Document baeDvYVqMb1YN4JQYBmMM6Rr3

Oin-C OC`^ THE DOW CHEMICAL COM PA N Y October 25, 1974 BENNETT BUILOING Z030 DOW CENTER MIDLAND, MfCHtGAN <48640 Mr. K. D. Johnson Manufacturing Chemists1 Assoc. 1825 Connecticut Ave., N.W. Washington, D.C. ' 20009 Mr. H. L. Kusnetz Shell Oil Company Room 1574, One Shell Plaza Houston, TX 77002 Three protocols are attached. The first summarizes briefly the current study at IBT. The second summarizes the study the committee developed Sept. 18, 1974 and which it agreed should be discussed with the Rail Committee._ The third is a proposal I put together since I don't like proposal #2. I see no reason to omit hamsters and.I would like to delay the start of more mice until we have metabolic data. My proposal accomplishes both. * I'll be calling you next week. Sincerely, kJcol Q. <-k'i.kcUcn^ Theodore R. Torkelson Corporate Medical Department kjf end. see 5-0542 l'lANUFACTO 1\IAG fUILiCrtVS f ALOrr; iation. INC CHRONIC VARGA IhAV AT JON TGAUivyv STUDY WITH VaCUT,GRID'" INDUSTRIAL l 0-TG5T LAROHATORIES DEC/ 'UK, ILLINOIS Oatl:i re of Inver 1 rga tz.o]i 7\. Type and Length: 9-month vapor inhalation in White Mice + 9 months observation 12-month vapor inhalation in Albino Rats + 12 months obsorva1;.i 12-month vapor inhalation in Hamsters + 12 months observation. r . ITiob'n ol Aninv-J:;: 800 M: co * 9 00 Kct-S. 800 'Rasters. i:. LiAuilSui 0- ;> - i H." (1 U l l_, ;ic:Vv-iii mriii- r. ije;r ild.'J . Live days per week. D. Tost Koooriols^ E. 0 r q an i s a t io n: Vinyl Chi e-ride (Ethylene de::ive:f; See Table I. P, Dose Levels: See Table I- G- Exposures Started: Sept. 1973; mice, rats & hamster- Exposures Termor: a r edj_ June 1.9 74? nice. Sept. 1974; rats & hamsters. Terminal Autopsy: March 1975; mice*. Sept. 1975; rats 6 hamsters. 1(/wt r'SX'T/J, Excess mortal ty made it necessary to sacrifice all 'E-II and TR-III ;n;i e after 11 months on experiment. a- see 5-0543 : Material : '' _ i or 1C.0 ,v._;iene dsri ved) TAB 1,0 T CHRONIC VAPOR INHALATION TOXICITY STUDY Organisation of Groups Group M ice Males Females Number of Animals Rats Hamsters Males Females Males Females Control 100 100 100* 100* 100 100 TE-I Low Level 50 ppm .LOO TE-I I Intermediate Level 200 ppm .LOO TE~II High Level 2500 ppm 100 TE-LV High Level -2500 ppm with food - 100 100 100 - 100* 100* 100* 100* 100* 100* - 100 100 100 100 - 100 100 100 ~ of these rat groups were reduced by sacrifice of 5 rats for cytogentic and histopathological :inetion at the end of the 12th month of exposure. ui ...o - see -0544 'XI, Chamber Parameters Eacru group o l aor^als v;L.'.I bo exposed in a specially constructed st-j:inless steel and plexiglass inhalation chamber shaving a capacity of approximately S.3 M3, allowing animal loading of less than 2% when the animals reach maturity. Flow rate through the chamber will be at least 1.53 M^/min. providing a theoretical air change every six minutes. The chamber supply air will be filtered and maintained at 40% to 60% relative humidity and 70'"' to 75F. Food will be removed from all animal cages during exposure except Group TE IV rats. II. t j.;i.n:.cur All animalc will be observed daily for lesions and behavioral changes attributable to the test material. The time of appearance and location