Document 570g4DyL14zvEny3zkXVEY0R

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON. O.C. 20460 MW 301978 OFFICE OF RESEARCH AND DEVEUOFMENT MEMORANDUM SUBJECT FROM TO Preliminary Carcinogen Risk Assessment -fpr VI nyj IdelieyChl orl de lYaWtn L.N-rt1i3ersonV E xecutlve Director rxlnogen Assessment Group (RD-689) Joseph Padgett, Director Strategies and Air Standards Division, MD-12 As requested In your original memorandum of Ma.rch 31, V977, and later re-scheduled requests on November 17, 1977 and March 28, 1978, the Carcinogen Assessment Group h'as finished the Type I preliminary risk Assessment for vlnylldene chloride* We are transmitting the report to you. 5 Attachment cc: S. Gage S. Jelllnek W. Barber J Padgett J. McGInnlty 0* Denney M. James D* Barth H. Beale AP00009025 THE CARCINOGEN ASSESSMENT GROUP'S PRELIMINARY RISK ASSESSMENT ON YINYLIDENE CHLORIDE Participating Members Elizabeth L. Anderson, Ph.D. Charles B. HI remath, Ph.D. Robert E. McGaughy, Ph.D. Lakshmi C. Mishra, Ph.D. Ruth Pertel, Ph.D. Dharm V. Singh, DVM, Ph.D. Wade T. Richardson, J.D. Todd W. Thorslund, Sc.D. Adrienne 0. Zahner, Ph.D. AP00009026 TABLE OF CONTENTS I. SUMMARY XI. INTRODUCTION III. CARCINOGENESIS STUDIES A. Maltoni, et al. (1977) B. Viola and Caputo C. Lee, et al. (1978) D. Dow (preliminary, 1977) E. Humlston, et al. (1977) F. Summary of Carcinogenesis Studies IV. CARCINOGEN RISK ASSESSMENT V. REFERENCES 1 .2 3 3 5' 5 6 7 9 11 :* .* j- 1 rff-* *V V *1 AP00009027 I Summary Ylnylldene chloride (VDC1 administered via Inhalation has induced kidney adenocarcinomas In male Swiss nice at 25 ppm and mammary fibroadenomas and carcinomas In female Sprague- Dawley rats at 150 ppm and less with an Incidence signlfIcantly higher In treated than In control, groups according to one report. Although negative results have been reported In rats via Inhalation exposure by three other authors, the short time of observation In one case and the lack of complete histological analysis In the other . two cases make :the negative results not conclusive. In two relatively well-executed'studies of chronic oral administration at dose levels of 28 mg/kg/day and less, no carcinogenic effect was observed. In an occupational study of 138 workers exposed to VDC vapors no excess t occurrence of cancer was. observed. Several reports have shown that with metabolic activation VDC causes both base substitution and frame shift mutations in Salmonella typhlmurium. It Is also mutagenic In E_j. col 1 with metabolic activation. The positive carcinogenic response to VDC In both rats and mlc.e;* along With Its ability to Induce mutations in bacteria with metabolic activation and Its structural similarity to vinyl chloride .,4. ^ A-quantitatlve risk anaylsls bssec o* the snlrrl studies 3: t : ?. 1 n1 a lifetime continuous exposure to 1 showed an Individual 15fst risk of than 3 x 10".' (f I'**'. `V'.*'." V. t-f V:'l --4 i ' ' ' '/ # 1fc{, s *. AP00009028 II. Introduction Vlnylldene chloride Is a volatile liquid with a boiling point of 37C. Its structure is H2C CCI2 (1.1-dlchloroethylene), which Is similar to vinyl chloride. It Is used In the production of methyl chloroform and In the formation, along with other mononers , : of plastics useful In food packaging sheets and other applications. An estimated 265 million pounds were produced In 1974 (EPA, 1976). A. detailed review of the toxicology and biochemistry of VDC has prepared (EPA, 1976). No attempt Is made here to repeat that Information. It Is toxic to the liver at high doses and It mutagenic In Salmonella typhlmurlurn and Col 1 with metabolic activation. III. Carcinogenesis Studies A. Hal ton! (1977) Maltonl reported the interim results of four chronic studies: a. Inhalation in Sprague-Dawley rats at doses of 0, 10, 25, 100, 150 ppm for 4 hrs/day, 4-5 days/wk for 1 year. To date, 82 weeks or 1.6 years of observation have been made. b. Inhalation in Swiss mice at doses of 0, 10, 25 ppm for the same dose schedule. Results are available after 82 weeks. c. Oral (gavage) In Sprague-Dawley rats at 0, 0.5, 5, 10, 20 t.ig/kg, for 4-5 doys/wk for I year, Results are avaflaole after 32 weeks. d. Inhalation In Chinese hamsters at 0 and 25 pp.Tt for the same dose schedule. Results are available after 74 weeks*l.4yrs. V * !, t A t5.