Institutional Animal Care and Use Committee (IACUC) Office of Research Compliance (ORC)

Transcription

1 Institutinal Animal Care and Use Cmmittee (IACUC) Office f Research Cmpliance (ORC) Nn-pharmaceutical and Pharmaceutical Grade Cmpunds in Research Animals FULL POLICY CONTENTS Plicy Statement Reasn fr Plicy Prcedures Resurces Sanctins Cntact ADDITIONAL DETAILS Web Address References Effective: 7/1/2013 Last Updated: -- Respnsible University Officer: Fred H. Cate Vice President fr Research Plicy Owner: Blmingtn Institutinal Animal Care and Use Cmmittee Plicy Cntact: IACUC Administratr Plicy Statement Pharmaceutical-grade cmpunds are t be used in research and teaching animals when available thrugh human r veterinary suppliers. Nn-pharmaceutical grade medicatins can be used nly in research/teaching activities if reviewed and apprved by the IACUC. The fllwing elements must be prvided t the IACUC fr cnsideratin: The research activity requires the use f nn-pharmaceutical grade medicatins fr reasns f scientific necessity. Acceptable veterinary r human pharmaceutical grade medicatins are nt available. Reasn fr Plicy T remain cmpliant with the guidance prvided by the Office f Labratry Animal Welfare (OLAW), the United States Department f Agriculture Animal Plant Health Inspectin Service

2 (USDA-APHIS), and the 8 th editin f the Guide fr the Care and Use f Labratry Animals, this dcument details what is required fr the use f nn-pharmaceutical grade chemicals r cmpunds in labratry animals at IUB. Animal welfare must be cnsidered when using all nn-pharmaceutical grade drugs. Drugs used fr anesthesia and analgesia must be prperly prepared, recnstituted, labeled, and stred. WHAT DO THE REGULATIONS SAY? 8 th editin f the Guide fr the Care and Use f Labratry Animals (p. 31) The use f pharmaceutical grade chemicals and ther substances ensures that txic r unwanted side effects are nt intrduced int studies cnducted with experimental animals. Pharmaceutical grade chemicals shuld be used, when available, fr all animal-related prcedures (NIH 2008; USDA 1997b). There may be circumstances when the use f a nnpharmaceutical grade chemical r substance is necessary t meet the scientific gals f a prject r when a veterinary r human pharmaceutical grade prduct is unavailable. The use f nnpharmaceutical grade chemicals r substances shuld be described and justified in the animal use prtcl and be apprved by the IACUC (Wlff et al. 2003). Cnsideratin shuld be given t the grade, purity, sterility, ph, pyrgenicity, smlality, stability, site and rute f administratin, frmulatin, cmpatibility, and pharmackinetics f the chemical r substance t be administered, as well as animal welfare and scientific issues relating t its use (NIH 2008). OLAW OLAW and USDA cnsider that the use f nn-pharmaceutical grade cmpunds shuld be based n: scientific necessity; n availability f an acceptable veterinary r human pharmaceutical-grade cmpund; and specific review and apprval by the IACUC. Investigatrs and IACUCs shuld cnsider relevant animal welfare and scientific issues including safety, efficacy, and the inadvertent intrductin f new variables. Cst savings alne d nt adequately justify the use f nn-pharmaceutical-grade cmpunds in animals. Althugh the ptential animal welfare cnsequences f cmplicatins are less evident in nn-survival studies, the scientific issues remain the same and the principles and need fr prfessinal judgment utlined abve still apply.

