Document 5LX9eKweRmKLEvVnO4ry51gY8

TO: Interoffice Communication FROM: DATE: SUBJ: Distribution TGG: JCL: ERT: MJH: T. G. Grumbles June 12, 1990 yp PVC CARCINOGENICITY STUDY: ORAL ADMINISTRATION OF DOSE 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 WV 000013038 f The Wny/ Institute A Division of The Society of The Plastics Industry, Inc. Roy T. Gottesman Executive Director 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' MaIton i 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 Oncologia 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. RTGsg Enc. VVV 000013039 Wayne Interchange Plaza U 755 Route 46 West Wayne, NJ 07470 (207) 890-9299 SOLVAY& Cie soaete anonyme cSrection rationale pour le benelux drecton ccmmerctale matieres piastques 2 4 m. iss: NON TQXICITE DU PVC - ETUDE MALTONT 1989 Par notre telefax du 12 octobre 1989, nous vous signal-ions 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 et4 administres en suspension dans 1'huile d'olive par gavage a deux groupes de 40 (20 males et 20 femelles) rats SPRAGUE-DAWLEY, ag4s 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 mime fagon et n'ingerant que de 1'huile d'olive. Les animaux furent observes jusqu'i leur mort spontanee. Aucun effet cancerigene n'a 4t4 .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 mime Professeur MALTONI avait mis en evidence les effets cancerigenes, le polymere PVC est lui totalement inoffensif sur ce plan. W p7esenl7^ous"avon regu,"du Professeur HALTONlI I'-autorisation d'utiliser %t de communiquer son dtude/^ deux ^conditions : * * ^ T- signaler que Vetude sera prochainement publiee dans la revue medicale 1 italienne ACTA ONCOLOGICA 0*1989/4, F communiquer 1'etude dans son entiirete, sans omettre le curriculum vitae de 1'auteur. VVV 000013040 Nous vous communiquons en annexe le texte de Vetude, tel que nous Vavons regu, et la traduction frangaise approuvee par le Professeur MALTONI. ANNEXE In startma su Acta Oncolooica 1989/4 LONG-TERM CARCINOGENICITY BIOASSAYS OF POLYVINYLCHLORIDE (PVC) ADMINISTERED BY INGESTION fGAVAGE1 ON SPRAGUE-DAWLEY RATS Cesare MALTONI Institute of Oncology *F. ADDARII", Bologna, Italy CURRICULUM VITAE OF PROFESSOR CESARE MALTONI. 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 Academie Internationale de Lutfcce, and of the "Academie des Sciences, des Arts et des Lettres". General Secretary of Collegium RAMAZZINI. 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) vinvl 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 000l304i I. INTRODUCTION ---2 - # 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 000013042 3- - I Implants of PVC and PVCA squares, discs or films in experi mental rodents were shown to cause the onset of local sarco mas (IARC, 1979) (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 debate. 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- i [ fl j j 4 l 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 mul tipotential 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 VVV 000013043 *1- disseminated Into all the organs (where Individual particles can be found a long time later). XI. MATERIALS, METHODS, PLAN AMD 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 Sprague-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 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, kidneys, 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- vvv 000013044 5- - 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* rv. 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. ^ 00001 3045 riassunto Folvere fine dl PVC, prodotta con polimerizzazione per sospenslone ed emulsione, sospesa In olio dl ollva, ft stata somminlstrata per gavagglo, rlspettlvamente a due gruppl dl 40 (20 maselii e 20 femmine) rattl Sprague-Dawley, dl 10-11 settima ne dl etk all'inizlo dell'esperimento. Due Dg dl polvere dl PVC sono statl sommlnlstratl una volta ogni 2 settimane, per 52 settlmane (27 trattaroenti). Un gruppo dl anlmall, trattatl nello stesso modo con solo olio dl ollva, e stato usato come controllo. Gil anlmall sono statl tenutl sotto osservazlone flno a morte spontanea. Kegll anlmall trattatl con PVC non sono statl riscontrati effettl cancerogenl. i VVV 000013046 REFERENCES Brand I., Buoen L.C., and Brand K.G.: Foreign-body tumors of alee: 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.: Premallgnant cells in tuaorigenesis Induced by plastic film. Nature, 213, 810, 1967 a. Brand K.G., Buoen L.C., and Brand I.: Carcinogenesis from polyner implants: new aspects from chromosomal and transplantation studies during premalignancy. J. Nat. Cancer Inst., 39, 663679, 1967 b. i| ; [ i 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 1984. 