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Br J Ind Med. 1960 July; 17(3): 190–200.
PMCID: PMC1039179

A Study on the Acute Toxicity of the Tri-aryl Phosphates Used as Plasticizers


Paralysis in man and the domestic fowl caused by “ToCP” (tri-cresyl phosphate, tri-tolyl phosphate or TTP) is reviewed, and the search for a non-toxic plasticizer derived either from TTP or tri-xylenyl phosphate (tri-dimethylphenyl phosphate or TXP) is described. It had been previously shown that the ortho-tolyl esters are toxic but we found that their removal does not make the mixture non-toxic. The meta- and para-tolyl esters were known to be free from toxic effects and the 2: 4 and 2: 5 dimethylphenyl esters were equally shown to be non-toxic except in massive doses. We confirmed that the tri-ortho-ethylphenyl ester was non-toxic, but found the mono- and di-ortho-ethylphenyl phosphates to be highly toxic. We showed that TTP made from phenols with all the ortho-cresol and ortho-ethylphenol removed is non-toxic.

With TXP, however, elimination of all ortho-cresol and ortho-ethylphenol from the raw materials does not result in a non-toxic plasticizer. Tri-ortho-n-propylphenyl phosphate was shown to non-toxic but esters containing one or two ortho-propylphenyl groups are toxic.

The toxicity of the ortho-tolyl, ortho-ethylphenyl and ortho-propylphenyl groups is much reduced in the presence of the 3: 5-dimethylphenyl group. This influence is greatest in mono-ortho-propylphenyl-di-3: 5-dimethylphenyl phosphate which is non-toxic in five consecutive daily doses of 500 mg./kg. body weight.

The removal of all ortho-cresol, ortho-ethylphenol and ortho-propylphenol from the raw material results in a non-toxic product which we termed non-toxic plasticizer “NTP”. This has been fed in various doses to a variety of mammals and a large number of chickens in short term tests without toxic effects.

Our experiments showed that tri-meta-ethylphenyl phosphate is non-toxic but tri-para-ethylphenyl phosphate is highly toxic. The mixture from which NTP is made contains 10% of para-ethylphenol. Based on chemical statistics the tri-para-ethylphenyl ester can be present only in minute quantities, and we have shown that esters containing one or two para-ethylphenyl groups are non-toxic. An ester with a methyl group in the ortho, and an ethyl group in the para position in the same benzene nucleus (tri-2-methyl-4-ethylphenyl phosphate) we showed, surprisingly, to be non-toxic.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • ALDRIDGE WN. Tricresyl phosphates and cholinesterase. Biochem J. 1954 Feb;56(2):185–189. [PubMed]
  • BARNES JM, DENZ FA. Experimental demyelination with organo-phosphorus compounds. J Pathol Bacteriol. 1953 Apr;65(2):597–605. [PubMed]
  • CAVANAGH JB. The toxic effects of triortho-cresyl phosphate on the nervous system; an experimental study in hens. J Neurol Neurosurg Psychiatry. 1954 Aug;17(3):163–172. [PMC free article] [PubMed]
  • CLOUGH M, COCK AG. Variability of inbred and incross chickens. Nature. 1957 May 18;179(4568):1030–1031. [PubMed]
  • EARL CJ, THOMPSON RHS. Cholinesterase levels in the nervous system in tri-ortho-cresyl phosphate poisoning. Br J Pharmacol Chemother. 1952 Dec;7(4):685–694. [PubMed]
  • HENSCHLER D. Die Trikresylphosphatvergiftung; experimentelle Klärung von Problemen der Atiologie und Pathogenese. Klin Wochenschr. 1958 Jul 15;36(14):663–674. [PubMed]
  • HENSCHLER D, BAYER HH. Toxikologische Untersuchungen über Triphenylphosphat, Trixylenylphosphate und Triarylphosphate aus Mischungen homologer Phenole. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol. 1958;233(6):512–517. [PubMed]
  • HINE CH, DUNLAP MK, RICE EG, COURSEY MM, GROSS RM, ANDERSON HH. The neurotoxicity and anticholinesterase properties of some substituted phenyl phosphates. J Pharmacol Exp Ther. 1956 Feb;116(2):227–236. [PubMed]
  • POIRIER LJ, AYOTTE RA, GAUTHIER C. Modification of the Marchi technic. Stain Technol. 1954 Mar;29(2):71–75. [PubMed]
  • SMITH HV, SPALDING JM. Outbreak of paralysis in Morocco due to ortho-cresyl phosphate poisoning. Lancet. 1959 Dec 5;2(7110):1019–1021. [PubMed]
  • SUSSER M, STEIN Z. An outbreak of tri-ortho-cresyl phosphate (T.O.C.P.) poisoning in Durban. Br J Ind Med. 1957 Apr;14(2):111–120. [PMC free article] [PubMed]

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