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Evaluation of Plasticisers for PVC for Medical Devices 5 The feasibility study
5.1 Plasticiser selection criteriaThe relevance of the applied selection criteria for Plasticisers for PVC for Medical Devices is described below. The list refers to the criteria mentioned in the plasticiser performance matrix, which is described in clause 6.2 and enclosed as appendix 1. 5.1.1 AvailabilityA plasticiser needs to be commercially available in large quantities (ton lots) to satisfy current demand for plasticised PVC for Medical applications. 5.1.2 Compatibility towards PVC resinsThe compatibility could be expressed as: To what extent is a substance capable of forming a stable compound with the polymer? The compatibility is often measured as the solution temperature, i.e. the temperature at which a mixture of plasticiser and suspension PVC apparently changes to a single-phase state. A plasticiser needs to be compatible with PVC resins. If a substance is incompatible it will exude to the surface of an article and can be more easily extracted; i.e. an incompatible plasticiser will not plasticise PVC properly. Furthermore, a plasticiser should be tolerant to the stabilisers and other additives in the compound to avoid exudation in the process or/and a sticky surface of the final article. The volatility of the plasticiser should be low - at least not higher than that of DEHP. 5.1.3 Plasticising efficiencyThe plasticising efficiency of a plasticiser determines the level of plasticiser in a compound that is needed to achieve the required degree of modification of the compound. In this work the hardness of PVC compound has been chosen as the reference parameter. The more efficient the less plasticiser will be required. The efficiency is an important property when determining overall cost. 5.1.4 ProcessabilityA PVC material is made up from a blend of ingredients: PVC resin (the polymer that makes the material a plastic), plasticiser(s), stabilisers and lubricants. The ingredients are blended together in a high-speed mixer or a ribbon blender. During this process the plasticiser is absorbed into the PVC resin particles. This blend can then be processed directly into an article by extrusion, by injection moulding and by calendering. It can also go through an intermediate step of compounding. This is where the blend is fed into an extruder and by means of heat and pressure it becomes molten. The molten mass is extruded (pressed through a spaghetti die) and the solidified strands are cut into small pellets called granulate. The pellets are cooled from approx. 150°C to ambient temperature. The pellets can then be used to form articles by extrusion, by injection moulding and by calendering. Injection moulding A plasticiser should be sufficiently stable to withstand the heat and the deformation associated with the injection moulding process. No sweating should occur. A low vapour pressure is also desirable. Extrusion A plasticiser should be sufficiently stable to withstand the heat and the deformation associated with the extrusion process. No sweating should occur. A low vapour pressure is also desirable. Calendering A plasticiser should be sufficiently stable to withstand the heat and the deformation associated with the calendering process. 5.1.4.3 Fabrication operations Welding and bonding A plasticiser should not harm the assembly process. No sweating should occur. Machinability and printability A plasticiser should not harm the machining or the printing processes. No sweating should occur. 5.1.4.4 Post fabrication operations Radiation sterilisation A plasticiser should be sufficiently stable towards the energy disposition associated with the radiation sterilisation process. No sweating should occur. Ethylene oxide (EO) sterilisation A plasticiser should be sufficiently stable towards the heat, humidity and chemicals associated with the ethylene oxide sterilisation process. No sweating should occur. Steam sterilisation A plasticiser should be sufficiently stable towards the heat and humidity associated with the steam sterilisation process. No sweating should occur. A low vapour pressure is also desirable, so the plasticiser does not distil away. 5.1.5 CostThis breaks down into two sections and related to the overall cost/performance/efficiency of the system. Plasticiser cost combined with plasticising efficiency needs to be as low as possible to keep materials cost low and to remain competitive. Processing cost needs to be considered. The plasticiser has major influence on processing cost (see Processability) Toxicity is the effect of the plasticiser on life forms and plant material. Plasticiser needs to have low toxicity - food contact approval being one means of determining current toxicity status. Plasticiser should be safe to handle and not cause any adverse effect upon industry employees. Material will be handled in large quantities i.e. > 1 tonne. In addition