Document ga09NRQOeqMNz3enO4zxQO7ON

r t rlcZftni MANUFACTURING CHEMISTS ASSOCIATION y 1925 CONNECTICUT AVENUE. N.W., WASHINGTON. D.C. 20009 - TELEPHONE. (202) 329-*200 TELEX: 19617 (MCA WSH) January 11/ 1979 Tos Vinyl Chloride Audit Task Group (ATG) / Z. G. Bell, Jr. - PPG Industries/ Inc. T. J. Benya - Ethyl Corporation W. M. Busey - Experimental Pathology Laboratories, Inc. G. K. Hatfield - Diamond Shamrock Corporation R. K. Hinderer - The BFGoodrich Company, Chemical Division C. D. Kary - Shell oil Company T. R. Torkelson - The Dow Chemical Company Subjects ATG Report Members: Enclosed are copies of the following documents: 1. Appendix index 2. Retyped draft of ATG report 3. Appendixes If another meeting of the ATG is held/ it will be at the call of the Chairman. Sincerely, LCHtpmt Enclosures Lucille C. Hens.chel Acting Project Manager Vinyl Chloride Research THE WRITER'S DIRECT OtAL NUMBER IS (202) 32S- 4250 APOOOt 3089 Appendix 1 Report by Dr. William M. Busey, Experimental Pathology Laboratories, Inc. Appendix 2 Protocols - February 1, 1973 - May 22, 1973 - September 7, 1973 - January 30, 1975 - August 2, 1973 -- August 3, 1973 Appendix 3 Site Visits June 15, 1973 letter - August 6, 1973 letter - August 10, 1973 letter - April 17, 1974 letter (necessity of this questioned) - February 19-24 Record of Meeting * AP00013090 DRAFT -------------------- Pinal Report of Audit Task Group on LIFETIME INHALATION STUDY ON VINYL CHLORIDE at Industrial BIO-TEST Laboratories, Inc. Introduction In 197?U 31 vinyl chloride (VC) producers and users through the coordination of the MCA, contracted with the Industrial BIO TEST Laboratories (IBT) to conduct a long-term carcinogenic study in rats, mice and hamsters. Because of the absence of a final report and subsequent questions on other studies by IBT, an Audit Task Group (ATG) was established by the Technical Panel on VC Research on January 12, 1978. The group, including technical representatives of the companies and William M. Busey, D.V.M., Ph.D.of the Experimental pathology Laboratories, Inc, (EPL), who was retained as an independent consultant, have conducted a partial audit of the histopathologic record's. The findings and recommenda tions from this audit are presented in this report, including Dr. William M. Busey's Vinyl Chloride Pathology Report, January 9, 1979. (Appendix 1) History * Based on available information, a protocol for a lifetime study was designed which included exposure of male and female rats, mice i and hamsters to either 0, 50, 200 or 2500 ppm. (See Appendix 2) The contract for this study was let in February 1973 and exposures ' ^j i started on September 15, 1973. Reports of site visits conducted during the study are in Appendix 3. .; APOOOf309f -2- jnterim reports vtert periodically received by MCA and have #n transmitted to the Technical Panel. Since no final report v44 received, an ATQ vas formed by the Technical Panel to determine feasibility of obtaining a valid document. This was further -peed by inadequacies in other studies performed by IBT. p^cedure The ATG recognized several questions that would have to be. .mswered properly if this study was to be considered of adequate technical quality to be useful. However, after inspection of the ' Available IBT records, it seated more appropriate to the ATG to '' conduct a partial audit to assess the quantity and quality of the autopsy and histopathological data. Depending upon whether adequate tissues, blocks and slides were available or not, it would be possible to determine the usefulness of extending the audit to . animal records, exposure records, source of animals, and other equally important questions, if it was found that adequate autopsy material v* not available, nothing would be gained by several months effort to conduct a complete audit. Therefore, this partial audit of pathology records was conducted. With the cooperation of remaining IBT personnel at the Decatur location, the ATG and its consultant. Dr. William M. Busey, divided Ssb(Appendix 3) itself into three teams/ The activities of the first team were described in Dr. Busey*s report of January 9, 1979. The other two teams examined the autopsy records to determine the disposition of APOOO13092 the experimental animals and the number that had been sacrificed and saved for histological examination. The totals are included in Tables X, II and III of the January 9, 1979 report. In addition, the ATG examined a small sample of the wet tissues to determine if the number of organs required by the protocol had been taken at autopsy. The findings suggested that the number of organs was deficient and IBT was requested to do a complete inventory of tissues, blocks . and slides. This was subsequently done and the totals of available tissues are presented in Tables V, VI, and VII of the January 9, 1979 report. The ATG estimates that the full group has spent more than 800 hours in completing this partial audit, in addition to several weeks by MCA staff and IBT personnel. Conclusions and Recommendations The ATG concludes that the conduct of the study by IBT is scientifically unacceptable and makes the following recommendations: i,1* That Dr.'William Busey's report be accepted by the Technical Panel as the final report of this study. 2. That as recommended by Dr. Busey "no further pathology work be done on this study". 