1、API TFi*404 95 O732290 0554756 043 I , Health and Environmental I Sciences Department American Petroleum 11 Institute An Inhalation Oncogenicity Study of Commercial Hexane in Rats and Mice Part I-Rats Final Abridged Report MARCH 1995 TOXICOLOGY REPORT NUMBER 404 CAIS NO. 41-33231 API TRx404 95 07322
2、90 0554757 TBT 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 PROP
3、ERLY TRAIN AND EQUIP WIR EMPLOYEES, AND OTHERS EXPOSED, CONCERNING HEALTH AND SAFETY RISKS AND PRECAUTIONS, NOR UNDERTAKING THEIR OBLIGATIONS UNDER LOCAL, STATE, OR FEDERAL LAWS. NOT“G CONTAINED IN ANY API PUBLICATION IS TO BE CONSTRUED AS GRANTING ANY RIGHT, BY IMPLICATION OR OTHERWISE, FOR THE MAN
4、UFACTURE, SALE, OR USE OF ANY METHOD, APPARATUS, OR PRODUCT COVERED BY LETTERS PATENT. NEITHER SHOULD ANY- THING CONTAINED IN THE PUBLICATION BE CONSTRUED AS INSURING ANYONE AGAINST LIABILITY FOR INFRINGEMENT OF LETTERS PATENT. Copyright Q 1995 American Petroleum institute API TR*404 95 m 0732290 05
5、54758 9Lb m ACKNOWLEDGMENTS THE FOLLOWING PEOPLE ARE RECOGNIZED FOR THEIR CONTRI- BUTIONS OF TIME AND EXPERTISE DURING THIS STUDY AND IN THE PREPARATION OF THIS REPORT - Richard Rhoden, Ph.D., Health and Environmental Sciences Department OF THE COMMERCIAL Hm, TOEOLOGY WORKGROUP Wayne C. Daughtrey, P
6、h.D., Exxon Biomedical Sciences, Inc. Jeffrey S. Duffy, Ph.D., Texaco Inc.* Daniel W. Kelly, Ph.D., Phillips Petroleum* Linda S. Haddock, Unocal Corporation Thomas S. Keenan, Ph.D., Ashland Chemical *No longer with this organization - API TR*i404 95 0732290 0554759 852 PREFACE This publication highl
7、ights summary text and pertinent data from commercial hexane oncogenicity studies done on rats by Bio/dynamics, Inc. under contract to NI. 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 conduct
8、ed pursuant to section 4 (a) of the Toxic Substances Control Act (TSCA) 40 Code of Federal Regulations Part 799.21551. The complete set of multi-volume reports from which this summary document has been compiled is titled, An Inhalation Oncogenicity Study of Commercial Hexane in Rats and Mice, and is
9、 available for viewing by the public at the NI Library, 1220 L St., Washington D.C. 20005. The seven 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 abr
10、idged document. A API TR*404 95 0732290 0554760 574 American Petroleum Institute Health and Environmental Sciences Department QUALITY ASSURANCE/GLP COMPLIANCE STATEMENT RE-ISSUED 12/14/93 Study Title: Hexane in Rats An Inhalation Oncogenicity Study of Commercial Testing Facility: Bio/dynamics, Incor
11、porated Testing Facility Number: 88-8137 API Product Safety Number: PS-71 This study was reviewed by API Quality Assurance personnel under the direction of API Management on the dates indicated below for compliance with EPA TSCA Good Laboratory Practice regulations. TSCA GLP regulations with the fol
12、lowing exemption. As indicated in a letter from M. Shapiro (EPA) to Dr. Drew (API) 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 dispose
13、d of prior to the issuance of the final report. Appropriate records of this disposal were maintained, per M. Shapiros letter. (GLP) These studies were conducted in accordance with EPA Copies of reports by API Quality Assurance personnel are available upon written request to the Director of the Healt
14、h and Environmental Sciences Department of the American Petroleum Institute or his designee. Date(s) of InsDection/Review (Reported to Management) 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-
15、25/91 (7/26/91) Type of Insriection Protocol Evaluation Protocol Evaluation Pre-initiation inspection and data audit in-life inspection and 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 d
16、ata audit API TRt404 95 = 0732290 0554763 400 Study Title: An Inhalation Oncogenicity Study of Comercial Hexane in Rats Page 2 9/13/91 (9/13/91) 12/18-19/91 (12/23 /91) 1/14-15/92 (1/16/92) 1/11-14/93 (1/20/93) 4/1-2/93 (4/2/93) 4/16/93 (4/16/93) ADDED : 10/14/93 (10/15/93) 12/2/93 (12/2/93) 12/14/9
17、3 (12/14/93) Christine Seksmikh, B.S. Progress report review in-life inspection and data audit Sacrifice, data review Draft report audit Second draft report audit Final Report Acceptance Final Report Amendment #1 Review Protocol Amendment #7 Review Final Report Amendment #1 Acceptance /z/fL/93 Date
