Originally Published MDDI April 2001
Medical Plastics and Biomaterials
A Comparison of Plasticizers for Use in Flexible Vinyl Medical ProductsData from three studies suggest that using trimellitates can reduce the amount of plasticizer that may migrate from PVC devices.
Richard C. AdamsThe use of plasticized polyvinyl chloride (PVC) for toys and medical devices has been under attack from various environmental and healthcare activist groups. Their concerns are related to the contention that, under certain conditions, small amounts of the plasticizer may leave the flexible PVC compound—an act referred to as leaching, migrating, or extraction. This extracted plasticizer could then enter the human body and, allegedly, cause damage ranging from hormone disruption to cancer. The plasticizer under the most scrutiny is di(2-ethylhexyl) phthalate, commonly known as DEHP or DOP. More DEHP is employed worldwide than any other plasticizer, and it is the most widely used plasticizer for PVC medical devices, in which it conveys critical processing advantages.
There has been much contention and conflicting evidence from both sides in the debate over the effects of plasticizers on the human body. This article does not address the relative toxicity of plasticizers, but rather looks at the various mechanisms under which plasticizers can leave flexible PVC medical devices. It also reviews available information on the migration and extraction characteristics of various plasticizers, including DEHP, trioctyltrimellitate (TOTM), citrates, and adipates, and discusses potential selection criteria based on plasticizer permanence.
EXPERIMENTAL PROCEDURES
The extraction data reported in this article are all derived from published sources. Although the test methods described in the sources are similar, in the aggregate the procedures are not as controlled as if they had been completed in one laboratory in the same time frame and with identical extraction media. In addition, variations in sample thickness must be taken into account, as thicker samples will show a lower percentage of weight loss in a particular medium for a given time.
Data were selected from published information detailing three studies.1–3 In comparing extraction resistance data, the similar plasticizers used across each study—typically DOP but also dioctyladipate (DOA) and TOTM, used in two studies each—were taken as reference points assuming that their time-to-time and batch-to-batch extraction characteristics were relatively constant.
Flexible PVC is used for a range of products, such as this trimellitate-plasticized blood bag.
In Study 1, plasticizer levels were adjusted to create molded compounds that were at a constant or standard 100% modulus value.1 The compounding procedure was designed as follows: ingredients were mixed well by spatula and then placed on a two-roll, 6 x 13-in. mill heated to between 140° and 177°C, depending on the compound, for 5 minutes from the point that the material fluxed. The milled sheet was then compression molded to its final thickness at 177°C for 5 minutes at 145 kPa (1000 psi). Samples were die-cut and placed in a constant temperature and humidity room at 23°C and 50% relative humidity for a minimum of 40 hours prior to testing.
For extraction testing in Study 1, three die-cut samples, 2 in. (50.8 mm) in diameter by 20 mil (0.5 mm) thick, were accurately weighed and suspended in the extraction media. The samples were held at temperature for the time period shown in Table I. After extraction, the specimens were dried, aged, and reweighed. The weight loss was then computed as a percentage of the original weight of the sample.
| Plasticizer | DOP | TOTM | DOA | H-640 | |
| Concentration (phr) | 54 | 56 | 42 | 62 | |
| Hardness (Shore A) | 80 | 84 | 81 | 84 | |
| 100% modulus (MPa) | 10.3 | 10.5 | 10.3 | 10.4 | |
| Tensile strength (MPa) | 18.3 | 18.6 | 17.6 | 16.8 | |
| Elongation (%) | 330 | 370 | 380 | 320 | |
| Brittleness temperature (TB, °C) | –27 | –22 | –45 | –15 | |
| Weight loss by extraction (%)
Water (24 hr @ 50°C) 1% soapy water (24 hr @ 50°C) Mineral oil (24 hr @ 50°C) Hexane (1 hr @ 25°C) |
0.2 5.3 11.6 22.0 |
0.13 0.12 7.1 23.8 |
.40 16.5 18.1 32.0 |
0.52 4.6 1.9 1.7 | |
| Data derived from Technical Information Bulletin, Hatco Corp. | |||||
Table I. Performance of plasticizers compounded to a standard modulus (0.5-mm film).
Study 2 took a different approach, holding the amount of plasticizer in the compound constant for all plasticizer types and allowing the hardness and modulus to vary.2 The ingredients were mixed and then placed on a two-roll mill for 5 to10 minutes at 163°–171°C. The milled stock was compression molded for 3 minutes at l71°–l82°C at 4640 kPa (32,000 psi). For extraction, 40-mil (1-mm) sheet was first conditioned for 48 hours at 24°C before being exposed to various extraction media, as revealed in Table II. As opposed to the other studies, Study 2 reports not the percentage of weight lost from the flexible PVC compound but, rather, the percentage of plasticizer in the compound lost.
