PVC Biological Behavior

Assessment under Food and Water Legislation

PVC, on its own and manufactured to the current standards, is accepted as having very low toxicity (bearing in mind that no materials are truly non-toxic) and is a safe material. The maximum residual vinyl chloride monomer (VCM) concentration standard in PVC resin destined for food and medical applications is now being met at <1 g/ton. However, the main issues come with the use of different additives in the formulation and possible by-products from polymer degradation.

In addition to being suitable for the intended application, the main requirements for food contact and potable water use are that the PVC article must not impart odor or taste. Another signi?cant criterion is the migration of additives, monomer, catalyst residues, polymer degradation products, etc., into the food or water. The migration of these species is a function of time, temperature, and extractant type. At unacceptable levels, these species could produce potential health hazards or the formation of undesirable flavors or odors.

Food Contact

The application of PVC in contact with food and water has been covered by the relevant standards/regulations by different authorities in different countries. Within the EU there have been various directives to bring together the national standards and regulations, based on the approvals already generated nationally. The most important national standards have been generated in Germany through the BFR (Federal Institute for Risk Assessment), previously BGVV and BGA, who have access on their website to databases for plastics recommendations (www.bfr.bund.de). In the EU (https://europa.eu.int/comm/food/food/chemicalsafety/foodcontact/spec_dirs_en.htm), food contact plastics are regulated by Directive 2002/72/EC which consolidated Directive 90/128/EEC and its amendments. This directive lists approved monomers with vinyl chloride and vinyl acetate referenced in Annex II, Section A. This reference quotes compliance to a much earlier Directive 78/142/EEC that is speci?c to PVC.

For VCM (a known carcinogen), the EU limit states that it should not exceed 1 mg/kg (1 ppm) in the ?nal product and that PVC articles must not transfer any residual monomer to food when tested at an analytical sensitivity of 0.01 mg/kg (10 ppb). PVC manufacturers in Europe produce PVC resin speci?cally for use in food contact and medical applications that meets the 1 mg/kg requirement, obviating the need for the converter to test the packaging material for residual monomer. Vinyl acetate monomer has a restriction that the migration level into food should not exceed 12 ppm.

In the USA, the Food and Drug Administration (FDA), following risk assessments carried out in different food contact applications, has taken the viewpoint that a residual VCM content of 5–50 ppb in the PVC article, depending on the application, is considered as safe.

To enforce overall and particular migration limits, special directives have set out procedures for analysis. Basic rules for migration tests, such as the conditions of contact (time, temperature, and food simulants), are supplied in Directive 82/711/EEC and amendments 93/8/EEC and 97/48/EC. If a product complies with the compositional requirements of Directive 2002/72/EC, then it can subsequently be tested for the desired condition of use. If it meets the migration requirements, then it is deemed suitable for use in applications covered by the appropriate test method. Directive 85/572/EEC gives a list of food simulants to be used in migration tests for various foodstuff types, using water, ethanol, acetic acid, and olive oil.

The Scienti?c Committee on Food (now the European Food Safety Authority, EFSA) evaluates the toxicological data of an additive and sets a corresponding maximum tolerable daily intake using a signi?cant margin of safety. The directives (90/128/EEC consolidated into 2002/72/EC) have now established:

? An overall migration limit of 10 mg/dm2 of material per article or 60 mg of substance/kg of foodstuff or food simulants for all substances migrating from a material into foodstuffs.

? A positive list of authorised monomers and other starting substances, with restrictions on their use (such as speci?c migration limits, SML) were applicable. Some monomers remain provisionally authorised at national level, pending a re-evaluation by the EFSA.

? A list of authorised additives and, for some of them, restrictions on their use (such as speci?c migration limits). In addition there also exists national limits of authorised additives. The following deadlines have been set to transform the list of authorised additives into a positive list:

- 31 December 2006, submission to EFSA for all additives currently on national lists that have not yet been evaluated.

 - 31 December 2007 at the latest, EC to establish a provisional list of additives that may continue to be used, subject to national law, until evaluated by the EFSA.

? The procedures for adapting, revising, and/or completing the list of authorised substances. Food contact plastics also include materials and articles that are in contact with water intended for human consumption, but do not cover ?xed water supply equipment.

