1、API TR*405 95 O732290 0558920 319 American Petroleum 11? Institute Health and Environmental Sciences Department An Inhalation Oncogenicity Study of Commercial Hexane in Rats and Mice Part Il-Mice Final Abridged Report MARCH 1995 TOXICOLOGY REPORT NUMBER 405 CAIS NO. 41-33232 - API TR*405 95 0732290
2、0558923 255 FOREWORD API PUBLICATIONS NECESSARILY ADDRESS PROBLEMS OF A GENERAL NATURE. WITH RESPECT TO PARTICULAR CIRCUMSTANCES, LOCAL, STATE, AND FEDERAL LAWS AND REGULATIONS SHOULD BE REVIEWED. API IS NOT UNDERTAKING TO MEET THE DUTIES OF EMPLOYERS, MANUFACTURERS, OR SUPPLIERS TO WARN AND PROPERL
3、Y TRAIN AND EQUIP THEIR EMPLOYEES, AND OTHERS EXPOSED, CONCERNING HEALTH AND SAFETY RISKS AND PRECAUTIONS, NOR UNDERTAKING THEIR OBLIGATIONS UNDER LOCAL, STATE, OR FEDERAL LAWS. NOTHING CONTAINED IN ANY API PUBLICATION IS TO BE CONSTRUED AS GRANTING ANY RIGHT, BY IMPLICATION OR OTHERWISE, FOR THE MA
4、NUFACTURE, SALE, OR USE OF ANY METHOD, APPARATUS, OR THING CONTAINED IN THE PUBLICATION BE CONSTRUED AS INSURING ANYONE AGAINST LIABILITY FOR INFRINGEMENT OF LETTERS PATENT. PRODUCT COVERED BY LETTERS PATENT. NEITHER SHOULD ANY- Copyright O 1995 American Petroleum institute API TRa405 95 = 0732290 0
5、558922 191 ACKNOWLEDGMENTS THE FOLLOWING PEOPLE ARE RECOGNIZED FOR THEIR CONTRI- BONS OF TIME AND EXPERTISE DURING THIS STUDY AND IN THE PREPARATION OF THIS REPORT - Richard Rhoden, Ph.D., Health and Environmental Sciences Department Wayne C. Daughtrey, Ph.D., Exxon Biomedical Sciences, Inc. Jeffrey
6、 S. Duffy, Ph.D., Texaco nc.* Daniel W. Kelly, Ph.D., Phillips Petroleum* Linda S. Haddock, Unocal Corporation Thomas S. Keenan, Ph.D., Ashiand Chemical *No longer with this organization PREFACE This publication highlights summary text and pertinent data from commercial hexane oncogenicity studies d
7、one on mice by Biodynamics, Inc. under contract to MI. This abridged document has been prepared to provide study results and to call attention to the existence and availability of this research. The Study was conducted pursuant to section 4 (a) of the Toxic Substances Control Act (TSCA) 40 Code of F
8、ederal Regulations Part 799.21551. The complete set of multi-volume reports from which this summary document has been compiled is titled, An Inhalation Oncogeniciy StucS, of Commercial Hexane in Rats and Mice, and is available for viewing by the public at the API Library, 1220 L St., Washington D.C.
