Document jDd4mdeN1ERerxLjKZdEB6wN

WHAZLOTON 3301 KINSMAN BLVD. L&BCNMIORIES ANERICA, INC. P.O.BOX 7546 MADISON, WISCONSIN 53707 Chemical& BloMedicalSciencesDivision PHONE (608)241-4471 TLX 703966HAZRAL MDS UD V FINAL RFPORT @IAANN 22 77vU11M9"E93888 ROGER G. PFRKlt4S MINNESOTA MINING Tnxicnt-oGy SFRVICFS ST. PAUL., MN 55101 MANUFACTURING COMPANY SAMPLE: T-41.n2 PIJRCHASE,OPDFR NI.JMBEP: T837389-410 754 SAMPL- UMBFR: SAMPLE ENTERFD: REPORT PRINTED: 70905762 09/25/a7 Ol./21/88 FNCLOSED: ACUTE DFRMAL, TOXICITY STUDY TN RABEITS 0 Key Per5onnel 0 Method 0 c-;tmjma r -,j 0 Indi".)i@ual Pathology 0 References Pathology Report Rai.i Data Appendix Comments (OECD GUIDELlf-JES) ';TGNEn: '.I.@/...-.@.NM..I.....-......... STEK)FN M. GI-AZA STUDY DIRECTOR ACUTE TOXICOLOGY .......-.k-..@-@ DATE ....... IFIH"ALZLrm%CN \W LABCXZATORlr=S ANAERICA. INC. Chemical& B!oMedicaSlciencesDivision 3301 KINSMAN BLVD. o P.O.BOX 7545 MADISON, WISCONSIN 63707 o PHONE (6082)41-4471a TLX 703956HAZRAL MDS UD C;AMPLE NLIMBER: SAMPLE: T-4ln2 70905762 PAGE 2 KEY PERSONNEL Acute Toxicalooki Steven M. Glaza Study Director Calvin L. Horton GrouD Leader Sijpport Service.,s Sharen L. Howery Report Coordinator Ot.ialit@)A-@surance Debra Curley Arndt Manager Anatomical Patholoo@! Thomas E. Palmer., PhD Anatomical Patholonist Robert Salava Senior Section Suoerkoisor Dennis Hoffman Group Leader Necropsy Anne Masher Group Leader Pathology Data Laborator$2 Animal Ueterinarian Cindy J. Cary, Dk@M Diplomate, ACLAM HAZLETON LABCX*.=:3qlES ANERICA. INC. 3301 KINSMAN BLVD. o P.O.BOX 7545 a MADISON, WISCONSIN 53707 Chemical& B!oMedicaSlciencesDivision PHONE (608)241-44719 TLX 703966HAZRAL MDS UD c;AtIPLE NUMBER: 70905762 SAMPLE: T-4102 PAC@E 3 OECD DERMAL SCREEN Objectik@e: To asse55 the 55J5teMiC toxicity and relative skin irritancp of a test material when it i5 applied to the skin according to the Organisation for Economic Cooperation and Development'5 Guidelines for Testing of Chemicals. Test Material: T-4102 Ph-,jsical Description: Pi.irit-a,n)d Stability: ,-;torageand Retention: Safety PreC8LItions: Dark amber liquid Sponsor a55UMe5 responsibility for purity and stability determinations. The test material Wa5 stored at room Any unused material will be discarded to HLA Standard Operating Procedure. Normal handling procedures were U5ed to HLA Standard Operating Procedure. temperature. according accordinq Test Ani.mal: Young adult rabbits of the New Zealand White -,train were procured, maintained individually in 5creen-bottom cages in temperati-ire- and humidit5j-controlled quarters, provided access to water ad libitum and a measured amount of Purina Hioh Fiber Rabbit Chow, and held 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 Animals". If variations from the prescribed environmental conditions existed, they were documented and considered to have no effect on the stijd,)outcome. No contaminant-. were expected to ha-,.,beeen present in the @eed or water which would have interfered with or affected the rp-5ii1ts of the study. Five male and five female acclimated rabbits, weighing between 2097 g and 2345 9, were chosen at random, treated, and maintained during the ob5er- Qmtion period as specified for the