Water (tap) (24 hr @ 60°C)
1% soapy water (24 hr @ 60°C)
Mineral oil #3 (24 hr @ 60°C) 0.7 2.7 11.3 1.5 11.0 34.7 1.2 9.5 10.9 1.9 5.4 13.8 1.7 2.2 15.7 Table II. Performance of plasticizers compounded to a standard modulus (1.0-mm film). The compound formulation by weight was PVC (100), plasticizer (50), calcium/zinc stabilizer (2.5), and stearic acid (0.25).
In Study 3, like Study 2, the level of plasticizer was held constant.3 The ingredients were mixed in a planetary mixer and then placed on a two-roll mill for 10 minutes at 163°–166°C. This milled sheet was then compression molded to the desired thickness (40 mil/1 mm) for 8 minutes at 174°C and 145 kPa (1000 psi). From the molded sheet, 2-in.-diam (50.8-mm-diam) disks were cut. These sample coupons were then exposed to the conditions listed in Table III, and then dried before weighing.
% weight loss after 24 hr @ 90°C
% weight loss after 48 hr @ 90°C 0.4 0.4 1.7 3.0 0.3 0.3 0.6 0.6 0.6 0.7 % weight loss after 48 hr @ 90°C
% weight loss after 72 hr @ 90°C 0.1 0.3 3.2 7.6 0.1 0.3 4.0 5.6 6.3 7.9 % weight loss after 24 hr @ 70°C 2.5 3.2 3.5 1.5 2.0 % weight change after 24 hr @ 23°C –12 –11 –18 +2 +2 % weight loss after 7 days @ 70°C
% weight loss after 7 days @ 90°C 0.1 0.2 0.3 0.8 0.1 0.2 0.3 0.4 0.3 0.4 Table III. Comparison of trimellitate, phthalate, and polymeric plasticizers in a general-purpose compound (1.0-mm sheet). Compound formulation by weight was PVC (100), plasticizer (50 or 62), barium-cadmium stabilizer (2), zinc stabilizer (0.5), and stearic acid (0.5).
DISCUSSION
In the literature, several factors are discussed that influence the rate of extraction for a plasticizer to a particular medium.4 The surface area of the test specimen and the diffusion rate of the plasticizer through PVC control the plasticizer's extraction rate. The efficiency at which a given test medium can remove plasticizer from the surface of a test specimen is the first level of control on the rate of plasticizer extraction or migration. If the medium is very efficient at removing plasticizer from the surface, then diffusion of the plasticizer through PVC becomes the controlling factor. The size and the shape of the plasticizer molecule control the diffusion rate: the larger and bulkier the plasticizer molecule, the slower the diffusion. It has also been determined that plasticizers produced from branched alcohols diffuse at lower rates than do those based on linear alcohols. As a result, if one wanted to reduce the diffusion rates, one would choose a bulky plasticizer molecule that was manufactured with branched alcohols.
In addition to the previously mentioned factors influencing the extraction resistance of a plasticizer to a given test medium, the ability of the medium to permeate into the flexible PVC mix can be an additional factor influencing the diffusion rates of the plasticizer and its compatibility with PVC.
The presence of even small amounts of materials that can hold large amounts of plasticizer in a liquid that is otherwise a poor extractant can completely change the rate and extent of extraction. The most prevalent example of this is the presence of micelles formed by soap and other surfactants in water. Another common example is that of natural body fluids, such as blood, which have much the same effect. Extraction studies using various dilutions of blood plasma and saline solution (up to 100% blood plasma) indicate that as the concentration of blood plasma protein increases, the amount of plasticizer extracted into the extraction media also increases.5
The plasticizers in the three studies were evaluated in a number of different extraction media, but this article focuses on data from water, soapy water, and mineral oil tests to determine their relative extraction resistance. Hexane extraction has been included for reference purposes, even though it does not seem to be representative of any medical exposure medium.
At present, DOP is the main plasticizer used for medical applications, but citrate plasticizers are being touted as lower-toxicity alternatives. Besides comparing DOP and citrates, this article tabulates data regarding trimellitate and polymeric plasticizer to demonstrate a wider range of extractabilities.
