11K flt:CO2Y AD IITRI Project No. L6.21 Study No. 7 DETERMINATION OF THE CHRONIC MAMMALIAN TOXICOLOGICAL EFFECTS OF RDX Twenty-Four Month Chronic Toxicity/Carcinogenicity Study of Hexahydro-1,3,5-Trinitro-l,3,5-Triazine (RDX) in the B6C3F1 Hybrid Mouse Final Report Phase VI, Vol. 1 Paul M. Lish Barry S. Levine E. Marianna Futedi John M. Sagartz Rac =,LECT Vladislava S. April 1984 (DD (0) U.S. 00 71j Supported by: ARMY MEDICAL RESEARCH AND DEVELOPMENT COMMAND Fort DetLick, Frederick, MD 21701-5012 Contract No. DAMD17-79-C-9161 IIT Research Institute 10 West 35th Street Chicago, IL 60616 Jesse J. Barkley, Jr. Project Officer: U.S. Army Medical Bioengineering Research and Development Laboratory Bldg. 568, Ft. Detrick Frederick, Maryland 21701-5010 DOD DISTRIBUTION STATEMENT Approved for public release; distribution unlimited The findings in this report are not to be construed as an official Department of the Army position unless so designated by other authorized documents. 87 6 1 078 DISCLAIMER NOTICE DOCUMENT IS BEST QUALITY PRACTICABLE. THE COPY FURNISHED TO DTIC CONTAINED A SIGNIFICANT NUMBER OF PAGES WHICH DO NOT REPRODUCE LEGIBLY. "THIS Unclassified - CUm.I rY CLASSIFICATION OF THIS PAGE Form Approved REPORT DOCUMENTATION PAGE OMB No 0704.0188 - REPORT SECURITY CLASSIFICATION Exp. Date: Jun 30, 1986 lb. RESTRICTIVE MARKINGS Unclassif ied 3. DISTRIBUTION/AVAILABILITY SECURITY CLASSIFICATION AUTHORITY DECLASSIFICATIONI/DOWNGRADING SCHEDULE 5. MONITORING ORGANIZATION REPORT NUMBER(S) PERFORMING ORGANIZATION REPORT NUMBER(S) L6121 IITRI Project No. 6b. OFFICE SYMBOL NAME OF PERFORMING ORGANIZATION .J. OF REPORT Approved for public release; distribution unlimited 7a, NAME OF MONITORING ORGANIZATION (If applicable) lIT Research Institutej 7b. ADDRESS (City, State, and ZIP Code) ADDRESS (City, State, and ZIP Code) 10 West 35th Street Chicago, Illinois 60616 o. NAME OF FUNDING/SPONSORING ORGANIZATION U.S. Army Medical 8b OFFICE SYMBOL I 9. PROCUREMENT INSTRUMENT IDENTIFICATION NUMBER (If applicable) Contract No. Research & Development Comman] DAMI17-79-C-9161 10. SOURCE OF FUNDING NUMBERS I TASK PROJECT PROGRAM .. ADDRESS (City, State, and ZIP Code) ELEMENT NO. Fort Detrick Frederick, Maryland 21701-5012 NO 3E1- 62720A8351 62720A WORK UNIT ACCESSION NO NO I 00 101 . TITLE (Include Security Classification) ical Effects of RDX Determination of the Chronic Mammalian Toxico 2. PERSONAL AUTHOR(S) P.M. Levine, Lish, B.S. 'inal, phase V Vol.1I J. Furedi E.1. 13b TIME .3a, TYPE OF REPORT FROM...'' 1 V.S. SaRartz, Rac 14. DATE OF REPORT (Year, Month, Day) 115. PAGE COUNT .OVCREL) TO 368 1984Aril 4/84 16. SUPPLEMENTARY NOTATION Subtitle: COSATI CODES 17. IFIELD 6 I Twenty-Four Month Chroni Toxicity/Carcinogenicity Triazine (RDX) in the I GROUP 15 6 20 IS 'UBJECT -F1 TERMS (Continue on reverse if necessary and identify by block number) C) -Reg. RDX 1...Hexahvdro-1,3,5-trinitro-1,3,5-triazine, SUB-GROUP .~~~~B.C-)`F Study of Hexahydro-l,3,5- No-.4-2-1-82-P-'- Chronic toxicity) Hepatocarcinogen) ~ybrid mouse ýHepatotoxicitvCacn a Adoa I STRACT (Continue on reverse if necessary and identify by block humber) This study was conducted to evaluate the toxicity of the munitions compound hexahydro-1,3,5,3,5-triazine (RDX: CAS Reg. No. 121-82-4) in B6C3F1 mice when administered in trinitr.-] RDX purity was established to be 89.2-98.7% with the main their diet for un to 24 months. Groups of 85 mice per sex received RDX at doses of 0, 1.5, 7.0, 35.0 contamlnant of IIMX. This last dose was reduced from 175 mg/kg/day in Test Week 11 due to or 100.0 mg/kg/day. Ten mice/sex/dose were killed following 6 and 12 months on test with surhigh mortality. Toxicologic endpoints included clinical viving animals killed after 24 months of treatment. signs, body weights, food consumption, hematology, clinical Chemistry, ophthalmology, organ weights, and gross and tissue morphology. The major toxic effects observed (luring the administration of RDX to B6C3FI mice for up to and testicular de24 months Included hepatotoxicitv, possible CNS involvement, in addition, hepatocellular adenomas and/or carcinomas were more prevalent generatlon. (cons ,mod~ 20 DISTRIBUTION /AVAILABILITY OF ABSTRACT 0 UNCLASSIFIED/UNLIMITED El SAME AS RPT lUa NAME OF RESPONSIBLE INDIVIDUAL 21 ABSTRACr SECURITY CLASSIFICATION 0 DTIC USERS d Un(laasincld 22b TELEPHONE (include Area Code) I Mrs. Virginia Miller DD FORM 1473, 84 MAR 83 APR edition may be used until exhausted. All other editions are obsolete 22c OFFICE SYMBOL R163-732Rn-q SECURITY CLASSIFIIATION OF THIS PAGE Un CPassi t I ed / IF.M911;Iv -19. ABSTRACT (concluded) Whether serum cholesterol >for RDX-treated females than for corresponding controls. levels and/or the incidence of hepatocellular tumors were increased at the 7 mg/kg/ The no-effect level under the conditions day dose level is equivocal. of the present study is 1.5 mg/kg/day. iv I%~c r TiTA F - 77- 7N r Contract No. IITRI DAMD17-79-C-9161 Project No. L6121 Study No. 7 DERMINATION OF THE CHRONIC MAMMALIAN TOXICOLOGICAL EFFECTS OF RDX Twenty-Four Month Chronic Toxicity/Carcinogenicity Study of Hexahydro-1,3,5-Trinitro-1,3,5-Triazine (RDX) in the B6C3F1 Hybrid Mouse Final Report Phase VI, Vol. 1 Paul M. Lish Barry S. Levine E. Marianna Furedi John M. Sagartz Vladislava S. Rac April 1984 Supported by: U.S. ARMY MEDICAL RESEARCH AND DEVELOPMENT COMMAND Fort Detrick, Frederick, MD 21701-5012 IIT Research Institute 10 West 35th Street Chicago, Project Officer: Advisor Life Sciences Research COPy! 60616 Jesse J. Barry S. i Scientific IL INSe Barkley, Jr. El Levine,D.Sc. Senior Toxicologist Life Sciences Research 0 Alan M. Shefner Associate Director Life Sciences Research -0 *, Cedes - /or I EXECUTIVE SUMMARY munitions compound hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX; CAS Reg. No. 121-82-4) in B6C3Fl mice when administered in Groups of 85 mice per sex their diet for up to 24 months. received RDX at doses of 0, 1.5, 7.0, 35.0 or 100.0 mg/kg/day. This last dose was reduced from 175 mg/kg/day in Test Week 11 due tc high mortality. Ten rats/sex/dose were killed following 6 and 12 months on test with surviving animals killed after 24 months Toxicologic endpoints included clinical signs, of treatment. food consumption, hematology, clinical chemistry, body weights, ophthalmology, organ weights, and gross and tissue morphology. The administration of 175 mg/kg/day of RDX to male and female B6C3F1 mice resulted in death during the first ten weeks Test This dose was reduced to 100 mg/kg/day in of treatment. Week 11. Subsequently to this, the slope of the survival curves were similar for this treatment group and control animals for the duration of the study. Although these high dose animals showed slight reduction in body weight gains, food consumption was not affected. Surviving males in this high dose group demonstrated significant skin lesions apparently associated with fighting wounds. RDX is known to induce behavioral changes including hyperreactivity to approach and fighting with cage mates. However, histologic evaluation failed to detect treatment-related lesions of the central nervous system. Liver injury at 175/100 and to a lesser extent 35.0 mg/kg/day was evidenced by several observations. These included elevated serum cholesterol and triglyceride levels and hepatomegaly. With the exception of hepatocellular tumors (discussed below), histopathologic lesions of the liver were not observed. At the 6, 12 and 24 month kill, kidney weights were elevated for mice of both sexes administered 175/100 mg/kg/day. Cytoplasmic vacuolation of renal tubules appeared to be more prevalent for RDX-treated males than corresponding control animals after six months of treatment. This lesion was subsequently seen at 12 and 24 months as frequently for control as for treated animals. Although statistically not significant, an increased incidence of hepatocellular carcinoma was seen in RDX treated female but not male mice. The combined incidences of hepatocellular carcinoma and adenoma were statistically greater for female mice receiving 7.0 mg/kg/day and higher doses than for the concurrent female co-..trol group. When historical control 3 data were included in the statistical analyses, the two top dose demonstrated significant increases in the incidence levels still When these historical of combined liver carcinomas and adenomas. control data were compared to this study data, the incidence values for hepatocellular carcinoma for historical controls fell between the incid,-,¢.c for control and high dose mice. in increase significant non-statt&tically A carcinomas was seen in high dose male and alveolar/bronchiojur Comparison of study controls to the appropriate female mice. of incidence the that showed controls historical alveolar/bronchiolar carcinomas and adenomas for study control mice was within the range of incidences of alveolar/bronchiolar An carcinomas in both sexes of historical control mice. additional scatistically significant observation was an increased lungs of the female mice receiving number of histiocytes in 175/100 mg/kg/day. 175/100 An additional toxic effect seen primarily at accompanying without hearts enlarged included mg/kg/day Although not statistically significant, histologic lesions. increased incidences of testicular degeneration were seen for the male mice at the 175/100 and 35 mg/kg/day dose levels when to the concurrent controls or to the historical compared Absolute or relative testicular weight change failed controls. to accompany this histopathological finding. In summary, the major toxic effects observed during the administration of RDX to B6C3FI mice for up to 24 months included and testicular CNS involvement possible hepatotoxicity, In addition, hepatocellular and alveolar/bronchial degeneration. carcinomas and adenomas were more prevelant for RDX-treated mice The incidence of hepatocellular than for corresponding controls. was significantly carcinomas and adenomas) tumors (combined On this basis, the increased at the 7 mg/kg/day dose level. 1.5 no-effect level under the conditions of the present study is mg/kg/day. 4 NAN~~~ I Q) 'k FOREWORD The U.S. Army Medical Bioengineering Research 'and Development Laboratory (USAMBRDL), Fort Detrick, Frederick, MD, has been conducting a research program since 1973 for the purpose of developing the scientific data base necessary for recommending water quality criteria for compounds unique to the munitions industry. A water quality criterion (as defined by the amended Clean Water Act, 1977) is a qualitative or quantitative estimate of the concentration of a pollutant in ambient waters that, when not exceeded, will ensure a water quality sufficient to protect a specified water use. The criterion is a scientific entity based solely on data and scientific judgement. It does not reflect considerations of economic or technological feasibility. Currently, a water quality criterion consists of two separate numerical limits, one for tne protection of human health and the other for the protection of aquatic organisms. These numbers, when translated by the appropriate regulatory agency, can be the basis of enforceable discharge or effluent limitations in a point source discharge permit issued under the Clean Water Act. Since a water quality criterion is to protect designated water uses, a diverse, multidisciplinary research program was developed by USAMBRDL that includes "effects" studies on laboratory and domestic animals, wildlife species, aquatic organisms, plants, and economically important crops. In addition, extensive chemical and biological fate and persistence tests are conducted to provide information on the behavior of a pollutant in the aqueous environment. These kinds of data are especially useful for making site-specific translation of criteria into enforceable discharge limits. This report represents a portion of the mammalian toxicology data base being developed by USAMBRDL on hexahydro-1,3,5trinitro-1,3,5-triazine. In conducting the research described in this report, the investigator(s) adhered to the "Guide for the Care and Use of Laboratory Animals," prepared by the Committee on Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resounrces, National Research Council (DHEW Publication No. (NIH) 78-23, Revised 1978). L05 1WO5 ACKNOWLEDGMENT This report was prepared at IIT Research Institute, 10 West 35th Street, Chicago, Illinois, 60616, une'er U.S. Department of DAMDi7-79-C-9161 (IITRI "roject No. L06121) Army Contract No. entitled "Determinaticn of the Chronic Mammalian Toxicological Jr., Health Effects Mr. Jesse J. Barkley, Effects of RDX". Officer's the Contract served as USA!:i.RDL, Division, Research Technical Represent%)%ve for this program. o The work reporLt. herein was conducted in the Toxicology and Pharmacology Section of the Life Sciences Division, and represents a portion of the overall effort of the above named Lish, Ph.D., Scienti.fic Advisor, research program. Paul M. D.Sc., Barry S. Levine, servid as Principal .nvestigator. Senior Toxicologist, served as study director and was responsible for t'%e overall conduct of the study. Eva M. Furedi-Machacek, DVM, ierved cs stucyv toxicologist and was also responsible for the .:erv~.sioi, of the technical support personnel. John M. Burn. DV.. Sei:ior Veterin..:ry Pathologist, Bobby R. Collins, DVM, , -"id %'-.P'•,slava S. Rac, DVM, M.S., were consecutively resporn' .... e •Ec , ervisi'n of gross necropsies. Carol A. Thompson, DVM, 11 , tabulated the gr-ss necropsy data. Drs. Burns 6d L, served as consecutive heads of the clinical pathology lab-&tory, and Samuel Terese, B.S,(ASCP-MT), and Debbie L. Sava, B.S.(k'SCP-MT), were responsible for generation of clinical pathology data. Donovan E. Gordon, DVM, Ph.D., Consultant. Veterinary Pathology, was responsible for tabulation and evaluation of histopathology data. Bobby R. Collins, DVM, M.S., an(: Joserl. B. Harder, DVM, served as clincal veterinarians and supervised aniroal care personnel. Joann M1. Hinz, B.S., and Robert M. Renaud, B.S., were responsible for the collection of test data. Dorothy Davis (ASCP-HT) was responsible for preparation of histology slides. C. Susan West, DVM, performed the ophthalmic examinations. Josephine M. Reed, M.M., M.S., Supervisc;r, Quality Assurance, was responsible for the quality assurance program. Robert Remaly, B.S., Senior Engineer, was responsible for preparation of the test article premixes. Fugh J. O'Neill, Ph.D., Manager, Analytical Chemistry, Walter C. Eisenberg, Ph.D., Senior Chemist, and Richard Schonfeld, M.S. and Debra Cunninghem, B.S., Assistant Chemists, were responsible for chemical analyses of test articles, test article premixes and test diets. Ms. Jean Graf provided the particle size analyses. Robert D. Gibbons, Ph.D., provided sta;tistical and computational assistance. 6 0 QUALITY ASSURANCE STATEMENT Biological laboratory inspections of critical phases were performed on 25 occasions between January 7, 1981 and May 19, 1983. Data audits were performed between July 21 and 22, 1981, January 21, April 30 to May 3, August 2, 19 and 20, November 4 to 8, 1982, January 12 to 13 and October, 6, 1983, January 11 to 18, and February 20 to March 2, 1984. The final draft report was audited between February 23 and March 3, 1987. Inspections and audits were performed by Josephine M. Reed, Julie McPhillips and Kirit PA74kh. The study was found to meet Life Sciences Quality Assurance criteria. Specimens and raw data generated during the study will be retained in the IITRI Life Sciences Archives as specified ir standard operating procedures. MaJorphinte M. Reed M'anager, Quality Assurance 7 TABLE OF CONTENTS Page No. Volume I I. II. INTRODUCTION ............................................ 13 MATERIALS 13 A. B. C. D. E. III. AND METHODS ................................... Test Article ........................................ Test Diets .......................................... Test Animals ........................................ Experimental Design .................................. Statistical Analysis ................................. RESULTS ............................................................. 23 A. B. C. D. E. F. G. H. I. J. 23 23 23 24 24 24 24 25 25 25 Test Diets .......................................... Food and Water Contaminants ........................ Mortality/Clinical Observations ...................... Body Weight ......................................... Food Consumption .................................... Hematology .......................................... Clinical Chemistry .................................. Ophthalmology ....................................... Organ Weights ....................................... Pathology ........................................... IV. DISCUSSION ........................................ 27 V. REFERENCES ........................................ 29 APPENDIX APPENDIX APPENDIX APPENDIX I II III IV APPENDIX APPENDIX V VI APPENDIX VII APPENDIX VIII APPENDIX APPENDIX APPENDIX IX X XI TEST ARTICLE ANALYSIS .......................... 5002 CERTIFICATION PROFILE/ANALYSIS ....... TEI ANALYTICAL CHEMISTRY METHODS .......... HEMATOLOGY METHODOLOGY .......................... CLINICAL CHEMISTRY METHODOLOGY ............ INDIVIDUAL ANIMAL DATA .................... CHLORTETRACYCLINE CONTENT OF 5002 ......... NITRATE, NITRITE AND MERCURY CONTENT OF 5002 .......................................... CHICAGO WATER CHEMICAL ANALYSIS ........... OPHTHALMOLOGY NARRATIVE REPORT ............ PATHOLOGY NARRATIVE REPORT ..................... DISTRIBUTION LIST ........................................ 8 13 14 16 17 22 105 141 . 143 147 ... 151 M 39 341 343 ... 345 353 364 TABLE OF CONTENTS (CONCLUDED) VOLUME II* APPENDIX X Page No. OPHTHALMOLOGY REPORT (COMPLETE) ........... 339 PATHOLOGY REPORT (COMPLETE) .................. 595 VOLUME III* APPENDIX XI *Requests for Volumes II and III should be directed to Health Effects Research Division, U.S. Army Medical Bioengineering Research and Development Laboratory, Fort Detrick, Maryland 21701-5012. 9 LIST OF TABLES Table 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 31a 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 10 Page Male Actual Doses Received ............................. Female Actual Doses Received ........................... Test Diet Concentrations of RDX ........................ Mean Survival Time ..................................... Male Body Weights ...................................... Male Body Weight Gains .................................. Female Body Weights .................................... Female Body Weight Gains ............................... Male Food Consumption Measurements ..................... Female Food Consumption Measurements .................... Male Hematology Values - Test Week 14 .................. Female Hematology Values - Test Week 14 ................ Male Hematology values - Test Week 26 .................. Female Hematology Values - Test Week 26 ................ Male Hematology Values - Test Week, 53 .................. Female Hematology Values - Test Week 53 ................ Male Hematology Values - Test Week 79 .................. Female Hematology Values - Test Week 79 ................ Male Hematology Values - Test Week 105 ................. Female Hematology Values - Test Week 105 ............... Male Clinical Chemistry Values -- Test Week 14 .......... Female Clinical Chemistry Values - Test Week 14 ........ Male Clinical Chemistry Values - Test Week 26 .......... Female Clinical Chemistty Values - Test Week 26 ........ Male Clinical Chemistry Values Test Week 53 ............ Female Clinical Chemistry Values - Test Week 53 ........ iqale Clinical Chemistry Values - Test Week 79 .......... Female Clinical Chemistry values -* Test Week 79 ........ Male Clinical Chemistry Values - Test Week 105 ......... Female Clinical Chemistry Values - Test Week 105 ....... Incidences of Cataracts ................................ Incidences of Cataracts (Revised) ....................... Male Mean Relative Organ Weights - Test Week 26 ........ Female Mean Relative Organ Weights - Test Week 26 ...... Male Mean Relative Organ Weights - Test Week 53 ........ Female Mean Relative Organ Weights - Test Week 53 ...... Male Mean Relative Organ Weights-Test Weeks 105-106 .... Female Mean Relative Organ Weights-Test Weeks 105-106 . Male Mean Organ Weights - Test Week 26 ................ Female Mean Organ Weights - Test Week 26................ Male Mean Organ Weights - Test Week 53 .................. Female Mean Organ Weights - Test Week 53 ............... Male Mean Organ Weights Test Weeks 105-106 ............. 1'emale Mean Organ Weights - Test Weeks 105-106 ......... Statistical Evaluation of Histopathologic Lesions (M). Statistical Evaluation of Histopathologic Lesions (F).. Statistical Evaluation of Liver Tumors ................. 32 36 40 41 42 45 48 51 54 57 60 61 62 63 64 65 66 67 68 069 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 2 93 94 96 97 LIST OF FIGURES Figure Page No. 4 Survival Curves for Control and High Dose Males ....................................... Survival Curves..................................... for Control and High Dose Females Incidence of Fighting Wounds and/or Skin Lesions For Male Mice .................................... Mean Cholesterol Values ............................ 