Draft Guidance for Preparation of PMA Applications for Testicular Prostheses
DRAFT GUIDANCE FOR PREPARATION OF PMA APPLICATIONS FOR TESTICULAR PROSTHESES Urology and Lithotripsy Devices Branch Division of Reproductive, Abdominal, Ear, Nose and Throat, and Radiological Devices Office of Device Evaluation Center for Devices and Radiological Health March, 1993 TABLE OF CONTENTS I. PREFACE . . . . . . . . . . . . . . . . . . . . . . . . . 1 II. DEVICE DESCRIPTION. . . . . . . . . . . . . . . . . . . . 1 III. BACKGROUND. . . . . . . . . . . . . . . . . . . . . . . . 1 IV. GENERAL REQUIREMENTS OF PREMARKET APPROVAL (PMA) APPLICATIONS FOR TESTICULAR PROSTHESES. . . . . . . . . . 1 1. Manufacturing Data . . . . . . . . . . . . . . . . . 2 1.1 Chemical Characterization of Device Components. . . . . . . . . . . . . . . . . . . 2 1.1.1 Process tree. . . . . . . . . . . . . 2 1.1.2 Master List . . . . . . . . . . . . . 3 1.1.3 Chemical characterization of Polymer Precursors. . . . . . . . . . 3 1.2 Sterilization processes.. . . . . . . . . . . . 4 1.3 Quality Assurance/control.. . . . . . . . . . . 4 2. Preclinical data . . . . . . . . . . . . . . . . . . 5 2.1 Device physical and chemical characterization. . 5 2.1.1 Tensile Testing . . . . . . . . . . . 5 2.1.2 Tear Resistance of Shells . . . . . . 6 2.1.3 Abrasion Resistance and Analysis. . . 8 2.1.4 Integrity of Adhered or Fused Joints. . . . . . . . . . . . . . . . 10 2.1.5 Fatigue Life. . . . . . . . . . . . . 11 2.1.6 Silicone Bleed. . . . . . . . . . . . 13 2.1.7 Cohesivity of Gel . . . . . . . . . . 17 2.1.8 Valve Competence. . . . . . . . . . . 19 2.1.9 Testing of Explanted Materials (Biodegradation). . . . . . . . . . . 19 2.1.10 Chemical characterization of the Finished Device . . . . . . . . . . . 20 2.2 Toxicological Evaluations . . . . . . . . . . . 22 2.2.1 Pharmacokinetics Studies. . . . . . . 23 2.2.2 Mutagenicity Testing. . . . . . . . . 24 2.2.3 Acute, subchronic, and Chronic Toxicity, Carcinogenicity, Teratogenicity, and Immunotoxicity. . 24 3. Clinical data. . . . . . . . . . . . . . . . . . . . 25 4. Labeling . . . . . . . . . . . . . . . . . . . . . . 30 V. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . 33 APPENDIX I - EXTRACTION GUIDELINES FOR SILICONE IMPLANTS . . . .34 APPENDIX II - SELECTED BIBLIOGRAPHY OF ANALYTICAL METHODOLOGIES . . . . . . . . . . . . . . . . . . . 39 DRAFT GUIDANCE FOR PREPARATION OF PMA APPLICATIONS FOR TESTICULAR PROSTHESES I. PREFACE This guidance document addresses the preparation of FDA Premarket Approval (PMA) applications for testicular prostheses. It may also be useful in the preparation of Investigational Data Exemptions (IDE) applications, reclassification petitions, and master files. Development of this document is based upon scientific review and analysis by the FDA and by published and unpublished studies. II. DEVICE DESCRIPTION A testicular prosthesis is an implanted device that consists of a solid or gel-filled silicone rubber prosthesis that is implanted surgically to resemble a testicle. III. BACKGROUND In the FEDERAL REGISTER of November 23, 1983 (48 FR 53023), FDA issued a final rule classifying the testicular prosthesis into class III (21 CFR 876.3750). In the FEDERAL REGISTER of January 6, 1989, (54 FR 550), FDA published a notice of intent to initiate proceedings to require premarket approval of 31 preamendments Class III devices, including testicular prostheses. In the Federal Register of January 13, 1993 (58 FR 4116), FDA issued a proposed rule requiring a PMA for testicular prostheses. These proceedings were enacted on _____________________, requiring a PMA for these devices be filed with the agency within 90 days. IV. GENERAL REQUIREMENTS OF PREMARKET APPROVAL (PMA) APPLICATIONS FOR TESTICULAR PROSTHESES A PMA must be submitted by all distributors of testicular prostheses. Any PMA submitted must meet the content requirements contained in Section 515(c)(1) of the Federal Food, Drug and Cosmetic Act (the act) and 21 CFR 814.20. A PMA must also include a detailed discussion, with results of preclinical and clinical studies, of the safety and effectiveness of the device. In particular, the PMA shall include all known or otherwise available data and other information regarding: (1) any risks known to the applicant that have not been identified in this document, and (2) the effectiveness of the specific testicular prosthesis that is the subject of the application (or, if adequate justification can be provided, applicable effectiveness information for other testicular prostheses). Valid scientific evidence, as defined in 21 CFR 860.7, addressing the safety and effectiveness of the device should be presented, evaluated and summarized in a section or sections of the PMA separate from known or otherwise available safety and effectiveness information that does not constitute valid scientific evidence (e.g., isolated case reports, random experiences, etc.). This must include but not be limited to: 1. Manufacturing Data: Complete manufacturing information must be submitted in accordance with the "Guidance for the Preparation of PMA Manufacturing Information". This guidance is available upon request from the Division of Small Manufacturing Assistance (HFZ-220), Center for Devices and Radiological Health, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. In addition, the following specific chemical processing, sterilization, amd quality assurance information is required to assess the safety and effectivness of testicular prostheses. 1.1 Chemical Characterization of Device Components Manufacturing and process tree information show how the components of a device are made from starting materials. This identifies potentially leachable chemicals and immediate precursors of crosslinked polymers. Only a limited amount of chemical characterization can be done on highly crosslinked polymers. For such polymers, it is important to characterize the immediate precursors to assure the quality of the base polymers and crosslinking agents. The viscosity and molecular weight distribution are very basic characteristics of all polymers that greatly influence the mechanical and physical properties of the device. Determination of volatile content, extent of chemical crosslinking, and the sol fraction of components characterizes the curing processes that are used. These determinations should be done on 10 or more lots to establish that control of the chemical processing exists. 1.1.1 Process tree Chemical formulation and manufacturing information, presented in a step-by-step process, from the starting materials to composites to the final products, including, but not limited to, all nonreactants and reactants (including catalysts, curing agents, and intermediate precursors) must be provided for all device components. On this tree, any substance or material identified by some sort of company name or code must also be identified by a corresponding common chemical name. 1.1.2 Master List A complete master list of common chemical names and alternate names (company, trade and code) for all nonreactants, reactants (including intermediate precursors), additives, catalysts, adjuvants, and products should be provided. The same name for each specific compound must be utilized throughout the document. 1.1.3 Chemical characterization of Polymer Precursors Chemical characterization of the elastomer intermediates (i.e., network precursors) of the various components of the device sufficient to demonstrate control of chemical processing of the device materials should be provided. This should be based on lot-to-lot comparisons (minimum of 10 consecutive lots) of the following information: a. the molecular weight distribution, expressed as weight average molecular weight (Mw), number average molecular weight (Mn), and polydispersity (MWD) of these precursors. b. analyses for volatile and nonvolatile (if applicable) compounds, such as cyclic oligomers, to establish the upper limit of these compounds and to show that they are being controlled. c. if copolymers are being used, data to show that the composition of these copolymers is under control and that a consistant product is being made. Usually, such data would consist of analyses of the group content of the copolymer, for example, phenyl, fluoro, vinyl, hydroxyl number, acid number, peroxide, etc. as appropriate. d. when viscosity is used as the variable that is measured for production control, a comparison of viscosity, Mn, and volatile content should be given on a lot-by-lot basis to show that viscosity monitoring is sufficient to control the chemical processing. e. if composites or filled or reinforced polymers are being used the fillers should be characterized. The particle size or surface area of any reinforcing and nonreinforcing filler should be given. If silica is being used the percent crystallinity should be provided. 1.2 Sterilization Processes Standard operating procedures for sterilizing and qualifying the sterilization process must be provided. Provided information should include the method of sterilization; the detailed sterilization validation protocol/results; the sterility assurance level; the type of packaging; the packaging validation protocol/results; residual levels of ethylene oxide, ethylene glycol, and ethylene chlorhydrin remaining on the device after the sterilization quarantine period, if applicable; and the radiation dose, if applicable. 1.3 Quality Assurance/control A QA/QC plan that demonstrates how raw materials, components, subassemblies, and any filling agents will be received, stored, and handled in a manner designed to prevent damage, mixup, contamination, and other adverse effects must be provided. This plan shall specifically include, but not necessarily be limited to, a record of raw material, component, subassembly, and filling agent acceptance and rejection, visual examination for damage, and inspection, sampling and testing for conformance to specifications. Written procedures for finished device inspection to assure that device specifications are met must be provided. These procedures shall include, but are not limited to, that each production run, lot or batch be evaluated and, where necessary, tested for conformance with device specifications prior to release for distribution. A representative number of samples shall be selected from a production run, lot or batch and tested under simulated use conditions and to any extremes to which the device may be exposed. Furthermore, the QA/QC procedures should include appropriate visual testing of the packaging, packaging seal, and product. Sampling plans for checking, testing, and release of the device shall be based on an acceptable statistical rationale (21 CFR 820.80 and 820.160). 2. Preclinical Data 2.1 Device Physical and Chemical Characterization Appropriate physical and chemical properties of the device must be characterized. Each item must be supported by complete reports (i.e., protocols with a full description of test methods and raw data). These reports must be from the testing of an adequate number of samples obtained from sterilized devices produced by the standard manufacturing procedures. Each and every distinct type of shell, patch, gel, and all other components critical to the integrity of the devices must be tested separately to account for any variations in chemical composition, physical texturing, component thickness, sterilization method, etc. (but not simple variations in size of devices or device components). 