Document zdQLOwbVozjGdrB8RKK3ejYkB

TO: Distribution 3BSr<*etj ERT: *WHr AJ0: RF XF: '0 ~ Interoffice Communication FROM: DATE: SUBJ: 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 000013062 f The Vinyl 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 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 Oricologia 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 000013063 Wayne Interchange Plaza II 155 Route 46 West Wayne, NJ 074 70 (207; 890-9299 SOLVAY& Cie socifete anonyrne direction rationale pour ie benelux drection commeiciale matieres plasbques 2 hVr. iss: NON TOXICITE DU PVC - ETUDE MALTQNI 1989 Par notre telefax du 12 octobre 1989, nous vous signalions l'existence de 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 1'huile d'olive par gavage a deux groupes de 40 (20 males et 20 femelles) rats SPRAGUE-DAWLEY, ages de 10 a 11 semaines au debut de 1'experimentation. Oeux mg de poudre de PVC ont ete administres en une fois toutes les 2 semaines durant 52 semaines (27 traitements). le groupe controle etait constitud d'animaux traites de la meme fagon et n'ingerant que de 1'huile d'olive. Les animaux furent observes jusqu'a 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 MALTONI avait mis en evidence les effets cancerigenes, le polymere PVC est lui totalement inoffensif sur ce plan. p7esenl:7^oiis'`avohT^regu,"du Professeur MALTONI* 1 'autorijation d'utiliser t <ie communiquer son dtude/^i deux renditions : * ' ' -- T- signaler que 1'etude sera prochainement publiee dans la revue medicale 1 italienne ACTA ONCOLOGICA n*1989/4, F communiquer 1'etude dans son entierete, sans omettre le curriculum vitae de V auteur. VVV 000013064 Nous vous communiquons en annexe le texte de 1'etude, tel que nous l'avons regu, et la traduction frangaise approuvee par le Professeur MALTONI. ANNEXE In stampa su Acta Oncolooica 19B9/4 LONG-TERM CARCINOGENICITY BI0AS5AYS OF POLYVINYLCHLORIDE fPVC) ADMINISTERED BY INGESTION fGAVAGEl 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 Lutece, 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 000013065 I. INTRODUCTION -z- , 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. OOOOi-^066 VVV 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 (IAPC, 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 i [ i cellular environment (solid carcinogenesis ). It cannot be ruled out, however, that the carcinogenic effect is a consequence 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 000013067 r disseminated into all the organs (where individual particles can be found a long time later). XI. 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 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 000013063 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. IV. CONCLUSIONS Repeated administration of PVC dust in olive oil suspen sion, in the tested experimental conditions, did not show carcinogenic effects. ! i I j. 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) Sprague-- Dawley rats, 10-11 weeks old at the start of the experiment. Two 1 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. VVV 000013069 -c- RIASSUNTO Polvere fine di PVC, prodotta con polimerizzazione per so- spensione ed enrulsione, sospesa in olio di diva, d stata somministrata per gavaggio, rispettivamente a due gruppi di 40 (20 maschl e 20 femmine) ratti Sprague-Dawley, di 10-11 settima ne di etS, all'lnizio dell *esperimento. Due mg di polvere di PVC sono stati somministrati una volta ogni 2 settimane, per 52 settimane (27 trattamenti). Un gruppo di animali, trattati nello stesso modo con solo olio di oliva, e stato usato come controllo. Gli animali sono stati tenuti sotto osservazione fino a morte spontanea. Negli animali trattati con PVC non sono stati riscontrati effetti cancerogeni. wv 000013070 -4- -R--E--F--E--R--E--N--C--E--S- t Brand I., Buoen L.C., and Brand K.