Document eKZdn7vX44eJyo00EoL07N2m

STATE OF CALIFORNIA AIR RESOURCES 1102 Q STREET P.O. BOX 2815 SACRAMENTO, CA 95812 BOARD May 31, 19U4 GEORGE DEUKMEJIAN, Governor received JUN 13 1984 Environmental Affairs Dear Sir or Madam: Subject: Request for Information Regarding Ethylene Di$hTdr1de;: I am writing to request information on the health effects of ethylene dichloride as part of our toxic air contaminant program. This program is based on legislation enacted in September 1983, Assembly Bill 1807 (Tanner). AB 1807 (Health and Safety Code Sections 39650, et seq.) requires the ARB to identify compounds as toxic air contaminants and once identified to develop and adopt control measures for such compounds. After consultation with the staff of the Department of Health Services (DHS), we have selected ethylene dichloride as a candidate toxic air contaminant to be evaluated in accordance with the provisions of AB 1807. Before the ARB can formally identify a compound as a toxic air contaminant, several steps must be taken. First, the ARB must request the Department of Health Services to evaluate the health effects of candidate compounds. Second, the ARB staff must prepare a report which includes the health effects evaluation and then submit the report to a Scientific Review Panel for its review. The report submitted to the Panel will be made available to the public. Information submitted in response to this request will be considered in the ARB report to the Panel. Although, any person may also submit information directly to the Panel for its consideration, I urge you to submit all information at this time for our consideration in the development of the report for the Panel. The Panel reviews the sufficiency of the information, methods, and data used by the DHS in its evaluation. Lastly, after review by the Scientific Review Panel, the report with the written findings of the Panel will be considered by the Air Resources Board and will be the basis for any regulatory action by the Board to officially identify a compound as a toxic air contaminant. Prior to formally requesting the DHS to prepare a health effects evaluation of ethylene dichloride, we are providing, pursuant to the provisions of Section 39660(e) of the Health and Safety Code, an opportunity to interested parties to submit information on the health effects of ethylene dichloride SL 039078 `J -2- May 31, 1984 which he or she believes would be important in DHS's evaluation of ethylene dichloride as a candidate toxic air contaminant. iw 1 In May 1984, ARB staff received a reference search on ethylene dichloride health effects using the MEDLARS II and DIALOG Information Services. These information services include material available to the public on or before November 1983. The attached bibliography lists the references from this information search. We are requesting pertinent information on ethylene dichloride health effects, including any material that may not be available to the public, that is not included in the attached bibliography. I would appreciate receiving any relevant information you wish to submit by June 30, 1984. To expedite the review process, we ask that any information which you believe should be regarded as "trade secret" be clearly marked and separated from other information. Your help in expediting our review will be greatly appreciated. You may identify portions of the information you submit as "trade secret" in accordance with Health and Safety Code Section 39660(e). The claim of trade secrecy must be supported upon the request of the Air Resources Board. Other information claimed to be trade secret and information otherwise claimed to be exempt from disclosure may be identified as confidential in accordance with Section 91011, Title 17, California Administrative Code. Section 91011 requires that the claim of confidentiality be accompanied by specified supporting information. Pursuant to the provisions of the Public Records Act (Government Code Sections 6280 et seq.), the information you provide will be a public record and subject to public disclosure, except for trade secrets which are not emission data or other information which is exempt from disclosure or the disclosure of which is prohibited by law. The information may also be released to the Environmental Protection Agency, which protects trade secrets and confidential information in accordance with federal law, and to other public agencies, which are also required to protect such information. Please send the information to the attention of: William V. Loscutoff, Chief Toxic Pollutants Branch Re: Ethylene Dichloride California Air Resources Board P. 0. Box 2815 Sacramento, CA 95812 If you have any further questions regarding health effects information, please contact Mr. John Batchelder at (916) 323-1505. For any other questions, please contact Mr. Don Ames at (916) 322-8285. SL 039079 -3- May 31, 1984 If you are not the person to whom this request should be addressed, please forward it to the appropriate person in your organization. Also, please let us know whether you would like to continue to receive information inquiries for other candidate compounds, and if not, if there is anyone in your organization to whom such requests should be sent. Sincerelv. Peter D. Venturini. Chief Stationary Source Division cc: Alex Kelter, DHS Lori Johnston, DFA Wayne Morgan, President CAPCOA Jan Bush, Executive Secretary CAPCOA David Howekamp, EPA Region IX Assemblywoman Tanner APCO's Attachment SL 039o80 EOC REFERENCES (5/10/84) 1. 