2.1.1 Tensile Testing (Determination of Uniaxial Tensile Strength, Ultimate Elongation, and Energy to Rupture) of shells and patches of liquid-filled or filled testicular prostheses Shell rupture and subsequent liquid or gel leakage are anticipated outcomes in some unknown percentage of implanted filled testicular prostheses. Whether this rupture is primarily caused by externally-induced damage, by biodegradation, or by fatigue of the materials due to repeated loading is unknown. It is clear, however, that the shell and patch materials (and any other elastomeric materials that comprise a lumen of the finished device) must possess a minimum level of mechanical strength and energy absorbing capacity in order for the implant to be able to withstand anticipated service loads without rupture. As a minimum baseline data set, the uniaxial tensile properties of the shell and patch materials, in the form and configuration representative of as-implanted devices, must be known. Because the morphology of the materials can be affected by processing, and because liquid or gel absorption into the shell and patch material can affect tensile properties, test samples must be cut from finished devices rather than from specially-cast material or unplaced shells or patches. Also, because tensile properties can be significantly affected by various sterilization cycles and by the existence of fold flaws in the material, these parameters must be studied as well. Measured tensile properties of the elastomeric components of the devices must include tensile strength, elongation at failure, and strain energy at failure. The methodology of tensile testing should be in accordance with ASTM Method D412. Because test-to-test variability appears to be significant in some cases, statistical assessment of variability and raw data must be reported. 2.1.2 Tear Resistance of Shells and Patches of Liquid Filled or Gel-Filled Testicular Prostheses Shell rupture and subsequent liquid or gel leakage are anticipated outcomes in some unknown percentage of implanted filled testicular prostheses. Whether this rupture is primarily caused by externally-induced damage, by biodegradation, or by fatigue of the materials due to repeated loading is unknown. It is clear, however, that the shell and patch materials (and any other elastomeric materials that comprise a lumen of the finished device) must possess a minimum level of mechanical strength and energy absorbing capacity in order for the implant to be able to withstand anticipated service loads without rupture. The exact mechanism of failure in elastomeric materials is difficult, if not impossible, to determine based on morphological changes. Thus, it is not known whether fatigue, creep, tensile overload, or some other mechanism is involved. Whether losses in shell integrity are initiated by material failure or externally induced puncture, the shell material must provide some protection against catastrophic propagation of a tear or puncture with consequent loss of liquid or gel from the lumen. This material characteristic is generally called tear resistance, and the methodology is covered in ASTM Method D624. Because the morphology of the material can be affected by processing, and because liquid or gel absorption into the shell material can affect properties, test samples must be cut from finished devices rather than from specially-cast material or unplaced shells. Also, because material properties can be significantly affected by various sterilization cycles, effects of these treatment(s) on tear resistance must be studied. Because test-to-test variability appears to be significant in some cases, statistical assessment of variability and raw data must be reported. In addition to shell materials, tear resistance of patches and any other elastomeric components comprising a lumen of the finished device must be determined. As is the case with shells, a propagated tear in any of these other components could conceivably lead to loss of liquid or gel from the lumen. 2.1.3 Abrasion Resistance and Analysis of Abraded Surfaces of Solid Silicone and Silicone Liquid-Filled or Gel-Filled Testicular Prostheses Silicone elastomers used in testicular prostheses are relatively soft and are prone to abrasive degradation at their surfaces. While being placed in the incision in the scrotum of a patient, a prosthesis is rubbed against scrotal tissue. When the patient moves, tissue or other anatomic structures move over the prosthesis and/or its fibrous capsule. Formation of a hernia or fold in the shell in a filled device could conceivably cause portions of the shell to rub against itself. Rubbing actions such as these can abrade the surface of the device. Concern over abrasion is heightened when the surface of the device is textured. Depending upon the nature of the texturing process, the topography of the surface may be either regular or irregular. In either case, some portion of the surface material will project from the bulk material of the shell. Shear stresses exerted on this projected surface material will be greater since the shear forces will be distributed over smaller areas. Thus, when compared to smooth surface material, textured surface material is more prone to crack formation, tearing, and abrasion for a given shear force. Abrasion can lead to weakening of the device surface making it more prone to mechanically induced trauma. Abrasion can also release small particles of silicone elastomer into the body. These small particles can be attacked by white blood cells which try to digest the particles. However, because of the relative inertness of the silicone particles, they cannot be digested by the white blood cells. Instead, the white blood cells are destroyed (lysed) by the attempt to digest the silicone, which can then result in the formation of a mass of chronically inflamed tissue (i.e., a silicone granuloma), which must be surgically removed (Ref. 1). If the particles are sufficiently small, they can be transported to other regions of the body where the same processes can produce distant silicone granulomas. In addition, the literature reports that abrasion of a silicone elastomer can expose the particles of silica added to reinforce the elastomer (Ref. 2). Crystalline silica is recognized as a sclerogen, i.e., an agent which produces hard or sclerotic tissue, capable of causing adverse reactions when placed in the body (Ref. 3). Amorphous fumed, rather than crystalline, silica is typically used to reinforce the silicone elastomers of these devices. However, there are still concerns over the presence of minute crystalline silica impurities in the reinforcer and whether there is any significant in vivo conversion of amorphous silica into crystalline silica. The abrasion resistance of the surface of the silicone testicular prosthesis and the particle size distribution of the material abraded from the prosthesis must be known in order to determine whether the device is safe and effective. In order to respond to unanswered questions concerning the adverse effects of exposing silica in the body, abrasion resistance testing, followed by examination of the abraded surface for the presence or absence of silica, must be performed to determine whether a testicular prosthesis is safe and effective. Reports on abrasion resistance testing of solid silicone testicular prostheses and shell materials of liquid filled or silicone gel-filled testicular prostheses must contain relevant information on the equipment and abrader used, identification and dimensions of specimens, and detailed protocols. In particular, a standard abrasion test machine, or equivalent specialized equipment, must be used to conduct the testing. In addition, a complete description of the test apparatus must be provided. A description of the apparatus used, including the number of specimens that can be tested simultaneously, the dimensions (width and length) of both the maximum sample size and the maximum abrading area, and the manner in which specimens are held, must also be provided. The material used to abrade specimens must be identified, and a rationale for choosing this material must be provided as well. Properties of the abrading medium including hardness, roughness, etc., that are pertinent to the abrasion process, also must be identified. As usual, test specimens must be obtained from shells of sterilized finished devices manufactured according to the sponsor's standard methods. Testing must be conducted on each and every silicone elastomer (comprising the outer surface of the device) of all varieties of composition and surface texture. Significant weight losses in abraded material must be induced, and the total number of passes (by the abrasive medium) required to induce this observed weight loss must be reported. Averages, standard deviations, detailed protocols, cycling rates, and raw data must be reported. Examinations for exposed silica (particularly crystalline silica) of both the abraded surfaces and abraded particles from test specimens must be conducted and reported. Percentanges of crystalline silica and the total content of crystalline silica in these abraded particles must be analyzed for and reported. Particle size distributions of abraded particles must be reported. 2.1.4 Integrity of Adhered or Fused Joints of Liquid-Filled or Gel-Filled Testicular Prostheses. It is anticipated that leakage of liquid or gel from filled testicular prostheses occurs in some unknown percentage of implanted devices. In addition to rupture of the primary shell material, failure of a joint associated with a seal of the filling hole patch or valve is a potential source for liquid or gel leakage. Consequently, it is necessary that the joints between the various components comprising the shell of the device be as strong as possible so that the strength of the shell is not compromised. At the very least, the breaking force, normalized to joint thickness, must be provided for tensile specimens containing each and every type of joint critical to the integrity of a lumen in the device. In addition, because it is known that shells of filled testicular prostheses are perfused by swelling agents from the liquid or gel contained in the devices, and because sterilization could affect the integrity of a seal, the specimens used for joint testing must be obtained from finished, manufactured devices that have been sterilized. Raw data, including joint thicknesses of each and every test specimen, must be provided. (It is noted that unlike the test methods outlined in section 7.2 of ASTM standard F703, testing of adhered and fused joints must be conducted to the failure points of the specimens.) 2.1.5 Fatigue Life of Solid Silicone and Liquid-Filled or Silicone Gel-Filled Testicular Prostheses (Construction of Applied Force/Number of Cycles to Failure Curve for Device) Most materials are subject to a finite fatigue life when repeatedly stressed or flexed. Repeated compression, folding, bending, or flexing of the device, with time, weakens the silicone elastomer of a device and may eventually lead to failure of the device. Rupture or failure of the shell of a silicone gel-filled testicular prosthesis can cause release of the silicone gel into the body, possibly leading to migration of silicone to regional lymph nodes and other organs. (Thus, from the standpoint of safety, it is much more important that fatigue testing be conducted on silicone gel-filled devices as opposed to testing of solid silicone devices.) Rupture of the shell can also lead to deflation of a liquid-filled or gel-filled testicular prosthesis, producing a deformity requiring surgical intervention in order to be corrected. Failure mechanisms of these devices are addressed by compressive fatigue testing in which a constant compressive force is cyclically applied to an intact silicone (solid or filled) prosthesis until the device fails. The number of cycles the prosthesis can endure prior to shell failure is an indirect estimate of the maximum amount of time the device can remain intact in the body. Other effects of immersion in a biological system may reduce this estimated lifetime, but the fatigue life of the prosthesis is a good measure of the absolute maximum working life a patient can expect from a testicular prosthesis. Full characterization of the compressive fatigue life of a filled testicular prosthesis is more involved and time-consuming than simple uniaxial (i.e., one-dimensional) tensile testing of the device's shell material. However, the results of compressive fatigue testing are much more pertinent to an assessment of the safety and effectiveness of a testicular prosthesis. A prosthesis subjected to compressive fatigue testing experiences a complex