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 0000130*7 I Oppenhelmer B.S., Oppenhelmer E.T., and Stout A.P.: Sarcomas induced in rodents by embedding various plastic films. Proc. Soc. Exp. Biol., 49, 366-369, 1952. Oppenhelmer B.S., Oppenhelmer E.T., Stout A.P., and Danishefsky I.: Malignant tumors resulting from embedding plastics In rodents. Science, 118, 305, 1953. Baikhlin N.T., and Kozan A.H.: On the develpment and mallgnlzatlon of connective tissue capsules around plastics Implants. Vop. Onkol., 7, 13-17, 1961. Russel F.E., Slmers M.H., Hirst A.E., and Pudenz R.H.: Tumours associated with embedded polymers. J. Nat. Cancer Inst., 23, 305-315, 1959. I Volkheimer G.: Hematogenous dissemination of ingested polyvinyl chloride particles. Ann. N.Y. Acad. Sci., 246, 164-171, 1975. J i ! VVV 000013048 Test materials Chemical characters Physical charac tors Table 1. Studies on PVC carcinogenicity Animals Species and strain N. at start N. corrected Sits or implant Tumors at the site of implant Bearing animals Type N. % (flret parti Deferences PVC (commercial , with some midi lives) PVC (Idem) PVC (pure) ' Squares or disks (15 mm wide* 0.0-1 thick) tflstar rats Idem, perforated Wlstar rots Film (0.03mm thick) Vistar rats 45 * Idem Cotton PVC G1 ass Wistor rats Film (5X4 mm wide, 0.16 mm thick) tflstar rata S1mllar size Wistor rats 50 35 25 44 (1) Abdominal wall 27 (2) Idem Idem Idem 30 (4) Introabdominal 20 (4) Idem Sarcomas _ Sarcomas Sarcomas Fibromas _ 17 38.6 Oppenhelmer et al.. 1952,1953, 1955 0 4 (3) 0 1 1 0 ; (_D 1 ` . r* * f i.i.., Russel 'et si. 1959 n;a . ..*- . \ *' i* * < c o o o Vjj o f* .> ft Teat materials Chemical characters Physical characters PVC Capsules PVC PVC Film Pcrforated film Table 1. Studten on PVC corclnogenlcity Animals Speciea and strain N. ot start N. corrected Rite of implant nats 16 Kidney Rats note 5 idem .5 idem (second part) Type Tumors at the alto of implant Bearing animals . N. X Sarcomas 5 31 Sarcomas Sarcomas 2 40 1 20 References ` i **,. 1 . r* 4 Kogan `and . Tugarinova, . 1959 * V ** * - ? * : * * . * . f -o r PVC Film Albino rots PVCA - PVCA Film (15X22 nun ulrich 0.2 mm thick) CDA/N-T6 mice - CDA/II-T6 mice Particles CDA mice < (50-100 micron, < corresponding by weight to 2 o o films 15X22X0.2 o mm) o UJ 00 16 (5) Around kidney Sarcomoa 02 00 - Subcutaneous tlaiiue - Sarcomas - 76 Sub- Sarcomas cutaneous tissue 6 V`. 37 ; Ralkhllh and.:--: '* r Kogan ,1961 ;,: 1V CO 65 (6) Brand et al., eslOO (7) 1967 m, b, P 1975 0- .. ' 4. ? -V ... - ; 1 Brand at al^, - 1975 . i . '* Test materials - Chemical characters Physical charocters Toble 1. Stndlcn on PVC carcinogenicity c'- Animalo Species and strain N. at start N. corrected Bite of implant Type Tumors at the aita of imnlont Bearing animals N. % (third part) References PVCA Film (15X22X0.2 mm) (15X7X0.2 mm) Mice of 10 different strains 0-124 Sub cutaneous tinoue Tumors at the site of Implant were observed in 16 of 18 strains* The incidence voried from strain to strain. The females were more re sponsive than the males (except in one strain) Brand at al.. 1967 -V\r (1) Alive at the appearance of the first tumor (2) At risk (3) Preliminary results after S33 days from implont (4) Alive after 300 days (5) Alive after 205-365 days (6) Tn males, after 0-12 months (7) In females, after 7-12 months < < < o o o o t-- h* I Table 2. Experiment DT20: Expoourc by Ingestion (stomach tube) to PVC duat in olive oi1, at the olngle dose of 2 mg, once every 2 weeks, for 52 weeks PLAN OF THE EXPERIMENT Group N. Tent mnter ini I PVC suspension granules II PVC emulsion granules HI Olive