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 polymer implants: new aspects from chromosomal and transplantation studies during premalignancy. J. Nat. Cancer Inst., 39, 663679, 1967 b. [ t it t j 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 II* 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 000013071 -S - I 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 I.: Malignant tumors resulting from embedding plastics in rodents. Science, 11B, 305, 1953. Raikhlln 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. I Volkheimer G.: Hematogenous dissemination of ingested polyvinyl chloride particles. Ann. N.Y. Acad. Sci., 246, 164-171, 1975. wv 000013072 Teat mntcrinls Chemical characters I /C commercial , I Lh some id 1 lives) Physical charac hers Squares or disks (IS mm wl tie t 0.04 thick) VC idem) idem. perfornted VC >inrc') c Film (0.03mm thick) Table 1. Studies on PVC carcinogenicity Animal a Species and strain N. at start N. corrected Site of Implant ' Type Tumors at the site of implant Bearing animals N. X (first pert) References tflotar rats 45 44 (1) Abdominal wall Sarcomas Viator rats Wlfltar rats idem 27 (2) idem idem Sarcomas 17 38.6 Oppenheimer et el.a 1952,1953, 1955 0 4 (3) ; CO .i - .'<! it ton rc Inoo Viator rata Film (5X4 mm wide, 0.16 mm thick) Similar size WLstar rats Viator rats 50 35 25 Idem 30 (4) Introabdominal 20 (4) Idem - Sarcomas Fibromas -- < c o. o o o u> o 0 '" V> *' .* * ;!.. 1 Russel ' et si.. 1 1959 ' 0-- t* * '* .. . y e*-* * : . V.5v..Y5 *4 , . . P .* v* ' ' r* >v '\. e 5 G & O c ouau u >e. co ec jj to Ja3 *- I Test materials - Chemical i characters Phyaical characters Table 1. Studies on PVC carcinogenicity Anlmalo Species and strain N. at start N. corrected Site of implant Type Tumors at the site of Implant Bearing animals N. % (third part) Ttaferencee |pVCA j Film (15X22X0.2 mm) (15X7X0.2 mm) Mice of 10 different strains 9-124 Subcutaneous tissue Tumors at the site of Implant were observed in 16 of 18 strains. The incidence varied from strain to strain. The females were more re sponsive then the males (except in one strain) Brand et al., 1967 (1) Alive at the appearance of the first tumor (2) At risk (3) Preliminary results after 533 days from Implant (4) Alive after 300 days (5) Alive after 205-365 days (6) Tn males* after 0-12 months ;(7) Tn females* after 7-12 months < o o o o H* u> o --4 I Table 2. Experiment BT20: Expoouro by ingestion (stomach tube) to PVC dust in olive oil, at the single dose of 2 mg, once every 2 weeks, for 52 weeks PLAN OF THE EXPERIMENTI 11 (roup N. Test mnterlnl I PVC suspension granules 11 PVC emulsion granules III Olive oil (control) Total < < < O o o o jj O' Hone (every 2 weeks) (mg) 2 2 Animals (Sprogue-Dawley rats. 10-11 weeks old) Sex N. at start M F M+F M F M+F M F M+F M F M+F 20 20 40 20 20 40 75 75 ISO 115 1X5 230 Table 3. Experiment BT28: Exposure by ingestion (stomach tube) to PVC dust, in olive oil, at the single dose of 2 mg, 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 treatoent 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. i ! i oooox**1 Table 4. Experiment I1T20: Kxponnre by ingestion (otomoch tube) to PVC duot in ol ive oil, nl: the single dose of 2 mg, once every 2 weeks. for 52 weekn Duration of the btophnoo: 13G weeks THE