of all tumors that occur among both control and test animals will be recorded. Mortality records will be kept on ail groups of animals. A3.3 animals which die during the study will be necropsied and their tissues processed in accordance with the methods given in the Anatomic Pathology Section. Care will be exercised to minimize loss of tissues through cannibalism or autolysis. Animals in a moribund state will be sacrificed in_ extremis when death is imminent. B. Body Weights Individual body weights will be recorded once before exposure and after 1, 2r 3, and 4 weeks of testing. SCC 5-0545 Thereafter , mean group body wo.L gh ts will be determined monthly up to the 12-month point of study. C. Clinical Pathology Hemoglobin, hematocrit, total erythrocyte and total leukocyte counts will be performed at 18 and 24 months on 30 (15 male and 15 female.) rots of the control and each test group. Differential leukocyte, counts will be performed on alJ anima]n having high total leukocyte counts. D. Anatomic Pathol.o~v -f C- Upon, completion of the study, all survivors wi 11 be sacrif ic0d by e.sanguinaf.icn foilov;ing carbon dioxide anesthesia.. 2. Gross Pathology Complete necropsies will be performed on all animals which die or are sacrificed and all macroscopic lesions will be recorded. The lungs will be inflated with formalin fixative. 3. Histopathology Representative specimens of the following organs and tissues will be taken from all animals at time of sacrifice and fixed in 10.OS neutral buf fared forma], in : -A- SCC 5-0546 Adrenal Glands All G;:oss Ac-sions Bone (femur , hersal and itictatarsal, including long bones of all four limbs) Bone Marrow (siernal) Brain Both Boro (external auditory canal with ceruminal (gvmbaj.'s) glands) Esopha.gus Eye Gonads (testes and ovaries) Kidneys Large Intestine (caecum and colon) Liver Lungs Lymph Nodes (tracheobronchial, cervical and mesenteric) Optic Nerve Pancreas Parathyroid Gland Pituit r:y Gland Prostate Salivary Gland V *V > .t. W U 0 >k in Small Intestine (duodenum, Spleen Stomach Thymus Thyroid Gland Tracheo Urinary Bladder Uterus jejunum and ileum) The above tissues, from animals of the control, TE-II, and TE-III will be processed by conventions methods, embedded in paraplast, sectioned (4-6 p) , stained with hematoxylin and eosin, and evaluated by light microscopy. If drug-related lesions are detected in tissues from the high or intermediate dose (TE-II or.TE-III) animals, affected tissues from the TE-I group animals will be processed and examined in the same mariner as the above.. 3CC Only major organs (1 i vor; kidroy, spleen, heart, lungr) and neoplasms ftow -minia.Is which die and are round vu an advances st.e tf. of auroiyir< will be processed for h intopatbolog icai evaluation * IV.. Reports Quarterly summaries of mortalities, clinical observations* clinicopathologic and ana tomc p at ho logic findings will be prepared. Upon completion ci the study, a complete report will be prepared and issued. October 23, 1974 see 5-0548 PROPOSED PRGTCCOIi__ A MANUFACTURING CHEMISTS' ASSOCIATION', INC. CHRONIC VAPOR INHALATION TOXICITY STUDY WITH VINYL CHLORIDE Cm- .i.ne of Investigation A. Type and Length*; 9-m.onth vapor inhalation exposure in White Mice plus 9 months observation. 