Document 7Vxek7XxxpJNyzXjMV0RB5qV

FILE NAME Talc TALC DATE 2014 DOC TALC169 DOCUMENT DESCRIPTION Govt Report - Stimuli to the Revision Process of Asbestos Testing in USP Talc 5 40 Stimuli to the Revision Process Modernization of Asbestos Testing in USP Talc Page 1 of 21 STIMULI TO THE REVISION PROCESS Stimuli articles do not necessarily reflect the policies of the USPC or the USP Council of Experts Modernization of Asbestos Testing in USP Talc Lawrence H. Block Detlef Beckers Jocelyn Ferret Gregory P. Meeker Aubrey Miller Robert E. Osterberg Dilip M. Patil Julie W. Pier Steve Riseman Martin S. Rutstein Gary P. Tomaino Drew Van Orden James S. Webber Jeffrey Medwid Steven Wolfgang Kevin Moore ABSTRACT In response to a request from the U.S. Food and Drug Administration through the FDA Monograph Modernization Task Group the USP Talc monograph is being modernized to ensure that the tests for asbestos have adequate specificity The USP Excipients Expert Committee of the Council of Experts approved the formation of a Talc Expert Panel which is charged with modernizing the USP Talc monograph This Stimuli article outlines the current thinking of the USP Talc Expert Panel and discusses several test procedures and measurement criteria that are under consideration The Talc Expert Panel is considering these procedures and criteria for recommendation to the USP Excipients Expert Committee for control of Absence of Asbestos in USP Talc This article concludes with a summary of the adverse health effects resulting from asbestos exposure and a proposal for updating the Definition and Labeling sections of the USP Talc monograph The USP Talc Expert Panel's recommendation for revision of the test for Absence of Asbestos will include omission of the infrared spectroscopy test and inclusion of a revised ray diffraction procedure in combination with one or more microscopic evaluations polarized microscopy transmission electron microscopy or scanning electron microscopy 1. INTRODUCTION As part of USP's initiative to update and improve its monographs for drug substances and products in the U.S. Pharmacopeia and National Formulary USP USP is focusing on monographs recently identified as high priority by the U.S. Food and Drug Administration FDA through the FDA Monograph Modernization Task Group MMTG On November 16 2010 the FDA MMTG sent a letter to USP indicating the desire to modernize the priority USP Talc monograph1 The request for revision was stated as follows Labeling should be revised to match the statements that are provided in the Talc FCC monograph thereby assuring that Talc is not sourced from mines that are known to contain asbestos Also USP should consider revising the current tests for asbestos to ensure adequate specificity http://www.usppf.com/pf/pub/data/y404/GEN_STIMULI_404_s20htp:/w1.uspf.com/pf1ub/dat/y40/GEN8_STIMUL_40s204184.html .html htp:/ww.uspf.com/pf/pub/data/y404/GEN_STIMULI_404_s20184.html 7/7/2014 40 Stimuli to the Revision Process Modernization of Asbestos Testing in USP Talc Page 2 of 21 The current USP Talc monograph contains a test for Absence of Asbestos that includes three procedures Analysts are given the option to perform either Procedure 1 or Procedure 2 which consist of infrared spectroscopy Identification General 191 ) and ray diffraction ( Characterization of Crystalline and Partially Crystalline Solids by Ray Powder Diffraction XRPD ( 941 ) respectively If either test gives a positive result then the third procedure consisting of optical microscopy Optical Microscopy 776 ) must be performed to confirm The infrared spectroscopy IR and ray diffraction XRD methods as currently written can lead to negative results which could allow talc samples with asbestos contamination to pass the Absence of Asbestos test in the USP Talc monograph Even after applying the current USP microscopy method the analyst cannot rule out the presence of hazardous fibers in a sample of talc In addition the lack of identification procedures in the optical microscopy section of the method could lead to positive results This underscores the need to modernize the current monograph for two reasons ) both the IR and XRD methods have relatively high detection limits for asbestos and 2 there is no known safe level of asbestos exposure In response to FDA's request to modernize the USP Talc monograph the USP Excipients Expert Committee EXC EC formed a Talc Expert Panel EP The Talc EP consists of volunteer members from among talc suppliers pharmaceutical manufacturers regulatory and government agencies academia and instrument manufacturers The charge of the EP is to update and modernize the methodology for testing that is described in the USP Talc monograph thereby establishing a quality standard based upon defined specifications and analytical methods This modernization will ensure that the production of talc meets an appropriate standard for the Absence of Asbestos using currently available methods set ; below the feasible limits of detection This Stimuli article outlines the current thinking of the Talc EP and details its objectives and charge The article then discusses several test procedures and measurement criteria under consideration by the TalEcP for recommendation to the EXC EC for the control of Absence of Asbestos in USP Talc Section 2 discusses the derivation of talc and the formation and composition of talc deposits whereas section 3 addresses the mineral chemistry and morphology of asbestos species potentially encountered in commercial talc deposits Section 4 highlights the current USP test procedures for determination or analysis of asbestos in a talc matrix while section 5 introduces methods under consideration for asbestos testing in USP Talc Section 6 discusses the adverse health effects from asbestos exposure and outlines why asbestos contamination is a serious concern for USP Talc thereby underscoring efforts to ensure that asbestos levels are below the feasible limit of detection when using current state methodology Finally section 7 addresses labeling while section 8 includes the conclusions and summary http://www.usppf.com/pf/pub/data/v404/GEN_STIMULI_404_s201184.html 7/7/2014 40 Stimuli to the Revision Process Modernization of Asbestos Testing in USP Talc Page 3 of 21 2. TALC DERIVATION OF FORMATION AND COMPOSITION OF TALC DEPOSITS Talc is a member of the phyllosilicate sheet silicate group of silicate minerals."Talc's normative chemical formula is Mg3S14010 with generally small amounts of substitution of other elements in more than trace amounts These substitutions which include Fe for Mg Al for Si and F for OH generally do not have a major effect on the mineral's desirable properties Structurally talc is composed of a layer of OH in octahedral coordination sandwiched between two