ICALEO_2009_Presentation_Caristan_et_al

Product Safety Laboratories2394 Highway 130Dayton, NJ 08810Tel: 732.438.5100Fax: 732.355.3275e-mail: PSL@Page 1 of 14PRODUCTVital OxideSTUDY TITLEAcute Oral Toxicity Up And Down Procedure In RatsDATA REQUIREMENTU.S. EPA Health Effects Test Guidelines, OPPTS 870.1100 (2002)AUTHORGeorge E. Moore, B.S.STUDY COMPLETED ONSeptember 26, 2005PERFORMING LABORATORYP roduct Safety Laboratories2394 Highway 130Dayton, New Jersey 08810LABORATORY STUDY NUMBER17854STATEMEN T OF N O DA TA C ON FIDE NTIA LITY C LA IMSNo claim of confidentiality is made for any information contained in this study on the basis of its falling within the scope of FIFRA 10 (d) (1) (A), (B) or (C).Company:VITAL TECHNOLOGIESCompany Agent:Name TitleSignature DateGOOD LAB OR ATOR Y PR AC TICE C OMPLIA NC E STATEMEN TVital OxideThis study meets the requirements of 40 CFR Part 160: U.S. EPA (FIFRA) with the following exception: Specific information related to the determination of the stability, identity, strength, purity, and composition of the test substance as received and the concentration as tested is the responsibility of the study Sponsor (see Test Substance section).Study Director:George E. Moore, B.S.Product Safety LaboratoriesDateSubmitter:SignatureDateSponsor:SignatureDateQU ALITY ASSU RA NC E STATEMEN TThe Product Safety Laboratories’ Quality Assurance Unit reviewed this study for adherence to PSL’s Standard Operating Procedures, the study protocol, and all applicable GLP standards. This final report was found to be an accurate representation of the work conducted. Records of QA findings are kept on file. The summa ry below provides verifica tion of sta tements ma de in the fina l report section tha t addresses Quality Assurance audits.QA activities for this study:QA Activity Date Conducted Date Findings Reported To Study Director AndManagementProtocol review8/20/041; 9/18/058/20/04; 9/21/05 In-process inspection:Day 10 in-life observationsfor Animal #37477/25/059/21/05 Raw data audit9/18/059/21/05Dra ft report review9/18/059/21/05Final report reviewRhonda S. Krick, B.S.Quality Assurance DirectorProduct Sa fety La bora tories1 PSL’s “generic” protocol used for this study was reviewed by the Quality Assurance group on this date.OF C ON TE NTSTA BLESTATEMEN T OF NO DATA CONFIDENTIALITY C LAIMS (2)GOOD LABORATORY PR ACTIC E COM PLIAN CE ST ATEMENT (3)QUALIT Y ASSUR ANCE ST AT EMENT (4)TABLE OF CONTENTS (5)ACU TE OR AL TOXICITY UP AND D OWN PROCED URE IN RATS (6)1.PURPOSE (6)2.SUMMARY (6)3.MATERIALS (7)4.METHODS (7)5.PROCEDURE (8)6.STUDY CONDUCT (9)7.QUALITY ASSURANCE (10)8.DEVIATIONS FROM FINAL PROTOCOL (10)9.FINAL REPORT AND RECORDS TO BE MAINTAINED (10)10.RESULTS (10)11.CONCLUSION (10)SIGNATUR E (11)TABLE 1: INDIVIDUAL BOD Y WEIGHTS AND D OSES (12)TABLE 2: INDIVIDUAL CAGE-SID E OBSERVATIONS (13)TABLE 3: INDIVIDUAL NEC ROPSY OBSERVATIONS (14)AC UTE OR AL TOXIC ITY UP A ND D OWN PR OC ED UR E IN R ATS PROTOCOL NO.:P320.UDPAGENCY:EPA (FIFRA)STUDY NUMBER:17854SPONSOR:VITAL TECHNOLOGIESP.O. Box 2026Hobe Sound, FL 33475TEST SUBSTANCE IDENTIFICATION:Vital OxideBatch #CS062305-1TEST SUBSTANCE DESCRIPTION:Colorless liquidDATE RECEIVED:June 30, 2005PSL REFERENCE NO.:050630-2DSTUDY INITIATION DATE:July 13, 2005DATES OF TEST:July 15 - August 1, 2005 NOTEBOOK NO.:05-59: pages 18-241. PUR POSETo provide information on health hazards likely to arise from a short-term exposure to Vital Oxide by the oral route.2. SUMMARYAn acute oral toxicity test (Up and Down Procedure) was conducted with rats to determine the potential for Vital Oxide to produce toxicity from a single dose via the oral route. Under the conditions of this study, the acute oral LD50 of the test substance is greater than 5,000 mg/kg of body weight in female rats.An initial limit dose of 5,000 mg/kg was administered to one healthy female rat by oral gavage.Due to the absence of mortality in this animal, two additional females received the same dose level, simultaneously. Since these animals survived, no additional animals were tested. Females were selected for the test because they are frequently more sensitive to the toxicity of test compounds than males. All animals were observed for mortality, signs of gross toxicity, and behavioral changes at least once daily for 14 days after dosing. Body weights were recorded p rior to administration and again on Days 7 and 14 (termination) following dosing. Necropsies were performed on all animals at terminal sacrifice.All animals survived, gained body weight, and appeared active and healthy during the study.There were no signs of gross toxicity, adverse pharmacologic effects, or abnormal behavior. No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.3. MATE RIALSSubstanceA. TestThe test substance, identified as Vital O xide, Batch #CS062305-1, was received on June 30, 2005 and was further identified with PSL Reference Number 050630-2D. The test substance was a colorless liquid and was stored at room temperature. The sample was administered as received.Documentation of the methods of synthesis, fabrication, or derivation of the test substance is retained by the Sponsor.The following information related to the characterization of the test substance was provided by the Sponsor:Composition: Stabilized chlorine dioxide 0.2% wt.Quaternary ammonium chlorides 0.25% wt.Other ingredients 99.55% wt.pH: Approx. 