12--month vapor inhalation in Albino Rats plus 3.2 months observation. Number of Animals Exposure Duration: >r f- Mr-: ' n'*" ^ S . S ^ Mice Y,-t Rats Seven hours per day. Five days per week. Vinyl Chloride (imM n t sa t rt.i * Dose Levels: See Table i U Proposed Schedule Terr Group Exposures Start Exposures Stop Mice: Control, TE-I t .TE-II, TE Dec. 1974 Sept. 1975 Rats: Control, TE-I, TE-II, TE<<LV} Dec. 1974 Dec. 1975 De: -1 see 5-05^19 CHRONIC VAPOR IN H A LA T IO N T O X IC IT Y STUDY V IN Y L CHLORIDE i n ft ;i5 --<MTJl H; & U) <-Hl) rd 32 <4-1 0 cn u0> r<Hu .Q 03 s H<u 25 AS<OH-DH Cm w r<HD 03 s r* I. pi > <* > A m a, 3 o u* VJ 1--) yj fc! O > 0) -rl -i-j i o 4-> } H c tton M O rH ft o '^1 Oj -!-i /} I /*o\ r--1 <3J > <D i-3 g O, 5 ft 03 <U fH <V ft 4-> ft r: U1 H 0) > (U 1-4 g ft ,C ft -H(0. KW v_ M M H M M M 11l w c-t M Eh W EH 3 M O-t t o-i 5 see 5-0550 II. Chamber Parameters Each group of animals will be exposed in a specially- constructed stainless steel and plexiglass inhalation chamber having a capacity of approximately 9.3 f allowing animal loading of less than 2% by volume when the animals reach maturity. Flow rate through the 3 chamber will be at least 1.53 M /min. providing a theoretical air change every six minutes. The chamber supply air will be filtered and maintained at 40% to 60% relative humidity and 70 to 75F. Mice are to be individually caged; rats will be ca.ged in groups. Food and 'water will be provided ad libitum. III. Animal Parameters A. Clinlcal Observations r All animals will be observed daily for lesions and' behavioral changes attributable to the test material. The time of appearance and location of all tumors that occur among both control and test animals will be recorded. Mortality records will be kept on all groups of animals. All animals which die during the study will be necropsied and their tissues processed in accordance with the methods given in the Anatomic Pathology Section. Caro will be exercised to minimize loss of tissues through cannibalism or autolysis. Animals in a moribund state will be sacrificed in extremis v:hcn death is imminent. see 5-0551 ZQGO-S DOS -fr- ATqxx:j uT-f-suuoj qqxt\ poqT3UT q i'[iw GiDimq* qx *ppj:o3x q XTTM suotsst oxdoosojiDeui XX pu pooTjTJo^s 3 Jto exp qoxqtt sxurtu XT UO pUUOJ J5d q XXT^ ssisdojosu qxd.moo A&oioqqa SSOJ3 *z ' Tseqqssxrs Gpxxoxp uoqxo 5ut/-\oxxJ uoxqisiiTn&ire-sx Aq pOTqx;ios q TTT sjoATA.xns xx' J-^pnqs otR ?o uoxqaxSwoo uodn o;)-rgpo?S 30 spoqqsH X - S'^U'ioo roq.Xnoqnox Xqoq qfixq, 6uxAq s [GuiTxre XT uo psuixcqaed q jtxm qunoo qAoqnx x^xquBaG^jxa *dr.o;iJj qsq qo pa Toxqaoo qq 50 sqx {[weq sq pu xui 51) OP wo sqquoui T/ pu sx q pluao-j:jd q x\TA squnoo qAooqaT Tqoq pu qAooxqqnj: Tqoq ' qx:tDcquiDq 'uxqoT6ottH Aficroinici IbpuTXD Apnqs qq 50 qtrtcd xrxuom-^T qq cq cln Axqquui pU'puijqop XTT^ sqqbxsrt Apoc; daojiS upiu J .lyqqeoxoqj, `Buxqsoq :to nq/--. o pr/c ' c 'p ' r Taq.p pa ^"i-joaxo ^Qiaq duo pp;iooo.i =>q x tTA f;qq&T0/A Apoa xanp'L'ATpui ST;. 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H- CL rt' 3 >- sr a POj H C CD d ft C5 P* a- p P* c3 7? c-q p* M O ft 3 O P JoS <x> '3 O cP 3ft f-tf Pft H 00 03 3ft ft L'i ft rf ft p CL ft p Pft P r.