Document wDdOEkodNbOBQnYkRV9Daq6XE

TO: Interoffice Communication FROM: DATE: SUBJ: Distribution TGG: JCL: ERT: MJH: AJO:?RFe A/ . ** *-' XF:___ _------ ---------------- T. G. Grumbles June 12, 1990 PVC CARCINOGENICITY STUDY: ORAL ADMINISTRATION OF DOSE VISTA Attached is a study conducted to assess the carcinogenic potential of PVC resin when administered by gavage (force feeding). In summary, PVC resin (suspension and emulsion), when suspended in olive oil and administered by gavage to rats every 2 weeks for 52 weeks, did not show any carcinogenic effects. The attached is provided for your information. The Product Safety Assessment Group will review the study to determine if revisions should be made to our resin MSDS's. T. G. Grumbles dlj .105 Attachment Distribution: Brent White-OKC, Bruce Trego-Aber, Dave Penney, A. M. Nielsen, J. R. Roheim, Diana Fenton, Lee Matheson, Curt Elsik, John Kirkpatrick-Austin, W. L. McClain cc: w/o attachment T. H. Huffman R. W. Seymour-Aber, H. Garrison-Okc VVV 0000010A7 The Vinyl Institute A Division of The Society of The Plastics Industry, inc. Roy T. Gottesman May 21, 1990 To: VI Health Safety & Environment Committee VI Technical Committee's Medical Subcommittee Jerome H. Heckman, Esq. RE: Non Toxicite Du PVC Etude' Maltoni 1989 Through the courtesy of Nancy Russotto of the European Council of Vinyl Manufacturers, I have received the enclosed document giving the results of a recent study by Professor Cesare Maltoni. The report concludes that repeated administration of PVC dust in olive oil suspension by gavage to rats did not result in any carcinogenic effects. Please note that the dissemination of this text must mention that the study will shortly be published in the Italian medical review, Acta Oncoloqia N 1989/4. Further, it is re quired that the study must be circulated in its entirety, with out omitting the curriculum vitae of the author. RTG: g Enc. VVV 000001048 Wayne Interchange Plaza II 755 Route 46 West Wayne, NJ 074 70 (201) 890-9299 SOLVAY& Cie scofei^ariorvme drectbn natbnale par le benefux drectbn ccxnrnerdaJe matieres plas&ques 2 4 An. 19S3 NON T0X1CITE DU PVC - ETUDE HALTONI 1989 Par notre telefax du 12 octobre 1989, nous vous signalions l'existence oe cette etude dont le resume est : "De la fine poudre de PVC, produite respectivement par polymerisation en suspension et en emulsion, a ete administree en suspension dans I'huile d'olive par gavsge a deux groupes de 40 (20 males et 20 femelles) rats SPRAGUE-DAWLEY, tges de 10 a 11 semaines au debut de 1'experimentation. Deux mg de poudre de PVC ont ete administres en une fois toutes les 2 semaines durant 52 semaines (27 traitements). Le groupe controle etait constitue d'animaux traites de la meme fagon et n'ingerant que de Vhuile d'olive. Les animaux furent observes jusqu'i leur mort spontanee. Aucun effet cancerigene n'a ete .observe chez les animaux traites au PVC." En bref, cela veut dire que 1'on peut ingerer de la poudre de PVC sans encourir de risque de cancer. Ainsi, contrairement au monomere chlorure de vinyle, dont le meme Professeur HALTONI avait mis en evidence les effets cancerigenes, le polymere PVC est lui totalement inoffensif sur ce plan. W presen1t7*nous"avons'regu,"du Professeur HALTONI, V-autorisation d'utiliser HSt-de communiquer son ^tude,r~i deux Conditions : * " ' T- signaler que -Vetude sera prochainement publiee dans la revue medicale 1 italienne ACTA ONCOLOG1CA n`1989/4, communiquer 1'etude dans son entierete, sans omettre le curriculum vitae de 1'auteur. Nous vous communiquons en annexe le texte de 1'etude, tel