18、Quality Assurance Coordinator API TR*4La4 75 0732270 05547b2 347 m TABLE OF CONTENTS (abridged report) Section Abstract . i Introduction . 1 Materials and Methods . 2 Results and Discussion 23 Conclusion 29 Amendments to Final Report Appendix 1 Mortality Summaries . Appendix 2 Physical Observations
19、. Appendix 3 Body Weight Changes . Appendix 4 Pathology Report Appendix 5 Laboratory Quality Assurance Appendix 6 Statement of Compliance . Appendix 7 Table of Contents to Unabridged Report Appendix 7 . . API TR*404 95 0732270 0554763 283 Bio/dynamics, Inc. PROJECT NO. 88-8137R AN INHALATION ONCOGEN
20、ICITY STUDY OF COMMERCIAL HEXANE IN RATS AND MICE PART I - RATS ABSTRACT This study, conducted for the American Petroleum Institute, was designed to assess the oncogenic effect of commercial hexane. administered by whole-body inhalation as a vapor to Fischer 344 rats and B6C3F1 mice (50/sex/group/sp
21、ecies). This report presents the results from the rat portion of the study. The mouse 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 900, 3000 and 9000 parts per million
22、 (ppm Y 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 29 January 1992. Exposure levels were analyzed hourly using
23、an infrared spectrophotometer (IR). Gas chromatographic (GC) confirmation 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 were made monthly. Detailed physical exam
24、inations were conducted weekly on al 1 animals. Ophthalmoscopic examinations were performed on all animals pretest, and prior to sacrifice. recorded pretest on Test Days -11, -5 and O, weekly through Week 13, monthly through Week 101 and just prior to sacrifice. Differential white blood cell counts
25、were analyzed pretest for all animals and at Month 12, Month 18 and prior to termination of Group I and IV survivors. exposure, all survivors were sacrificed. Complete macroscopic examinations were conducted for all animals. Microscopic examinations were performed of the lungs in all animals and of
26、selected tissues in all Group I and IV animals and for all animals which died or were sacrificed moribund prior to their scheduled sacri fi ce. The test substance was Body weight measurements were Following the two years of The cumulative mean exposure concentrations as determined by IR were 900, GC
27、 analyses confirmed these exposure levels and indicated 3000 and 9016 ppm. commercial hexane was stable over the duration of the study with a mean composition (%) of: (16.1), 2-methylpentane (12.9), cyclohexane (3.3) and 2,4-dimethylpentane (0.17). test substance aerosol was present in the exposure
28、chambers. n-hexane (51.5), methylcyclopentane (16.0), 3-methylpentane Particle size distribution determinations indicated that no significant At termination of the study the control group survivorship was 67% in the males and 76% in the females. survivorship among the control or exposure groups. The
29、re was no significant difference in P.O. Box 2360 Mettlen Road East Millstone, New Jersey 08875-2360 e (908) 873-2550 FAX (908) 873-3992 - - API TR*404 75 0732270 0554764 LLT 88-8137R io/dy nim 1 om. in c Physical observations, hematological and ophthalmoscopic examinations found no signs of any com
30、mercial hexane related effects except for excess lacrimation which was increased in the commercial hexane exposed males at 3000 and 9016 ppm. Body weight gain was significantly reduced in the 3000 and 9016 ppm exposure groups. At study termination, the mean male and female body weights in the 9016 p
31、pm group were 7 and 11 percent lower than control values respectively. 3000 ppm group, mean male and female body weights were 5 and 3 percent lower than control values, respectively, at study termination. reduced in the commercial hexane exposure groups but was not dose related. In the Food consumpt
32、ion was There were no macroscopic morphologic abnormalities which were considered to be related to exposure to commercial hexane. Microscopic morphologic abnormalities which were considered related to commercial hexane were found in the nasal turbinates and the larynx. Hyperplasia of the respiratory
33、 epithelium was seen most frequently in males and females from Group IV (9016 ppm). Hypertrophy/hyperplasia of goblet ce1 Is was seen most frequently in males and females from Group IV, followed by Group III (3000 ppm); the severity, greater in the exposure groups than in the controls, was severe in