5 Mean Female Triglyceride Values .................... 1 2 100 101 102 103 104 11 2 S•.. .: • •:... ..-.• •.... • ... ••...•..._-• •_ .!•.-•_.• . • , • .• /• •. • :• • 'g- , • • •_0 0 12' :, i2 !J '°S I. INTRODUCTION The U.S. Army Medical Research and Development Command (USAMRDC) has been directed to evaluate the potential hazards to living systems of wastewater discharges from munitions facilities. Of primary concern are the toxico3ogic effects to mammalian systems of hexahydro-1,3,5-trinitro-l,3,5-triazine (RDX; CAS Reg. No. 121-82-4). This high explosive is routinely used in filling shells and bombs. Wastewaters resulting from the loading of this explosive into shells the environment without significant treatment and are are discharged subject to into limitations imposed by governmental regulatory agencies. Evaluation of the potential hazards of these wastewaters to human health is therefore a necessary portion of the data-base required to establish comprehensive environmental criteria. The present study was conducted to aid in this evaluation and assessed the chronic toxicity and carcinogenicity of RDX in B6C3Fl mice when administered in the diet for at least 104 weeks. Information ultimately derived from this comprehensive long-term toxicology study will aid USAMRDC in developing criteria for the of effluent standards and in defining levels of establishment treatment for its pollution abatement program. The study reported herein was conducted in accordance with the IITRI Quality Assurance Program designed to comply with FDA Good Laboratory Practice Regulations (1). Thus, all terms used in this report, e.g. test article, raw data, specimens, etc., are in agreement with the definitions set furth in the aforementioned document. II. MATERIALS AND METHODS A. Test Article Hexahydro-l,3,5-trinitro-l;3,5-triazine (RDX: CAS Reg. No. 121-82-4), batch No. HOL 435-37, 100 pounds, was made available for this study from stocks at the IITRI Lingsoury Ordnance Plant (KOP) Explosive Facility, La Porte, In. The test article was stored at the facility at ambient room temperature and relative humidity, and in the dark. Upon initiation and at termination of the treatment phase of the study, 30 g samples were taken and stored under conditions similar to those for the batches. The purity of the test article was determined by high performance liquid chromatography with analytical standards provided by the Sponsor as described in Appendix I. RDX purity was analyzed three times during this study. Results were as follows: May 1981 (91.0 + 2.9%), May 1982 (89.2 + 8.0%) and Ap'il 1983 (98.7 + 2.0%). The main contaminant was HMX and represented approximately -1i0% of the sample (estimated concentration on the basis of percent area integration). The other impurities were not determined. 13 A A Particle size analyses of approximately 10% premixes were performed in November 1979 and in March 1981 by the Fine Particle Research Section of Chemical Engineering Division of IITRI. The results of premix analyses were as follows: Date S-• (um) <22 22-44 44-66 66-110 110-220 220-330 330-440 >440 B. November 1979 Number % Cummul. 355 184 75 38 22 10 2 i 51.7 26.8 10.9 5.5 3.2 1.5 0.3 0.1 % 51.7 78.5 89.4 94.9 98.1 99.6 99.9 100.0 November 1981 Number % Cummul. 105 216 92 41 38 8 0 0 21.0 43.2 18.4 8.2 7.6 1.6 % 21.0 64.2 82.6 90.8 98.4 100.0 Test Diets Premixer of the test article, (approximately 10% in Purina Certified Rodent Chow No. 5-0102, Ralston Purina Co., St. Louis, MO., hereafter referred to as 5002), were prepared on a monthly basis in 4 kg quantities at the Kingsbury Ordnance Plant facility by IITRI Chemistry Department personnel. Undiluted RDX was handled in accordance with procedures for explosive and fire hazards. The test article was ball milled with equal parts of 5002 and subsequently diluted with additional 5002 in a twin shell blender to yield approximate 10% premixes. Each RDX premix was tested for homogeneity, concentration and recovery of the test articles by HPLC. Homogeneity testing consisted of analyzing for test article concentration of each batch of premix taken from 6 random locations of its container. Premix stability was established for a period of seven and later for a period of nine weeks by conducting homogeneity tests at the initial and the terminal point of the 7, as previously reported (2), or 9 week period (see below). Recovery tests for premix consisted of adding a known quantity of test article to a weighed quantity of untreated 5002 in a measured volume of acetonitrile (the solvent used in the extraction procedure) to achieve the calculated premix concentration. The spiked samples subsequently underwent the identical procedures as the actual premixes. Toxicology Section personnel received the test articles as approximate 10% premixes in 5002. These premixes posed little explosive or fire hazard as previously demonstrated (2). Results of premix analyses were as follows: 14 •• ?•.~ V~ * -'- . •'- -• "'; -- o -i- DATE PREPARED DATE ANALYZED 1-35-8 1-08-81 1-20-81 135-9 135-12 135-15 2-27-81 3-13-81 4-16-81 3-03-81 3-23-81 4-27-81 10.53 10.24 10.65 0.30 u0.52 0.40 13-27-08-81 135-25 163-4 8-12-81 9-29-81 7-22-81 8-27-81 10-02-81 9.44 9.53 9.99 0.58 0.51 0.54 163-5 10-19-81 10-28-81 9.46 163-6 163-7 163-9 163-10 163-11 163-12 11-12-81 12-18-81 1-18-82 2-12-82 3-23-82 4-26-82 11-23-81 12-21-81 1-27-82 2-23-82 4-01-82 5-05-82 10.29 9.37 10.29 10.68 10.62 10.52 6-03-82 8-06-82 6-08-82 8-17-82 7-13-82 8-16-82 9-10-82 10-18-82 11-22-82 12-20-82 7-16-82 8-20-82 9-20-82 10-25-82 12-02-82 12-29-82 LOT NO. 135-17 135-21 5-1-1 6-16-81 Fj 163-15 163-15 ** 163-16 163-17 163-18 163-20 163-21 163-22 ** ** % COMPOSITE + S.D.* 10.58 +0.33• 0.36 05 5-181 9.88 6-26-819.7 _ 0.61 0.46 T 0.27 + T 0.79 T 0.63 • 0.41 T 0.36 10.38 0.30 10.04 + 0.37 _ 10.44 9.99 10.79 10.63 11.01 11.06 T 0.43 0.32 T 0.45 1 0.34 T 0.30 + 0.19 Six sampling locations Nine week stability test Following chemical analysis of the premixes to determine test article concentration (Appendix I), sufficient quantities were diluted with 5002 in a twin shell blender by toxicology personnel to achieve the concentrations of the test article necessary to administer the required dose levels on a mg/kg/day basis. The two previous periods' body weight and food consumption measurements for each test group by sex w, :e used to project vody weight and food consumption values for the next period. Based on these values, the desired dietary concentrations of the test article was calculated. Ten and later 8 kg of each test diet were routinely prepared on a weekly basis. Unused portions of 10% premixes were returned to KOP for disposal in accordance with instructions for safe disposal of explosives. Surplus and uneaten portions of test diets were incinerated. Thirty test diet concentrations (2 diets/sampling week) used in Test Weeks 1, 13, 28, 39, 45, 51, 57, 63, 70, 75, 81, 87, 93, In 98 and 104 were analyzed for accuracy and homogeneity. addition, two test diets were monitored for stability under animal cage conditions for one week. First, they were sampled 15 :L1I- -X tr1 11 L .'P' -V--A=k the day they were placed in the animals' cages and again one week later from the uneaten portion of the diet. Recovery studies of test diets consisted of adding a known quantity of RDX (spiking) to a weighed quantity of untreated 5002 in a measured volume of The acetonitrile (the solvent used in the extraction procedure). spiked samples subsequently underwent the identical analysis as the actual diet samples and the percentage of recovery was calculated. One sample of 5002, lot March 24 82 G, was analyzed during Park Ridge Ii. the course of the study by Trace Elements, Inc. (TEI) for those contaminants listed in the 5002 certification The references to the profile as shown in Appendix II. procedures used by TEI are in Appendix III. On the basis of the analytical results for chlortetracycline content, aliquots from this and three additional reserve samples of 5002 were sent to In addition, aliquots from these four reserve TEI for analysis. Louis, Inc., St. samples were sent to Scientific Associates, and Harris Laboratories, Mo., Woodson-Tenent Laboratories, Inc. Samples of for chlortetracycline analysis. Inc., Lincoln, Neb. each 5002 lot used in the study were also analyzed for nitrate, The results are shown in nitrite and mercury content by TEl. Appendices VII and VIII. C. Animals Breeding Charles River obtained from mice B6C3F1 MA, Portage, MI facility were used for Laboratories Wilmington, this study. Five hundred and seventy six males and 573 females They were 3 were received in good condition on January 7, 1981. to 4 weeks old upon arrival and random body weights recorded within three days of receipt were 16.5+ 2.6 g (males) and 14.6 + 1.6 g (females). one for The shipment was housed in two quarantine rooms, pretest during quarantine, The animal room conditions each sex. and test periods were as follows; 21-25 degrees centigrade, ambient relative humidity (30-70%), and 12 hour light /12 hour The No other test animals were in the rooms. dark cycle. animals were housed five per polycarbonate cage (16.5" x 8"; 8" Rochelle height) with Ab-sorb-dri bedding (Ab-sorb-dri Inc., Animals were N.J.) from arrival until their termination. Park, Each animal was transferred to clean cages twice weekly. identified during the quarantine period by a combination of cage Test animal selection was done at the number and tail mark. onset of Test Week -2 (2 weeks prior to initiation of treatment). Animals placed on test received a study-unique test animal number which appeared as a combination ear punch and toe clip. (N=850) necropsy The identifing ears and paws were included with also card that cage the on This number appeared specimens. the In addition, contained the study number,dose level and sex. cage cards were color coded as to the dose level and sex. 16 Upon arrival at the IITRI animal facility, the animals were During this period, they were for 12 days. held in quarantine unthriftiness, poor coat, general observed for signs of disease, Any animals discharge from body openings, abnormal feces, etc. found to be unhealthy were eliminated from the test animal At the end of the quarantine period, five selection process. Extensive gross necropsies animals of each sex were sacrificed. Blood were performed under the supervision of the pathologist. clincal and of hematology samples were collected for measurments chemistry parameters (see section II.D.) Results of pretreatment health screen were within normal limits for the mice of the mice Microbiological examination of the of this strain and age. molds yeasts, digestive and respiratory system for pathogens, parasites and Mycoplasma pulmonis was also performed for for the Serum antibody titer was above mice with negative results. GD-VII virus, K determined for the following murine viruses: Pneumonia Reovirus 3, Sendai virus, virus, Mouse Adenovirus, Polyoma virus, Lymphocytic Choriomeningitis, virus of mice, These tests Minute virus of mice, Mouse Hepatitis and Ectomelia. for antibody titers were negative as measured by Microbiological Associates, Bethesda MD. Animals received 5002 rodent chow from arrival until their except during a 2 to 5 hour fast prior to blood termination, The food was available collection and/or scheduled sacrifice. Co.). from powdered diet feeders (Model LC-207/C, Wahman Mfg. City of Chicago drinking water was available ad libitum from glass or plastic bottles. D. Experimental Design Following the quarantine period, test-eligible animals were assigned to five treatment groups by a stratified randomization Following assignment to procedure (blocked by body weight). treatment groups, all animals were randomly assigned test animal Body weight ranges at randomization were numbers as shown below. This procedure and 16.0-18.9 g (females). 16.0-24.8 g (males) The animals were was performed at the onset of Test Week -2. approximately 6-7 weeks old upon initiation of treatment and body weight ranges recorded during Test Week -1 (the most recent data prior to initiation of treatment) were 18.3-28.3 g (males) and The first day of exposure to the test 15.4-22.3 g (females). Dietary administration continued article was February 9, 1981. until Test Week 106 (February 18, 1983). 40 17 Treatment Group Allocation: Treatment Animals Dose Level Group per Sex (mg/kg/day) I. II. III. IV. V. 85 85 85 85 85 0.0 1.5 7.0 35.0 175.0/100.0* Test Animal No. (Males) 1- 75, 151-225, 301-375, 451-525, 601-675, 751-760 771-780 791-800 811-820 831-840 Test Animal No. (Females) 76-150, 226-300, 376-450, 526-600, 675-750, 761-770 781-790 801-810 821-830 841-850 The 175.0 mg/kg/day dose level resulted in high mortality for The dose was of both sexes through Test Week 10. mice subsequently lowered to 100.0 mg/kg/day commencing with Test Week 11 (4-20-81). * diets were available to the test The adappropriate animals libitum fromtest Test Day 1 until their termination except during a-- to5hour fast prior to either blood collection in Test Weeks 14, 26, 53, 79 and 105 or scheduled sacrifice in Test Thus, all animals received the Weeks 26, 53 and 105-106. appropriate test diet until approximately one day prior to their scheduled sacrifice. Test diets were prepared weekly for each treatment group, by sex, on the basis of projected body weight and food consumption data. Commencing with Test Week-2 until their termination, all animals were observed once daily in the morning for any pharmacologic and/or toxicologic signs. Afternoon mortality checks were initiated on Test Day 1. Physical examinations which included body weights and palpations for masses were conducted weekly from Test Week -2 until Test Week 13, then biweekly until Test Week 104. Food consumption was measured weekly for each cage of test animals commencing with Test Week -2 through Test Week 13, then biweekly through Test Week 104. Mean daily food consumption per animal was calculated from these data. During Test Week 64 food consumption was measured instead of Test Week 63, when it was inadvertantly omitted and actual doses delivered were not calculated for this period as shown in Tables 1 and 2. All surviving animals were subjected to ophthalmic examinations during Test Weeks -2, 25, 51, 78 and 103. The examination consisted L indirect ophthalmoscopy and biomicroscopy. Only animais found to be free of clinically apparent lesions in the pretest examination were used in the study. Blood samples, approximately 0.3 ml, were collected for measurments of hematology and clinical chemistry parameters for 10 randomly selected mice/sex/dose level, exclusive of Test Weeks 14 and 26 when due to errors in randomization the number of 18 mice/sex/dose level ranged from 8 to 12. During Test Weeks 26, 53, and 105, the selected mice were sacrificed and approximately 1.0 ml of blood was collected prior to necropsy. During Test Weeks 14 and 79, one set of 10 mice/sex/dose level, except as stated above, was randomly selected for hematology tests and a second of mice At was Test selected measurments clinical chemistrysetparameters. Week 79,forblood samples of were not collected from the mice at the 175.0/100.0 mg/kg/day dose level. This was done in an attempt to avoid nontreatment-related stress Blood was collected from each animal for this group of animals. via the orbital sinus. The samples were collected and analyzed in a tandomized order over a 3 or 4 consecutive day period and the following parameters were measured: Hematology: Hematocrit (HCT) Hemoglobin (HGB) Mean corpuscular volume (MCV) Mean corpuscular hemoglobin (MCH) Mean corpuscular hemoglobin concentration (MCHC) Erythrocyte count (RBCs) Leukocyte count (WBCs), total and differential Platelet count (PLT) Clinical chemistry: Glucose (GLU) Blood urea nitrogen (BUN) Serum glutamic-pyruvic trans:minase (SGPT) Triglycerides (TRIG) Total cholesterol (CHOL) Total protein (T PRO) Albumin (ALB) Globulin (GLOB), (calculated value) ALB/GLOB ratio (calculated value) Gamma glutamyl transferase kGGT) determinations were not performed due to insufficient blood volume collection. Methods used to measure the above parameters are listed in Appendix IV (hematology) and Appendix V (clinical chemistry;. All animals which were sacrificed in a moribund state or died on test were necropsied regardless of autolytic state. Ten randomly selected animals/sex/dose level, after exclusion of animals designated for blood -%ollection, were sacrificed during each of Test Weeks 26 and 53. At the 175.0/100.0 mg/kg/day dose level during Test Week 26, 12 males and 8 females were sacrificed due to a randomization error. Three hundred and twenty two surviving test animals were sacrificed and necropsied in random order during Test Weeks 105 and 106. Terminal body weights were recorded immediately prior to sacrifice. Euthanasia was 19 by accomplished with carbon dioxide anesthesia followed exsanguination from the abdominal aorta or the orbital sinus. The necropsy procedure was a thorough and systematic examination of the animal viscera and carcass with collection and fixation of th-. following tissues: Adrenal s Bone marrow smear *BrSain Cecum Colon Costochondral junction, rib Duodenum Epididymes Esophagus Eyes Gall bladder Gross lesions *Heart Ileum Jejunum *Kidneys Larynx *Liver Lungs and mainstem bronchi Lymph nodes (mandibular and mesentericX Mammary gland Muscle Nasal turbinates ovaries Pancreas Pituitary gland Prostate Rectum Salivary gland Sciatic nerve Seminal vesicles Skin, abdominal Spinal cord (cervical, thoracic, lumbar) *Spleen Sternum, including bone marrow Stomach *Testes Thymus Thyroids (parathyroids) Tissue masses Trachea Urinary bladder Uterus *These organs were weighed during scheduled necropsies. 20 All tissues, except eyes, testes and bone marrow, were fixec, at a thickness: not exceeding 0.5 cm in 10% neutral buffered formalin (NBF) which was changed 24 hours later. Eyes and testes 3% aqueous glutaraldehyde and Bouin's Solution, were fixed in They were transferred to 50% ethanol respectively, for 24 hours. Bone marrow smears then placed in 70% ethanol. for 24 hours, were prepared from the femur using the "paint brush technique". Lungs and They were air-dried and fixed in absolute methanol. urinary bladder were inflated with NBF prior to immersion in this The stomach was opened and flattened on paper prior to fixative. fixation. All tissues examined microscopically were cut at a thickness of 4 to 6 microns and stained with hematoxylin and eosin. Tissues from all animals receiving 0.0 and 175.0/100.0 to comprehensive histopathologic were subjected mg/kg/day examination, defined as microscopic examination of the following tissues and/or organs: Adrenals *Brain (3 sections) Cecum Colon Duodenum Epididymes Eyes and optic nerves Gall bladdpr Gonads Gross lesions Heart Ileum Jejunum Kidneys Liver Lungs and mainstem bronchi Mammary gland Mesenteric lymph node Pancreas Pituitary gland Prostate Rectum Spinal cord (cervical, thoracic and lumbar) Spleei. Sternum including bone marrow Stomach Tissue masses Thyroids (parathyroids) Trachea Urinary bladder Uterus *(i) frontal cortex and basal ganglia; thalmus; and (3) cerebellum and pons. (2) parietal cortex and 21 Tissues from all animals receiving 1.5, 7.0 and 35.0 mg/kg/day as defined examination to limited subjected were and/or tissues at least the following of histopathologic examination microscopic organs: *Brain (3 sections) Gonads Heart Liver **Lungs Kidneys Spleen Spinal cord (cervical, Tissue masses thoracic and lumbar) *(1) frontal cortex and basal ganglia; thalmus; and (3) cerebellum and pons. **Lungs were examined for mice after 12 months on test. E. which (2) died parietal or were cortex and sacrificed Statistical Analysis body e.g. Those variables that were repeatecly measured, food consumption, and ýlinical. pathology parameters were weight, statistically analyzed using a multivariate analysis of variance Variables that were for repeated measurements model. (MANOVA) organ weights, were analyzed using measured a single time, e.g. both univariate and multivariate analysis of variance procedures. In the presence of significant analysis of variance (ANOVA) a series of post-hoc analyses were conducted by results, Dunnett's test appropriate to a single control for comparison. such as incidences of mortality, organ weights, Frequency data, log-linear and histopathologic lesions were compared using Time to death data were analysis techniques where appropriate. analyses. regression Cox analyzed using Kaplan-Meier and Individual animal data can be found in Appendix VI. Statistical packages for MANOVA (both fixed-effect and "growth curve" model) were conducted rsing the computer program MULTIVARIANCE at the University of Chicago and is based on the Log-linear models which were used for 1975 (3). work of Bock, the analysis of "quantel data" were fitted using MULTIQUAL also This at the University of Chicago and written by Darrell Bock. model is equivalent to probit analysis in that the logistic distribution is 1.7 times the normal throughout almost all of its Cox regression models were fitted using SAS and Life range. The program estimator) using BMDP. Table models (Kaplan-Meier used is at the University of Chicago and was developed in the Department of Statistics for tabulations of this kind and has been thoroughly tested for accuracy. 