- ft 0* rt PP-1 U'. p- < P 03 ft G* ft 03 X- Cl 00 rii ft Q hc: hfi fh 0-3 ft ft w ftP 0) ft CL o ; PM* Pj__-j ft p P! 3 Pi O PPi cr 03 p i--'- 0 0 3O f-h ft ft v H ft P Uj^ ft P* 3 300 # Cj 3 P rh P Q P- P' rS O P CD 3 g b -M ft P- P* H* p M <T Wu. p. 0 \-p rt' c. 0 ft I--1 see 0553 Only major organs (liver, kidney, spleen, heart, lungs) and neoplasms from animals which die and are found in an. advanced state of autolysis will be. processed for h is top at hoi ogle evaluation.. f_ V,, Re ports- Quarter!.y summaries of mortalities, clinical observations, clinicopathologic and anatcmcpathologic findings will be prepared* Upon completion of the study, a complete report will be prepared and issued. October 23, 1974 -6~ sec 5'0554 ssso-g 33S ) l. 6 T O0G 9/.6T Si 61 imp '6-ii-skl ' 6- 1-3.1. :ooiW ) /. 61 * DOCI * oeC ? /- 6 T *oa Aye ioqnv j'trU ':iuas`v, Si6T * D3Q SA6T * oa Si 61 imp doqs ssjnsodxa *1 PL6X osa 'ZT-II-HJ. '2T-I-HX : sjaq sureH VL61 * OOQ VL6X ' oa 2I-III--3J, 'ST-II-ai 'ET-I-SIJi `9-m-aj. '9-ii-sj. '9-I-HX JXOJquoD = sqea qjEqs soansodxa dno:ro 3>S : X^P*-PS pysodo^a :si`3A9n; osoq 'D 'I spxaoxMO ;cs>d sA-ep satj Asp J0d s.iaoi{ usas : aoTqezTUEp-TO qs<l "3 a uoi'?f`2in(i sansodXH "o oop'W 008 y-isun?h 008 ~ -r - cl yui< l suquoui f5 * UOTqEAItSSqO otpj qxqM we u<: : 4-t>x^HT-i';- jccx^sa qqAioiit~$ ' UOT'-lEAICSSqO sqquoiu ZX sngd nneqsuren tit uOT3f?X-quT ^odeA uquoui-^x 'UOTqEAJSSqO i-qucui z.X snxd squy ouTqxv UT uott.ex^HUt aodsA qquotu-sx 'uoTqEAjasqo -A qquoui ox engd steic ou'cqxv UGTqs^quT aociEA qquoui-9 : *qq>u&'i pus dAx, *V uoT-qsbTqssAul go uTxqno *1 aaiHGrIKD TAM IA H./.lM ACUUS A7.;>IXG.L NOI J,Vrl\THMI ITOd.VA 0IN.0HH3 * dn:c J Ko.iivioossv ; sj,siMti-io GMnia.LOvjnMwi p .-:0'v lO'ici casodoud /- C H R O M IC VAPOR IN H A L A T IO N T.C'AiC IT Y STUDY V IN Y L C H LO R ID E W - -! O o o o 10 O o o o g rH rH r-r 0 'll o Tn "H <0 0oo o o H o o o o v0-< l-H <~l I--4 <H M CL 3 o O e> CO mh f'-' O Pi o u ci CL *rs o +J u0 OU w **! C O' otH 10 r--! U3 OJ a) r-l 0 q to g 0) <y pH 4-1 4~> ow e to u ctf 0 0) SB rH & td S 3 55 03 0 rH as 2 L0 0 rPt & Cm to 0 rH r*-5r o o o o rH O O rH O o *H rH O CL 3 .p Oc JH o Ou ooO oa o i--! <~i rH ooo ooO rH rH rH OO OOO o Oo o o O o r--t M rH rH <H rH oOOoOo o ,_{ O , o r--> o -H O rH O rH iJ rH rH Q0 > t> 00 1 t--{ 0 > (0 r-1 S CL |5_CL S''cA S' \ H 1 W Eh 03 +J *H TJ 0 g a5h S 0 +J a. C H io W W 1 w Eh 1 rH > 0) t-3 S A JO Cl4 O' M JH M 1 W Eh 1 *-H > 0 S a CL o A <N to 1 M 1 HEh 0 jj -<H T3 0 P6 0 CL P 04 A to to 1 H M 1 w Eh ( rH <y > 0 W cl JB CL O' *H O CB rH to 1 H H Hi l w Eh rH 0 -H U 0 4-> 0 .t.i Cfi fG_>j TOTAL 700 700 400 400 400 400 sec 5-0556 II, Chambe:: Pciram-: ters Each group of an imal s will bo gx/.o^od in a specially constructed si-, a in ler.s steel and plexiglass i; ': - Lution chamber having a capacity of approximately 3.2 'A'*, allowing anima.l loading of less than 2% by volume when the animals reach maturity. '3 Flew rate through ere chamber wit2. bo at least 1.53 II /min. providing a theoretical a is: change every six minutes. The chamber supply air will bo filtered and maintained at 40% to 60% relative humidity and 70 to 75F. Mice are to be individually caged; rats will be caged in groups. Food and water will be provided, ad. lititurn. All rats and hamsters vjill be