combination of tensile, torsional, compressive, and radial forces not experienced by shell specimens in uniaxial tensile testing. Thus, the mode of testing closely mimics the one, two, and three-dimensional forces which are likely to be experienced by an actual implanted testicular prosthesis. Compressive fatigue testing is also advantageous over uniaxial tensile testing in that the test device remains intact (until the point of rupture) for the duration of the testing. In compressive fatigue testing, unlike uniaxial tensile testing, the tested shell material of a filled device maintains contact with the liquid-fill or gel-fill of the device. This is not the case for specimens for tensile testing excised from the shells of gel-filled testicular prostheses. Implanted testicular prostheses are subjected to a variety of compressive loads of differing magnitudes and differing frequencies of occurrence. Given the variability in frequency and magnitude of compressive loadings on implanted testicular prostheses, it is important that a full range of compressive forces be used in fatigue testing of the devices. Thus, an applied force versus number of cycles to rupture of the device (AF/N) curve must be constructed for each and every model of testicular prosthesis. The resultant data points used to construct each curve must be sufficient to plot the asymptotic endurance, or "fatigue force" limit, of the device and to approximately determine the "elbow point", i.e., the location of the maximum change in curvature of the AF/N plot, if any exists. Each curve must also contain an average value for failure of the device due to a single blow, i.e., a single stroke of loading. Data from the AF/N plot should be used to calculate and report the applied force corresponding to 6.5 million cycles times the anticipated and/or labelled lifetime of the device in years. (6.5 million cycles per year corresponds to an adult male walking 5 hours per day at one step per second, i.e., 1 hertz.) The theoretical applied force, experienced during walking, on an actual implanted testicular prosthesis should be calculated (along with a suitable safety factor) and reported. A comparison of the theoretical in vivo and experimentally determined applied forces to the testicular prosthesis should be reported. A frequency of 1 Hertz must be used for the cycling rate of the testing. This frequency approximates the frequency of loading experienced in walking and also avoids undesirable heating effects which can occur at higher testing frequencies. 2.1.6 Silicone Bleed of the Shell and Patch Materials of Silicone Gel-Filled Testicular Prostheses Silicone bleed permeation, which is the seepage of silicone fluid components of the internal gel fill through an intact shell of a silicone gel-filled testicular prosthesis, is one means by which the device can release silicone into the human body. The body is essentially a fluid receptacle for the liquid silicone released by the device. As the liquid silicone emerges from the shell, it can dissipate into the body by at least two mechanisms. The silicone bleed product can be transported away from the device by simple diffusion, that is, liquid flow in the extracellular fluid as this fluid perfuses the region adjacent to the surface of the prosthesis. The bleed product can also be taken up by white blood cells, primarily macrophages in the tissues, and carried to lymph nodes or other organs. Because the liquid silicone is constantly removed from the region of the prosthesis, the bleed process cannot come to a halt. This results in the body acting as an "infinite sink" for the liquid silicone. Determination of liquid silicone bleed rates is particularly important in the case of silicone gel testicular prostheses. A large percentage of these devices are implanted in infants. Thus, small quantities of silicone bleed products may have proportionately larger effects when body weights are small and immune systems are not as fully developed as in adults. Steady-state diffusion coefficients for silicone bleed permeation rates from silicone gel-filled testicular prostheses must be determined so that sound estimates can be made of long-term accumulations of silicone into a patient's body. These steady-state diffusion coefficients must be determined for individual components of the silicone bleed as well. Silicone molecules in gel bleed product have a range of molecular weights, which cannot be assumed to be representative of the range of molecular weights found for molecules of silicone fluid in the gel inside the device. In fact, it is likely that silicone molecules of smaller molecular weight possess higher permeability rates through intact shells of testicular prostheses than do silicone molecules of higher molecular weight. Thus, the composition of the bleed product is likely, at any given time, to be skewed toward lower molecular weight components in comparison to the composition of the fluid components of the gel inside the device. These lower molecular weight silicone molecules are also more likely to stimulate biological activity. Therefore, accurate assessments of the likelihood of long-term toxicological response to an implanted prosthesis (that remains intact) require accurate dose rates of individual liquid silicone components in the bleed, especially those of the lowest molecular weights. Various methodologies for performing liquid silicone bleed permeation testing have been used or proposed. Measured coefficients for diffusion of components of liquid silicone through a prosthesis are largely dependent upon the receptacle medium used to collect the bleed. It is possible to conduct the experiment using either a solid-state medium or a liquid-state medium. While, in general, solid-state receptacles are easier to use, there are major drawbacks associated with them. The major drawback to using a solid-state medium is the potential for significant loss of volatile silicones of low molecular weight. Unlike a liquid receptacle diffusion cell, the placement of a testicular prosthesis on a disk or a filter is an experimental system open to air or vacuum. Substantial amounts of volatile silicones may be lost (during the bleed experiment and/or during subsequent extraction of the disk or filter) and thus excluded from compositional analysis of the bleed product. Yet, as explained earlier, it is vital that accurate short-term and long-term dose rates of these low molecular weight, volatile silicones be established. Therefore, a liquid-state receptacle medium must be used to conduct liquid silicone bleed experiments in order to adequately assess the potential risks attributable to liquid silicone bleed from silicone gel-filled testicular prostheses. A stirred receptacle medium of physiological saline is the best means of emulating actual in vivo bleed rates. Stirring of the saline medium is necessary to more accurately account for the "infinite sink" conditions which, as discussed earlier, exist in the body. Stirring of the saline medium transports a portion of the poorly soluble silicones from the membrane surface such that a concentration gradient in the vicinity of the surface is maintained. In summary, bleed permeation experiments must be conducted as following: A standard liquid diffusion cell, maintained at a temperature simulating physiologic conditions must be employed. The upper compartment must consist of gel obtained from a sterilized, finished, and manufactured testicular prosthesis. The membrane must consist of shell and/or patch material obtained from the same sterilized, finished, and manufactured device from which the gel sample was obtained. The bottom compartment must consist of the receptacle medium for the liquid silicone bleed product. The outer-most gel contacting shell material must be tested, as well as any patch material comprising the same lumen as this shell. Each variety of shell and/or patch material varying significantly in thickness or design must be tested separately. Each variation in gel must be tested separately. Control cells must also be employed to correct measurements for background levels of silicone. Stirred physiological saline should be used as a receptacle medium. While CDRH believes that useful information (as to a "worst possible case" scenario) can still be obtained from a bleed experiment into a hydrocarbon solvent, the priority for testing into stirred saline is much greater. In any case, if a manufacturer believes that a different solvent is more suitable to the bleed experiment, full justification must be provided to CDRH as to the choice of solvent. Sufficient amounts of liquid silicone bleed must be collected and analyzed on a time-course basis such that both short-term accumulation amounts and long-term, i.e., steady-state, diffusion coefficients of both total bleed and individual components of liquid silicone bleed can be estimated. Analyses of bleed permeation data indicate that limiting steady-state coefficients can be obtained from properly conducted experiments provided sufficient time is allowed to establish equilibrium bleed rates. The intervals at which bleed product is analyzed for chemical identity and molecular weight shall be determined by the manufacturer, but must be such that steady-state diffusion coefficients, particularly of low molecular weight silicones, can be determined with sufficient accuracy. It is not sufficient for a manufacturer to simply measure the total weight of liquid silicone bleed as a function of time. The bleed product must be adequately analyzed and resolved in order to determine accurate dose rates of smaller linear and cyclical silicones of, e.g., molecular weights of 1500 or less. All extraction procedures for these low molecular weight silicones must be validated for percent recovery. Additional parameters needed to estimate long-term in vivo accumulation rates of liquid siicone components must also be provided. These parameters include the normalized cross-sectional area of each and every membrane tested, the average thickness of each and every membrane tested, estimates of the total surface area (for the intact device) of each testicular prosthesis tested, and estimates of the minimum and maximum surface areas for the size range of each type of silicone gel-filled testicular prosthesis tested. As with all other physical and chemical testing reports, detailed protocols, calculation methods, all raw data (on a time-course basis), and calculated averages with standard deviations must be provided. 