Cresyl phosphate

The wide variety of ketomethylene and amino ketone monomers that could be synthesized, and the abiUty of the quinoline-forming reaction to generate high molar mass polymers under relatively mild conditions, allow the synthesis of a series of polyquinolines with a wide stmctural variety. Thus polyquinolines with a range of chain stiffness from a semirigid chain to rod-like macromolecules have been synthesized. Polyquinolines are most often prepared by solution polymerization of bis(i9-amino aryl ketone) and bis (ketomethylene) monomers, where R = H or C H, in y -cresol with di-y -cresyl phosphate at 135—140°C for a period of 24—48 h (92). 

Chemical Designations - Synonyms TCP Tri-p-tolil phosphate Tri-p-cresyl phosphate Chemical Formula (p-CH3CjH40)jP0. 

A neurotoxic isomer of tricresyl phosphate (tri-ort/20-cresyl phosphate) altered testicular morphology and function as well as reproductive function after oral exposure in rats (Somkuti et al. 1987a, 1987b) (see Section 2.5). 

None of the calves of 10 cows showed clinical signs of neurotoxicity after the cows were orally exposed to an unknown quantity of a Fyrquel hydraulic fluid reclamation waste that according to the authors possibly contained tri-ort/20-cresyl phosphate (TOCP), and that was applied liberally to their backs one time as a treatment for ringworm (Julian et al. 1976). The cows were seen licking their backs and the backs of other cows thus, the cows were orally and dermally exposed to organophosphate ester hydraulic fluids. 

The material was poured over the backs of the animals as a ringworm treatment. Exposure was expected to have been by the oral route as well as by dermal contact, because the cows were seen licking their backs or the backs of other cows 14 of 50 cows died within 4 weeks of exposure. The authors stated that this fluid may have been contaminated with tri-ort/zo-cresyl phosphate. 

After a single dermal exposure to waste from the reclamation of a Fyrquel hydraulic fluid that may have been contaminated with tri-or/7 o-cresyl phosphate (TOCP), no apparent signs of neurotoxicity were observed in calves of 10 cows that manifested neurotoxicity just after the birth of the calves. The cows were apparently also exposed orally concurrent to the dermal exposure (Julian et al. 1976). No intermediate- or chronic-duration dermal studies examining developmental effects in animals were located. 

Studies of excretion in animals following oral administration of TOCP and tri-para-cresyl phosphate suggest that organophosphate esters found in hydraulic fluids may be extensively absorbed by the gastrointestinal tract (Abou-Donia et al. 1990a, 1990b Kurebayashi et al. 1985 Suwita and Abou-Donia 1990). 

One day after oral administration of single 7.8-mg/kg doses of [methyl-14C]tri-para-cresyl phosphate (in DMSO) to male rats, radioactivity in urine, feces, expired air (as C02), and bile represented approximately... 

A recent series of experiments with cats, chickens, or rats exposed to [uniformly labeled 14C-phenyl]-TOCP shows that a complex array of oxidized and dearylated metabolites are found in excreta and various tissues including the liver, kidney, testis, and brain (Abou-Donia et al. 1990a, 1990b Nomeir and Abou-Donia 1986 Somkuti and Abou-Donia 1990). Cats and chickens, like humans, are sensitive to TOCP-induced delayed neuropathy (Baron 1981). A similar array of oxidized and dearylated derivatives of tri-para-cresyl phosphate (but no cyclic metabolites) were identified by mass spectrometry in the urine and... 

Figure 2-7. Metabolic Pathway for Tri-orfho-Cresyl Phosphate (TOCP)... 

Studies with rats treated orally with triaryl or trialkyl phosphate esters (which may be found in organophosphate ester hydraulic fluids) indicate that these compounds and their metabolites are readily excreted in the urine, bile, feces and, to a limited extent, in expired air (Kurebayashi et al. 1985 Somkuti and Abou-Donia 1990a Suzuki et al. 1984a Yang et al. 1990). Urinary excretion of metabolites appears to be the predominant elimination route in rats for tri-ort/zo-cresyl phosphate and tri-para-cresyl phosphate, but biliary excretion of parent material and metabolites is also important (Kurebayashi et al. 1985 NTP... 

Fecal excretion may gain relative importance as an excretory route for tri-/xrra-cresyl phosphate as doses approach levels of 100 mg/kg (Kurebayashi et al. 1985 NTP 1988). Fecal excretion of tn-m-cresyl phosphate appears to be predominant in rats even at a dose level of 200 mg/kg (NTP 1988). 

Patterns of excretion in rats differed among [14C]labeled tricresyl phosphate isomers administered by gavage at dosage levels ranging from 0.5 to 200 mg/kg (NTP 1988). Radioactivity from tn-ortho-cresy phosphate was excreted within 24 hours predominately in urine at all dosage levels ( 70% of applied doses). Radioactivity from trww-cresyl phosphate was excreted predominately in feces at all dosage levels. 

