PHIL

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PHTHALATE ESTERS IN MEDICAL DEVICES

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Questions and Answers from the industry Phthalate Ester Panel

A. Compound Use and Applications

1) What are phthalate esters and how are they used?

Phthalate esters are liquids, very much like vegetables oils, which are added to a hard plastic called polyvinyl chloride (PVC or vinyl). The liquid phthalate esters act as a softener causing the plastic to become flexible. For example, rigid vinyl with no plasticizer could be a pipe under a sink or the vinyl siding of a house. When plasticizers are added, a wide range of products can be created such as toys, wire and cable, flooring and shower curtains. Vinyl is one of the most popular plastics in the world as a result of its durability, low cost and versatility.

2) Why are phthalate esters used in medical devices?

When selecting material, medical device manufacturers consider many different factors, such as, design flexibility, cost-effectiveness, finished product safety, quality and performance. Phthalate esters allow vinyl products to meet all of these requirements. These unique plasticizers make vinyl medical devices affordable, durable, weldable, clear and gas permeable. These compounds have also been extensively tested from a toxicological and environmental viewpoint. Plasticized vinyl offers medical device manufacturers, hospitals, and doctors a wide range of durable, flexible and affordable products.

3) What types of medical devices contain phthalate esters?

Flexible vinyl medical devices fall into three basic categories: containers, protective tubing/molding and gloves. Vinyl medical containers include flexible bags used for intravenous or nutritional fluids, solutions, drugs or anticoagulants. Flexible containers are also used to collect/store blood and plasma, and urine. Examples of flexible tubing include blood circuit tubes, infusers, catheters and endotracheal tubes. Phthalate esters give vinyl gloves the strength and durability to resist tears, protecting both doctors and patients. Flexible vinyl gloves also prevent the spread of infectious disease and germs, a core concern for hospitals and other care facilities. All of these medical products help with day-to-day hospital management and saving lives.

4) How is plasticized PVC different from other plastics used for medical devices?

Flexible vinyl is different from other plastics due to its fabrication process. Most other plastics are single grade materials which don't vary appreciably in flexibility, hardness or other properties. The plastic supplied to the processor can be molded or shaped, but the material's characteristics cannot be changed. In contrast, vinyl may start as a rigid plastic, but adding phthalate esters during product manufacture will actually soften the material to its desired level of flexibility. This means devices, like tracheal tubing, have the flexibility to safely navigate a patient's airway or a blood bag has collapsibility to prevent life threatening pockets of air from entering the bloodstream. Quite simply, phthalate esters provide an incredible versatility to vinyl medical devices.

5) Are phthalate esters safe when used properly in medical products?

Yes. Based on the best evidence to date, the Panel strongly believes phthalates are safe when properly used in vinyl medical products and pose no hazard to patients. Producers of phthalate esters are committed to manufacturing safe products. For 40 years these compounds have been researched and tested so they can be used safely. Producers of phthalates are committed to ongoing research and testing of these compounds and will work closely with FDA and other government agencies so that these products can continue to be used safely.

6) Do phthalate esters leach from flexible PVC bags or containers? Does this include blood?

We are aware that some flexible vinyl medical devices allow phthalate esters to enter a patient's blood stream. For example, vinyl bags have been used to store the blood supply in this country for more than 40 years. It is well known that whole blood absorbs small amounts of plasticizer from the bag. Probably the most common potential for exposure occurs when patients receive fluids, nutrients, whole blood or blood components intravenously from flexible vinyl bags or containers. This possibility occurs because small amounts of the plasticizer may be absorbed by the fluids contained in the bags during the storage and administration process. The amount of plasticizer that a fluid absorbs depends on the fluid properties, storage time, storage temperature and type of plasticizer used. However, phthalates are quickly metabolized and eliminated from the human body, including patients receiving dialysis for kidney disease. Because phthalate esters have been researched, tested and safely used for more than 40 years without any confirmed reports of adverse health effects in people, producers of the plasticizers strongly believe that they are safe when properly used in vinyl medical products, including blood bags and other storage applications and pose no health hazard to patients.

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B. Health and Safety Research

1) Do phthalate esters cause cancer in humans?