products manufactured from the compound will be widely handled by Medical staff and come into skin contact with the patients and it is imperative that there is no allergic reaction to such products as observed by some latex products etc. Medical Devices made from this material should have no adverse effect on the users and the material should meet USP class VI (USP = United States Pharmacopoeia). Material should also not interact with substances (e.g. drugs) that it will come into contact with. Drug efficiency should not be impaired. These aspects has primarily been described for DEHP. 5.1.7 Environmental statusEmissions during plasticiser manufacture The production process should not have any detrimental effect upon the environment. Waste products and emissions need to be considered. Emissions during processing Material should not have any adverse effects on the environment during processing. Emissions and residues should be taken into account. Emissions in use Material should not have any adverse effect on the environment during use Due to the risk of spreading of infections all Medical Devices should be disposed of via incineration. Therefore plasticiser should be suitable for incineration without adverse effects i.e. emissions or residues. 5.1.7.3 Sustainable development Plasticiser selection should consider whether the material can demonstrate sustainability, i.e. materials made from natural products being more sustainable than materials made from non renewable resources. 5.1.8 Physical properties of plasticiserColour Colour is considered important in that it conveys "purity of product" to the user. Plasticisers should give colourless compounds and articles. A lot of PVC additives either produce materials that are semi-opaque or yellow in appearance. They are by the Medical industry and the hospital staffs perceived to be imperfect or contaminated. Clarity Plasticiser needs to give a clear/transparent material. This allows for the end user to see the contents of any article or device made from the material. Material made with plasticiser should not have any odour, as odour indicates emission. 5.1.9 Physical properties of compoundsTensile strength The material needs to have sufficient strength to ensure that the article remains durable and intact throughout its entire service life. Any likely abuse of material needs to be considered. Properties need to be maintained throughout the service life of the product. Cold flexibility The material needs to retain its flexibility at low temperatures, as products are likely to be used or stored in low temperature environments. This property needs to be maintained throughout the service life of the product such as blood storage. Elastic recovery The rate or degree at which a material returns to its original shape after being deflected - the elastic recovery - is important at many applications and especially in flexible PVC tubing for use in peristaltic pumping applications. 5.1.10 Public perceptionThe public perception is the way the general public reacts to a description of a material or a product. (E.g. a substance called di-hydrogen oxide would probably be considered bad, but described as water it would be considered harmless). 5.2 Plasticiser performance matrixA performance matrix for Plasticisers for PVC for Medical applications has been prepared based on the best knowledge collected by the project partners (see appendix 1). Data and comments in the matrix are primarily based on the experience of the partners and on the general literature (e.g. ref. 19 and 34). In the performance matrix the term "Unknown" means unknown to the project workers for the moment. Many aspects have not been investigated and therefore data are not existing. Some aspects have been considered as being less important and therefore no effort has been made to search for data. An asterisk (*) refers to knowledge transferred from DEHP or DEHP plasticised PVC. Phthalates being assessed in the risk assessment program in the EU are marked with EU). The plasticising efficiencies indicated are based on information from Hydro Polymers. The abbreviations used in the matrix are explained in table 1: Table 1
5.3 Substances selected for further investigationThe substances listed below are considered as having the highest potential for success as a plasticiser for PVC for Medical applications and therefore they have been selected for further investigations. PVC compounds based on these substances have been prepared and substantial properties have been determined by testing and compared with the properties of a reference PVC compound plasticised with DEHP, so DEHP is also in the list: Table 2