que nous l'avons regu, et la traduction frangaise approuvee par le Professeur HALTONI. VVV 0000010^9 ANNEXE In stampa su Acta Oncolooica 1989/4 LONG-TFRH CARCINOGENICTTY BIOASSAYS OF POLYVINYLCHLORIDE fPVCl ADMINISTERED BY INGESTION fGAVAGE) ON SPRAGUE-DAWLEV RATS Cesare MALTONI Institute of Oncology "F. ADDARII", Bologna, Italy CURRICULUM VITAE OF PROFESSOR CESARF WALTONI. MD Born in Faenza (Ravenna) Italy, on November 17, 1930. Graduated in Medicine and Surgery at the University of Bologna. Docent in General Patho logy and Oncology. Director of the Institute of Oncology of Bologna since 1964. Professor at the school of Oncology of the University of Bologna. Past President and Honorary President of Italian Society of Tumor Prevention, Detection and Therapy. Member of the Italian National Board of Health, and of the Italian Commission of Carcinogenesis, Teratogenesis and Mutagenesis. Past Chairman of International Committee of Human Tumor Charac terisation. Member of the Academic Internationale de Lutce, and of the "Academie des Sciences, des Arts et des Lettres". General Secretary of Collegium RAKAZZINI. He is author of more than 320 scientific publications, and co-editor and contributing editor of several scientific series of books, and scientific journals. His major contributions were : 1. the promotion of large scale screenings for early diagnosis of tumors, 2. the promotion of health surveillance of groups at carcinogenic risk, 3. the foundation of the Tumor Registry of Bologna, and, 4. the setting up of a large Experimental Unit of Industrial, Occupational and Environenmental Carcinogenesis (when it was shown that : 1) vinyl chloride is experimentally a multipotential carcinogen, causing, among other tumors, angiosarcoma of the liver, 2) benzene is an experimental multipotential carcinogen, and, 3) many other widely produced and used compounds are carcinogens on experimental system. VVV 000001050 I. INTRODUCTION A wide variey of vinyl chloride (VC) based resins, homo- polymers (PVC) and copolymers, are available, with varying properties, for different, specific applications. The co polymers are made with low levels of other comonomers, such as vinyl acetate (PVCA) or ethylene. VC resins are used for the production of rigid, semirigid and flexible plastics. The rigid plastics are processed essentially without plastic izers. The semirigid, and flexible plastics contain plas- tizers, among which the most commonly used are the dialkyl phthalates. Other materials are also used in the production of VC plastics, such as pigments, fillers and light-and heat- stabilizers . VC resins are among the most widely industrially produced polymers: world production may be evaluated in millions of tons (in some years over 10 millions). The uses of VC plastics were as follows: building and con struction industries, consumer goods, electrical appliances, packaging, transportation, and several other miscellaneous uses, which include plastic material for medical applications. The mayor uses of VC plastic packaging are in plasticized film, bottles and bottle-cap liners and gaskets. VC plastics are largely used for packaging of food and of non alcoholic beverages. Packaging for alcoholic beverages was withdrawn because of the high migration of VC into the alcohol. VVV 000001051 3- - Implants of PVC and PVCA squares, discs or films in cxperi mental rodents were shown to cause the onset of local sarco mas (IABC, 1379) (Table 1). The mechanism by which PVC and PVCA, as well as other solid materials (plastics, metals, etc.), can cause local tumors was