No. The producers of phthalate esters strongly believe there is no validated scientific evidence to indicate that phthalate esters pose a cancer hazard for humans. Some phthalates have shown the potential to induce liver or kidney tumors when fed to laboratory animals at high doses for extended periods of time. A wealth of information shows that rodents are uniquely sensitive to phthalate esters and research results for these compounds cannot be automatically extrapolated to humans. For example, liver tumors seen in rodents are not seen in other mammals more closely related to humans (i.e., monkeys). Humans and other species respond very differently to the ingestion of the material. In short, extremely high quantities of phthalate esters may pose health problems for rodents, but there is no validated scientific evidence indicating the compounds pose any health risk for humans at realistic exposure levels. Based on the best evidence to date, we strongly believe phthalates are safe when properly used in vinyl products and pose no hazard to patients.

2) What do independent scientists say about a possible cancer hazard?

Recent reviews by independent scientists have concluded that DEHP is not likely to pose a cancer risk to humans [1]. DEHP is what is known as a "peroxisome proliferator," meaning that it causes a component in the liver cells of mice and rats to multiply. If the rats or mice are exposed to large amounts of a peroxisome proliferator for a long period, the liver cell changes eventually lead to tumor formation. Peroxisome proliferators do not act in humans the same way as in rodents. A paper published recently in the Journal of Regulatory Toxicology and Pharmacology summarized an international workshop organized by the International Life Sciences Institute (ILSI) in December 1995, to consider specifically whether peroxisome proliferating compounds pose a liver cancer hazard to humans [2]. The symposium included approximately 100 scientists from government agencies, academia and industry, including leading researchers in the field from the United States and Europe. The paper states, "The conclusion was reached that it is unlikely that peroxisome proliferators are carcinogenic to humans under anticipated conditions and levels of exposure, although their carcinogenic potential cannot be ruled out under extreme conditions of exposure." [3]. A separate section of the article authored by an EPA scientist states, "No evidence exists to suggest that these agents [peroxisome proliferators] are carcinogenic in the human liver. . . . [I]t would appear that it is highly unlikely that these peroxisome proliferators/rodent hepatocarcinogens are human liver carcinogens at expected levels of human exposure . . . ." [4]

3) What do government agencies say about a possible cancer hazard?

Both Canada and the Commission of the European Communities have concluded that DEHP should not be regulated as a human carcinogen. Health Canada has classified DEHP as "Unlikely to be Carcinogenic to Humans." [5]. The official decision of the Commission of the European Communities states that DEHP, "shall not be classified or labeled as a carcinogenic or an irritant substance." [6]. The World Health Organization (WHO) Environmental Health Criteria document for DEHP concludes: "Currently there is not sufficient evidence to suggest that DEHP is a potential human carcinogen." [7].

4) What about EPA's cancer classification?

The U.S. Environmental Protection Agency (EPA) has not formally reevaluated the carcinogenicity classification of DEHP it made more than 10 years ago ("probable human carcinogen"), but it has recognized in various forums that DEHP-caused tumors in rodents have questionable relevance to humans. For example, in its evaluation of another compound, EPA stated: "As human liver cells are refractory to induction of peroxisome proliferation, the relevance of the liver tumors in rodents induced by peroxisome proliferators appears to be questionable in humans." [8]. Similarly, in a letter to the Department of Health and Human Services National Toxicology Program, EPA stated, "diethylhexylphthalate [DEHP] may produce tumors by processes not relevant to humans." [9]. Also as already noted, an EPA scientist at the 1995 symposium on peroxisome proliferators concluded that it is "highly unlikely that these peroxisome proliferators/rodent hepatocarcinogens are human liver carcinogens at expected levels of human exposure."

5) Are dialysis patients, or those in critical care units, at higher risk from PVC medical devices because of long-term exposure to phthalates?

Research indicates that exposure to phthalate esters through medical devices does not pose a human health risk to dialysis patients. The primary phthalate used in the medical arena, di (2-ethylhexyl) phthalate (DEHP), has been used for more than 40 years without any confirmed reports of adverse health effects in patients. In fact, an independent 1996 risk assessment of DEHP, which reviewed more than 500 studies, including worst case exposure scenarios, concluded that the threat of cancer in humans is extremely unlikely, even in patients exposed to maximum levels of DEHP .

6) Do phthalate esters cause reproductive or developmental problems in humans?

Long-term, high dose level studies with DEHP in primates did not produce reproductive organ damage. Studies in rats and mice have shown that if DEHP is given in high doses during certain phases of pregnancy, adverse effects can occur. The observation of developmental or reproductive toxicity in one species does not mean that the same or related toxicities will appear in other species. For example, the same type of study in hamsters does not show these effects and when testing with intravenously-administered DEHP is performed in pregnant rabbits, no adverse effects are produced in the embryo or developing offspring. There also is a great deal of evidence that indicates the effects seen in laboratory animals will not be seen in humans. This information has been summarized and provided to government regulators, and incorporated into manufacturing and production specifications for flexible vinyl products.