oil (control) Total < < < O o o O M UJ O M Hone (every 2 weeks) (mg) 2 , 2 - Animals (Sprogue-Dowley rots, 10*11 weeks old) Sex N. at start M F M+F M F MF H F MtF M F MfF 20 20 40 20 20 40 75 75 150 115 115 230 -- -4 "5- Table 3. Experiment BT28: Exposure by ingestion {stomach tube) to PVC dust, in olive oil* at the single dose of 2 ag, once every 2 weeks* for 52 weeks CONDUCT OF EXPERIMENT -- 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 controlled twice daily. -- The animals were submitted to clinical examination for gross changes every 2 weeks. -- The animals were wei^rted every 2 weeks during the treataent period* and then every 8 weeks. -- Full necropsy and systemic histopathological 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. li * i ! i VVV 000013053 *4 0 6 X 0 0 0 0 -h f- Table 4. Experiment DT2G: Exposure by ingestion (otomoch tube) to PVC duot in olive oil, nl: the single dooo of 2 mg, once every 2 weeks. Tor 52 weekn Duration of tho biophnoo: 136 weekn T1IK INCIDENCE (X) OF TOTAL TUMOJIS Group N. Test material I II III PVC suspension granules PVC emulsion granules Olive oil (control) Animals Sex N. at ntnrt M F MiP M F M+F H F M*F 20 20 A0 20 20 A0 75 75 150 % of animolo bearing tumors TIIMT(l) KT(2) ' 10.0 55.0 32.5 10.0 65.0 37.5 17.3 52.0 34.7 10.0 20.0 15.0 _ 10.0 5.0 8.0 22.7 15.3 N. of malignant tumors per 100 animals 10.0 20.0 15.0 _ 10.0 5.0 8.0 24.0 16.0 (1) Total benign and malignant tumoro (2) Molignont tumoro c c / Table 5. Experiment DT20: Exposure by indention (stomach tube) to PVC duot In olive oil, at the elngle doae of 2 mg, once every 2 weeks, for 52 weeks Duration of the hlophano: 136 weeks THE INCIDENCE (X) OF MAMMATIY TUMORS, LEUKEMIAS. PHEOCimOHOCVTOHAS AMD PUEOCMnOHODLASTOHAS Group N. Test material I 11 III PVC suspension granules PVC emulsion granules Olive oil (control) Animals Sex N. at start M F M+F M F M+F M F H*F 20 20 40 20 20 40 75 75 150 % of animals bearing tumors Mammary tumors Leukemias Phoochromo I1MT(1) MTU) cytomas 50.0 25.0 10.0 5.0 GO.O 30.0 5.0 2.5 _ -- _ 5.0 2.5 rj - 5.0 - 2.5 2.7 46.7 24.7 9.3 4.7 5.3 4.0 4.7 2.7 2.7 2.7 Pheochromo biastomes -- .. - -- _ - (1) Benign (fibromas and fibroadenomas) ond malignant (adenocarcinomas) tumors (2) Malignant tumors Group N. Table 6. Experiment DT2G: E xpoaure by Ingestion (stomach tube) to PVC duet in olive oil, at the single done of 2 mg, once every 2 weeks, for 52 weeko. Duration of the blophnae: 136 weeks THE INCIDENCE (X) OF OTIIEH TYPES OF TUHOhS (first part) Test material Animalo Sex N. at start % of animals bearing tumors Benign Malignant 1 < 11 PVC suspension granules PVC cmulpion granules M F MF M F M*F 20 20 40 20 20 40 Skin nconthoma Neurilemmoma - Total 5.0 5.0 - 5.0 heydig cell tumor Polypuo of the uterus 5.0 5.0 Total 5.0 Cholanglocarcinoma Islet cell carcinoma 5.0 5.0 Skin carcinoma 5.0 Total 10.0 mm _ Total -- < < < o o o M W cr / Table 6. Experiment DTPfl: Exposure liy Ingestion (stomach tube) to PVC dual In olive oil, at the single done of ? ng, once every 2 weeks. for W weeks* Duration of the blophnnc; 136 weeks TI1K INCIDENCE (%) OK OTIIKU TYPES OK TUMOng (second part) ' Group Test muterIni Anina1s ! N. Sex N. At nl.nrt * or animals bearing tumors Denign Kalignant ~ tr Ill 011vo ol1 (control) M 75 Exocrine pancreas 2.7 Meningioma 1.3 adenomas Forestomach aesntho 2.7 Oligodendroglioma 1.3 mao * K 7b Polypus of the glnn 1.3 Zymbal gland carcinoma 1.3 dular stomach Cholongloma Adrenal gland cortl 1.3 1.3 Kidney adenocarc1noma 1.3 Adenocarcinoma of the 1.3 cal adenoma uterus Fibrosarcoma of the 1.3 uterus Ependymoma 1.3 Meningioma 1.3 011godendrogl1omaa 2.7 MF 150 Total 4.7 Total 6.7 VVV 000013057 Figure 1. Experiment QT28: Survival of malo Sprague-Dawloy rals. Start ol lha iraalmont -13 Figure 2. Experiment BT20; Survival of female Sprague-Dawley rals. Start ot Ihe traalmoni I 8 CU r 3 e oe rg Pow CM <0 o vvv 000013059 Flguro 3. Exporimonl DT20; Body weight of male Sprague-Dawloy rats. Start of tha treatment - lik - .9* i Figure 4. Exporimonl DT28: Body weight of lomale Spraguo-Dawlay rats. Start ol tho troatmonl i t & CM s s I C3 cm to o OCM CM <o a VVV OOOl3061