2.1.7 Cohesivity of Gel in Silicone Gel-Filled Testicular Prostheses Gel cohesivity testing is designed to measure both the rheological, or flow, properties of the gel and the integrity, or connectivity, of the gel. In the event of device (and enclosing capsular tissue) rupture, it is important that the gel maintain some degree of consistency and cohesiveness in order to facilitate surgical removal. A less cohesive gel may thwart substantial recovery of the gel, and portions of it may be more prone to migrate throughout the body. A desired consistency of silicone gel is obtained by blending several polymeric components together. Cohesivity tests are designed to measure the inseparability of these various components as well as to indicate the flow characteristics of the gel by looking at the extrusion of the gel through a specified orifice under the influence of gravity. Since it is possible for the rheological properties of the gel to change as a function of sterilization cycle(s), the materials used in gel cohesivity testing must be from finished, sterilized manufactured devices. Specifications for cohesivity testing in the ASTM F703 Standard for gel-filled breast prostheses state that the silicone gel contained in the finished product is to be considered acceptable if there is no total separation of any component of the pendant gel, and if the pendant portion does not exceed 4.5 cm after 30 minutes at room temperature in a die with specified dimensions and tolerances. A similar methodology of testing would be appropriate for silicone gel-filled testicular prostheses. Reported results for gel testing must include the actual measurements of gel slump in gel cohesivity testing and/or measurements of penetrometer fall in gel penetration testing. Detailed protocols, raw data, averages and standard deviations, and the manufacturer's specific pass-fail criteria must be provided. The chosen test method(s) must be adequately sensitive to detect significant variances in gel cohesivity and/or stiffness. Cohesivity of the gel can, in many respects, be predicted from detailed chemical characterization of the gel product. Knowledge of information such as molecular weight averages of gel components, percentages of cross-linked and uncross-linked silicones, and average degrees of functionality for precursors of cross-linked silicones, is important in predicting the degree of cohesion in a silicone gel, as well as its relative tendency to bleed liquid silicone components. This information must be provided as well. 2.1.8 Valve Competence Leakage via a partially or fully failed valve of a fluid-filled testicular prosthesis may or may not (depending upon the degree of toxicity of the fill) pose a safety concern to the patient. In any case, however, maintenance of valve integrity is necessary to the efficacy of fluid-filled testicular prostheses employing valves. Manufacturers must demonstrate that valve integrity is maintained at actual anticipated maximum service loads (with an appropriate safety factor). The most informative means of performing this testing is to gradually increase the induced pressure in the test devices until valve failure occurs and a maximum service pressure can be defined for the device. It should also be determined whether the failed test valves reseal upon removal of the excess failure-inducing pressures. 2.1.9 Testing of Explanted Materials (Biodegradation) The effects of implantation, including the stresses of the biological environment, on device materials and integrity should be determined by appropriate animal testing. Complete material, chemical and physical characterization should be performed on devices explanted from animals after an appropriate implantation duration. Results on tests of explants should be compared to results on unimplanted devices and conclusions about degradation of materials or components drawn. The results of this testing should also be compared to failure rates determined in in-vitro tests and clinical studies, in order to demonstrate that the animal model and study duration are appropriate. 2.1.10 Chemical characterization of the Finished Device 188.8.131.52 Crosslinking If fabrication of the device involves curing of polymeric components by chemical crosslinking, then data establishing the extent and reproducibility of the crosslinking should be provided. This may be done by a various methods, for example; a. Measurement of Young's modulus at low strain as this is approximately proportional to crosslink density. b. Measurement of equilibrium swelling of the polymeric component by a good solvent. c. Measurement of the soluble (sol fraction) content of a gel. Determination of total extractables using a good solvent could accomplish this. d. Determination of the amount of unreacted crosslinker from its concentration in the total extractables. 184.108.40.206 Leachable Chemicals Determination of the extractable or releasable chemicals in an implant device are necessary for assessment of the safety of the device. Chemical identification and quantification of releasable chemicals is necessary to facilitate the determination of safe levels by dose-response toxicological methods. Migration rates of the releasable chemicals from various components of the device may also be evaluated when providing toxicology data. Knowledge of the levels of volatiles and residues in the device provides an upper limit to the amount of releasable chemicals from the various components as they are found in the final sterilized device. This is necessary to relate amounts of releasable chemicals back to device characteristics as these are factors that should and can be controlled in the manufacturing process. Complete identification and quantification of all chemicals, such as; a. residual monomers, cyclics, and oligomers; b. known toxic residues such as polychlorinated biphenyls (PCBs) if dichlorobenzoyl peroxides are used, heavy metals, aromatic amines if polyurethanes are used, and residues of transition metal catalysts; c. residues of ethylene oxide if that is used for sterilization; d. additives and adjuvants used in the manufacture of the device, such as plasticizers, antioxidants,etc.; below a molecular weight of 1500, exhaustively extracted from each of the individual structural components as they are found in the final sterilized device should be reported. The solvents used for extraction should have varying polarities and should include, but not be limited to dichloromethane and ethanol/saline (1:9). Other, more contemporary extraction techniques such as supercritical fluid extraction, may also be useful - at least for exhaustive extraction of the silicone materials. Experimental evidence must be provided to show that exhaustive extraction has been achieved with one of the solvents, and the percent recovery, especially for the more volatile components, be reported. Extracts that may contain oligomeric or polymeric species must have the molecular weight distribution provided, along with the number and weight average molecular weights and the polydispersity. Guidelines for extraction and a selected bibliography of analytical methodologies are included as Appendix I and II respectively. All experimental methodology must be described, and raw data (including instrument reports) provided along with all chromatograms, spectrograms, etc. The practical quantitation limit (PQL) (see "Compilation of EPA's sampling and analysis methods, Lewis publishers 1992) must be provided when the analyte of interest is not detected. Laboratory test methods and animal experiments used in the characterization of the physical, chemical (other than exhaustive extraction), and mechanical properties of the device should be applicable to the intended use of the device in humans. 220.127.116.11 Surface Composition Infrared measurements of the surface of device components as they occur in the final sterilized product should be provided. This establishes the major chemical characteristics of the surface which may differ from the bulk. This information will provide baseline characterization for comparison with explants. 2.2 Toxicological Evaluations The synthetic polymeric materials used in testicular prostheses should not present a toxic risk upon long-term intimate contact with the body. The high molecular weight polymeric material used in silicone testicular prostheses contains low molecular weight components, such as monomers, oligomers, and catalysts which can leach out into the body. Therefore, one important requirement of the preclinical toxicology testing of the device is to determine the potential toxicity of these releasable chemicals as they appear in the final sterilized device. These tests should reveal the potential for local as well as systemic toxicity (including genotoxicity, carcinogenicity, adverse reproductive effects, teratogenicity, and immunotoxicity) of any leacable substance. Thus, the chemicals recovered by extraction of the final sterilized implant material, when appropriate, should be used as the test article in animal studies after they are separated, quantified and identified. In addition, the primary concern for any implanted device is its potential to cause cancer. This potential may arise not only from chemical leachables and degradation products from the device, but also from physical effects of the device at the implanted site. Therefore, adequate long-term studies with implantation of device materials should be conducted to evaluate the carcinogenic potential of testicular implants. The Tripartite Biocompatibility Guidance for Medical Devices (September 1986) lists suggested short-term (irritation tests, sensitization assay, cytotoxicity, acute systemic toxicity, hemocompatibility/hemolysis, pyrogenicity (material-mediated), implantation tests, pharmacokinetics studies, mutagenicity (genotoxicity)) and long-term (subchronic toxicity, chronic toxicity, carcinogenesis bioassay, reproductive and developmental toxicity) biological tests that might be applied to evaluating the safety of medical devices. The guidance may also be used in selecting appropriate tests for the evaluation of testicular implants. 2.2.1 Pharmacokinetics Studies Pharmacokinetic/biodegradation studies of all materials contained in the finished sterilized device must be reported. Of special concern are questions regarding the ultimate fate, quantities, sites/organs of deposition, routes of excretion, and potential clinical significance of silicone shedding, retention and migration. For the polyurethane foam covered designs, FDA believes that in vivo implant studies must be performed to identify and determine the bioabsorption, distribution, and elimination of the polyurethane coating (as well as its degradation products) in experimental animals. It is also important to identify and determine the mechanism and rate of degradation, as well as the quantity of toluene diamine (TDA) generated by the breakdown of polyurethane foam covered testicular prostheses after prolonged exposure under physiological conditions in animals. 2.2.2 Mutagenicity Testing Complete reports from the mutagenicity testing of chemicals extracted from the finished, sterilized components of the device must be provided. The testing must, at minimum, consist of bacterial mutagenicity, mammalian mutagenicity, DNA damage, and cell transformation assays. 2.2.3 Acute, Subchronic and Chronic Toxicity, Carcinogenicity, Teratogenicity, and Immunotoxicity Acute, subchronic, and chronic toxicity, carcinogenicity*, reproductive and teratological effects* and immunotoxicity* studies should be conducted on the final sterilized product, using either device materials and/or appropriate extracts of the device materials. In particular, studies should assess compounds extracted from the materials of the final sterilized device for estrogen-like antigonadotropic activity in an appropriate animal model using scientifically valid methods. Complete reports from acute and subchronic toxicity testing of extractable chemicals contained in the final sterilized device should include gross and histopathological studies in appropriate tissues both surrounding and remote from the implanted site. *For specific and detailed guidance on these studies, please contact the urology and Lithotripsy Devices Branch at (301) 427-1194. 