The plasticizers used to render PVC flexible constitute about a third of the vinyl compound by weight and have a significant effect on overall properties and performance. The most widely used plasticizer in medical applications, DEHP (di(2-ethylhexyl) phthalate), has been shown to engender biological activity when metabolized in rodents (though not in humans). As a result, there is pressure on medical manufacturers to identify the best alternative plasticizers from a defensive public perception standpoint.

Fig. 1 – NOAEL* of Two Orthophthalates Compared with Alternative Plasticizers. (Credit: EU Health & Consumer Protection, SCENIHR)

While DEHP has been the preferred plasticizer for medical-grade PVC because of an outstanding cost-performance profile, a few alternative plasticizers under consideration are promising because they most closely approach the performance of DEHP, have the least potential for regulation, or are especially cost-efficient. Others may prove valuable for meeting special end-use requirements.

In reviewing the alternatives to DEHP-plasticized PVC in this article, the author draws upon the company’s history as a custom compounder of medical-grade PVC, a diversified manufacturer of plasticizers, and a formulator using plasticizers produced internally and those purchased from other suppliers.

Types of Plasticizers for Use with Medical-Grade PVC

Fig. 2 – Percentages of Plasticizer in 75 Shore A PVC Compound.
There are multiple families of plasticizers with potential for medical PVC applications. Most fall into the category of monomeric plasticizers. These have molecular weights ranging from roughly 400 to 600 grams per mole. By comparison, polymeric plasticizers have molecular weights that are typically four times as great.

Fig. 3 – Plasticizer Solubility Weight Change of 75 Shore A PVC After 24 Hours in 2% Salt Solution.
The families classified as monomeric plasticizers are quite diverse:

Fig. 4 – Gamma Stability Change in Yellowness Index of 75 Shore A PVC Compound After 5 Megarads.

Phthalate esters: These include two subgroups based on molecular structure:

  1. Orthophthalates include DEHP, DINP (diisononyl phthalate), DPHP (bis(2-propylheptyl), and DIDP (diisodecyl phthalate). The main charge against DEHP is based on studies of how it is metabolized in the livers of rodents. Hydrolysis of DEHP yields a stable mono-ester product linked to biological activity, in this case called peroxisome proliferation. There are no such interactions known to occur in humans. All toxicological data on DEHP is based on rodent studies.
  2. Terephthalates like DOTP (di(2ethylhexyl) terephthalate, also known as DEHT) behave very differently in rodent livers. The mono-ester products of hydrolysis are not stable and are quickly reduced to starting materials not known to be biologically active. Among other terephthalate-based materials is the polymer polyethylene terephthalate (PET), used worldwide in water bottles.

Terephthalates are not defined as “phthalates” in government documents on phthalate toxicology. A review of phthalate substitutes by the U.S. Consumer Product Safety Commission (CPSC), for example, notes that because DEHT (DOTP) has “phthalate” as part of its name, it can be confused with orthophthalates, though it is not actually classed as such and “is not subject to specific U.S. EPA or CPSC regulations aimed at these compounds.” (Review of Exposure and Toxicity Data for Phthalate Substitutes, by Michael A. Babich, PhD, Jan. 15, 2010, p. 57.)

Fig. 5 – Per-Pound Cost Difference Versus DEHP-Plasticized PVC Compound.

Trimellitate esters: A common example is TOTM (trioctyltrimellitate). Although its molecule is much smaller than those of polymeric plasticizers, it is larger in comparison with other monomeric plasticizers and is less readily soluble in water.

Aliphatic esters: Common examples include adipates such as DEHA (di(2ethylhexyl) adipate), also known as DOA; sebacates such as DOS (dioctyl sebacate); and benzoates (oddly classified as aliphatics, because they are terminated with benzene rings). They are less compatible with PVC and tend to exude at soft durometers, resulting in surface tackiness.

Citrate esters: These are derived from citric acid and most closely resemble DEHP in terms of plasticizing efficiency and processability. Examples are ATBC (acetyl tri-n-butyl citrate) and BTHC (nbutyryl-tri-n-hexyl citrate).

DINCH (1,2-Cyclohexane dicarboxylic acid diisononyl ester): This plasticizer is commonly used in Europe.

Vegetable oil-based esters: These are bio-based compounds derived from renewable resources. Several have entered the market. One example is a substance called COMGHA, an acetylated monoglyceride based on fully hydrogenated castor oil.

This list indicates that there are many alternatives to DEHP. With the exception of the orthophthalates, all of the plasticizers noted above are non-phthalates. It is important, however, to distinguish between “non-phthalate” and “phthalate-free.” In the production of some non-phthalate plasticizers, for example, traces of DEHP may be unavoidable. A maximum DEHP content of 1,000 parts per million is considered acceptable when measured in the fully formulated vinyl compound.

Rodent Toxicology: An Overview of Non-Phthalates

The degree of an organism’s exposure to a plasticizer is a critical factor in making a toxicological assessment of the substance. One measure of this exposure is the amount of the substance that can be present in the organism without adverse effects. Called the No Observable Adverse Effect Level, or NOAEL, it is expressed in terms of milligrams per kilogram of body weight. Figure 1 compares DEHP with alternative plasticizers in terms of their rodent toxicology, including their potential adverse effects and their NOAEL figures, where a high figure is good.