7) What is the endocrine disruption hypothesis?

The endocrine disruption hypothesis asserts that exposure to small amounts of some chemicals in the environment may interfere with the endocrine system and lead to harmful effects in humans or wildlife.

8) Why are phthalates frequently listed as potential endocrine disruptors?

Recently, allegations have been made that phthalates, including DEHP, mimic estrogen in the body. The Phthalate Esters Panel has tested phthalate esters for possible estrogenic activity and has shown that DEHP does not act like estrogen. In addition, phthalate esters have been used for more than 40 years and there is no validated scientific evidence that these compounds cause adverse human health effects. Based on the effects observed in certain animal studies of phthalate esters, some phthalates have been included on lists of endocrine disruptors. However, DEHP has been tested for possible estrogenic activity and the results showed DEHP does not act like estrogen.

9) How were phthalates tested for estrogenic properties?

Testing methods included two assays(tests) using female rats to determine: the response of the uterus to phthalate esters (the uterotrophic assay); and the ability of the compound to mimic naturally occurring estrogen in inducing the estrous cycle (the vaginal epithelial cell cornification assay).
In each case, the activities of phthalate esters were compared to the activity of estradiol (the natural estrogen). Research showed that none of the phthalate esters tested elicited estrogenic activity as determined by the monitoring of uterine wet weight and vaginal cell cornification. Additionally, phthalate esters and their metabolic breakdown products were screened in cell culture systems using the human estrogen receptor. DEHP showed little or no estrogen-receptor activity in cell culture tests at high concentrations. In addition, when tested in animals, no estrogenic effects were seen. This study was published in December 1998 in Toxicological Sciences, a peer reviewed journal [10].

What is industry doing to address concerns expressed about phthalates?

Industry is moving ahead aggressively with ongoing research and the design of new research studies to examine issues such as endocrine disruption, while ensuring the broad distribution of the results. Specifically, the Phthalate Esters Panel continually conducts research on phthalate esters and monitors other new scientific research as it emerges. In addition, we work with international organizations to assist in providing appropriate standardized testing method(s) for measuring potential exposure to phthalates. The producers of phthalate esters are committed to continued research and testing so these compounds can continue to be safely used in vinyl products, including medical devices.

11) What is the Phthalate Esters Panel?

The Chemical Manufacturers Association Phthalate Esters Panel was chartered in 1973 to represent producers of phthalate esters in matters of safety, health and environmental issues relating to the manufacture and use of phthalate esters. The Panel also conducts extensive testing and research to evaluate this class of compounds.

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References:

[1] Lake, B.G. (1995). Mechanisms of Hepatocarcinogenicity of Peroxisome-Proliferating Drugs and Chemicals. Ann. Rev. Pharmacol. Toxicol. 35:483-507; Huber, W.W., Grasl-Kraupp, B., and Schulte-Herman, R. (1996). Hepatocarcinogenic Potential of Di(2-ethylhexyl) Phthalate in Rodents and Its Implications on Human Risk. Crit. Rev. Toxicol. 26:365-481. Additional information is provided in an overview document prepared by the Chemical Manufacturers Association Phthalate Esters Panel entitled, "THE CURRENT RESEARCH INDICATES THAT DEHP IN VINYL DOES NOT POSE A HUMAN CANCER HAZARD," (February 19, 1999).
[2] Cattley, R.C., DeLuca, J., Elcombe, C., et al. (1998). Do Peroxisome Proliferating Compounds Pose a Hepatocarcinogenic Hazard to Humans? Reg. Toxicol. Pharmacol. 27:47-60.
[3] Id. at 57.
[4] Id. at 55-56.
[5] Health Canada (undated), Priority Substances List Assessment Report: Bis(2-ethylhexyl) Phthalate, 26.
[6] Commission Decision of 25 July 1990 on the classification and labelling of Di(2-ethylhexyl)phthalate in accordance with Article 23 of Council Directive 67/548/EEC, Official Journal of the European Communities No. L 222/49 (Aug. 17, 1990).
[7] WHO (1992). Environmental Health Criteria 131: Diethylhexyl Phthalate. International Programme on Chemical Safety, page 18.
[8] 60 Fed. Reg. 39132 (Aug. 1, 1995).
[9] Letter from Victor Kimm, Deputy Director, OPPTS, and William Farland, Director, OHEA, ORD, to Kenneth Olden, Director, NTP (June 9, 1992).
[10] Critical Reviews in Toxicology 26:368-371

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