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Introduction 1. Terephthalic acid (TPA) is used as a starting material in the manufacture of polyethylene terephthalate (PET). PET has been used to coat the internal surface of food cans. 2. The European Commission's Scientific Committee for Food (SCF) had reviewed the toxicology of TPA in the 80's and set a temporary Tolerable Daly Intake of 0.125 mg/kg bw/day, which was based on 3-month and 2-year oral studies in rats (1). The TDI was temporary pending the submission of full reports of these studies. The major finding in the long-term study with TPA was the occurrence of malignant and benign tumours of the urinary tract at high doses. It was proposed that these tumours were likely to arise from urothial hyperplasia associated with bladder stone formation rather than a genotoxic mechanism. 3. In October 2000, the Committee on Toxicity (COT) considered the health effects of TPA in the context of a survey on the migration of this compound from can coatings into food (2). The COT concluded that the concentrations of TPA that had been determined in foods analysed in the survey were not of concern for public health on the basis of the then available information. However, the COT noted that the toxicity studies on TPA were not carried out to current standards. The COT requested that, in the light of the urinary tumours occurring in rats fed the highest dietary concentration of TPA in long-term studies, the view of the COM be sought on the potential in vivo genotoxicity of this compound. In Vitro mutagenicity data 4. Members noted that TPA contained no structural alerts for mutagenicity and was practically insoluble in water. The Committee agreed that the formation of oxalate based insoluble crystals in the bladder and subsequent chronic tissue damage was a plausible non-genotoxic mechanism for the induction of bladder tumours with this compound. 5. The Committee noted the availability of a number of reports of investigations of the in vitro mutagenicity of TPA in bacteria using Salmonella typhimurium strains (3,4,5). These studies were poorly reported and some used inadequate protocols or non-standard methods. However, TPA was consistently negative in these investigations. In one report (5), a range of TPA concentrations of up to 10.0 mg/plate was used in the presence and absence of an activation system with no evidence of toxicity in the bacteria. Although TPA was found to be negative, it was tested in Salmonella typhimurium strains TA98, TA100, TA1535 and TA1537 only. In other studies in Salmonella typhimurium strains which tested the activity of TPA at single (4) or multiple dose levels (3), insufficient details were provided to draw any conclusions. Overall, the Committee accepted that the evidence from the studies using bacteria suggests that TPA is not mutagenic in a limited number of Salmonella typhimurium strains. 6. The availability of an in vitro cytogenetics test in lung fibroblasts was also noted by the Committee (6). Although TPA was found to be negative when tested at a concentration of 2 mg/l using an exposure period of 48 hours, the study did not address the influence of an exogenous metabolic activation system. In addition, the effect of shorter exposure periods were not investigated. 7. The Committee was aware that TPA may be used in a large number of food contact applications and agreed that an adequately conducted in-vitro cytogenetics test in mammalian cells was required to bring the in-vitro mutagenicity data on this compound up to the recommended level for a compound with widespread exposure. In Vivo mutagenicity 8. Members reviewed a recent in-vivo micronucleus assay conducted with TPA in ICR mice (7). The test was conducted to current standards but was not supported by any toxicokinetic data and gave no direct measurement of exposure to the bone marrow. Signs of toxicity were reported which suggested that the test material had been absorbed into the systemic circulation and thus dose selection had been adequate. 9. The Committee agreed that this study had given negative results but this did not provide adequate reassurance regarding the mutagenic potential of TPA in the absence of an adequate in-vitro package of data. Conclusions 10. The Committee noted that TPA is used widely in food contact applications and agreed the following conclusions:
REFERENCES 1. Commission of The European Communities, Directorate General III (2000) Synoptic Document: provisional lists of monomers and additives notified to the European Commission as substances which may be used in the manufacture of plastics intended to come into contact with foodstuffs. Updated to 10 January 2000. 2. Food Surveillance Information Sheet No. 7/00. (October 2000). Chemical Migration From Can Coatings into Food - Terephthalic and Isophthalic Acids. 3. Brooks AL, Seiler FA, Hanson RL, Henderson RF. (1989) In vitro genotoxicity of dyes present in colored smoke munitions. Environ Mol Mutagen 13, 304-313. 4. Florin I, Rutberg L, Curvall M, Enzell CR (1980) Screening of tobacco smoke constituents for mutagenicity using the Ames' test. Toxicology 15, 219-232 5. Zeiger E, Haworth S, Mortelmans K, Speck W. (1985). Mutagenicity testing of di(2-ethylhexyl)phthalate and related chemicals in Salmonella. Environmental Mutagen 7, 213-232. 6. Ishidate M, Harnois MC, Safini T. (1988) A comparative analysis of data on the clastogenicity of 951 chemical substances tested in mammalian cell cultures. Mutat Res 195, 151-213. 7. Gudi, R. and Krsmanovic, L. (2001). Mammalian Erythrocyte Micronucleus Test. BioReliance Lab Study Number AA41MJ, 123.BTL.
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