acclimation period. Test animals were identified by animal number and corresponding ear tag. Approx- imately ti4ent.Y-fOLjhrours before test material application, each rabbit's back was -@ha,,,,weidth an electric clipper. The shaved area made up approximately 20% of the total body surface. Reason for Snecies Selection: Hi5torical]5), the New Zealand White albino rab@it has been the animal of choice due to the large amount of background information on thl'5 5pecie5. Preparation of Test Material: The 58MPle was dosed as received. individual dose i@tmscalculated and weighed out based uoc;n each bodk) tieight at initiation. An animal's w HAZLOZON LA.EOFIQ"ORIES AAIERICA. INC. - Chemical& BloMedicalSciencesDivision 330K1INSMABNLVDo.P.OB.OX754o5MADISOWNI,SCONS5I3N7097PHONE(60284)1-494T7L1X7039H6A6ZRAMLDSU-D C;AMPLNELIMPEP7:0905762 c,;AMPLE: T-4102 PACE 4 OECD DERMAL SCREEN (CONTINL.IED) Treatment: The test material was applied to each animal's back at a dose of 2.0 9/kg. The area of application was covered wi,th a 10 x 1.0-cm 98LJZe patch secured with paper tape and a-,.jerwrapped with Saran I)Jrap and Ela5toplast tape. T4ienty-four hours later the bandages were removed and the backs were iiashed with lukewarm tap water and wiped with di5p05- ablf-- paper toi.,iels. Collars were applied to restrain the test animals during the 24-hour exposure period. Reason for Route of Administration: Historically, choice i5 based on the method of Draize. this is the route of Observations: Each animal was observed for clinical signs and mortalit@j at 1) 2.5 and 4 hours minutes after removal after test material administration. Thirty of the test material-the initial dermal irritation reading was made. Sub5equent readings of dermal irritation were made on Studki Days 3.) 7) 10 and 14. The animal5 were observed daily for clinical signs and twice daily (morning and afternoon) for mortality. The animals were weighed just prior to test material application. E3ndk.,) t,,ieightswere taken again at 7 days and at study termination or at death. Pathologk,j: At study termination, 5Lirviving animals All animals., whether dying on test or euthanatized 51jbjected to a gross necropsy examination and all recorded. After necropsy, animals were discarded sak.)ed. were euthanatized. at termination, were abnormalities were and no ti55UF-'5 were. Stati5tiCal method Methods: Other was performed. than average body weights, no other 5tatistical Location report of Raw Data and Final Report: The raw data will be retained in the archives of HLA. and a cop@,t of the final HAZLOZON LO.EKopto%nDRIES AA/ERICA. INC. Chemical& SioMedicalSciencesDivision 3301 KINSMAN BLVD. o P.O.BOX 7545 9 MADISON, WISCONSIN 53707 o PHONE (608)241-4471 TLX 703956HAZRAL MDS UD '.;AMPLE NI-IMBFR: 7n9O5762 ';AMPI-F: T-41112 PAGE 5 OECD DERMAL SCREEN (CONTINUED) SUMMARY Test Animal: Albino Rabbits - New Zealand White Source; Hazleton Research Products, Date Animal5 Received: 11/03/87 Inc., Denver PA Method of Admini5tration: Dermal Application Date Test Started: 11/16/87 Date Test Completed: ll./3n/87 Estimated Dermal LD50: Male - Greater than 2.0 9/kg of body weioht Female - Greater than 2.0 g/kg of body 4j;-iqht Dose Level (G/I<Cl) 