INCIDENCE (%) OF TOTAL TUMORS Group N. Test material r it hi PVC suBpenslon granules PVC emulsion granules Olive oil (control) Animals Sex N. at ntnrt M F MiK M F M+F M F M4F 20 20 40 20 20 40 75 75 150 % of animals bearing tumors Tmrrd) ht(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 0.0 22.7 15.3 N. of malignant tumors per 100 animals 10.0 20.0 15.0 10.0 5.0 0.0 24.0 16.0 (1) Total benign and malignant tumoro (2) Malignant tumoro < < < o o o o h-' UJ o -4 05 / Table 5. Experiment DT20: Exposure by indention (otomach tube) to PVC dunt In olive oil, at the single dose of 2 mg, once every 2 weeks. Tor 52 weeks Duration of the biophonc: 136 weeks THE INCIDENCE (%) OF MAMMARY TUMORS, LEUKEMIAS, PHEOCHnOHOCYTOHAS AND PIrEQClfflOHOBLASTOMAS Group N. Test material I PVC suspension granules II PVC emulsion granules III Olive oil (control) Animals Sex N. at atari M F M+F M F M+F M F H+F 20 20 do 20 20 dO 75 75 150 % of animole bearing tumors Mammary tumors Leukemias Pheochromo MMT(l) MT(2) cytomas 50.0 25.0 10.0 ` 5.0 -- _ ** co.o 30.0 5.0 2.5 5.0 2.5 5.0 - 2.5 2.7 d6.7 2d.7 9.3 d.7 5.3 d.O d.7 2.7 2.7 2.7 Pheochromo blsstomae _ -- - - (1) Denlgn (fibromas and fibroadenomas) and malignant (odcnocarcinomos) tumors (2) Malignant tumors T a b le 6 , E x p e rim e n t DT20} E x p o s u rc b y In g e n tlo n (a to m a ch tu b e ) t o PVC d u e t In o liv e o i l , a t the s in g le done o f 2 mg, once every 2 weeks, fo r 52 weeks. D u rn tio n o f the blophase; 136 weeks A &-- 4J cac au o3g ^Xa&4* "Sc4C u a V A rB* a e ca ft* o X. & M ccVs o o o o in in in o e 8 E 0 E0 C4 uo c4 o cu8 o3 o ^8c4 o HH41 O 44 4C4 c HOi 8 O 4e4 ot 8CJ 4J3e1C CO 5 Ho l1 1 |1 48J 0 o o irt in 1 O m 8 j4E0;4 c8Oe c JtoC "a s0gg ft) "u1 ac 2 J _8J 10- Oo % mm o in u 44 H J4S4 <M cft) w 0 a&a aaCo> > 4 3 CJ c0. ^4 484 0 H , 4J 4-1 B 8 (. 48J oe\j oC\J o o e\j eo\] O u a E X CD <c X tVo X u. h. X X Cjl. b< X 8 l. V4 8 JJ H88 3C. u0 2 o <Q a catw. Ve(4 a c0 o>c. aaaa 44 V' a a 3 C8L ' DA co *4 o3 >c. Eft) 4444 VVV 000013080 Croup N. III VVV 0 0 0 0 1 3 0 8 1 Table G. Experiment IIT2fl: Exposure by In^cs Li on fntomncli Lube) to PVC dust In olive oil, at the ningle done of ? mg, once every 2 weeks, for 52 weeks. Duration of Uio hlophnnc: 136 weekn TIIK INCIDENCE () OK OTIIKW TYPES OF TUMOnS (oecond part) Test material Anima1s Sex N. at ntart % of animals bearing tumors Den1gn MaiIgnont Olivo oil (control) H 75 Exocrine pancreas 2.7 adenomas Forcetomach acantho 2.7 mao K 75 Polypus of the glon 1 .3 dular otomoch Cholangioma 1.3 Adrenal gland cortl cal adenoma 1.3 MF 1 GO Total <1.7 Meningioma Oligodendroglioma 1.3 1.3 Kymbal gland carcinoma 1.3 Kidney adenocarcinoma Adenocarcinoma of the uterus Fibrosarcoma of the uterus Ependymoma Meningioma 01igodendrogl1omas 1 .3 1 .3 1.3 1.3 1.3 2.7 Total 6.7 - A% Figure I, Exporimenl 0T20: Survival ol malo Sprague-Dawley rals. Start ol the trealmonl Figure 2. Experiment QT20: Survival oi aale Sprague-Dawiey rats. --is- Flguro 3. Gxporimonl 0T20: Bod/weigh. malo Sprague-Dawloy rats. Start of lha treatment 00001308^ Figure 4. Experiment BT28: Body weight o. .omalo Spraguo-Dawioy rats. Weight (g) 700 -t* 650 -600 -j- ** Suspension PVC In ollva oR * Emulsion PVC In diva oil Oliva oB alone 550 500 450 400 350 300 250 200 150 -- too 50 -0 _|-------------1-------------1-------------1-------------1-------------|-------------1-------------1-------------1-------------1-------------1-------------1-------------1-------------1-------------1-------------1 0' 0 16 24 32 40 40 5G 64 72 00 00 90 1 04 112 120 Wooks -c Start ol the Iroatmonl <