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Toiicol Res Projects Directory 5(4): 31 Carere, A and Horpurgc, C (1911) Comparison of the mutagenic activity of pesticides in vitro in various shortterm assays. Prog Mutat Res. 2 17-114 32. Cheh. A M , Hooper, A 8 , Skochdopole, J., Henke, C. A. and McKinnell, R. C. (1918) A comparison of the ability of frog and rat S-9 to activate proautagens in the Aaes test. Environ Mutagen (UNITED STATES) . 2 (4) :417509 33 Chu. K C and Hilaan, H. A (1911) Review of experimental carcinogenesis by compounds related to vinyl chloride. Environ Health Perspect (UNITED STATES) 41-211-29 34 Conso, F 0979) (Hepatotoiicity of chloride solvents derived from aliphatic hydrocarbons and of vinyl chloride). Med Chit Dig 6(5) 431-433 35. Davidson, ! V., Suaner, D. D and Parker, J C. (1912) Ethylene dichlorrde: a review of its metabolism, mutagenic and carcinogenic potential Drug Chem Toxicol (UNITED STATES) . 5 (4) .319-18. 36 Dernier, M., Schaumburg, F and Klein, E (1978) Environmental Health Sciences Center. 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(1913 ) Induction of diphtheria tonn-resistint intints in huein cells by hilogemted compounds J Cincer Res Clin Oncol (GERMANY, West) 105 (D 111-112 12 ftlser, J C md Bolt, H N (1 979 ) Pharaacokinetics of hilogemted ethyienes in rits Arch Toiicol 42 (2 ) 123134 43. Fishbein, L ( 1974 ' Industrul intigens md potentul antigens I Hilogemted iliphitic derivittves Hntit Res. 32:247-308 44 Fishbein, L ( 1 779 ) Potent i11 hilogemted indostrii! circinogemc md antigenic chencils ilktnols md ethers.. Science of the Total Environment 11:223-257 HI Alkme halides, 45. Cembitskii, E. V md Bor.itenko lulu ( 1983 ) (Mechanism of the tone effect of dichloroethme!. Voen Mod Ih (USSR) . (9) .17-20 44 Cocke, E., Wild, D , Eckhirdt, K md King, H ?. <19831 Mutigenicity studies with the mouse spot test.. Hntit Res 117(1-21.201-212 47. Gold, L. S. ( 1990 ! 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Infante, F F and Mu low, F B (1910) Evidence (or the carcinogenicity of (elected halogenated hydrocarbons including ethflene dichlonde Banbury Report 5 217-30!. ill Ivanetich, E. M,, Manca, V. and Harrison, G. G (1901) Influence of two haloaltanes on the redot behavior of hepatic microsomal cytochrome b-5 and its possible relationship to stearate desaturase.. Res Common Chen Pathol Pharncol 39(3)073-914 41 Jakobson, I , Vahlberg, J 1, Holnberg, I. and Johansson, G. (1902) Uptake via the blood and elimination of 10 organic solvents following epicutancons enposnre of anesthetiied gninea pigs.. Tonicol. Appl. Pharnacol. 43:101107. <2 Janssen, D. et al (1979) Cheiical mutagenicity in Salmonella and Chinese haister V79 ceils after ictabolic activation in an isolated liver perfnsion system Notat Res 09:120. <3. Jenssen, D. and Ranel, C (1900) The Hicronoclens test as party of a short-term mutagenicity test program for the prediction of carcinogenicity evaloated by 143 agents tested. Kntat Res. 70:191-201. <4 Johnson, N E (1947) Metabolism of chloroethanol in the rat. Riochem. Pharmacol.. 14:103-199. <5 Panada, T and Uycta, H. (1970! Kotagenk . screening of organic solvents in microbial system. Notat Res. 04:110. 44 Xarstadt, H , Bobal, R and Selikoff, 1. J. (1901) A ssrvcy of availability of epidemiologic data on homans ciposed to animal carcinogens. Banbury Report 9:223-244. <7 Kellam, R. G. and Dusetrina, H G. (1900) Homan exposure to ethylene dichloride:PotentiaI for regulation via EPA's proposed airborne carcinogen policy In: Banbury Report No. 0 Ethylene dichlorride: A potential health risk?. 145-174 <0. Eerster, K V. and Schaeffer, I) J (1903) Brine shrimp (Artemia salina) nauplii as a teratogen test system.. 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Ciliberti, 1 ind Cirretti, D (1707) Eiperiaentil contributions in identifying briin potenti*l ciretnogens in the pttroehtiicil industry Run MY Acid Sci. 381:214-247. 80 HcCiII, 5. N , Jurgens, P. ind Itinetich, R K. (1713) Hopitic nierosomil aetibolisa of the dichloroethmes Biochea Phiraicol (ENGLAND) . 31 (2) :207-13. 81, HcCiun, J., Siaaon, V., Streitwieser, D. ind Anes, B. 1C. (1775) Hutigenicity of chloroicetildehyde, i possible aetibolic product of 1,2-dichloroethme (ethylene Bichloride), chloroethinol (ethylene chlotohydr in), vinyl chloride, ind cyclophosphinide.. Proc Hi11 Acid Sci USA 72 (8) 3170-3173 82 Hillit, J 0. (1777) Ethylene dichloride (1,2-dichloroethme).. Vet Hua Toiicol 21 <11:31-3. 83. Hitrin, E et il (1782) The relitionship between eiposure of worters to chlorimted hydrocirbons ind soae neurologic, psychologic md genetic aodificitions. Ret [g Bicteriol Virusol Pintitol Epidemiol Pneuaoftisiol Serig. 31(1)47-42. 84. (foody, D. E. et il (1781! Correlitions laong the chinges in hepitic aicrosoail components ifter intoiicition with iltyl ha 1 idea nd other hepitotoiins Hoi Phirmicol. 20(31:485-473 85. Horiyi, H., Ohti, T., Vitinibe, K., Hiymwi, T., Rito, R ind Shirisu, T (1783) further antigenicity studies on pesticides in bicteriil retorsion issiy systeas. Hat it Res. 114(3-4):185-214. 84. Nitioni! Cincer Institute (1778) Bioissiy of 1,2-dichloroethtne for possible circinogenicity. NCI circinogenesis technicil report series no. 55.. 78-1341 (7 Nitionil Institute for Occupitianil 5ifety ind Heilth (1774) Criterii for i Recoanended Stindird. Occupitionil Eiposure to Ethylene Dichloride.. 157pp 88. Kits ink. H. V. ind Chekain, l. S. (1775) [Level of nicotiniaide coeniyaes in the liter ind myocirdiua of rits poisoned with dichloretbinel. Bin 11 Eksp Biol Hed . 