22 Log-linear models were used to test overall treatment effects. comparisons were obtained by fitting ratios of the maximum likelyhood estimates to their standard errors for individual treatment vs control comparisons (i.e. Wald's test). These estimates are a byproduct of the log-linear model. Andividual 40 The Type 1 error rate was set to 5% (i.e., < 0.05) a-priori. Fisher's exact tests were only performed in the presence of a significant main effect of dosage obtained in the log-linear model, therefore the Type 1 error rate of p < 0.05 was maintained in spite of the multiple post-hoc comparisons. To adjust for the quantel data analyzed Bonferroni's inequality. III. problem of multiple comparisons for using Fisher's exact test, we used RESULTS A. Test Diets Doses received by test animals based on their body weights and food consumption, and theoretical concentrations of RDX in the diet are shown in Tables 1 and 2. Analytically determined concentrations of RDX in test diets were found to be very close to their intended concentrations. The overall percent mean + S.D. for the analyzed/intended ratio was 94.3 + 7.5% (Table 3)B. * Food and Water Contaminants The TEI analytical results of a 5002 sample for those contaminants listed in Lhe 5002 certificationi profile (Appendix II) are shown in Appendix III. The results of the repeat testing of 5002 samples for chlortetracycline content are contained in Appendix VII. The three reference laboratories which reanalyzed the 5002 samples following TEl generally reported negligible quantities of chlortetracycline. A sample from each 5002 lot was analyzed for nitrate, nitrite and mercury content. The results are shown in Apperdix VIII. Analytical results obtained from a sample of Chicago water are contaized in Appendix IX. C. Mortality/Clinical Observations RDX at 175 mg/kg/day was lethal to many male and female mice during the first: ten weeks of treatment. At the onset of Test Week 11, this dose level was reduced to 100 mg/kg/day. Although additional deaths were observed in this treatment group for a few weeks following dose level change, survival curves for these 23 in general, similar to those for control animals animals were, beyond Test Week 12 (Table 4, Figures 1 and 2). The incidence of fighting wounds and/or skin lesions was greater for males at the highest dose (175/100 mg/kg/day) than This was for males in the other treatment or control groups. seen primarily during the first part of the study (approximately Subsequently, all male treatment and through the first year). control groups demonstrated high incidences of these observations A single occurence of convulsions was seen for one (Figure 3). male at the 35.0 and one female at the 175/100 mg/kg/day dose Slightly more female level during the last month of the study. This "barbering effect" than male mice were seen with hair loss. common for was not observed in a dose-related fashion and is multiple housed mice of this strain. D. Body Weig ht Reductions in body weight gains were observed for males and Females at this females at the 175/100 mg/kg/day dose level. dose demonstrated reduced body weight gains throughout the entire study. For males, this occurred primarily during the first 12 weeks of treatment which corresponded to administration of 175 mg/kg/day. A slight reduction was also seen for these males from Test Week 93 through study termination. Sporadic reductions in body weight gains were als: zeen for As this was not observed for males receiving 1.5 mg/kg/day. this males at the intermediate doses, either 7 or 35 mg/kg/day, observation was considered to be spurious (Tables 5-8). E. Food Consumption Food consumption did not appear to be altered by RDX Sporadic increases and decreases were observed which treatment. were -tot dose-related and were not, therefore, considered to be biologically significant (Tables 9 and 10). F. Hematology unaltered by RDX Hematology parameters were, in general, tteatment. Slight reductions in hematocrit and hemoglobin concentration were seen for high dose females at Test Week 53, however, this was not seen at any other sampling time (Tables 11-20). G. Clinical Chemistry Hypercholesterolemia was apparent for RDX-treated mice of Elevated both sexes. The effect was more pronounced in females. serum cholesterol levels were seen earlier (Test Week 14) and to Only 175/100 mg/kg/day-treated a greater extent for this sex. LW-N 24 C males were affected whereas female mice given mg/kg/day demonstrated hypercholesterclemia. 35.0 and 7.0 Serum triglyceride levels rtay have been altered by RDX treatment. They were elevated for females administered 35 mg/kg/day and sampled in Test Week 79 (mice giveu 175/100 mg/kg/day were not bled at that time) At Test Week 105, mean serum criglyceride levels were higher for RDX-treated females than for controls, however these changes were not statistically significant. This parameter did not appear to be affected for male mice. No other clinical chemistry parameters appeared to be altered by RDX treatment (Tables 21-30; Figures 3 and 4). H. Ophthalmology The Narrative Ophthalmology Report is contained in Appendix X. The complete Ophthalmology Report can be found in Vol. II*. Initially, a statistically significant increased incidence of cataracts was seen during Test Week 103 only for the male mice administered 175/100 mg/kg/day, however, when animals used for orbital bleeding were eliminated for the purpose of statistical evaluations, this treatment-related effect was no longer apparent. All other ophthalmologic abnormalities observed occurred in random fashion and were not considered to be treatment-related (Tables 31 and 31a). I. Organ Weights Hepatomegaly and increased relative kidney weights were seen primarily for males and females administered 175/100 mg/kg/day of RDX. This was observed at both interim kills and at study termination. For mice given 35 mg/kg/day, hepatomegaly was observed during Test Week 53 (females), and relative renal weights were elevated at study termination (males). In addition, relative heart weights were significantly increased for 175/100 mg/kg/day-treated mice of both sexes after two years of treatment. No other organ weights appeated to be altered by RDX (Tables 32-4;). J. Pathology The Narrative Pathology Report appears in Appendix XI. The entire Pathology Report can be found in Vol. III*. At the six month kill, red lungs, dark red spleen and liver, and distended red fluid-filled urinary bladders appeared more frequently for mice receiving 175/100 mg/kg/day than for control animals. *Requests for Volumes II and III should be directed to Health Effects Research Division, U.S. Army Medical Sioengineering Research and Development Laboratory, Fort Detrick, Maryl.and 21701-5012. 25 Histopathologic lesions related to these observations, however, The incidence of renal tubular cytoplasmic were not in evidence. vacuolation was greater for males at all dose levels than for the corresponding controls. At the 12 and 24 month kills however, this lesion was observed for control animals as frequently as for animals treated with RDX. No other renal changes were seen in this study. Throughout the study, histologic evidence of chronic dermatitis and ulcers for RDX-treated males was supported by gross observations. As discussed under Clinical Observations (Section III.C), these lesions were interpreted as fighting wounds associated with RDX-induced behavioral changes. With the exception of fighting wounds, neither gross nor histopathologic lesions related to RDX treatment were apparent at the 12 month kill. By 24 months of treatment, several histologic changes were ascribed to the administration of RPX. Statistically significant findings for male mice were decreased incidence of hepatocellular adenomas at the 7.0 mg/kg/day and increased incidence of lymphoid hyperplasia in the spleen at the 1.5 and 7.0 mg/kg/day dose levels. However, the biological significance of these changes could not be established. A non-statistically significant increase in alveolar/bronchiolar carcinomas was seen in high dose male and female mice. Incidence of alveclar/bronchiolar carcinomas and adenomas for study controls were within the range of incidences of alveolar/bronchiolar carcinomas in both aexes of historical control mice. Although statistically not significant, there was an increased incidence of testicular degeneration seen for males mice given either 35.0 or 175/100 mg/kg/day when compared to the corresponding control animals or historical controls (6). Both of these treatment groups demonstrated incidences of approximately 10-11% compared with 0% for control animals and 1.5% incidence in the historical control group. The incidence of hepatocellular carcinoma showed an increase, however statisti.cally not significant, in female mice receiving either 35.0 or 175/100 mg/kg/day compared to control female mice. Only when combined adenoma/carcinoma data were analyzed, were statistically significant increases observed for both 7.0, 35.0 and 175/100 mg/kg/day females compared to either concurrent or historical control data. This was apparent even though concurrent controls had a significantly lower incidence than historical controls. Historical control data from the National Toxicology Program (5) were subsequently included in the statistical analyses as the female concurrent control group demonstrated a low incidence of liver tumors. When this was 26 F_- performed, female mice receiving 35.0 mg/kg/day still significant increase in liver carcinomas and adenomas. showed a An additional microscopic change in the lungs was a statistically significant increased number of histiocytes for females administered 175/100 mg/kg/day. All other lesions observed microscopically were considered spontaneous, naturally occuring degenerative, inflammatory and/or neoplastic diseases which commonly occur in an aging male and female mouse population of the B6C3Fl strain (Tables 44-46). IV. DISCUSSION The administration of 175 mg/kg/day of RDX to male and female B6C3r1 mice resulted in death during the first ten weeks of treatment. This dose was reduced to 100 mg/kg/day in Test Week 11. Subsequently the slope of survival curves were similar for this treatment group and control animals for the duration of the study. Although these high dose animals showed slight reduction in body weight gains, food consumption was not affected. Surviving males in this high dose group demonstrated significant skin lesions apparently associated with fighting wounds. RDX is known to induce behavioral changes including hyperreactivity to approach and fighting with cage mates (3). Histologic evaluation failed to detect treatment-related lesions of the central nervous system. Liver injury at 175/100 and to a lesser extent 35.0 mg/kg/day was evidenced by several observations. These included hypercholesterolemia, elevated serum triglyceride levels and hepatomegaly. With the exception of hepatocellular tumors (discussed below), histopathologic lesions of the liver were not observed. At the 6, 12 and 24 month kill, kidney weights were elevated for mice of both sexes administered 175/100 mg/kg/day. Cytoplasmic vacuolation of renal tubules appeared to be more prevalent for RDX-treated males than corresponding control animals after six months of treatment. This lesion was subsequently seen at 12 and 24 months as frequently for control as for treated animals. Although statistically not significant, an increased incidence of hepatocellular carcinoma was seen in RDX treated female but not male mice. The combined incidences of hepatocellular carcinoma and adenoma were statistically greater for female mice receiving 7.0 mg/kg/day or higher doses than for the concurrent female control group. When historical control data were included in the statistical analyses, the two top dose 27 levels still demonstrated significant increases in the incidence of combined liver carcinomas and adenomas; however, the actual historical control incidences fell between that of the study control and treated female mice. A non-statistically significant increase in alveolar/bronchio]ar carcinomas was seen in high dose male and female mice. Comparison of study controls to the appropriate historical controls showed that the incidence of alveolar/bronchiolar carcinomas and adenomas for study control mice was within the range of incidences of alveolar/bronchiolar carcinomas in both sexes of historical control mice. An additional statistically significant observation was an increased number of histiocytes in lungs of the female mice receiving 175/100 mg/kg/day. Additional toxic effects seen primarily at 175/100 mg/kg/day included enlarged hearts without accompanying histologic lesions. Although not statistically significant, increased incidences of testicular degeneration were seen for the male mice at the 175/100 and 35.0 mg/kg/day dose levels (11.1% and 10.2% respectively), when compared to the concurent controls (0%) or to the historical controls (1.5%) (6). Absolute ot relatite testicular weight change failed to accompany this histopathological finding. In summary, the major toxic effects observed during the administration of RDX to B6C3Fl mice for up to 24 months included hepatotoxicity, possible CNS involvement and testicular degeneration. In addition, hepatocellular and alveolar/bronchial carcinomas and adenomas were more prevelant for RDX-treated mice than for corresponding controls. The incidence of hepatocellular tumors (combined carcinomas and adenomas) was significantly increased at the 7/mgfAg/day level. On this basis, the no-effect level under the conditions of the present study is 1.5 mg/kg/day. 28 -UM M F .R:1 - _.A 'a1w __W V. REFERENCES 1. Good Laboratory Practice Regulations. CFR Part 58. 60013-60020, 1978. 2. Levine, B.S., Furedi, E.M., Gordon, D.E., Burns, J.M., and Lish, P.M. Thirteen Week Oral (Diet) Toxicity Study of Trinitrotoluene (TNT), Hexahydro-l,3,5-trinitro-1, 3,5-triazine (RDX) and TNT/RDX Mixtures in the Fischer Final Report No. L6116/L6121, Study No. 1. 344 Rat. 3. Levine, B.S., Furedi, E.M., Sagartz, J.W., Rac, V.S., and Lish, P.M. Twenty-Four Month Month Chronic Toxicity/ Carcinogenicity Study of Hexahydro-1,3,5-trinitro-1,3,5triazine (RDX) in the Fischer 344 Rat. Final Report No. L6121, Study 6. 4. Reference on NTP historical control data. Bulletin 10). 5. Bock, R.D. Multivariate Statistical Methods in Behavioral Research. McGraw-Hill, New York, 1975. 6. Ward, J.N., Goodman, D.G., Squire, R.A., Chu, K.C., Linhart, M.S. Neoplastic and Nonneoplastic Lesions in Aging (C57BL/6NX C3H/HeN)Fl (B6C3Fl) Mice. NCI, Vol. 63, No. 3, 1979. Fed. Reg. -IA 21 (i.e., NTP 29 (Ar. fin Is: 11 13L 2 (9'13; mo 0? a L- 3 mm? .W w-Wamw . ?qm l' 4% dating. HUI y- H- ?mmH>mrmm giw??f rmun I. -.cme In ML. ?71? 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I I.E 010 0 n > D5 I- & I20 Ull.LL 'wv 0 N 0 W" (0 C) 4 wN 0 ,NN0 N .~0i0.fl~0 40WD V0 0 N.O 04'I!'N oa0N a, '- 4t 40 D 0 m' 0. N a4 , ,000 ý'00.0 K 0 l-0')N () Ni 4) SC I0' iU000000000000000000000000000000 R iooooo66oo666dd6o66oooo6ooooooo M w I0 cc 0z uw x- z' 4 0C'i 000000000000000000000000000000 0000000066000000000000000000000 W .4 0 I2 I- U W I M14. 0 x z U)'1 I-x I- >. >)1 wI I .P 41 I-+1 '-'I 404 -, orv Ewl y 'w KP w, -L PPJrF 2, 4s VP ;jw & W TABLE 4 TWENTY-FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITY HEXAHYDRO-1,3,5-TRINITRO-1,3,5-TRIAZINE IN THE B6C3F1 STUDY'OF HYBRID MOUSE MEAN SURVIVAL TIME DOSE imgLkaLed * MEAN SURVIVAL TIME ._wks.. SEX l.f 0.0 M F 98.1 + 1.8 100.9 . 1.1 1.5 M F 95.9 ± 2.2 99.3 . 1.7 7.0 M F 97.4 + 1.9 102.9 ± 0.8 35.0 M F 93.7 + 2.4 99.9 ± 1.3 175.0/100.0 M F 61.5 ± 5.1* 60.8 ± 5.3* Significantly different from control group, p< 0.05. 41 >- - -. --. - S( - +1 +1 n N' C-1 C- '~in (1 C-4 J In I 0 n 0L w f0 +1 +1 +1 (D t(4 N('cq I 0D ('4 I n 0 0M0 +1 +1 C 0 - n - - -. - I I n I (N C') C- ( +I + + 0ý +1 + ~ + C 0 I C +1 ) 0) +1 +1 + IP 0) 0 CO C4 0) 04 0) (1) C' ()C, Cl) In In + +1 m - 0D cl 0 +1 - C) 0) (N - C4* C) 0 co - 0) 0 +1 - D C ~~~~~~~0 Cr 0 0 I +1 0 nn 0 0 0 +1 +1 +1 - -~ I n -' n - +1 I +1 I 11 -o C.) m C.; m t') Cl) MCl) n In n In n In n - Iw- m- * V, XTIn , +1 4 + ), V) -4 In -. v 0W I W, C') WN n M0 n C') m' 0 WI ' (' w w w 'w w +1 +i +1 +1 +1 011 DC)O +1 +1 +1 41 +1 +1 +1 +1 +1 +1 0 03 0I-m LM(9 > UJ-4 ý ZX Zu - - - - - - - - -- - 4 - - 00t 0 W 0- 0 W t- W t in-4 0 '-~t-4C- N C-C r- l - N N - .0 - - - - --- 0M N o N - D- 0 (ZfI-- IL - 0-- W <"-.I LA - * M I- w4 N- 0 v 0 t m m (N (N (N n l N 0) m In 0 Ix < 7 CV N r, 0 t M M0 0 C' m m) m 0) mN m C 0w< *ý (ND ( D m- m L m :to 4 U 00 0 I0.IxO- [z0 - t- 0 -' - D O m - - (D 0CO -- m m N - -. 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SEX 25 51 78 103 0.0 M F 0/84 0/85 2/73 0/75 2/58 0/63 4/49 3/51 1.5 M F 0/83 0/85 2/71 2/73 3/57 1/60 7/42 2/46 7.0 M F 0/84 1/85 0/72 1/74 0/58 0/64 0/41 9/55 35.0 M F 0/84 1/85 1/70 0/74 1/54 0/61 3/38 0/46 F 1/54 0/49 1/38 0/41 2/25 0/30 6/20* 1/26 175/100 Significantly diferent from the appropriate control group, p<0.05 .•d.• II I° I! A TABLE 31 TWENTY-FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITY STUDY OF HEXAHYDRO-1,3,5-TRINITRO-1,3,5,-TRIZINE IN THE B6C3F1 HYBRID MOUSE INCIDENCES OF CATARACTS* (REVISED) TEST WEEK DOSE SEX 25 51 78 103 M F 0/54 0/3.; 0/71 0/75 0/56 0/63 2/47 2/50 1.5 M F 0/83 0/85 0/69 0/71 0/54 0/59 2/41 1/37 7.0 M F 0/84 0/84 0/72 0/73 0/58 0/64 0/41. 6/52 35.0 M F 0/84 0/84 0/69 0/74 0/53 0/61 2/37 0/46 175/100 M F 0/53 0/49 0/37 0/41 0/23 0/30 2/16 1/26 T2 7kg/day) 0.0 *Animals with cataract where the eye was used for blood collection were eliminated from the statistical analysis Sr 81 &W ¾ 0000000) Z, I E +1 v - Cý ( +1 + v N 0 +1 +* t- v C' ) 0 C m' O 0 > C') 0U. 01 (D0 0 ea1 I. 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Z Lu 31 ~ ~0 0 1 U m 0. 0 +1 +1I f- w L cv (NOmm -J LL' I m '0 < c +9 1 41 - cc Z U) a)z > In Z *~~ 0 0 M_.N~ I < -j93 TABLE 44 TWENTY-FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITY STUDY OF HEXAHYDRO-1,3,5-TRINITRO*-1,3,5-TRIAZINE IN THE MALE B6C3Fl MOUSE Statistical Evaluation of Histopathologic Lesionsa Dose (mg/kg/day) 0.0 SKINb, Chronic Dermatitis 26/63 (41.3%) 7.0 35.0 21/23*** 25/26*** 16/27 21/28** (75.0%) (59.2%) 5/23* (21.7%) 6/26* (23.1%) 4/28* (14.2%) 0/27 (0%) 3/62 (4.8%) 7/59 (11.9%) 5/27 (18.5%) 1.5 SKIN 5 , Ulcer 0/63 (0%) LUNG, LUNG, Alveolar/Bronchiolar Carcinoma 6/60 3/63 (4.8%) (10.0%) 175/100 Alveolar/Bronchiolar Adenoma 6/63 (9.5%) 5/60 (8.3%) 5/62 (8.1%) 7/59 (11.9%) 1/27 (3.7%) LUNG, Alveolar/Bronchiolar Carcinoma and Adenoma (Combined) 6/27 14/59 8/62 11/60 9/63 (22.2%) (12.9%) (23.7%) (14.3%) (18.3%) LUNG, Histiocytosis 2/63 (3.2%) KIDNEY, 1/60 (1.7%) 0/62 (0%) 2/59 (3.4%) 3/27 (11.1%) Malignant Lymphoma 1/63 2/60 (3.3%) (1.6%) 4/62 (6.4%) 4/59 (6.8%) 1/27 (3.7%) Statistical analyses were conducted on the combined data collected from animals which either spontaneously died or were sacrificed in a moribund state following the 12 month sacrifice and from animals at the 24 month scheduled sacrifice. bSkin and eyes were microscopically examined for animals at the 1.5, 7.0 and 35.0 mg/kg/day dose level only when a gross lesion was noted at necropsy. - Significantly different from the control group, •*= Significantly different from the control group, = Significantly different from the control group, * 94 p < 0.05. p < 0.01. p < 0.001. . TABLE 44 (contd) TWENTY-FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITY STUDY OF HEXAHYDRO-1, -, 3-TRINITRO-1,3,5-TRIAZINE IN THE MALE B6C3Fl MOUSE Statistical Evaluation of Hietopathologic Lesionsa Dose (mg/kg/day) EYEb, 0.0 Subcapsular Cataract 4/63 (6.3%) LIVER, LIVER, LIVER, LIVER, SPLEEN, 1.5 '.0 35.0 0/1 0/0 1/1 3/27 (11.1%) 4/62 (6.4%) 5/59 (8.5%) 0/27 (0%) Malignant Lymphoma 0/63 1/60 (0%) (1.7%) Hepatocellular Carcinoma 175/100 13/63 20/60 16/62 18/59 (10.6%) (33.3%) (25.8%) (30.5%) (22.2%) 7/59 (11.9%) 7/27 (25.9%) Hepatocellular Adenoma 8/63 6/60 (12.7%) (10.0%) 1/62** (1.6%) Hepatocellu -, Carcinoma and Adenoma (Combined) 21/63 26/60 17/62 25/59 (33.3%) (43.3%) (27.4%) (42.4%) Lymphoid Hyperplasia 6/63 18/60** (9.5%) (30.0%%) 17/62* (27.4%) 9/59 (15.2%) 6/27 13/37 (48.1%) 1/27 (3.7%) TESTES, Degeneration 01,'63 2/60 2/62 6/59 3/27 (0%) (3.3%) (3.2%) (10.2%) (11.1%) aStatistical analyses were conducted on the combined data collected from animals which either spontaneously died or were sacrificed in a moribund state following the 12 month sacrifice and from animals at the 24 month scheduled sacrifice. bSkin and eyes were microscopically examined for animals at the 1.5, 7.0 and 35.0 mg/kg/day dose level only when a gross lesion was noted at necropsy. * - Significantly different from the control group, p < 0.05 ** - Significantly different from the control group, p < 0.01 - Significantly different from the control group, p < 0.001 95 0-11Vi I, 1 N W0 0 M. TABLE 45 -TWENTY-FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITYTHESTUDY OF HEXAHYDRO-1,3,5 TRINITRO-1,3,5-TRIAZINE IN FEMALE B6C3F1 MOUSE Statistical Evaluation of Histopathologic Lesions a DOSE (mg/kg/day): 0.0 LUNG, Alveolar/Bronchial 3/65 -4.6%) LUNG, 1.5 Carcinoma 1/62 (1.6%) Alveolar/Bronchial Adenoma 4/65 2/62 (9.2%) (3.2%) 7.0 35.0 175/100 3/64 (4.7%) 3/64 (4.7%) 4/31 (12.9%) 5/64 (7.8%) 9/64 (14.1%) 3/31 (9.7%) LUNG, Alveolar/Bronchial Carcinoma and Adenoma (Combined) 7/65 3/62 8/64 12/64 7/31 (10.8%) (4.8%) (12.5%) (18.8%) (22.6%) LUNG, Histocytosis 1/65 (1.5%) LIVER, 1/62 (1.6%) 3/64 (4.7%) 3/64 (4.7%) 9/31** (29.0%) Hepatocellular Carcinoma 0/65 4/62 (0%) (9.7%) 3/64 (4.7%) 6/64 (9.4%) 3/31 (9.7%) 6/64 (9.4%) 6/64 (9.4%) 3/31 (9.7%) LIVER, Hepatocellular Adenoma 1/65 (1.5%) LIVER, 1/62 (1.6%) Hepatocellular Carcinoma and Adenoma (Combined) 1/65 5/62 9/64* 12/64* (1.5%) (8.1%) (14.1%) (18.8%) 6/31* (19.4%) a Statistical analyses were conducted on the combined data collected from animals which either spontaneously died or were sacrificed in a moribund state following the 12 month sacrifice and from arnimals at the 24 month scheduled sacrifice. - Significantly different from control group, p < 0.05 *- Significantly different from the control group, p < 0.01 96 4 V: TABLE 46 TWENTY-FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITY STUDY OF HEXAHYDRO-1,3,5 TRINITRO-1,3,5-TRIAZINE IN THE FEMALE B6C3F1 MOUSE Statistical Evaluation of Histopathologic Lesions'a Versus Historical Controls 175/100 Controlsb 6/64 (9.4%) 3/31 (9.7%) 101/2469 (4.1%) 6/64' (9.4%) 3/31 (9.7%) 98/2469 (4.0%) Hepatocellular (Combingd) 5/62 and Adenpma 9/64• 12/64 c,° 6/31,c 1/65 Carcinoma 199/2469 7.0 35.0 Hepatocellular Carcinoma 0/65 4/62 (0%) (6.4%) 3/64 (4.7%) Hepatocellular Adenoma 1/65 1/62 (1.5%) (1.6%) 6/64d (9.4%) DOSE (mg/kg/day): LIVER, LIVER, LIVER, 0.0 (1.5%) 1.5 (8.1%) (14.1%) (18.8%) (19.4%) (7.9%) aStatistical analyses were conducted on the combined data collected from animals which either spontaneously died or were sacrificed in a moribund state following the 12 month sacrifice and from animals at the 24 month scheduled sacrifice. bNTP Technical Bulletin No. 10. c Significantly different from control group, p < 0.05 d Significantly different from historical control, p < 0.05 ,9 9 I- 4h 4 on mm I. '9 "W-wx 6:3 b53313.? re??g??q?gk??gga?ggm?gk? - . M?ng? EM .. [hm .5: mm "bud-drumml. Wu?