Document 8jzkLb487nyR99GZyM43K6Oo

w P F IZ E R I N C . , 2 3 5 E A S T 4 2 n d S T R E E T , N E W Y O R K , N. Y. 1 0 0 1 7 W ILLIAM J. GOEBELBECKER Trade Regulation Counsel December 26, 1973 Hearing Clerk Food and Drug Administration Room 6-86 5600 Fishers Lane Rockville, Maryland 20852 Gentlemen: In the Federal Register of September 28, 1973^ the Food and Drug Administration published a proposal regarding asbestos par ticles in food and drugs (38 Fed. Reg. 2 70 76 ). We are an interested person in that our Company produces and markets a variety of food and drug products, including talc, that would be affected by this proposed order. We agree in principle with the Commissioner that the amount of asbestos fiber in foods and drugs should be minimized, within exist ing technology, notwithstanding the pervasive nature of asbestos fibers in our environment. We find several problems in the proposal, however, on which we wish to comment. Test Method: Our major problem relates to the method proposed in new Section 121.2006 for determining asbestos fibers in food-grade talc. That method assumes that only three types of compounds are present, namely tremolite, talc and chrysotile/amphibole. It divides these compounds into three distinct classes: those compounds having in dicies of refraction no higher than 1.574 (these compounds are all classified as tremolite); those compounds having indicies of refrac tion between 1 .5 7 4 and 1.5 9 0 (these compounds are all classified as talc); and those compounds having indicies of refraction higher than 1.5 9 0 (these compounds are all classified as chrysotile or amphibole asbestos). Our first objection is that there may be other compounds present in the talc that have indicies of refraction in these ranges that are not either tremolite, talc or chrysotile/amphiboles and have an aspect ratio of 3 to 1. A good example of this is chlorite, of which there are 32 different types having indicies of refraction ranging from 1.56 2 to 1.80. Chlorite can appear to have a fibrous morphology and be mistaken for tremolite or chrysotile/amphibole depending upon its index of refraction. A number of other compounds ? Hearing Clerk Food and Drug Administration Page 2 # often associated with talc, including calcite, dolomite and musco vite, could give rise to the same misidentification. Another problem arises from the fact that the FDA proposed method assumes the indicies of refraction of talc are between 1*574 and 1.590. Recent work has indicated that for talc the alpha range is from 1.539 to 1 .5 5 0 , the beta range is from 1 .58 5 to 1.594 and the gamma range is from 1.575 to 1.600. Thus talc itself could., under the FDA method, be confused with and classified as tremolite, at the lower range, and chrysotile/amphibole* at the upper range. The proposed FDA method also presents what we might call mechan ical problems. For instance, it would require the operator to weigh out two samples of one milligram each. Using the most common type of analytical balance employed today, the so-called 4-place balance, in repeated trials we had several different chemists using several different balances perform this weighing operation and we found errors of plus or minus 30$. Obviously weighing errors of this mag nitude could result in passing some talcs that actually contained^ more than the FDA proposed maximum amount of chrysotile, and failing some talcs that actually contained less chrysotile than the proposed FDA maximum. Similar errors in results could arise from the require ment that the talc samples be mixed or dispersed in the refractive index liquid with a needle. This relatively crude method of disper sion might not be very effective and could result in incorrect values. Again, the FDA test demands the highest quality optical microscope and the most skillful operator to detect and classify particles meet ing the test criteria. This and other aspects of the test are quite vulnerable to human error. Beyond this, the time required for the FDA proposed test is unduly long, taking approximately one man-day to test one specimen for chrysotile and tremolite. As a substitute for the test proposed by FDA, we instead pro pose the adoption of a test method we at Pfizer have employed routinely for some time. The method essentially employs X-Ray diffraction step-scanning to detect tremolite down to approximately 0 .2$ by weight and chrysotile down to 0.5$ by weight in the absence of chlorite. The analysis for chrysotile and the other amphiboles is then performed by transmission electron microscopy coupled with selected area electron diffraction. Using this method, chlorite does not interfere and chrysotile and the amphiboles can be determined^at the 0.1$ by weight level, possibly lower. A copy of this method in the form of a paper entitled "The Detection and Identification of Asbestos and