Organophosphate Ester Hydraulic Fluids. No studies were located regarding excretion in humans after dermal exposure to organophosphate ester hydraulic fluids. However, a human study using the tricresyl phosphate isomer tri-orf/w-cresyl phosphate (TOCP) was located. 

In severe cases, paralysis may also affect the upper limbs. Recovery is usually slow and is not always complete. Tri-ort/20-cresyl phosphate (TOCP), an isomer found in tricresyl phosphate, was the first organophosphate ester linked to OPIDN, being responsible for an epidemic of paralysis in the southeastern United States that led to the name "ginger jake paralysis" (Smith 1930) (see Section 2.4). Current manufacturing processes for organophosphate ester hydraulic fluids are designed to minimize production of this isomer, although it is possible that fluids disposed of in the past may be contaminated. 

Tricresyl phosphate (a complex mixture containing tri-o, Xn-m-, and tri-para-cresyl phosphate that is used in certain hydraulic fluids) and TOCP are demonstrated testicular toxicants in rodents (Carlton et al. 1987 Somkuti et al. 1987a, 1987b). Tricresyl phosphate also has been shown to impair in vivo fertility in rats and mice (Carlton et al. 1987 Chapin et al. 1988a). In addition, tricresyl phosphate-treated female rats displayed vacuolar cytoplasmic alteration of ovarian interstitial cells (Carlton et al. 1987 NTP 1994). Reproductive effects have also been seen after oral exposure to butylated triphenyl phosphate (Latendresse et al. 1994b). 

Organophosphate Ester Hydraulic Fluids. A number of studies have been conducted on organophosphate ester hydraulic fluids because of the well known neurotoxic effects caused by organophosphorus insecticides, organophosphorus nerve gases, and tri-ort/w-cresyl phosphate (TOCP). The following manifestations of acute exposure to organophosphorus compounds have been described ... 

An organophosphate ester commonly used in hydraulic fluids, tricresyl phosphate (TCP), and tri-ortho-cresyl phosphate (TOCP), a possible contaminant of older formulations of TCP, have been shown to alter testicular morphology, testicular function, and reproductive function in rodents after oral exposure (Carlton et al. 1987 Chapin et al. 1988 NTP 1994 Somkuti et al. 1987a, 1987b). 

A mixed isomer preparation of TCP (containing <0.1% tri-ort/zo-cresyl phosphate) produced histological changes in reproductive organs in both sexes of rats and female mice in 13-week and 2-year bioassays (NTP 1994). Ovarian interstitial cell hypertrophy occurred in female mice and female rats exposed to gavage doses of 50-800 mg/kg/day for 13 weeks, in female rats exposed to dietary doses of 65 and 120 ng/kg/day for 13 weeks, and in female rats exposed to dietary doses of 9 or 18 mg/kg/day for 2 years (NTP 1994). Atrophy of the seminiferous tubules occurred in male rats that received gavage doses of 400 and 800 mg/kg/day for 13 weeks and in male rats exposed to dietary doses of 470 and 940 mg/kg/day for 13 weeks (NTP 1994). 

The first commercial trialkyl phosphate esters (TAP) were tricresyl phosphate (TCP) and trixylenyl phosphate (TXP), referred to as "natural" phosphate esters because the cresols and xylenols used as raw materials are derived from petroleum oil or coal tar (Marino and Placek 1994). These products are not commercially significant at present however, at waste disposal sites, contaminants from older product formulations may be encountered, particularly those containing the neurotoxic tri-o/T/io-cresyl phosphate isomer. "Synthetic" phosphate esters are derived from synthetic feedstocks. Specific synthetic reactions have been developed to produce triaryl, trialkyl, and alkyl Aryl esters. The triaryl phosphates are currently... 

One of the main human health concerns about organophosphate esters is the potential for neurotoxicity reactions, in particular a condition known as organophosphate-induced delayed neurotoxicity (OPIDN). Tri-ort/20-cresyl phosphate (TOCP) has been identified as one of the more potent OPIDN neurotoxins in humans, and was formerly a constituent in some organophosphate ester hydraulic fluid products (Marino 1992 Marino and Placek 1994). Production processes now routinely remove virtually all the TOCP. For instance, tricresyl phosphate (TCP) products now typically are manufactured to contain over 98% meta and para isomers and virtually no TOCP (Marino and Placek 1994). Products containing these compounds associated with OPIDN have now entirely disappeared from commercial use, and the vast majority of the industrial organophosphate esters are based on triaryl phosphates with no halogenated components (Marino 1992). At waste disposal sites, however, site contaminants from older product formulations containing the ortho form may be encountered. 

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