8.5.Solubility: Soluble in water, methanol, and ethanol.Stability: Test substance was expected to be stable for the duration of testing.Expiration Date: Not applicable.B. Animals3.B.1Number of Animals: 33.B.2Sex: Female, nulliparous and non-preg nant.3.B.3Species/Strain: Rat/Sprague-Dawley derived, alb ino.3.B.4Age/Body weight: You ng adu lt (10 and 11 weeks)/205-213 grams at experimentalstart.3.B.5Sou rce: Received from Ace Animals, Inc., Boyertow n, PA on June 28, 2005.4. ME THODSA. Husbandry4.A.1Hou sing: T he animals were singly hou sed in suspended stainless steel cag ing withmesh floors which conform to the size recommend ations in the most recent Guidefor the Care and Use of Laboratory Animals DHE W (NIH). Litter paper was placedbeneath the cag e and was changed at least three times per week.4.A.2Animal Room T emperature Range: 20-24ºC4.A.3Photoperiod: 12-hour lig ht/dark cycle4.A.4Acclimation Period: 17 or 20 days4.A.5Food:Purina Rod ent Chow #50124.A.6Water: Filtered tap water was su pplied ad-libitum by an automatic water dispensingsystem.4.A.7Contaminants: T here were no known contaminants reasonab ly expected to befou nd in the food or water at levels which wou ld have interfered with the results ofthis stu dy. Analyses of the food and w ater are conducted at least once a yea r and therecords are kept on file at Product Safety Lab oratories.B. Identification:4.B.1Cag e: Each cag e was identified with a cag e card ind icating at least the stu d y number,dose level, identification and sex of the animal.4.B.2Animal: A number was allocated to each rat on receipt and a stainless steel ear tagbearing this number was attached to the rat. T his number, tog ether w ith a seq uentialanimal number assigned to stu dy number 17854, constitu ted unique identification.5. PRO CE DUR EAnimalsofA. SelectionPrior to each dosing, experimentally naive rats were fasted overnight by removing the feed from their cages. During the fasting period, the rats were examined for health and weighed (initial).Three healthy female rats were selected for test.CalculationsB. DoseIndividual doses were calculated based on the initial body weights, t aking into account the specific gravity (determined by PSL) of the test substance.C. DosingThe test substance was administered using a stainless steel ball-tipped gavage needle attached to an appropriate syringe. Following administration, each animal was returned to its designated cage. Feed was replaced approximately 3-4 hours after dosing.Individual animals were dosed as follows:S – SurvivalD. Body WeightsIndividual body weights of the animals were recorded prior to test substance administration (initial) and again on Days 7 and 14 (termination) following dosing.E. Cage-SideObservationsThe animals were observed for mortality, signs of gross toxicity, and behavioral changes during the first several hours post-dosing and at least once daily thereafter for 14 days after dosing.Observations included gross evaluation of skin and fur, eyes and mucous membranes, respiratory, circulatory, autonomic and central nervous systems, somatomotor activity and behavior pattern.Particular attention was directed to observation of tremors, convulsions, salivation, diarrhea, and coma.F. NecropsAll rats were euthanized via CO2 inhalation at the end of the 14-day observation period. Gross necropsies were performed on all animals. Tissues and organs of the thoracic and abdominal cavities were examined.6. STU DYCO NDUCTThis study was conducted at Product Safety Laboratories, 725 Cranbury Road, East Brunswick, New Jersey 08816. The primary scientist for this study was Jacek Ochalski, D.V.M. This study was conducted to comply with the Good Laboratory Practice (GLP) regulations as defined in:•40 CFR 160: U.S. EPA GLP Standards: Pesticide Programs (FIFRA)and in accordance with:•U.S. EPA Health Effects Test Guidelines, OPPTS 870.1100 (2002)ASSUR ANCE7. QUALITYThe final report was audited for agreement with the raw data records and for compliance with the protocol, Prod uct Safety Laboratories Standard Operating Procedures and appropriate Good Laboratory Practice Standards. Dates of inspections and audits performed during the study and the dates of reporting of the inspection and audit findings to the Study Director and Facility Management are presented in the Quality Assurance Statement.8. DE VIATIO NS FR OM FINAL P ROTOCOLNone.9. FIN AL RE PORT AND R E CORD S TO BE MAINTAINE DThe original, signed final report will be forwarded to the Sponsor. A copy of this signed report, together with the protocol and all raw d ata generated at Prod uct Safety Laboratories, is maintained in the Product Safety Laboratories Archives. PSL will maintain these records for a period of at least five years. After this time, the Sponsor will be offered the opportunity to take possession of the records or will be charged an archiving fee for continued archiving by PSL.10. RE S ULTSIndividual body weights and doses are presented in Table 1. Individual cage-side and necropsy observations are presented in Tables 2 and 3, respectively.All animals survived, gained body weight, and appeared active and healthy during the study.There were no signs of gross toxicity, adverse pharmacologic effects, or abnormal behavior. No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-d ay observation period.11. CON CLUSIONUnder the conditions of this study, the acute oral LD50 of Vital Oxide is greater than 5,000 mg/kg of body weight in female rats.SIGN ATUR EVital OxideI, the undersigned, declare that the methods, results and data contained in this report faithfully reflect the procedures used and raw data collected during the study.George E. Moore, B.S.DateStudy DirectorProduct Safety LaboratoriesTAB LE 1: IN DIVIDU AL B OD Y WE IG HTS AN D DOSE S1 The test substance was administered as received. Specific Gravity – 0.991 g/ml.TA BLE 2: IND IVID UA L CA GE-SID E OB SE RVATIONSAnimal Day of Number Findings Occurrence5,000 mg/kg Dose Level3747, 3794, 3795Active and healthy0-14TA BLE 3: IND IVID UA L NE CR OPSY OBSER VA TION SAnimalNumber Tissue Findings5,000 mg/kg Dose Level3747, 3794, 3795All tissues and organs No gross abnormalities。