and still is matter of de bate. It may be hypothesyzed that the carcinogenic effect is due to physical change brought by solid material into the cellular environment (solid carcinogenesis ). It cannot be ruled out, however, that the carcinogenic effect is a conse quence of the migration of soluble, reactive compounds (among which, in the case of polymers residual monomers) from the implanted material to the surrounding animal tissues. In the case of VC-based resins, this.possibility is of particular relevance due to the fact that VC has been shown to be a multipoter.tial carcinogen in experimental rodents and in humans (Maltoni et al., 1984). Up to present the carcinogenic effects of PVC and PVCA have been studied only in experiments in which the material, under various forms, was implanted within the animal tissues. In our opinion, the long-term biological effects of PVC deserve further and more specific research, also in considera tion of its wide use for food and beverage packaging. The present experiment was performed to study the long term effects of PVC dust on rats, following repeated admini strations by ingestion (gavage). With this type of treatment, gastro-intestinal mucosa is particularly exposed. However it must be also considered that after oral administration of PVC dust to experimental animals (including the rat), PVC particles are persorbed through the intestinal mucosa, can be found in the blood, and via the bloodstream they are 000001052 VVV -H- disseminated into all the organs (where individual particles can be found a long time later). II. MATERIALS, METHODS, PLAN AND CONDUCT OF THE EXPERIMENT Fine PVC dust, produced by suspension and by emulsion poly merization, was tested on Sprague-Dawley rats, by ingestion (stomach tube). Male and female Spragpje-Dawley rats 10-11 week old at the start of the experiment were used. The animals, were of the breed currently employed at the Experimental Unit of the Bolo gna Institute of Oncology, in Bentivoglio (BT). The plan of the experiment is shown in table 2. Details on the conduct of the experiments are given in I table 3- Systematic and standardized histopathological examinations were performed on: brain and cerebellum, Zymbal glands, inter scapular fat, salivary glands, Harderian glands, tongue, thymus, lungs, diaphragm, liver, kidney, adrenals, spleen, oesophagus, stomach, various segments of the intestine, urinary bladder, uterus, gonads and any other organs with pathological lesions. III. RESULTS The experiment ended after 130 weeks from start. The treatment with PVC did not affect the survival rate and the body weight of the animals (Figures 1-4). In rats of the strain used, the most frequently expected tumors on the basis of the literature and of the historical constrols of the BT Experimental Unit, are mammary tumors (benign and malignant), leukemias, pheochromocytomas and pheo- Wv 000001053 chromoblastomas. Moreover, a variety of other miscellaneous tumors are also observed. No tumors were observed in the digestive tract of rats administered with PVC. No increase was found in the treated groups, either in the percentage of animals with benign and malignant tumors, and of animals with malignant tumors, and in the number of malignant tumors per 100 animals (Table 4). No differences in the incidence of benign and malignant mammary tumors, leukemias, pheochromocytomas, and pheochromoblastomas were observed among the various groups (Table 5). The tratment did not affect the incidence of other benign and malignant tumors (Table 6). No unexpected tumors were found in the