layers of Si in tetrahedral coordination The tetrahedraltetrahedral units o are linked together by relatively weak van der Waals bonds which result in the characteristic friability or cleavage of talc layers Figure ) Figure 1. Crystal structure of Talc The atoms are shown as small balls magnesium yellow silicon blue and oxygen red with orange for OH Silicon surrounded by four oxygen atoms occupies the tetrahedral site while magnesium surrounded by six oxygen atoms occupies the octahedral sites of the unit cell The unit cell shown with the dashed black line has dimensions of 5.3 ^ 9.2 ^ 9.5 A. Created with CrystalMakerfiversion 8.7 Talc can form when the requisite stoichiometric combination of elements is present in the initial rock protolith at sufficient temperature pressure and length of time Talc can also form as an temperature prograde or temperature retrograde reaction product The preservation of talc from elevated metamorphic conditions depends largely on cooling rates and the chemical flux of volatiles especially water and carbon dioxide http://www.usppf.com/pf/pub/data/v404/GEN_STIMULI_404_s201184.html 7/7/2014 40 Stimuli to the Revision Process Modernization of Asbestos Testing in USP Talc Page 4 of 21 Macroscopic talc forms individual crystals and masses of crystals that separately and collectively have a platy or plate appearance 2 Talc plates can be relatively -micrometers across relatively -centimeters or more across 3 Figure 2 Aggregates of the plates have been described as having a sample texture that is micaceous or foliated Foliated means that the flattened talc grains are largely oriented as parallel plates PRIGM TALC scale ya Z8 nanomi^tors itd ae = Figure 2. Scanning electron microscopy Image of typical lamellar Talc The physical form of talc rock is related to the geologic source protolith and the geologic conditions during the formation of the deposit Talc's platelet size determines its lamellarity Highly lamellar talc informally classified as macrocrystalline talc has large stacked platelets whereas microcrystalline talc has small randomly oriented platelets The lamellar aggregates are accumulations of individual crystals that are approximately equidimensional in the equatorial plane and relatively thinner perpendicular to that plane Occasionally talc will grow faster in the shortest atomic direction and produce a gross shape that is elongated lamellar which is similar to a ribbon and is informally described as ribbon talc When the growth in a single direction is extreme the talc can develop a fibrous morphology Given the variability of pressure temperature and chemical flux in the geologic environment it is not uncommon for talc to undergo alteration via chemical and structural changes to other minerals Talc may even be found occasionally in a transitional state when a reaction is incomplete and frozen http://www.usppf.com/pf/pub/data/v404/GEN_STIMULI_404_s201184.html 7/7/2014 40 Stimuli to the Revision Process Modernization of Asbestos Testing in USP Talc Page 5 of 21 The four types of geologic environments most typical for talc formation are 1. Large geographic areas regionally of prograde metamorphic sedimentary rocks derived from either rich carbonates dolomites or shale clay- and quartzrich sediments 2. Magnesium silica ultramafic rocks undergoing serpentinization an alteration process that results in hydration and enrichment in silica followed by chemical alteration arising from the influx of carbon dioxide fluid 3. Amphibole metamorphic rocks undergoing retrograde metamorphism 4. broad variety of protoliths undergoing local metamorphism because of elevated heating contact metamorphic effects 2 4 Talc ores are sometimes classified into two major groups based on the type of geologic environment talc deposits with amphibole minerals as important components of the host rock and talc deposits that are essentially amphibole free The majority of globally produced commercial talc is formed by the prograde sequence of sedimentary rocks Type 1 or to a lesser extent derivation from ultramafic igneous rocks Type 2 Ultramafic is the most abundant deposit worldwide but metasedimentary is by far the most widely exploited commercially and accounts for more than 70 of world production of all talc including pharmaceutical grade 2 For the remaining -30 industry experts have estimated that only a minor segment of all markets uses talc derived from amphibole metamorphic rock and this has declined in recent years 5 6 Figure 3 Talc derived from host deposits with amphiboles is of primary concern because of the possible presence of amphibole and serpentine asbestos in the final product Historically tremolitic talc Type 3 has not been used in the United States for pharmaceutical applications Figure 3 represents the current estimated world production of talc 5 divided into the four types http://www.usppf.com/pf/pub/data/v404/GEN_STIMULI_404_s201184.html 7/7/2014 40 Stimuli to the Revision Process Modernization of Asbestos Testing in USP Talc Page 6 of 21 Alatantorphic Hen BY 6 sadamnatory WASH,,o RAS yt e Sib sadimentary tonals Host Figure 3. Current estimated world production of Talc 3. MINERAL CHEMISTRY AND MORPHOLOGY OF ASBESTOS SPECIES POTENTIALLY ENCOUNTERED IN COMMERCIAL TALC DEPOSITS A large number of accessory minerals may be found in talc deposits depending on the formation conditions of the deposit These minerals include but are not limited to dolomite magnesite calcite and quartz as well as a variety of micas chlorites feldspars serpentines and amphiboles Of particular concern for this discussion are minerals which under certain conditions can occur in an asbestiform growth habit and also the minerals that may interfere with detection of asbestos during analysis Chlorites typically clinochlore and chamosite have the general composition 4010 OH and are fairly common in some rich rocks and ores Chlorite group minerals are layered silicates phyllosilicate that are composed of chemical sandwiches similar to talc but with an additional layer of Mg inserted into the stacking sequence Chlorites are highly variable in composition and structural complexity and typically do not form fibrous morphologies Asbestos is a commercial term applied to certain naturally occurring minerals when these minerals crystallize in the asbestiform habit generally defined as minerals with the growth form similar to commercial forms of asbestos The commercially desirable properties of asbestos include flexibility tensile strength and resistance to heat electrical conductivity and chemical corrosion Certain asbestiform minerals are regulated under the rubric asbestos in numerous federal and international regulations These regulations are based primarily on the asbestos minerals that were used commercially