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Draft Guidance for Preparation of PMA Applications for Testicular Prostheses (Text Only)


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


I.   PREFACE . . . . . . . . . . . . . . . . . . . . . . . . .  1

II.  DEVICE DESCRIPTION. . . . . . . . . . . . . . . . . . . .  1

III. BACKGROUND. . . . . . . . . . . . . . . . . . . . . . . .  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


          METHODOLOGIES  . . . . . . . . . . . . . . . . . . . 39

                      TESTICULAR PROSTHESES 


     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.

     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.

     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


     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

     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

                    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

          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

          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

                    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
                    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

                    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

                    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

                    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

               2.1.9     Testing of Explanted Materials

                    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
               2.1.10    Chemical characterization of the
                         Finished Device


                         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

            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
                              a. residual monomers, cyclics, and

                              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

                              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

                         Guidelines for extraction and a selected
                         bibliography of analytical methodologies
                         are included as Appendix I and II

                         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

            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

          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

               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

                    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

          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

          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

          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

          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

          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

          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

     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.


     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).


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

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

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

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

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.

Appendix II    Selected bibliography of analytical methods

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"Selective Detection of Cyclic Silicon Compounds Extracted from
Silicone Breast Implants"; DET Report No. 22, March, 1992;
DETector Engineering & Technology, Inc., Walnut Creek, CA.