3 USDA Investigatrs are expected t use pharmaceutical-grade medicatins whenever they are available, even in acute prcedures. Nn-pharmaceutical- grade chemical cmpunds shuld nly be used in regulated animals after specific review and apprval by the IACUC fr reasns such as scientific necessity r nn-availability f an acceptable veterinary r human pharmaceutical-grade prduct. Cst savings is nt a justificatin fr using nn-pharmaceuticalgrade cmpunds in regulated animals. The IUB-IACUC acknwledges nn-pharmaceutical-grade cmpunds ften are necessary fr scientific research. Where the use f nn-pharmaceutical-grade substances may be essential fr the cnduct f science, the gal f the IUB-IACUC is t cnsider the health and well-being f the animals while aiding the researcher in minimizing ptentially cnfunding experimental variables and maximizing reprducibility f the research. pdf DEFINITIONS Pharmaceutical grade cmpund: OLAW: Is a drug, bilgic, r reagent that is apprved by the Fd and Drug Administratin (FDA) r fr which a chemical purity standard has been established by the United States Pharmacpeia-Natinal Frmulary (USP-NF), r British Pharmacpeia (BP). USDA: Pharmaceutical-grade cmpund is any active r inactive drug, bilgic, reagent, etc., which is apprved by the FDA fr which a chemical purity standard has been written r established by any recgnized pharmacpeia, which is a bk r a cmpendia, such as the US Pharmacpeia [USP], the Natinal Frmulary [NF], the British Pharmacpeia [BP], the Pharmacpeia f the Cuncil f Eurpe [EP]. Nte the USP and the NF have cmbined their standards int ne cmpendia [ Analytical Standards: Certificate f Analysis is a dcument that accmpanies each prduct run. This certificate lists the frmula fr the ingredients as well as the amunt f each raw material/ingredient. The prduct name and lt number are listed t avid cnfusin with ther batches. The Certificate f Analysis als may cntain results f tests fr cntaminants. Analytical Grade: ~99% purity; Certificate f Analysis usually available; apprpriate preparatin is imperative. Reagent ACS: This designates the highest quality cmmercial chemical. The ACS is the American Chemical Sciety. A Certificate f Analysis is available upn request. Reagent Grade: The highest quality cmmercial chemical; hwever, ACS has nt set specificatins fr materials. A Certificate f Analysis is usually nt available.

4 GUIDANCE FOR COMPOUNDS FOR WHICH PHARMACEUTICAL GRADE ALTERNATIVES EXIST Althugh pharmaceutical grade chemicals/cmpunds shuld be used in experimental animals whenever pssible, the use f nn-pharmaceutical-grade chemicals/cmpunds in experimental animals is an acceptable practice under certain circumstances. PIs shuld use apprpriate knwledge f the cmpunds available t ensure that the preparatin, evaluatin, strage, use, and dispsal standards are maintained. When selecting anesthesia and analgesic cmpunds, the fllwing ptins are ptentially available: FDA apprved veterinary r human pharmaceutical cmpunds; FDA apprved veterinary r human pharmaceutical cmpunds used t cmpund a needed dsage frm; Drug btained via ne f the cmpunding pharmacies in the Resurces sectin f this dcument; Use ne f the recipes included in this dcument. Nte that these recipes have been apprved by a IU SOM pharmacist; Justify the use f nn-pharmaceutical grade drugs (see discussin belw). Prcedures HOW DO I FIND OUT IF A COMPOUND EXISTS IN PHARMACEUTICAL GRADE? A Ggle search with the terms pharmaceutical grade and an agent f interest may yield the best results with the least amunt f effrt. Alternatively, OLAW and the USDA suggest cnsulting the FDA database. The Orange Bk is the reference fr FDA-apprved human drugs. The Green Bk is the reference fr FDA-apprved veterinary drugs. FDA database: Orange Bk: Green Bk: m HOW DO I KNOW WHEN I NEED TO JUSTIFY THE USE OF A NON-PHARMACEUTICAL GRADE COMPOUND, AND THEN, HOW DO I JUSTIFY IT? The gal is fr the BIACUC and Investigatrs t wrk tgether in determining an ptimal way t cnduct experiments within the cntext f humane animal care while minimizing the level f pain and distress. If a pharmaceutical grade cmpund is available and an Investigatr seeks t prvide scientific justificatin fr using a nn-pharmaceutical grade, the deliberatin f the IUB- IACUC regarding scientific justificatin will rely n the fllwing tw factrs: Will purity differences result in txic and adverse effects? Will there be an increase in pain and distress?