and most regulations and approved analytical methods http://www.usppf.com/pf/pub/data/v404/GEN_STIMULI_404_s201184.html http://www.usppf.com/pf/pub/data/v404/GEN_STIMULI_404_s201184.html htp:/w .uspf.com/pf/pub/dat/v40/GEN_STIMULI_40_s20184.html htp:/w.uspfcom/pubdat/v40GEN_STIMUL_40s2184.html htp:/w.uspf.com/pfub/dat/v40/GEN_STIMUL_40s20184.html http://www.usppf.com/pf/pub/data/v404/GEN_STIMULI_404_s201184.html 7/7/2014 40 Stimuli to the Revision Process Modernization of Asbestos Testing in USP Talc Page 7 of 21 specifically list those minerals because of early epidemiological studies linking commercial asbestos with disease Historically analytical methods used for identification of regulated asbestos rely on the commercial and physical properties of the minerals rather than properties that may be associated with the etiology of disease The asbestos minerals typically listed in regulations and methods include chrysotile a member of the silicate group and five amphibole minerals of the silicate group These five are amosite cummingtonite asbestos crocidolite riebeckite asbestos tremolite asbestos actinolite asbestos and anthophyllite asbestos Historically chrysotile has been the most commonly used asbestos in industry approximately 90 Chrysotile is still being mined in a few countries however most countries have banned the mining of all types of asbestos because of the demonstrated and perceived health risks of the material Although there is general agreement in the international community it is important to note that there is no uniformly and universally accepted group of asbestos minerals nor are there universally accepted definitions for asbestos and asbestos particles A tabulation of definitions for asbestos asbestiform and other asbestos terminology used in this article can be found in Lowers and Meeker 2002 and ASTM D7712-11 7 8 3.1 Serpentine Serpentine is a subgroup of minerals with the composition Mg Si O Roc5 ks containing serpentine minerals can contain serpentine asbestos chrysotile if formed under specific shear conditions There are three principal forms of serpentine antigorite and chrysotile with approximate compositions of Mg3Si205 The most abundant is lizardite and the least is chrysotile but the latter is perhaps the best known 9 Chrysotile is a layered silicate mineral with the nominal composition Mg3S205 The mineral generally forms as bundles of extremely thin fibers that can split into single units called fibrils Chrysotile fibrils can measure as little as a few tens of nanometers in diameter with lengths up to tens or hundreds of micrometers These fibrils form as the mineral grows growth habit because of a slight atomic mismatch between altemating layers of SiO tetrahedra and MgO octahedra The atomic forces generated by this mismatch cause the layers to curve into a tight scroll during growth thereby producing the individual fibrils 3.2 Amphibole The amphibole minerals have a double structure composed of layers of rings of SiO4 tetrahedra held together by alternating chains of octahedral units and interlayer cations htp:/w .uspf.com/pf/pub/dat/v40/GEN_STIMULI_40_s20184.html http://www.usppf.com/pf/pub/data/v404/GEN_STIMULI_404_s201184.html 7/7/2014 40 Stimuli to the Revision Process Modernization of Asbestos Testing in USP Talc Page 8 of 21 Amphiboles have a general chemical formula of A0-1B2C5T8022W2 where only the most common ions for each crystallographic site are as follows A Na K = Na Ca C = Mg Fe Al T = SI AI W = OH F CI As suggested by the formula above amphiboles can be extremely complex chemically and more than 80 mineral names are currently designated based on chemistry by the International Mineralogical Association IMA 10 11 Amphiboles are fairly common forming minerals and occur in a variety of growth habits depending on origin and conditions of formation Single amphibole crystals are generally elongated along the c crystallographic direction and typically form in a prismatic prism habit Amphiboles can also form as acicular needle crystals and very rarely as asbestiform crystals Amphibole asbestos fibrils can measure less than a hundred nanometers in diameter with lengths up to tens or hundreds of micrometers Amphibole asbestos has been mined commercially in the past and two types amosite and crocidolite were widely used in a variety of commercial applications until the 1970s when rising health , concerns caused most countries to cease commercial production In many cases chrysotile is easy to define and identify because of its thin fibers unique rolled sheet structure and simple chemistry but the same cannot be said of amphibole asbestos The reasons for this include the extensive chemical substitution that can occur in amphiboles and the fact that the IMA system of nomenclature is based on mineral chemistry Mineral identification using the IMA nomenclature requires highly accurate chemical analyses particularly where amphibole minerals are not close to pure member compositions 12 13 For example pure member tremolite has the composition Ca2MgSiO22 If however fluids rich in sodium potassium and iron were present during formation the resulting mineral might have a composition such as Na Ca 5Si022 due to chemical substitutions The resulting mineral although very similar to tremolite would be classified by the IMA as winchite This example is significant because most current regulations list tremolite as regulated but winchite is not even addressed although the two minerals are associated with similar health risks 14-17 In addition to chemistry particle morphology is used to determine if a single amphibole particle or population of particles is asbestos Again the analytical methods rely on properties of commercial asbestos rather than properties directly tied to health effects As stated above amphiboles can form in a variety of morphologies ranging from prismatic to asbestiform 4. CURRENT USP TEST PROCEDURES FOR DETERMINATION OR ANALYSIS OF ASBESTOS IN A TALC MATRIX htp:/ww.uspf.com/pf/pub/data/v404/GEN_STIMULI_404_s20184.html http://www.usppf.com/pf/pub/data/v404/GEN_STIMULI_404_s201184.html 7/7/2014 40 Stimuli to the Revision Process Modernization of Asbestos Testing in USP Talc Page 9 of 21 The current USP Talc analytical procedure for Absence of Asbestos utilizes either infrared spectroscopy IR or ray powder diffraction XRD the choice is left to the user These initial screening methods are useful for evaluating the overall quality of the talc Both the IR and XRD procedures as written in the USP Talc monograph are pass tests that do not provide specific detection limits If there is any indication in the test results that minerals which may have an asbestos component are present a positive result then the current USP method requires that the sample