3. Clinical data Valid scientific evidence, as defined in 21 CFR 860.7, should include well-controlled, prospective, clinical studies, with statistically justified sample size and detailed long-term follow-up, in order to provide reasonable assurance of the safety and effectiveness of the testicular prosthesis. A detailed protocol for the clinical trial, with explicit patient inclusion/exclusion criteria, clear study objectives, and a well-defined follow-up schedule, should be specified. FDA believes that at least five year follow-up data (or until physical maturity of the subject, whichever occurs later) are necessary in order to characterize the safety and effectiveness of the device over its expected lifetime; however, appropriately justified alternate follow-up schedules will be considered. Any deviations from the protocol should be stated and justified. Time course presentations of patient satisfaction with and psychological benefit from the implantation of this device, as well as information on the anatomical effects of the testicular prosthesis (including all adverse events), should be provided. Full patient accounting should be reported, including: (1) theoretical follow-up (the number of patients that would have been examined if all patients were examined according to their follow-up schedules); (2) patients lost to follow-up, including measures taken to minimize such events (with all information obtained on patients lost to follow-up); (3) time course of revisions, including all explant data; and (4) time course of deaths (stating the cause of death, including the reports from any postmortem examinations). As part of this, each clinical report should clearly state the date that the database was closed to the addition of new information. Detailed patient demographic analyses and characterizations should be presented, and should show that the patients included in the study are representative of the population for whom the device is intended. A statistical demonstration, based on the number of patients who complete the required study period, should show that the sample size of the clinical study is adequate to provide accurate measures of the safety and effectiveness of the device. The statistical demonstration should identify the effect criteria; reasonable levels for Type I (alpha) and Type II (beta) errors; anticipated variances of the response variables; and provide any assumptions or statistical formulas with copies of any references used and all calculations made. A complete description of any patient randomization techniques used, and how these techniques were employed to exclude potential sources of bias, should be provided. Statistical justifications for pooling across several variables such as the etiology and duration of scrotal abnormality, patient age, anatomical abnormalities of the genitalia, device usage (initial implantation versus revision), type of device (solid or silicone gel-filled, polyurethane foam coated or uncoated, size, etc.), type of device surface, investigational site, surgeon experience and technique, and incision site should be provided. The data collected and reported should include all possible relevant variables in order to permit stratification and analysis of the study data. This is necessary in order to evaluate the risk/benefit ratio for each unique subpopulation of patients. Appropriate control/comparison groups should be included and justified and, if not, their absence must be justified. All hypotheses to be tested must be clearly stated. Appropriate statistical techniques must be employed to test these hypotheses and support claims of safety and effectiveness. For each relevant subgroup, a sufficient number of patients needs to be followed for a sufficient length of time to adequately support all claims (explicit and implied) in any PMA submission. To evaluate the risks to the patient from the testicular prosthesis, such studies should include time course presentations of clinical data demonstrating the presence or absence of device migration, skin erosion, implant extrusion, rupture/leakage, fibrous capsular contracture, infection, patient dissatisfaction leading to removal, or any other device malfunction or adverse health event, including any effects on the immune system (both local to the device and systemic) and the reproductive system, without regard to the device relatedness of the event. The diagnostic criteria for each type of immunological and allergic phenomenon should be defined at the beginning of the study, and all cases should be well documented utilizing these criteria. Patients must be regularly monitored for the occurrence of such adverse events for a minimum of five years post-implantation, or until physical maturity of the subject (whichever occurs later). FDA recognizes that the primary benefit of the testicular prosthesis is cosmetic in nature. The effectiveness of the device can probably be measured by assessing: (1) the degree of maintenance or enhancement of a male's psychological well-being post-implantation; and (2) the anatomical effect provided by the device in vivo; both of which can be balanced against any illness or injury from the use of the device. FDA understands that evaluation of the degree of benefit, in part, involves an assessment of patient satisfaction and psychological well-being, particularly in light of the function of the device. Such evaluation includes subjective factors, relates to patient expectations, and may be transient in nature. Assessments of the implant's anatomical presence post-implantation, on the other hand, should provide some objective measure of device effectiveness. The evaluation parameters for this portion of the clinical study should be structured for an objective and standardized recording/measurement of: (1) the psychological benefit of the device to the implant recipient, including any improvement in quality of life; and (2) the anatomical effect of the implant. The primary requirements for an acceptable scientific documentation of psychological benefits of the device are the use of (1) prospective research designs, including pre- and post-surgical repeated measures; (2) appropriate control/comparison groups; and (3) standardized test instruments rather than informal, yet-validated questionnaires. Any questionnaire utilized in the documentation of the psychological consequences of testicular prostheses must be shown to provide a scientifically valid measure of the psychological effects of testicular loss/absence upon males. Documentation of these psychological consequences shall include (1) pre-surgical baseline assessments of psychological status, including measures of the perceived loss that these subjects experience and their expectations for improvement with the device; (2) regular post-surgical follow-up of any changes in psychological status for at least five years, or until physical maturity of the subject (whichever occurs later); (3) statistical comparison of post-surgical psychological test scores versus pre-surgical test scores within the group of treated patients; (4) statistical comparison of psychological test scores of treated patients versus untreated control patients at all pre-surgical and post-surgical assessment intervals; and (5) correlation of the psychological data with the physical outcomes of the implantation procedure. Documentation of the anatomical outcome of implantation of a testicular prosthesis shall include: (1) regular post-surgical evaluations of the stiffness and dimensional characteristics of the device, as well as assessments of the status of the device's anatomical position, for at least five years post-implantation; (or until physical maturity of the subject, whichever occurs later) and (2) patient assessments of the physical presence of the implant during this follow-up period. Any PMA for the testicular prosthesis should separately analyze the degree of device safety and efficacy by the following variables: (1) etiology and duration of testicular loss/absence; (2) age of implant recipient; (3) anatomical abnormalities of the genitalia; (4) device usage (initial implantation versus revision); (5) type of device (solid or silicone gel-filled, polyurethane foam coated or uncoated, size, etc.); (6) type of device surface; (7) investigational site; (8) surgeon experience and technique; and (9) incision site. Furthermore, for each explantation procedure performed on the study subjects, the following information must be provided: (1) the mode of failure of the removed device; and (2) whether or not the explanted device was replaced with a new device (and, if a new device was implanted, the manufacturer, type, and model of the new device must be provided). Additionally, the effect of the presence of these implants upon future medical diagnoses/treatments involving the scrotum in testicular implant recipients must be analyzed. Any accessories that are sold with the testicular implant must be shown to have been effectively used in implant procedures without adverse effects. Finally, the clinical investigation should validate the physician and patient instructions for use (labeling) that were utilized. For the polyurethane foam covered prosthesis, the following information needs to be presented: (1) the kinetics of the end products generated from the degradation of the polyurethane foam (in vivo); (2) the frequency and incidence of infection and complication of retrieval of the implant by surgeons using both polyurethane foam covered and uncoated prostheses in a retrospective cohort study; and (3) the neoplasticity of the material as well as its general toxicity, including neurological, physiological, biochemical, and hematological effects, as well as pathology following prolonged and repeated exposure to polyurethane foam covered testicular prostheses. Any epidemiological studies should contain enough subjects to detect a small but significant increase in one or more connective tissue diseases (especially scleroderma) that may be associated with the use of the device. The agency believes that insufficient time has elapsed to permit a direct evaluation of the risks of cancer and immune related connective tissue disorders posed by the presence of silicone in the human body and that sufficient epidemiological data or experimental animal data are not available to make a reasonable and fair judgement. Therefore, the agency will require long-term postapproval follow-up for any testicular prosthesis permitted to continue in commercial distribution. Well-designed clinical prospective studies with long-term follow-up together with experimental animal studies will be considered as essential in the determination of safety and effectiveness of the device. Further, these clinical studies must collect long-term data on the teratogenic/reproductive effects of the device as well as later effects on offspring (from those patients with a unilateral, functional testicle). The risk/benefit assessment (as with the entire PMA) must rely on valid scientific evidence as defined in 21 CFR 860.7(c)(2) from well-controlled studies as described in 21 CFR 860.7(f) in order to provide reasonable assurance of the safety and effectiveness of the testicular prosthesis in the surgical correction, restoration, or construction of the male scrotal anatomy. 4. Labeling Copies of all proposed labeling for the device, including any information, literature, or advertising that constitutes labeling under section 201(m) of the act (21 U.S.C. 321(m)), should be provided. The general labeling requirements for medical devices are contained in 21 CFR Part 801. These regulations specify the minimum requirements for all devices. Additional guidance regarding device labeling can be obtained from FDA's publication "Labeling: Regulatory Requirements for Medical Devices," and from the Office of Device Evaluation's "Device Labeling Guidance"; both documents are available upon request from the Division of Small Manufacturers Assistance (HFZ-220), Center for Devices and Radiological Health, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. Highlighted below is additional guidance for some of the specific labeling requirements for testicular prostheses. The intended use statement should include the specific indications for use and identification of the target populations. Specific indications and target populations must be completely supported by the clinical data described above. For example, it may be necessary to restrict the intended use to the specific subpopulations of patients in whom safety and effectiveness have been demonstrated. The directions for use should contain comprehensive instructions regarding the preoperative, perioperative and postoperative procedures to be followed. This information includes, but is not necessarily limited to, (1) a description of any preimplant training necessary for the surgical team; (2) a description of how to prepare the patient (e.g., prophylactic antibiotics), operating room (e.g., what supplies must be on hand), and testicular prosthesis (e.g., handling instructions, resterilization instructions) for prosthesis implantation; (3) instructions for implantation, including surgical approach, sizing, device handling, and any intraoperative test procedures to ensure implant integrity and proper placement; (4) and instructions for follow-up, including whether antibiotic prophylaxis is recommended during the postimplant period and/or during any subsequent dental or other surgical procedures, how