tested animals. XV. CONCLUSIONS Repeated administration of PVC dust in olive oil suspen sion, in the tested experimental conditions, did not show carcinogenic effects. SUMMARY Fine PVC dust, produced by suspension and by emulsion polyme rization, suspended in olive oil, was administered by gavage to two groups respectively of 40 (20 male and 20 female) SpragueDawley rats, 10-11 weeks old at the start of the experiment. Two mg of PVC dust were given once every 2 weeks for 52 weeks (27 treatments). Another group of animals, treated in the same way with olive oil alone served as a control. The animals were kept under observation until spontaneous death. No carcinogenic effects were observed in PVC dosed animals. - c- RIASSUNTO Polvere fine di PVC, prodotta con polimerizzazione per so- spensione ed emulsione, sospesa In olio di oliva, & stata somministrata per gavaggio, rispettivamente a due gruppi di 40 (20 maschi e 20 feminine) ratti Sprague-Dawley, di 10-11 settima ne di etk all'inizio dell1esperimento. Due mg di polvere di PVC sono stati somministratl una volta ogni 2 settimane, per 52 settimane (27 trattamenti), Un gruppo di animali, trattati nelZo stesso modo con solo olio di oliva, e stato usato come controllo, Gli animal! sono stati tenuti sotto osservazione fino a morte spontanea, Negli animali trattati con PVC non sono stati riscontrati effetti cancerogeni. VVV 000001055 REFERENCES Brand I. Buoen L.C., and Brand X.G.: Foreign-body "tumors of mice: strain and sex differences in latency and incidence. J. Nat. Cancer Inst., 58, 1443-1447, 1977. Brand K.G., Buoen L.C., and Brand I.: Premalignant cells in tumorigenesis induced by plastic film. Nature, 213, 810, 1967 a. Brand K.G., Buoen L.C., and Brand I.: Carcinogenesis from poly mer implants: new aspects from chromosomal and transplantation studies during premalignancy. J. Nat. Cancer Inst., 39, 663679, 1967 b. Brand K.G., Buoen L.C., and Brand I.: Foreign-body tumorigenesis by vinyl chloride vinyl acetate copolymer: no evidence for chemical cocarcinogenesis. J. Nat. Cancer Inst., 54, 1259-1262, 1975. Kogan A.K., and Tugarinova V.N.: On the blastomogenic action of polyvinyl chloride. Vop. Onkol., 5, 540-545, 1959. Maltoni C., Lefemine G., Ciliberti A., Cotti G., and Carretti D.: Experimental research on vinyl chloride carcinogenesis. Archives of Research on Industrial Carcinogenesis. Princeton Scientific Publishers, Princeton, N.J., Vol - lit 1964. Oppenheimer B.S., Oppenheimer E.T. .Danishefsky I., Stout A.P., and Eirich F.R.: Further studies of polymers as carcinogenic agents in animals. Cancer Res., 1_5, 333-340, 1955. VVV 000001056 Oppenheimer B.S., Oppenheimer E.T. , and Stout A.P.: Sarcomas induced in rodents by embedding various plastic films. Proc. Soc. Exp. Biol., 49, 366-369, 1952. Oppenheimer B.S., Oppenheimer E.T., Stout A.P., and Danishefsky X Malignant tumors resulting from embedding plastics in rodents. Science, 118, 305, 1953. Raikhlin N.T., and Kozan A.H.: On the develpment and malignization of connective tissue capsules around plastics implants* Vop. Onkol., 7, 13-17, 1961. Russel F.E., Simers M.H., Hirst A.E., and Pudenz R.H.: Tumours associated with embedded polymers. J. Nat. Cancer Inst., 23, 305-315, 1959. f Volkheimer G.: Hematogenous dissemination of ingested polyvinyl chloride particles. Ann. N.Y. Acad. Sci., 246, 164-171, 1975. 000lO57 1953, MtAe>. p<MueHMi 4eBmUeVc0o paEcH X mMonm4si Mci MaJ Mp"CSeHi. cB MctCteo_t z au Vo_ 3 * oc. M>i caww4waC4) (j0c.j L0* moJ' to MM*cacE>J*. C>cJ. oc VH 5 , z >m(uoumJ- oo J to poH aia- B M<Eee M) 8 Z M-uoajJ C83 6 tOco c MaU8J1 *V3 . uCE ' ccVa a ipnH peH pim0nH5 <o . 