77 (4) 51-40. 87 Nitsiuk, H. V. ind fednrot, V. V (1774) Effect of aethyluncil on oiiditite phosphorylition in the hepitic aitochondrii of nts poisoned with dichloroethine. Boll Eip Biol (fed 77 (4) 371-3. 78. Nitsiuk, H. V md Hudritstii, A. D. (1774) CClinicil biochenicil chiricteristics of the lesions of the liter md kidneys in icute dichloroethine poisonings!. Voen Hed Zb . (18) :48-58. 71. Nestamn, E. R., Lee, E. G., Hituli, T. I., Douglis, G. R ind Hueller, J. C. (1780) Hutigenicity of constituents identified in pulp md piper aiil effluents using the Silaonelli/aiamilim-aicrosone issiy Hutit Res . 77 (3).203-12. 72. Korpoth, K. H. ind Girner, R. C. (1780) Short-tera test systeas for detecting circinegens. 417pp 73 Kylinder, P. 0., Olofsson, H , Rismuson, B md Stahl in, H. ( 1778) Hutigenic effects of petrol in Drosophilt aelinogister I. Effects of bensene ind 1,2-dichloroethine.. Hutit Res . 57 (2) :143-147. 74. Perocco, P ind Prodi, G. (1781) DNA diaige by hiloilkines in huam lymphocytes cultured in titro.. Cmcer Lett (NETHERLANDS) 13(3) :213-8. 75 Frincipe, P et i! (1781) Hutigenicity of chemicils of industriil ind igricultoril reletince in Silmonell, Streptoayces md Aspergillus. J Sci Food Agric 32(81:824-832. 74 Rinnug, U. (1780) Genotoiic effects of 1,2-dibroaoethine ind 1,2-dichloroethine Hutit Res 74 (3):247-75. SL 039085 97. Rinnng, U (1980! The use of different aetibolising systeas in the elucidition of the antigenic effects of ethylene dichloride in Silaonelli Binbnry Report. 5:83-95. 98 Rmnug, U md Beije, 8. (1979) The auUgenic effect of 1,2-dichIoroethine on Silaonelli typhiauriua. It. Activation by the isolated perfused rat liver . Chet Biol Intend 14 (3) 245-285 99. Rmnug, U. md Riael, C. (1978) Hntigenicity ind aetibolism of 1,2-dichoroethine Hntit Res. 53:251-252 IOC. Rmnng, U. ind Riael, C (1977) Hntigenicity of wiste products froa vinyl chloride industries. J Toticol Environ Heilth. 2(51.1019-1029 101. Rinnng, U , Snndvill, A md Riael, C (1978) The antigenic effect of 1,2-dichloroethiae on Silaonelli typhiauriua !. Activition through conjugition with glutithion in vitro . Chea Biol Intenct 20 (11:1-14. 102 Rio, K S , Hurriy, J S , Deicon, K. H., John, J. A., Cilhoun, l L. ind Toung, J T. (1980) Tentogenieity ind reproductive studies in iniails tnhiling ethylene dicbloride.. Binbnry Report. 5:149-144. 103 Reiti, R H , Foi, T R., Doaondtki, J. Y., Quist, J. F., Lingvirdt, F. md Vitmibe, P C. (1980) Phiraicokinetics ind aicroaoleculir intenctions of ethylene dichloride:Coapirison of oril ind inhiUtion eiposnres Binbnry Report 5:135-148 104. Beits, R. H , Foi, T. R., Riasey, J. C., Quist, J. F., Lingvirdt, F. V. ind Vitinibe, F. C. (1982) Fhiraicotinetics md aicroaolecnlir intenctions of ethylene dichloride in rats if ter inhilition or givige.. Toticol Appl Phiraicol (UNITED STATES) . 42 (2) :190-204. 105. Rice, J K (1981) Frenitil susceptibility to circinogenesis by icnobiotic substmees including vinyl chloride. Environ Heilth Fersped 41 179-188 104. Siiaon, A C , Jones, R B ind Hiclrodt, V C (1981) Hicrosoail dechlorinition of chloroethines: structure- reictivity relitionships.. Ienobiottci (ENGLAND) 11 (11) 723-34 107. Sito, A., Nikijiai, T. ind Koyiai, Y. (1983) Intenction between ethmoi md cirbohydnte on the aetibolisa in rit liver of iroaitic ind chlorimted hydrocirbons.. Toticol Appl Phiraicol (UNITED STATES) . 48 (2) :242-9. 108. Sito, A., Nikijiai, T. ind Koyiai, 7 (1981) Dose-relited effects of i single dose of ethmoi on the aetibolisa in nt liver of soae iroaitic md chlorimted hydrocirbons Toticol Appl Phiraicol 40(11:8-15. 109 Sergeev, S. K. md Bereshnoi, R V. (1977) CChmge in the distribution of nt liver md ayocirdiif cirbonic inhydns ictivity in icute dichloroethme pisening (histophotoaetric study)!. Biull Eksp Biol Ned . 83 (1) 91-3. 110. Siaaon, V. F. (1980) Review of nonbicteriil tests of the genotoiic ictivity of ethylene Bichloride.. Binbnry Report. 5 97-103. Ill Siaaon, V. F. et il (1978) Hntigenic Activity of cheaictls identified in drinking witer (aeeting ibstriet). Hutit Res 53(2).242. 112. 5iaaon, V. F , Kiuhinen, K. ind Tirdiff, R. C. (1977) Hntigenic ictivity of cheaicils identified in drinking witer Dev Toiieol Environ Sci 2:249-258. 113 Sopikov, N F ind Gorshanovi, A 1 (1979) [Uptike, distribution ind etcretion of dichloroethme in ntsl Gig Tr Prof Zibol (4).34-40. 114 Spreifico, F, Zuccito, E , Hnrcurei, F md et il. (1979) Distribution ind aetibolisa of 1,2-dichloroethine (EDO in etperiaentil mini Is Report Nos 3 md 4 to Cheaicil Hinoficturers Assoc.. 115 Spreifico, F., Zuccito, E. , Hurcurei, F. md et il. (1980) Phiraicekinetics of ethylene dichloride in tits treited by different routes md its long-tern inhilitory tosicity.. In Binbnry Report No. 5, Ethylene dicbloride; A potentiil heilth risk? 107-133 SL 039086 1U. Spreifico, f , Zuccito, E., Hurcurei, F. ind et il. (1773) Netibolisa of 1,2-dichloroethme in experiaentil minis . Report Nos. t md 2 to Cheaicil Hmuficturetes Assoc. 117. Store, R. 0., Bank, T. A. ind'ConolIy, R. D. (1711) In rim genotoxic effect of 1,2-dichloroethme in ule BAC3F1 ice.. Toiicolofist. 2:127. 111. Storer, R. D. md Conolly, R. B. (1713) Coapiutive in vivo genotoxicity md icnte hepitotoxicity of three 1,2-dihiIoethmes.. Circinogenesis (UNITED STATES) . 1 (11) :1471-U74. 117. Stncti, G., Krebser, U. md leisinger, T. (1713) licteriil growth on 1,2-dichloroethme.. Eipericntii (SVITZERLAnd), 37(111:1271-1273. 