<v j*~ J*;'- ' :.'T AP00009029 \ The Results of the Haltoni study are as follows: t V a*. Rat Inhalation The tumors observed were: 1) mammary tumors (fibroadenomas ; and carcinomas) In both the treated and control groups; 2) oneZymbaV gland carcinoma In the 100 ppm group (none in control and 3) leukemia In both treated and control groups at the rate of about 1 per 60 animals. A summary of the mammary tumor Incidence Is tabulated below. Table 1 - Incidence of Mammary Tumors In Rats Inhaling VinylidcnecnTcride (V5ET * Dose (ppm) 0 10 25 50 . 100 150 Number with tumors TliJmSer 1 nTtfal Ty 32/100 15/30 12/30 15/30 18/30 35/60 Incidence p value _____ 0.32 0.50 &,21 0.40 0.45 0.50 0.21 0.60 0.58 0.044 0.007 b. Mice Inhalation The following tumors were observed: 1) kidney carcinomas at the highest dose (25 ppm) with a large Incidence In males but In only, one out of 112 females. None were observed at 10 ppm. The time when the first animal was observed with a kidney adeno carcinoma was 55 weeks; 2) mammary adenocarcinomas in females at 2* ppn; 3} leukemia, pulmonary adenonss ini' seel 1 a nec-.i s uners scattered equally in control and treated groups. The observations are summarized in tables 2 and 3. AP00009030 Table 2 - Incidence of Kidney Adenocarcinomas in Mice Inhaling VOC Males Females 0 ppm 10 ppm 25 ppm 0 ppm lOoom 25 ppm Number with tumors 0/126 Survivors at time of first tumor 0/25 16/98 0/158 0/26 1/112 Incidence 0 0 0.163 0 0 0.0089 p value 8.5x10-7 0.41 Table 3 - Incidence of Mammary Adenocarcinomas 1n Female Mice Receiving VDC Via Inhalation 0 ppm 10 ppm 25 ppm Number with tumors Survivors at time of kidney adenocarcinomas 2/158 1/26 7/112 Incidence 0.013 0.039 0.063 p-value 0.068 0.029 Therefore In this mouse strain a strong carcinogenic response is seen In the kidney of males and a moderate response Is observed In the mammary gland of females* c. Rats, oral (Savage): Mammary carcinomas were observed with an incidence of between 22% and 42% In both treated and control groups. Other tumors at " * sc 11 a n so-: s sites -/are obs :* "va C but not at s i j:: 1 f i ;ri tly filthy'1 rates than control groups. <5. Hamsters, inhalation No tunors were observed. \ v..'v.v V if-.-*.-*. 'A* . ' r v- *** V'*-' a-**V* * x'"f; AP00009031 B. Viola and Caputo v Wistar albino rats were exposed via Inhalation to VDC at a concentration of 200 ppm for 5 months, then 100 ppm for an r* additional 7 months, then held for observation for the remainder of their lifespan. The exposures lasted 4 hrs/day, 5 days/week. Reticulum cell sarcomas were observed In the abdominal cavity with a frequency of about 30% In females and 15% In males, with no difference In Incidence between control and treated animals. The authors also exposed ,'sprague-Dawley rats to concentrations of 75 ppm and 100 ppm via inhalation, presumably using the same dosage schedule as above. Subcutaneous fibromas were seen grossly In females In 50% to 60% of both control and treated'animals, and In males miscellaneous tumors were observed In treated and control groups. The tissues had not been examined microscopically when the report was written. C. Lee, et al (1978) Albino CD-I mice and CD rats (Charles River) were exposed to 55 ppm of VDC for 6 hours/day, 5 days/week until the terminal sacrifice at 12 months. In mice the following tumors were observed in both males and females with slightly higher Incidence in the treated than in the control groups: bronchioloalveolar c*le::-n* $ , ngi o = r z '" cf ra live1" ann hepatoma. Ins differences were not statistically significant. In rats henan- gioiius wars seen ir. two of 36 tre.itsc r.sues* out no tutors were seen in either control or treated females. a longer time for i *..