17 tBE0I0eom MC0 <EO3 pp83HH pp. <3r L3O _B0tJ. MJ08.i - 9-' ` *. * Sk ' * .'^.:*V'*^.*jf, * rV* * ". pH * r ^ p 0 .* pS0BB3H OmO)il M1f 1*1. i -1 1 n' o3 o pH pH 1 taEOou3eo **E03" 3E0 OJ CM 3<0EM M80Ui M0Uai M--308UMJ M0Lai 3 i Co0E0LaBO QQ <*htHQ.. 3E0 MMeuc1i pc0H 3AEOe _ no 1 3Ey _. nr cy Cm mo MaLa.i Moaui MA0080l u00mi 33 iNn Moi 0L Mtagl 3 ua 8Uo a c uu a>i E mcaL00m. tE! mi.QMU-mB4 8o 0 0 C0SoUe8j. L' Uo tu000sCo JmouCm 3 e* J EE '-pH- MuS oC 3M0L0i --"E0C <L0t2. AU W | ---hE. n o >o -- 8 uu00S0 0g0a J pa>o^ mJ 22 PM >CJ 30 -- b > 3t. r< m 30 J0C "5 J |1 pH tb XU1 o p o 0N a (HmH. g io Mc) uC > (3 ge 3 3' WV 00000X058 Teat motorlalo Chemical chnroctcra Physical chnrnclorn PVC Capsules Toblo 1 Studlcn on PVC carcinogenicity Animals Species nnd strain N. at start N. corrcc ted Rite of implant Rats 1G Kidney (second part) Type Tumors at the site of implont Hearing animals . N. % References i |. Sarcomas . . * 4 5 31 Kogan 'and . Tugarlnova, 1959 a PVC PVC PVC PVCA Film Perforated fl lm Film Rate Rots Albino rats FI lm (15X22 mm Wdefi 0.2 mm thick) C0A/II-T6 mice a idem .5 idem Sarcomas Sarcomas 00 16 (5) Around kidney Sarcomas 02 Sub- Sarcomas cutaneous tissue 2 40 1 20 : V* * G 37 ; r;'-.. . Ralkhlin'and ; . Kogan*-1961 `V GO 65 (0) Drond et al.* 100 (7) 1967 a. b* 1975 *' - PVCA - CHA/II-TG mice Particles CDA mice (50--100 micron* corresponding by weight to 2 films 15X22X0.2 mm) 00 7G -- Sub- cu tancous tl noiio Sarcomas 0- -- aJ * * . * ,* * *.* *r 1 Brand et ali, 1975 . * ^; , ; * . -o r 6$otoqoo 0 AAA Teat materials - Chemical characters Physical chnrnctern Table 1. Studied on PVC carcinogenicity Anlmala Species and strain N. at dtort N. corrected Cite of implant Type Tumora at the sits of Implant Searing animals N. * (third part) References PVCA Film (15X22X0.2 mm) (15X7X0.2 mm) Hi ce of 10 different trains 9-124 Sub cutaneous tinaue Tumora at the site of implant were observed in 16 of 10 strains. The incidence varied from strain to strain. The females were more re sponsive than the maleo (except in one strain) Drand et al., 1967 (1) Alive at the appearance of the first tumor (2) At risk (3) Preliminary resulta after 533 days from implant (4) Alive after 300 days (5) Alive after 205-3G5 days (5) In males, after 3-12 months (7) In females, after 7--12 months Table 2. Experiment UT20: Expooorc by ingcation (stomach tube) to PVC dust In olive oil. at the Dingle doac of 2 mg, once every 2 veckn, for 52 weeko Pl.AN OF THE F.XPEH1HENT Group N. Tent material 1 PVC aoapenoion granules 1 I PVC emulsion granules HI Olive oil (control) To tal Pone (every 2 wcekn) (mg) 2 * 2 - AnJmolD (Sprogue-Dawley rota, 10-11 weeks old) Sex N. at start M F M+F M F H+F H F M+F M F M+F 20 20 40 20 20 40 75 75 150 115 115 230 VVV 00000X 061 - >13- Table 3. Experiment BT28: Exposure by Ingestion (stooach tube) to PVC dust, in olive oil, at the single dose of 2 mg, once every 2 weeks, for 52 veeks CONDUCT OF ECTERIXENT - The animals were exposed by ingestion (stomach tube), to 2 mg of suspension or emulsion PVC, in 1 ml of olive oil, once every 2 weeks, for 52 weeks (27 treatments). - All the animals were kept under control until spontaneous death. - The status and behavieur of the animals were conta*olled twice daily. - The animals were submitted to clinical examination for gross changes every 2 veeks- The animals were veigTted every 2 weeks during the treatment period, and then every 8 weeks. - Full necropsy and systemic histopathologieal examination were performed on all the animals. - The housing and the diet of the animals were the same, highly standard ized ones, adopted in the BT Experimental Unit over the last 15 years. Ji * i VVV 000001062 - -4q- t8 a rl 6) C. O a <-i a. a o oo oH Nc tHii Oo 1 o Irt o oft o 0^0 M^ T a b le A. E x p e rim e n t M '2G : K x p o a u rc b y in d e n tio n (o to m a c h tu b e ) to PVC d u n t in o liv e o l.l, n t th e d in g le tloao o f 2 mg, once e v e ry 2 wcelia, f o r 52 weekn D n rn tlo n o f th e blophnno? 