2.0 Hour-, 0-4 mF n0 1 MF 0a MORTALITY SUMMARY 2 MF 3 MF Dav-s 4 MF 0a 00 1 0 (NUMBER OF DEATHS) 5 6 MF MF 00 00 7-14 MF 00 Total m F Both 1/5 0/5 i./lo Male Female Ave rani-- Body Weights (9) Initial Day 7 Terminal 218/2193 1784 2148 1671 2374 HAZLOTON LMBCNX'CRIES AT.IERICA. INC. Chemical& BioMedicaSlciencesDivision 3301 KINSMAN BLVD. o P.O.BOX 7545 - MADISON, WISCONSIN 53707 o PHONE (608)241-44719 TLX 703956HAZRAL MDS UD ,;AMPLE NI.IMBER: 70905762 SAMPLE: T-4102 PAGE 6 OFCO DERMAL SCREEN (CONTINUED) Clinical Signs (No. of Animals Affected) Hours 1.0 2.5 4.0 Da@2s 1 2 3 4 5 6 7 8 9 10 11 3,2 13 14 Males Appeared Normal 5 5 5 5 444 000 0 0 0 0 0 0 0 Thin appearance 0 a 0 0 1 1 0 0 a I1 1 3 3 3 3 3 H"poactivitki n 0 0 011001333 3 3 3 2 3 Soft stool 0 0 0 0 0 a 0 1 1 1 1 1 1 a 0 1 1. Loss of appetite 0 a 0 00 002 3333 3 3 3 2 2 Few feces 0 0 0 00 0 033 333 3 3 3 3 3 Diarrhea ne.9th 0 0 0 000000002 2 1 1 1 n 0 0001 000a0 0 0 0 a 1 Females Appeared Normal 5 5 5 5 5 5 5 4 4 4 4 4 4 4 4 1.5 5 Few feces 0 0 0 0 a 0011 1 1 1 1 1 1 0 0 L-05.--,of appetite 0 0 0 0 0 0a11 1 1 1 1 1 1 0 0 Upon transferring animals to the necrop5y area, Animal No. F20575 appeared to go into a 5ubcon,.,,ul5iue state for approximately 3 to 5 minutes. At this time the animal wa-, necropsied a5 a moribund sacrifice. Comments: Dermal irritation observed dliring the sti-id@cjonsisted of sliqht to moderate ervthema and desquamation and slight edema and fissuring. dab HAZLETON LABORATCRlr=S ANAERICA. INC. Chemical& B!oMedicalSciencesDivision 3301 KINSMAN BLVD. o P.O.BOX 7545 a MADISON, WISCONSIN S3707 o PHONE (608)241-4471 TLX 703956HAZRAL MDS UD SAMPLE NUMBER: 70905762 SAMPLE: T-4102 PAGE 7 OECD DERMAL- SCREEN PATHOLOGY (CONTINUED) Dn-@e L.e,,)el:2.0 g/kg of body weight An i ma I Test Day Number Sex Died Sacrificed Necropsy Comments F20455 m 14 Perianal stains appears thin. brown; animal F20491, m 14 F2057r? m - 14 F20493 m 4 - Animal thin. Perinal appears stains thin. tan; animal Treated skin - diffusely red; perineum - stained brown; colon contents unformed; cecum - contents dr.y to impacted; cecum and ileum - 5erosa has multiple red areas,, up to 5.0 x 2.0 cm. F201364 m 14 Colon - contains clear, frothti fluid.; perianal stains - green,: animal appears thin. F?f)1331.5 F 14 Perianal stains - green; subcutaneous tissue underneath treated skin - multiple red, pinpoint foci. F2nr?58 F 14 Parianal stains - dark brown; left axillary lymph node - diffusely dark red: animal appears thin. F201370 F 14 Subcutaneous tissue underneath treated skin - multiple, red areas.,up to 1.2 x 0.8 cm; treated skin - thickened. F20465 F 14 Subcutaneou5 skin underneath treated skin - multiple, red, pinpoint foci. F204815 F 14 Sijbcutaneous skin underneath treated skin - multiple, red areas, up to 0.2 x 0.1 cm. HAZLOTON LM3C*UWCRIES AWERICA. INC. Chemical& B!oMedicaSlciencesDivision 3301 KINSMAN BLVD. o P.O.BOX 7545 a MADISON, WISCONSIN 63707 o PHONE (608)241-44719 TLX 703956HAZRAL MDS UD C;AMPLE NIJMF3FR: 7n905762 C;AMPLE: T-4102 PAGE a OFCD DERMAL SCREEN (CONTINUED) Reference5: 1. Organisation for Economic Cooperation and Development'5 Guidelines for Testing of Chemicals, Section 402, Acute Dermal Toxicity, Adopted May 12, 1981. 