9、 20005. The five parts that make up the complete study are too voluminous for distribution on a routine basis. For your convenience, the table of contents to the complete report is included as an appendix to this abridged document. American Petroleum Institute Health and Environmental Sciences Depar
10、tment QUALITY ASSURANCE/GLP COMPLIANCE STATEMENT Study Title: An Inhalation Oncogenicity Study of Commercial Hexane in Mice Testing Facility: Bio/dynamics, Incorporated Testing Facility Number: 88-8137 API Product Safety Number: PS-71 This study was reviewed by API Quality Assurance personnel under
11、the direction of API Management on the dates indicated below for compliance with EPA TSCA Good Laboratory Practice (GLP) regulations. These studies were conducted in accordance with EPA TSCA GLP regulations with the following exemption. As indicated in a letter from M. Shapiro (EPA) to Dr. Drew (API
12、) dated July 13, 1989, a conditional exemption to the GLP regulations for the disposal of the test substance storage containers was granted. Therefore, the test substance storage containers for this project were disposed of prior to the issuance of the final report. Appropriate records of this dispo
13、sal were maintained, per M. Shapiros letter. Copies of reports by API Quality Assurance personnel are available upon written request to the Director of the Health and Environmental Sciences Department of the American Petroleum Institute or his designee. Date(s) of Type of Inspection/Review (Reported
14、 to Management) Inspection 12/2/88 (12/2/88) 7/19/89 (7/19/89) 1/11/90 (1/16/90) 1/25/90 (2/2/90) 4/24/90 (4/24/90) 6/18-19/90 (6/19/90) 9/5-7/90 (9/11/90) 2/4-6/90 (2/11/90) 7/23-25/91 (7/26/91) Protocol Evaluation Protocol Evaluation Pre-initiation inspection and data audit In-life inspection and
15、data audit Progress report review In-life inspection and data audit In-life inspection and data audit In-life inspection and data audit In-life inspection and data audit Study Title: An Inhalation Oncogenicity Study of Comercial Hexane in Mice Page 2 9/13/91 (9/13/91) 12/18-19/91 (12/23/91) 1/14-15/
16、92 (1/16/92) 219-11/93 (2/26/93) 5/18-19/93 (5/19/93) 5/26/93 (5/26/93) 5/28/93 (5/28/93) 6/2/93 6/2/93) Christine Sexsmidh, B.S. Quality Assurance Coordinator Progress report review In-life inspection and data audit Sacrifice, data review Draft report audit Second draft report audit Third draft rep
17、ort audit Fourth draft report audit Final Report Acceptance Date - API TR*:405 95 0732290 0558926 837 TABLE OF CONTENTS (abridged report) Section Page Abstract . i Introduction . 1 Materials and Methods . 2 Results and Discussion 23 Conclusion 31 Mortality Summaries . Appendix 1 Physical Observation
18、s . Appendix 2 Pathology Report Appendix 3 Survivorship/Tumor Analyses Appendix 4 Quality Assurance Statement Appendix 5 Statement of Compliance . Appendix 6 Table of Contents to Unabridged Report Appendix 7 - API TRJ405 95 W 0732290 0558927 773 W Bio/dynamics, I nc. PROJECT NO. 88-813711 AN INHALAT
19、ION ONCOGENICITY STUDY OF COMMERCIAL HEXANE IN RATS AND MICE PART II - MICE ABSTRACT This study, conducted for the American Petroleum Institute, was designed to assess the oncogenic effect of commercial hexane. lhe test substance was administered by whole-body inhalation as a vapor to Fischer 344 ra
20、ts and B6C3F1 mice (50/sex/group/species). This report presents the results from the mouse portion of the study. The rat results are presented in a separate report. The test substance was administered for six hours per day, five days per week, for approximate1 two years at target concentrations of 9
21、00, 3000 and 9000 parts per million (ppm J of air. The 9000 ppm high exposure level was based upon the results of a 90-day subchronic study. In addition, 9000 ppm is approximately 80% of the lower explosive limit. Exposures were initiated on 23 January 1990 and completed on 20 January 1992. Exposure
22、 levels were analyzed hourly using an infrared spectrophotometer (IR). Gas chromatographic (GC) conf i mat i on of the commercial hexane chamber exposure levels as well as analysis for the six major components were also conducted. Particle size distribution measurements of any background aerosol wer