120. Styles, J. A. (1710) Stndies on tke detection of circinogens osing i maailiin cell trinsforntion issiy with lifer honogenits ictiffition. Short-tern test syst detect circinog proc syap(1773). P221-231. 121. Tiiborro, C. H. tnd Greenberg, R. A. (1710) Identifiention of hram toiicity md circinogenicity by ethylene derifitites. Dee Toiicol Enfiron Sci. 1:317-333. 122. Tin, E. L. end Hsie, A. V. (1711) Hutigenicity md cytotosicity of hiloethmes is stndied in the CHO/HGPRT systea.. Hit it. Res.. 70(21:113-171. 123. U.S. EFA (1777) Popnlition Exposure to EDC. Drift Report. SRI Internitionil, Henlo Park, CA. Contrict No. 43-022033: 124 U.S. EPA (1714) Heilth issessient doennent for !,2-dichIoroethine ( drift report ). EPA-100/1-I4-001A. Part 112. 'i 123. Vm Blideren, P. J. it il (1711) The reiition between the stricture of ficinil dihilogen conponnds ind their otigenic ictifition fit conjugition to glntithione. Circinogenesis 2:477-303. 121. Vin Door on, B L. (1710) Circinogenicity ind ictibolin of soae hilogemted oleftnic md iliphitic hydrocirbons. Bmbnry Report. 3:117-201. 127 Vin Dnsren, B. L. et il (1777) Circinogenicity of hilogemted olefinic md iliphitic hydrocirbons in aice. JNCI. 13(1):1433-1437. 121. Vin Danren, B. L., Goldschaidt, B. H., Uewengirt, G., Saith, A. C., Helchionne, S , Seldain, I. md Roth, D. ( 1777) Circinogenicity of hilogemted olefinic md iliphitic hydrocirbons in nice . JNCI 13 (l):1433-7. 127 Voxoxinii, H. A. (1771) (Effect of low concentntions of bensene, dichloroethine md their coabimtion on the reprodoctixe function of minis) Gig Sinit . (11:100-2. 130 Voiouyi, H. (1777) The effect of dichloroethine on the seioil cycle md eabryogenesis of experiaentil minis 1777.. Akusk. Ginekol. (Koscow).. 2:37-37. 131 Voiouyi, H. (1773) The effect of low concentntions of bensene, dichloroethine, ilone md their coabimtion on the repordoctire function minis md on the defelopaent of progeny. Gig Tr Prof. Zibol.. 7:20-23. 132. Vird, J H. (1730) The circinognicity of ethylene dichloride in Osborne-Mendel nts md B1C3F1 aice. Bmbnry Report. 3:33-33. 133. Ueisburger, . K. (1777) Circinogenicity studies on hilogemted hydrocirbons. Environ Heilth Perspect ."7-14. . 21 134. Vithey, J R. md Collins, B. T. (1710) Chlorimted iliphitic hydrocirbons used in the foods industry: the coapiritive phiraicokinetics of aethylme chloride, 1,1-dichloroethine, chlorofora md trichloroethylene ifter I V idainistrition in rat. J Environ Pathol Toxicol. 3(5-4):313-312. SL 039087 135 Wither, J E , Collins, B T and Collins, F C (1783) Effect of vehicle on the phariicokinetics ind uptake of four halogenated hydrocarbons froi the gastrointestiml tract of the tit.. J Appl Toiicol (UNITED STATES) 3 (5! 20-253 135 Tllnet, S. (1771) Hetibolisi of chloroacetate-l-ltC in the loose.. Acts. Phariicol Toiicol 30:51-11. 137 Yllnet, S. (n.d.) Chlorinated illiphitic hydrocarbons used in the foods industry. The coiparatite phirucohinetics of lethylene chloride, t,2-dichloroethane, chlorofon, and trichloroethylene after IV. adiinistration is the rat.. 3. Eneiron. Pathol. Toiicol. 3:(in press). 138 Zajdeli, F. et al (1780) Carcinogenicity of chloroethylene oiide, an altinate reactive letabolite of rinyl chloride, and bis(chioroiethyl)ethtr after snbcotaieons administration and in initiation-proiotion eiperiients in nice. Cancer Bes. 52 (2): 352-355 137. Inora, F. 3., Benson, J. H , Li, A. P. and Brooks, A. L. (1783) Efilnition of an eiposnre systci using cells grown on collagen gels for detecting highly volatile intagens in the CHO/KGPIT eolation assay.. Entires Hstagen (UNITED STATES) 5 (5) : 775-801. SL 039088 PPG Industries, Inc. One PPG Place Pittsburgh, Pennsylvania 15272 (412) 434-2801 A. Philip Leber. Ph.O. Manager of Industrial Toxicology Environmental Affairs Industrial Chemical Division July 3, 1984 Willi am V. Loscutoff, Chief Toxic Pollutants Branch California Air Resources Board P.0. Box 2815 Sacramento, CA 95812 Dear Dr. Loscutoff: Re: Ethylene Dichloride This is in response to your request for information on the chemical ethylene dichloride (EDC). In reviewing our toxicology files for this material, only one relevant reference was found that was not included in your reference list. A copy of this article is attached to this letter. PPG appreciates the opportunity to contribute to California's efforts in developing rational assessments of hazards from airborne chemicals. Sincerely, mec Attachment cc: S. Angrist R. Davis A. Philip Leber SL 039089 YOV', 62 Martin et al.: Clinical Features, Pathogenesis and Management of Dichloroerhanc Poisoning Germ. med. Mib., Vol. XIV (4) Clarke, C. A.: Personal communication (1968). (J) Gorman, J. G., V. J. Freda: Personal communication (1968). (6) Jennings, E- R.: Personal communication (1968). (7) Gorman, J. G.: Personal communication 1967. (8) Zipursky, A,, L. G. Israels: Canad. med. An. J. 97 (1967), 124J. - Uwis, M.; Bowman, J, M.; Peddle, L.-, Kaita, H., B. Chown: Personal communication (1967). (9) Robertson, J. G.; Communication read at Europ. Congr. of Perinatal Med., at Berlin, 27.-30. 3. 1968. (10) Bartsch, F.: Personal communication (1968). (11) Vermylen, C.: Personal communication (1968). (12) Hamilton, E. G.: Obstet. and Gynec. 30 (1967), 812. - Personal communication to J. G. Robertson, C. A. Clarke. (U) Hindemann, P.: Bibl. gynaec. (Basel 1966), p. 23. (14) Pollack, W., H. O. Singher, J. G. Gorman, V. J. Freda: The prevention of Isoimmunization to the Rh-Factor by passive immunization with Rho (D) Immune>Globulin (Human). American Association of Blood Banks Oct. 21.-24. 