- . 1m??mwv ?a I Hum Kw . . . . .... .. . ... . .. . 0 4 LAu 4-4 0 oU w L) LIL) . e40 *) U 0 U C. L) *-U LO4 (L) 0U C t .- u 0~ w .- N I- I- F-C~ 0 0 0 ->. 0- I. 4- m-C- 0Af UtI-4-4 ( 0 .r.- 0 Ln < 0 3 in fm L 004 - 4 Cci 4 U L * 4 40 n f- 4- In - 0 ncl tc 4 4- 4+0 0 C)O C.)4 CLO 41 4J40 C l C)C + .- u&0 0- .C. -W- 0LN 4J * 0v .( u- 04-JI )C.C CLD 0S. * 0ry'~ 00- jL uC)--' L 0 0 i E 0,xr 0u• .100 v-i oo. 0O Z w , 00 ow~ 1. '-E- .1 4 0 tj4 0 r < 0I 0 0,. 13 <0 04 o 00 o9i *< 0 0 -,n. • .- D 0~ Ar ai 000 OE:f 14J 4 -t 14 0 o . ..O 4 •- .. - , . -v- 0Ul - 000 120 1 -q 102~c %00 X 03IN - E4 FIGURE 4i Fs TWmNTY FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITY STUDY OF __HEXAHYDRO-1,3,5-TRINITRO-1,3,5-TRIAZINE(RDX) IN THE B6C3F1 MOUSE -- EAN CHOLESTEROL VALUES (MG/DL) YS TIME MALES AND FEMALES COMBINED Si804 ,f 16•0-: 60 - , E ti50- : E SI A E .4 L 130 D i 20L ilO-.- I, ~' ... / L -2 0 '10 20 30 40 50 60 -i,70 80 90 '100 WEEK LEGEND-. TX C0 MG/IKG/D C--.+ S•--• 175/100 MGIKGID ,-->7 v 'x. I . . . -.i-..5 MGIKGID 35 MG/IKG/D ,2--s-- MGIKG/D . . . .. . . . . I**'*I 103 FIGURE 5 TWENTY FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITY STUDY OF HEXAHYDRO-1,3,5-TRINITRO-1,3,5-TRIAZINE(RDX) IN THE B6C3FI MOUSE MEAN FEMALE TRIGLYCERIDE VALUES (MG/DL) VS TIME 180-1 70-/: mN A 60:/ / NN EI C / 16 R t;< N4- /,,- ! . 1/ L 140E N R /*/ I'; / 1 130-' D / ,' EI E /" ' / / , .2, ! •/, "" / . ,.- . A920 L / ~ If 0 20 80 30 40 , 50 60 70 80 90 '.00 WEEK LEG-END. 1lo4 TX ±--+0.0 MG/KG~/D 175/100 Mo/K/DA.7 MG/KG/D x-s-e- 1.5 MC'KG./D 35 MG'KG'D K .1 1mm? . marmun. wit-Irw- .- kin-.41? MAu_pm< x.ozwmm< 1. 1 I A MMJW I 4 "n 4 ??hdhh #11 "an? .. w. A w. Hf war unfit ?t an: 11L 5: an human?" K5534 Mun?uu? mug m: um, die ANALYSES OF THE RDX TEST ARTICLE SCOPF, 1.1 The procedure describes the analysis of the RDX test article for purity. 1.2 This method is recommended for use only by experienced analysts familiar with High Performance Liquid Chromatography (HPLC) or under close supervision of such oualified persons. INTERFERENCES 2.1 Solvents, reagents, glassware and other sample processing hardware wrlay yield discrete artifacts and/or elevated baselines causing misinterpretation of chromatograms. All of these materials must be shown to be free from interferences under the conditions of the analysis by running method blanks. EQUIPMENT 3.1 Higher Performance Liquid Chromatography , constant flow, isocratic pumping system reverse phase column, 10 li - 3.9 mm x 30 cm p-Bondapak Ci8 column ultraviolet detector capable of monitoring X = 254 nm chart recorder and electronic integrator capable of measuring 'strip peak areas and performing an internal standard calculation. REAGENTS "4.1 Propiopnenone, an internal standdrd, Aldrich Chemical Company (Purity 990) 4.2 Methanol, Actronitrile, and Water, HPLC Grade or equivalent 4.3 RDX, Standard Army Reference Material (SARM), supplied by Sponsor, (Purity 99.8%). CALIBRATION 5.1 1o6 Calibration standards were prepared from stock solutions containing RDX, and propiophenone pe, ml acetonitrile so as to bracket _00 jOig the working range of the chromatographic system. These concentrations were: 2 vg/ml, 10 ij•Lml.,.O .u20m,.ard-4D..uo~ml. 5.2 A constant injection volume of 15 lil was employed for all measurements. 5.3 In order to determine the precision of the HPLC system, a series of 6 replicate injections of the 20 ig/ml solution were made. 5.4 Retention times should remain relatively constant (within + 5% day to day) with RDX being 3.7 minutes, and propiophenone 7.3 min5tes under the specified conditions. If the retention times are not within + 5%,!1 supervising chemist should be informed prior to the analysis and corrective action should be taken. K QUALITY CONTROL 6.1 Before processing any samples, the analyst should demonstrate through the analysis of a blank that all glassware and reagents are interfer- ence free. 6.2 6.3 In a typical sample set, a minimum of one blank and five samples will be analyzed. The analyst will follow each step in an analytical protocol without deviation or improvisions in order to accurately assess the performance of the method. Prior to making any changes in the procedure, analyst will consult. te supervision chemist and the supervising chemist and Q.A. cfficor will review and approve all the changes. SAMPLE PREPARATIONA 7.1 The test article will be spread on a sheet of paper, and five samples will be takin from different areas. Each sample shall have a weight of '150 ma. The samples will be collected in amber vials and stored at refrigerator temperatures in the dark until analysis. 7.2 A portion of the sample (100 mg) will be weighed and transferred to a 100 m! volumetric flask. The internal standard will be added and it will be diluted to volume. It will be further diluted to a concentration of 20 jig/ml and analyzed by high performance liquid chrcmatography. 7.3 If the sample is not analyzed immediately it will be stored at refrigerator temperatures in the dark I HIGH PERFORMANCE LIQUID CHROMATOGRAPHY (HPLC) 8.1 Each sample was analyzed by reverse phase HPLC using the conditions described below: Column, 3.9 mm x 30.0 cm V-Bondpak Cle; Solvent System, methanol:water (55%:45%, v/v); Flow Rate, 1.5 ml/min; the retention times Detection, UV at 254 nm; Sensitivity, 6.1 AUFS. 107 Zý _-- •o-' of RDX and propiophenone were 3.7 and 7.3 minutes, respectively. The limit of detection was 2 jig RDX/ml acetonitrile and is defined by 5x the background nouse. The representatibe chromatoaram is Figure 1. 8.2 8.3 The chromatoqraphic system was calibrated daily with a minimum of two injections of one standard representative of chromatographic range. An injection volume of 15.0 p1 was used for each sample. If the peak area exceed the linear range of a sample it was diluted and reanalyzed. CALCULATIONS 9.1 •, • Determine the concentration fo RDX using the formula: .. (Wis) x D X 100 (Ax) • RDX DX inSample= in Sam (Fx) Ais (Ws) Where Ax = Area (X) where x is RDX Ais = Area (internal standard) Fx =Area (x) x Weight (is) Area (is) x Weight (Wx) Wis = Weight of the internal standard Ws = Weight of the sample D = The dilution factor Wx = Weight of component x is RDX 9.2 The results should be reported in percent RDX. Where replicate samples are analyzed, all data should be reported. All results were recorded in standard IITRI logbooks and these plus chromatograms and data tapes are retained in the Chemistry Division Q.A. files. 108 -- -" • "Rx {. ,w " N.Z••I-- ,' ,' . " ' "• ,'',- -• - • " " - - - . ANALYSIS OF RDX IN DIET PREMIXES SCOPE AND APPLICATION 1.1 This method covers the determination of RDX in diet premixes. at 10% and 50% levels. 1.2 The sensitivity of this method is usually dependent on the level of interfere;lces present in the samples, rather than the instrumental 1imitations. 1.3 This method is recommended for use only by experienced analysts familiar with High Performance Liquid Chromatography (HPLC) or under close supervision of such qualified persons, SUMb7A4Y OF THE WETEOD 2.1 A weighed quantity of the premix was stirred with 50 ml of acetonitrile for 30 minutes. The suspension was filtered through a porous glass filter and the filtrate was transferred with washings to a volumetric flask. Propiophenone, the internal standard was added to the filtrate or a portion, thereof and this solution was diluted to its final volume. The samples were analyzed using reverse phase high performance liquid chromatography. Each was eluted on 3.9 mm x 30.0 cm iu-Bondapak Cl8 column with methanol :water (55%:45%) and the eluant was monitored with an ultraviolet absorption detector at X = 254 nm. INTERFERENCES 3.1 Solvents, reagents, glassware and o,',%er sample processing hardware may yield discrete artifacts and/or elevated baselines causing misinterpretation of chromatograms. All of these materials must be shown to be free from interferences under the conditions of the analysis by running method blanks. 3.2 Interferences coextracted from the samples will vary considerably from source to source, depending on the type of animal feed used in the study. MATERIALS 4.1 Erlenmeyer flasks, 125 ml 4.2 Filtering apparatus, vacuum flask, 125 ml; fritted glass filters, porosity M, ASTM 10-20 microns. 109 5.1 5.2 Mettler Granmatic Analytical Balance, No. 1-910 Corning Hot Plate Stirrers, BC 351 0 5.3- Buchi Evaporator, Model R 5.4 .5.5 Sample Clarification Kit, Organic (Water's Associates) Higher Performance Liquid Chromatography ; ; o # constant flow, isocratic pumping system reverse phase column, 10 p - 3.9 mm x 30 cm p-Bondapak Cle column ultraviolet detector capable of monitoring X = 254 nm strip chart recorder and electronic integrator capable of measuring peak areas and performing an internal standard calculation. REA GENIS 6.1 Propiophenone, an internal standard, Aldrich Chemical Company (Purity 99%) 6.2 Methanol, Acetonitrile, and Water, HPLC Grade or equivalent 6.3 RDX, S.A.R.M., supplied by the sponsor (Purity 99.8%) CAL, RAT.IN Calibration standards were prepared from stock solutions containing 200 vg RDX, and propiophenone per ml acetonitrile so as to bracket the working range of the chromatographic system. These concentrations 1.g/ml, 10 pg/ml, 20 pg/ml, and 40 pg/ml. were: 7.2 A constant injection volume of 15 jpl was employed for all measurements. 7.3 In order to determine the precision of the HPLC system, a series of 6 replicate injections of the 20 vg/ml solution were made. 7.4 Retention times should remain relatively constant (within + 5% day to day) with RDX being 3.7 minutes, and propiophenone 7.3 minutes under the specified conditions. If the retention times are not within + 5%, supervising chemist s~hould be informed prior to the analysis and corrective action should be taken, 7.1 I 110 ; 110 - QUALITY CONTROL 8.1 8.2 8.3 Before processing any samples, the analyst should demonstrate through the analysis of a blank that all glassware and reagents are interference free. Each time a set of samples is extracted or there is a "change in reagents, a method blank should be processed as a safeguard against laboratory contamination. Standard quality assurance practices were used with this method. A minimum of 6 replicate spiked samples were analyzed to validate the accuracy of the method. If doubt should arise concerning the identity of the peak on a chromatogram, confirmatory techniques such as mass spectrometry should be used. In a typical sample set, a minimum of one blank and scheduled samples will be analyzed. A control sample will be prepared by adding a known concentration of RDX to the sample. The concentration will be in the working range of chromatographic system as determined by calibration experiment. 8.4 The analyst will follow each step in an analytical protocol without deviation or improvisions in order to accurately assess the performance of the method. Prior to making any changes in the procedure, analyst will consult the supervising chemist and the supervising chemist and the Q.A. officer will review and approve all the changes. 8.5 The typical analysis will consist of the following samples shown in the diagram. One blank sample, 6 premix samples as is, 3 spiked samples. Anaty.6Z6 o~ Sam7pP-ez 6 PA.em~x Samptes[ SCtznk Sampee 3 Paemix Samte S Analyzed 3 Prelmix SampZe Analyzed AA• Jk I AA 7A I me OAigJwat Ex~taet Ext PZu6 me. Spike ÷I 50 mP-50 + nit ~:wJ . M - - -------- ýV IIfiL6 JM _-,J SAMPLE COLLECTION 9.1 Samples are collected and stored prior to analysis according to SOP 81-sample collection (TNT & RDX Premix) SAMPLE EXTRACTION 10.1 The appropriate amount of sample is weighed into a 125 ml Erlenmeyer flask using standard operating procedures. The sample amount for both the 10 percent and 50 percent premix is one gram. Approximately 50 mls of acetonitrile is added to the flask and it is stoppered. The sample is extracted by stirring for 30 minutes at room temperature. 10.2 Following extraction, the fritted glass filter. In swirled to form a uniform glass funnel. A stirring from the flask. 10.3 The extraction flask was rinsed with three portions of acetonitrile of approximately three mils each, and the rinse is poured into the funnel. This procedure is repeated three times, then the vacuum is reapplied and the washing process is completed. sample was filtered through a medium porosity this operation the extraction mixture was suspension and immediately poured into the rod was used to drain the last drop of liquid 10.4 The filtrate is transferred via a short-stem funnel into a volumetric flask. The filtering flask is rinsed three times, with approximately 6 ml portions of acetonitrile, and the rinses are added to the volumetric flask. The size of the volumetric flask and the subsequent treatment of the sample depend on the initial RDX concentration in the sample. The dilution for sample is shown in Table 1. 10.5 An aliquot (approximately 10 ml) is filtered using a Water's Organic Sample Clarification Kit using 0.5 pm filter. The sample is now ready for analysis for HPLC. STORAGE OF SAMPLES 11.1 All samples including premixes and blank feed will be stored in the dark at refrigerator temperatures. 11.2 If the sample preparation procedure is stopped atany point during the working day, the samples should be stored in stoppered vessels in the dark at refrigerator temperatures. 112 TABLE 1. DILUTION SCHEME FOR SAMPLE EXTRACT Premix Concentration Original Extract Volume Secondary Dilution 10% 50% 100 ml 500 ml 1 ml extract plus 1 ml I.S. to volume of 50 ml with acetonitrile 1 ml extract plus 1 ml I.S. to volume of 50 ml with acetonitrile 1. I.S. solution concentration is - 1000 pg/ml 2. In the case of a sample analyzed by the method of standard addition I ml of the original extract was diluted with 50 ml acetonitrile, and 1 ml of the extract added to 1 ml of the spiking solution of known concentration was diluted with acetonitrile as above. 11.3 Samples that are ready for HPLC analysis will be stored in the dark at refrtgeration temperature:" 11.4 Similarly, RDX and p;-c:-icphenone standards and all standard solutions will also be storec,'"dark at refrigerator temperatures. VIGH PERFORMANCE LIQUID CHJJ.'.2"OGRAPHY (HPLC) 12.1 Each sample wra analyzed by reverse phase HPLC using the conditions described below. Column, 3.9 mm x 30.0 cm p-Bondpak C1 9; Solvent System, methanol :water (55%:45%, v/v); Flow Rate, 1.5 ml/min; Detection, UV at 254 nm. The retention times of RDX and proplophenone were 3.7 and 7.3 minutes, respectively. The limit of detection was 2 vg RDX/ml acetonitrile and is defined by 5x the background noise. The representative chromatogram is Figure 1. 12.2 The chromatographic system was calibrated daily with a minimum of two injections of one standard representative of chromatographic range. 12.3 An injection volume of 15.0 01 was used for each sample. If the peak area exceed the linear range of a sample it was diluted and reanalyzed. Best 113 Q 12.4 Following the completion of an analysis or set of analyses, a gradient going from initial solvent conditions to 100% methanol in 15 minutes will be used to elate polar compounds from the column. Elution at 100% methanol will be continued for at least 1 hour. CALCULATIONS 13.1 Determine the concentration of RDX using the formula: %RDX in Sample = (Ax)(Wis) x D x 100 %Fx) Ais (Ws) Where Ax = Area (X) where x is RDX Ais = Area (internal standard) Fx = Area(x) x Weiaht(is) Area(is) x Weight(Wx) Wis = Weight of the internal standard Ws = Weight of the sample D = The dilution factor W'x = lit of component x is RDX. 13.2 The results should be reported in percent RDX composite. This is the RDX actually used in the toxicity study. Where replicate samples are analyzed, all data should be reported. All results are recorded in standard IITRI logbooks and these plus chromatograms and data tapes are retained in the Chemistry Division Q.A. files. SAFETYI 14.1 Safety regulations will be followed at all times especially with regard to the handling of toxic materials. When the premix samples are being handled, a lab coat, gloves and a mask will be appropriate attire. When solutions as extracts are being handled, a lab coat and gloves should be worn when there is the change of direct contact with these materials. 114. rI .. '. 4 Fi gur e 1. I wC-,! p1 Chr onma t o gr ar n o f F.D X ( I ) Pro p i op h e none ( 2) St a nda r d, 20 pg/rl [ (~ 115 ANALYSIS OF RDX IN DIETS SCOPE AND APPLICATION 1.1 This method covers the determination of RDX in diet samples at 0.0005% to . 0.100% level. 1.2 The sensitivity of this method is dependent on the level of interferences present in the samples, rather than the instrumental limitations. 1.3 This method is recor, ended for use only by experienced analysis familiar with High Performance Liquid Chromatography (HPLC) or under close superVision of such qualified persons. SL,?4ARY OF THE METHOD 2.1 A weighed quantity of the diet was stirred with 50 ml of acetonitrile for 30 minutes. The suspension was filtered through a porour glass filter and the filtrate was transferred with washings to a volumetric flask. Propiophenone, the internal standard was added to the filtrate or a portion, thereof and this solution was diluted to its final volume. The samples were analyzed using reverse phase high performance liquid chromatography. Each was eluted on 3.9 mm x 30.0 cm p-Bondapak C18 column with methanol: water (55%:45%) and •he eluant was monitored with an ultraviolet absorption detector at X = 254 nm. IATERFERENCES 3.1 Solvents, reagents, glassware and other sample processing hardware may yield discrete artifacts and/or elEvated baselines causing misinterpretation of chromatograms. All of these materials must be rhown to be free fror, interferences under the conditions of the analysis by running method blanks. 3.2 Interferences coextracted from the samples will vary considerably from source to source, depending on the type of animal feed used in the study. MATERIALS 4.1 Erlenmeyer flasks, 125 ml 4.2 Filtering apparatus, vaccum flask, 125 ml; fritted glass filters, porosity M, ASTM 10-20 microns. 116 iL EQUIPMENT 5.1 Mettler Grammatic Analytical Balance, No. 1-910 5.2 5.3 5.4 Corning Hot Plate Stirrers, BC 351 Buchi Evaporator, Model R Sample Clarification Kit, Organic (Water's Associates) 5.5 Higher Performance Liquid Chromatography • constant flow, isocratic pumping system * reverse phase column, 10 p - .3.9 mm x 30 cm p-Bondapak Cl8 column • ultraviolet detector, capable of monitoring X = 254 nm 0 strip chart recorder and electronic integrator capable of measuring peak areas and performing an internal standard calculation. REAGENTS 6.1 Propiophenone, an internal standard, Aldrich Chemical Company (Purity 99%) 6.2 Methanol, 6.3 RDX, S.A.R.M. Supplied by sponsor (Purity 99.8%) ActAonitrile, Water HPLC grade or equivalent CALIBRATION 7.1 Calibration standards were prepared from stock solutions containing 200 pg RDX, and propiephenone per ml acetonitrile so as to bracket the working range of the chromatographic system. These concentrations were: 0.5 pig/ml, 2 wpg/ml, 10 pg/ml, 20 pg/ml, and 40 pg/ml. 7.2 A constant injection volume of 15 ul was employed for all measurements. 7.3 In or.'er to determine the precision of the HPLC system, a series of 6 replicate injections of the 20 Vg/ml solution were made. 7.4 Retention times should remain relatively constant (within + 5% day to day) with RDX being 3.7 minutes, and propiophenone 7.3 minutes. If the retention times are not within + 5,%; supervising chemist should be informed prior to the analysis and corrective action should be taken. A 117 QUALMITY CONTROL 8.1 Before processing any samples, the analyst should demonstrate through the analysis of a blank that all glassware and reagents are interference free. Each time a set of samples is extracted or there is a change in reagents, a method blank should be processed as a safeguari against laboratory contamination. 