be examined using optical microscopy Currently there are no standard reference materials available that can be used to document a laboratory's effectiveness in detecting asbestos in a talc matrix In addition the pharmacopeial test procedures for determination or analysis of asbestos IR XRD and optical microscopy do not detect all particles thought to be hazardous but only the subset of particles that are amenable to routine detection and quantification by the specific analytical test procedure being used Because fibrous minerals in talc are contaminants rather than commercial materials added for their desirable properties it is important to recognize that applying analytical methods developed for commercial asbestos may not be adequate in terms of sensitivity and specificity for determining the absence of asbestos in talc for use in pharmaceutical products Table 1 In addition other minerals such as chlorite or kaolinite can occur in talc both cause interference in the detection of asbestos in talc As with any analytical procedure certified reference materials are necessary to properly calibrate the system Table 1. Current Methods for Asbestos Detection and Quantification in a Talc Matrix Method IR absorption spectroscopy ray diffraction Description in current USP monograph Advantages Disadvantages 758 - cmmay indicate the presence of tremolite or chlorite If the absorption band remains after ignition of the substance at 850 for at least 30 min this indicates the presence of 1 tremolite In the range 600 cm to 650 cm using scale expansion any absorption band or shoulder may indicate the presence of serpentines Instrumentation is typically available for companies that need to perform pharmaceutical testing Cannot distinguish asbestos from nonasbestos forms of the same mineral The method is subject to interferences with other minerals Detection limit is unknown The presence of amphiboles is detected by a diffraction peak at 10.5 -0.1 2 and the presence of serpentines is detected by diffraction peaks at Important in fully characterizing mineral assemblage Cannot distinguish asbestos from nonasbestos forms of the same mineral Provides information about bulk purity Limit of detection http://www.usppf.com/pf/pub/data/v404/GEN_STIMULI_404_s201184.html 7/7/2014 40 Stimuli to the Revision Process Modernization of Asbestos Testing in USP Talc Page 10 of 21 Optical microscopy 24.3 0.1 20 12.1 20 Can give information about the origin of the talc deposit and the associated risk may be too high for public health and regulatory purposes Detection limit of serpentine is Can indicate if severely affected by problematic levels of presence of chlorite any phase are present May give false- negative result if used as a screening method The presence of suspect fibers is inferred from the occurrence of particles with length ratios in the range from 20 to 100 or higher for fibers longer than 5 ...m Identification considers particle morphology Particles of milled material may be disaggregated and inconsistent with typical asbestos morphology Particles of milled material may be below resolution limit Due to lack of identification procedures may give a positive result Limit of detection may be too high for public health and regulatory purposes 5. METHODS UNDER CONSIDERATION FOR ASBESTOS TESTING IN TALC Talc analytical methods have been a subject of development by ASTM International 18 The Asbestos Analytical Committee D22.07 has been working on a series of detailed procedures covering XRD polarized microscopy PLM and transmission electron microscopy TEM analyses specifically for pharmaceutical Talc To date drafts of all three procedures have been reviewed by the ASTM committee although the TEM method has progressed the furthest The Expert Panel is monitoring these methods and is working with ASTM where appropriate to further their development 5.1 ray Diffraction http://www.usppf.com/pf/pub/data/v404/GEN_STIMULI_404_s20htp:1/w.uspf.com/pf1ub/datv40/GEN_ST8IMUL_40s2184.ht4ml .html htp:/ww.uspf.com/pf/pub/data/v404/GEN_STIMULI_404_s20184.html 7/7/2014 40 Stimuli to the Revision Process Modernization of Asbestos Testing in USP Tak = Page 11 of 21 XRD is used for qualitative determination identification and quantitative determination weight percent of crystalline substances The dimensional structure of crystalline substances generates elastic ray scattering called diffraction and satisfies the Bragg Equation n2dSin8 wheren is an integer called the order of the reflection lambda ^ is the wavelength of the characteristic line of the tube anode material typically Cu K-d is the interplanar spacing of given crystal planes of a crystal and theta * is the ray incidence angle Bragg angle under a given instrument geometry The Bragg equation represents an inverse relationship where low theta 9 values would have a corresponding high spacing usually expressed in Angstroms and vice versa When using XRD consideration should be given to the differences in the particle size distribution crystallinity and interferences among others matching of the standard and test materials and their preparations are important criteria to meet in order to achieve precise and accurate results XRD provides an important initial screening of the talc product for ancillary mineral phases especially for those of total amphibole and total serpentine Amphibole and serpentine minerals are typically nonasbestiform but they can exist more rarely as an asbestiform variety However XRD does not delineate the asbestiform and asbestiform varieties of amphibole or serpentine therefore XRD should be combined with one or more microscopic techniques For total amphibole conventional XRD provides a qualitative detect at < 0.5 in talc XRD performed with extended count times can achieve lower detection limits such as < 0.1 For serpentine XRD provides qualitative and quantitative detection limits that will vary because of interference from the chlorite group minerals here detection limits could be as low as 0.1 or as high as % 5.2 Polarized Light Microscopy Polarized microscopy PLM is used to identify a substance based on its optical properties The fibers in talc product that satisfy defined criteria for optical properties including refractive index sign of elongation and extinction angle as well as dimensions and morphology will be identified as asbestos based on specific regulatory methods PLM can be used for quantitation of asbestos often using a count method 19 The detection limit can be improved by increasing the number of points counted Accurate PLM quantitation depends on resolution and identification of asbestos and asbestos particles The fibers with particle sizes below the wavelength of illumination cannot be resolved by PLM The unresolved fibers are not counted