Document JJXb66z6aKonKm2bkBox4BjXv

HAZLEZON L*AcmnmrowA= 33DI Klk$"N BLVD. P.O. BOX 7546 MADISON, WISCONSIN 53M Chemical & BloM*dlcal Sciences Division PHONE (M 241-4471 TLX 703M MAZRAL MDS UD FINAL REPORT N02 0J)A(iC 02 1 ROGER G. PERKINS MINNESOTA MINING & MANUFACTURING TOXICOLOGY SERVICES ST. PAUL, MN 55101 COMPANY SAMPLE: T-4101 PURCHASE ORDER NUMBER: T837389-410 753 OAPPLE NL)MBER: 70905393 SAPVPLE. ENTERED: T PRINTED: 09/23/87 01/17ZSB ENCLOSED: ACUTE DE:RMAL TOXICITY STLJDY IN RABBITS Key Personnel Method Su@ary Individual Pathology .o References Pathology Report Raw Date Appendix Comments COECD GUIDELINES) SIGNED: STEVEN M. SLAZA STUDY DIRECTOR ACUTE TOXICOLOGY ........r DATE (gah HAZLE%CN ,OAICP%,Crcpmm Ahoe=C-A. WC Chemical& SloMedicalSciencesDivision MADISON, WISCONSIN 53707 - PHONE (NO 241-4471- TLX 703866MAZRAL MDS UD 3301 KINSMAN BLVD. & P.O.BOX 7%5 SAMPLE NUMBER: SAMPLE: T-4101 70905393 PAGE 2 KEY PERSONNEL Acute Toxicoloa!g Steven M. Glaze Study Director Calvin L. Horton Group Leader Support Services Sharon Report L. Howery Coordinator OualitU Assurance Debra Curley Manager Arndt Anatomical Pathol2gU Thomas E. Anatomical Palmer, PhD Pathologist Robert Senior Salava Section Supervisor Dennis Hoffman Group Leader Necrop*5,4 Anne Mosher Group Leader Pathology Data LaboratcrU Cindy J. Diplomats, Animal Veterinarian Cary, DVM ACLAM IFI"LHAZLE%CN A LAAOPAUDMM AAOERCA. WQ-- w 3301 KINSMAN BLVD. - P.O.BOX TS45 - MADISON, WISCONSIN Chemical & SloMedical Sciences Division S3707 - PHONE (MM 241-6471 - TLX TMW HAZRAL MDS UD SAMPLE NUMBER: SAMPLE: T-4101 70905393 PAGE 3 OECD DERMAL SCREEN Objective: To assess the systemic toxicity and relative skin irritancy of a test material when it is applied to the skin according to the Organisation for Economic Cooperation and Development's Guidelines for Testing of Chemicals. Test Material: T-4101 Physical Description: Purity and Stability: Storage and Retention: Safety Precautions: Amber liquid Sponsor assume& responsibility for purity and stability determination&. The test mgterial was stored at room Any unused material will be discarded to HLA Standard Operating Procedure. Normal handling procedure* were used to HLA Standard Operating Procedure. temperature. according according Test Animal: Young adult rabbits of the Now Zealand White strain were procured, maintained individually in screen-bottom cages in temperatureand humidity-controlled quarters, provided access to water ALd libitum and a measured amount of Purina High Fiber Rabbit Chow, and hold for an acclimation period of at least 7 days. Animal husbandry and housing at HLA comply with standards outlined in the "Guide for the Care and Use of Laboratory Animal&". If variations from the prescribed environmental conditions existed, they were documented and considered to have no effect on the study outcome. No contaminants were expected to have been present in the food or water which would have interfered with or affected the results of the study. Five male and five female acclimated rabbits, weighing between 2041 g and 2343 g, were chosen at random, treated, and maintained during the observation period as specified for the acclimation period. Test animals were identified by animal number and corresponding ear tag. Approximately twenty-four hours before test material application, each rabbit's back was shaved with an electric clipper. The shaved area made up approximately 20% of the total body surface. Reason for Species