* -V.;s>. .v'-/V,' >' i. AP00009032 0. Dow studies (preliminary reported by Norr1s,1977) According to the advance text'of a presentation to have been delivered In January 1977, (Norris, 1977) the Manufacturing Chemists* Association Is sponsoring the following chronic studies: a) 90-day and 2-year drinking water studies at 60, 100 and 200 ppm and b) 90- day and 2-year inhalation studies In rats at 10 and 40 ppm Initially, but Increased to 25 and 75 ppm after 30 days of the lower exposure. The.2-year drinking water study has been described In detail by Humiston, et al (1977) and Is discussed below (part E). In the Inhalation studies the only adverse effects found were minimal microscopic changes In the liver with a higher Incidence at 75 ppm than at 25 ppm. In all other respects there was no observed difference between control and treated groups. E. Humiston. et al. (1977) Sprague-Dawley rats were given VDC at concentrations of 0, 50,100 and 200 ppm In drinking water for 24 months. Complete'data on food and water consumption, body weights, blood and urine chemistry, and histological examination of 37 tissues were reported. The result Is that no adverse effect was observed In any of the treated groups compared to controls with two exceptions. In females the 50 ppm group iinj statistically sfoniffcAtt hiihar iof * t*/:; - rf jlan-l acsfionas than controls. This was not co n s \ de r so effect oF the treat-ur-t, slnca *t .;ss to; ?: c- : * -. f- . historical sp:oton*cus r-.'fe of tbe*e : ' j vtf 1 ?: 1 : i i Scrsnuo-Da-./l iy The offr*: '. '.`i 5 r''f'f'' V' V.'C'A-'.J.kV ~.V * .. .W wCT-*'.' ft'`v*.' r . fc\r AP00009033 statistically significant Incidence of liver lesions, described as fatty degeneration, which was more marked In female than males. Accompanying this was atrophy of the centrllobular cells and, hypertrophy of the periportal liver cells. Treatment related necrosis of cells was not observed. F Summary of Carcinogenesis Studies Of the 5.reports on chronic studies only Maltoni's studies showed positive results. The principal findings are tabulated below. The tabulation shows that In both studies where VDC was given orally in Sprague-Dawley rats, no carcinogenic response occurred. In the inhalation studies with Sprague-Dawley rats there is an apparent conflict between Maltoni's findings of mammary carcinomas and the Viola and Caputo, Lee, et al. and Norris reports which report no-carcinogenic response. However, the negative findings of the latter authors can be explained by different factors. No microscopic examination of the tissues was reported In the Viola and Caputo and the Norris papers, and the almost complete lack of any effect in the Norris (and Humlston) experiment raises the question of whether the dose was high enough. In the Lee, et al. studies the duration of observation was too short to observe the development of tumors. For these reasons, the Msltonl, et al . finalngs of card nogenlci ty in *"8ts and dee ret contraai-ctsd by the negative results of .the other studies. / V'Ji. .**.* Aw AP00009034 ! <- i y *' : t* i* |J ! i -i- - ; t ' lr C- :'i *' r 'v 7. *' ' * ' i. * *? V v H . . . V* !? i 'V t*. .r i.*-.* V t;V!;.. r -.. V l- *. . fr .V , * -i .? j y ,i , . il s! * i \ o i- ' ** O; Oo,i }: *; o o! > * \t **s / lts of Carcinogenesis .loassays of Vlnylldlne Chloride f*-' ,'u . `:$r [:.< ! oni , ( ! * 7 ! Specie*; SpragueDavit ^y rats Swiss mice Dose Route of Administration 10, 25, 50, 100, 150 ppm for 12 months Inhalation i 10, 25 ppm for 12 months Inhalation Duration of Observations 82 weeks * 82 weeks v j.