which may lead to negative results For this reason http://www.usppf.com/pf/pub/data/v404/GEN_STIMULI_404_s201184.html htp:/ww.uspf.com/pf/pub/data/v404/GEN_STIMULI_404_s20184.html http://www.usppf.com/pf/pub/data/v404/GEN_STIMULI_404_s201184.html 7/7/2014 40 Stimuli to the Revision Process Modernization of Asbestos Testing in USP Talc Page 12 of 21 amphibole and serpentine detected by XRD may be unresolved by PLM 5.3 Electron Microscopy Electron microscopy including transmission electron microscopy TEM and scanning electron microscopy SEM overcomes the resolution limitations of PLM and has the ability to detect extremely small asbestos fibers The minimum fiber width that can be routinely characterized by TEM is on the order of 0.03 ...m19 20 corresponding to the typical width of single chrysotile fibrils TEM is the only method that can accomplish this although the modern field emission SEM can approach this capability TEM and SEM provide elemental composition data through energy dispersive ray spectroscopy EDS an important component of the identification of the mineral TEM also provides information on crystalline structure through selected area electron diffraction SAED and recent developments using electron scattered diffraction EBSD may enable analysts to derive similar crystallographic information with SEM 21 In recent review of the draft National Institute for Occupational Safety and Health NIOSH roadmap for asbestos research the Institute of Medicine of the National Academies stated The need to develop new analytical methods based on electron microbeam techniques is critical and should not be limited by existing regulatory constraints or existing policy 14 15 A comparison of the methods described above outlining their advantages and disadvantages is presented in Table 2 Table 2. New Microscopy Methods Under Consideration Method Description Polarizing light presence of asbestos is microscopy light confirmed by the occurrence of particles with asbestos morphology and their identification as an asbestos mineral based on optical dispersion staining Advantages Identification is based on morphology and phase determination which can be conclusive Particles characterized by PLM are in the size Disadvantages Normal quantitation limit may be too high for public health and regulatory purposes if concentration techniques are not used Particles of milled material < 5 mmay be below resolution limit range where they are easily distinguished as asbestos compared with non- asbestos Good method for larger products htp:/w.uspf.com/pfub/dat/v40/GEN_STIMUL_40s20184.html htp:/w.uspf.com/pfub/dat/v40/GEN_STIMULI_40_s20184.html http://www.usppf.com/pf/pub/data/v404/GEN_STIMULI_404_s201184.html htp:/ww.uspf.com/pf/pub/data/v404/GEN_STIMULI_404_s20184.html htp:/w.uspf.com/pf/pub/dat/v40/GEN_STIMULI_40_s20184.html 7/7/2014 40 Stimuli to the Revision Process Modernization of Asbestos Testing in USP Talc Page 13 of 21 Scanning electron microscopy SEM Transmission electron microscopy TEM typical of personal care talc products The presence of asbestos is confirmed by the occurrence of particles with asbestos morphology that are identified as an asbestos mineral by EDS elemental analysis A larger sample size grange is analyzed relative to TEM Identification is based on morphology and elemental analysis Resolution is better than with PLM Capable of disclosing surface morphology Fibrils of chrysotile may be below the resolution limit of older microscopes Because it is a presumed identification based on chemistry and morphology alone the test may give a falsepositive result Structural information methods are currently in development Interferences include anthophyllite etc. The presence of asbestos is confirmed by the occurrence of particles with asbestos morphology that are identified as an asbestos mineral by EDS elemental analysis and electron diffraction Identification is based on morphology elemental analysis and electron diffraction structural information May be the only method with resolution high enough to routinely detect fibrils of May be prohibitive for quality control due to protracted analysis time high cost irreproducibility and small sample size ng range May miss the larger fibers associated with amphibole asbestos false negative chrysotile 5.4 Additional Sample Concentration Techniques Detection of asbestos in talc by the instrumental methods outlined above can be enhanced through the concentration of asbestos particles or separation of asbestos from obscuring or confounding particles Several sample preparation techniques are being evaluated each targets a specific type of particle to analyze These techniques are ) air elutriation for the purpose of evaluating the fraction of particles that may become airborne 2 aqueous elutriation also for evaluating particles that may become airborne and 3 wet sieving which effectively concentrates asbestos in the larger more easily characterized size fraction and lowers the overall detection limit of the methods http://www.usppf.com/pf/pub/data/v404/GEN_STIMULI_404_s201184.html htp:/ww.uspf.com/pf/pub/data/v404/GEN_STIMULI_404_s20184.html htp:/ww.uspf.com/pf/pub/data/v404/GEN_STIMULI_404_s20184.html 7/7/2014 40 Stimuli to the Revision Process Modernization of Asbestos Testing in USP Talc Page 14 of 21 5.4.1 FLUIDIZED BED ASBESTOS SEGREGATOR The fluidized bed asbestos segregator FBAS is a sample preparation instrument that utilizes air elutriation to separate particles on the basis of aerodynamic diameter which correlates positively with particle size and inversely with particle density Asbestos structures fibers fiber bundles and bundles in matrices are collected on a filter which can then be analyzed by TEM or other appropriate microscopic techniques The performance of the FBAS preparation method was recently evaluated by the U.S. EPA using a variety of performance PE standards that spanned different matrix materials soil and vermiculite and different types of asbestos chrysotile and amphibole Results for these PE standards show that there is an approximately linear relationship between the concentration of asbestos in the PE standard as mass percent and the mean concentration estimated by the TEM analysis following preparation by FBAS expressed as asbestos structures captured on the filter per gram of test material g Method detection limits achievedin these studies ranged from 0.002 to 0.005 by weight which is approximately 100 times lower than the detection limits that are usually achieved using other analytical methods for asbestos in soil and other solid media The FBAS unit is compact fitting into a standard laboratory fume hood and components of the unit are relatively easy to decontaminate or are disposable The FBAS unit construction and operation costs are