1967 (New York). Scientific Exhibit and abstract in "Transfusion" (N, Y-). To be published. (Requests for reprints should be addressed to:- Universitats-Frauenklinik 78 Freiburg, Germany) v_ > w' ILL*1 JAN 151975 Clinical Features, Pathogenesis and Management of Dichloroethane Poisoning1 G. Martin, K. Knorpp, K. Huth, F. Heinrich and c` Mittermayer Department of Medicine (Joint Directors! Prof. H. J. Dengler, Prof. H. A. KGhn and Prof. H. C. Lasdi) and the Department of Pathology (Director! Prof. W. SandKrver), Universiry of Giessen Summary:- A 57-year-old man died of therapy-resistant cardiovascular failure 24 hours after ingestion of an didiloroethane-containing embrocation. Apart from gastro-enterocolitis and hepatic necrosis he developed a severe haemorrhagic diathesis. The complex disturbance of the haemostatic mechanism, which included thrombocytopenia and reduced activity of all clotting factors examined (Factor I, II, V, VII and XIII), was ascribed to consumption ("using up") of these substances by disseminated intravascular coagulation ("Verbrauchskoagulopathie") and secondary hyperfibrinolysis. Therapeutic principles for the management of oral dichloroethane poisoning are suggested taking into account thfe likely pathogenesis. They include prompt gastric lavage with addition of paraffin (in which dichloroethane dissolves), measures to protect the liver, continuous supervision and adjustment of blood gases. Incipient consumption of the clotting factors is counter acted by heparin infusions. Cardiovascular function is supervised by continuous registration of the electrocardiogram, even after apparent improvement in the patient's condition or subsidence of the initial stupor. Should renal failure occur, treatment is the same as for other types of acute renal failure. Some analgesic and anti-inflammatory embrocations in clude dichloroethane (CH2-C1-CH2-C1) as their main hyperaemia-inducing constituent. Accidental or deliberate ingestion of such embrocations which are meant solely for external use, may result in severe and sometimes fatal dichloroethane poisoning (2, 3,13). To the few reports of poisoning by swallowing di chloroethane a further case is added here. It was character ized by very severe cardiac arrhythmias and disturbances of the clotting mechanism causing a haemorrhagic diathe sis due to intravascular consumption of clotting factors. Case Report At about 18.30 on November 4, 1966, patient R., a57-ycar-oldman, swallowed, presumably with suicidal intent, about 40 ml of an initially unidentified embrocation used by him for the relief of rheumatic complaints. He was admitted to hospital at 20.00 on the same day in a somnolent condition. As the patient could not be roused, information about the poison swallowed was unobtainable. 1 Translated from Drsch. med. Wschr. 93 (1968), 2002. Relatives could not be contacted. The expired air smelled strongl; of camphor. A few minutes after admission ro hospital the parien vomited about 300 ml of a bilious liquid smelling of camphor ant about 30 minutes later voided copious, apparently normal, faeces oi three occasions. Otherwise there were no alarming signs of sever poisoning. Clinical Features and Course Apart from a postgastrectomy scar external appearance was not mal. There were no demonstrable neurological defects, cyanosi dyspnoea, oedema, jaundice, skin rash or haemorrhagic diathesi' Blood pressure was constant at 140/80 mm Hg. The electrocardic gram (ECG) showed sinus tachycardia of about 100/minute an ventricular cxtrasystoles but normal A-V conduction. Serum glutamic-oxaloacetic transaminase (SCOT) and serut glutamic-pyruvic transaminase (SGPT) activities were normal (4.5 1 and 6.7 1U, respectively). After gastric lavage, which produced on! smalt quantities of food residue, infusion of a JV. Ringer-laevulo1 solution combined with strophanthin and antibiotics was insdtute> Oral paraffin, which binds ethane dichloride and in this way pr< vents or delays its absorption, was not given as there was no it formation on the type of poison (9). A gas analyser which woul have immediately detected the presence of halogenated hydrocarbor SL 039090 No.Si February IW Martin et ah: Clinical Features, Pathogenesis and Management of Dichlorotrhane Poisoning 63 'in the expired air wax not available at that time. In view of the con After successful resuscitation by external cardiac massage for tinued improvement in the patient's condition no further therapeutic 25 minutes and artificial respiration with oxygen (by intubation) the measures were adopted. ECG showed complete atrio-ventricular block with a regular idio the morning of November 5th, twelve hours after admission to ventricular rate of 70/minute. The P-waves, so far as they were dis ^B^ital, the patient responded to stimuli. It was only then, 14 hours cernible, indicated an atrial rate of 75/niinutc (Fig. 1). after the accident, that the patient and relatives who had since been The ventricular and atrial rates responded to the intravenous in summoned by telephone provided the information that he had swal jection of 1.0 mg orciprenalinc with a rise to 85/minute and 120/min lowed Marament. This embrocation is made up of; 100 g dichloro- ute respectively. Finally, complete A-V block subsided and a regular ethane, 2.0 g oil of pine-needles, 02. g methyl salicylate, 0.05 mg rhythm of 110/minute returned (Fig. 2). cobra (Naja tripudians) toxins and an unspecified emulsifier in 100 mi Rapid infusion of Haemaccel, sodium bicarbonate, 5/ Ringer- of the liquid. laevulose solution and noradrenaline succeeded at about 10.40 (two At about 8.30, almost immediately after the toxic nature of hours after cardiac arrest) in restoring the circulatory state to nor the remedy had become known, the patient's condition suddenly mal. Unaided by adrenergic agents the blood pressure rose to 105/85 deteriorated with, dyspnoea, orthopnoea and progressive clouding of mm Hg and the patient responded to stimuli. consciousness. Blood pressure could no longer be recorded. At 8.40, during attempts at improving the circulation, cardiac arrest sudden ly supervened. ECG recordings (precordial leads) showed episodes of right bundle branch block. 