Asbestiform Minerals in Talc," by Harold D. Stanley and Robert E. Norwood, is enclosed. Production and Control Procedures: We also have several comments regarding the proposed new para graph (j) to be added to Section 133.8. # J Plearing Clerk Food and Drug Administration Pages 3 # The words "fiber" and'asbestos fiber" are used inconsistently. In order to avoid possible ambiguity* the word "fiber" should be pre ceded wherever it appears by the word "asbestos". Because an asbestos-containing filter does not necessarily re lease asbestos fibers, the second sentence of proposed paragraph (j) should be revised to read., "No asbestos-contained and asbestos fiber releasing filter may be used, etc." There are other fine porosity filters today which are non-asbesto containing or non-asbestos-releasing in addition to the membrane type, and there may be additional ones in the future. Therefore, the use of the explanatory phrase "such as a membrane filter" is acceptable in the third sentence of paragraph (j). However, in the last sentence it is too limiting to refer to "membrane filter" and the word "membrane" should be deleted. Although no doubt affected manufacturers have programs under way to minimize the use of asbestos-containing filters, considerable time will be required to implement the necessary revisions in production procedures. Problems must be solved with regard to such things as capability of achieving sterility, solvent compatability, filtration rate and degree of clarity. Equipment availability, media availabili ty and delivery, trial runs and other potential complications require that a substantial period of time be allowed before the proposed re strictions on asbestos filters in parenteral drug production take effect. We suggest that 24 months would be a reasonable time period. Thank you for the opportunity to comment on this proposal. Very truly yours, WJ G :ak end. William J. Gbebelbecker !/' The U.S. Department of Labor established and published its standard, effective in mid 1972, for exposure to asbestos dust under the Occupational Safety and Health Act. This standard limits the 8 hour time-weighted airborne concentrations of asbestos fibers, to which employees are exposed, to 5 fibers per cubic centimeter of air. In addition, a ceiling concentration of 10 fibers is not to be exceeded. This regulation defines tremolite, actinolite, and other acicular minerals commonly associated with some industrial talcs as asbestos. Wide-spread need in industry to comply with the new OSHA standards, and possible future FDA regulations, adds significance to the contents of the following research study report. The Detection and Identification of Asbestos and Asbestiform Materials in Talc Harold D. Stanley and Robert E. Norwood Pfizer Inc.--Minerals, Pigments & Metals Division INTRODUCTION The pneumoconiotic and cancer-inducing health hazards of exposure to asbestos and asbestiform minerals often found associated with talc have been appropriately identified by recent research and mass-media publica tions (1-6). Because of Pfizer's position as a supplier of talc to many industries, a reliable method of detecting and identifying asbestos and asbestiform minerals pos sibly present in the talc had to be developed. Ideally the technique should be simple and direct but above all it must be positive and unambiguous. Talc is a naturally occuring hydrous magnesium silicate having a general formula of Mg4 (Si80 2o) 2 Mg (OH)2. The mineral, talc, is felt to be formed by the hydro thermal alteration of serpentine and tremolite. Talc can be derived from minerals containing various amounts of tremolite, Mg4 (Ca2Si80 22) Mg (OH)2, chlorite, Mg4 (Si8O20)*8 Mg (OH)2 , chrysotile Mg4 (Si8O20) 8Mg (OH)2, and a group of chrysotile-like minerals called amphiboles or asbestiform minerals. Chief among these asbestiform minerals are anthophyllite, (Mg,Fe++)7 Si80 22 (OH)2 , amosite, (Mg,Fe++) 7 Si80 22 (OH)2, crocidolite, Na2F e ^ F e ^ (Si80 22) (OH)2 and actino lite, Ca2 (Mg,Fe++)s Si80 22 (OH)2. From the above chemical formulas one can get an ap preciation for the interrelatedness of talc and the asbes tos type minerals, particularly when one considers that the degree of replacement of one element for another is seldom in exact proportion. Although talc itself has not been shown to induce the irreversible health problems (7), its chemical near-neighbors have (8). The exact causes of the undersirable reactions of the human body when exposed to asbestiform minerals is not entirely clear at the time of this writing but it is felt to be some how linked to the fiberous nature of the asbestos-like minerals. Currently available methods and methodology for detec ting asbestos, tremolite and the asbestiform minerals in the presence of talc were reviewed. The three most likely candidates were: 1. Light microscopy 2. X-ray