Four plasticizers were chosen for comparison from the literature for Study 1: DOP, TOTM, DOA, and H-640, a polymeric plasticizer (Hatco Corp.; Fords, NJ) with a theoretical molecular weight of 2500. From the Study 2 literature, five plasticizers were selected: DOP, DOA, and three citrate offerings (all from Morflex Inc; Greensboro, NC): acetyltri-n-butyl citrate (Citroflex A-4), acetyltri-n-hexyl citrate (Citroflex A-6), and n-butyryltri-n-hexyl citrate (Citroflex B-6). The plasticizers from Study 3 results included DOP, TOTM, and two polymeric adipate-type plasticizers (BP Amoco Chemicals; Naperville, IL) with molecular weights of 3300 and 1800. When comparing Studies 1 and 2, the relative extractabilities of the common plasticizers DOP and DOA were used, whereas when comparing those two studies with Study 3, only the relative extractability of DOP was used.
Water is by far the least aggressive medium reviewed here. Water is unlikely to be as aggressive as blood plasma; rather, it is similar in aggressiveness to a standard saline solution. In this medium, TOTM was the least extracted, followed by DOP (Tables I and II). It would appear that DOA, H-640, and the citrate plasticizers fall into the same range of extractability. By comparing their extractability with that of DOP and DOA from Studies 1 and 2, a relative extraction resistance ranking can be made for the other plasticizers.
Soapy water is a far more aggressive medium than water. The main reason is that the soap micelles are more efficient at removing any plasticizer at the surface of the test specimen and isolating it so that it cannot migrate back into the PVC. The proteins in plasma are reported to have a similar effect. Once again, the TOTM is the least extractable of the plasticizers, followed by all the polymeric plasticizers and n-butyryltri-n-hexyl citrate.
In mineral oil, polymeric plasticizers function the best, followed by TOTM. Acetyltri-n-butyl citrate performs better than does DOP in mineral oil.
CONCLUSION
Based on extraction studies, trimellitates are a good choice if the desired outcome is to reduce the amount of plasticizer that is extracted from a flexible PVC medical device by a variety of media. Although citrates are being marketed as nontoxic alternative plasticizers, they are extracted at a rate that would appear to be higher than that of TOTM and, most often, higher even than that of DOP. As with any material selection decision, there are often many factors to be considered beyond the issue of extractability alone. The property of extraction resistance examined in this article may not be the main criteria for all medical device applications.
REFERENCES 1. Technical information bulletins from Hatco Corp. (Fords, NJ). Richard C. Adams is a research associate at BP Amoco Chemicals (Naperville, IL).
Photo courtesy of BP Amoco Chemicals
Copyright ©2001 Medical Device & Diagnostic Industry
Plasticizer DEHP (DOP) DEHA (DOA) ATBC ATHC BTHC Concentration (phr) 50 50 50 50 50 Hardness (Shore A) 79 78 78 81 81 100% modulus (MPa) 9.4 7.5 9.3 10.9 9.4 Tensile strength (MPa) 18.9 12.4 19.7 20.5 20.2 Elongation (%) 395 414 400 390 427 Brittle point (°C) –24.5 –56.5 –18.5 –26.0 –33.5 Plasticizer loss by extraction (%)
Data derived from Technical Bulletins 101 and 103, Mortlex Inc.
Plasticizer TOTMa DOPa TOTMb Adipate MW 3300b Adipate MW 1800b Concentration (phr) 50 50 62 62 62 Hardness (Shore A, 10 sec) 93 86 86 86 86 100% modulus (MPa, ASTM D412) 13.5 10.3 9.4 11.0 10.3 Tensile strength (MPa, ASTM D412) 19.7 17.5 17.7 19.3 18.9 Elongation (%, ASTM D412) 330 350 390 380 400 Brittleness Temperature (°C, ASTM D746) –26 –27 –37 –15 –16 Carbon volatility (ASTM D1203)
Soapy water extraction (ASTM D1239)
Mineral oil extraction (ASTM D1239)
Hexane extraction (ASTM D1239)
Humidity compatibility
Data derived from Bulletin TM-46d, BP Amoco Chemical Co. a 50 parts/100 resin. b 62 parts/100 resin.
2. Technical Bulletins 101 and 103 from Morflex Inc. (Greensboro, NC).
3. Bulletin TM-46d, BP Amoco Chemical Co. (Naperville, IL).
4. JK Sears and JR Darby, The Technology of Plasticizers (New York City, Wiley, 1982).
5. MS Jacobson, "An In Vitro Evaluation of a New Plasticizer for Polyvinylchloride Medical Devices," Transfusion, 20, no. 4 (1980): 443–447.
