Toxicological Evaluation and Limit Values for Nonylphenol, Nonylphenol Ethoxylates, Tricresyl, Phosphates and Benzoic Acid 6. SummaryDescription Tricresyl phosphate (TCP) is the common name for mixtures of 10 different isomers, where the ortho-, meta- and para-cresyl groups can vary in number from zero to three. Industrial-grade tricresyl phosphate contains predominately the meta- and para-isomers and modern mixtures contain less than 1% of the ortho-isomer. Irrespective of the isomer composition, TCP’s used for industrial purposes are generally high boiling, inflammable liquids with a wide variety of uses. Environment TCP does not occur naturally in the environment but due to its many uses it can be found in air at concentrations up to 70 ng/m3, in water at levels of about 4 ng/l, and in soil at contaminated sites up to 4 mg/kg have been found. In sewage sludge up to 12 mg/kg dry matter have been detected. TCP has also been found in fish and shellfish in concentrations up to 40 ng/g. TCP released into water is readily adsorbed on to sediment particles, and little or none remains in solution. TCP is relatively immobile in soil as it adsorbs strongly to soil and is not expected to leach. Biodegradation is the dominant degradation process in aerobic waters and in soil. The degradation pathway most probably involves stepwise enzymatic hydrolysis to orthophosphate and phenolic moieties; the phenol would then be expected to undergo further degradation. 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. Toxicokinetics TCP’s are readily absorbed from the intestine of rats after oral dosing. Absorption after dermal application varies greatly depending on species with poor absorption in the dog, better absorption in man, and even better absorption in cats. After absorption it is distributed to the various organs with the highest concentrations in liver, blood, kidney and lung. o- and p-TCP are metabolised in essentially the same way to hydroxybenzoic acid. For o-TCP there is a "bypass", as a ring structure can be formed after the first cresyl moiety has been split off. This results in the formation of saligenin cyclic o-tolyl phosphate, a substance, which is at least five times more neurotoxic that o-TCP. No studies on the metabolism of m-TCP have been found. For the three isomers o-TCP, m-TCP-, and p-TCP up to 90-100% of an oral dose was excreted in urine and faeces within three days. At a dose of 2 mg/kg b.w. elimination was predominantly in urine, whereas at the dose of 200 mg/kg b.w. elimination was predominantly via faeces. Human toxicity Neurotoxicity and especially organophosphorous induced delayed neurotoxicity (OPIDN) is the critical effect of o-TCP in man. A single dose of 0.15 g o-TCP (2 mg/kg b.w.) is stated to produce toxic symptoms (type not specified) in man and severe neurological disturbance (OPIDN) developed after a single dose of 0.5-0.7 g o-TCP (7-10 mg o-TCP/kg b.w.). After short term ingestion of 5-10 mg TCP/kg b.w./day severe neurotoxic symptoms and/or OPIDN were seen. The TCP was stated not to contain o-TCP. After multiple ingestion of an estimated dose of 47.5-76 mg TCP containing 20% o-TCP/day, mild nausea and weakness were seen in 85 individuals and OPIDN in 91 persons. After long term ingestion of TCP often of unknown o-isomer content several reports of OPIDN have been described involving up to 50,000 people. Animal toxicity A summary of all short and long term animal studies is given in tables as an appendix. oral, short term TCP and the pure tricresyl esters have low acute lethal toxicity, however, large species differences exist, apparently with chicken/hens being the most sensitive species and rats and mice being the least sensitive species. After a single oral dose to hens, TCP’s not containing an o-cresyl ring are without capability of inducing OPIDN. If one o-cresyl ring is present, the substance is ten times more potent than o-TCP. Substances with two o-cresyl rings are 5 times more potent that o-TCP in inducing OPIDN. After a single oral dose of 100 mg o-TCP/kg b.w. cats, dogs, cows, sheep and chicken are susceptible to OPIDN-related paralysis (the critical effect of o-TCP in man), whereas rats and mice are less susceptible to the ataxia but susceptible to the pathological changes. A number of studies are available to assess the short term oral toxicity of TCP isomers. However, only one can be used to set a clear NOAEL. In that study, a NOAEL of 0.875% TPC in the diet applied to mice, as piloerection, tremors, and diarrhoea were observed at higher doses. oral, long term In 90 day studies using hens, ataxia and neuropathological changes were found at oral doses of 5 to 20 mg o-TCP/kg b.w./day. These are considered the critical effects of o-TCP. The NOAEL from these studies is 2.5 mg/kg b.w./day. In long term studies, the chronic toxicity of TCP-isomers with less than 0.1% o-TCP has been described. The best are the two-year studies, which also provide the lowest NOAELs. In the 2-year rat study, a NOAEL of 150 ppm in the diet equal to 7 mg/kg b.w./day was found based on the occurrence of ovarian interstitial hyperplasia in females at the higher doses. No signs of neurotoxicity were seen in this study. In the 2-year mouse study, a NOAEL of 60 ppm in the diet equal to 7 mg TCP/kg b.w./day can be set based on the occurrence of a significant increase in early signs of liver toxicity (clear cell foci, fatty change, and ceroid pigmentation) at the higher doses. No signs of neurotoxicity were seen in this study. Further good quality studies are the four 13 week studies in rats and mice, please refer to appendix. Reproductive and developmental effects A dose of 100 mg o-TPC/kg b.w./day caused pathological changes in rooster testes (disorganisation of the seminiferous epithelium) and affected the fertility of male rats in a one-generation study. In a teratogenicity study o-TCP did not show teratogenic effects in rats at doses up to 175 mg/kg b.w./day. In male rats and male mice given TCP by gavage for 13 weeks, the NOAEL for reproductive effects (semen parameters) was below 50 mg/kg b.w./day. In a mouse continuous breeding study a NOAEL for effects on fertility (reduced number of pups) was set at 62.5 mg/kg b.w./day. Mutagenic and genotoxic effects TCP has been tested in a number of in vitro and one in vivo genotoxicity test without showing genotoxic potential. Carcinogenicity TCP has been tested for carcinogenicity in two-year rat and mouse feeding studies without finding evidence for carcinogenicity.
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