Selection: Historically, the Now Zealand White albino rabbit has been the animal of choice due to the large amount of background information on this species. Preparation o f Test Materials The sample was dosed as individual -dose was calculated and weighed out based body weight at initiation. received. upon each An animal's HAZLC%CN L,%gep%offrXMM AAAL@PCA ^C 7545 - MADISON, WISCONSIN 3301 KINSMAN BLVD. - P.O. BOX Chemical & BIOMedical Sciences Division S37o? . PHONE fWl) 241-4471 * TLX 703OS6 MAZAAL MOS UD SAMPLE NUMBER: 70905393 SAMPLE: T-4101 PAGE 4 OECD DERMAL SCREEN (CONTINUED) Treatment: The test material was applied to each animal's back at a dose level of 2.0 g/kg. The area of application was covered with a 10 x 10-cm gauze patch secured with paper tape and overwrapped with Saran Wrap and Elastoplast tape. Twenty-four hours later the bandages were removed and the backs were washed with lukewarm top water and wiped with disposable paper towels. Collars were applied to restrain the test animals during the 24-hour exposure period. Reason for Route of Administration: Historically, this is the route of choice based on the method of Drairs. Observations: Each animal was observed for clinical signs and mortality at 1, 2.5 and 4 hours after test material adminia-tration. Thirty minutes after removal of the test material the initial dermal irritation reading was made. Subsequent readings of dermal irritation were made on Study Days 3, 7, 10 and 14. The animals were observed daily for clinical signs and twice daily (morning and afternoon) for mortality. The animals were weighed just prior to test material application, at 7 days and at study termination. Pathology: At study termination, all animals were euthenatizedp subjected to a gross necrapay examination and all abnormalities were recorded. After necropsy, animals were discarded and no tissues were saved. Statistical Methods: Other than average body weights, no other statistical method was performed. Location of Raw Date and Final Report: The raw data and a copy of the final report will be retained in the archives of HLA. HAZLE%CN LOACP%WCPIM ANOWPCA W%C Chemical& SloM*dlcalSciencesDivision 3301KINSMAN BLVD. - P.O.BOX 7S45 - MADISON, WISCONSIN S3?07 - PHONE (606)241-4471- TLX 7039U HAZRAL MOS UD SAMPLE NUMBER: 70905393 SAMPLE: T-4101 PAGE 5 OECD DERMAL SCREEN SUMMARY (CONTINUED) Test Animal: Albino Rabbits - Now Zealand White Source: Hazleton Research Products, Inc., Denver PA Date Animals Received: 11/03/87 Method of Administration: Dermal Application Date Test Started: 11/16/87 Date Test Completed: 11/30/87 Estimated Dermal LD50: Male - Greater than 2.0 9/kg of body weight Female - Greater than 2.0 9/kg of body weight Dose Level (G/KG) 2.0 Hours 0-4 mF 00 1 MF a0 MORTALITY SUMMARY (NUMBER OF DEATHS) Daus 2 3 4 5 6 MF M F M F MF MF 7-14 _ MF m Total F Both 00 0 0 0 0 0a a0 a 0 0/5 0/5 0/10 Average Initial Body Weight& (g) Day 7 Terminal Mala Female 2209 2130 2275 2038 2495 2194 Clinical Signs (No. of Animals Affected) Hours 1.0 2.5 4.0 Dinum 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Males (2.0 g/kg) Appeared Normal 5 5 5 5 5 5 55 5 5 5 5 5 5 5 5 5 Females (2.0 g/kg) Appeared Normal 5 5 5 55 5 53 2 1 11 1 1 1 2 2 Few faces a 0 0 0 0 00 123 34 4 4 4 1 1 Hypoactivity 0 0 0 00 0 023 33 3 3 3 3 3 3 Lose of appetite 0 0 0 0 00 0 0122 3 3 3 3 1 1 Thin appearance 0 0 a 0 0a 0 00a 0 0 0 0 0 a 1 Comments: Dermal irritation observed during the study consisted of slight to moderate erythema and edema and slight stonia and desquamation. HAZLB%CN 9@"@ LI.MCX%MTCXMM At.