Tri-orthocresyl phosphate

Freudenthal RI, Rausch L, Gerhart JM. 1993. Subchronic Neurotoxicity of Oil formulations containing either Tricresyl Phosphate or Tri-Orthocresyl Phosphate. Journal of the American College of Toxicology 12(4) 409-416. 

The 2003 ACGIH threshold limit valuetime-weighted average (TLV-TWA) for tri-orthocresyl phosphate is O.lmg/m with a notation for skin absorption. 

A few other organophosphates cause this effect, notably tri-orthocresyl phosphate, as described in Chapter 10. It seems to be due to the interaction between the organophosphate and a protein, which may be an enzyme, in the peripheral nerves. The protein seems to have a critical function and the binding to it is irreversible, causing the nerve to degenerate. The result is paralysis in the legs. The cause of this effect does not seem to be related to the interaction with acetylcholinesterase. The effect appears one or two weeks after exposure to the organophosphate. 

When the federal authorities became aware of the problem, which was growing to epidemic proportions, samples of the jake used by affected victims were collected and analysed by the Treasury Department s Bureau of Industrial Alcohol. The chemists soon found that a substance identified as tri-orthocresyl phosphate (TOCP) was present to the extent of about 2 per cent in the adulterated samples. In experiments the adulterated samples were found to produce similar effects when given to rabbits. Calves that had been fed the adulterated jake for medicinal reasons also developed the syndrome but, curiously, monkeys and dogs did not. Eventually it was discovered that monkeys and dogs were not susceptible, unlike rabbits, due to differences in the absorption of the TOCP from the digestive system. It was suggested that differences in the way TOCP is broken down in the different species may also account for the differences in susceptibihty between the types of animals (see box). 

Why had TOCP been added to the ginger extract Tri-orthocresyl phosphate was readily available as it was a constituent of lacquers and varnishes, and was extensively used in the leather industry. It was seen as an ideal solvent to use in the preparation of jake because it was odourless, tasteless, colourless, and cheap. It was also miscible with the resinous extract of ginger and soluble in alcohol. Unfortunately, it was very toxic to humans, a fact that appears not to have been known. At the time there was no law requiring food additives or medicinal products to be tested for safety, and thus the suppliers had broken the law, not by supplying a contaminated and unsafe product, but by selling a product that was not as described in the US pharmacopoeia. In June 1930 twenty-one men and six New York corporations were indicted for conspiracy to violate federal laws. 

The oil was in fact for industrial use, produced to withstand the high temperatures in turbo jet engines, the tri-orthocresyl phosphate being a specific additive. Due to a change in engine design the oil had been discarded, and someone had taken the fateful decision to sell it as cooking oil. At least 2,000 people suffered toxic effects from the contaminated oil, but thankfully there were no deaths. In this case the majority suffered only relatively mild and probably reversible paralysis. 

Gasoline is a mixture of aliphatic straight and branched chains and aromatic hydrocarbons with toxicity attributable to toluene, xylene and perhaps hexane and additives including methyl ter butyl ether and tri-orthocresyl phosphate. ... 

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