to determine when patients are ready to resume normal activities, and how to evaluate, and how often to evaluate, implant integrity and placement. The directions should instruct caregivers to specifically question patients prior to surgery for any history of allergic reaction to any of the device materials. Troubleshooting procedures should be completely described. The directions for use should incorporate the clinical experience with the implant, and should be consistent with those provided in other company-provided labeling. The labeling should include both implant and explant forms to allow the sponsor to adequately monitor device experience. The explant form should allow collection of all relevant data, including the reason for the explant, any complications experienced and their resolution, and any action planned (e.g., replacement with another implant). Patient labeling must be provided which includes the information needed to give prospective patients (or their parents/guardians) realistic expectations of the benefits and risks of device implantation. Such information should be written and formatted so as to be easily read and understood by most patients and should be provided to patients prior to scheduling implantation, so that each patient has sufficient time to review the information and discuss it with his physician(s). Technical terms should be kept to a minimum and should be defined if they must be used. Patient information labeling, if possible, should not exceed the seventh grade reading comprehension level. The patient labeling should provide the patient (or parents/guardians) with the following information: (1) The indications for use and relevant contraindications, warnings, precautions and adverse effects/ complications should be described using terminology well known and understood by the average layman; (2) the anticipated benefits and risks associated with the device must be provided to give patients realistic expectations of device performance and potential complications. The known, suspected and potential risks of device implantation should be identified and the consequences, including possible methods of resolution, should be described; (3) any alternatives available to the use of the device, including no treatment, should be identified, along with a description of the associated benefits and risks of each. The patient should be advised to contact his physician for more information on which of these alternatives might be appropriate given his specific condition; (4) instructions for how to care for the device must be provided to the patient. This information should include the expected length of recovery from surgery and when to resume normal activities following implantation, warnings against certain actions that could damage or rupture the device, how to identify conditions that require physician intervention, who to contact if questions arise, and other relevant information; (5) the fact that the implant may not be a "lifetime" implant must be emphasized. Where possible, the patient labeling should provide information on the approximate number of revisions necessary for the average patient, and indicate the average longevity of each implant so patients are fully aware that additional surgery for device replacement or removal may be necessary. This information must be supported by the clinical experience (i.e., not merely bench studies) with the implant or by published reports of experience with similar devices. The physician's labeling should instruct the urologist or implanting surgeon to provide the implant candidate with the patient labeling prior to implantation to allow each patient (or his parents/guardians) sufficient time to review and discuss this information with his physician(s). The adequacy and appropriateness of the instructions for use provided to physicians and patients should be verified as part of the clinical investigations. Applicants should submit any PMA in accordance with FDA's "Premarket Approval (PMA) Manual." The guidance is available upon request from the Division of Small Manufacturers Assistance (HFZ-220), Center for Devices and Radiological Health, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD. 20857. V. REFERENCES 1. Travis, W.D., Balogh, K. and Abraham, J. L.; Silicone Granulomas; Report of Three Cases and Review of the Literature: Human Pathology, Vol. 16: No. 1, pp. 19-27, January 1985. 2. Benjamin, E., Ahmed, A., Rashid, A.T.M.F., and Wright, D.H.; Silicone Lymphadenopathy., A report of two cases, one with concomitant malignant lymphoma", Diagnostic Histopathologv, 5:133-141, 1982. 3. Transcript of FDA GPS Device Panel Meeting, November 12, 13, 14, 1991. Vol. II, pp. 109-111, (115-120). APPENDIX I - EXTRACTION GUIDELINES FOR SILICONE IMPLANTS I. Leachables Most polymeric materials contain in addition to the relatively inert, high molecular weight polymer, other components such as residual monomers, oligomers, catalysts, processing aids, etc. These are present at varying levels depending on the raw material sources, the manufacturing processes, and intended function of additives. Also, additional chemical species may be generated during manufacturing processes such as heat sealing, welding, or sterilization of the device. All of these may migrate from the device into the human body and should be the subject of risk assessments. The rate of migration from the shell itself will very likely be controlled by diffusion processes in the shell elastomer itself unless there is partitioning in the external phase, in this case, body fluids and tissues. The latter cannot hold if metabolic processes convert the migrant into another chemical species or if it is eliminated. In either case, the situation is equivalent to migration into infinite volume and corresponds to exhaustive extraction. The effect of the external phase is treated in a paper by R. C. Reid, K. R. Sidman, A. D. Schwope and D. E. Till, Ind. Eng. Chem. Prod. Res. Dev., 19(4), 1980, p. 580-587. The rates of migration may be very slow so that the levels of migrants in short term animal studies may not be high enough to elucidate any responses. Toxicological testing of migrants allows for determination of dose response curves and "no adverse effect levels." For the shell, initial levels plus migration rates would allow calculation of dose rates. In order to carry out such risk assessments, the identity and levels of the potential migrants must be established. Presently, exhaustive extractive experiments are the best approach for accomplishing this. II. Samples Each of the individual structural components (shell, outer patches, sealants, etc.) as they are found in the final sterilized device should be subjected to extractions. No additional processing or curing should be performed on these samples. A major fraction of each structural component as it is in the final device should be subjected to extractions. Two approaches are possible; 1. Several replicate samples can be taken from each of the structural components of the finished devices and these samples can be subjected to extractions. 2. Several replicate samples can be taken from the structural components before final assembly, but the components must have undergone all processing, curing and sterilization treatments that the finished device receives. This approach can be used provided that the content and chemical identity of the extracts is the same as (or closely represents) that found using approach 1. Both of these approaches require that the ratio of the sample weight to the device structural component weight be known so that levels of extractants can be referred back to the entire device as implanted. That is, the grams of migrant per grams of the specific structural component is then multiplied by the total weight of the structural component to give the total amount per device. For the shell material, because the weight ratios may be inaccurate, the sample area should be reported so that the fraction of the shell area can be calculated to give the multiplier. III. Selection of Extracting Solvents Solvents should be chosen that are expected to solubilize the low molecular weight migrants thus facilitating exhaustive extraction. Inasmuch as the chemical nature of all of the migrants is not known, it is advisable to use solvents with different chemical characteristics such as polarity, aromaticity, etc. Both polar and non-polar solvents should be used. Charged or very polar species such as heavy metals, catalyst complexes, and inorganic chemicals may also migrate from the polymers and would not be soluble in non-polar solvents. Initial experiments should use a solvent of mixed polarity such as methylene dichloride. For highly crosslinked elastomers as are used in the shells, solvents which swell the polymer are desirable as they would enable completion of the experiments sooner. IV. Design of the Extraction Experiment A. Extraction vessel. An extraction cell should be used in which a sample of known weight and known geometric surface area is extracted by a known volume of solvent. An example of such a cell is described in an article by Snyder, R. C. and Breder, C. V., J. Assoc. Off. Anal. Chem., 68(4) 1985, p 770f. Such a cell may work for polymer plates such as cut from the shell. Mild agitation of the solvent is recommended. Although immersion of samples allows for two-sided extraction, calculation should be based on the sample weight or the area of one side when doing exhaustive extractions. Additional considerations and helpful comments are given in the section "Design of the Extraction Experiment, part D.1.a, Extraction Vessel" of the Recommendations for Chemistry Data for Indirect Food Additive Petitions obtainable from the Division of Food Chemistry and Technology, CFSAN, FDA, Harvey W. Wiley Federal Building, Room 1B-018, 5100 Paint Branch Parkway College Park, MD 20740-3835. B. Extraction Sample General considerations on sampling are given above. Because migration is a diffusive process plate geometry is desirable; the experimental time can be further minimized by using thin samples. The sample geometry, thickness, weight and solvent volume must be reported. The ratio of volume of solvent to the area of the sample is not so important for exhaustive extraction as described below. However, if cloudy solutions or precipitation is noticed during the first time interval, then the solvent volume to sample surface area is too low. C. Temperature and Time of Extractions For the determination of residual levels of low-molecular weight components of polymeric materials, experiments can be accelerated since only the levels are of interest here and not the kinetics. Exhaustive extractions should be carried out as described below in order to determine residue levels. This will also provide the maximum amount of migrants per sample which should be used for further chemical characterization and for toxicological tests. Extractions can be done at 37 C or at elevated temperatures in order to accelerate the experiment. However, the petitioner is advised that elevated temperatures may cause chemical reactions to produce additional extractants. Also, if elevated temperatures are used they should be chosen so that no additional curing or crosslinking of the polymers takes place during the extraction experiment. For exhaustive extractions, the duration of the extraction cannot be prescribed in advance but can be dealt with in the following manner. A series of successive extractions is carried out by exposing the sample to the solvent for a period of time, analyzing the solvent for extractants, replacing with fresh solvent and again exposing the sample for a period of time, analyzing and repeating the process. When the level of the analyte for the ith successive extraction is one-tenth (.1) of the level in the first extraction the extraction may be deemed complete. It is possible that this condition may not occur because of extremely slow migration of the higher molecular weight material. The test can be applied to the contents of the extract with molecular weights below 1500. All