@ORICA, W4-- Chemical& elom@dicslSciencesDivision HAZRAL MOS UD 3301 KINSMAN BLVD. * P.O. BOX 7S" - TAADISON, WISCONSIN S3707 - PHONE (GM 241-"71 - TLX 70=W SAMPLE NUMBER: 70905393 SAMPLE: T-4101 PAGE 6 OECD DERMAL SCREEN PATHOLOGY (CONTINUED) Dose Level: 2.0 g/kg of body weight Animal Number F20529 Test Day Sax Died Sacrificed m 14 Necropsy Comments Axillary lymph nodes (bilateral) diffusely dark red. F20468 m F20516 m 14 Treated skin - diffusely thickened. 14 Treated skin - diffusely thickened with subcutaneous tissuo under- neath the treated skin having multiple red areas, up to 3.5 x 2.5 cm. F20513 m F20515 m F20531 F F20519 F F20498 F F20496 F F20569 F 14 No visible lesions. 14 No visible lesions. 14 Animal appears thin; cocum - serosal surface has multiple red areas, up to 0.3 x 0.2 cm; cocum, colon and stomach - contain green fluid; perianal stains - green. 14 Treated skin - diffusely thickened with subcutaneous skin under- neath the treated skin having multiple red areas, up to 1.0 x 2.0 cm. 14 No visible lesions. 14 No visible lesions. 14 No visible lesions. HAZLr;%C)N IFVII w 3301 KINSMAN BLVD. LAMOPAffORIES AMERCA 6%c - - P.O. BOX 750 - MADISON, WISCONSIN Chemical & SloMedical Sciences Dlvision S3707 - Pt4ONE (606)24144?1 - TLX 703956 MAZRAL MDS UD SAMPLE NUMBER: SAMPLE: T-4101 70905393 PAGE 7 OECD DERMAL SCREEN (CONTINUED) References: 1. Organisation for Economic Cooperation and Development's Guidelines for Testing of Chemicals, Section 402, Acute Dermal Toxicity, Adopted May 12, 1981. 2. Draize, J.H., "Appraisal of the Safety of Chemicals in Foods, Drugs, and Cosmetics - Dermal Toxicity", Association of Food and Drug Officials of the U.S., pp. 46-59 (1975). 3. OECD Principles of Good Laboratory Practice, Annex 2, C(81)30 (Final). 4. NIH Publication No. 85-23 (revised 1985). HLA LAS NO. 7090539J PATHOLOGY REPORT Acute Dermal Toxicity PAGE 8 Ten rabbits (five males, five females) were euthanatized and necropsied at tne termination of the study. The dose level, day of deatn, and gross ooservations recorded for each animal are on page 6 of this report. Tne treated SKin of tnree raooits was diffusely tniCKenea; two of tne tnree had multiple red areas in the subcutaneous tissue. All otner ooservations were considered incidental findings unrelated to treatment. Thomas L. vainmeer,-FW a-td Pathologist (1734mcs) Personnel Signature Shoot Acute Toxicology MLA NO job Title -4K BKky Beckwith Steve soloungy Kon Bridges Pat Crary Sr. Lab. Animal Asst. Lab. Animal Asst. Sr. Lab. Animal Asst. Sr. Lab. Animal Asst. Shane Eith Sh&%M Frazier Steven N. 61aza Ulb Animal Asst. Lab Animal Asst. Group Leader Molly Hahn Kevin PAMITON Jeff Hicks Calvin Morton SharonL. Newry Gregory Johnson Paul Krebs way" ftdison Scott fteonmil Shelley ftcomwll Dam Conant Admin. Clark Lab. Animal Asst. sr. Ukb. AnimalAsst. groo Leader AdministrativeAsst. Lab. Animal Tech. Lab. Animal Asst. Section Saervisor Lab. Animal Tack. Lab. Animal Toc.b. Sr. Lab. Animal Asst. Dan Novi s ftbin Olson Patricia Pedghm Joseph J. D@ MichaelPat2m 3*M Paulsm Jane ftinow Domis a. Stainer NicMel TMsirq Lab. Animl Asst. Lab. Animal Asst. Tom Leader Lab. Animal Asst. Lab.Animl Asst. Sr. Lab.'Animal Asst. Lab. Animl Tech. Lab. Animal Tech. Ub. Aninl ASST. Paul& a. vanw Albert Olson AdministrativeAsst. ftnpower Jim Jirschole LTE Ben Haley Sr. Lab Animal Asst. Eileen M. McConnell Admin. Clerk Annette R. Turner @lanpower Sionature Initiall IU L 7= -taL.,Ikmsr"AL,LL ILI-= AL A- Mgt.," ;W,k.'t,U5A@L CIL-I Qo.