8.2 8.3 8.4 8.5 Standard quality assurance practices were used with this method. A minimum of six replicate spiked samples were analyzed to validate the accuracy of the method. If doubt should arise concerning the identity of the peak on a chromatogram, confirmatory techniques such as mass spectrometry should be used. In a cypical sample set, a minimum of one blank and scheduled samples will be analyzed. A control sample will be prepared by adding a known concentration of RDX to the sample. The concentration will be in the working range of chromatographic system as determined by calibration experiment. The analyst will follow each step in an analytical protocol without deviation or improvisions in order to accurately assess the performance of the method. Prior to making any changes in the procedure, analyst will consult the supervising chemist and the supervising chemist and Q.A. officer will review and approve all the changes. The typical analysis will consist of the following samples. one blank sample, 6 diet samples as is, 3 feed samples spiked for the recovery determination at the diet concentration. 118 0 0 - 0 V TABLE 1. DILUTION SCHEME FOR RDX DIET SAMPLES Diet Level % 0.0005 Extract Volume (ml) Extract Diluted (ml) Propiophenone (IS) Added Final Volume (ml) 1 ml, 50 pg/ml I ml, 500 pig/ml 1 ml, 1000 pig/mi 100 100 100 10 1 ml, 500 pg/ml 25 10 1 ml, 1000 pg/ml 50 - 0.0050 0.0100 100 100 100 0.0500 100 0.1000 100 - . 7 r t.I SAMPLE COLLEC'ION Sampler are collected and stored prior to annalysis according to SOP 81- 9.1 sample collection (TNT and RDX diet samples). SAMPLE EXRA4CTION The appropriate amount of sample is weighed into a 125 m! Erlenmeyer flask using standard operating procedures. The sample amount for the 10.1 diet mixture is ten grams. Approximately 50 mls of acetonitrile is added to the flask and it is stoppered. The sample is extracted by stirring for only 30 minutes at room temperature. sample was filtered through a medium porosity this operation the extraction mixture was suspension and immediately poured into the rod was used to drain the last drop of liquid 10.2 Following extraction, the fritted glass filter. In swirled to form a uniform glass funnel. A stirring from the flask. 10.3 The extraction flask was rinsed with three portions of acetonitrile of approximately 5 mls each and the rinses are poure.' into the funnel. The vacuum is reapplied and the washing process is completed. 10.4 The filtrate is transferred via a short-stem funnel into a volumetric flask. The filtering flask is rinsed three times, with approximately 5 ml portions of acetonitrile and the rinses are added to the volumetric flask. The size of the volumetric flask and the subsequent treatment of the sample depend on the initial RDX concentration in the sample. The dilution for various sample levels is shown in Table 1. Diet samples will be diluted to a volume that places them in the working range of the chromatographic system. 10.5 An aliquot (approximately 10 ml) is filtered using a Water's Organic Sample Clarification Kit using 0.5 pm filter. The sample is now ready for analysis for HPLC. )@ 120 STORAGE OF SAPIPLES 11.1 All samples including diet and blank feed will be stored in the dark at refrigerator temperatures. 11.2 If the sample preparation procedure is stopped at any point during the working day, the samples should be stored in stoppered vessels in the dark at refrigerator temperatures. 11.3 Samples that are ready for HPLC analysis wi1l be stored in the dark at refrigerator temperature. 11.4 RDX and propiophenone standards and all standard solutions will be stored in the dark at refrigerator temperatures. HIGH PERFORMAI4NCE LIQUID CHROPMTOG.M4PHY (HPLC) 12.1 Each sample was an=lyzed by reverse phase HPLC using the conditions described below: Column, 3.9mm x 30.0cm u-Bondpak C_8 ; Solvent Systel, Methanol:Water (55%:45%, v/v); Flow Rate ,.5 ml/min; Detection,UV at 254 nm. The retention times of RDX and propiophenone were 3.7 and 7.3 minutes, respectively. The limit of detection was 0.2 ug RLX/ml acetonitrile and is defined as 5x the background noise. The representative chromatogram is Figure 1. For lerels at and below 0.005% RDX, the chromatographic conditions have to be changed, since UV absorbing compounds interfere with the RDX quantitation. The eluting solvent in these cases is Methanol:Water (45%:55%, v/v) at a flow rate of 1.5 ml/min. "12.2 The chromatographic system vas calibrated daily with a mininum of two injections of one standard representative Iof the chromatographic range. 12.3 An injection volume of 15.0 ul was used for each sample, below 0.0010% level. except at or The injec-tion volume at 5 & 10 ppm was 25.0 ul. If the peak exceeds the linear range of a sample it was diluted and reanalyzed. 12.h For levels of 0.005% and below the retention times are 4.8 and 12.9 minutes for RDX and propiophenone respectively. 12.5 Following the completion of an analysis or a set of' analyses, a gradient doing from the initial solvent conditions to 100% methanol in 15 minutes will be run and the column will be eluted with 100% methanol for at least one hour. 121 CALCULATIONS 13.1 Determine the concentration of RDX using the formula: (Ax(Wis) x D x 100 % RDX in Sample =FxVx) Ai Ais (Ws) Where Ax = Area (X) where x is RDX Ais = Area (internal standard) Fx = Area(x) x Weight (Wx) _ Area (is) x Weight (Wx) Wis = Weight of the internal standard Ws = Weight of the sample D Wx -%) 13.2 = Dilution factor = Wt of component x is RDX The results should be reported in percent RDX composite. This is the RDX actually used in the toxicity study. Where replicate samples are analyzed, all data should be reported. All results are recorded in standard IITRI logbooks and these plus chromatograms and data tapes are retained in the Chemistry Division Q.A. files. SAFETY 14.1 Safety regulations will be followed at all times, especially with regard to the handling of toxic materials. When the diet samples are being handled, a lab coat, and gloves will be appropriate attire. When solutions or extracts are being handled, a lab coat and gloves should be worn when there is the chance of direct contact with these materials. 122 122 A -~ -~ - __-A I'" t ) .. .i -- 4.-.; I I t 1__ I 2 1123 F~gure 1. 20Chrormatogramgi• of RDX (1) Propiophenone (•) Standard, • 123 STANDARD OPERATING PROCEDURES FOR THE PREPARATION OF TNT AND RDX DIET PRE-MIXES 1. OBJECT The object of this Standard Operating Procedure (SOP) is to set down procedures which, when followed, will assure quality from lot to lot 3f the subject pre-mixes. It also provides a guide to safe practices in the handling of these explosives materials. 2. HEALTH AND SAFETY The materials (TNT and RDX) being handled in these feed preparations are not only explosive but are also toxic. It would appear that the greatest risk is incurred by the covert )nhalation of the aerosolized finely divided powders produced by filling and emptying the ball mill and the V blender. Accordingly the following rules are hereby promulgated. 2.1 When charging or emptying the ball mill or "V" blender a respirii.or mask, and gloves must be worn. The 3M "Dust and Mist Respirator," 09910 is available to the Chemistry Storeroom and is recomiended. Surgeons gloves are recommended for use when handling these materials. They are also available in the storeroom. The above are considered disposable and will therefore be discarded: the respirator mask at the end of the day and the gloves immediately after they are removed. They will be incinerated along with all other expendable materials at the end of the work day. This will be done by the resident staff at KOP. These people should be made aware of the nature of the material to be burned. 2.2 Safety glasses, with side shields supplied by IITRI will be worn at all times in the operating areas. 2.3 Cleanup of contaminated surfaces will be accomplished with damp wipers, by washing or wet mop. Dry sweeping is not permitted. 124• 0 S-4 I I Spills will be cleaned up immediately. The spilled material should be discarded and not returned to the processes. Spilled material should be placed in an appropriate container, given to the KOP staff, with explanation of its nature, for disposal. General cleanup will be performed between mixes, i.e., say after preparing a TNT pre-mix and before starting on an RDX pre-mix. All work surfaces, the ball mill, "V" blender, and balance will be cleaned at the end of each work day. 3. 2.4 Only a sufficient amount of explosives material for immediate (one or two days operation), will be removed from the explosives magazines to the work area. This will be done by the approved resident KOP staff. Overnight storage of explosives is permitted only in designated areas within the facility. Explosives material will be stored and transported in appropriate "Velostat" containers. Explosives in proper container& should be kept on the bench top, not stored in drav.ers. 2.5 After the pre-mixes have been prepared and further work is not planned for the following day, residual bulk explosives will be returned to the storage area. This will be done by KOP resident staff. 2.6 Hands, forearms, and face will be washed upon leaving the work area. 2.7 Eating and drinking in the work area is strictly prohibited. GENERAL 3.1 Logbooks All activity and supporting data will be recorded in the approved IITRI laboratory logbook. 125 I I: 3.2 Sample and Lot Designation Samples or lots of pre-mix are designated by a number relating it to a logbook and page as follows: NNN-nn.j where i h I . s "NNN" is the last three digits of logbook registration number, -nf" is the page number in that logbook and ".j" is the sample number. For example: Sample 838-14.5 would be described on page 14 of IITRI Logbook 24838 and would be the fifth sample on that page. "PRE-MIXES" prepared for the feeding program will be designated as "PRE-MIX" using a similar code. For example: TNT PRE-MIX 838-13.1. 3.3 Data Format The data regarding the preparation of the pre-mixes shall be kept in the logbook in a prescribed manner. 3.4 The format proposed is shown in Figure 1. Labeling TNT pre-mixes, contained in "Velostat" bags will be identified with yellow tape and with a label as: 10% TNT PRE-MIX Wt Kg Lot No. (see 3.2) Date: mm/dd/yy Initials of the preparer RDX pre-mixes contained in "Velostat" bags will be identified with blue tape and with a label as: 10% RDX PRE-MIX Wt Initials of the preparer 126 -- __Kg Lot No. (see 3.2) Date: mm/dd/yy ix 4. PREPARATION OF TNT OR RDX/FEED PRE-MIXES 4.1 Introduction Animals are to be fed the test materials (TNT or RDX) at very low doses. This requires that gram quantities of these materials be dispersed as uniformly as possible among large quantities of feed. In order to accomplish this the test materials are first dispersed at a concentration of 10% in feed. This is known as the PRE-MIX. Appropriate quantities of the PRE-MIX are then blended into large quantities of feed to attain the required dosage level. The correct preparation of the PRE-MIX is the subject of this SOP. TNT is a soft waxy substance with a low melting point which is difficult to grind. The starting material is TNT flake which must be reduced in particle size to meet the needs of this program. This cannot be done by ball-milling the TNT without a "grinding aid". The aid used in this s.idy is the certified feed material; an animal feed in the form of a finely divided meal. Equal portions, i.e., 50/50 by weight of TNT and feed, are ground in a ball mill to form a TNT CONCENTRATE. This 50/50 CONCENTRATE is subsequently blended with more feed in a P-K "V" blender for form the 10% PRE-MIX. The same procedure is followed for the preparation of the RDX PRE-MIX. While it was not necessary to ball mill the RDX with feed as a grinding aid this procedure was followed to avoid introducing another variable in the feeding programs. Thus the preparative procedure is the same for the TNT and the RDX PRE-MI XES. 4.2 Preparation of TNT Pre-Mix The required amount of materials are shown in Table 1. The following stepwise procedure is to be followed for the preparation of a 10% TNT PRE-MIX. 127 43 -3 Table 1 MATERIALS REQUIRED For Pre-mix Wt (kg) FEED CONCENTRATE Ball Mili TNT (a) + Feed z) >- PRE-.I X Blend W.ith Feed (g) 1 100 100 800 2 200 200 1600 3 300 300 2400 4 400 400 3200 5 500 500 4000 6 600 600 4800 A 11 I. I I; i ~128 = 4.2.1 4.2.2 4.2.3 4.2.4 4.2.5 4.2.6 Determine the appropriate quantities of feed and TNT (from Table 1) to be weighed out to prepare the 50/50 TNT/feed concentrate. Weigh out the appropriate amount of TNT and feed. Examine the ball mill jar and balls to be sure they are clean. The ball charge should weigh approximately 3.83.9 kg and is a mixture of 3/4" and 1/2" balls. (See logbook C24838 pg. 3). Place the balls in the jar, pour in the weighed feed and then the TNT. Fir-ly fasten the jar cover and place on the mill. Turn the mill on and record the time. Ball mill for 40 minutes. Record the exact time in the logbook. Remove and open the ball mill jar. Sift the powdered feed/TNT from the balls onto a large piece of paper. (Use the large hardware cloth basket provided to separate the balls and powder.) Weigh this feed concentrations and record in the logbook. Weigh out the larger amount of feed into an appropriate bucket. Record the weight. Put about Open the blender top on each leg of the "V". 1/3 of the concentrate into the blender (i.e., at the Pour about 1/2 of the feed into the point of the "V"). blender. Put another 1/3 of the feed, in the blender, Pour the dividing it between the two legs of the "V". rest of the feed into the blender (1/2 into each leg) and divide the rest of the concentrate between the two legs Close the blender. of the "V". 4.2.8 Run the blender for 15 minutes without the intensifier bars on. Turn the intensifier bars on for 15 min. Turn off the blender. Note and record the total blender time. 4.2.9 Open the cover at the apex of the V and dump the content of the blender into a Velostat bag. Make sure the blender is completely empty. Seal the bag and label (see 3.4). 4.2.10 Clean the Llender by running with about 2 kg. of feed material only. Repeat this twice. Discard the feed material, Disconnect the blender from the wall outlet, clean the blender with damp wipers. 4.2.7 129 U0• Clean the ball mill by a similar procedure, i.e,, milling feed only, repeated twice followed by a damp wiping. 4.2.11 Notify the proper individual that the PRE-MIX is available and expected date of shipment to the Chicago laboratory. 4.2.13 The PRE-MIX procedures will be witnessed by second indiviual and second individual will sign the logbook as witnessed. 4.3 Preparation of RDX PRE-MIX The required amounts of materials are shown in Table 2. The following stepwise procedures are to be followed for the preparation of a 10% RDX PRE-MIX. 4.3.1 " about one kg of alcohol wet RDX is placed in a wide mouth gallon jar containing ½ gal of distilled water " the jar is agitated for five minutes by rolling on the ball-mill or by shaking "• the RDX water-slurry is decanted through a 60 mesh or finer seive muslin cloth. The crystal cake is drained to remove excess water " the water wet crystals are then returned to the jar and the above procedure repeated two more times "• after the final wash the crystals are spread on paper toweling and let dry overnight or dried in oven at approximately 100'F overnight 4.3.2 4.3.3 4.3.4 4.3.5 0 Determine the aDpropriate quantities of fccd and the washed and dried RDX (from Table 2) to be weighed out to prepare the 50/50 RDX/feed concentrate. Weigh out the appropriate amount of RDX and feed. Examine the ball mill jar and balls to be sure they are clean. The ball charge should weigh approximately 3.83.9 kg and is a mixture of 3/4" and 1/2" balls. (See logbook C24838 pg. 3) Place the balls in the jar, pour in the weighed feed and then the RDX. Firmly fasten the jar cover and place on the mill. Turn the mill on and record the time. 130 4A 0 Ir Table 2 MATERIALS REQUIRED For Pre-mix FEED CONCENTRATE Ball Mill Wt (kg) RDX (g) + Feed (g) IO0 100 1 PRE-MI4X Blend With - Feed (g) 800 2 200 200 1600 3 300 300 2400 4 400 400 3200 5 500 500 4000 6 600 600 4800 131 ~" 4.3.6 Ball mill for 40 minutes. Record the exact time in the logbook. Remove and open the ball mill jar. Sift the powdered feed/RDX from the balls onto a large piece of paper. (Use the large hardware cloth basket provided to separate the balls and powder.) Weigh this feed concentrate and record in the logbooK. 4.3.7 Weigh out the larger amount of feed into an appropriate bucket. Record the weight. 4.3.8 Open the blender top on each leg of the "V'. Put about 1/3 of the concentrate into the blender (i.e., at the point of the "V"). Pour about 1/2 of the feed into the blender. Put another 1/3 of the feed, in the blender, dividing it between the two legs of the "V". Pour the rest of the feed into the blender (1/2 into each leg) and divide the rest of the concentrate between the two legs of the "V'. Close the blender. 4.3.9 Run the blender for 15 minutes without the intensifier bars on. Turn the intensifier bars on for 15 min. Turn off the blender. Note and record the total blender time. 4.3.10 Open the cover a" the apex of the V and dump the contents of the blender into a Velostat bag. Make sure the blender is completely empty. Seal the bag and label (see 3.4). 4.3.11 Clean the blender by running with about 2 kg of feed material only. Repeat this twice. Discard the feed material. Disconnect the blender from the wall outlet, clean the blender with damp wipers. Clean the ball mill by a similar procedure, i.e., milling feed only, repeated twice followed by a damp wiping. 4.3.12 Notify the proper individual that the PRE-MIX is available and expected date of shipment to the Chicago laboratory. 4.3.13 In the first four months of this program 8 k9 of the RDX PRE-MIX will be required each month. This exceeds the capacity of the available ball mill and bledder The following procedure is to be used. 4.3.13.1 Prepare two (2) 4 kg pre-mixes by following steps 4.3.1 through 4.3.10 above. This will result in two sub-batches for the final lot, identified as sub-batch 1 and 2. [ 132 V. Ký % 0 fA 74 4.3.13.2 Blend one-half of sub-batch 1 with one half of sub-batch 2 in the "V" blender for 10 minutes with the intesifier bar "on". Repeat with the remaining halves of the sub-batches. These become two new sub-batches, Repeat the procedure. 4.2.13.3 Combine the results by alternately dumping portions of the resulting sub-batches into the large Velostat bag. Periodically shaking the bag and mixing the contents. Proceed with steps 4.3.11 and 4.3.12. 4.3.13.4 The premix procedure will be witnessed by second individual and second individual will sign the logbooks as witnessed. 4.4 Any deviation from this procedure must be first cleared with the project leader and must be recorded as an addendum or revision to the SOP. Record any unusual occurrence in the logbook and advise the project leader immediately. In cases of uncertainty contact Robert Remaly, ext. 4309 or Barry Levine, ext. 4901 before proceeding. 4.5 Transmittal Record Transmittal record will be initiated by the person who is preparing the premix. All the pertinent information must be filled. The test article premix record must accompar.y the premix. Copies of the transmittal record can be obtained from the Principal Investigator. 133 .SAMPLE COLLECTION AND STORAGE (TNf AND/OR RDX PREMIX SAMPLES) Scope. 1.1 This procedure covers the collection and storage of TNT and RDX premix samples prior to analysis. Materials and Equipment 2.1 Small scoop 2.2 Powder funnel 2.3 Amber vials with plastic screw cap Sample Collection 3.1 Personnel of the Life Sciences Division will inform the supervising chemist and the analyst when they receive TNT or RDX premixes. The analyst will collect 6 samples from the'Velostat baq container, one from each of four corners and two from the middle. At least 5.0 gram quantities of premix will be collected in order to permit the extraction and analysis steps to be performed in duplicate. All samoles will be identified according to the Chemistry Division. identification system. All detailed information will be placed in the sample identification logbook imnediately. The sampling procedure for the premix will be performed as follows: One sample is removed from the center of the storage bag with a small scoop which will permit the removal of a 5.Og quantity. The second sample will also be removed from the center of the container in the same manner as the first sample but at a deeper level. j - .- -- I-1311 -AI awW t j.