17 hours after the accident the sinus rhythm was again disturbed by occasional ventricular extrasystoles which became more frequent in the course of the next half hour (Fig. 3). j,:-j- *'*.* ; 25mm/fc*c After a further wo hours, P-waves were no longer discernible; but the possibility that they were fused with the preceding T-waves could not be excluded. j 50mm/sec A During the day the ventricular extrasystoles be came more frequent and changes in the site of im pulse origin resulted in episodes of parasystole. 24 hours after ingestion of the poison the blood pressure fell rapidly within 30 minutes and cardiac arrest occurred. During resuscitation attempts prolonged bleeding from venipunctures drew attention to an increased bleeding tendency. 50mm/*c Fig. 1. Electrocardiogram recorded on 5 November 1966, after successful resuscita tion: probably complete atrio-ventricular dissociation with changing site of pace maker. At -10.40, after nodal rhythm and stable circula tory conditions had become re-established and con sciousness was gradually returning, massive haematemesis occurred, presumably due to profuse bleeding from the gastro-intestinal mucosa. It ef fectively precluded oral administration of paraffin which even then might still have proved beneficial. Up to 14.00 a total of 1,500 ml of blood-containing gastric contents had been evacuated, partly by vomiting and partly by suction catheter. An analy sis of the clotting factors (at 15.00) showed maximal reduction of Factors II, V, VII and XUI and com plete defibrination, fibrinogen being no longer de monstrable in the tyrosine-tryptophan test (12). The platelet count had dropped to 14,300/mm', fibrino lysis (Piper's method [10]) was increased to four times its normal value and pro-activaror levels were below 10*/. The thrombelastogram showed the blood to be incoagulable. Thrombin time after fibrinogen substitution was 59 seconds instead of the normal 12 seconds. V i ." i 1--| ' _vi .-r'3-i.V 4' wt--J -i i\ . n -- after a third dose of 2 ml. orclprenaline SOmm^ce The complex coagulation disorder with thrombo cytopenia and reduced activity of all coagulation factors was attributed to the consumption of these substances in a process of disseminated. intra vascular coagulation ("Verbrauchskoagulopathie") and to secondary hyperfibrinolysis (5, 7). The patient was given 5,000 U heparin by intravenous drip over a period of two hours and he was also given intravenously Cohn's fraction as a fibrinogen substitute, 4.0 g of t-amino-caproic acid as an antifibrinolytic agent and 2.0 ml Vitamin K, (phytomenadione). 10 50mm/Mc Fig. 2. Electrocardiogram recorded at 10.10-10.47 a, m. on 5 November 1966: sinus tachycardia after injection of a total of 6.0 ml of orciprenalinc (Alupent). A further estimation of clotting factors at 18.00 showed a rise in fibrinogen level to 16 mg/100 ml and in the platelet count to 20,000/mm*. Factors II, V and VII remained low. As was subsequently confirmed at necropsy, the liver at that time was already irretrievably damaged. The steep rise of SGOT to 1,860 IU, of SGPT to 450 IU and of t B it SL 039091 64 Martin et al.: Clinical Features, Pathogenesis and Management of Didilorocthanc Poisoning Germ. mol. Mth., VolTXIV lactate dehydrogenase to 4,5.55 ItJ and the reduction of serum-albumin concentration to 1-59 g/100 ml and of plasma-cholesterol to 76 mg/100 ml were presum ably attributable to fulminating yellow atrophy of the liver. The abnormally high lactate-dehydrogenase ac tivity may have possibly been due to haemolysis. Blood-gas analysis (Astrup's method) after massive infusion of a total of 920 mEq. of sodium bicarbonate revealed extreme acidaemia (pH 6.8) which was partly of metabolic (reduced base excess and standard bicar bonate) and partly of respiratory origin (marked in crease in CO, tension). At the time the blood samples were taken the patient was already moribund. He died at approximately 20.00, about 24 hours after ingestion of the poison, of irreversible cardiac and circulatory failure. * ,T"i : i , r.i * - - .> ria4-:' !' -I"""' ~ ,-- V '> * w SI? J/O/O/O/vJ/V |rtfL-r.v:':j . -irrA`, Necropsy Findings The most striking feature was acute yellow atrophy of the enlarged (1,800 g) and flabby liver. The cut sur face showed irregular yellowish-brown mottling. Through the microscope the lobular structure was - * tL*;: nsvF --4 ---- " * * '*i A- - t "' ' ' r , r 7^7. i V- ' r ` f - - *,-**- ! -- p \ ; -7 1. r discernible only as a shadow outline. Fig. 3. Electrocardiogram taken at 10.53--10.58 a.m. on 5 November 1966. The The portal canals were crowded closely together. Goldner's stain revealed very dark, homogeneous and lumpy hepatic cells with only a few nuclei. tracings (the leads were not recorded simultaneously) show, first, sinus tachy cardia with some extrasystoles; on the reight: complete right bundle branch block has developed which may indicate acute cor pulmonale. Distended