started simultaneously. After 6 months of exposure groups TFj-I-6,- TH-II-6 and TE-III-6 will be removed from exposure and hope for IS months observation. The expo euros of the mice v.'iil then commence. Therefore, all terminal autopsies will fake place simultaneously 24 months after the start of the experiment. III. Animal Parameters A. Clinical Observationsi All animals will be observed daily for lesions and behavioral changes attributable to the test material. The time of appearance and location of all tumors that occur among both control and test animals will be recorded. Mortality records will be kept on all groups of animals. All animals which die during the study will be necropsied and their tissues processed in accordance with the methods given in the Anatomic Pathology Section. Care will be exercised to minimize loss of tissues through cannibalism or autolysis. Animals in a moribund state will be sacrificed in_ extremis when death is imminent. SCC 5-0557 B. Body Weights Individual body weights will be recorded once before exposure and after X, 2, 3, and 4 v/cof testing. Thereafter, mean group body weights will be determined monthly up to the 12-month point of the study. C. Clinical Pathology Hemoglobin, hematocrit, total erythrocyte and total leukocyte counts will be performed at 18 and 24 months on 30 (15 male and 15 female) rats of the control and each test group. Differential leukocyte counts will be performed on all animals having high total leukocyte counts. D. Anatomlc Pathology 1. Methods of Sacrifice Upon completion of the study, all survivors will be sacrificed by exsanguinatior. following carbon dioxide anesthesia. 2. Gross Pathology Complete necropsies will be performed on all animals which die or are sacrificed and all macroscopic lesions will be recorded. The lungs will be inflated with formalin fixative. -4" SCC 5-0558 ip;: the 1 Penrose; via ti vc specimens of the following organs and tissue? will be taken from all animals at time of sacrifice and fixed in 10.0% neutral buffered formalin: Ad r <?. n_ 1 Gland s All Grc^s Lesions Bone (femur, tarsal and metatarsal, including long bones of all four limbs) Bone Marrow (sternal) Brain Both Ever, (external auditory canal with ceruminal (Zymbal!s) glands) Esophagus Eye Gonads (testes and ovaries) Kidneys Large Intestine (caecum and L ivc;; colon) Lungs Lymph hodes (tracheobronchial, cervical and winsoTH-.Civi p \ Optic Nerve Pancreas l-ara thyroid Gland Pituitary Gland Prostate Salivary Gland Seminal Vesicles Skin Small Intestine (duodenum, Spleen Stomach jejunum and ileum) Thymus Thyroid Gland Tracheo Urinary Bladder Uterus The above tissues, from all animals, will be processed by conventional methods, embedded in paraplast, sectioned (4-6 p), stained with hematoxylin end eosin, and evaluated by light microscopy. see 5-0559 IV. Only major organs (liver, kidney, spleen, heart, lungs) and neoplasms from animals which die and are found in an advanced skate of autolysis w;<13. be processed for histopathologic evaluation. Reports Quarterly summaries of mortalities, clinical observations, clinicopathologic and anatomopathologic findings will be prepared. Upon completion of the study, a complete report will be prepared and issued. October 23, 1974 -6-