23、e made monthly. Detailed physical examinations were conducted weekly on all animals. Ophthalmoscopic examinations were performed on all animals pretest and prior to sacrifice. Body weight measurements were recorded pretest on Test Days -12, -7 and O, weekly through Week 13, monthly through Week 101
24、and just prior to sacrifice. Differential white blood cell counts were analyzed pretest for all animals and at Month 12, Month 18 and prior to termination on Group I and IV survivors. Following the two years of exposure, all survivors were sacrificed. Complete macroscopic examinations were conducted
25、 for al 1 animals. Microscopic examinations were performed in the lungs in all animals, in selected tissues in all Group I and IV animals, and in all animals which died or were sacrificed moribund prior to their scheduled sacrifice. of Group II and III males and females and in the pituitaries of the
26、 Group II and III females. In addition, microscopic examinations were conducted in the livers The cumulative mean exposure concentrations as determined by IR were 900, 3000 and 9018 ppm. GC analyses confirmed these exposure levels and indicated commercial hexane was stable over the duration of the s
27、tudy with a mean composition (%) of: n-hexane (51.5), methylcyclopentane (16.0) , 3-methylpentane (16.1) , 2-methylpentane (12.9) , cyclohexane (3.3) and 2,4-dimethylpentane (0.17). Particle size distribution determinations indicated that no siani cant test substance aerosol was present in the expos
28、ure chambers. the males and 80% in the females. survivorship among any of control or exposure groups. .o At termination of the study, in the control group survivorship was 85% There was no significant difference in n P.O. 2360 Melers Road East Millstone, New Jersey 08875-2360 (908) 873-2550 FAX (908
29、) 873-3992 Physical observations , hematological and ophthalmoscopic examinations found no signs of any commercial hexane related effects. Mean body weights and body weight gains in the exposed animals were not statistically different from control values in the male mice. consumption in the 9018 ppm
30、 group was lower than controls on 29 of the 35 measurements obtained over the duration of the study. In the females however, at 9018 ppm, body weight gain was reduced. The mean body weight in the 9018 ppm female group was significantly lower than control weights after week 29. By week 53 the 9018 pp
31、m female mice weighed 14% less than the control mice. Similar to the males, mean food consumption values were not statistically different from control values in the mice exposed to the mid and low concentration of commercial hexane. However, in the 9018 ppm group, food consumption was lower than con
32、trol values on 19 of the first 20 food consumption measurements at the beginning of the study. liver masses and nodules among the females in the 9018 ppm group but not among the males. There was a slight dose related decrease in the incidence of cysts in the uterus. However, food Macroscopic examina
33、tions found an apparent treatment related increase in Microscopic examinations found a treatment related increase in hepatocellular neoplasms (adenoma and carcinoma) among females in the 9018 ppm group. Liver tumors among males were not treatment related. The incidence of liver tumors in the Group I
34、V females is similar to the incidence in control males. Male mice of this strain have a higher spontaneous incidence of hepatocellular- tumors than females. There was also a treatment related decrease in the severity and a slight decrease in the incidence of cystic endometrial hyperplasia of the ute
35、rus among the females in the 9018 ppm group. There was an increase in the incidence of pituitary proliferative changes (hyperplasia, adenoma and adenocarcinoma) among al 1 treated groups of females but not among males. The treatment relationship of this observation is unclear because of a lack of do
36、se response. The incidence of these changes is also within the historical range of data for control females. In conclusion, under the exposure conditions of this study, commercial hexane is an oncogen in female mice. The NOEL for the neoplastic changes (hepatocellular tumors in females) was 3000 ppm