> ŽŽ Q&SX1..1- ~ ? After center sampling, the surface of the premix is restored by leveling and four additional samples will be removed with a small scoop from each of the four corners of the bag at gradually increasing depths by lifting the corners of the bag. The 6 samples will be labeled and placed in amber vials with plastic screw caps. The label will contain Date Sampled, Sample Number, Premix Identification, Lot NLmber and Sampled by Initials. Sample Storage All samples will be stored at refrigerator temperatures in the dark prior to analysis. This includes feed that will be used for blanks 4.1 and control samples. will be changed. Every three months (from manufacturing date) feed This manufacturing date will be supplied by Life Science Transmittal Record Transmitted record will be completed by responsible personnel. A copy of Test Article Premix (T.A.P) and/or T.A.P. Sample Transmittal (or custody) record is attached. 5.1 Sample Disposal 6.1 Samples or parts of samples will be returned to the Safety Officer for disposal. 135 :I TEST ARTICLE PREMIX (T.A.P.) AND/OR T.A.P. SAMPLE TRANSMITTAL (OR CUSTODY) RECORD Project No. - Study No(s). Lot No. T.A.P. T.A.P. Prepared (K.O.P.) Intended Concentration: Date/By: % Quantity (kg): Logbook No./Page No. 5002 Lot No.: Storage Conditions of T.A.P. T.A.P. Received (L.S.R.) Date/By: _ (KO.P.): Logbook No./Page No.:_ Storage Conditions of T.A.P. in L.S.R.: T.A.P. SAMPLING AND ANALYSIS T.A.P. Sampled Date/By: Logbook No./Page No.: Witnessed By/Date: Storage Conditions of T.A.P. Sample by Chemistry Personnel: Extraction Performed By/Date: Logbook No./Page No.: Analysis Performed By/Date: Logbook No./Page No.: Data Reviewed & Approved By/Date: Analytical Report Prepared By/Date: Checked By/Date: Quality Assurance Check By/Date: Analytical Report Received (L.S.R. Supervisor) By/Date: T.A.P. First Used By/Date: T.A.P. Last Used By/Date: Excess T.A.P. Submitted to K.O.P. Personnel for Disposal by Burning By/Date: Quanti÷' Excess T.A.P. (kg) Received By/Date: Key K.O.P. = Kingsbury Ordinance Plant, La Porte, IN. 5002 = Purina Certified Rodent Chow 5002 136 UJruv% WbJ SAMPLE COLLECTiON AND STORAGE (TNT AND/OR RDX DIET SAMPLES) Scope 1.1 This procedure covers the collection and storage of TNT and RDX diet samples prior to analysis. Materials and Equipment 2.1 Small scoop 2.2 Large scoop 2.3 Powder funnel 2.4 Amber vials with plastic screwcap Sample Collection Personnel of the Life Sciences Division will inform the supervising chemist and the analyst when the TNT or RDX diets are available. The analyst will collect 6 samples from the plastic tub container, one from each of four corners and two from the middle. The tubs receiving the rat diets are rectangular with a capacity of 42 liters. The tubs receiving the mouse diets are square with a capacity of 27 liters. At least 30.0 gram quantities 3.1 of diet will be collected in order to permit the extraction and analysis steps to be performed in duplicate. All samples will be identified according to the Chemistry Division identification system. All detailed information will be placed in the sample identificat.ion logbook immediately. The sampling procedure for the diets will be performed as follows: One sample is removed from the center of the storage container at the surface of the diet. This sample will be removed with a small scoop which will permit the removal of a 30.Og quantity. The second sample will also be removed from the center of the container about half the distance to the bottom after toxicology personnel have exposed the sampling site by shifting the 137 diet toward the side of the container using a large scoop. After this sampling, the surface of the diet will be restored by leveling. Four additional samples will then be removed with the small scoop, one from each of the four corners of the container at gradually increasing depths within the container, again using the large scoop to expose the sampling sites. The 6 samples will be labeled and placed in amber vials with plastic The label will contain Date Sampled, Sample Number, Diet Identification and Lot Number and Sampled by Initials. screw caps. Sample Storage 4.1 0 All sampies will be stored at refrigerator temperatures in the dark prior to analysis. and control samples. will be changed. This includes feed that will be used for blanks Every three months (from manufacturing date) feed This manufacturing date will be supplied by Life Science Personnel. Transmittal Record 5.1 Transmittal record will be completed by responsible personnel. A copy of transmittal record for diet sample analysis is attached. Sample Disposal 6.1 Samples or parts of samples will be returned to the Safety Officer for disposal. 138 %N@ TRANSI.lITTAL RECORD FOR DIET S,",PLE ANALYSIS Study No. Species Test Week_ Test Article Lot. No. % Conc. of Premix Diets calculated by: Datp" Premix weighed by: Date; Diet prepared by: Date: Dose level: mg/kg/day sex: Dose level: mg/kg/day sex: Diets Stored in the Refrigerator (4°C) From: _ _ 5002 Lot No.(s) T.W. intended conc. mg/g .T.W. intended conc. mg/g To:_ ___ First Day of Test Animals Exposure to the Diet: Dict Samples Taken By/Date Loghook No./Page No._ Witnessed By/Date: Storage Conditions of Diet Samples in Chemistry Division _ Extraction Performed By/Date: Logbook No./Page No. Analysis Performed By/Date: Logbook No./Page No. Results Logbook No./Page No. Calculated By/Date: Data Reviewed and Approved By/Date: Analytical Report Prepared By/Date: Quality Assurance Check By/Date: Results Reveived By: Date: KEY: T.W.= TEST WEEK 5002 Purina Certified Rodent Chow 5002 139 V -, 0 ei [ I *1 I 0I '1 r 140 Lw.FrrMrRr,.jtrAr.rArA-Aprar.AnAraflx-aftjr¶jtuE-ui 'I V 'fl'SMfliiXJM XM ¶Wad1tkPx th ZM 1 fl-fl-thb - - - - ta k s. w. . .r mum. .h z: . an Ear556.1%. mqmmomm Noon 4 x.ozwmm< gun?- I. rEr mm. wr?: .. ?Km?Ad?uni. wn-W' i NM. 0511!. I - ?Hh dw?d?h ME 41mmINF. Ibu?f $3333.!!ka lrriied Disu~talon................. .5ppm S Met~hyl Parathion .......... 5 ppm P~~~~~~~~aralhion .................. .. S ppm Paraf~~thoan.................... .5ppm, 5 ppm Ethion ...................... ent lodent 5002 Fat % ...... Fiber % .... NF b i~r~e TD%.........77C ID I ..... .2C. *........5Mltin............pm ... Gross Energy. KUe --.......... 1 . 5ppm As%.............. 5 This product is manufactured Ina plant whore antibiotics and synthetic estrogens ate strictly prohibited Routine monitouing lor over a decade has not showin any delectable leel of these substances. No drugs or Cacu%............ S Trithion ..................... Dusand Estrogens - 7 Pnoassium~ V% ............... 2EE % .................. ftagrsslum ertiied Rodent Chow is a controlled Soiuane-m %....... ............ 321 :inslant nulirent roderit diet recommended .40 Chorinm %................ )rife cycle feeding cl f'als. mice end 2msters. A sample of lhis product has Fluorine. ppm................. aen assayed for certain environmental Iron. ppm.....................100 ~nt~mna'is Maimumdietconta' ~manufacturing. storage or warehousing to Znpm........5 avoid any contamination of Lab ChowsMagnep.......60 ýhievecl by pre-ana'ysis monitoring of key fl~rienis anid ce.1a~n contamninating dit.copper, ppm .................. 13 J~bstances, Diet conltol helps minimize Other Contaminants - It additional Cobalt, ppm .................... 6 3riables in research siudies. contaminants assas are needed, these Iodine. ppm .................... 1.2 ~uaanted nalsiscan bi ordering such analyses Vitamins mm............20ys0% priorbetoobtained manufacture. Cost of these Carotene, ;ppm.. .............. 5 6 :rude protein, mn........ 00 additional assays wviil be charged based on Monadione (added), ppm ......... rude fat, mnin................. 4.5% curreant analyses rates at time of assay Thiamin. ppm.................. 13 ý .!ude fiber. max............ 60% P.:oolavin. ppm................. 80 - .sthicstoesaeerrted 'h, max .............. 80 dded minerals, max ........... 22 5% erifctin rfieground .erifizton roflegerm ascd on anEfysis of a comnposite sample, package conta~ns no,, more than ,ese maxin",Jrn concentraiions of the ,llowing sutst'ances. eavy Maximum 'etals Concentration *renic ........... I........ 1.0 ppm 'ad mium I....... I.......... .5 ppm 1.5 ppm ................... ?ad. ýercury ................... .2 ppm flatoxln................... 10 pp hloinaed ydrcaronsandPCB ...... .... 5 Ppm .....I..... 05 ppm ach ndrin ........ . 05 ppm 05 porm ep'.chlor ....... . ... I... ... eptachlor Epoxide ........... .05 ppm ,ndane ...... I .. .- .05 ppm ,hiordane . ... ý............. .05 ppm 07T Rela'ted S~ibslences....... .15 ppm .15 ppm CS..................... ýrganophosphates hirr-el ........... ......... .5 pprri iiaiinon .................... .5ppm Ingredients: Ground extruded corn, soybean meal, oat groats. dried beef pulp, wheat meal, fish rmeal. brewers' dried yeast, d~ehydralted alfalfa mneal, cane molasses, dried milk products, meat and bone meal, wheat rmiddlings, animal tat preserved with BHA, calcium carbonate, dicalcium phosphate, salt, animral liver meal, Calcium iodate. vitamin Sip supplement, rnelhionine hydroxy analogue calcium, calcium pantohenate, choline chloride, lohie acid, riboflavin supplement. thiamin, niacin, pyridoxine hydrochloride, ferrous sulfate, vitamin Atupplement, 0 activated animal sterol, vitamin E supplemnent, iron oxide, coproie ic oxide. croae oxid Che mical Composition"' Nutrients-~ Protein %..................... 20.0 A'gnn Labtf!v ,.,onlrol eclorlo 1 3 Fcic Acid, ppm................. 40 Pyridoxine. ppm................. 60 B~otin. ppm..................... .13 B-12, mcg~b .................. 90 Vitamin A,lU/gm............... 117.6 Vitamin D,lU~gm................2 22 Alpha-tocopherol, WIU.!) .......... 300 Asco~rbic Acid, mg'gm..............4- FOcdiflg Directions Feed ad iibilurrt to roants, Plenty 01 fresh. clean water shou'd be availablo to the an:mals at all times. Ats - A.'-.;! tails v*i eat, 12 to IS g..a 4 die per uj Fev.ce-e in,rat ca~e., should be desi;ned to hold two to three days supply of feed a-, one time. Mice - Adult mice veill eat 4 to 5 grams 01 p lee aind iyS~n ftelre -Ib eU P siie%.........1 elterationma dalya Smc as th lrarg er st prainsimay , ashuchda Feat be gampber dypraia edsol eaai on a free choice basis in wire feeders above the floor of th~e cage. Hamsters - Adults will eat 10-14 grams per day, Cystine %..................... .27 .866 G'l'cine % .................... Histidine %.................... .49 lsoleucirne % ................... 1.03 Leucirne %..................... 1.58 Lysine %...................... ¶118 t'/ethionifle % ... . . . . .. . . 43 Prhenyla'anine %. 88....... I Threonine % ,................,..... 78 'rryptophan %V.................. .24 Valine 142 ............ NMacin, ppm.................... 600 Pantothenic Acid, ppm ........... 17.0 Cho!ine. ppm 00lO .............. 18 3 %V...................... l Waiq-itoore~rt 6fvori~ i'.g 1.05 futit to'ue to a naiurgl Pcia,r0lo 6"Ce~i~ib~~ a eC p V9111% M"ysi 0M. 01", fecl." TE ll' .llad'?h'? ?u Inu- :lill'lh? I l' . 'anmru .. . 3?1. APPENDIX ll! ANALYTICAL CHEMISTRY METHODS 7: .. i?a- In: Inn-Ii war-x nu- animus-n . 1&3 *W?h :ii'i L L-1 ANALYTICAL, INC. 460 SOUITH NORTH WEST-HIGHWAY *PARK RIDGE. ILUNOIS &60068 # 312/696-2D70 [ October 29, 1982 LA O A O YR P R Page Iof 2 paces Dr. Marianna Furedi IIT Research Institute 10 West 35th Street Chicago. Illinois 60616 P.O. 116092 Sample rereived June 9, 1982 [TEI-14080J. Rodent Chow 15002 - M~arch 24-822G Result in p~ 1,itrate Nitrogen Nitrite Nitronen iiercury Arsenic Leadrin Penicillin * 7.030 7.030 25.103 JAOAC 60.813 0.01 25.05 Snell&L not detected Chlor-tetracycline Method 19.0 0.24 <0.05 0.014 < 10 Total Estrogen Affatoxin Aflatoxin Aflatoxin Aflatoxin Diledrin Lndrin Aidrin 9166 39.000 1 to be reported dat at a later 61 G, 4 0.005 0.02 < 0.005 G2 <0.005 0.01 S,? < 0.001 < 0.001 IC0.00W <~ 0.001' < 0.OCl Hleptachilor Epoxide BHC .0 26.003 26.003 26.003 26.00" 29.000 29.0010 29.000 29.030 29.000 - iL. 460 TEl ANALYTIC AL, lIC.j SOUTN NORTHWEST HIGHWAY * PARK RIDGE. ILUNOIS 9 60068 , 312/696.2070 LABORATORY REPORT October 29, 1982 #9166 Page 2 of 2 pacies Dr. Marianna Furedi 1IT Research Institute 10 West 35th Street P.O. 116092 Chicago. Illinois June 9, 1982 (TEI-14080) Sample received 606?6 Rodent Chow 15002 - March 24-822G Result in ppm Lindan? DDT Total ýethoxychlor Chlordane < 0.001 < 0.001 * Method < 0.001 < 0.001 29.OOC 29.. 0 29. '1 29..-T Toxaphene < 0.001 < 0.001 29.000 29.000 Strobane < 0.001 29.000 HCb 29.000 Polychlorinated Dioxins Parathion flethyl Parathion Enthion Carbophenothion INalathion konnel < 0.001 < 0.001 < 0.006 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 28.128 29.000 29.000 29.000 29.000 29.000 29.; - 0 Vlazinor, < 0.001 29.OUO Disul feton Phorate < 0.001 < 0.001 29.000 29.000 Mirex PCL 29.000 *Official Methods of Analysis of the Association of Official Analytical Chenists. ~~W a.W L ~ ~~ N ~.145~ ANALYTICAL PROCEDURES USED BY TEl ANALYTICAL, INC. PARK RIDGEi IL TO ANALYZE PURINA CERTIFIED RODENT CHOW NO. 5002 FOR IMPURITIES Limit of D r-nedjun u± Chlorinated Pesticide Screen Phosphated Pesticide Screen Polychlorir.ated Biphenyls (PCBs) Hexa-, hepta-, octachlorodibenzo-p-dioxin Heavy Metals Arsenic Cadi um Lead ?Mercury bi±.L 10 ppb 50 ppb 100 ppb <100 ppb 1.0 10 10 <1 <1.0 <1.0 2.0 <2.0 SNitrates Nitrites Aflatoxins Penicillin 1.0 ppm 1.0 ppm Butylated hyoroxytoluene Butylated hydroxyanisole Estrogens A.O.A.C. - ppb ppb ppb ppb ppal ppm ppb ppm 10.0 ppm Chlortetracycl ine Referenc..es A.O.A.C. A.O.A.C. A.O.A.C. A.O.A.C. 29.000 29.000 29.000 28.128 J.A.O.A.C. 60.813 A.O.A.C. 25.026 A.O.A.C. 25.058 A.O.A.C. 25.103 7.030 A.O.A.C. 7.030 A.O.A.C. A.O.A.C. 26.003 Snell and Snell, Colorimetric M~ethods of Analysis Vol IV AAA, pa. 221 Snell and Snell, Colorimetric I-ethods of Analysis Vol IV AAA, pp. 184 J.A.O.A.C. 60.505 J.A.O.A.C. 60.505 A.O.A.C. 39.000 Official method- of analysis of the Association of Analytical Chemists. Official 1I l46 .i~; .~ f,~ ~ ~ W • APPENDIX IV HEMATOLOGY METHODOLOGY 147 ,'. A M•., ", ' ' " ' , • t• , ., .,. ', .,•' • , ,• ' , ,." .;V . • •,,"• • .• • .< .. " Iz•, Cyanmnethemo~iobin method Coultar Counter Model S System Indirect method; calculated value based on erythrocyte count and mean corpuscular volume Coulter Counter Model S System Erythocyt CoQurn Electronic Counting Procedure Coulter Counter Model S System -Count 01• Electronic Counting Procedure Coulter Counter Model Mean .orpus S System ar 2Volume LC Electronic Siztng Procedure Coulter Counter Model S System &A QCopusj-,v.Qr H:emIog•Lobi (MCH) Indirect method; calculated value based on erythrocyte count and hemoglobin Coulter Counter Model S System MeAn Corpuscula emoglob * oncentration (MCHC) Indirect method; calculated value based on hematocrit and hemoglobin Coulter Countter Model S System Neutrophils - Immature Neutrophill - Mature Monocytes Basophils Lymphocytes Eosinophils Wright stain procedure Schalm, O.W., Jain, N.C. and Carroll, E.J. Veterinary Hematology, Color Plates Chapter, 3rd Edition, Lee and Febiger, 1975. 14 Wright stain procedure Schalm, O.W., Jain, N.C. and Carroll, E.J. Veterinary Hematology, Color Plates Chapter, 3rd Edition, Lee and Febiger, 1975. Direct Method Schalm, O.W., Jain, N.C. and Carroll, E.J. Veterinary Hematology, p. 69, 3rd Edtlon, Lee and Feblger, 1975. t 149 M?qH?l??x. omp .1. 4% 4 4.4444444. 4 .4 44 4.5.4.441: Wtwisuvu} 44.1.4?. 44 4 .4. . APPENDIX V CLINICAL CHEMISTRY METHODOLOGY 151 ~~¶.~~Af m- b in It, . I . ~ ~ ~ .22 ' . A i~ui GI ucose Hexokinase method Centrifichem Centrifugal Neeley, W.E. Clin. Chem. Analyzer System 18, 509, 1972. Modified urease technique Centriflchem Centrifugal Analyzer System Karmen, A. J. Clin. Invest. U4, 131, 1955 Glu ami - y _Uy Transam -lnase (SG PTI)• Modified Wroblewski and LaDue technique Centrifichem Centrifugal Analyzer System Henry, R.J., Chlamori, N., Golub, O.J., and Am. J. Clin. Path. 3A, 381,1960. Berkman, S. Biuret technique Centrifichem Centrifugal Analyzer System Failing, I.F., Jr., Buckley, M.W. and Zak, Am. J. Clin. Path. Ul, 83, 1960. B. Bromocresol green method Centrifichem Centrifugal Analyzer System Rodkey, I.L. Clin. Chem. 11, 478, 1965. Tetrazollum salt reduction method Centrifichem Centrifugal Analyzer System Klotzsch, S., Serrlcchlo, M. ana Furedl, R. Advances in Automated Analysis Vol. 1, Mediad Inc., Tarrytown, N.Y. p 111, 1973. Cholesterol esterase-cholesterol oxidase method Centrifichem Centrifugal Analyzer System Roseschlaw, P., Bernt, E. and Gruber, W. Z. Lin. Che. u. Kiln. Blochem. 12, 226, 1974. F. 15 S 152 •'•'=•='•,'3;w~fr• • • • .'•= • *•" N• •_ • • • • • • • • • • • ••5 • -. ° ° ,•-.•.• •,• •• •.• t • • • •r. • .•. -J.1.II . L55. .3. 1t Ion; L..- . .kk 93 head an an .. ?Q'u .51; ?immune (.53 .2233 fozmnruz ."In? - 411,. 1 .L ?i ?W?v?y run My SEE 5. rd 5.. nunr?mr?rf rm? 5. hr JunieL6121- 7 TWENTY FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITY STUDY OF HEXAHYDRO-1,3,5-TRINITRO-1,3,5-TRIAZINE(RDX) IN THE BC 3 F, MOUSE SURVIVAL RATE DATA A N 1 M A L T R N O * G R 0 U P S E X 001 002 003 I 1 1 M M M 03/22/82 02/07/83 07/29/82 005 006 007 008 009 010 011 012 013 014 015 016 017 018 019 020 021 1 1 1 1 1 1 ! 1 1 11/29/82 02/07/83 02/07/83 02/07/83 02/07/83 02/07/83 02/07/83 02/07'/83 01/28/83 02/09/'82 12/30/81 09/20/82 02/07/83 09/06/82 02/02/83 05/14/82 02/10/82 0 1 1 1 1 1 1 1 0 1 1 M M M M M M M M M M M M M M M M M 022 " M 02/07/83 i 023 024 025 . i 1 M M M 01/27/83 02/07/83 02/10/82 0 1 1 027 - M 02/07/83 004 S026 1 1 1 1 1 0276M 029 030 031 032 033 2 034 154 IV, 1 M M M M M M 1 1 1 035 036 037 038 039 040 041 154 M 1 1 M M M M M ! 1 ! M E V E N T D A T E 0 1 0 02/11/82 1 0 0 1 0 0 0 1 02/07/83 !' 02/07/83 02/07/83 02/07/83 02/07/83 02/07/83 10/07/82 02/07/83 1 1 1 ! 0 0 02/07/83 04/19/81 02/07/83 02/07/63 02/07/83 02/07/83 12/27/82 1 0 1 i 1 £ 0 Event code is: 0 = Died or moribund sacrifice; 1 = Scheduled sacrifice TR Group 1 = Control ' t J J~- & ~A ? ~.'. •A TWENTY FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITY STUDY OF HEXAHYDRO-I,3,5-TRINITRO-1,3,5-TRIAZINE(RDX) IN THE BCF, MOUSE SURVIVAL RATE DATA A N I L6121-7 T M A L R 042 043 G R 0 U P 2. 1 S E X M M D A T E 02/07/83 02/07/83 044 1 M 02/07/83 1 045 1 M 02/07/83 1 046 047 1 1 M M M M M M M M M M M M M M M M M M M M M M 02/07/83 02/09'/82 02/10/82 02/07/83 02/07/83 02/07/83 02/07/83 02/07/83 02/07/83 01/26/83 02/07/83 02/11/82 02/11/82 02/07/83 02/07/83 02/09/82 02/11/82 08/04/82 09/21/82 12/22/82 07/11/82 1 1 1 1 1 1 i i 1 0 1 1 N 048 049 050 051 052 053 054 055 056 057 058 059 06C 061 062 063 064 065 066 i 1 1 1 1 1 1 1 1 1 1 i 1 1 1 E V E N T 1 1 1 1 1 1 0 0 0 0 067 i M 02/07/83 i 06E 069 070 071 072 073 074 075 076 1 1 i 1 1 1 M M I. M V M M M M F 02/07/83 02/07/83 02/07/83 10/27/82 02/07/83 08/27/82 02/07/83 02/07/83 02/10/82 1 0 1 0 1 1 1 077 1 F 02/07/83 1 078 079 0801 08fu 082 1 1 F F F F F 02/07/83 12/30/82 02/09/82 02/07/83 02/07/83 1 0 _ 1 Event code is: 0 = Died or moribund sacrifice; 1 = Scheduled sacrifice TR Group 1 = Control 155 TWENTY FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITY STUDY OF HEXAHIYDRO-I,3,5-TRINITRO-1,3,5-TRIAZINE(RDX) IN THE B6 CF, MOUSE SURVIVAL RATE DATA L6121-7 --------------------------------------------------------------------------------A N T M R A L G E R D V N 0 S A E 0 U E T N • P X E T --------------------------------------------------------------------------------083 1 F 02/07/83 1 084 1 F 02/07/83 1 085 1 F 02/07/83 1 086 1 F 02/09/82 1 087 1 F 02/07/83 1 088 2 F 02/07/83 1 089 i F 02/11/82 1 090 1 F 02/07/83 1 091 1 F 02/07/83 1 092 F 02/07/83 1 093 1 F 02/07/83 1 094 F 02/07/83 1 095 1 F 02/09/82 1 096 1 F 02/07/83 097 1 F 02/07/83 1 098 F 02/07/83 12 099 2 F 02/07/83 1 100 F 02/07/83 i i01 F 02/09/82 1 102 F 10/06/82 0 103 F 02/07/83 ! 104 F 02/07/83 1 2105 7 F 10/20/62 0 106 F 02/07/83 1 107 F 02/07/83 i 108 F 02/07/83 1 109 F 02/07/83 1 210 F 02/11/82 1 2.! i F 02/07/83 i .12 113 114 115 . F 02/07/83 1 1 1 F F F 06/18/82 10/11/82 02/07/83 i 0 0 1 116 i F 02/07/83 2 117 1 F 02/07/83 1 "118 L F 02/07/83 1 119 F 02/10/82 2 120 F 02/07/83 2 .212 F "2/16/82 0 122_F 02,/07/83 123 1 F 02/07/83 L --------------------------------------------------------------------------------Event code is: 0 = Died or moribund sacrifice; 1 TR Group 1 = Control 156 i - - Scheduled sacrifice - L6121-7 TWENTY FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITY STUDY OF HEXAHYDRO-1,3,5--TRINITRO-1,3,5-TRIAZINE(RDX) IN THE B6 CF, MOUSE SURVIVAL RATE DATA A NI M T L G R C U P A N O . 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 14" 142 143 144 145 "146 147 148 149 i50 15-1 152 153 154 155 156 157 158 159 160 161 162 163 164 R i 2 2 2 2 2 2 2 2 2 2 2 2 2 2 S E X F F F F F F F F F F F F F F F F F F F F F F F F F F F M M M M V M V M M M M V V D A T E 02/07/83 12/29/82 08/10/82 02/07/83 10/02/82 02/07/83 02/07/83 02/11/82 02/07/83 06/04/82 10/17/82 02/07/83 02/07/83 02/C7/83 02/01/83 02/10/82 10/23/82 02/07/83 08/11/82 02/07/83 02/07/83 02/07/83 01/25/83 02/07/83 02/07/83 02/07/83 10/06/82 02/07/83 02/07/83 02/07/83 02/09/82 02/07/83 02/07/83 02/07/83 02/07/83 02/07/83 02/07/83 02/07/83 02/07/83 07/26/82 02/10/82 E V E N T 1 0 0 1 0 1 1 1 1 0 0 1 1 1 0 1 0 1 0 1 1 1 0 1 1 1 0 1 i 1 1 1 1 1 1 1 1 0 1 Event code is: 0 = Died or moribund sacrifice; 1 = Scheduled sacrifice TR Group 1 = Control; 2 1.5 mg/kg/day RDX 157 TWENTY FOUR MONTH CHRONIC TOXICITY/CAACINOGENICITY STUDY OF HEXAHYDRO-1,3,5-TRINITRO-1,3,5-TRIAZINE(RDX) L6121-7 IN THE B6 C3 F1 MOUSE SURVIVAL RATE DATA A N I M T R A L G N R 0 E D A V E T N E T P S E X 165 166 2 2 M M 08/14/82 02/07/83 0 1 167 168 169 170 171 172 173 2 2 2 2 2 2 2 M M I M M M M 174 01/17/83 02/09/82 02/17/82 02/07/83 02/07/83 02/07/83 01/13/83 2 0 1 0 1 1 1 0 M 12/03/82 0 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 M M V M M M M M M I M M I M 02/10/82 12/301/82 12/17/82 09/06/82 02/07/83 02/07/83 12/02/82 02/07/83 08/08/82 02/07/83 09/28/82 n 09/30/82 02/07/83 02/07/83 02/07/83 02/07/83 02/10/82 07/27/82 06/19/81 10/05/81 195 2 M 02/09/82 196 197 198 199 200 202 202 203 204 2 2 2 2 2 24 2 2 2 M 12/31/81 02/07/83 02/07/83 06/11/81 10/10/82 02/07/83 02/07/83 02/07/83 02/07/83 205 2 F02/07/83 0 U M F M M M M M M M M 0 0 0 1 0 1 0 1 0 C i 1 1 1 1 0 0 0 1 0 1 0 0 2 2 2. 