5 When cnsidering the use f nn-pharmaceutical grade cmpunds, IUB faculty can use the fllwing decisin criteria when preparing a prtcl/amendment: Justificatin that is always acceptable when supprted by apprpriate ratinale. Knwn impact n measured experimental utcmes, which is substantiated by data r published reprts. Nt available frm a veterinary r medical supplier. Nt available frm a veterinary r medical supplier in the desired cncentratin (e.g., high cncentratin f penicillin t prduce seizures; supersaturated slutin f ptassium chlride t euthanize pigs) r cannt be achieved by simple dilutin f an existing prduct. Mre pure in a reagent grade versin than a pharmaceutical grade versin. Use is required in rder t prduce data that is cmparable t previus data, if there is a scientific ratinale fr direct cmparisn with previus data. Acceptable use f chemical-grade reagent includes: The nging cllectin f data fr experiments that are nt yet cmpleted; The need t replicate methds frm previus studies; r The pharmaceutical grade cntains unwanted fillers r nn-txic vehicles. T avid the inadvertent intrductin f new variables, a nn-pharmaceutical grade cmpund is scientifically necessary if a vehicle cntrl is nt available using USP materials. An available USP cmpund des nt meet the nn-txic vehicle requirements fr the specified rute f administratin. Pharmaceutical grade nly is available in a frm nt suitable fr the rute f administratin. Exrbitant csts make the cmpund lgistically unavailable. When dilutin r a change in frmulatin f an USP cmpund ccurs, there may be n additinal advantage gained by using the USP frmulatin. In this situatin, use f the highest grade reagent may have the advantage f single-stage frmulatin and als may result in purity that is equal t r higher than the human r veterinary drug. N pharmaceutical grade is available. Justificatin that is generally acceptable: Detailed cncerns abut ptential detrimental effects n established mdels r experimental paradigms.

6 Pssible adequate justificatin, requiring particular attentin t details: Unpublished, anecdtal experience n benefits f the mdel r detrimental effects f alternatives. Experimental lgistics r persnnel safety, which include: Access t specialized equipment (e.g., fume hds, vaprizers/scavengers); Interference with measurements r prcedures; Based upn perfrmance standards affrding utcmes that are nn-injurius t animal subjects; r Security f regulated drugs (in rare circumstances). Inadequate justificatin, when n additinal justificatin is present: Cst savings; Administrative burden f acquiring and maintaining a DEA license; r Cnsideratin/eliminatin f nly ne pharmaceutical-grade alternative. When pssible, the descriptin justifying the use f nn-pharmaceutical grade drugs shuld include the chemical grade f the agent(s) being used (see definitins belw), surce f the reagents, as well as a descriptin f the apprpriateness f the agent, its frmulatin and vehicle. Frmulatins and vehicles may need t be adjusted depending n the rute and site f administratin, as well as the species under cnsideratin. The recipe fr frmulating the cmpund mixture shuld be detailed in the prtcl. WHAT DOES A GOOD JUSTIFICATION LOOK LIKE? The XXX prtein used will be synthesized and purified in several variatins in ur lab. This will be carried ut using autmated chrmatgraphy equipment t ensure the tightest, mst reprducible clumn-based purificatin pssible. Hwever, given the nature f the prcess, it is nt practically pssible t generate pharmaceutical-quality prtein reagent in a basic research lab, as the equipment, training, and facilities required are specialized. The cmpund I injectin, YYY, will be used in a 10 micrliters/dse. The cmmercially available cncentratin is t lw t dse the animal with the apprpriate vlume. Cnsideratin will be given t the grade, purity, sterility, ph, pyrgenicity, smlality, stability, site and rute f administratin, frmulatin, cmpatibility, and pharmackinetics f the chemical r substance t be administered. This is a very cmprehensive list. Nt all f these factrs may be applicable in all circumstances. The IUB IACUC may nt need all parameters in every situatin.