37、. API TRx405 95 0732290 0558928 bOT = API TR*405 95 0732290 0558729 546 = -1- 88-8 137M Bio/dynmnicm, nc I. INTRODUCTION: This study, conducted for the American Petroleum Institute, was designed to assess the oncogenic effect of commercial hexane when administered by whole-body inhalation as a vapor
38、 to Fischer 344 rats and B6C3F1 mice (50/sex/group/species). This report presents the results from the mouse portion of the study. The rat results are presented in a separate report. substance was administered for six hours per day, five days per week, for approximately two years at target concentra
39、tions of O, 900, 3000 and 9000 parts per million (ppm) of air. The 9000 ppm high exposure level was established based upon the results of a 90-day subchronic study. approximately 80 percent of the lower explosive limit. The test In addition, 9000 ppm is Species and strain of test animal, method and
40、route of test substance administration and target exposure levels were determined by the sponsor. This study was mandated by an Environmental Protection Agency test rule (Federal Register, Vol 53, No 24, February 5, 1988; pp 3382-3395) issued under TSCA section 4(a) and was performed in compliance w
41、ith 40 CFR Part 798.3300 as modified 799.2155 and 40 CFR part 792, the TSCA Good Laboratory Practice Regulations for Nonclinical Laboratory Studies. The facilities of Bio/dynamics, Inc., and this study were operated/conducted in accordance with the requirements and recommendations of the Animal Welf
42、are Act (P.L. 89-544 as amended by P.L. 91-579 and P.L. 94-279), and other applicable federal, state and local laws, regulations and policies. This study was conducted at Bio/dynamics, Inc., Mettlers Road, East Millstone, New Jersey 08875-2360. All raw data, specimens, the original study protocol an
43、d the original final report are stored in the Archives of Bio/dynamics, Inc. API TR*405 95 = 0732290 0558930 268 -2- 88-8 137M II. MATERIALS AND METHODS: A. Study Dates: Study Initiation Date: (Date Study Director signed the protocol) 14 September 1989 Receipt of Test Animals: 27 December 1989 Initi
44、ation of Exposures: 23 January 1990 (Experimental Start Date) Termination of Exposures: 20 January 1992 Necropsy: 13-21 January 1992 Study Completion Date: Date final report is signed by Study Di rector. B. Test Substance: Supplier: Cornierci al Hexane CAS : 110-54-3 American Petroleum Institute (AP
45、I), manufacturing records are on file with API. Dates Received: A single batch of the test substance was prepared, stored in 55-gallon drums and then delivered on an as need basis. The drums were received on: 7 February 1989 (Drum Nos. 3 - 10) 12 February 1990 (Drum Nos. 13 - 20) 13 March 1990 (Drum
46、 Nos. 21 - 25) 17 April 1990 (Drum Nos. 26 - 31) 25 May 1990 (Drum Nos. 32 - 37) 26 June 1990 (Drum Nos. 38 - 43) 24 July 1990 (Drum Nos. 44 - 49) 28 August 1990 (Drum Nos. 50 - 55) 27 September 1990 (Drum Nos. 56 - 61) 5 November 1990 (Drum Nos. 62 - 67) 4 December 1990 (Drum Nos. 68 - 73) 10 Janua
47、ry 1991 (Drum Nos. 74 - 79) 14 February 1991 (Drum Nos. 80 - 85) 20 March 1991 (Drum Nos. 86 - 91) 22 April 1991 (Drum Nos. 92 - 97) 28 May 1991 (Drum Nos. 98 - 103) 27 June 1991 (Drum Nos. 104 - 109) 31 July 1991 (Drum Nos. 110 - 115) 9 September 1991 (Drum Nos. 116 - 121) 88 -8 13 7M API TR8405 95
48、 W 0732290 0558733 LT4 W -3- Bio/dynrmicm, no. II. MATERIALS AND METHODS (cont.): B. Test Substance (cont.): Dates Received (cont.) : Lot No.: Concentration: Descri pt i on : Anal ys i s : Physical Properties: Stabi 1 i ty and Purity: Storage: Di sposi ti on : C. Test Animal: St rain : Just if icati
49、on for Animal Selection: 10 October 1991 (Drum Nos. 122 - 127) 8 November 1991 (Drum Nos. 128 - 133) 13 December 1991 (Drum Nos. 134 - 137) 1-26-89 100% Active Ingredient Clear, water-white liquid; mild, bland petroleum odor. The identity, strength, purity and composition; and synthesis, fabrication, and/or derivation of the test substance have been documented by the sponsor. The nature of the test substance and its solubility, melting/boiling point, vapor pressure and fl ammabi 1 i ty have been documented by the sponsor. The stability and purity of the test substa
