1、 API TR*403 95 ssll 0732290 0554723 bT7 E Health and Environmental Sciences Department Closed-Patch Repeated Insult Dermal Sensitization Study of Tertiary Amyl Methyl Ether (TAME) in Guinea Pigs (Buehler Method) FEBRUARY 1995 TOXICOLOGY REPORT NUMBER 403 CAIS ABSTRACT NO. 41 -541 6 API TR*403 95 W 0
2、732290 0554724 533 = Straiqliw f.r Tdy i Envinmmmial Parinmbip One of the most significant long-term trends affecting the future vitality of the petroleum industry is the publics concerns about the environment. Recognizing this trend, API member companies have developed a positive, forward-looking s
3、trategy called STEP: Strategies for Todays Environmental Partnership. This program aims to address public concerns by improving our industrys environmental, health and safety performance; documenting performance improvements; and communicating them to the public. The foundation of STEP is the API En
4、vironmental Mission and Guiding Environmental Principles. API ENVIRONMENTAL MISSION AND GUIDING ENVIRONMENTAL PRINCIPLES The members of the American Petroleum Institute are dedicated to continuous efforts to improve the compatibility of our operations with the environment while economically developi
5、ng energy resources and supplying high quality products and services to consumers. The members recognize the importance of efficiently meeting societys needs and our responsibility to work with the public, the government, and others to develop and to use natural resources in an environmentally sound
6、 manner while protecting the health and safety of our employees and the public. To meet these responsibilities, API members pledge to manage our businesses according to these principles: O To recognize and to respond to community concerns about our raw materials, products and operations. O To operat
7、e our plants and facilities, and to handle our raw materials and products in a manner that protects the environment, and the safety and health of our employees and the public. 9 To make safety, health and environmental considerations a priority in our planning, and our development of new products an
8、d processes. *:* To advise promptly, appropriate officials, employees, customers and the public of information on significant industry-related safety, health and environmental hazards, and to recommend protective measures. + To counsel customers, transporters and others in the safe use, transportati
9、on and disposal of our raw materials, products and waste materials. O To economically develop and produce natural resources and to conserve those resources by using energy efficiently. To extend knowledge by conducting or supporting research on the safety, health and environmental effects of our raw
10、 materials, products, processes and waste materials. e3 To commit to reduce overall emission and waste generation. 9 To work with others to resolve problems created by handling and disposal of hazardous substances from our operations. O To participate with government and others in creating responsib
11、le laws, regulations and standards to safeguard the community, workplace and environment. To promote these principles and practices by sharing experiences and offering assistance to others who produce, handle, use, transport or dispose of similar raw materials, petroleum products and wastes. API TR*
12、403 95 = 0732290 0554725 47T W 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
13、TO WARN AND PROPERLY 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 OT
14、HERWISE, FOR THE MANUFACTURE, 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 ACKNOW
15、LEDGMENTS THE FOLLOWING PEOPLE ARE RECOGNIZED FOR THEIR CONTRIBU- TIONS OF TIME AND EXPERTISE DURING THIS STUDY AND IN THE PREPARATION OF THIS REPORT: API STAFF CONTACT Richard Rhoden, Ph.D., Health and Environmental Sciences Department MEMBERS OF IlEAIR/FUELS TOXICOLOGY HEN .TH EFFECTS WORKGROUP Ru
16、ssell D. White, Ph.D., Chuimn, Chevron Research positive control). Challenge treatments fol lowed the same administration procedure as the Induction Phase but at naive sites. In order to differentiate dermal reactions produced by irritation from those produced by sensitization, ten (5/sex) previousl
17、y untreated animals were subjected to the same challenge procedures, with Light Mineral Oil, DNCB and TAME applied at three separate sites. Observations for mortality were made twice daily. Body weights were obtained pretest and two days after challenge. Animals were also observed prior to treatment
18、 and weekly during the study for general health. Dermal evaluations were made approximately 24 and 48 hours after the first induction exposure and 24 and 48 hours after the challenge exposure. The chamber was All animals survived throughout the study. Most animals gained weight throughout the study;