2- Event code is: 0 = Died or moribund sacrifice; I = Scheduled sacrifice 158 2 = 1.5 mg/kg/day RDX TR Group 1 = Control; j 0 j ... ..... 7 TWENTY FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITY STUDY OF HEXAHYDRO-1,3,5-TRINITRO-1,3,5-TRIAZINE(RDX) IN THE BC3F, MOUSE SURVIVAL RATE DATA L6121-7 A V N I M A L T R G R D E V N O 0 U S E A T E N * 206 207 208 P 2 2 2 X M M M E 02/07/83 02/07/83 02/07/83 T 1 1 1 209 210 2)1 212 2 2 2 M M M VM 02,'11/82 02/07/83 02/07/83 01/21/83 1 1 1 0 213 2 M 02/10/82 1 214 215 216 217 218 219 2 2 2 2 2 2 M V M V M H 01/23/83 02/07/83 02/11/82 02/07/83 02/11/62 02/07/83 0 1 1 1 1 1 220 2M 02/07/83 1 221 222 223 224 225 226 2 2 V F 03/22/82 02/07/83 02/07/83 10/29/82 02/07/83 02/26/82 0 1 1 0 1 0 227 228 Z 2 F F 1/82 1/2 02/07/83 229 230 2 2 F F 02/07/83 02/07/83 1 1 V M HM 2H 231 F 02/07/83 232 233 1 2 2 F F 11/30/82 06/04/82 0 0 234 2 F 02/07/83 1 235 236 237 238 239 240 241 242 243 244 245 246 2 F F F F F F F F F F F F 02/09/82 11/16/82 02/07/83 11/15/82 02/10/82 12/01/82 02/10/82 01/21/83 02/07/83 02/07/83 02/07/83 01/13/83 1 0 1 0 1 0 i 0 1 1 2 2 2 2 2 2 2 2 0 Event code is: 0 = Died or moribund sac-ifice; 1 = Scheduled sacrifice TR Group 1 AA = Control; 2 = 1.5 mg/kg/day RDX 159 L6121-7 TWENTY FOUR-MONTH CHRONIC TOXICITY/CARCINOGENLCITY STUDY OF L HEXAHYDRO-1,3,5-TRINITRO-1,3,5--TRIAZINE(RDX) IN THE B6 CF, MOUSE SURVIVAL RATE DATA A Nw I T M A R L N O G R 0 U * P S ET x 247 248 249 2 2 2 250 251 252 253 254 D A E V E N E T F F F 02/07/83 02/07/83 02/07/83 1 1 1 2 2 2 2 2 F F F F F 02/07/83 12/27/82 02/07/83 05/07/82 11/23/82 255 256 2 2 F F 02/10/82 02/n7/83 1 0 1 0 0 1 257 258 259 2 2 2 F F F 02/C7/83 02/07/83 02/22/82 1 1 1 260 261 262 2 2 2 F F F 02/07/83 02/07/83 02/02/83 1 1 0 263 264 265 2 2 2 02/07/83 02/07/83 02/07/83 1 1 1 266 267 2 2 F F F F 268 I F 02/07/83 02/07/83 2 F 02/07/83 1 1 269 2 F 09/21/81 0 270 271 272 273 274 2 2 2 2 2 F F F F 02/07/83 02/09/82 02/07/83 02/07/83 02/07/83 2 1 1 1 1 275 2 F 12/16/81 0 276 277 278 279 280 281 282 283 284 285 286 287 2 2 2 2 2 2 2 2 2 2 2 2 F F F F F F 02/07/83 02/07/83 02/07/83 02/07/83 12/27/82 02/07/83 11/11/82 02/07/83 02/07/83 02/01/83 02/07/83 02/07/83 ! 1 1 J 0 1 0 1 1 0 1 1 F F Event code is: 0 = Died or moribund sacrifice; 1 = Scheduled sacrifice TR Group I = Control; 2 = 1.5 mg/kg/day RDX 160 0 L6121-7 [ TWENTY FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITY STUDY OF HEXAHYDRO-1,3,5-TRINITRO-1,3,5-TRIAZINE(RDX) IN THE BCF, MOUSE SURVIVAL RATE DATA A N I M A L T R N G R 0 O . E S D A L U E T N P X E T 288 289 290 291 292 293 294 295 296 297 2 2 2 2 2 2 2 2 2 2 F F F F F F F F F F 02/11/82 02/07/83 01/11/83 02/07/83" 02/07/83 02/07/83 12/15/82 02/09/82 12/03/82 02/07/83 1 1 0 1 1 1 0 1 0 ! 298 2 F 02/11/82 1 299 300 301 302 303 304 305 306 307 308 309 310 311 312 2 2 F F VM M M M M M M M M M VM VM 11/06/82 02/07/83 02/07/83 01/25/83 02/07/83 12/27/82 02/10/82 02/07/83 02/07/83 12/27/82 02/11/82 02/05/83 06/14/82 02/07/83 0 i 1 C 1 0 i 1 1 0 i 0 0 M 02/07/83 02/07/83 01/06/82 07/20/82 01/14/83 02/07/83 02/07/83 08/06/81 12/01/82 02/07/83 12/25/82 08/24/82 02/07/83 02/11/82 02/07/83 07/25/82 1 1 0 0 0 J. 1 . 0 1 0 0 1 1 1 0 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 3 3 3 3 3 M M M 3 q 3 3 3 3 3 3 3 3 M M MV M I M Xi M VM 1 Event code is: 0 = Died or moribund sacrifice; 1 = Scheduled sacrifice TR Group 1 = Control; 2 = 1.5 mg/kg/day RDX; 3 = 7.0 mg/kg/day RDX 161 L6121-7 TWENTY FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITY STUDY OF HEXAHYDRO-1,3,5-TRINITRO-2..3,5-TRIAZINE(RDX) IN THE BCF, MOUSE SURVIVAL RATE DATA A N I M A L T R E V E N T N 0 . G R 0 U P S E X 329 330 331 332 333 334 335 336 3 3 3 3 3 3 3 3 M M M M M M M M 02/07/83 02/07/83 02/07/83 02/07/83 02/07/83 02/11/82 02/07/83 02/07/83 2. 1 1 1 1 1 1 1 337 338 339 340 341 342 A43 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 3 3 1 M M M M M M M M M 02/09/82 02/07/83 07/06/81 08/06/82 02/07/83 02/07/83 02/07/83 06/29/82 02/07/83 02/07/83 02/07/83 02/07/83 02/07/83 02/07/83 02/07/83 01/17/83 02/07/83 02/1G/82 02/09/82 02/07/83 02/10/52 02/07/83 02/07/83 11/29/82 02/07/83 02/09/82 10/08/82 10/18/82 02/07/83 01/03/83 02/07/83 12/04'/82 12/12/82 1 J 0 0 1 . 1 0 1 1 1 3 3 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 M M VM M M M M M M M M M M M M M M M M M VM M M D A T E 1 1 0 1 1 1 1 1 1 0 1 i 0 0 0 1 0 0 Event code is: 0 = Dieu or moribund sacrifice; 1 = Scheduled sacrifice TR Group I = Control; 2 = 1.5 mg/kg/day RDX; 3 = 7.0 mg/kg/day RDX 162 ! 4 L6121-7 TWENTY FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITY [ HEXAHYDRO-1,3,5-TRINITRO-I,3,5-TRikZINE(RDX) SURVIVAL RATE DATA A N I STUDY OF IN THE BCF, MOUSE T R M A L N 0 •P G R 0 U SE x D A T V E N E T 370 3 M 12/15/82 0 371 372 3 3 M M 02/07/83 09/14/81 1 0 373 374 375 3 3 3 M M M 02/10/82 02/07/83 02/07/83 1 1 1 376 3 F 01/18/83 377 3 F 0 02/07/83 1 378 379 380 381 3 3 3 3 F F F F 02/07/83 02/07/83 06/07/82 12/30/82 1 1 0 0 382 3 F 02/07/83 1 383 384 3 3 F F 02/07/83 02/07/83 F F 02/07/83 10/26/82 1 1 1 0 385 386 387 3 3 3 F 02/07/831 388 3 F 02/07/83 1 3890 3 F 02/10/82 1 F 02/07/83 2 390 391 3 F 02/07/83 1 392 393 3 3 F F 01/28/83 01/10/83 0 0 F 02/07/83 1 3941 395 396 397 398 398 400 401 3 3 3 3 3 3 3 402 3 F 02/07/83 1 403 404 405 3 3 3 3 3 3 3 3 3 F F F 09/15/82 02/07/83 02/07/83 002/07/83 02/07/83 02/10/P2 11/28,'82 02/07/83 0 A, 407 408 409 4e0 F F F F F F F F F F 02/07/83 02/09/82 02/07/83 02/07/331 02/10/82 02/07/83 02/07/83 1 1 1 1 1 1 1 1 0 Event code is: 0 = Died or moribund sacrifice; 1 = Scheduled sacrifice TR Group 1 Control; 2 = 1.5 mg/kg/day RDX; 3 = 7.0 mg/kg/day RDX 163 -K z TWENTY FOUR MONTH CHRONIC TOXICITY/CARCIYOC;ENICITY STUDY OF HEXAHYDRO-1,3,5-TRINITRO-l,3,5-TRIAZINE(RDX) IN THE BCF, MOUSE SURVIVAL RATE DATA L6121-7 L2 A A N I M A L I T R G R 0 U N o SP 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 426 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 3 3 3 3 3 3 3 3 3F 3 3 D A T E S E X F F F F F F F F 3 3 3 3 3 3 F F F F F F F F F F F F F F F F F F F F F F F F F F F F F F 12/19/82 02/07/83 12/03/82 02/07/83 02/07/83 02/07/83 02/04/83 02/07/83 02/11/82 02/07/83 02/07/83 02/07/83 02/07/83 02/11/82 02/07/83 02/07/83 02/07/83 02/07/83 0K/07/83 11/08/82 02/07/83 02/07/83 02/07/83 02/07/83 02/07/83 02/07/83 09/02/81 02/09/82 02/C7/83 02/11/82 02/11/82 02/07/83 02/01/83 02/07/83 02/09/82 02/07/83 02/07/83 02/07/83 02/07/83 450 3 F 02/07/83 451 4 M 12/19/82 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 Event code is: 0 = Died or moribund sacrifice; 164 E V E N T 0 1 0 1 1 1 0 1 1 1 1 1 1 1 1 1 1 1 1 0 1 1 1 1 1 i 1 1 . 0 1 1 1 ! 1 0 I = Scheduled sacrifice TR Group I = Control; 2 = 1.5 mg/kg/day RDX; 3 = 7.0 mg/kg/day; 4 = 35.0 mg/kg/day RDX R 1 TWENTY FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITY STUDY OF IN THE BCF, MOUSE HEXAHYDRQ-1,3,5-TRINITRO-1,3,5-TRIAZINE(RDX) SURVIVAL RATE DATA A N I M A L N 0 * T R G R 0 U P S E X D A T E E V E N T M M m M M M M m M M M 02/07/83 02/10/82 02/07/83 02/09/82 02/07/83 02/07/83 02/07/83 02/07/83 02/07/83 02/07/83 02/11/82 1 1 1 1 1 1 1 i 1 1 I M 10/27/82 - M M M M M M Y M lv M M 02/07/83 02/09/82 02/07/83 02/07/83 02/07/83 02/07/83 2 1 1 i 1 2 08/03/1 0 1/1.5/82 10/21/82 02/07/83 0 0 M 02/07/83 1 475 lV. 02/07/83 12 476 m 02/07/83 i 477 472 4790 480 4 MH H 4 M 10/20/82 04/21/82 02/11/62 02/07/83 0 0 i 1 4 4 M H 02/07/83 05/27/82 02/07/83 ! 0 i 4 4 4 4 M V y 02/07/83 02/02/83 02/07/83 0 1 M 02/07/83 mv V. 11/16/82 01/22/83 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 470 472. 472 473 4 474 4 4821 482 483 484 485 486 487 488 489 490 492. 492 4 4 4H02/07/83 4 4 . M 122"7/82 2248 Event code is: 0 = Died or moribund sacrifice; 1 = Scheduled sacrifice TR Group 1 = Control; 2 = 1.5 mg/kg/day RDX; 3 = 7.0 mg/kg/day RDX; 4 = 35.0 mg/kg/day RDX 1 0 0 0 0 165 TWENTY FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITY STUDY OF HEXAHYDRO-1,3,5-TRINITRO-1,3,5-TRIAZINE(RDX) IN THE BCF, MOUSE SURVIVAL RATE DATA L6121-7 A N j M A L T R G E R N 0 0 U P S E X 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 4 4 4 4 4 4 4 4 4 4 4 4 4 4 M M M m M M M M M M M M 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 528 529 530 531 532 533 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 44 4 4 4 4 D V A T E E N T 1 M M M M F 02/09/82 12/24/82 02/07/83 02/10/82 12/29/82 03/04/82 11/09/82 02/07/83 12/27/82 01/26/82 10/01/82 09/13/82 02/07/83 02/07/83 02/11/82 06/11/82 02/07/83 11/28/82 02/07/83 02/11/82 08/06/81 02/07/83 02/07/83 02/07/83 02/10/82 02/07/83 02/07/83 02/07/83 11/09/81 12/17/81 05/20/82 01/30/83 08/24/81 09/26/82 F F 02/07/83 02/07/83 2 ! F F F F 02/07/83 02/07/83 02/07/93 02/10/82 1 1 M M M M M M M M M M M M m M M M M M FF 02/07/83 02/07/83 0 2 1 0 0 0 1 0 0 0 0 1 1 1 0 1 0 1 1 2 1 1 2 1 1 1 0 0 0 0 0 0 2 2 Event code is: 0 = Died or moribund sacrifice; 1 = Scheduled sacrifice TR Group 1 = Control; 2 = 1.5 mg/kg/day RDX; 3 166 4 = 35.0 mg/kg/day RDX = 7.0 mg/kg/day RDX; K I L6121-7 TWENTY FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITY STUDY OF HEXAHYDRO-1,3,5-TRINITRO-1,3,5-TR-IAZINE(RDX) IN THE B4 CF, MOUSE SURVIVAL RATE DATA A N I M A L " T R G R 0 U P S E X 534 4 F 02/07/83 1 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 4 4 4 4 4 4 4 4 4 4 4 4 4 F F F F F F F F F F F F F F F 0 0 1 1 1 1 1 0 ! 1 0 0 0 1 1 0 1 0 1 1 0 566 F F F F F F F F F F F F F F F 4 12/29/82 07/02/82 02/07/83 02/11/82 02/07/83 02/07/83 02/07/83 01/18/83 02/07/83 02/07/83 01/01/83 12/27/82 12/21/82 02/07/83 02/07/83 10/16/82 02/11/82 10/07/82 02/07/83 02/07/83 11/15/82 02/11/82 02/07/83 02/07/83 07/06/82 02/07/83 09/17/82 02/07/83 02/09/82 02/07/83 02/09/82 F 08/12/82 0 4 4 4 4 4 4 4 4 F F F F F F F F 02/07/83 02/07/83 02/07/83 02/07/83 02/03/83 02/07/83 01/25/83 02/07/83 N 0 * 567 568 569 570 571 572 573 574 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 D A T E Event code is: 0 = Died or moribund sacrifice; 1 = Scheduled sacrifice TR Group 1 = Control; 2 = 1.5 mg/kg/day RDX; 3 = 7.0 mg/kg/day RDX; 4= 35.0 mg/kg/day RDX E V E N T , 1 ! 0 1 0 ! 1 1 1 1 1 0 i 167 L6121-7 TWENTY FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITY STUDY OF HEXAHYDRO-1,3,5-TRINITRO-1,3,5-TRIAZINE(RDX) IN THE BC 3 F, MOUSE SURVIVAL RATE DATA A N I M A L N G R D E V 0 S A T N P 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 X E T 593 594 595 575 0 U E E F 02/07/83 1 F F F F F F F F F F F F F F F F 01/20/83 04/16/82 02/07/83 02/07/83 02/07/83 02/07/83 02/07/83 02/07/83 02/09/82 02/07/83 02/07/83 02/09/82 02/10/82 11/12/82 02/07/83 02/07/83 0 0 1 0 1 1 1 1 1 1 I 1 1 0 596 4 4 44 F F FF 11/21/82 02/07/83 02/07/83 02/07/83 0 1 !1 597 598 599 4 44 F FF 02/07/83 02/07/83 02/07/83 1 2 1 600 4F 01/05/82 0 M M 04/19/82 02/09/82 02/26/81 02/07/83 04/15/81 0 1 C ! C M M M M M M M M M M 02/09/82 12/10/82 03/03/81 03/03/81 0:,/07/83 03/11/81 02/07/83 03/12/81 03/12/81 03/11/81 1 0 0 0 i 0 1 0 C 0 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 592 592 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 168 T R 4 5 5V 5 5 5 5 5 5 5 5 5 5 5 5 F M M 02/10/82 a 1 1 Event code1 =is:Control; 0 = Died2 or moribund sacrifice; 1 =Scheduled sacrifice TR Group = 1.5 mg/kg/day RDX; 3 = 7.0 mg/kg/day RDX; 4 = 35.0 mg/kg/day RDX; 5 = 175/100 mg/kg/day RDX L6121-7 STUDY OF TWENTY FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITY IHEXAHYDRO-I,3,5-TRINITRO-I,3,5-TRIAZINE(RDX) IN THE BC 3 F, MOUSE SURVIVAL RATE DATA IS A N I M L A T R G R N 0 0 U . 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 D D E V S E A T E N P X E T 5 5 5 5 5 5 5 5 5M 5 5 M M M M M M M M : 5 5 5 5 5 5 635 636 637 638 639 640 64-642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 5 5 5 5 5 5 5N 5 59 5 5 5 5 5 5 5 5 N M M Mi M M M M M N Vi Vi M N M M M N N N N V N M V V yi N V 02/10/82 03/02/81 02/07/83 02/15/82 02/27/81 02/09/82 10/10/81 02/10/82 03/08/81 02/07/83 03/13/81 1 0 1 0 0 1 0 1 0 1 0 08/04/81 02/07/83 02/07/83 07/22/82 04/02/82 02/07/83 1 1 03/12/81 0 04/17/81 09/10/81 0 0 10/29/82 0 02/21/82 02/07/83 02/07/83 03/04/81 02/07/83 06/06/82 08/05/82 04/14/81 04/01/81 02/07/83 08/04/81 04/14/81 03/11/81 02/07/83 02/07/83 02/07/83 02/07/63 02/07/83 10/27/82 . 1 1 0 i 0 1 0 0 1 1 0 0 1 2 1 1 i 0 02/09/82 Event code is: 0 = Died or moribund sacrifice; 1 = Scheduled sacrifice TR Group 1 = Control; 2 = 1.5 mg/kg/day RDX; 3 = 7.0 mg/kg/day RDX; 4 = 35.0 mg/kg/day RDX; 5 = 175/100 mg/kg/day RDX '3 0 0 1 169 _ [ L6121-7 TWENTY FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITY STUDY OF HEXAHYDRO-1,3,5-TRINITRO-1,3,5-TRIAZINE(RDX) IN THE BC 3 F, MOUSE SURVIVAL RATE DATA "A N I M A L G R D E V A T E E N T N O 0 U P S E X 657 5 M 02/10/82 1 658 659 660 661 662 663 664 665 5 5 5 5 5 5 5 5 5 5 5 5 M M M M M M M M M M M M M 03/16/81 02/07/83 02/07/83 04/15/81 02/07/83 09/16/81 04/11/81 03/12/81 08/06/81 09/15/81 02/11/82 08/04/81 08/04/81 02/11/82 0 1 1 0 1 0 0 0 1 0 1 1 1 1 5 5 5 5 5 5 55 M 04/20/81 0 681 682 683 684 685 686 687 688 689 690 691 692 693 693 695 696 5 5 5 5 5 5 5 5 5 5 55 5 5 5 F F F F F F F F F F F FF F F F 11/30/82 02/07/83 02/07/83 02/07/83 03/02/81 08/05/81 02/28/81 04/06/81 02/07/83 08/16/82 02/07/83 02/07/83 02/07/83 02/07/83 02/25/81 02/22/81 0 1 1 1 0 i 0 0 1 0 1 11 1 0 0 697 5 F 03/01/81 0 667 668 669 670 671 672 673 674 675 676 677 678 679 680 170 T R 502/28/81 M M M M F F FF 02/07/83 02/24/81 02/07/83 02/07/83 04/01/81 02/07/83 02/24/81 1 0 1 1 0 1 0 0 Event code is: 0 = Died or moribund sacrifice; 1 = Scheduled sacrifice TR Group 1 = Control; 2 = 1.5 mg/kg/day RDX; 3 = 7.0 mg/kg/day RDX; 4 = 35.0 mg/kg/day RDX; 5 ui 175/100 mg/kg/day RDX X k L6121-7 TWENTY FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITY STUDY OF L HEXAHYDRO-1,3,5-TRINITRO-I,3,5-TRIAZINE(RDX) IN THE BCF, MOUSE SURVIVAL RATE DATA I A N I M A L N 0 * T R G F 0 U P S E X D A T E E V E N T ------------------------------------------------------------------------------0 02/27/81 F 5 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 7215 722 723 724 725 726 727 728 729 730 731 732 733 734 27.5 5 5 5 5 5 5 736 737 738 F F F F F F F F F F F F F F F F 02/07/83 02/07/83 01/14/83 02/10/82 03/03/81 08/06/81 02/07/83 02/07/83 04/01/81 08/05/81 02/28/81 02/25/81 02/10/82 04/16'/81 03/31/81 02/10/82 02/09/82 02/24/81 02/09/82 04/15/81 02/10/82 04/01/81 02/19/81 02/24/81 02/07/83 03/04/81 02/07/83 04/05/82 04/19/81 02/25/81 04/03/81 02/07/83 02/07/83 02/07/83 02/07/83 02/07/83 02/11/82 5 F 02/24/81 0 5 5 F F 11/21/82 02/24/81 0 0 5 F F F F F F F F F F F 5 5 5 a 5 5 5 5F 5 5 5 5 5 5 5 5 5 5 5 F F F F F F F F F Event code is: 0 =Died or moribund sacrifice; 1 = Scheduled sacrifice TR Group 1 = Control; 2 = 1.5 mg/kg/day RDX; 3 = 7.0 mg/kg/day RDX; 4 = 35.0 mg/kg/day RDX; 5 = 175/100 mg/kg/day RDX 1 1 0 1 0 1 1 1 0 1 0 0 1 0 0 1 1 0 1 0 1 0 0 0 1 0 1 0 0 0 0 1 1 1 1 1 171 4 L6121-7 TWENTY FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITY STUDY OF HEXAHYDRO-1,3,5-TRINITRO-1,3,5-TRIAZINE(RDX) IN THE BC 3 F, MOUSE SURVIVAL RATE DATA A N I M A L I 172 S G R D E V A T E E N T N 0 0 U P S E X 739 740 741 5 5 5 F F F 02/07/83 02/07/83 02/11/82 1 1 1 742 743 5 5 F F 02/11/82 02/07/83 1 1 744 745 746 5 5 5 F F F 08/06/81 02/25/81 02/24/81 1 0 0 747 748 749 750 751 752 753 754 755 756 757 758 7590 760 761 5 5 5 5 1 1 1 1 1 1 1 1 01/28'/83 02/07/83 02/24/81 02/09/82 08/05/81 08/05/81 08/04/81 08/06/81 08/05/81 08/04/81 08/04/81 08/06/81 08/04/81 08/06/81 08/06/81 0 1 0 1 1 1 1 1 1 1 1 1 F F F F M M M M M M M M M M F 762 1 F 08/06/81 1 763 764 765 766 767 768 769 770 771 772 773 1 1 F F F F F F F F M M M 08/04/81 08/05/81 08/05/81 08/06/81 08/05/81 08/06/81 08/05/81 08/04/81 08/05/81 08/05/81 08/06/81 1 1 . 1 1 1 1 1 1 1 1 775 776 777 778 779 2 2 2 2 2 M M M 08/06/81 08/06/81 08/04/81 08/04/81 08/05/81 1 1 774 [ T R 1 1 1 1 1 2 2 2 2 M V M 08/04/81 1 1 1 1 1 Event code is: 0 = Died or moribund sacrifice; 1 = Scheduled sacrifice TR Group 1 = Control; 2 1.5 mg/kg/day RDX; 3 = 7.0 mg/kg/day RDX; 4 = 35.0 mg/kg/day RDX; 5 = 175/100 mg/kg/day RDX L6121-7 TWENTY FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITY HEXAHYDRO-1,3,5-TRINITRO-1,3,5-TRIAZINE(RDX) STUDY OF IN THE B , CF, MOUSE SURVIVAL RATE DATA A N I T R L G R M A D E V N 0 S A E o U E T N * P X E T 780 781 782 783 2 2 2 2 M F F F 08/06/81 08/06/81 08/05/81 08/04/81 1 1 1 1 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 F F F F F F F M M M M M 1 1 1 1 1 1 1 i 1 i 0 1 M M V V, F F F 08/04/81 08/06/81 08/04/81 08/04/81 08/05/81 08/05/81 08/06/81 08/04/81 08/04/81 08/06/81 08/03/81 08/05/81 08/06/81 08/05/81 08/04/81 08/05/81 08/05/81 08/05/81 08/04/81 08/05/81 804 805 3 3 F F 08/06/81 08/04/81 1 3 806 807 808 809 3 3 3 3 F F F F 08/05/81 08/06/81 08/06/81 08/05/81 1 1 1 1 810 3 F 08/06/81 1 811 812 813 814 815 4 4 4 4 4 V M 1 i V M 08/04/81 08/04/81 08/05/81 08/06/81 08/06/81 8i• 4 M 0I/05/81 1 817 818 819 820 4 4 4 4 M V VM l, 07/13/81 08/05/81 08/04/81 08/04/81 0 M M 1 1 1 1 1 1 1 4 ! 1 1 Event code is: 0 = Died or moribund sacrifice; 1 = Scheduled sacrifice TR Group = Control; 2 = 1.5 mg/kg/day RDX; 3 = 7.0 mg/kg/day RDX; 4.= 35.0 mg/kg/day RDX; 5 _4 = 175/100 mg/kg/day RDX 'w106Z *VW~~qýý 173 STUDY OF TWENTY FOUR MONTH CHRONIC TOXICITY/CARCINOGENICITY HEXAHYDRO-1,3,5-TRINITRO-1,3,5-TRIAZINE(RDX) IN THE BCF, MOUSE SURVIVAL RATE DATA L6121-7 --------------------------------------------------------------------------------- A N I M A L N 0 . 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 T R G R 0 U P ------------------------------------ 4 4 4 4 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 S E D A T X E F F F F F F F F F F M M M M M M M M M M F F F F F F F F F F 08/06/81 08/04/81 08/06/81 08/06/81 08/05/81 08/05/81 08/05/81 08/04/81 08/06/81 C0/04/81 01/02/81 04/17/81 04/14/81 08/04/81 03/04/81 08/04/81 08/05/81 08/04/81 08/04/81 08/06/81 08/05/81 02/17/81 02/28/81 08/06/81 04/16/81 08/06/81 03/31/81 08/05/81 02/20/81 02/19/81 E V E N -- T ----------- 1 1 1 1 1 1 1 1 1 1 0 0 0 1 0 1 1 1 1 1 1 0 0 1 0 1 0 1 0 0 I 174 Died or moribund sacrifice; 1 = Scheduled sacrifice Event code is: 0 TF Group 1 Control; 2 = 1.5 mg/kg/day RDX; 3 = 7.0 mg/kg/day RDX; 4 = 35.0 mg/kg/day RDX; 5 = 175/100 mg/kg/day RDX t I , .. . . . . . . . , . . . . . .. . . . . . . . . . . . . . . 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'00000 a .. .. ... . .N 00CO0000000006000*000000000 Ln LiI ýc,- w-I < N C.CNC .ý ,0c-000cO0000000006000000600000000 c* o~o z~ ix~ mA > U0 0 c iD m,- n. m- a, N is o~ w IDWIDIZD D~ Ir D U) IZ I- 338co-00CO000000000 cr o' ~ mj 00ir, c, o L) w m qm0 1.--LDIDI I r-;. n. k-k-k-k-k-M-IC -k- . .a?m??wa??wx fauwhxa?f? gnu; Aymara: ggd? gij?Mam-m? ?aim Noam no hasul?h?lk aLClum?llml aha-Li?nl?rm NEE nmngagga gags; 1ý WAt CHLORTETRACYCLINE CONTENT OF 5002 ANALYTICAL RESULTS (ppm) SAMPLE IDENTIFICATION SOURCE OF ANALYSIS A TEI ANALYTICAL, INC.* TEX ANALYTICAL, INC.* HARRIS LABS, Sample Sample Sample Sample * A B C D 12 Lot Lot Lot Lot D INC** No. No. No. No. 9.9 7.7 1.72 1.20 1.64 ND ND) ND ND <0.05 <0.05 <0.05 <0.05 1.76 INC.** = - C 9.9 SCIENTIFIC ASSOCIATES** WOODSEN-TENENT LABS, B 10.2 Sept.18.81 Dec.10.81 March.24.82 (Original lot) Sept.10.82 Method: Snell and Snell, Vol IV AAA, pg. 184 Colorimetric method of analysis. **Method: AOAC, XIII, pg. 722-723, Detection limit >0.1 ppm paragraph 42.211-42.214; ND = None Detected Note: The manufacturer's specification states absence of antibiotics and hormones in the "certified feed". 340 APPENDIX VIII NITRATE, NITRITE AND MERCURY CONTENT OF 5002 PERFORMED BY TRACE ELEMENTS, INC. 341 NITRATE, LOT NUMDER OCT 29--AC ;N NOV 19-802K DEC 02-801G JAN 08-811J JAN 15-812E FEB 03-811B JAN 21-811N MARCH 05-811A MARCH 17-811M APRIL 30-811D MAY 13-812K JUNE 01-812D AUG 04-811T SEPT 18-811A OCT 07-811J NOV 12-811G DEC 10-811A JAN 22-821K FEB 09-821C MARCH 24-822G MAY 12-822F JUNE 04-821K JULY 29-821G SEPT 10-822J OCT 20-822L NOV 23-821M 342 NITRITE, AND NERCURY CONTENT OF 5002 NiITRATES(ug/g) 5.6 3.4 1.1 14 32 9.2 32 13 <3 <3 15.3 <2.0 28 <2.0 6.3 16 12 14 7.2 19.0 16.4 17.0 11.8 5.0 4.7 15.4 NITRITES(ug/g) 0.4 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 0.3 0.2 0.6 O.r. <0.1 0.2 0.4 <0.2 <0.2 0.4 0.24 0.1 0.1 0.1 0.1 0.1 0.2 MERCURY(ug/g) 0.06 0.05 0.04 0.04 0.02 0.04 0.11 0.14 0.02 0.0O <0.06 <0.1 0.03 0.05 0.15 <0.02 0.09 <0.05 0.05 <0.05 <0.05 <0.05 0.06 0.2 0.2 0.05 - 31" (PI-mewmu? m' ZM?nL-?cw man uxmmwamjm ?31? or? ,5 ?1 APPENDIX 1X CHICAGO WATER CHEMICAL ANALYSIS 3153 ZVMTAV. TAMAMA in~ I.- 1z an : v 0 v .0 2 cc' bi I- w IL IL~ rw a soo 10 C5 C;V' 0; C 19 n - 00w Ut- *U fL wI I W~~3 m ZcnCS vzx V;!2Zv 0- goI-A 00 'a., o w 1 w 1-04I F ! 344L w CP Žc-~zy~ ~~~' ?lly-inwuiw?wf?tl asg-15nu?gL div. .7: 11:13.: r1454 1dEuwmzc; ?gkg?gf?x ?amerw. 1.