@ 'ABOEL) .7 KLA: ACUTE DERMAL APPLICATION LDSO IN NEW ZEALAND WHITE RABBITS Test Katerial: -r- qlo I ---5-I ------r- Vehicle: PDhoyssaigceaLl,Dtevs*cl(r9i/pkzglo)n*:da2dYoK@re- 19 t"t1:mals Cl d: -/I,:/;]/F? Room Source: Mazieton_Researcn Proauczs Date Animal Race ived:-,-L-,H&i DOSE CALCULATIONS tiocyw ignt DOS* Lev* (k /k Dose Animal ,rt.M-IA COMPOUND litElARAi!Um OE: MTS -rare weight Total W*ignt =Pil Wtlgn li@ -/.3t -3 q. q7 7 .6 FL- At 1.- 4 ILA f 1,7q I 1 clrl ated by: Verified by-. Scale used: CLs Animal NuMer s- q, A: D&w Date: 6, CorAlle.-Pm tiy-. Approved br. 'T-7,t IIr1 9-*) F-& 6 1 q. 1 g.16 4jr, A-6 Date: Date: -Bdc w*ianr-si in Prv Sex I Stua u @Ag efy i r,'-zk e,,,ror cliqo oqqp a An oqq& F W@h"ician Fate C2 al(Al C91,1 AA fff2' ip @cale Used I - Intact NA A - Abraded (witha clipperblade) IPAQ f%li4- '2@ r-Ztib Not Appliable Reviewed By (00261/vfft) Date /rsl-(@41;Z W-24-ti *eom wm* %W, ZUDM gilt'lod Iso 0 en en Not re JE 'HE a e4 CL CL i sc 119 =ul "a Cb -c I c a 3@-Z CL- 60.i 0 c w 41 a v t- c c 3. OC 1; ro CC VoOlVg,obe-6 roc C= c-2 I N ITn-IT77n I I LL I N I II NI I A 1 1 114 eb tn 0 3b 0 1; 1 C a w 0.16 4n 0c10 atom @ 3.1 c 1; r *.,CC 0 b. sm -1 w 00 V0,10 c r.oC-O c Cc, IL c.c 10 ,;.; All roc CM 'a 4n ag 1m0 04 I' f I 1iN I, 10 I J "@T II Ni II I I I I 1+141 Ni I I so 41 4.1 -CC \L 1 1 4el Ila a- 1 ffI ilroy@- mA z CO co C 40 MLA: ACUTE DERMAL IRRITATION OBSERVATIONS Test material: Dose level: -F-qir)l &4 lqAO7i-7 Anion I Erythem II Ed@= I Atonia 0 Descusmation Coriactousness LutiagL@ "&its k,ilI N 0 8 15 0 Observation Pe 10 14 I 41.iu a bradtd 0 0 e5 e) iod (Days) Femiles 3 7 %72-@ A irrn-, e) 0 14 -"/,iL ta-cl/Abraded Erythem Edam Atonia Dosaua=tion Coriaceousness Fissurina Anion No.:Fz 18)44416&f n I II I I- --I es ip n t5 0 0 0 n 0 Abraded I Animal No.: F: 9-!@)44A4lD-ac&Abraded el% I1 -1!5 1 o 0 n 0 , e) I 0- 4n tn el A 0 ti 0 0 tl 0 0 n Eryth;@ Edam Animal N to 2 Atonia Desau&Wtion- n Coriaceousnoss_ n Fissurina . n 9t nt Abraded 1 1t 1 0 n 0 r% --Z- Animal Me.:FL-O"l I 0 0 n 0 0 radod c-, I Eryth Ede Atonia Desouamation Coriaceousness Fissurina An a No.:F:2-NSI:lA@Abradleadd 10 -@-10 01 AnimalNo.:F'-- le A!brrdaode@d ti 0 e:) C) e) e5 Erythem Edam Atonis Desouamation Coriaccousness Fissur Lin@ -Technician Oat@ iqFr7 Anin ft.:FZ-Oslgi I 1 0 raded n ej Animal NO.:FZ n .0 1 .2 0 e) 0 (> e-f i t e) 0 4J., _12.,42 1 'Y.'7 I Cta-cDAbrad*d A - Subcutaneous hm 8 - Blanching. C - Scab formation. 0 - Eschar. E - Exfoliation. rrhage. e rro,,s lylt,47 Reviewed by: Date: 1,@01,A7 HLA: SCALE FOR SCORIM6 ACUTE DERMAL REACTIONS ERYTHERA 0 - None 1.0 - Slight 2.0 - Moderate (well defined) 3.0 - Severe (beet rod) EDEPQA 0 - None 1.0 - Slight (barely perceptibleto well defined by definite raising) 2.0 - *Worst@ (raised approximately I=) 3.0 - Sever* (raised more than I m) ATORIA 0 - None 1.0 - Slight (slight impairmentof elasticity) 2.0 - Moderate (slow return to norml) 3.0 - Marked (no elasticity) DESCUARATION 0 - None 1.0 - Slight (slightscaling) 2.0 - Moderate (scales and flakes) 3.0 - Marked (pronounced flaking with denuded areas) CORIACEOUSPESS 0 - *one 1.0 - Slight (decreasein pliability) 2.0 - Moderate (leathery texture) 3.0 - Marked (tough and brittle) FISSURING 0 - None 1.0 - Slight (definite cracks in epidermis) 2.0 - Moderate (cracks in dermis) 3.0 - Narked (cracks with bieeding) (00261/vwt)