13C wcekn (2 ) H o )1g n n n t ooo o in v <-l oo rOf V) ft tsft n ONNIH1) C= oX o o in O lO n o ^ HO LL*5i O(M O Li N -h o n NH INfl ^Pi occ cv cv ^ ooo N PI T U1 Li O >>s o z H X u. - X t*. X b. eu 3 C D --Vi a L. =J 3 c a C C t_ ai c c4J c. c 0 Va* a CJ 3 3 a > Eu 0o L. c >C 0 u o .j ca c QO aB t: cs ai. o c 3E --wa Cc .3 3O1O_. w vvv 000001063 Tabic 5. Experiment UT20: Kxponurc by indention (atomnch tube) to PVC duot In olive oil, at the oingle dooe of 2 mg, once every 2 weeko, Tor 52 weeka Darn Hon of the blophonct 13G wceko THE TNCinENCE (X) OF HAHHAnY TUMOIIS, LEUKEMIAS, PIIKOCHnOHOCVTOHAS AND PlfEOCHROMODLASTOHAS Group N. Test material I II III PVC BUspennion granules PVC cmuloion granules Olive oil (control) Animals Sex N. at start M F M+F M F MfF M F MF 20 20 40 20 20 40 75 75 150 X of animals bearing tumors Mammary tumora Leukemias Phoochromo llMT(l) MT(2) cytomas 50.0 25.0 _ co.o 30.0 2.7 46.7 24.7 _ 10.0 5.0 5.0 2.5 _ 9.3 4.7 - 5.0 2.5 5.3 4.0 4.7 - 5.0 - 2.5 2.7 2.7 2.7 Pheochromo bloatomas - -- -- - -- (1) Dcnlgn (flbromoo and flbroadenomaa) and malignant (adcnocarclnomad) tumors (2) Malignant tumors *L. O a o o a *+ a O' & / w-. Croup N. Table 6. Experiment: DT20: Exposure by Ingentlon (stomach tube) to PVC dust In olive oil. at the ningle dose of 2 mg, once every 2 weeka, Tor 52 vccka. Duration of the biophaoe: 13G veeha THE INCIDENCE (%) OF OTHKIt TYPES OF TUMOHS (first port) Tent material Anlmala Sex N. at atart % of animals bearing tumore Dcnlgn Malignant I ( XI PVC Guapcnnlon granules PVC cmulpion granuleo H r H*F K F H*F 20 20 40 20 20 40 Skin acanthoma Neurilemmoma - Total 5.0 5.0 5.0 l.cyillg cell tumor Polypus of the uterue To Lai 5.0 5.0 5.0 Cholongtocarclnoma Islet cell carcinoma- 5.0 5.0 Skin carcinoma 5.0 Total 10.0 _ Total -- "9r < < < Oo o o o O' / vjn VVV 000001066 Hroup N. I 11 '<*wK Table 6. Experiment I1T20: Kxponurc by ingestion (ntomnch Lube) to PVC duot In olive oil, nl; the single done of ? mg, once every 2 weeks, for M weeks. Duration of the hlophnnc: 136 weekn TlIK INCIDENCE (X) OK OTIIKH TYPES OK TUMORS (occond part) Test material An 1 ma 1 s Sex N. nl. start X of animals bearing tumors DcnJgn Mailgnant 01ivo ot1 (control} M 75 Exocrine poncreae 2.7 Meningioma 1.3 ndenonoo Forcotomach ocantho 2.7 01lgodendroglioma 1.3 RIOO K 75 Polypun of the glon 1 .3 Zymbnl gland carcinoma 1.3 dulor ntomach Cholangloma Adrenal gland cortl 1.3 1.3 Kidney adenocarcinoma Adenocarcinoma of the 1.3 1.3 cal odenoma uterus Fibrosarcoma of the 1.3 uterus Ependymoma 1.3 Meningioma 1.3 Oligodendrogliomas 2.7 MF ISO Total 4.7 Total 6.7 ~ iK - -W3- Flguro 1. Expoiimonl DT20: Survival ol malo Spraguo-Dawloy rals. Sfart of Ilia traatmonf WV 000001067 i Figuro 2. Experiment DT20: Survival of lomalo SpraguO'DawIoy rats. Slait o( th liealmonl -- Flguro 3. Oxporimont DT20: Dody weight ol malo Spraguo-Dawloy rats. Start ol the treatment VVV 000001069 Woighl (g) Figure 4. Exporimonl DT20: Dody weight ot lomalo Spraguo-Dawloy rals. ** Suipnibn PVC In ellv* ol Emulsion PVC In dlv* oil * Olv* ol (on* \ -"A \ I uyM 000001070 * Slart ol iho tioalmonl Wooks -+ 00 00 90 104 112 120