Both orthophthalates shown in Figure 1, DEHP and DINP, exhibit low NOAEL figures relative to all of the non-phthalates listed. By far the highest figure is that for the vegetable-oil based COMGHA, suggesting that it is potentially the least toxic alternative plasticizer. However, a PVC compound with COMGHA entails more added cost relative to a comparable DEHPplasticized compound than any other alternative plasticizer.

Underscoring the difference between orthophthalates and terephthalates discussed earlier, the secondhighest NOAEL figure on the table is that of the terephthalate DOTP. It is not well absorbed through the gastrointestinal tract (significant amounts were found in feces and urine). The substance undergoes almost complete metabolism back to its starting molecules, with very little of the mono-ester linked to biological activity.

The citrate ATBC is well absorbed in the body and rapidly metabolized and excreted. It is unlikely to accumulate in the body after frequent exposure. It has been observed to be non-genotoxic and a very mild hepatic peroxisome proliferator in rats. No dose-related tumors were found in rats in a lifetime bioassay study.

The trimellitate TOTM is excreted primarily in its unmetabolized state, with no single water-soluble metabolite identified. While TOTM exhibits morphological and biochemical changes in rat livers similar to those of DEHP, the level of observed damage was much lower, in part because TOTM is less soluble.

Unlike DEHP, the adipate DEHA does not show specific toxicity on the reproductive organs of rat pups after in utero exposure, but other foetotoxic effects have been observed. An NOAEL figure of 200 mg/kg of body weight for developmental toxicity and foetotoxicity can be established.

Cost-Performance Comparisons with DEHP-Plasticized PVC

To make an “apples-to-apples” comparison of the various alternative plasticizers, this article uses as its starting point a standard medical compound, Apex® 3300R-75 NT, a gamma-stable material with a DEHP content of 32.2 percent. Formulations with alternative plasticizers were adjusted as needed to duplicate the 75 Shore A hardness of this compound. Plasticizer loading can be an important factor in the overall cost of a compound.

In the study, plasticizer levels required to achieve 75 Shore A hardness varied from 30.5 to 36.1 percent (See Figure 2). Only the citrate plasticizer was used at the same level as DEHP, 32.2 percent. The lower the percentage, the more efficient the plasticizing activity of the substance.

An important factor in potential toxicity is the solubility of a plasticizer in aqueous solutions, as measured by water absorption (See Figure 3). In the compounds tested, the polymeric plasticizer showed significantly greater water absorption than the monomeric types.

An important way of gauging the stability of a material upon exposure to gamma irradiation (or other forms of energy) is yellowness index: a measure of the degree to which the color of a substance differs from white. Color change upon exposure to 5 megarads of radiation is shown for various tested compounds shown in Figure 4. The citrate-plasticized compound exhibits a color change comparable to that of the compound with DEHP.

With plasticizer making up a third of the weight of a flexible PVC compound, cost is a critical factor. Currently a very basic, high-volume, 75 Shore A medical-grade flexible PVC compound containing DEHP costs under US $1.50 per pound. As shown in Figure 5, all of the alternative plasticizers entail an increase in compound cost, but the increase varies widely—from 3 cents to 45 cents per pound of compound. The smallest increase for a non-orthophthalate was for the terephthalate DOTP and for a 75/25 blend of DOTP with the citrate ATBC.

Promising Alternative Plasticizers

It is possible to draw a few general conclusions based on available toxicological information and the study comparing a DEHP-plasticized compound with those containing alternative plasticizers.

Based on rodent studies thus far, DOTP appears to be the least likely of the non-phthalate alternative plasticizers to be regulated. It is also the most costefficient. While somewhat less compatible with PVC than DEHP, it processes similarly and exhibits the same level of water extractability.

Citrates like ATBC are another promising alternative. Of all the alternative plasticizers, ATBC most closely resembles DEHP in terms of plasticizing efficiency, gamma stability, processability, and compatibility with PVC. In rodent toxicological studies, it has not been shown to exhibit reproductive toxicity. Compared with DEHP, however, it has a greater tendency to migrate into and craze rigid plastics like polycarbonate in procedural kits, and a greater tendency to water blush in aqueous solutions.

Other alternative plasticizers show promise in meeting special requirements. As a result of their larger molecules, for example, polymeric plasticizers are not extractable in lipid-based solutions such as oil-based drugs. TOTM is not readily soluble in aqueous solutions. Vegetable oil-based plasticizers have been cited for their potential to help make the carbon footprint of flexible PVC smaller than that of many alternative polymers.

While there is no denying the superiority of DEHP on the basis of cost-performance, the toxicological issue will not go away. Fortunately, a number of alternative plasticizers are available for use in medical PVC compounds— including a few that show promise. To identify the best alternative for a given application, device manufacturers and their compound suppliers will need to consider a wide range of factors.

This article was written by Peter M. Galland, Industry Manager, Vinyl Division, Teknor Apex Company, Pawtucket, RI. For more information, Click Here .

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Medical Design Briefs Magazine

This article first appeared in the June, 2014 issue of Medical Design Briefs Magazine.

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