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Review Article

Toxicological review and oral risk assessment of terephthalic acid (TPA) and its esters: A category approach

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Pages 28-67 | Received 25 Jul 2011, Accepted 09 Sep 2011, Published online: 04 Nov 2011
 

Abstract

Polyethylene terephthalate, a copolymer of terephthalic acid (TPA) or dimethyl terephthalate (DMT) with ethylene glycol, has food, beverage, and drinking water contact applications. Di-2-ethylhexyl terephthalate (DEHT) is a plasticizer in food and drinking water contact materials. Oral reference doses (RfDs) and total allowable concentrations (TACs) in drinking water were derived for TPA, DMT, and DEHT. Category RfD and TAC levels were also established for nine C1–C8 terephthalate esters. The mode of action of TPA, and of DMT, which is metabolized to TPA, involves urinary acidosis, altered electrolyte elimination and hypercalciuria, urinary supersaturation with calcium terephthalate or calcium hydrogen terephthalate, and crystallization into bladder calculi. Weanling rats were more sensitive to calculus formation than dams. Calculi-induced irritation led to bladder hyperplasia and tumors in rats fed 1000 mg/kg-day TPA. The lack of effects at 142 mg/kg-day supports a threshold for urine saturation with calcium terephthalate, a key event for calculus formation. Chronic dietary DMT exposure in rodents caused kidney inflammation, but not calculi. Chronic dietary DEHT exposure caused general toxicity unrelated to calculi, although urine pH was reduced suggesting the TPA metabolite was biologically-active, but of insufficient concentration to induce calculi. Respective oral reference doses of 0.5, 0.5, and 0.2 mg/kg-day and total allowable drinking water concentrations of 3, 3, and 1 mg/L were derived for TPA, DMT, and DEHT. An oral RfD of 0.2 mg/kg-day for the terephthalate category chemicals corresponded to a drinking water TAC of 1 mg/L.

Acknowledgments

The authors gratefully acknowledge the assistance of the following members of the NSF Health Advisory Board (Edward Ohanian, Michael Dourson, David Blakey, Steven Bursian, Craig Farr, Robert Hinderer, Ernest McConnell, Jennifer Orme-Zavaleta, and Calvin Willhite) who served on a voluntary (uncompensated) basis to peer-review unpublished risk assessment documents on TPA, DMT, and DEHT that became a part of this review. The authors gratefully acknowledge the assistance of the staff of Eastman Chemical Company who provided copies of unpublished documents.

Declaration of interest

This review was conducted by NSF International under a fixed fee contract for the Eastman Chemical Company. NSF International is a not-for-profit, non-governmental organization that develops national standards and provides third-party conformity assessments representing the interests of stakeholder groups that include industry, the regulatory community, and the public. NSF International requires drinking water evaluation levels (TACs) for the terephthalates in the event that they are detected, as a result of their use as monomers or plasticizers, in extraction testing of materials or components under CitationNSF/ANSI Standard 61 (2010) or the several NSF/ANSI drinking water treatment unit standards. The Eastman Chemical Company is an international corporation that produces both TPA and DMT for use as intermediates in the production of polyester plastics, and produces and markets DEHT as Eastman 168™ and DBT as Eastman™ DBT for use as plasticizers. The sponsor’s input to the conduct of the review was restricted to providing the unpublished documents and one of the Study Directors employed by the company responding to a clarifying question on a study protocol. The content and writing of the review are the exclusive professional responsibility of the authors identified on the cover page. The views expressed are not necessarily those of the Eastman Chemical Company nor do they represent the individual or collective views of the members of the NSF Health Advisory Board.

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