-u C> i i : C /* vvl ot *i,(1y 7 >0 [J o f i* 1 2 SpragueOawl oy rats Chi nose? Hamsters HI stir -** 1 Li 11|0 rats SpragueOawley rats CD rats CD-I mit e liats 32, 3.2 6*4, 13 mg/kg/day 25 ppm 142 ppm 12 month average 75, 100 ppm 12 months 55 ppm 55 ppm 24, 74 ppm Oral (garage) 93 weeks Inhalation Inhalation 74 weeks . --Lifetime Inhalation Lifetime Inhalation Inhalation Inhalation ' 52 weeks 52 weeks 104 weeks . W is ton, 5 .) 1 . I."//) SpranU"- Daw oy 9, 14, 28 mg/kg/day 1 Orlnklng water 104 weeks . Significant Findings Mammary card nomas* dose-related excess over Controls. Kidney carcinomas (none in controls) Mammary tumors at 25 ppm Hone None None* no histology None* no histology None . None None*1nter1m result onfy None IV Risk Assessment A risk assessment can be made Independently for each of the observed positive responses* The risk of continuous Inhalation of 1 ug/ra3 of VOC for a lifetime Is calculated from the one-hit dose-response model with the dose In units of ppm* The ppm equivalent of 1 ug/m3 VOC Is found from the following formula, where Myoc and Mafr are the respective molecular weights; 1 ug/m3- 10-3/(1.2xMVDC/air) - 10-3/(1.2x97/28.8) - 2.5 x 10"4 ppm A. Maltonl mouse kidney adenocarcinoma In males The lifetime average exposure for the 25 ppm group Xi, Is: , X_1 25 x 4/24 x 4.5/7 x 1/2 - 1.34 ppm The dose-response slope of the one-hit curve Is: B - (l/Xi) In [1/(1-P)3 - (1/1.34) x 1n(1/1-0.163) 0.133 where Xi Is the lifetime average VDC concentration and P Is the tumor Incidence, 16/98 * 0.163. Therefore, the risk at a lifetime exposure of Xg * 1 ug/m3 Is: R - 8X2 * 0.133 x 2.5 x 10*4 3.32 x 10-5 ' . wjf, *. 1 .'-.rt';'- < '.**.*.* V-'*<: m ... ,*L..* _ *.i*.>, . ../ . ; AP00009036 \S-r/' B. Maltonl rat mammary tumors The response et the two upper doses (150 and 100 ppm) can be used to get two Independent estimates of the slope B. Since the control Incidence, p0 Is not zero, the probability of tumors dub to the 150 ppm treatment. Pi, Is: Pi * <Pt-Po>/U-p0) * (35/60-32/100)/(l-32/100) - 0,39 The lifetime average exposure of the 150 ppm group, Xi# {5 Xi 150 x 4/Z4 x 4.5/7 X 1/2 * 8.04 ppm Therefore one estimate of the slope B, is: Bi - (1/ x 1) x 1n[l/(l-Pi)] * (1/8.04) x ln[l/( 1-0.39)] 0.061 In a similar calculation for the 100 ppm group, It Is found that Bz0.099, which is close enough to Bi to verify that the one-hit model Is not grossly inaccurate. Therefore the value of 0.099 Is taken to be the slope. The risk at a continuous lifetime exposure of 1 ug/m3 is therefore: R * BX2 U.099 x 2.5 x jC'1 = 2.5 x 10-5 The risk estimate based on the mice kidney data Is only abo^t 30 % higher than the estimate* based on rat mammary tj?.0- data. a\ . iv-`v' ; v.'t' *4 AP00009037 References 1. EPA "Health and Environmental Impacts: Task 1, Vlnylldene Chloride". EPA Contract report 560/6-76-023. October 1976. 2. Humlston, C.G, O.F. Quast, C.E. Wade, J. Ballard, J.E. Beyer and R.W. Llsowe. "Results of a Two-Year Toxicity Study with Vlnylldene Chloride Incorporated In the Drinking Water of Rats*" Dow Chemical, ll.S.A. December 19, 1977. 3. Lee, C.C., J.C. Bhamdarf, J.M, Winston, W.B. House, R.L. Dixon and J.S. Woods. "Carcinogenicity of Vinyl Chloride and Vlnylldene Chloride" J. Toxicology and Environmental Health 4, 15-30 (1978). 4. Maltonl, C., G. Coltl, L. Horsl and P. Chleo. "Carcinogenicity Bioassays of Vlnylldene Chloride: Research Plan and Early Results" La Medlclna del Lavoro 68 (4) 241-262 (1977). 5. Morris, J.M. "Presentation on the MCA-Toxlcology Program for Vlnylldene Chloride to be given at the 1977 European Toppl Meeting In Hamburg, Germany, January 26, 1977". 6. ott, M.G.; W.A. Flshbeck, J.C. Towsend and E.J. Schneider "A Health Study of Employee Exposed to Vlnylldene Chloride J. of Occupational Medicine 18, 735-738 (1976). 7. Viola, P.L, and A. Caputo."Carcinogenicity Studies on VinylIdene .Chloride" pre-print, undated. ,*rv*ViW-! V'*?/ AP00009038