- .110REVISION TO THE FINAL OPHTHALMOLOGY REPORT of Twenty-Four Month Chronic Toxicity-Carcinogenicity Study of Hexahydro-1,3,5-Trinitro-1,3,5-Triazine (RDX) in B6C3F1 Hybrid Mice A reanalysis of incidences of cataracts was carried out at the Animals that were suggestion of the draft final report reviewers. used for orbital blood collection were eliminated from the statistical As a result of it the significant increase of cataracts for analysis. (See male mice receiving 175/100 mg/kg/day was no longer apperent. Table 31 and 31a.) 346 STUDY NUMBER: L6121-7 TEST ARTICLE: RDX SPECIES: MOUSE KEY NOTE: Animals used for orbital bleeding were indicated on the ophthalmic incidence data sheets by the letters 1'L'' or "1R"1 when it was known which eye was used for orbital sinus bleeding. The letter "U" indicated that the animals were either bled from both eyes or the eye used was not known. SUMMARY OF OPHTHALMIC FINDINGS Ocular conjunctivitis, discharge, and corneal scarring were observed in all test groups throughout the study and probably were a resuit of chronic external irritation from normal sources. Throughout the study, a number of animals which were bled from the orbital sinus demonstrated cataracts, phthisis, enophthalmia, iritis, synechia, iris prolapse, and retinal vascular attenuation. Ocular trauma or penetration could have been responsible for the aforementioned abnormalities. Prominent lens nuclei (nuclear sclerosis) and suture lines, vitreal strands, and vitreal precipitates on the posterior lens capsule (posterior capsular opacities/ cataracts - "PC") are normal aging changes that were observed in all groups, especially at Test Week 103. At Test Week 25, one animal (601) was observed to have vitreal hemorrhage present, which was resolved by Test Week 51. At Test Week 78, findings of note were orbital masses (U387, 403) and dilated retinal vessels (#504, 566). At Test Week 103, there was an overall increased incidence in cataracts observed. Many of these cataracts were associated with aging and vitreal precipitates adhering to the posterior lens capsule. A statistically significant increase in the incidence of cataracts was seen for 175/100 mg/kg/day males but not for the females, although a dose response relationship was not apparent. At Test Week 103, it was not possible to dilate the pupils of one animal with miosis (#55) in order to evaluate the deep structures of the eyes. The orbital mass in animal #387 was still observed. With the possible exception of cataracts, all of the aforementioned observations occurred randomly with respect to control and treatment groups, and were not considered to be treatment-related. C. Sue West, D.V.M. Diplomate, American College of Veterinary Ophthalmologists Date 2vp~ 347 0 0 tit 0 o 0 - v 0 0 0 N (1 C ' 0 -. 0 0' N Cl 01 o. 0 0 0 to 0 m E 348 i -. Z zl' W~~ '-v V~( Cv 0 S.l(2 1 CL L w uc 4 C 0) C I OP 0' ELIE ±100 0 0 0 I 0 0 0 v 0 0. 0 0 0 N1 to 0 0.. 0 0 o. 0 W 0 M . NN In. r0' w w u 3d z I.- U) N 0 6 4' N ON N ON ON 00 4IL N - NO N N N 00 0~~ 0ri M 0 rd 0 M 0 0 0 NN W0 tC a 4b4 0 0 00 0 000 - 0 - 0 i') m4 000 C') r) o o 000 00 C" 0 m) In r) r) pi r) h) r, ) I o o 0 0o 0 '0 0 4) 0 0 .0~ .0 ~n .0z 0 0 0 0 0 0 0 0 0 -0 - 0 0i 3 4) Q C) Q U') 0 C) 4 In . 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'•• •4L•• " ' " •• • X., ••• • • J. ,-4•j•,• • rr.r -. , ••J, ,i, • . •P , •• • .• • ,,, ..• • •, • • -• • -••• -- Ll Ema-3mm 1n I 37*" 5 4v *l 93:; w- an .m?z-me- M. it APPENDIX x: i PATHOLOGY NARRATIVE REPORT z. ?5 32? .. .. ?aws. .913.? W7 1.2.21? .1 1 353 TWIQWKAW h1VISIONS TO THE FINAL PATHOLOGY REPORT of Twenty-Four Month Chronic Toxicity-Carcinogenicity Study of Hexahydro-1,3,5-Trinitro-1,3,5-Triazine (RDX) in B6C3F1 Hybrid Mice A reanalysis of histopatology data was carried out at the The statistical suggestion of the draft final report reviewers. significance resulted in changes of certain pathology findings. These changes are reported in the following revisions and are noted by underlining. 2. Histopathology TWENTY-FOUR MONTH TERMINAL SACRIFICE "o Microscopic examination of tissues from mice after the terminal sacrifice did not reveal stastically significant compound induced at the 35 and 175/100 mg/kg/day dose testicular---deg-neration levels (Table 44). "o The statistically significant increase of the hepatocellular carcinomas was not observed in female mice (Tables 45 and 46). "o Historical contr-?5 data from the National Toxicology Program (NTP 10) were also included in the analysis as the female rulletin No. aoncurrent control group demonstrated a low incidence of liver tumo-s. On reanalysis female mice receiving 35 mg/kg/day did not show a significant increase in hepatocarcinomas (Table 46). o The incidence of alveolar/bronchial carcinoma in male mice was not statistically significant at the 175/100 mg/kg/day level-Table 44). dose SUMMARY AND CONCLUSIONS o Microscopic examination revealed a statistically significant and adenomas increased incidence of combined hepatocellular carcinomas in female mice for 7.0, 35.0 and 175/100 mg/kg/day dose levels which was a possible carcinogenic effect of RDX in the B6C3F1 strain when treatd for twenty-four months. o In male mice testicular degeneration was considered to be induced although the by RDX at the 35 and 175/100 mg/kg/day dose levels, increased incidences were not statistically significant. o The occurence of combined alveolar-bror-hial carcinoma/adenona male mice was not statistically significant at any dose level. in However, incidences of alveolar/bronchial carcinomas for male mice receiving 175/100 mg/kg/day were increased. 354 FINAL PATHOLOGY REPORT of Twenty-four Month Chronic Toxicity-Carcinogenicity Study of Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in B6C3F1 Hybrid Mice March 25, 1984 IITRI Project Number L6121 Study Number 7 355 QUALITY ASSURANCE STATEMENT L6121 SN 7 Necropsy and histology procedures were inspected on January 1, August 4, and November 11, 1981; February 10, April 21, and November 29, 1982; and January 26, February 8, April 25 and May, 19, 1983. Draft Pathology Reports were audited January 21, May 3, and August 19 and 20, 1982; January 12 to 17, and October 6, 1983; and January 12 to 18, February 29 to March 2 and March 28 to 30, 1984. Inspections and audits were performed by Josephine M. Reed and Julie McPhilips. The study was found to meet Life Sciences Quality Assurance criteria. Specimens and raw data generated during the study will be retained in the IITRI Life Sciences Archives as specified in standard operating procedures. Josep hne M. Reed Supervisor, Quality Assurance 356 TABLE OF CONTENTS MATERIAL AND METHODS .................................................. 601 1. Gross Pathology .............................................. 601 2. Histopathology ............................................... 602 PATHOLOGY RESULTS ..................................................... 602 1. Gross Observations ........................................... 2. 3. 602 Six Month Observations ....................................... Twelve Month Observations .................................... Twenty-four Month Observations ............................... 603 603 603 Histopathology ............................................... 604 Six Month Interim Sacrifice .................................. Twelve Month Interim Sacrifice ............................... Twenty-four Month Terminal Sacrifice ......................... 604 604 604 Summary and Conclusions ............................. ........ 605 PATHOLOGY APPENDIX I: ................................................. 607 Six Month Interim Sacrifice ...................................... A Gross Pathology Table I ................................... B Histopathology Incidence Tables ........................... C Incidence Comparison Tables ............................... D Incidence of Lesions Considered to be Treatment-Related ... PATHOLOGY APPENDIX II: ................................................ Twelve Month Interim Sacrifice ................................... A Gross Pathology Table II .................................. B Histopathology Incidence Tables ........................... C Incidence Comparison Tables ............................... PATHOLOGY APPENDIX III: ............................................... Twenty-four Month Terminal Sacrifice ............................. A B C D 608 609 628 667 672 673 673 675 690 718 725 725 Gross Pathology Table III A, III B ........................ 727 Histopathology Incidence Tables ........................... 771 Incidence Comparision Tables .............................. 1153 Incidence of Lesions Considered to be Treatment-Related .. 1181 357 TAKE OF CONTENTS (Continued) PATHOLOGY APPENDIX IV: .............................................. Statistical Evaluation ......................................... 1. Statistical Evaluation of Histopathologic Lesions MALE B6C3F1 HYBRID MOUSE - Table IV ................... 2. 3. 1182 1182 1182 Statistical Evaluation of Histopathologic Lesions FEMALE B6C3F1 HYBRID MOUSE - Table V .......... 1186 Statistical Evaluation of Histopathologic Lesions MALE B6C3F1 HYBRID MOUSE (LIVER, Adenoma and Carcinoma) - Table VI ............. 1188 PATHOLOGY APPENDIX %1: Addendum - Histopathology Report - Lung Sections From 1.5, 7.0 and 35.0 mg/kg/day Dose Groups ........................ 1......................................... 1189 0 358 FINAL PATHOLOGY REPORT of Twenty-four Month Chronic Toxicity-Carcinogenicity Study of Hexahydro-1,3,5-trinitro-l,3,5-triazine (RDX) in B6C3FI Hybrid Mice MATERIAL AND METHODS In accordance with the amended experimental protocol gross and histo- pathologic examinations were performed on organs and tissues of B6C3F1 hybrid mice for IITRI Project L6121, Study Number 7. The mice were divided into five groups, each consisting of 85 males and 85 females. Four of the five groups were each treated with different doses of HEXAHYDRO-1,3,5-TRINiTRO-1,3,5-TRUAZINE (RDX) for twenty-four months. The mice of the fifth group did not receive RDX and did serve as a control group. The group number, treatment, number of mice per group, and the corresponding dcse levels are outlined below. Treatment Grouo I Treatment Number of Males -85 Numbe, of Females Dose Level mq/ko/dav 8 0.0 1.5 7.0 35.0 175.0/1.0C* i1 III RDX RDX 85 85 IV RDX 85 85 85 85 V RDX 85 8C • Due to high mortality, dose level of 175 mg/kg was reduced for both sexes to lOU mg/kg, commencing on 4/20/81 (Week 11 of the Study). In accordance with the experimental design, 10 mice per sex, per dose level were sacrificed after six months and twelve months of the study. All surviving mice were sacrificed after twenty-four months of the study. All mice were anesthetized by carbon dioxide 1. Gross Pathology inhalation and exanguinated from the orbital sinus orabominal aorta. Mice that died or were sacrificed moribund were also necropsied. At necropsy thoracic, abdominal, and cranial cavities of each mouse were opened and organs were examined and collected in buffered neutral 10% formalin. Trhe lungs were fixed by intratracheal perfusion of formalin. Eyes were fixed in 3% glutaraldehyde, testes were fixed in Bouin's solution for 24 hours, and then .laced in 700% ethanol before processing. The brain, heart, kidneys, liver, spleen, testes were weighed at necropsy before fixation except for spontaneous deaths and moribund sacrifices. 359 The fo iowin: -rssues were cc ;e:ZeC. *adrenals *brain (frontal, parietal, cerebellar) *cecum *colon costobrondial junztion, rib *duodenum *epididymes *esophagus *eye and optic nerves gall -ladder *heart *ileum *jejunum *kidneys *larynx *liver *lungs with mainstem bronchi lymph nodes: mandibular *mesenteric muscle, skeletal nasal turbina-es and any other tissues wizh *gross lesions. 2. Histopathclocv ovaries *pancreas pituitary *prostate rectum salivary gland seminal vesicles sciatic nerve *skin/mammary gland *spinal cord (cerival, thoracic, lumbar) *spleen *sternum with marrow *stomach testes thymus *thyroids/parathy;-Gid• *trachea *uterus *urinary bladder bone marrow smear *tissue masses Tissues marked with an asterisk from control and high oese level(175,/0O, mg/kg) were paraffin embedded, sectioned at 5 11, stained with hematoxylin and eosin and examined microscopically. The liver, brain, spinal cord, kidneys, heart, spleen, gonads, lungs, gross lesiins and tissue masses were exa-r nec' microscopi:ally for all remaining test mice. The grading syste. an- abbreviations used in the tables are as follows. Grade I = minimal severity Grace 2 mild severity Grade 3 = moderate severity Grade 4 = marked severity N = Within Normal Limits M = Tissue Not Present - = Tissue Not Applicable P = Lesion Present, No Grade PATHOLOGY RESULTS 1. Gross Observations A summary of gross observations is presented by group and sex for Six Month Interim Sacrifice, Pathology Appendix I Table I; Twelve Month Inr.erim Sacrifice, Pathologq Appendix II - Table Ii; and Twenty-Four Month Ter-inal Sacrifice, Pathology ApDendix III - Tables lilA Rnd iii. 360 0 SIX MONTH OBSERVAT:ONS - TABLM i There was fighting among the male mice, especially at the 175/100 mg/kg! day dosage level. This fighting induced damage to external genitalia and induced skin lesions. These lesions were considered to be only secondary to the compound administration. Crusty and dark red skin was observed at these fiahting wounds. Thirty male and 36 female mice that died durina the first six months of the study at the 175/100 mg/kg/day dose level had dark red mottled lungs, dark red spleen and dark red liver. Diszended with red, yellow and brown fluid urinary bladder was observed in 1A/39 male mice at the 175/100 mo/kg/day dose level. These lesions observed at necropsy were considered to be induced by the RDX administration. TWELVE MONTH OBSERVATIONS - TABLE Ii Mice that died or were sacrificed moribund between six and twelve monzhs and all mice that were sacrificed at twelve month interim period and were treated with RDX did not have lesions observed at necropsy in areater frequency than those observed in the control group. TWENTY-FOUR MCNTH TERMINAL SACRIFICE - TABLE TIT A, 17 B Lesions observed at necropsy in mice that died spontaneously or those sacrif iced as moribund between twelve and twenty-four months are present in Pathology Appendix IIi in Tables IIA and IIIB. Mice which were treated with RDX when compared with the control group, appear to have hiqher incidences of liver nodules or masses and enlarged livers than the control grouo. Gross observations at terminal sacrifice are presented in Table ITT B. Lesions observed at necropsy in female mice as liver nodules or masses appear to occur in higher incidences in RDX treated female mice which was probably related to the compound administration. All other lesions observed at necropsy at six month interim sac, iices, twelve month sacrifce and in mice that were sacrificed at the twenty-four month of the study and all mice that died spontaneously or were sacrificed as moribund during the study were considered to be spontaneously occurring inflammatory, degenerative and/or neoplastic lesions which are commonly observed in this s.rain of mice and were considered to be unrelated to the administration of RDX. 361 SIX MONTH INhTER: SACRDFICE Microscopic examination of tissues from mice sacrificed after six months, mice that died spontaneously or were sacrificed moribund during this study period, revealed renal tubular cytoplasmic vacuolization in male mice at all dose levels. Renal tubular cytoplasmic vacuolization was seen in one control mouse, 10 mice receiving 1.5 mg/kg!day, 12 mice receiving 7.0 mg/kg/day, 11 mice receiving 3..0 mg/1kg/day and 12 mice receiving 175/100 mg/kg/day. In this lesion, single or multiple sharply delineated cytoplasmic vacuoles were found in renal tubular epithelium. Renal tubular cytoplasmic vacuolization was considered to be compoundinduced at six month interim sacrifice but was not considered to be RDXinduced at the twelve month interim sacrifice and at the twenty-four month terinal sacrifice. There was excessive fighting in male mice causing cutaneous trauma and an increased incidence of dermatitis in male mice. Thi-: increased incidence of skin lesions is a secondary compound effect. TWELVE MONTH INTERIM SACRIFICE No compound-related microscopic lesions were observed in male and fenaie mice sacrificed after twelve months of the study, mice that died The increased spor.;an~ously nor in mice which were sacrificed moribund. incide,,Le of dermal lesions reflects compound-induced behavioral changes (fighting wounds) rather than specific effects on the skin as a target orqan. TWENTY -FOUR MONTH TEM'INAL SACRIFICE Microscopic examination of tissues from mice after the terminal sacrifice revealed statistically significant (at p< 0.05) compound-induced testicular degeneratiorn at the 35 and 1T5/100 mg/kg/day dose level (Pathology Appendix IV - Table IV). T -re was necrosis of Germinal epithelium, interstitial ficrosis and aspermia in male mice. The statistically significant increase of the heDatocellular adenoma/carcinoma was observed in female mice at the 7., 25, and 175/100 mg/kg/day dose level (Pathology Appendix IV - Tables V and V.). Chronic dermatitis observed in male mice was a compound-induced hyperesthesia and fight-induced dermal lesion. Historical control data from the National Toxicology Program (NTP Bulletin #10) were therefore included in the analyses as the female concurrent conzrol group demonstrated a low incidence of liver tumors. When this wds performed (Pathology Appendix IV - Table VI) female mice receiving 3K mg/kg/day still showed a significant increase in hepatocarcinomas, A p valu(e of = 0.09 was, however, seen for 175/100 mg/kg/day-treated females when compared to historical controls. The small number of surviving animals ir thi'. hiah dose group (3K) compared to 60-65 for the other groups may have cc~trilbuted to this statistic as the ac:ual incidence (9.7c) was greater tran t.lt seen at 35 mg/kg/day (9.4'). When combined adenoma/carcinoma data were ajtklv:ed, statistically significant increases were observed for both 3S and 175,'100 mg/kg/day females compared to either concurrent or historical cc'ýtrcl data. This was apparent even though concurrent controls had a s',niiican:'y lower incidence than historical controls. e I the: RDX is a suspect carcinoger.. 362 The data therefore ) The incidence of alveolar/bronchiolar c3rcinoma in male mice (Pathciooy Appendix IV - Table IV) was statistically significant only az the 175/200 mg/kg/day dose level. All other lesions observed microscocically in tissues from %he twenty-four month chronic toxicity/carcintcenicity s:udy of HEXAHYDRO-1,3,5TRINITRO-I,, 5-TR AZNE (RDX) were considered soontaneous, naturally oc:urirc degenerative, inflammatory and/ce' neopiastic diseases which commonly occur in an aging mouse population of the BEC3F1 strain (see References 1 and 2). SUMMARY AND CONCLUSIONS Gross lesions observed at six months of the study for the 175/100 mg/kg/day dosage level as red lungs, dark red soleen, dark red liver, distended with red fluid urinary bladder were considered to be induced by RDX. Compound-related lesions observed in kidneyvs for male mice as renal tubular cytoplasmic vacuolizaticn (Six Mcnth Interim Report) at all dosage levels was not observed in male mice at the Twelve Month nor the Twenty-four Month Histopathologic Examination a- any dosage level. Increased incidence of dermatitis in male mice was considered to be a secondary compound effect. No compound-related gross nor histopathologic lesions were observed at the Twelve Month interim Sacrifice. The increased incidence of dermal lesions during this study period reflect compound-induced behavioral changes (fighting wounds) rather than specific effects on the skin as a target organ. Lesions observed at necropsy at the terminal sacrifice for female mice as liver nodules and masses were considered to be compound-induced. Microscopic examination revealed statistically significant increased incidence of hepatocellular adenomas and carcinomas in female mice for 7.0, 35.0, and 175/100 mg/kg/day aose levels which was a carcinogenic effect of RDX in the B6C3F1 strain when treated for twenty-four months. In male mice testicular degeneration was considered to be induced by RDX at the 35 and 175/100 mg/kg/day dosage levels. The oc:urrence o0 combined alveolar-bronchial carcinoma/adenoma in male mice was statistically significant (at p < 0.05) only at the 175/100 mg/kg/day dose level. On the basis of compound-induced his.opathologic lesions observed in this study, no effect levels for RDX in B6C3F1 Hybrid Mice were 7.0 mg/kg/day for male mice and 1.5 mg/kg/day dose level for female mice. Vladislava S. Rac, D.V.M., M.S. Head, Pathology Pathology Section Life Sciences Research 363 DISTRIBUTION LIST 25 copies 4 copies Commander ATTN: SGRD-UBG U.S. Army Medical Bioengineering Research and Development Laboratory Fort Detrick, Frederick, MD 21701-5010 Commander U.S. Army Medical Research and Development Command ATTN: SGRD-RMS Fort Detrick, Frederick, MD 21701-5012 12 copies Defense Technical Information Center (DTIC) ATTN: DTIC-DDAC Cameron Station Alexandria, VA 22304-6145 1 copy Dean School of Medicine Uniformed Services University of the Health Sciences 4301 Jones Bridge Road Bethesda, MD 20814-4799 1 copy Commandant Academy of Health Sciences, U.S. Army ATTN: AHS-CDM Fort Sam Houston, TX 78234-6100 1 copy Commander U.S. Army Medical Bioengineering Research and Development Labcratory ATTN: SGRD-UBD-A/Libratian Fort Detrick, Frederick, MD 21701-5010 364