cells, hyaline bodies and large intra cellular fat droplets were also seen. Only a few hepatic cells were of normal appearance. not develop until after a latent period of 24-48 hours (9). Cardiac arrhythmias and particularly ventricular fibrilla Both ventricles were hypertrophied and the right one was also dilated. On microscopic examination the myocardial fibres were thickened and the cell nuclei enlarged and irregular. There were also recent, predominantly perivascular, focal necroses of the myocardial fibres (Fig. 4*). The coronary arteries were slightly arteriosclerotic but not narrowed. tions have been observed after poisoning with chloroform and carbon tetrachloride (4) and Friese (3) also noticed in a case of ethane dichloride poisoning a transient in version of the T-wave in leads Vj-V5 such as occurs in rudimentary infarction of the anterior wall. The haemor The lungs showed bilateral chronic emphysema, membranous rhagic tendency that accompanies carbon tetrachloride pleural adhesions, considerable congestion and oedema. Microscopic examination revealed both occluding and non-occluding thrombi in the small lung arteries and capillaries, of not quite recent origin (Figs. 5 and 6). and dichloroethane poisoning has been ascribed to a mas sive reduction in prothrombin concentration. The post-mortem examination in our case revealed not The haemorrhagic diathesis manifested itself in haemorrhages into only the signs of haemorrhagic diathesis but also thrombi the mucosae of oesophagus, stump of the stomach (after a Billroth II gastrectomy) and rectum, and into the subepicardial, subendocardial and myocardial tissues. Bleeding into the intestinal wall was notice able in some jejunal loops. The attempts at resuscitation had re sulted in fracture of several ribs, subpleural haematoma and haemothorax of minor degree on the left side. in the pulmonary arterioles and capillaries. Taking into account the complex changes in the haemostatic mechan ism and the not unfavourable effects of heparin admin istration, the assumption appears justified that the drama tic reduction in the platelet count and clotting factors was a sign of their marked depletion, the substrates having Discussion The signs and symptoms presented by this case of dichloroethane poisoning corresponded closely to the clinical picture described by others. Characteristic features were an initial stage of stupor followed by the develop ment of gastro-enterocolitis, hepatic necrosis, haemor rhagic diathesis and cardiogenic shock within 48 hours. The frequently observed involvement of the kidneys was absent in our case. Toxic effects of dichloroethane resemble those produced by other halogenated hydro carbons, especially carbon tetrachloride, chloroform and ethane tetrachloride. All these agents have in common that, being fat-soluble, they have narcotic effects and taken orally they cause gastrointestinal damage and necro sis of the liver and kidneys. The renal lesions generally do been consumed in the process of coagulation (8). This in terpretation receives support from the fact that fibrinogen has a half-life of 3-4 days (1): the drop in the platelet count and plasma Factor I could not, therefore, be ac counted for by the onset of hepatic necrosis and the re sulting interference with the formation and synthesis o: plasma clotting factors. As to the accompanying hyper fibrinolysis, this was presumably a reactive process to dis solve the fibrin thrombi as is frequently observed in gener alized intravascular clotting (7). Whether dichloroethane can trigger intravascula clotting is so far unknown. Being a fat solvenr it migh damage the platelet membrane and thereby release pla telet Factor 111; or it might activate the clotting process fainducing haemolysis and thereby releasing pro-coagulan erythrocytic lipoproteins (erythrocyrin [11]). The snak * Figs. 4-6 are on p. 66. venom in the embrocation (snake bites may cause intra SL 039092 For the article by Turina et al. (pp. 49-50) Crohn's Disease of the Oesophagus 65 Fig. 1. Crohn's disease of the oesophagus. Oesophagratn: severe de gree of stenosis with thread-like irregular lumen immediately above the diaphragm. Conical narrowing of the oesophagus above the stenosis. Fig. 2. Same case as Fig. 1. Resected specimen of the distal oesopha gus and proximal part of the stomach showing a 2 cm long granu lomatous stenosis (S) below the upper margin of the resection. i Fig. 3. Same case. Ulcer floor with non-specific granulation tissue and compact Kmph follicles in the residual parts of the tunica propria, also in the submucosa which is fibrotic and hyperaemic. Magnification -< 35. SL 039093 Fig. 4. Same case. Muscularis propria with compact lymph follicles. Magnification X 88.  