2. Draize., J.H., "Apprai5al of the Safety of Chemical5 in Foods, Drug5, 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. NTH Pt.iblicationNo. 85-23 (revised 1985). HLA LAB NO. 70905762 PATHOLOGY REPORT Acute Dermal Toxicity Page 9 Ten rabbits (five males, five females) were necropsied. One male died on test and the remaining animals were euthanatized at the termination of the study. The dose level, day of deatn, and gross observations recorded for each animal are on page 7 of this report. The subcutaneoustissue of the treated skin of four females had multiple red foci or areas of variable size. The treated skin of one of these appeared to be thickened. Several animals were noted to be thin. All otner observationswere considered incidental and unrelated to treatment. The treatedskin of the died on test male was diffuselyred. This animal's death was attributed to enteritis of unknown etiology and unrelated to treatment. Thomas E. -Palmer, P-h@@ Uate Pathologist (1734mcs) HLA No. 'PersonneSlignatureShoot Acute Toxicology Nam Job Title Signature Becky Beckwith Steve Beloungy Ken Bridges Pat Crary Sr. Lab..Animal Asst. Lab. Animal Asst. Sr. Lab. Animal Asst. Sr. Lab. Animal Asst.- Shane Eith Lab Animal Asst. Shawn Frazier Lab Animal Asst. Steven M. Slaza Group Leader Molly Mhn Admin. Clerk Kevin Hamilton Lab. Animal Asst. Jeff Hicks Sr. Lab. Animal Asst. Calvin Norton Group Leader Sharon L. Howery Administrative Asst. Gregory Johnson Lab. Animal Tech. Paul Krebs Lab. Animal Asst. Wayne Madison Section Supervisor zd. Scott ftconnell Lab. Animal Tech. I&, Shelley McConnell Dawn Conant Lab. Animal Tech. Sr. Lab. Animal Asst. Don *avis Lab. Animal Asst. Robin Olson Lab. Animal Asst. Patricia Padqlhm Joseph J. Daun Tom Leader Lab. Animal Asst. Michael Patzka Lab. Animal Asst. John Paulson Sr. Lab.'Animal Asst. Jane Polnow Lab. Animal Tech. Dennis B. Steiner Lab. Animal Tech. Michael Thesing Lab. Animal Asst. Paula G. Vangen Albert Olson Administrative Asst. Manpower Jim Jirschele LTE Ben Haley Sr. Lab Animal Asst. Eileen M. McConnell Admin. Clerk Annette R. Turner Manpower -/7t5rl@..IW, Initials -JE- 441%4191 i"W-- HLA: -1 @,g C,51 ACUTE DERMAL APPLICATION LD50 IN NEW ZEALAND WHITE RABBITS Test Material: @-T- q iCQ Physical DescT.iptidn: Ar..V, Dosage Level (9/kg): Q.DQJI.< Date Animal Received: II)f Vehicle: A)iQ Date AnitnalsClipped:lll.,;/e7 lechnician:__igrL_ Source: Hazleton Research Proaucts' Room No.: ,2.c,.L CK. tl/l-i/97. Animal Nu DOSE CALCULATIONS boidy Weight Dose Level (kg) (g/kg) p -6@@. 19(p Q,o o4@il 11A du.5,@4 6qq3 6?. i COMPOUND PREPARATION WET.GHTS oz@@D-M Dose Tare Weight Total Weighi mple Weignt Animal (g) (a) (9) (g) oo @-zq-sq. 5. @q;z tl5,7 5.V! 71 /.g3 /o,/.5- 4.40.6 c,. 5'. @/o -s-. @y I f,&,3 Calcu-latedtry: Verified by: Scale Used: Animal Number oqql I VO Da-te./:/,/6-97 Conrivirtabiyi-. Date: Approved by- /0,0? C-,-AA Animal Bocv weiants tg) Skin 0 study Day Prep Sex 7 14 %8 --i:- Ler 6)114- Date:ll-l6-f7 Date: o e..?se-T (2 C? 16 !QqlK@g ?IIRG7 YS Yil n6-?o 0q %y 9- I -AL, I 9- 2a24@l KO ;2"2al Iz4siS-7. chnician ate 'Vito kg Yaz 1)11116 f;@@t -ilLiz.6,.L icale Used kw'-4-447e %@ WP 1 1;-)-2R - I - Intact NA - Not Applicable A - Abraded (with a clipper blade) Reviewed By Date (00261/vmt) HLA MORTALITY REPORD Test material: Dose level: Animal Number Observation Period (D vs) 2 3 4 5 6 7 18 9 10 1 AN PH AN PN M PH AN Plf Afq_ PH AN I PH AN P[41AN PH AN PN AN PH AN V/ vj v---v/ e v@ L/ PH AN 6qg,3 ekPlINo, v v/ 0510 0 q(0!