7 WHAT ABOUT USE IN NON-SURVIVAL PROCEDURES? A euthanasia slutin (e.g., Euthasl, Fatal Plus) may nt be used as an anesthetic (alne) fr survival r nn-survival prcedures. OLAW in cncert with USDA agree that a prcedure may be perfrmed as a part f euthanasia. This wuld be limited t terminal perfusin r exsanguinatin. In bth cases, death is an immediate utcme f the prcedure. Hwever, it is acceptable t use nn-sterile euthanasia slutin (e.g., Euthasl r Fatal Plus) fr euthanasia as well as nn-pharmaceutical grade pentbarbital as lng as it is administered apprpriately. WHAT IF I CAN OBTAIN A COMPOUND THAT IS NO LONGER AVAILABLE IN THE U.S. FROM A SUPPLIER IN ANOTHER COUNTRY? The cmpund will be cnsidered nn-pharmaceutical grade. Yu will be required t scientifically justify its use in the animal prtcl and t fllw the dcumentatin and ther practices in this dcument. GUIDANCE FOR NOVEL TEST COMPOUNDS & COMPOUNDS WITH NO ACCEPTABLE PHARMACEUTICAL GRADE ALTERNATIVE The IUB IACUC acknwledges that many test cmpunds and experimental agents are used in research and generally classifies these agents as nn-pharmaceutical grade cmpunds withut an acceptable pharmaceutical grade alternative. As such, their use is an acceptable practice. Hwever, PI s shuld use apprpriate infrmatin ensuring that chemical prperties f the cmpund are apprpriate fr the study and the rute f administratin (e.g., the purity, grade, stability in and ut f slutin, slutin vehicle prperties, ph, smlality) The cmpatibility f the slvent and ther cmpnents f final preparatin shuld be knwn t ensure that the nnpharmaceutical grade agents are prepared under sterile cnditins and stred prperly. When Preparing Test Cmpunds: When drugs r chemicals are frmulated fr injectin, they must be prepared in a sterile manner. This requires sterile cnstituents (e.g. sterile pwder, sterile diluents), a sterile cntainer, and a means f keeping the preparatin sterile. Injectin vials (samples and rdering infrmatin are available frm LAR) are preferred as they make it easier t lad a syringe and allw remval f slutin withut expsing the cntents t utside cntaminants. Diluents r vehicles must be specified in the animal use prtcl. Use f slvents will be evaluated n a case-by-case basis. Use f such slvents may limit amunts, cncentratin and rutes f administratin. See list f acceptable slvents belw. Cntainers must be labeled with the drug, cncentratin, and date f preparatin. Nte that sterile injectin vials can be btained frm LAR.

8 When pssible, prepared slutins must be passed thrugh a syringe filter (typically 0.22 t 0.45 um but culd be finer) at the time f preparatin. This can be dne in the prcess f transfer t an injectin vial. If there is any questin abut the sterility f a stred slutin, it must als be filtered at the time f use. If filtering is nt pssible (e.g., nanparticles), sterile cmpnents shuld be mixed using sterile technique. Prepare nly as much as can be used in a reasnable perid f time. Drug slutins prepared and stred prperly in a suitable injectin vial can be stred fr up t six mnths. Drugs must be stred prperly (e.g., freezer, refrigeratr). Slutins must nt be used if they are cludy, disclred, precipitated, etc. Expired drugs must be dispsed f prperly. If nt discarded, expired drug cntainers must be labeled expired and stred separate frm drugs in use. Cntrlled substances cannt be discarded withut apprpriate paperwrk. All cntrlled substances must cntinue t be stred in an apprved secure cabinet r safe until discarded apprpriately. ph f slutins must be between ph 4.5 and 8.0. Use f a slutin with a ph utside this range must be addressed in the animal use prtcl. Pyrgens, such as endtxins, may cause fever when injected int an animal. All pharmaceutical drugs are tested fr pyrgens. Sterility des nt ensure that pyrgens are nt present. Filtering des nt remve pyrgens. Pyrgen testing is nt practical fr small lts f prepared drug. Pyrgenicity is a ptential experimental variable that researchers shuld be aware f when using nn-pharmaceutical grade drugs. Acceptable slvents Distilled water PSS (0.9% NaCl), PBS, balanced salt slutin (e.g., Hanks) 60% (v/v) prpane-1:2-dil (prpylene glycl) 0.5% (w/v) carbxymethyl cellulse 10% (v/v) Tween 80 (plyxyethylene (20) srbitan mn-leate) 10% (v/v) ethyl alchl* 50% (v/v) dimethylfrmamide 50% (v/v) dimethylsulphxide (DMSO) Cycldextrins 5 (e.g. 2-hydrxyprpyl-beta-cycldextrin, Trappsl ) USP il fr injectin *Exceptins can be apprved n a prtcl-by-prtcl basis.