relatively low and sample throughput is high up to 20 samples per day Current research using the FBAS unit is ongoing and an interlaboratory validation study is in progress 15 Although the FBAS method has not yet been applied to the evaluation of asbestos contamination in a talc matrix this approach appears to have promise as a fairly inexpensive and highly sensitive method for the identification of low levels of asbestos in talc 22 5.4.2 AQUEOUS ELUTRIATION This elutriation technique uses water rather than air to separate particles 23 24 sample is suspended in a funnel of water which is constantly flushed with water coming in from the bottom The flow rate is controlled to flush out of the top of the funnel only particles smaller than a determined aerodynamic diameter This portion is filtered and prepared for TEM analysis The use of water removes any undesirable electrostatic interactions that can occur in air samples Method detection limits vary based on the duration of elutriation and the differences in the aerodynamic diameters of the target particles and matrix particles as is the case for FBAS 5.4.3 WET SIEVING TECHNIQUE htp:/w.uspf.com/pfub/dat/v40/GEN_STIMULI_40_s20184.html http://www.usppf.com/pf/pub/data/v404/GEN_STIMULI_404_s201184.htmlhttp://www.usppf.com/pf/pub/data/v404/GEN_STIMULI_404_s201184.html 7/7/2014 40 Stimuli to the Revision Process Modernization of Asbestos Testing in USP Talc = Page 15 of 21 The technique of wet sieving a milled talc product capitalizes on the natural characteristics of asbestos i.e. flexibility and durability which make it resistant to grinding After milling the sieve acts to concentrate any asbestos present by removing the easier matrix material i.e. talc with a softness of 1 on the Mohs Scale of Hardness Although the size fraction analyzed is not that which includes the finest particles this technique is an easy and effective way to indicate whether or not asbestos is present Studies have shown that even in the finest micronized talc median particle size of 1 ...masbestos was easily detected by conventional microscopy techniques The effect of concentration also lowers the detection limit for example samples with 100-500 ppm confirmed by were effectively detected by PLM 25 In addition asbestos particles in the larger fraction are more likely to maintain the unique characteristics of asbestos which facilitates an unambiguous identification An inexpensive standard 325- to mesh laboratory sieve is used with standard laboratory procedures to achieve these results 6. ADVERSE HEALTH EFFECTS FROM ASBESTOS EXPOSURE Health effects associated with workplace asbestos fiber exposures were clearly identified in the early part of the twentieth century and continue to be further elucidated through research and ongoing health studies The major cancer health effects associated with airborne asbestos exposure increase with increasing levels of exposure and include pleural effusions pleural fibrosis both circumscribed disease plaques and diffuse disease and interstitial fibrosis also known as asbestosis The observable onset of these conditions which can occur in combination usually takes more than 20 years from initial exposure latency period and can progress in severity from asymptomatic to disabling and fatal despite cessation of exposure years earlier 26 The risk for asbestos malignancies also rises with increasing levels of exposure Among these malignancies lung cancer is the most common However the types of lung cancer observed with asbestos exposure are similar to those seen with cigarette smoking and often may not be identified as asbestos given the high prevalence of smoking exposures It should be noted that the risk for lung cancer is greatly increased by the combination of asbestos and smoking exposures Mesothelioma is a very rare cancer of the pleura outer lining of the lungs and abdomen peritoneum that is predominantly caused by asbestos exposure it is not related to smoking and usually occurs 20-40 years after the initial exposure According to the Centers for Disease Control and Prevention the annual U.S. death rate due to mesothelioma is about 14 per million people for those over 25 years of age 27 The risk for mesothelioma increases with greater asbestos exposure however there are numerous cases of seemingly inconsequential dose paraoccupational and http://www.usppf.com/pf/pub/data/v404/GEN_STIMULI_404_s201184.html htp:/ww.uspf.com/pf/pub/data/v404/GEN_STIMULI_404_s20184.html htp:/w.uspf.com/pfub/dat/v40/GEN_STIMULI_40_s20184.html ht p:/ w w.usp f.com/pf/pub/data/v404/GEN_STIMULI_404_s201 84.html 7/7/2014 40 Stimuli to the Revision Process Modernization of Asbestos Testing in USP Talc PagePage 16 of 21 environmental asbestos exposures that are associated with this malignancy Per the International Agency for Research on Cancers IARC there is sufficient evidence in humans that all forms of asbestos chrysotile crocidolite amosite tremolite actinolite and anthophyllite cause mesothelioma and cancer of the lung larynx and ovary Positive associations also have been observed between exposure to all forms of asbestos and cancer of the pharynx stomach and colorectum 19 28 Although the relationship between airborne asbestos exposure and respiratory disease is clear associations between ingestion of asbestos fibers and gastrointestinal GI cancers or other cancers due to translocation of fibers from the pulmonary or gastrointestinal tract is more difficult to assess Studies in humans and animal models have provided differing evidence for ingestion GI cancers which were estimated to be elevated by the EPA 7. and the National Academy of Sciences 29 There are currently no established safe levels of asbestos exposure This underscores the efforts of the Talc EP to identify strategies and methods for reducing the potential for asbestos contamination of talc to the lowest feasible levels More effective analytical approaches are needed to achieve much lower levels of detection than those traditionally used to evaluate asbestos contamination of bulk materials The existing methods are not necessarily adequate for assessing the potential health risks of these materials Research by the U.S. EPA and others has shown that disturbance of matrices e.g. soil vermiculite insulation containing asbestos concentrations identified by the lower detection limits of PLM below % asbestos by weight the limit historically used by the U.S. EPA to define an Asbestos Containing Material generate potentially hazardous exposures 30 32 This issue while not currently evaluated may be particularly relevant for the talc used in ; powders and cosmetics Current standards and recommendations have generally focused on controlling asbestos mineral fiber exposures chrysotile crocidolite amosite