The EU continues to work (Synoptic Document) on this ‘positive list’ (https://europa.eu.int/comm/food/ fs/sfp/food_contact/synoptic_doc_en.pdf). This document is not intended to include polymerisation aids, colorants, inks, and adhesives (although some appear). Pigment use must be selected from national lists, e.g., the French positive list of pigments or from the Council of Europe resolution on colorants. There is also discussion as to whether solvents should be included in the additive list. Substances have been split into different lists (0–9), with the aim being that those substances on lists 0–4 are included on the positive list. As an example, vinyl chloride is on list 4. Essentially, those substances on the other lists have negative or insuf?cient data, or have toxicity concerns. Lists W7–W9 are waiting list substances, considered as new (never having been approved at national level) and lacking requested data.

It is important to note that some of these additives can be used without restriction provided they do not exceed an overall migration limit, whereas others, such as organotin stabilisers and adipate plasticisers, have restrictions imposed on them with corresponding SML. Currently SML are based on the worst case scenario whereby it is assumed that a person may consume up to 1 kg daily of food in contact with the relevant food contact material. There are discussions concerning proposed re?nements to consider a fat (consumption) reduction factor of 5 (as normal consumption is < 200 g daily in Europe) and a plastics use factor to take account of the fact that different plastics are used for packaging materials, each having a percentage share. This is similar to the Food and Drug Administration (FDA) situation, already mentioned, where the consumption factor has been derived for each plastic in relation to the types of food with which it comes into contact. The use of migration modelling is permitted, to reduce the need for complex and expensive analysis, for new product approval.

In the USA, the FDA, an agency within the Department of Health and Human Services of the federal government, has responsibility for the listing of suitable raw material ingredients, from which the material manufacturer can select for packaging materials and medical devices. The regulations also provide certain speci?cations regarding composition and properties. Assuming all the standards have been met, the resulting article or material is then deemed to be FDA compliant. In addition, it has also taken on board the evaluation of the impact that clearance of a packaging material may have on the environment (assessment of potential impacts from use and disposal). PVC is held up in this process at the time of writing, but PVC is still used due to earlier FDA listing under the CFR (Code of Federal Regulations) Title 21, Chapter 1, Subchapter B, particularly Part 178. The part is divided into sections identi?ed by a chemical family and indicates physical, chemical, and compositional requirements, in addition to acceptable service conditions for food contact. There may be a maximum permitted addition level. There is usually also a limit of extractable substance when exposed to particular and relevant solvents.

Within the FDA, there is no formal process of inspection of materials produced for food contact use.

Drinking Water Approval

Drinking water safety is protected by the guidelines of the World Health Organisation (WHO). In Europe, drinking water quality is controlled by Directive 98/83/EC. The main change, from a PVC point of view, was to reduce permitted lead content from 50 to 10 μg/l over a 15-year transition period (by 2013, with an interim standard of 25 μg/l by 2003). This was aimed at allowing time for replacing lead distribution pipes but in?uenced the use of lead stabilisers in PVC pressure pipe.

Another directive, known as the Construction Products Directive (89/106/CE), also includes plumbing installations. One section covers hygiene, health, and the environment, and includes pollution or poisoning of water or soil, among other considerations.

However, there is no conformity in an approval scheme, as different national approval schemes exist. As a further complication, national approval in one country may not be accepted in another member state. In the UK, government approval is required via the Committee on Products and Processes for Use in Public Water Supply (CPP) which provides expert advice with the Drinking Water Inspectorate (DWI) providing technical and administrative support to the CPP. The DWI is the technical regulator for the water companies. In Germany, the Kunststoffe und Trinkwasser (KTW) and German Association of the Gas and Water Trade (DVGW) approval processes apply. In the Netherlands, the Dutch Water Authority (KIWA) standards are relevant.

A European Acceptance Scheme (EAS) is being developed by the EC to establish a common European regulatory approach for construction products in contact with drinking water, primarily to achieve a single market for these items.

In the USA, the NSF International (formerly the National Sanitation Foundation) approval process applies via the NSF/American National Standards Institute (ANSI) Standard 61. This is recognised by the US Environmental Protection Agency (EPA) as the criteria for determining the suitability for health effects of materials that convey potable water.