19、 Animal No. 8082 (found dead one week after study termination) lost 18 grams of weight during the study. All ten control animals challenged with 100% light mineral oil were free of significant dermal responses, as were the irritation control animals. The Incidence Index of sensitization to the miner
20、al oil was 0%. The Severity Indices at 24 and 48 hours were O, for both mineral oil-treated animals and irritation control animals. API TR*403 95 m 0732290 0554729 O15 92 - 6222 All ten positive control animals treated with 0.3% DNCB exhibited clear dermal responses which were of greater incidence a
21、nd severity than the responses seen in the irritation control animals to the same concentration. The Incidence Index of sensitization to DNCB was 1001. The Severity Indices at 24 and 48 hours were 1.8 and 2.1, respectively, for the positive control animals, compared the indices of 0.2 and 1.4 for th
22、e irritation control animals. response to a known sensitizer demonstrated the susceptibility of this shipment of animals to sensitization. This positive All twenty animals challenged with 100% TAME were free of dermal responses as were the irritation control animals. The Incidence Index of sensitiza
23、tion to TAME was 0%. The Severity Indices at 24 and 48 hours were O, for test material- treated animals and irritation control animals. Under conditions of this study, TAME did not exhibit any potential to produce dermal sensitization in guinea pigs. API TRm403 95 = 0732290 0554730 837 92-6222 TABLE
24、 OF CONTENTS . I . INTRODUCTION 1 II . EXPERIMENTAL DESIGN . 1 III . DATES OF STUDY 2 IV . STUDY PERSONNEL . 2 V . MATER1 ALS A . lest and Control Materials 2 B . Test Animals 3 VI . METHODS A . Route of Administration . 5 B . Justification for Route of Administration . 5 D . Doses . 6 F . Preparati
25、on of Test and Control Materials . 6 6 . Induction Phase . 6 C . Range-Finding Study . 5 E . Preparation of Animals 6 H . Challenge . 7 VI1 . EXPERIMENTAL EVALUATION A Viability Check . 7 B . Body Weights 7 C . Observations 7 D . Evaluation of Dermal Response . 7 VI11 . POS.RT. 8 IX . EVALUATION OF
26、RESULTS . 8 X . RESULTS AND DISCUSSION 9 XI, CONCLUSION io TABLES I . Body Weights . 11 II . Individual Dermal Scores at First Induction 12 III . Incidence of Dermal Responses at Challenge . 13 IV . Individual Dermal Scores at Challenge 14 APPENDICES A . Range-Finding Study . 17 B . Evaluation of De
27、rmal Irritation . 18 C . Qual i ty Assurance Statement . 19 D . Statement of Compliance . 20 E . Report Amendments . 21 API TR*403 95 O732290 05547311 773 PHARl4ACO:LSR PHARMACO LSR STUDY NO. : 92-6222 CLOSED-PATCH REPEATED INSULT DERMAL SENSITIZATION STUDY OF TERTIARY AMYL METHYL ETHER (TAME) IN GU
28、INEA PIGS (Buehler Method) Performed by: Pharmaco LSR Inc. Toxicology Services North America P.O. Box 2360, Mettlers Road East Millstone, New Jersey 08875-2360 Submitted to: American Petroleum Institute 1220 L Street, Northwest Washington, D.C. 20005 Attn: Robert T. Drew, Ph.D. Date: October 8, 1993
29、 Amended Report Date: September 8, 1994 API TR*403 95 0732290 0554732 bOT -1- 92-6222 This study was conducted for American Petroleum Institute in order to evaluate the allergic contact sensitization potential of Tertiary Amyl Methyl Ether (TAME) in guinea pigs. This study was performed at Pharmaco
30、LSR Inc., Toxicology Services North America, P.O. Box 2360, Mettlers Road, East Millstone, New Jersey 08875-2360, and used procedures based on the methods described by E.V. Buehler in “Delayed Contact Hypersensitivity in the Guinea Pig“, Arch. Dermatol. 91: 171-175, (1965) and H.L. Ritz and E.V. Bue
31、hler in “Planning, Conduct and Interpretation of Guinea Pig Sensitization Patch Tests“, in Current Concepts in Cut- Toxicitv (Victor A. Drill and Paul Lazar, eds.), pp. 25- 40; Academic Press , 1980. This study was designed to follow the Buehler Test method which is the method specified in the follo
32、wing guideline: TSCA (Toxic Substances Control Act) : Office of Toxic Substances; Office of Pesticides and Toxic Substances, United States Environmental Protection Agency, September 1985, Section 798.4100: Dermal Sensitization. Heal th Effects Test Guide1 ines; This report has been reviewed by the Q
33、uality Assurance Unit of Pharmaco LSR, Inc. to assure its conformance with the protocol and the raw data. All raw data and the original study protocol and final report will be retained on file in archives of the Testing Facility. II. FXPFmI OF= Concentrat ion f%l Challenae Number of GrouD Test!Contr
34、o1 Material Animals induction IA Light Mineral Oila 10 100% 100% IB Light Mineral Oil 10 - 100% i rri tat i on Control d IIA DNCB 10 O. 5%b O. 3Sc IIB DNCB 10 - O. 3%c (irri tat i on Control )d IIIA TAME 20 100% 100% IIIB TAME 10 - 100% ( I rri tat i on Control d asince TAME was administered at loo%