9 Resurces The fllwing cmpanies may prvide veterinary grade agents t researchers wh are able t supply a DEA Researcher License in lieu f a veterinary license. The IACUC cannt endrse these pharmaceutical firms, nr can it guarantee that these firms will cntinue t supply these pharmaceuticals in frms suitable fr animal studies. Butler Schein Animal Health, Vet Institute Extensin, , Ext.# 5406, Ask fr Clay. Researchers with state and DEA Researcher License can btain any drugs, including cntrlled substances, and any veterinary medical supplies. Indiana University Pharmacy, Blmingtn, cntact Dr. Randalyn Shepherd by r phne t verify availability f drugs and t arrange an rder. IU Pharmacy will need a letter requesting the drug frm the PI. The letter shuld include the PI s name, IACUC prtcl number, the drug requested, and a brief statement describing hw the drug will be used. Wedgewd Pharmacy, Veterinary Cmpunding Pharmacy, , ask fr Barry Yager. Cntrlled substances nt available, but they may be able t cmpund sme drugs nt readily available. A veterinary prescriptin is needed. MedVet Internatinal ( ) MedVet has an in-huse veterinarian wh reviews all veterinary prduct rders. The veterinarian may permit the purchase f these veterinary prducts (cntrlled r nncntrlled) with a DEA Researcher License, particularly if the recipient is with a research institutin. Suthern Anesthesia ( ask fr Cper ( ext 265) Currently, researchers hlding a DEA Researcher License may purchase veterinary drugs. TW Medical ( ) Diamnd Back Drugs ( Requires a written prescriptin. Currently, pharmaceutical grade pwdered Sdium Pentbarbital can be rdered frm PCCA (Prfessinal Cmpunding Centers f America). Cntact at r A cpy f the DEA-222 license will need t be mailed t PCCA fr regulatry purpses. Pharmaceutical Grade Tricaine Methanesulfnate (MS222) Finquel: Tricaine-S: Identifying surces f pharmaceutical grade cmpunds can be challenging. If the investigatr is having difficulty identifying a vendr that prvides a specific cmpund available in a

10 pharmaceutical grade, the University veterinarians can prvide assistance. Please cntact the university veterinarians at r phne# IU IACUC APPROVED RECIPE FOR SODIUM PENTOBARBITAL INGREDIENTS 6 Gm sdium pentbarbital 10 ml ethanl (95%) 40 ml prpylene glycl USP qs t 100 ml with 0.9% saline Disslve the pentbarbital pwder in the ethanl. Add 25 ml f saline - but nly after the pentbarbital is cmpletely disslved, then mix thrughly. Add 40 ml prpylene glycl, mix. Bring t final vlume (100 ml) with 0.9% saline. The pentbarbital cncentratin in the final slutin is 60 mg/ml. A dse f 50 mg/kg IP in rats is suitable. NOTES: Stck slutins must be prtected frm light and maintained at 4 C n lnger than 6 mnths. Stck slutins must be passed thrugh a sterile 0.2 micrn filter prir t being stred. Stck slutins must be prepared and stred in sterile tubes. Please see the sectin n Guidance fr Nvel Test Cmpunds & Cmpunds with N Acceptable Pharmaceutical Grade Alternative fr guidance n filtratin and preparatin. Wrking slutins can be prepared and maintained similar t stck slutins, but can be stred at rm temperature fr up t 30 days. Transfer f slutins must utilize sterile supplies and techniques (e.g. sterile needles and syringes). All cntainers must be labeled with material name, cncentratin, date prepared, strage requirements, expiratin date, and the initials f the persn making the slutin. Use must be recrded similar t ther cntrlled substances. Standard prcedures fr mnitring plane f anesthesia apply and supplemental dsing is t be given as needed.