diffraction 3. Transmission electron microscopy Samples of " pure" talc and tremolite were obtained from various deposits owned by Pfizer Inc. Samples of pure and carefully characterized asbestos minerals were obtained from the International Union Against Cancer, (U.I.C.C.), Pneumoconiosis Research Unit, Llandough Hospital, Penarth, Glamorgan, United Kingdom. The talcs and asbestiform minerals were examined in the pure or as-received state, their characteristics noted and mixtures made to determine if detection of asbestiform minerals was possible at low levels and, if so, what the minimum detection levels might be. EXPERIMENTAL X-ray diffraction patterns were obtained for all the minerals and mixtures used in this study employing the conventional technique of scanning at rates of 0.5 to 1.0 degrees 2 theta per minute. The samples were then subjected to scrutiny by optical and electron micros copy. During this procedure it was discovered that certain mixtures and mineral species shown to be free of asbestiform minerals by the conventional X-ray diffrac tion technique mentioned above and the light micro scope exhibited fairly large percentages, (5% and more), of tremolite and/or asbestiforms when viewed in the transmission electron microscope. Delineation of the reasons for this paradox enabled us to develop reliable techniques for detecting tremolite and the asbestiforms at the 0.25% and 0.5% levels respectively in most talcs by X-ray diffraction. Even lower levels of these minerals are detectable by transmission electron microscopy. X-RAY DIFFRACTION The d-spacings for talc, chlorite, tremolite and the asbestiform minerals are given in Table 1. The values given in Table 1 are averaged values for pure materials and can shift as much as 0.2 70.3 Angstroms de pending upon sample preparation and/or level at which the constituent is found in the parent mineral matrix and the specimens conformity to the idealized chemical compositions. When attempting to detect tremolite and the asbestiform minerals in talc at concentrations of 5% or below, it was found that the normal scanning rate of 0.5 to 1 degrees 2 theta per minute was not satisfactory for the following reasons: 1. The noise level is so high that a detection limit of 5% is the minimum possible. 2. It is difficult to accurately quantify data from a high noise level tracing. In order to avoid these difficulties, an automated step-scanning method was employed in which the diffractometer was moved in increments of 0.05 degrees 2 theta and the intensity of X-radiation at each step measured for a total of two minutes. An intensity versus degrees 2 theta plot over the area of interest was obtained from a Wang 720 programmable calculator with plotter/printer output. Figures 1 and 2 show the step-scan method plotted for tremolite. This method allowed the signal to noise ratio to be raised suffi- ciently to permit direct determinations below the 1% level. The percent tremolite/asbestiform mineral in talc was then calculated by determining the area under the appropriate X-ray peak utilizing a point by point integration technique. Calibration curves were estab lished by integrating the area under the appropriate X-ray diffraction peak of samples with 1% to 10% additions of the species under investigation to a sample of talc shown to be tremolite and asbestiform free by the method of transmission electron microscopy out lined below. Examples of these curves are shown in Figures 3 and 4. Extrapolation of these curves to zero percent addition yields the minimum amount of the mineral that can be detected in the talc matrix. For tremolite in talc the minimum detectable amount was found to be 0.25%. For chrysotile and the other asbestiform minerals the minimum detectable level obtained by this method is 0.5%, but this can only be achieved in the absence of chlorite. Attempts to remove the chlorite by a careful acid wash succeeded only in rendering the chrysotile amorphous to the X-ray beam with the result that no X-ray spectrum was obtained in the chrysotile region. Further experimentation revealed that the presence of tremolite at fairly low levels tended to mask or interfere with the detection of some of the asbestiform minerals. It was thus clear that another technique would be needed in these special cases in order to be able to achieve an unambiguous analysis. Automated step-scanning executed with X-ray diffraction. Dispersion staining technique with light or optical microscopy. LIGHT MICROSCOPY Techniques employing the optical microscope have been used to identify mineral specimens for a long time. One of the more interesting and useful of these techniques is the Cherkasov focal screening dispersion staining proce dure (9). This technique, often shortened to " Dispersion Staining," has been applied successfully to the identifica tion of asbestiform fibers (10,11). Fairly extensive data taken by Julian and McCrone have shown that the asbesti form minerals are readily distinguished from one another and that different samples of each of the various types are similar and will exhibit a family resemblance. The difficulty in applying this technique to the problem is that while it works well with pure samples of fairly massive fiber length (3 to 5 microns and larger), observa tions by transmission electron microscopy have shown that naturally-occurring asbestiform minerals often lie below the working resolution capabilities of the light microscope. While massive fiber bundles can often be observed by either light or electron microscopy, the observation of individual fibers smaller than 0.5 x 0.02 micrometers requires the high resolution capability of the transmission electron microscope. In addition, the limit of detection is confounded by the presence of talc " fibers" formed when a thin talc plate curls up at the edge and rolls up into a cylindrical morphology. The lower limit of positive fiber detection and identification by this technique and under these conditions is felt to be too high to be of commercial value. ELECTRON MICROSCOPY By virtue of its ability to examine individual particles in minute detail and at very high magnifications, the transmission electron microscope has been found by us to provide the technique, ancillary to X-ray diffraction, that is needed to complete the unambiguous detection and identification of asbestiform minerals. The mor phology of the asbestiform minerals and tremolite is generally described as acicular or fibrous. This im mediately serves to isolate them in the platy talc matrix even in the presence of chlorite, since the chlorite morphology closely resembles that of talc. If the sample made into a specimen for the transmission electron microscope is or can be made homogeneous and a careful examination of approximately 100 different fields of view fails to reveal any fiberous material, then that talc is felt to be free of tremolite, chrysotile and the asbestiform minerals. The lower detection limit of this technique is difficult of access since one is often dealing with individual crystals. However, a typical field of view of a talc which was originally asbestos-free but now contained a 1% addition of chrysotile showed between 5 and 15 fibers (a typical field of view can be seen in Figure 5). If one then assumes that as few as one to three fibers can be detected in each field of view than the lower detection limit can be postulated to be 0.2% or lower. Figure 6 shows Pfizer's Montana talc exhibiting its typical platy character and total lack of tremolite or asbestiform mineral. Figure 7 shows a commercial talc containing approximately 1% chrysotile which was obscured from detection by X-ray diffraction because of the presence of chlorite. Selected area electron diffraction was used in conjunc tion with the examination of morphology. Using this method one single crystal or particle can be selected and analyzed. Single particles usually yielded spot patterns but if a group or bundle of fibers was found and would transmit electrons, a polycrystalline ring type pattern would result. Table 2 lists the principle electron diffraction maxima for talc, tremolite and the asbestiforms. In almost all cases many more spots or rings were observed than are reported here. In Table 2, only the strongest lines which are most likely to be observed have been tabulated. Selected area electron diffraction was also used to prove that the pseudo fibers of talc caused by plate-edge curling were actually talc and not tremolite or an asbestiform mineral. A comparison of the selected area electron diffraction pattern of these pseudo fibers to that of the talc platlets showed that the identical compound, talc, was the only species present. CONCLUSIONS The present work has shown that properly prepared samples of talc can be step-scanned by an X-ray diffractometer to detect tremolite at levels down to 0.25% and asbestiform minerals at the 0.5% level in the absence of chlorite. In the presence of chlorite and at concentration levels lower than those stated above, the transmission electron microscope was found to provide reliable detection and identification of tremolite and asbestiform minerals. The transmission electron micro scope is the most sensitive method and appears to be a more or less referee technique since when morphology observations are coupled with selected area electron diffraction studies, there are no known interferences. Light microscopy was helpful only in screening samples with large particles and high concentrations of objection able fibers. Morphology observation by transmission electron microscopy. Using the above techniques we have been able to screen large numbers of talc specimens. We have found Pfizer Inc.'s Montana