anthophyllite asbestos tremolite asbestos and actinolite asbestos by using optical microscopy methods and counting all fibers with specified aspect ratios e.g. 3 or greater and fiber lengths e.g. > 5 m However the specified dimensional criteria length and aspect ratio used for the quantification of asbestos may not be optimal for protecting exposed individuals as these criteria are not based solely on health concerns 15 Animal studies and epidemiologic studies have found that various forms of asbestos or certain dimensional characteristics of fiber exposures were associated with different responses of the respiratory tract and different potency for disease such as mesothelioma 15 28 Generally the accepted physiochemical properties of asbestos fibers that are related to pathogenicity include 1 fiber dimensions i.e. length width aspect ratio 2 surface chemistry 3 surface area and 4 biopersistence Although the latter three properties are not reflected in the current analytical methods for http://www.usppf.com/pf/pub/data/v404/GEN_STIMULI_404_s201184.html 7/7/2014 ~ 40 Stimuli to the Revision Process Modernization of Asbestos Testing in USP Talc Page 17 of 21 identification of asbestos 15 28 33 efforts are underway to better understand the interrelationships of these physiochemical properties in association with observed health effects For example researchers from the U.S EPA and other federal agencies have recently shown that the role of surface area as well as other factors is important in understanding the toxicity of asbestos and other hazardous elongate mineral particles 33 Also exposures to certain nonregulated minerals such as fibrous forms of winchite richterite and antigorite are of concern Recent studies have found that such exposures are associated with increased risks of mesothelioma and other asbestos diseases 15 16 34 35 The USP Talc Expert Panel agrees that exposure risks can and should be mitigated by revising USP methods which will then allow for much lower detection limits for asbestos and if warranted other mineral fibers The Panel is not proposing to identify and exclude all mineral fibers under this standard but these methods appear capable of identifying other fibers that appear to be hazardous 7. LABELING FDA's November 2010 letter included the following requests Labeling should be revised to match the statements that are provided in the Talc FCC monograph thereby assuring that Talc is not sourced from mines that are known to contain asbestos Also USP should consider revising the current tests for asbestos to ensure adequate specificity However the existing FCC description 36 is informational qualitative and not easily defined Further the FCC monograph does not a include labeling statement or any methodology for asbestos detection . It is the conclusion of the Talc Expert Panel that mine suitability as a source of talc is not subject to USP quality standards Rather it is the responsibility of the talc supplier to supply a product that is asbestos free and can meet the USP compendial standards Based on the above the panel recommends updating statements in the definition and labeling sections to indicate that talc containing detectable asbestos is not pharmaceutical grade 8. CONCLUSIONS AND SUMMARY Proposed updates to the current official harmonized USP Talc monograph's test for the Absence of Asbestos will incorporate current analysis protocol Pass must include microscopy follow to XRD " Definitive microscopic identification and characterization of asbestos fibers is critical in the determination of the presence of asbestos http://www.usppf.com/pf/pub/data/v404/GEN_STIMhtUp:/wLw.uspfI.com/p_f/pub/d4ata/v4004/GEN_S4TIMULI__404_s20s184.ht2ml 0htp:1/w.uspf.com/p1fub/dat/v40/G8EN_STIMUL_40s420184.html .html htp:/ww.uspf.com/pf/pub/data/v404/GEN_STIMULI_404_s20184.html 7/7/2014 40 Stimuli to the Revision Process Modernization of Asbestos Testing in USP Talc Page 18 of 21 XRD or IR analysis provides for the detection of total amphibole or total serpentine Failure to detect amphibole or serpentine by XRD or IR does not provide adequate assurance regarding the absence of asbestos contamination The USP Talc Expert Panel's recommendation for revision of the test for Absence of Asbestos wiil include omission of the IR spectroscopy test and inclusion of a revised XRD procedure in combination with one or more microscopic evaluations PLM TEM or SEM The panel also recommends including additional sample concentration methods to improve the feasible limits of detection as indicated see section 5.4 These recommendations for method revision and labeling will help to ensure that talc does not contain asbestos or other hazardous mineral fiber contamination such as winchite or richterite as determined by current state procedures The analytical approach recommended by this Expert Panel consistent with the industry norm at present should continue to ensure that current supplies of talc are of the highest quality in accordance with current best practice procedures REFERENCES 1. Key Issue Monograph Modernization http://www.usp.org/sites/default/files/usp USPNF modernizationlistouderkirkseo.pdf Accessed 5 March 2014 2. McCarthy EF Genco NA Reade EH Talc In Industrial Minerals and Rocks 7th edition Kogel JE Trivedi NC Barker JM Krukowski ST editors Littleton CO Society for Mining Metallurgy and Exploration Inc. 2006 3. Personal communications Gary Tomaino 4. Van Gosen BS Lowers HA Sutley SJ Gent CA. Using the geologic setting of talc deposits as an indicator of amphibole asbestos content Environ Geol 920 939 5. Challenges with Updating the USP Talc Monograph Procedure Absence of Asbestos Julie W. Pier 2013 USP Science and Standards Symposium Excipient Track Baltimore MD 6. U.S. Geological Survey Commodity Statistics and Information http://minerals.usgs.gov/minerals/pubs/commodity/ Accessed 14 January 2014 7. Lowers H Meeker G. Tabulation of Asbestos Terminology 2002. U.S. Geological Survey Open Report 02-458 U.S Department of the Interior Geological Survey http://pubs.usgs.gov/of/2002/ofr-02-458/ http://pubs.usgs.gov/of/2002/ofr-02-458/ Accessed 12 March 2014 8. ASTM International Standard Terminology for Sampling and Analysis of Asbestos ASTM D7712 Book of Standards vol 11.07 http://www.usppf.com/pf/pub/data/v404/GEN_STIMULI_404_s201184.html 7/7/2014 40 Stimuli to the Revision Process Modernization of Asbestos Testing in USP Talc Page 19 of 21 Deer WA Howie RA Zussman J. An Introduction to the Forming Minerals 2nd edition Pearson Prentice Hall 1996 p 345 - 10. Leake BE et al Nomenclature of amphiboles report of the Subcommittee on Amphiboles of the International Mineralogical Association Commission on New Minerals and Mineral Names Canadian Mineralogist 35 219 246 11. Hawthorne FC et al IMA Report