35、, a sham control would have been adequate. However, because the protocol specified a vehicle control group, the vehicle used for the range-finding study was also used for the main study. bVehicle: 80% ethanol. CVehi cle: acetone. dIrritation control groups were treated at challenge only. The same te
36、n animals served as irritation controls for all three materials. 1 API TR*403 95 0732290 0554733 546 -2- 92-6222 III. DATFS OF STUDY Study Initiation: Animal Receipt: Range-Finding: 21 October 1992 5 October 1992 21 through 24 October 1992 IV, V, Indction: - Fi rst : 27 October 1992 Second : 3 Novem
37、ber 1992 Third: 10 November 1992 Challenge: 24 November 1992 Study Termination: 26 November 1992 - Study Di rector: Supervisor: Techni ci an-i n-Charge: Study Monitor MATERIALS A. Test Utrol Materials: Donna L. B1 asrcak, B.S. , Thomas D. Jones, B.A., A Daniel Walters Laura J. Kurowski, A.S. (Report
38、 Preparati on) : 1. Test Material: TAME (TAME-2) LotlBatch Number: MZ07905U Description : Colorless liquid Date of Receipt : Exoiration Date: Not provided 20 October 1992 Rekeived From: St orage : Sampling: 2. Positive Control Materi al : Lot Number: Date of Receipt: Expiration Date: Description: Su
39、pplier: Storage : Sampling: AALAS LAS L LATG TG Experimental Pathology Laboratory , Inc. Room temperature. Per sponsor request, refrigerated after 2 November 1992. An archival sample of approximately 10 mls of the test material is stored in the archives of the Testing Facility. 1-chl oro, 2,4-dini t
40、robenzene (DNCB) Al 1T 7 December 1989 December 1994 Yellow granules Eastman Kodak Company, Rochester, New York Room temperature An archival sample of approximately 5 g of positive control material is stored in the archives of the Testing Facility. API TR*:Y03 95 W 0732290 0554734 482 -3 - 92-6222 V
41、. - A. Jest and Control Material5 !cML)L 3 Control Materi al : Light Mineral Oil Lot Number: Date of Receipt: Expiration Date: Descri p t i on : Supplier: Storage: Sampling: 4. Vehicle: Lot Number: Date of Receipt: Expiration Date: Descri pt i on : Suppl i er: Storage: Preparation: 5. Vehicle: Lot N
42、umber: Date of Receipt: Expiration Date: Descri pt i on : Supplier: Storage: B. Jest Animals: Stock: Reason for Selection: Supplier: 6358 KHVY 15 April 1992 June 1997 Clear colorless viscous liquid Mallinckrodt, Paris, Kentucky Room temperature An archival sample of approximately 10 g of control mat
43、erial is stored in the archives of the Testing Facility. Reagent Alcohol (Induction) 7006 KHNE 13 December 1991 December 1996 Clear, colorless 1 iquid Mal 1 inckrodt, Paris, Kentucky Room temperature 160 mls of reagent ethanol was added to 40 mls of distilled water to produce an 80% v/v ethanol mixt
44、ure. Acetone (Chal lenge) KDSC 4 December 1989 December 1994 C1 ear 1 iquid Baxter Heal thcare Corporation McGaw Park, Il 1 i noi s Room temperature; away from heat, sparks and open flame. Albino Guinea Pigs Dunkin Hartley Haz: (DH)fBR Standard laboratory animal for dermal sensitization studies. The
45、 Hartley Albino stock was used because of its availability and because of the existing historical data base available for comparative evaluation. HRP, Inc. Denver, Pennsyl vani a -4- 92-6222 B. Test Animals ked: Number/Sex of Animals: 1. Range-Finding: 6 females 40 (20 males, 20 females) 2. Sensitiz
46、ation Study: 3. Irritation Controls: io (5 males, 5 females) Age (Sensitization Animals) : 3-4 weeks at receipt. 6-7 weeks old at study initiation. Weight Range at Initiation of Treatment (sensitization animals) : Males: 399 - 555 grams Females: 357 - 460 grams Equi 1 ibration Period: Range-Finding
47、Study: 16 days Sensitization Study: 22 days Observations : Hus bandry: Housing : Envi ronmental Conditions : Food : Water: All animals were checked for viability twice daily. Prior to assignment to study, all animals received a physical examination to ascertain sui tabi 1 i ty for study. Currently a
48、cceptable practices of good animal husbandry were followed, e.g., Guide for the Care and Use of laboratorv Animals; NIH Publication No 86-23, Revised 1985. Individually housed in suspended, stainless steel cages with wire mesh bottoms. 1. Temperature: monitored and recorded 2. Humidity: monitored an
49、d recorded twice dai ly . daily. 3. Light Cycle: 12 hours light, 12 hours dark (controlled by an automatic timer). Agway Prolab Guinea Pig Diet, ad libitum Automatic watering system, ad libitum, Municipal water supply (El itabeth Water Company) API TRx403 95 0732290 0554736 255 -5- 92-6222 B. Jest Animals front.): Contaminants: There were no known contaminants reasonably expected to be found in the food or water which would be expected to interfere with the results of this study. Ident if i cat ion: Each animal was identified with a monel ear tag, bearing