the separate analyte levels are added up to give the cumulative value and via the sample/solvent ratio referred back to sample levels and finally back to device levels. In order to minimize experimental time and provide for analysis choosing unequal time periods is desirable. Intervals based on a log or half-log scale generally work out well and minimizes the number of chemical analyses. For shells, this should also allow determination of migration rates by log-log plots of cumulative migration against time. V. Characterization of the Extracts A. Analytical Methodology Specific or non-specific analytical methods may be required depending on the situation. For example, size exclusion chromatography (SEC), high pressure liquid chromatography (HPLC) or some other chromatographic or separation methods may show that the extractants in a given solvent consist of several chemical species. Appropriate methodologies, such as atomic absorption (AA), ion chromatography, etc., should be employed to assess the presence of metallic, inorganic, organometallic, etc., leachables in polar solvents. For the purposes of performing the exhaustive extraction, determination of the total concentration of extractants by gravimetric or some other method would suffice. A bibliography of representative analytical methodologies which may be useful is given in Appendix II. It is necessary for the purposes of toxicological testing to identify the individual components in terms of their molecular composition and to determine the concentration of the individual components of the extract. Following separation and isolation, identification of the individual components in terms of chemical composition can be done by any number of chemical identification methods such as infrared, UV-visible (including diode array), NMR, or mass spectrometries (See Appendix II). Comparison to known structures will be beneficial. Determination of the individual concentrations may require a specific analytical method unless relative concentrations of the components can be determined and used together with the total concentration to give the individual concentrations. B. Description of Analytical Methods All analytical methods must be completely described. Calibration or standard curves should be supplied. The calibration curve should bracket the concentration of the migrant in the extract. All analytical methods should be validated. An excellent discussion of these points is given in the Section D.3 entitled "Analytical Methodology" in the Recommendations for Chemistry Data for Indirect Food Additive Petitions already cited above. Additional information with accompanying references concerning validation procedures can be found in papers by Vanderwielen and Hardwidge (Guidelines for Assay Validation, Pharmaceutical Technology, March 1982, pp 66-76) and by Ficarro and Shah (Validation of High-Performance Liquid Chromatography and Gas Chromatography Assays, Pharmaceutical Manufacturing, Sept 1984, pp 25-27). We agree with the recommendations given in those Guidelines. (2/18/93) Appendix II Selected bibliography of analytical methods GENERAL REFERENCES Wheeler, D.A., "Determination of Antioxidants in Polymeric Materials", Talanta, 15, 1315-1334, (1968). Majors, R.E., "High Speed Liquid Chromatography of Antioxidants and Plasticizers Using Solid Core Supports", J. Chromatogr. Sci., 8, 338-345, (1970). Schroeder, E., "The Development of Methods for Examining Stabilizers in Polymers and their Conversion Products", Pure Appl. Chem., 36, 233-251, (1973). Pacco, J., Mukherji, A.K., "Determination of Polychlorinated Biphenyls in a Polymer Matrix by Gel Permeation Chromatography using micro-Styragel Columns", J. Chromatogr., 144, 113-117, (1977). Crompton, T.R. Chemical Analysis of Additives in Plastics; International Series in Analytical Chemistry, Pergamon Press: New York, 1977; Vol. 46. Majors, R.E., Johnson, E.L., "High-Performance Exclusion Chromatography of Low-Molecular-Weight Additives", J. Chromatogr., 167, 17-30, (1978). Thompson, R.M., Howard, C.C., Crowley, J.P. DeRoos, F.L., Leininger, R.I., "Literature Review: Polymeric Material Leachables and their Biological Effects and Toxicology"; final report to Food and Drug Administration, Center for Devices and Radiological Health (formerly Bureau of Medical Devices) on Contract Number 233-77-5038; Battelle - Columbus Laboratories: Columbus, OH, 1979. Walter, R.B., Johnson, J.F., "Analysis of Antioxidants in Polymers by Liquid Chromatography", J. Polym. Sci.: Macromol. Rev., 15, 29-53, (1980). Shepherd, M.J., Gilbert, J., "Analysis of Additives in Plastics by High-Performance Size-Exclusion Chromatography", J. Chromatogr., 218, 703-713, (1981). Squirrell, D.C.M., "Analysis of Additives and Process Residues in Plastics Materials", Analyst, 106, 1042-1056, (1981). Low Molecular Weight Leachables from Medical Grade Polymers; U.S. Department of Commerce, National Institute of Science and Technology (formerly National Bureau of Standards). National Technical Information Service (NTIS), Springfield, VA, 1982; NBSIR 81-2436. Krause, A., Lange, A., Erzin, M. Plastics Analysis Guide: Chemical and Instrumental Methods; Hanser: New York, 1983. Crompton, T.R. The Analysis of Plastics; Pergamon Series in Analytical Chemistry, Pergamon Press: New York, 1984; Vol. 8. Vargo, J.D., Olson, K.L., "Characterization of Additives in Plastics by Liquid Chromatography-Mass Spectrometry", J. Chromatogr., 353, 215-224, (1986). Gibbons, J.J., "An Evaluation of Plasticizers by Fourier Transform Infrared Spectroscopy", American Laboratory, November, 78-85, 1987. Middleditch, B.S., Zlatkis, A., "Artifacts in Chromatography: An Overview", J. Chromatogr. Sci., 25, 547-551, (1987). Hopkins, J.L., Cohen, K.A., Hatch, F.W., Pitner, T.P., Stevenson, J.M., Hess, F.K., "Pharmaceuticals: Tracking Down an Unidentified Trace Level Constituent", Anal. Chem., 59(11), 784-790, (1987). McGorrin, R.J., Pofahl, T.R., Croasmun, W.R., "Identification of the Musty Component From an Off-Odor Packaging Film", Anal. Chem., 59(18), 1109-1112, (1987). Del Rios, J.K., "Polymer Characterization Using the Photodiode Array Detector", American Laboratory, January, 1988. Multidimensional Chromatography; Cortes, H.J., Ed.; Chromatographic Science Series 50; Dekker, New York, 1990. The Analytical Chemistry of Silicones, Smith, A. Lee, Ed.; Chemical Analysis: A Series of Monographs on Analytical Chemistry and Its Applications 112; Wiley-Interscience, New York, 1991. Braybrook, J.H., Mackay, G.A., "Supercritical Fluid Extraction of Polymer Additives for Use in Biocompatibility Testing", Polym. Int., 27, 157-164 (1992). Erickson, M.D., Analytical Chemistry of PCBs;Lewis:Boca Raton,1992. POLYOLEFINS Spell, R.L., Eddy, R.D., "Determination of Additives in Polyethylene by Absorption Spectroscopy", Anal. Chem., 32(13), 1811-1814, (1960). Crompton, T.R., "Identification of Additives in Polyolefins and Polystyrenes", Eur. Polym. J., 4, 473-496, (1968). Howard, J.M., "Gel Permeation Chromatography and Polymer Additive Systems", J. Chromatogr., 55, 15-24, (1971). Couper, J., Pokorny, S., Protivova, J., Holcik, J., Karvas, M., Pospisil, J., "Antioxidants and Stabilizers. XXXIII. Analysis of Stabilizers of Isotactic Polypropylene: Application of Gel Permeation Chromatography", J. Chromatogr., 65, 279-286, (1972). Wims, A.M., Swarin, S., "Determination of Antioxidants in Polypropylene by Liquid Chromatography", J. Appl. Polym. Sci., 19, 1243-1256, (1975). Lichenthaler, R.G., Ranfelt, F., "Determination of Antioxidants and their Transformation Products in Polyethylene by High-Performance Liquid Chromatography", J. Chromatogr., 149, 553-560, (1978). Schabron, J.F., Fenska, L.E., "Determination of BHT, Irganox 1076, and Irganox 1010 Antioxidant Additives in Polyethylene by High Performance Liquid Chromatography", Anal. Chem., 52, 1411-1415, (1980). Haney, M.A., W.A. Dark, "A Reversed-Phase High Pressure Liquid Chromatographic Method for Analysis of Additives in Polyolefins", J. Chromatogr. Sci., 18, 655-659, (1980). Lehotay, J., Danecek, J., Lisa, O., Lesko, J., Brandsteterova, E., "Analytical Study of the Additives System in Polyethylene", J. Appl. Polym. Sci., 25, 1943-1950, (1980). Schabron, J.F., Bradfield, D.Z., "Determination of the Hindered Amine Additive CGL-144 in Polypropylene by High-Performance Liquid Chromatography, J. Appl. Polym. Sci., 26, 2479-2483, (1981). Francis, V.C., Sharma, Y.N., Bhardwaj, I.S., "Quantitative Determination of Antioxidants and Ultraviolet Stabilizers in Polymers by High Performance Liquid Chromatography", Angew. Makromol. Chem., 113, 219-225, (1983). Choudhary, V., Varshney, S., Varma, I.K., "Degradation of Polypropylene: Effect of Stabilizers", Angew. Makromol. Chem., 150, 137-150, (1987). Munteanu, D., Isfan, A., Isfan, C., Tincul, I., "High-Performance Liquid Chromatographic Separation of Polyolefin Antioxidants and Light-Stabilisers", Chromatographia, 23 (1), 7-14, (1987). Padron, A.J.C., Colmenares, M.A., Rubinztain, Z., Albornoz, L.A., "Influence of Additives on Some Physical Properties of High Density Polyethylene - I. Commercial Antioxidants", Eur. Polym. J., 23 (9), 723-727, (1987). Padron, A.J.C., Rubinztain, Z., Colmenares, M.A., "Influence of Additives on Some Physical Properties of High Density Polyethylene - II. Commercial u.v. Stabilisers", Eur. Polym. J., 23 (9), 729-732, (1987). Raynor, M.W., Bartle, K.D., Davies, I.L., Williams, A., Clifford, A.A., "Polymer Additive Characterization by Capillary Supercritical Fluid Chromatography/Fourier Transform Infrared Microspectrometry", Anal. Chem., 60, 427-433, (1988). "Deformulating Polypropylene by HPLC", Polymer Notes, Waters Chromatography Division, 2(2), 1988. Neilson, R. C., "Extraction and Quantitation of Polyolefin Additives", J. Liquid. Chromatogr., 14 (3), 503-519, (1991). Waters Polymer Update, applications Brief No. RN101, "The Analysis of Additives in Polyolefins by Reverse Phase Gradient Chromatography", date unknown. POLYVINYL CHLORIDE (PVC) Pedersen, H.L., Lyngaae-Jorgensen, J., "Gel Permeation Chromatography Measurements on PVC Resins and Plasticisers", Br. Polym. J., 1, 138-141, (1969). Howard, J.M., "Gel Permeation Chromatography and Polymer Additive Systems", J. Chromatogr., 55, 15-24, (1971). Liao, J.C., Browner, R.F., "Determination of Polynuclear Aromatic Hydrocarbons in Poly(vinyl chloride) Smoke Particulates by High Pressure Liquid Chromatography and Gas Chromatography-Mass Spectrometry", Anal. Chem., 50,(12), 1683-1686, (1978). Shepherd, M.J., Gilbert, "Simple and Inexpensive Application of Steric Exclusion Chromatography for the Isolation of Low-Molecular Weight Additives form Polymer Systems", J. Chromatogr., 435-441, (1979). Perlstein, P., "The Determination of Light Stabilisers in Plastics by High-Performance Liquid Chromatography", Anal. Chim. Acta, 21-27, (1983). Preussler, V., Slais, K., Hanus, J., "The Use of Micro-HPLC with Gradient Elution for the Characterization of Phenol-Formaldehyde Resins", Angew. Makromol. Chem., 150, 179-187, (1987). POLYMETHYLMETHACRYLATE (PMMA) Pasteur, G.A., "Qunatitative Determination of Stabilizers in Tetraethylene Glycol Dimethacrylate by High Pressure Liquid Chromatography", Anal. Chem., 49(3), 363-364, (1977). Brauer, G.M., Termini, D.J., Dickson, G., "Analysis of the Ingredients and Determination of the Residual Components of Acrylic Bone Cements", J. Biomed. Mater. Res., 11, 577-607, (1977). Schoenfeld, C.M., Conard, G.J., "Monomer Release from Methacrylate Bone Cements During Simulated in vivo Polymerization", J. Biomed. Mater. Res., 13, 135-147, (1979). Brynda, E., Stol, M., Chytry, V., Cifkova, I., "The Removal of Residuals and Oligomers from Poly(2-hydroxyethylmethacrylate)", J. Biomed. Mater. Res., 19, 1169-1179, (1985). Huribut, J.A., Cummins, J.D., "Analysis of 2-Hydroxyethyl Methacrylate in Soft Contact Lenses by High Performance Liquid Chromatography with UV Detection", LC GC, 8(6), 478-479, (1990). POLYURETHANES Spagnolo, F., "Quantitative Determination of Small Amounts of Toluene Diisocyanate Monomer in Urethane Adhesives by Gel Permeation Chromatography", J. Chromatogr. Sci., 