3'. That IBT be instructed that no further work be done on this study and that all materials and records of this study be retained by IBT indefinitely according to conformity with the Good Laboratory Practice Regulations, as published in federal Reerister, December 22, 197B. APOdOt3093 4That IBT be instructed that this project is considered closed and that no further funds will be available from MCA* If the report of the ATG is accepted by the Technical panel that it be transmitted to the appropriate government agencies. a #: . <. APOOO13094 ^Aa*>***V l, . PROTOCOL manufacturing CHEMISTS * ASSOCIATION, INC. CHRONIC VAPOR INHALATION TOXICITY STUDY WITH VINYL CHLORIDE Outline of Investigation A. Type and Length*? 12-month vapor White Mice 12-month vapor Albino Rats 12-month vapor Uamsters inhalation inhalation inhalation in in in B. Number of Animals: 4 C. Exposure Schedule: <? D. Test Materials? GOO Mice 800 Rats 800 Hamsters Seven Hours per Day Five Days per Week Vinyl Chloride (Ethylene derived) E. Organization: See Tabic I P- Dose Levels: See Table I *After exposure, animals will bo maintained for observation and sacrifice at end of two-year period (IQ months for mice). -1- AP00015095  M a S oucH s t VI fll tn u 111 1t): Ho o oO o <J V (* *Uii <f0! 0 s t-<i4un IQ SC Ho Oo ^ oo oo (H o oo oo oo o o a o o 0E 1 1 a, -4 n <3 04 r-| *-i n O P, o n, *U O > u, > a. tt) O a 0 n 0 <u m u ^ u o 0 j-i G in > QJ Jj X. o in o O o C H o MX H H Kl M1 W1 M 1 M li) r.j H fr* C- TJ O M lO *H H H Vi g u O *U Cl a *1 .U c rt; oi nj 0 o i; < cS o r~t r | V n ; in i: ,i: V 1 41 C-* r m r fVI i I APOObt3096 ZZ Chamber Par.imuLor t; Each group of animals will be exposed in u specially constructed ploxiglas inhalation chamber having a capacity of approximately 6.0 M^, allowing animal loading of less than 2% when the animals reach maturity. Flow rate through the cham ber will be at least 0.60 M^/min. providing a theoretical air. change every ten minutes. The chamber supply air will be filtered and maintained at 40% to 60% relative humidity and 70 to 75F. III. Animal Parameters . A. Clinical Observations All animals will be observed daily for lesions and * \' behavioral changes attributable to the teat material. The time of appearance and location of all tumors that occur among both control and test animals will be recorded. Mor tality records will be kept on all groups of animals. All animals which dio during the study will be nucropsiod and . > their tissues processed in accordance with the methods given in the Anatomic Pathology Section. Care will be exercised to minimize loss of tissues through cannibalism or autolysis. Animals in a moribund state will bo sacrificed j_n extremia when death is imminent. -3- AP000I3097 U. Body Weights Individual body weights will be recorded once before exposure and after 1, 2, 2, and 4 weeks of testing. There after, mean group body weights will be determined monthly up to the 12-month point of the study. C. Clinical Pathology Hemoglobin, hematocrit, total erythrocyte and total leukocyte counts will be performed at 10 and 24 months on 3Q (15 male and 15 female) rats of the control and each test group. Differential leukocyte counts will be performed on all animals having high total leukocyte counts. D. % Anatomic Pathology 1. Methods of Sacrifice Upon completion of the study, all survivors will be .sacrificed by exsanguination.following carbon dioxide anesthesia. 2. ,Gross Pathology Complete necropsies will be performed on all ani mals which die or are sacrificed and all macroscopic lesions will be recorded. The lungs will be inflated with formalin fixative. 3. flistonatholodv Representative specimens of the following organs -l- AP00013098 and tissues will be taken from all animalc at time uC tiacrilicc and fixed in 10.0% neutral buffered formalin: Adrenal Glands All Gross Lesions Done (femur, tarsal and metatarsal, including long bones of all four limbs) Done Marrow (sternal) Drain Both Ears (external auditory canal with ceruminal (Zymbal's) glands) . Esophagus Eye Gonads (testes and ovaries) Kidneys Large Intestine (caecum and colon) Liver -Lungs Lymph Nodes (tracheobronchial, cervical and mesenteric) Optic Nerve * Pancreas Parathyroid Gland Pituitary Gland Prostate------------------------------------------ Salivary Gland Seminal Vesicles Skin Small Intestine (duodenum, jejunum Spleen Stomach * Thymus Thyroid Gland Trachco Urinary Bladder Uterus i and ileum) The above tissues, from animals of the control, . TE-II, and TE-IZZ will be processed by conventional methods, embedded in paraplast, sectioned (4-6/*.) , stained with hema toxylin and eosin, and evaluated by light microscopy. If -5- AP00013099 drug-related lesions ore detected in tissues from the high or intermediate dose (TE-II or T13-III) animals, affected tissues from the TE-I group animals will bo processed and examined in the same manner as the above. Only major organs (liver, kidney, spleen, heart, lungs) and neoplasms from animals which die and arc found in an advanced state of autolysis wiil be processed for histo pathologic evaluation. XV. Reports Quarterly summaries of mortalities, clinical observations, clinicopathologic and anatomopathologic findings will be pre pared. Upon completion of the study, a .complete report will be prepared and issued. % February 1, 19^3 -6- AP00013100