 Assessment under Medical Legislation 

 Biocompatibility

Biocompatibility is an important concept for any polymeric material that contacts the body in the form of a medical device. It can be expressed as the ability of a material, device, or system to perform without a clinically signi?cant host response in a speci?c application. The terms ‘blood compatibility’ and ‘tissue compatibility’ are often quoted and refer to blood–material or blood–device interactions, and the ability of the material to remain in situ without signi?cant host response and without interfering with surrounding tissue differentiation, respectively.

PVC compounds designed for medical devices will comply with these de?nitions as demonstrated by an ability to pass generally recognised biocompatibility test procedures. However, in common with many polymer systems, PVC interacts with blood, bio?uids, and tissue to set off a whole cascade of protein-mediated reactions, including complement activation. Some additional 25 biocompatibility parameters have been identi?ed, some of which may assume signi?cance in patients experiencing particular clinical complications. PVC–blood interaction studies (primarily di-2-ethylhexyl phthalate interaction) have been a major focus of ongoing research. In addition, surface modi?cation techniques have been developed to improve the biocompatibility of PVC surfaces.

Regulatory Status

PVC compounds to be used in medical devices must meet high standards of raw material selection, process, and quality control to ensure a high degree of con?dence in the ?nished product.

In selecting polymer additives for use in medical compounds, the starting point is a food contact approval list or a chemical listing taken from a pharmacopoeia monograph.

The European Pharmacopoeia is published by the European Directorate for the Quality of Medicines (EDQM). There are a number of European Pharmacopoeia monographs for polymeric materials. The speci?c monographs for PVC are listed in the European Pharmacopoeia:

? Materials based on non-plasticised PVC for containers for non-injectable aqueous solutions.

? Materials based on non-plasticised PVC for containers for dry dosage forms for oral administration.

? Materials based on plasticised PVC for containers for human blood and blood components.

? Materials based on plasticised PVC for tubing used in sets for the transfusion of blood and blood components.

? Materials based on plasticised PVC for containers for aqueous solutions for intravenous infusion.

? Empty sterile containers of plasticised PVC for human blood and blood components.

The Medical Devices Directive (93/42/EEC) and the corresponding national regulations make speci?c reference to the European Pharmacopoeia.

 Competent Authority Approval

All EU member countries have their own competent authority to protect public health and these authorities are responsible for the implementation of the three European directives that regulate the marketing and putting into service of medical devices.

In the USA, the Centre for Devices and Radiological Health (CDRH), as part of the FDA, has responsibility for safety assessments of materials used in medical devices.

If the formulation ingredient is not pharmacopoeia listed or food contact approved, another route is to check that the ?nished product containing the ingredient meets US Pharmacopoeia requirements for biological testing. Alternatively, satisfactory extraction resistance testing may also indicate it can be used as a component.

Formulation Disclosure

During formal registration or licence approval, one of the requirements placed upon the medical device manufacturer is to declare details of the components used in the ?nal medical device to the competent authorities. In the USA, the FDA operates a Drug Master File and Device Master File System which includes formula disclosures and physical and biochemical test results. This con?dential ?le is compiled for examination by any authorised body.

Product Conformance

Manufacturing controls for PVC compound to be used in medical applications are based on established systems, such as good manufacturing practice (GMP) and quality assurance (QA) standards. In particular, formal registration to the ISO 9001 scheme is now almost mandatory.

In addition to standard ?nished product testing speci?cations, PVC compounds for medical use will also include tests for ignition residue, heavy metal content, and residual VCM content.

Specialised medical testing (biological testing) is usually carried out at the ?nal development stages only. This testing is based on major recognised standards for biological testing, primarily ISO 10993, a set of harmonised standards that address the biological evaluation of medical devices. Appropriate biological tests on extracts from the compound, prepared by various extraction conditions and using appropriate media, include systemic toxicity, intracutaneous reactivity, and cytotoxicity. Appropriate biological tests, performed on the PVC compound itself, include implantation, cytotoxicity, and blood compatibility tests, such as haemolysis.