-5I,/v-, V I-o' k/ t./ V/ vl v,, echnician & 0-0 K6 ate 19r) 1 1) 6 NA - Not applicable. X Dead. WI Alive. 19 f -ktlqiAll/ @lgty9)6 (D6-n4r(i57rror it,/ (00261/vmt) v/ Reviewed by: Date: Dose level: r) ei // kr. ".i Animal Number (ga/Female Observations AvDeared Normal 3c@Cl -51ne, I ,Zip4oeA4 oqqi Appeared Norm] FetA3@ec-e--3 o@@aar, DD ared Nor=] 0575 L,@issro' App;vrrr i4!ePAAe-rijr- afty's F2-- 6q93 Appeared Normal APPEW-S Irati Hh*r@AC.Tr-) C-- OBSERVATIONS (Individual) Test material: I- 4110a HLA: 7 Pre- Hours dosg 1112,12.5 4 s udy Day 1 2 13 14 5 61 7 8 19 -PO10 11 12 1133M 14 -- - - ;70- - loe wo' -,ol /-roe A Api, Tot k) Survi submi necr( Techr Date -Al- It@2 -3) 6- Surv desig and d Tpchn Date hppeared Normal Li 1/1 .1000' eaths ollectedby iate 7a-,r-7 &-00' ,0" 7= - v In ex si si Co Fo 1 0 610 vio 10 -0 L7 f) n Revi e "M M. c@ Date: QsEr,@,,u3As L%Et@ As A rr@ootw.otot) r,fir.)@:.;:,a- m. c@wEc"r, -rc@ &-Ujr. %Eo -rD E<PLAIlkT)H;-:QAEFSL-TL,NXP,-47rT-161,1 Dose level: ",0,n e) le4 li -i Animal Male e Number Observations Appeared Normal OBSERVATIONS (Individual) Test material: 7-1//OQ Predose Hours 1-12..L 4 v Stud Day 1 2, 3J 4 1 5 1 6 -71 8 1 9 110 11 12 13 14 oo,I.- HLA: -7 ADDeared Normal I:kw @ ec e-,s @2i AppeareT or=ma 05 Appeared Normal F*@- - - - - -1 -v- L--,-,-oZ L,- - _Ile Lz Loo, Awl Lo Aepeared Normal OLi@@ %/ v "0'iz eaths loilectedby ate iqE7 "/Iw 'lilt u.Zz Surviv submit necrop Tochnll Date Surviv design and di Tpchni Date Ind exi si Sli Con Fou Revieto Date: HLA: ACUTE DERMAL IRRITATION OBSERVATIONS Test material: Dose level: fiA7 Erythema EdemaAtonia Desquamation Coriaceousness Fissuri Erythem Edema Atonia Desquamation Coriaceousness Fissurino Erythema Edema Atonia Oesquammaa@tniA Coriaceous@n@essns0ess Fissurina 1- -7 An imma i 0 ti 0 0 n1 Males 3 7 "]IcA "b3 No.:r-z-n4 o 0 0 o In observation Pe iod (Days) Females 10 14 3 7 -"L--i,-, '5730 ntactyA braded Vi -7 1 Animal No o In I 10 ntac T--T 14 IIf..46 A raded I n n I Anima No.: F2-ma I ntac Abraded I i Animal No t) -e) 1 Animi r) n 0 0 iff 0 f3 0 0 A I 067,r o :F?- 0 1 4n e;, 0 0 0 n e-, -6-V n ac -o 0 0 0 0 in e5 t) i I (I 10 r INIP7 Abraded Animal No- 0 1 1 0- 0 e> 12 Rti 0 e,) ntac Abraded -( I a t% 0 0 14.f) n I eN ^ -cg,7 Intac A raded 1 01 r) e@) C) Erythema Edema Atonia DesouamationCoriaceousness Fissurig&. AnifmmNao.: n-04q3'--In-ta@Abraded l@si; C) n 0 Animal No -oL)65:ntiact raded e) lop t) 6 ei 0 i t) A Erythema Edema Atonia Desquamation Coriaceousness Fissuring Technician Date An immaI No.: I 0 42 fl) 1) 0 -r&,4<i@"raded IliWA3 I eA\ 0 h 0 m i(b t A -2 n An ima 1 No. : Fl -0,4fSC I-n-ta-ct@Ab rad ed i TV-T-6 I rs 0 0 0 0 0 ri 0 0 n 0 a 00 Cl 0 A Subcutaneous hemorrhage. 8 - Blanching. C - Scab formation. 0 - Eschar. E - Exfoliation. F-- K&-64%--4Z7 0) (no25ll@imt) r,4ray Eae4aS KS U300f,@r.r--C-Oaes ENjreeEo 6.%tre@ytoc15.0.f1t-;k4-q? Reviewed by: 46cl- Date: Q:L-#@37