2. INTRODUCTION 介绍2.1 The adoption of ICH Q7 as the first truly harmonised GMP guideline for active pharmaceutical ingredients (APIs) and the associated development of regulatory frameworks to implement the guideline as a regulatory standard mark the beginning of a new era of regulation for medicines.采用ICH Q7作为真正意义上的原料药统一GMP指南，并伴随着法规框架的发展以实施指南作为法规的标准，标志着药品法规的一个新纪元。

2.2 The adoption of ICH Q7 by PIC/S occurred in May 2001 with the current version of the guideline having been available since 1 September 2007 as GMP PE 009 (Part II).2001年5月PIC/S采用了ICH Q7，现行版本指南GMP PE 009(第二部分)在2007年9月1日公布.2.3 The primary objective for implementing ICH Q7 is the reduction of the risks associated with the manufacturing quality of APIs and this cannot be achieved without an effective inspection system which addresses the specific aspects of the global API industry.实施ICH Q7的基本目标是减少原料药生产质量所伴随的风险，要达到这个目标，必须制订有效的检查体系，以说明全球原料药行业的各个独特方面。

ICTI商业行为规范（2009版）新增审核项国际玩具工业理事会《商业行为规范》（2009版）的修订于2008年得到认可，以英文和中文出版，为国际玩具工业理事会“关爱”程序奠定基础。

2009版国际玩具工业理事会《商业行为守则》分为《国际玩具工业理事会商业行为规范》（以下简称《规范》）和《国际玩具工业理事会“关爱”程序指引》两册。

2009版《规范》第一节：一般纲领分为“1.1：管理系统”和“1.2审核遵行情况的方法”两个部分。

新增“1.1：管理系统”见我协会“ICTI栏目”——“ICTI商业行为规范（2009版）”。

该管理系统为非检查项。

下面详细介绍《规范》2009版的新增审核项：第二节：审核清单分为十二个部分，综合了2004版“附录二：审核清单”、“附录二：指南文件”和“附录三：纠正措施计划”。

下表列出各部分新增审核项条数新增审核项的简要说明如下：第2部分：工作时数从这部分开始，每一审核项都分为“条款描述”、“工厂指引”和“审核结果”；“工厂指引”即2004版“附录二：指南文件”中对应的条款。

采用新的描述格式。

如下“2.2”所示。

2.2是否按法律法规要求与工人签订劳动合同？工厂指引·工厂应尽可能与所有工人签订合法的劳动合同。

·工人应有一份签了字的劳动合同副本。

·在不需要签订劳动合同时，工厂应提供表明雇用关系和劳资要点的文件。

审核结果2.5工时工资记录是否能准确反映所有工作时间？工厂指引·工时和工资记录必须准确的反映所有工作时数和报酬。

审核结果2.9工人是否每十四天内至少能获得一天休息？审核结果取消：2004版中“2.6每月最长加班时间是____小时。

此时数是否与法定的最长工作时数和工厂的成文规定相符？”第3部分：工资与补贴3.6 a. 工资中扣除的食宿费是否合理合法？新增：b. 工人是否可以自由选择放弃以上福利？工厂指引·从工资中扣除的伙食（正常3餐）、住宿和水电费用必须符合法律要求，且必须合理。