a series of related phosphorus esters. However, Ahmed and Glees (1971) showed that the application of 0.2 cm³/kg body weight of tricresyl phosphate daily for 10 d on the skin of the neck of simian primates produced general symptoms of intoxication. This observation has been confirmed in mice (Litau 1975). Following dermal application of tri-o-cresyl phosphate to a preclipped area on the back of the neck of male cats (Nomeir and Abou-Donia 1984), the compound reached its maximum concentration in plasma at 12 h, while its metabolites reached their maximum concentrations between 24 and 48 h. The subsequent disappearance of TOCP from the plasma followed monoexponential kinetics with a half-life of 1.2 d. Di-o-cresyl phosphate and o-cresyl phosphate were the major metabolites in the plasma, while dihydroxymethyl TOCP was present in trace amounts. Appreciable amounts of saligenin cyclic-o-tolyl phosphate were detected in the plasma at all time points. TOCP was the predominant compound in the brain, spinal cord, and sciatic nerve, while the liver, kidneys, and lungs contained mostly metabolites. The major metabolite identified in these tissues was ohydroxybenzoic acid, followed by di-o-cresyl phosphate. Di-o-cresyl phosphate and o-cresyl phosphate were the predominant metabolites in the brain, spinal cord, and sciatic nerve. Other metabolites identified in the tissues were ocresol, dihydroxymethyl TOCP, as well as the stepwise oxidation products of the methyl group of o-cresol. In chickens, after oral administration of radiolabeled tri-o-cresyl phosphate (Sharma and Watanabe 1974; Watanabe and Sharma 1973), nerve tissues accumulated the compound over a period of two weeks. Other tissues examined showed an increase over a period of 3-7 d, followed by a decline. During that period the principal metabolite, 2-(2-methylphenoxy)-4H-l,3,2-benzodioxaphosphorin- 2-oxide (CBDP), represented 71 and 74% of the total in the liver at 12 and 24 h. The concentration of TOCP and metabolites in the plasma at 24 h was only about 5% that of the liver. These workers suggest that CBDP is bound to tissues to a greater extent than TOCP, since low concentrations of the metabolite were found in plasma; TOCP was the major circulating compound. However, the total recovery of the administered radiolabeled compound over the first 3 d was relatively low, emphasizing the extended period of time this chemical remains in the body. Only 26.5% of the administered dose was excreted in 3 d. Eto (1969) has reviewed the pathways of metabolism of tri-o-cresyl phosphate.

UN2574 Tricresyl phosphate with >3% ortho (o-) isomer, Hazard Class: 6.1; Labels: 6.1-Poisonous materials.

Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, epoxides. Contact with magnesium may cause explosion. Organophosphates, such as tricresyl phosphate, are susceptible to formation of highly toxic and flammable phosphine gas in the presence of strong reducing agents such as hydrideds and active metals. Partial oxidation by oxidizing agents may result in the release of toxic phosphorus oxides.

TOCP is dissolved in a combustible solvent and burned in a chemical incinerator equipped with an afterburner and scrubber.