 Sterilisation

Single- and multi-use medical devices that come into contact with humans must be pre-sterilised before use, in order to minimise the risk of infection. In the case of single-use pre-sterilised medical devices incorporating PVC materials the choice is between steam, ethylene oxide, and a radiation sterilisation process.

Steam (Autoclave) Sterilisation

Autoclaves, which use steam under pressure at a temperature of 120–130 °C for approximately 30 minutes, can be suitable for PVC materials, but they are not commonly used for this material.

 Ethylene Oxide Sterilisation

Ethylene oxide (EO) gas sterilisation is widely used for single-use, pre-packed medical devices. It is very effective and can be used at temperatures below 60 °C . The sterilisation process normally takes more than four hours. EO has very good penetration ability, so the objects to be sterilised can be pre-packed in a variety of container types. PVC, in common with other polymeric biomaterials, absorbs considerable quantities of EO during the process and must be aerated for several days to ensure complete absence of the gas prior to use. However, new technology is being developed to eliminate the need for separate aeration. PVC is generally unaffected by this treatment. However, EO is a toxic and ?ammable gas and its use must be controlled under proper protocol.

Radiation Sterilisation

PVC is considered to have good radiation stability (particularly in the ?exible form) when formulated speci?cally for this application. Other polymers that have good radiation stability are ABS, PE, PC, and polyurethane. In contrast, PS has excellent radiation stability, but PP grades have relatively poor stability.

Gamma Irradiation

Gamma rays, using the radioisotope cobalt-60 source of ~1.11 x 107 Gbq, with a nuclear energy power output of ~5 kW, are the most widely used form of ionising radiation applied to the sterilisation of singleuse medical devices. They are extremely penetrating, bringing about a lethal effect on micro-organisms without any signi?cant temperature rise. Heat-sensitive items can therefore be sterilised in their sealed packs within the ?nal transport container without the permeability problems associated with either EO or steam sterilisation. The dose selection is based on knowledge of the radiation resistance of various microbial species together with scienti?c data revealing the in?uence of environmental conditions on such resistance. In Europe, the choice of a minimum dose of 2.5 Mrad, which is equivalent to 25 kGy, has been widely accepted. In the USA, the dose varies according to the nature and use of the device, taking account of the numbers and sterilisation resistance of the contaminants involved. Doses are usually in the range 1.5–2.5 Mrad (15–25 kGy). This is well below the gamma radiation dose rate limit of PVC (5 ? 102 Mrad) where damage, such as crosslinking and chain scission, occurs.

When PVC is irradiated (particularly after 2.5 Mrad), a yellow straw colour can develop. This is especially noticeable in formulations containing little or no plasticiser. At this stage, physical properties and biological performance are not affected, but the result is the same as the start of the PVC degradation process under heat. An equally important requirement for PVC is the prevention of further colour development (and some crosslinking) during long-term storage after radiation sterilisation. The effect can be minimised by careful selection of stabilisers and antioxidants, taking into account the need to still satisfy the various biological tests on extracts from the compound. The additives perform either as reactants, which readily combine with the radiation-generated free radicals, or as primary energy absorbers to prevent the interaction of the radiation energy with the polymer. The use of the most appropriate toning pigments can also have a positive in?uence.

Electron Beam Irradiation

Electron beam irradiation delivers the same results as gamma irradiation, but the source is less penetrating. It is therefore normal to irradiate individual pre-packed products under an electron beam. The electron beam, a concentrated, highly charged stream of electrons, is generated by the acceleration and conversion of electricity. The product may be treated from both sides.

A higher dose requirement than gamma irradiation is required to satisfy regulatory authorities, but the method is preferred for high-volume, low-value products. It is considered to be environmentally safer.

 Resistance to Micro-organisms

Rigid PVC is not a nutrient medium for micro-organisms and is therefore not attacked by them. However, ?exible PVC is a nutrient source because of the plasticiser available at the surface as a microlayer. The detrimental effects can be seen through loss of properties and change in aesthetic quality (dirt pick-up and/or odor generation). These effects are much more pronounced in warm and humid conditions. More information on microbiocides, which are added to a material to prevent the growth of micro-organisms.