34、 Group IV. Both findings were considered to be an expected response to mucosal irritation and injury. Intracytoplasmic eosinophilic material in the respiratory epithelial ce1 Is and sustentacular cells of the olfactory epithelium was seen in almost all of the males and females from the exposure grou
35、ps for which the nasoturbinal tissues were examined, and in numerous control animals. When compared to controls, the severity was increased and com arable in Groups III (3000 ppm) and IV (9016 ppm), followed by Group II (900 ppmr. While a common finding in aging and aged rats, the exact nature of th
36、is material (presumed to be secretory) and reasons for its increase following exposure to irritants are not known. The following changes were also seen: Inflammator cells/cell debris in the nasal lumen males, Groups II (900 ppm), III (3000 ppm J and IV (9016 ppm); and females, Group III; and subacut
37、e (chronic active)/chronic inflammation in the nasal mucosa, the incidence of which was greatest in males and females from Group IV. Squamous/squamoid metaplasia/hyperpl asia of the pseudostratified columnar epithelium was seen in a small number of animals from the exposure and control groups. In th
38、e males, the incidence was highest in Group IV (9016 ppm), followed by Group III (3000 ppm). In the females, the incidence in Groups III and IV was comparable and greater than that seen in Group I (O pprn). finding was considered to be a localized response indicative of irritation. There was no indi
39、cation of any oncogenic effect. This In conclusion, under the exposure conditions of this study, commercial hexane is not an oncogen in the rat. API TR*404 95 0732290 0554765 O56 -1- 88-8137R *o/dynrmicm no. I INTRODUCTION: This study, conducted for the American Petroleum Institute, was designed to
40、assess the oncogenic effect of commercial hexane vapor when administered by whole-body inhalation to Fischer 344 rats (50/sex/group) and 86C3F1 mice (50/sex/group). This report presents the results from the rat portion of the study. The mouse results are presented in a separate report. The test subs
41、tance was administered for six hours per day, five days per week, for approximately two years at target concentrations 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 perce
42、nt of the lower explosive limit. In addition, 9000 ppm is Species and strain of test animal, method and 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,
43、 No 24, February 5, 1988; pp 3382-3395) issued under TSCA section 4(a) and was performed in compliance with 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
44、 study were operated/conducted in accordance with the requirements and recommendations of the Animal Welfare 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., Me
45、ttlers Road, East Millstone, New Jersey 08875-2360. AI1 raw di 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, mel
46、ting/boiling point, vapor pressure and f 1 ammabi 1 ity have been documented by the sponsor. The stability and purity of the test substance over the duration of the study were documented by the Department of Metabol ism and Analytical Chemistry at Bio/dynamics, Inc. (See Appendix A, page A-9.) The t
47、est substance was stored in an ambient storage shed in 55 gallon drums away from ignition sources. A nitrogen headspace was maintained in the drum as the test substance was being dispensed. All containers of the test substance were returned to the sponsor. Rat Fi scher 344 Standard laboratory animal
48、 for inhalation toxicity studies. was used due to its availability and due to the existing historical data base for comparative evaluation. The Fisriizr 344 rat API TR*404 95 0732290 0554768 865 D -4- 80-0 13 7 R II. MATERIALS AND METHODS (cont.) : C. Test Animal (cont.): Number of Animals : Rece! v
49、ed : 557 total (279 males, 278 females) Placed on Test: 400 total (200 males, 200 females) Suppl ier: Charles River Breeding Laboratories, Inc. Ra1 ei gh , North Carol i na 27610 Date of Birth: 30 November 1989 Date Received: 28 December 1989 Age at Receipt (approx.) : Age at Initiation of 4 weeks Exposure (approx.): 0 weeks Weight at Initiation of Exposure (grams) : WRanae Mal es : Femal es : 167 120 - 181 119 111 - 126 Sentinel Control: Acclimation Period: Animals were acclimated for 26 days (28 December 1989 - 23 January 1990). All animals were examined
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