Nomenclature of amphibole supergroup American Mineralogist 2012 2031-2048 12. Hawthorne FC Oberti R. Amphiboles crystal chemistry In Hawthorne FC Oberti R Della Ventura G Mottana A editors Amphiboles crystal chemistry occurrence and health issues Reviews in Mineralogy and Geochemistry 2007 Mineralogical Society of America & Geochemical Society 13. Gunter ME Belluso E Mottana A. Amphiboles environmental and health concerns In Hawthorne FC Oberti R Della Ventura G Mottana A editors Amphiboles crystal chemistry occurrence and health issues Reviews in Mineralogy and Geochemistry 453 51Mi6 neralogical Society of America & Geochemical Society 14. Institute of Medicine and National Research Council A review of the NIOSH roadmap for research on asbestos fibers and other elongate mineral particles Washington DC The National Academies Press 2009 15. National Institute for Occupational Safety and Health NIOSH Current Intelligence Bulletin 62 Asbestos Fibers and Other Elongate Mineral Particles State of the Science and Roadmap for Research April 2011. Centers for Disease Control & Prevention National Institute for Occupational Safety and Health http://www.htp:/cw .cd.govd/niosh/doccs/201-159/.hgtotpv:///nwwiw.ocsdch./godv/oncioss/h/2do0c1s/12-0111-51959// Accessed 14 January 2014 16. Case BW Abraham JL Meeker G Pooley FD Pinkerton KE Applying definitions of asbestos to environmental and dose exposure levels and health effects particularly malignant mesothelioma J Toxicol Environ Health Part B 2011 3 39 17. Sullivan PA Vermiculite respiratory disease and asbestos exposure in Libby Montana update of a cohort mortality study Environ Health Perspect 2007 579-85 18. ASTM International Committee on Air Quality http://www.astm.org/COMMITTEE/D22.htm http://www.astm.org/COMMITTEE/D22.htm Accessed 6 March 2014 19. Perkins RL Harvey BW Methods for the determination of asbestos in bulk building materials U.S. Environmental Protection Agency EPA July 1993 20. U.S. Environmental Protection Agency ; htp:/w.epa.gov/superfund/asbetos/compendium/download/site http://www.epa.gov/superfund/asbestos/compendium/download/site Accessed 14 January 2014 ~~ http://www.usppf.com/pf/pub/data/v404/GEN_STIMULI_404_s201184.html 7/7/2014 40 Stimuli to the Revision Process Modernization of Asbestos Testing in USP Talc Page 20 of 21 21. Bandli BR Gunter ME Electron backscatter diffraction from unpolished particulate specimens Examples of particle identification and application to inhalable mineral particulate identification American Mineralogist 1269 1273 22. Januch J Brattin W Woodbury L Berry D Evaluation ofa fluidized bed asbestos segregator preparation method for the analysis of levels of asbestos in soil and other solid media Anal Methods 1658 1668 23. Webber JS Bopp RF Parekh PP Jackson KW Reconstruction of a century of airbome asbestos concentrations Environ Sci Technol 707 714 24. Webber JS Blake DJ Ward TJ Pfau JC Separation and characterization of respirable amphibole fibers from Libby Montana Inhal Toxicol 733 740 25. Pier Julie W. Presented at the ASTM Johnson Conference on Asbestos July 2011 and the ASTM Beard Conference on Asbestos January 2013 26. American Thoracic Society Diagnosis and initial management of malignant diseases related to asbestos Am J Respir Crit Care Med 691-715 27. Malignant mesothelioma mortality States 1999-2005 MMWR April 24 393-396 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5815a3.htm htp:/w.cd.gov/mwr/preview/mwrhtml/m5815a3.htm http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5815a3.htm htp:/w.cdgov/mwr/peviw/mrhtml/581a3.htm 28. International Agency for Research on Cancer IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Asbestos chrysotile amosite crocidolite tremolite actinolite and anthophyllite Monograph 100C 2012 http://monographs.iarc.fr/ENG/Monographs/vol100C/mono100C-11.pdf http://monographs.iarc.fr/ENG/Monographs/vol100C/mono100C-11.pdf Accessed 14 January 2014 29. Toxicological Profile for Asbestos September 2001. U.S. DHHS Public Health Service Agency for Toxic Substances and Disease Registry htp:/w.atsdr.cd.gov/toxprofiles/tp61.pdfhttp://www.atsdr.cdc.gov/toxprofiles/tp61.pdf Accessed 12 March 2014 30. U.S. Environmental Protection Agency Framework for investigating asbestos- contaminated superfund sites OSWER Directive 9200.0-68 September 2008 31. Addison J Davies LST Robertson A Willey RJ The release of dispersed asbestos fibres from soils 1988 Edinburgh Institute of Occupational Medicine IOM Report TM 32. Ewing WM Hays SM Hatfield R. Longo WE Millette JR Zonolote attic insulation exposure studies Int J Occup Envirion Health 279 290 33. Duncan KE Cook PM Gavett SH Dailey LA Mahoney RK Ghio AJ Roggli VL Devlin RB In vitro determinants of asbestos fiber toxicity effect on the relative toxicity of Libby amphibole in primary human airway epithelial cells Part Fibre Toxicol 2014 Jan 11 doi 10.1186 1743-8977-11-2 1743-8977-11-2 http://www.ncbi.nlm.nih.gov/pubmed/24401117 http://www.ncbi.nlm.nih.gov/pubmed/24401117 Accessed 11 February 2014 34. Baumann F et al Pleural mesothelioma in New Caledonia associations with http://www.usppf.com/pf/pub/data/v404/GEN_STIMULI_404_s201184.htmlhttp://www.usppf.com/pf/pub/data/v404/GEN_STIhtp:M/w.Uuspf.cLom/pfIub/dat_/v40/4GEN_STI0MUL_404s201_84.htmsl 201184.html htp:/ww.uspf.com/pf/pub/data/v404/GEN_STIMULI_404_s20184.html , 7/7/2014 40 Stimuli to the Revision Process Modernization of Asbestos Testing in USP Talc = Page 21 of 21 environmental risk factors Environ Health Perspect .695 700 35. Comba P Gianfagna A Paoletti L. Pleural mesothelioma cases in Biancavilla are related to a new edenite fibrous amphibole Arch Environ Health 2003,58 229-32 36. U.S. Pharmacopeia Food Chemicals Codex 8th edition 2012 pp 1111-1112 a Disclaimer The views expressed in this stimuli article are those of the authors and do not reflect the official views and policies of the USPC USP Council of Experts or the authors institutions including FDA b Chair USP Monographs Expert Committee C Member USP Talc Expert Panel d FDA Lialson USP Talc Expert Panel e Correspondence should be addressed to Kevin Moore PhD Manager Pharmacopeial Harmonization United States Pharmacopeial Convention 12601 Twinbrook Parkway Rockville MD 20852-1790 tel +1.301.816.8363 email KTM@usp.org f In accordance with USP General Notices and Requirements section 2.20 Official Articles the USP Talc article is capitalized g Geologists define a mineral as a naturally occurring homogeneous solid inorganically formed with a definite chemical composition and an ordered and periodic atomic arrangement http://www.usppf.com/pf/pub/data/v404/GEN_STIMULI_404_s20htp:/1w.uspf.com/pf1ub/dat/v40/GE8N_STIMUL_40s240184.html .html htp:/ww.uspf.com/pf/pub/data/v404/GEN_STIMULI_404_s20184.html 7/7/2014