14, 52-56, (1976). McFadyen, P., "Determination of Free Toluene Diisocyanate in Polyurethane Prepolymers by High-Performance Liquid Chromatography", J. Chromatogr., 123, 468-473, (1976). Guthrie, J.L. and McKinney, R.W., "Determination of 2,4- and 2,6-Diaminotoluene in Flexible Urethane Foams", Anal. Chem., 49(12), 1676-1680, (1977). Bagon, D.A., Hardy, H.L., "Determination of Free Monomeric Toluene Diisocyanate (TDI) and 4,4 -diisocyanatodiphenylmethane (MDI) in TDI and MDI Prepolymers, Respectively, by High-Performance Liquid Chromatography", J. Chromatogr., 152, 560-564, (1978). Unger, P.D., Friedman, M.A., "High-Performance Liquid Chromatography of 2,6- and 2,4-Diaminotoluene, and its Application to the Determination of 2,4-Diaminotoluene in Urine and Plasma", J. Chromatogr., 174, 379-384, (1979). Snyder, R.C., Breder, C.V., "High-Performance Liquid Chromatographic Determination of 2,4- and 2,6-Toluenediamine in Aqueous Extracts", J. Chromatogr., 236, 429-440, (1982). Lattimer, R.P., Welch, K.R., "Direct Analysis of Polymer Chemical Mixtures by Field Desorption Mass Spectroscopy", Rubber Chem. Technol., 53, 151-159, (19**). Hepburn, C., Polyurethane Elastomers, Applied Sci. Publ.: New York, 1982, Chapter 11. Owen, D.R., Zone, R., Armer, T., Kilpatrick, C., "Analytical Methods for the Determination of Biologically Derived Absorbed Species in Biomedical Elastomers", In Biomaterials: Interfacial Phenomena and Applications; Cooper, S.L., Peppas, N.A., Eds.; Advances in Chemistry 199; American Chemical Society: Washington, DC, 1982; pp 395-411. Guise, G.B., Smith, G.C., "Liquid Chromatography of Some Polurethane Polyols", J. Chromatogr., 247, 369-373, (1982). Kuo, C., Provder, T., Kah, A.F., "Application of HPGPC and HPLC to Characterise Oligomers and Small Molecules used in Enviromentally Acceptable Coatings Systems", Paint & Resin, 53(2), 26-33, (1983). Ernes, D.A., Hanshumaker, D.T., "Determination of Extractable Methylene (aniline) in Polyurethane Films by Liquid Chromatography", Anal. Chem., 55, 408-409, (1983). Ratner, B.D., "ESCA Studies of Extracted Polyurethanes and Polyurethane Extracts: Biomedical Implications", In Physicochemical Aspects of Polymer Surfaces, Mittal, K.L., Ed.; Plenum: New York, 1983; pp 969-983. Mazzu, A.L., Smith, C.P., "Determination of Extractable Methylene Dianiline in Thermoplastic Polyurethanes by HPLC", J. Biomed. Mater. Res., 18, 961-968, (1984). O'Mara, M.M., Ernes, D.A., Hanshumaker, D.T., "Determination of Extractable Methylenebis(aniline) in Polyurethane Films by Liquid Chromatography", In Polyurethanes in Biomedical Engineering, H. Planck, G. Egbers, I. Syré, Eds.;Elsevier:Amsterdam,1984;pp. 83-92. Ward, C.J.P., Radzik, D.M., Kissinger, P.T., "Detection of Toxic Compounds in Polyurethane Food Bags by Liquid Chromatography/Electrochemistry", J. Liq. Chromatogr., 8(4), 677-690, (1985). Rosenberg, C., Ainen, H.S., "Detection of Urinary Metabolites in Toluene Diisocyanate Exposed Rats", J. Chromatogr., 323, 429-433, (1985). Hirayama, T., Ono, M., Uchiyama, K., Nohara, M., J. Assoc. Off. Anal. Chem., 68(4), 746-748, (1985). Vimalasiri, P.A.D.T., Burford, R.P., Haken, J.K., "Chromatographic Analysis of Elastomeric Polyurethanes", Rubber Chem. Tech., 60, 555-577, (1987). Richards, J.M., McClennen, W.H., Meuzelaar, H.L.C., Shockcor, J.P., Lattimer, R.P., "Determination of the Structure and Composition of Clinically Important Polyurethanes by Mass Spectrometric Techniques", J. Appl. Polym. Sci., 34, 1967-1975, (1987). Noel, D., VanGheluwe, "High-Performance Liquid Chromatography of Industrial Polyurethane Polyols", J. Chromatogr. Sci., 25, 231-236, (1987). Marchant, R.E., Zhao, Q., Anderson, J.M., Hiltner, A., "Degradation of a Poly(ether urethane urea) Elastomer: Infra-red and XPS Studies", Polymer, 28, 2032-2039, (1987). Grasel, T.G., Lee, D.C., Okkema, A.Z., Slowinski, T.J., Cooper, S.L., "Extraction of Polyurethane Block Copolymers: Effects on Bulk and Surface Properties and Biocompatibility", Biomaterials, 9, 383-392, (1988). Hull, C.J., Guthrie, J.L., McKinney, R.W., Taylor, D.C., Mabud, Md.A., Prescott, S.R., "Determination of Toluenediamines in Polyurethane Foams by High-Pressure Liquid Chromatography with Electrochemical Detection", J. Chromatogr., 477, 387-395, (1989). Richards, J.M., Meuzelaar, H.L.C., Bunger, J.A., "Spectrometric and Chromatographic Methods for the Analysis of Polymeric Explant Materials", J. Biomed. Mater. Res., 23, 321-335, (1989). Richards, J.M., McClennen, W.H., Meuzelaar, H.L.C., "Determination of Additives in Biomer and Lycra Spandex by Pyrolysis Tandem Mass Spectrometry and Time Temperature Resolved Pyrolysis Mass Spectrometry", J. Appl. Polym. Sci., 40, 1-12, (1990). Belisle, J., Maier, S.K., Tucker, J.A., "Compositional Analysis of Biomer", J. Biomed. Mater. Res., 24, 1585-1598, (1990). Dillon, J.G., Hughes, M.K., "Determination of Cholesterol and Cortisone Absorption in Polyurethane I. Methodology Using Size-exclusion Chromatography and Dual Detection," J. Chromatogr., 572, 41-49, (1991). Shintani, H., "Solid-Phase Extraction and High-Performance Liquid Chromatographic Analysis of a Toxic Compound from -irradiated Polyurethane", J. Chromatogr., 600, 93-97, (1992). RUBBERS Protivova, J., Pospîsil, J., "XLVII. Behavior of Amine Antioxidants and Antiozonants and Model Compounds in Gel Permeation Chromatography", J. Chromatogr., 88, 99-107, (1974). Protivova, J., Pospîsil, J., "XLVIII. Analysis of the Components of Stabilization and Vulcanization Mixtures for Rubbers by Gel Permeation Chromatography and Thin-Layer Chromatographic Methods", J. Chromatogr., 92, 361-370, (1974). Weston, R.J., "Volatile Nitrosamine Levels in Rubber Teats and Pacifiers Available in New Zealand", J. Anal. Toxicol., 9, 95-96, (1985). Zwickenpflug, W., Richter, E., "Rapid Method for the Detection and Quantification of N-Nitrosodibutylamine in Rubber Products", J. Chromatogr. Sci., 25, 506-509, (1987). NYLONS Caldwell, J., Perenich, T., "Recovery and Analysis by HPLC of Benzoyl Peroxide Residues in Nylon Carpet Fibers", Textile Res. J., June, 1987. CELLULOSE ACETATE Floyd, Th.R., "Use of Two-Dimensional Liquid Chromatography in the Analysis of Additives in Cellulose Acetate Polymer", Chromatographia, 25(9), 791-796, (1988). SILICONES Horner, H.J., Weiler, J.E., Angelotti, "Visible and Infrared Spectroscopic Determination of Trace Amounts of Silicones in Foods and Biological Materials", Anal. Chem., 32(7), 858-861, (1960). Estes, Z.E., Faust, R.M., "A Colorimetric Method for the Determination of Silicon in Biological Materials", Anal. Biochem., 13, 518-522, (1965). Neal, P., "Note on the Atomic Absorption Analysis of Dimethylpolysiloxanes in the Presence of Silicates", J. Assoc. Off. Anal. Chem., 52(4), 875-876, (1969). Neal, P., Campbell, A.D., Firestone, D., "Low Temperature Separation of Trace Amounts of Dimethylpolysiloxanes from Food", J. Am. Oil Chemists Soc., 46, 561-562, (1969). Sinclair, A., Hallam, T.R., "The Determination of Dimethylsiloxane in Beer and Yeast, Analyst, 96, 149-154, 1971. Howard, J.W., "Report on Food Additives", J. Assoc. Off. Anal. Chem., 55(2), 262, (1972). Frick, R., Baudisch, H., "Physico-chemical Determination of Intravascular Silicone in Brain and Kidney", Beitr. Path. Bd., 149, 39-46, (1973). Cassidy, R.M., Hurteau, M.T., Mislan, J.P., Ashley, R.W., "Preconcentration of Organosilicons on Porous Polymers and Separation by Molecular-Seive and REversed-Phase Chromatography with an Atomic Absorption Detection System", J. Chromatog. Sci., 14, 444-447, (1976). Vessman, J., Hammar, C., Lindeke, B., Stromberg, S., LeVier, R., Robinson, R., Spielvogel, D., Hanneman, L., "Analysis of Some Organosilicone Compounds in Biological Material", In Biochemistry of Silicon and Related Problems; Bendz, G, Lindqvist, I., Eds.; Plenum: New York, 1977; pp 535-558. Pellenbarg, R., "Enviromental Poly(organosiloxanes) (Silicones)", Environmental Science and Technology, 13(5), 565-569, (1979). Abraham, J.L., Etz, E.S., "Molecular Microanalysis of Pathological Specimens in situ with a Laser-Raman Microprobe", Science, 206, 716-718, (1979). Buch, R.R., Ingebrightson, D.N., "Rearrangement of Poly(dimethylsiloxane) Fluids on Soil", Environmental Science and Technology, 13(6), 676-679, (1979). Doeden, W.G., Kushibab, E.M., Ingala, A.C., "Determination of Dimethylpolysiloxanes in Fats and Oils", J. Amer. Oil Chemists Soc., 57(2), 73-74, (1980). Abe, Y., Butler, G.B., Hogen-Esch, T.E., "Photolytic Oxidative Degradation of Octamethylcyclotetrasiloxane and Related Compounds", J. Macromol. Sci., Chem., A16(2), 461-471, (1981). Leong, A.S.-Y., Disney, A.P.S., Grove, D.W., "Spallation and Migration of Silicone from Blood-Pump Tubing in Patients on Hemodialysis", N. Engl. J. Med., 306(3), 135-140, (1982). Baker, J.L., LeVier, R.R., Spielvogel, D.E., "Positive Identification of Silicone in Human Mammary Capsular Tissue", Plast. Reconst. Surg., 69(1), 56-60, (1982). Kacprzak, J.L., "Atomic Absorption Spectroscopic Determination of Dimethylpolysiloxane in Juices and Beer", J. Assoc. Off. Anal. Chem., 65(1), 148-150, (1982). Mahone, L.G., Garner, P.J., Buch, R.R., Lane, T.H., Tatera, J.F., Smith, R.C., Frye, C.L., "A Method for the Qualitative and Quantitative Characterization of Waterborne Organosilicon Substances", Environ. Toxicol. Chem., 2, 307-313, (1983). Buch, R.R., Lane, T.H., Annelin, R.B., Frye, C.L., "Photolytic Oxidative Demethylation of Aqueous Dimethylsiloxanols", Environ. Toxicol. Chem., 3, 215-222, (1984). Watanabe, N., Yasuda, Y., Kato, K., Nakamura, T., "Determination of Trace Amounts of Siloxanes in Water, Sediments and Fish Tissues by Inductively Coupled Plasma Emission Spectrometry", The Science of the Total Environment, 34, 169-176, (1984). Bruggeman, W.A., Weber-Fung, D., Opperhuizen, A., Van der Steen, J., Wijbenga, A., Hutzinger, O., "Absorption and Retention of Polydimethylsiloxanes (Silicones) in Fish: Preliminary Experiments", Toxicol. Environ. Chem., 7, 287-296, (1984). McCamey, D.A., Iannelli, D.P., Bryson, L.J., Thorpe, T.M., "Determination of Silicone in Fats and Oils by Electrothermal Atomic Absorption Spectrometry with In-Furnace Air Oxidation", Anal. Chim. Acta., 188, 119-126, (1986). Anderson, C., Hochgeschwender, K., Weidemann, H., Wilmes, R., "Studies of the Oxidative Photoinduced Degradation of Silicones in the Aquatic Environment", Chemosphere, 16(10-12), 2567-2577, (1987). Watanabe, N., Nagase, H., Ose, Y., "Distribution of Silicones in Water, Sediment and Fish in Japanese Rivers", The Science of the Total Enviroment, 73, 1-9, (1988). Winding, O., Christensen, L., Thomsen, J.L., Nielsen, M., Breiting, V., Brandt, B., "Silicon in Human Breast Tissue Surrounding Silicone Gel Prostheses", Scand. J. Plast. Reconstr. Surg., 22, 127-130, (1988). Annelin, R.B., Frye, C.L., "The Piscine Bioconcentration Characteristics of Cyclic and Linear Oligomeric Permethylsiloxanes", The Science of the Total Environment, 83, 1-11, (1989). Parker, R.D., "Atomic Absorption Spectrophotometric Method for Determination of Polydimethylsiloxane Residues in Pineapple Juice: Collaborative Study", J. Assoc. Off. Anal. Chem., 73(5), 721-723, (1990). Nakamura, K., Refojo, M.F., Crabtree, D.V., "Factors Contributing to the Emulsification of Intraocular Silicone and Fluorosilicone Oils", Invest. Ophth. Vis. Sci., 31(4), 647-656, (1990). Nakamura, K., Refojo, M.F., Crabtree, D.V., Leong, F., "Analysis and Fractionation of Silicone and Fluorosilicone Oils for Intraocular Use", Invest. Ophth. Vis. Sci., 31(10), 2059-2069, (1990). Gaboury, S.R., Urban, M.W., "Spectroscopic Evidence for Si-H Formation During Microwave Plasma Modification of Poly(dimethylsiloxane) Elastomer Surfaces", Polym. Commun., 32(13), 390-392, (1991). Israeli, Y., Philippart, J.-L., Cavezzan, J., Lacoste, J., Lemaire, J., "Photo-oxidation of Polydimethylsiloxane Oils: Part I - Effect of Silicon Hydride Groups", Polym. Degradation. Stab., 36, 179-185, (1992). "Selective Detection of Cyclic Silicon Compounds Extracted from Silicone Breast Implants"; DET Report No. 22, March, 1992; DETector Engineering & Technology, Inc., Walnut Creek, CA.