The arguments for selecting or rejecting each of the substances are as follows DEHP: Yes! DEHP is necessarily selected as a reference plasticiser. DEHP is available in one grade that is pure enough to be Medical. DINP: Yes! During the work it became obvious to include diisononyl phthalate and diisodecyl phthalate, as they in the EU studies appear to be coming out reasonably favourable regarding their risk assessments. Anyway, it is too narrow to consider phthalates as a uniform group of substances; phthalates should be considered as individual substances. DINP is used in food contact and in toys, and we consider it as a potential substitute for DEHP for Medical Devices. Among phthalates DINP is probably the best alternative to DEHP. Commercial DINP is always a mixture of isomers, the composition of which varies from producer to producer. Depending on the way of synthesis DINP exist as two different products with two CAS numbers. Therefore the product to be investigated has been specified in detail by selecting a specific product. DIDP: No! One alternative phthalate is sufficient. Other phthalates: No! One alternative phthalate is sufficient. DEHA: Yes! DEHA is already being used for Medical applications. Some ecotoxicity problems have been considered. DEHA is available in one grade that is pure enough to be Medical. It is being used by at least one company. Other monomeric adipates: No! One monomeric adipate is sufficient. Polymeric adipates: Yes! A polymeric adipate is considered as the sole potentially relevant polymer to substitute DEHP as a primary plasticiser in PVC. Polymeric adipates are mixtures of polymers of different chain length, the composition of which varies from producer to producer. Therefore a specific grade to be investigated has been chosen and the product has been specified in detail. TEHTM: Yes! TEHTM is available in Medical grades and is already used in e.g. bags and infusion sets. ATBC: Yes! ATBC is currently being used in some special Medical applications. ATHC: No! No information of the existence of ATHC in Medical grades or Medical applications of ATHC has been found; one citrate is sufficient. BTHC: No! Occupational and health problems have been reported from the State University Hospital in Denmark, where BTHC plasticised PVC blood bags are being handled at the blood bank.One citrate is sufficient. Benzoates: Yes! Only little information is available but they seem promising. A choice between a number of products available from at least two suppliers has been made. Sulphonates: No! Sulphonates are rejected mainly because of the emission of SO2 (sulphur dioxide) during incineration as waste. Phosphates: No! Phosphates have poor technical properties, and they are forbidden according to the Nordic Pharmacopoeia (Ph. Nord. 63). Soya Bean Oil (epoxidised): No! Soya bean oils have limited compatibility and the processability is poor. However, soya bean oils are readily used as secondary Plasticisers and as stabilisers. DEHS: Yes! Di(2-ethylhexyl) sebacate has extensive FDA approval and is frequently used in the cosmetic industry. It is commercially available from many sources. Note: It is manufactured from sebacic acid, which is a by-product from cracking of castor oil. Thus is it produced from natural products. DEHZ: No! Di(2-ethylhexyl) azelate is commercially available from only a very few manufactures. The main raw material, azelaic acid, is only available from one source. The performance characteristics of DEHZ and DEHS are similar. Most compounders prefer to use DEHS. Naphthenates: No! Naphthenates are not commercial available in ton lots. Polyhydric alcohol esters: No! They are not commercially available in ton lots, not tested and probably the existing grades are not suitable for Medical applications. Aliphatic glycol esters. No! They are not commercially available in ton lots, not tested and probably the existing grades are not suitable for Medical applications. Ethylene-acrylate-carbon monoxide terpolymer (Elvaloy®): Yes! According to the producer these products can be used as a plasticiser on there own. Though only one producer is known it was considered worthwhile to include a suitable product for further investigation. Nitrile rubber: No! Generation of hazardous fumes when incinerated. Polyurethane: No! Polyurethanes are used as solid Plasticisers in conjunction with a primary plasticiser. They are not suitable as primary Plasticisers. Generation of hazardous fumes when incinerated. EVAC: No! EVAC is used as a solid plasticiser in conjunction with a primary plasticiser. It is not suitable as a primary plasticiser. Metallocene catalysed polyolefines: No! They are not readily available. The latest published development has not shown any reliable potential. They have limited compatibility with PVC, as polyolefines and PVC are generic very different from each other. DACM: No! DACM is commercially available only in small quantities. No Medical application is known. High price! Esters of palm oil, castor oil, corn oil and rapeseed oil: No! Limited availability - unsuitable as primary Plasticisers - no potential as substitutes for DEHP. An exception is castor oil, in that sebacates are based on castor oil.
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