11 IUB IACUC APPROVED RECIPE FOR MS-222 MS222 can be used fr axltls, aquatic salamanders, and fish. FINQUEL is the best frm f this material n the market. INGREDIENTS MS-222 pwder Artificial pnd water mixture Sdium Bicarbnate ph paper MIXING Disslve MS-222 in artificial pnd water (20% Hltfreter's Salts). Adjust the ph t abut 7.4 using nly pwdered Sdium Bicarbnate. Use a 5 pad ph paper (ph 2-14 frm Fisher) t mnitr the ph. NOTE MS-222 shuld be made fresh weekly. Fr surgical purpses, fresh slutin shuld be made fr every surgery t minimize cntaminatin and infectin. Discard ld MS-222 dwn the sink diluted with lts f fresh cld water. The cncentratin used fr anesthesia is % depending n the animal size. Use 10% strength f anesthetizing slutin (mst frequently 0.025% (wt/vl) MS 222) as an analgesic t reduce pain and surgery stress fr 20 minutes right after the surgery. MS222 des cause a GI respnse, as sme fish (especially thse larger in size) might vmit if feeding ccurs within the last 24 hurs. IU IACUC APPROVED RECIPE FOR URETHANE Urethane will prduce an extended perid f anesthesia with minimal physilgical changes in labratry animals. The use f urethane anesthesia fr nn-survival studies, clinical veterinary medicine, and ther applicatins is limited, due t adverse pst-perative health effects bserved in animals and suspected health risks t humans. Urethane has been classified as a mutagen (Lewis, 2004) and as a grup 2B carcingen by the Internatinal Agency fr Research n Cancer (IARC). It is readily absrbed thrugh the skin, targets multiple rgans, suppresses bne marrw, readily crsses the placenta, induces fetal tumr frmatin (in uter), and initiates preneplastic changes in the skin (Field and Lang 1988). These ptentially severe side effects make urethane expsure a significant health threat t labratry staff, animal handlers, and ther persnnel wh may be accidentally expsed.

12 NOTE: When handling urethane in the crystalline r pwdered frm and when mixing urethane int aqueus slutins, always use a fume hd, wear a lab cat, prtective eye-wear, and chemical resistant glves. Urethane shuld nly be heated if mixing takes place in a fume hd. Cntainers f urethane shuld never be pened utside f a fume hd. Once mixed int an aqueus slutin, urethane shuld then be transferred int a sealed bttle t prevent vlatilizatin and ptential emplyee expsure. Due t the teratgenic ptential, pregnant wmen shuld avid wrking with urethane. Urethane shuld be limited in use t nn-recvery prcedures due t its lng term carcingenic effects in labratry animals. PERSONAL PROTECTIVE EQUIPMENT Lab cat Nitrile glves ANSI Z-87 apprved safety glasses ANSI Z-87 apprved chemical safety gggles if a splash hazard exists Apprpriate labratry attire. Engineering Cntrls Certified fume hd INGREDIENTS Urethane (800 mg/kg) PBS alpha-chlralse (at least 99% pure, 80 mg/kg) MIXING Mix the urethane (800 mg/kg) in slutin with PBS. Add the alpha-chlralse (at least 99% pure, 80 mg/kg). Warm up the slutin while cntinuusly stirring, allwing the chlralse t disslve. Allw slutin t cl. Please see the sectin n Guidance fr Nvel Test Cmpunds & Cmpunds with N Acceptable Pharmaceutical Grade Alternative fr guidance n filtratin and preparatin. DOSING Inject 55 mg/kg IP Yu may want t give a female a smaller dse t start (~70% f male dse), then 20 minutes later, give 10% mre f the dse and check the level f anesthesia. Repeat this step until there is n respnse t tail pinching and the blinking reflex is gne.