talc to be free of tremolite and the asbestiform minerals. We have found some other com mercial talcs which contain tremolite and/or asbestiform minerals at low levels of concentration, (1% or less). Also, we have been able to detect asbestiform minerals FIG URE 6 -B A R IS 1 MICRON Pfizer Montana talc, free of asbestos and asbestiform content. S 03Q in low concentration, specifically chrysotile, by trans mission electron microscopy when its presence was masked by the presence of chlorite, (which was also present at less than 5% concentration). We, therefore, feel we have a technique that allows us to detect and identify tremolite and the asbestiform min erals under any circumstances at concentrations down to 0.1 to 0.2% and possibly lower. ACKNOWLEDGEMENTS The authors would like to thank Pfizer Inc. for permission to publish this work. We would also like to thank the Pneumoconiosis Research Unit, Llandough Hospital, Penarth, Glamorgan, United Kingdom for the samples of pure asbestiform minerals and all the helpful information on their physical and chemical charac terization. BIOGRAPHICAL SKETCHES Harold Stanley joined Pfizer Inc. in 1963 as a Research Investigator in Analytical Chemistry at Pfizer's M.P.M. Research Center. In 1964 he was transferred to the Physical Testing group where he built up a light and electron microscopy unit. In 1966 Mr. Stanley was given charge of the Physical Testing group and charged with the responsibility for the physical characterization of commercial and R & D materials. Mr. Stanley now has the title of Research Chemist and holds a Masters degree in Physical Chemistry from Lehigh University, Beth lehem, Pennsylvania. Robert Norwood joined Pfizer Inc. in 1960 as a Research Investigator in Analytical Chemistry at Pfizer's M.P.M. Research Center. In 1969 Mr. Norwood was assigned to the position of Group Leader for Physical and Chemical Testing with the responsibility of coordi nating the characterization of commerical and R & D materials. Mr. Norwood is now Research Manager for Administration and Services at Pfizer's M.P.M. Research Center. REFERENCES 1. F ibrou s and Mineral C ontent o f C osm etic Talcum P roducts; Cralley, L .J., Key, M.M., Groth, D.H., Lainhart, W.S. and Ligo, R.M .; J. Amer. Indus. Hyg. A sso c., Vol. 29, July Aug., p 3S0, 1968. 2. A Study o f Workers E xposed to Talc and Other Dusting C om poun d s in the R ubber In d ustry ; H ogue, W .L. Jr., and M allette, L .S ., J . Indus. Hyg. &, T o xical., V ol. 31, p 3 59, 1949. 3. Pulm onary Disability In A sb estos W orkers; Sm ith , K.W., Arch. Ind. Health, Vol. 12, p 198, 1955. 4. The E ffects of Inhaled Talc-Mining Dust on the Human Lung; Schepers, G.W.H., and T.M. Durkan, AMA Arch. Indus. Health, Vol. 12, p 182, 1955. 5. The Magic Mineral; Brodeur, P., New Yorker Magazine, p 12, October 1968. 6. Talc-Treated Rice and Japanese Stom ach Cancer; Merliss, R .R ., Science, Vol. 173, Sept. 17, 1971, p 1141, 1142. 7. " T alc" , Dangerous Properties o f Industrial Materials, N. Irving Sax, Ed., Reinhold Publishing C orp., New York, 1963 p 1217. 8. ibid p 469. 9. Dispersion Staining, Parts I and II, Brown, K.M., and McCrone, W.C., M icroscope Vol. 13, p 311 ff and Vol. 14 p 39 ff, 1963. 10. Identification o f A sbestos Fibers by Microscopical Dis persion Staining, Ju lian , Y ., and M cCrone, W.C., M icro scope, Vol. 18, p 1 ff, 1970. 11. Characteristics o f the International Union Against Cancer Standard Reference Sam ples o f A sbestos, Timbrell, V., Proc. Int. Pneum oconiosis Conf., Johannesburg, 1969. TABLE 1 PRINCIPAL LATTICE SPACINGS OF TALC AND RELATED M IN ER A LS BY X -R A Y D IF FR A C T IO N Cu K alpha Mineral Species Principal d-Spacings in Angstroms 1 2 34 56 Talc Chlorite Tremolite Chrysotile Amosite Anthophyllite Crocidolite 9.51 14.00 9.50 7.03 8.38 7.38 8.26 8.40 8.43 4.73 4.62 4.70 3.38 3.27 4.55 3.27 4.58 4.51 3.14 3.53 3.12 3.66 3.07 3.25 3.43 2.61 2.82 2.94 2.81 2.45 2.77 3.13 3.11 2.50 2.71 2.59 2.53 1.54 3.06 2.72 Central Research Laboratory, Easton, Pa., Pfizer MPM Division. TABLE 2 SELECTED AREA ELECTRON DIFFRACTION MAXIM A FOR TALC AND RELATED M INERALS* (IN ANGSTROMS) Talc Tremolite Chrysotile Amosite Anthophyllite 4.60 2.62 2.32 1.74 1.59 1.53 1.33 1.28 4.51 2.59 2.53 2.32 2.27 2.04 1.86 1.69 1.65 4.58 3.67 2.61 2.14 1.70 1.55 1.34 1.29 3.88 3.45 3.00 2.64 1.74 1.61 1.55 1.32 4.58 2.65 2.27 1.75 1.55 1.33 1.28 1.23 *The data for Chrysotile, Amosite and Anthophyllite were taken from reference (11). FIGURE 1 Step-scan plot of intensity versus degrees 2 theta for Pfizer Inc. Montana talc. FIGURE 3 Percent asbestos as a function of intensity of diffracted X-rays. COUNTS PER M INUTE F |GURE 2 Step-scan plot of intensity versus degrees 2 theta showing the effect of adding 1% and 5% tremolite to talc. FIGURE 4 Percent tremolite as a function of intensity of diffracted X-ravs