13 REDOSING The anesthetic shuld last fr at least 3 hurs withut needing supplementatin. Supplement with the same urethane-chlralse slutin (re-warm it and stir fr a shrt time befre using it), s that the cncentratin is the same, with n mre than 0.2 cc (~10-20% f the initial dsage) at the 4th hur after first injectin and every hur afterward r as needed. NOTES Urethane is fr nn-survival prcedures nly. STORAGE AND DISPOSAL D nt administer nn-sterile slutins, utdated slutins, high cncentrated slutins, r higher dses than recmmended abve. Stre the slutin in a sealed cntainer and accrding t the EHS Chemical Hygiene Plan. Urethane slutins are very stable and can be stred up t 6 mnths in sealed cntainers. Dispse f utdated urethane slutins using standard EHS chemical dispsal guidelines. Deviatins frm the IACUC plicy with respect t preparatin, dse, strage, and dispsal must be utlined and justified in yur IACUC prtcl. Fr mre infrmatin n the preparatin and strage f tribrmethanl, please refer t: Field, K. J. and Lang, C. M. (1988) Hazards f urethane (ethyl carbamate): a review f the literature. Labratry Animals 22, Henshaw PS and Meyer HC (1944) Minimal number f anesthetic treatments with urethane required t induce pulmnary tumrs. Jurnal f the Natinal Cancer Institute 4, Kay A. M. and Trainin N. (1966) Urethane carcingenesis and inductin. Cancer Research 26, Tannenbaum A., Vesslinvitch S. D., Maltni C. and Mitchell D. S. (1962) Multiptential carcingenicity f urethane in the Sprague-Dawley rat. Cancer Research 22, Klien M. (1954) Inductin f lung adenmas fllwing expsure f pregnant, newbrn, and immature male mice t urethane. Cancer Research 14, Vesselinvitch S. D., Mihailvich N., Ra K. and Itze L. (1971) Perinatal carcingenesis by urethane. Cancer Research 31, Lewis Sr., R. J. (2004), Sax s Dangerus Prperties f Industrial Materials. Sanctins Failure t cmply with IACUC plicies may result in nncmpliance reprts t the Institutinal Official, the Office f Labratry Animal Welfare (OLAW), the U. S. Department f Agriculture (USDA), and/r the suspensin f animal use privileges. In additin, the availability f

14 spnsred research funds may be affected when an Investigatr is fund t be in vilatin f these plicies. Cntacts Subject Cntact Phne Fax/ Availability and acquisitin f pharmaceutical grade drugs Labratry Animal Resurces (LAR) lar@indiana.edu Web Address fr this Plicy Related Infrmatin PHS Plicy n Humane Care and Use f Labratry Animals The Guide fr the Care and Use f Labratry Animals, 8th Editin USDA Plicy #3: Veterinary Care References Arizna State University Use f Drugs and Cmpunds in Animal Studies 8/13/12 Emry University IACUC Plicy fr Nn-Pharmaceutical Grade Drugs 3/4/09 Natinal Institutes f Health Guidelines fr the Use f Nn-Pharmaceutical Cmpunds in Labratry Animals University f Clrad Denver Use f Nn-Pharmaceutical-Grade chemicals/cmpunds 7/12/10

15 University f Illinis Plicy n Use f Expired Drugs and Materials and Nn-Pharmaceutical Grade Cmpunds in Animals 12/2/03 University f Wiscnsin Madisn SOP fr the Plicy n the Use f Nn-Pharmaceutical-Grade Cmpunds in Research Animals University f Hustn Use f Nn-Pharmaceutical Grade Cmpunds in Labratry Animals Pharmaceutical%20Grade%20Cmpunds_ pdf OLAW Webinar, March 1, Use f Nn-Pharmaceutical-Grade Chemicals and Other Substances in Research with Animals Fish, Brwn, Danneman and Karas (Eds) (2008) Burlingtn, MA Anesthesia and Analgesia in Labratry Animals, Academic Press. Suckw, Weisbrth, Franklin (Eds) (2006) Burlingtn, MA The Labratry Rat. Academic Press.