66 Fig. 4, Heart-muscle necrosis. Goldner's tridwme stain. Magnification X 140. Fig. 5. Hyaline thrombi in lung vessels. Goldner's trichome stain. Fig. 6. Hyaline thrombus in lung vessels. Goldner's trichome stain. Magnification X 140. Magnification X 240. For the article by Gedigk et al. (pp. 68-77) The Morbid Anatomy of Marburg Virus Disease SL 039094 Fig. 1. Irregularly arranged areas of necrosis (dark) affecting single cells and cell groups in the liver. Case 1 (I'M No. 378/67). Formalin, GoJdner. X 100. No* 2- February 1*6? Martin ct a!.: Clinical Features* pathogenesis and Management of Dichioroctnane Poisoning O/ * vascular Jotting) can be excluded as a causal factor as the poison was taken by mouth. The severe damage to the organs induced by dichloroethane could possibly bring ^^out the release of tissue thromboplastins which, in con^Biction with the excessive acidaemia and circulatory fail ure, could cause a shift in the physiological balance be tween fibrinolysis and clotting towards the latter. There is also the possibility that the cardiac arrhythmia and the consequent reduction in cardiac output (cardio genic shock) played a causal role in the pathogenesis of intravascular clotting. On the other hand, the dilatation of the right ventricle and development of acute cor pul monale with cardiac arrhythmia, cardiogenic shock and myocardial necroses could equally well originate from intravascular coagulation and the resulting, histologically proven, blocking of the pulmonary circulation by thrombi. If this latter hypothesis is accepted the haemorrhagic dia thesis, the cardiac arrhythmia and the disseminated ne croses in the intestine and kidneys could be attributed to the action of a single mechanism since the fully developed syndrome of intravascular coagulation is characterized by infarction of, and haemorrhages into, various organs. Conclusions The clinical picture presented by dichloroethane poisoning is determined by the quantity of poison ingest ed. In man the tolerated single dose is not more than 1,0 ml, with a maximal daily dose of 3.0 ml (9). As there ^yo known specific antidote, measures to counteract the ^Bcts of orally taken dichloroethane are primarily con^med to attempts at reducing or slowing down absorption of the poison from the gastro-intestinal tract. Further therapeutic measures aim at preventing acute hepatic failure and at restoring the disordered haemostatic mecha nism, acid-base balance and cardiovascular function. Selec tive therapy directed to the restoration of a particular functional system is impossible. From considerations of the pathogenetic mechanism, published reports and our own observations some general principles for dealing with oral dichloroethane poisoning emerge: 1) Alertness to the possibility-of dichloroethane poi soning is important. Inadequate specification of some dichloroethane-containing preparations as potentially dangerous is liable to mislead patients, relatives and the attending physician. 2) Analysis of the expired air by a gas analyser for the presence of chlorinated hydrocarbons, unless this type of poison can be absolutely ruled out. 3) Prompt gastric lavage, provided there is no contra indication, with addition of paraffin; then administration of 100-150 ml of paraffin and saline purges, either by aiouth or indwelling stomach tube. Paraffin administration repeated every 6-8 hours for the first 24-48 hours. 4) Prompt measures to protect the liver similar to those employed in acute yellow atrophy (6). Repeated laborato ry tests. 5) Supervision and constant adjustment of blood gases and steps to ensure excretion of an alkaline urine. Sodium bicarbonate administration should be supplemented by THAM, because the latter is more effective in counter acting intracellular acidosis. 6) Prompt and continuous analysis of the clotting fac tors to ensure that an incipient consumption of platelets and fibrinogen is immediately checked by an infusion of heparin (20,000 U in 24 hours). This therapy is applicable even in the presence of gastro-intestinal haemorrhage. If defibrination has already occurred, heparin combined with Cohn's fraction I as a fibrinogen substitute is given by infusion. 7) Continuous supervision of cardiovascular function with continuous recording of the ECG. 8) Administration of water and electrolytes as required and symptomatic treatment of the gastro-enterocolitis which is an almost invariable complication. Intestinal haemorrhages resulting in a critical reduction in haemo globin concentration may require blood transfusion. 9) Renal failure setting in 24--48 hours after ingestion of the poison is a potential complication of the third stage of dichloroethane poisdhing. Its occurrence depends on the quantity swallowed, the interval between ingestion and beginning of treatment and the success of the antecedent therapeutic measures. Treatment is the same as for acute failure from other causes. 10) An apparent improvement in the patient's condition after the initial stuporous stage has subsided must not lead to premature slackening of the therapeutic efforts. References (]) Amns, A., C. J. Amris: Thrombos. Diavhei. Haemorrh. (Stung.) 11 (1964), 404. (2) Brass, K.: Dtsdi. med. Wsdir. 74 (1949), 553, (3) Friese, G-, H. H. Sessner: Med, Wch (Stung.) 1961, 102, (4) Friese, G.: Differentialdiagnose der Herzstromkurve (Berlin-HcidelbergNew York, 1961). (5) Hardaway, R, M.: Syndromes of Disseminated Intravascular Coagulation (Springfield, 1966). (6) Knauff, H, G.: Miimit. med. Wschr. 105 (1963), I; 27, (7) Lasdi, H. G., D. Heene, K. Huth, W. Sandntter: Amer. J, Cardiol. 20 (1967), 381. (8) McKay, D., W. Margarerten; Ardi, inter. Med. 120 (1967), 129. (9) Moesdilin, S.: KJinik und Therapie der Vergiftungen (Stuttgart, 1959). (10) Piper, W., H, G. Budiberger: Med. Welt (Stung.) 1965, 385. (11) Quick, A. J,, J. G. Georgatsos, C. V. Hussey: Amer. J. med. Sd. 228 (1954). 207. (12) Ratnoff, O. D., C. Menaie: J. Lab. din. Med. 37 (1951). 316. (13) Sruhlert, H.; Dtsch. med. Wsdit. 74 (1949), 1542, (Authors* addresses:- Dr. G, Martin Universirats-FrauenkJinik Humboldralle, 34 Gottingen; Dr. K, Knorpp; Privardozent Dr. K. Huth; Dr. F. Heinrich Medizinische^Kliniken und Polikliniken KHnikstr. 32 b, 63 Giessen; Dr. C. Mirrermayer Pathologisches Insritut der Universitat 78 Freiburg/Br,, Germany) SL 039095 CHEMICAL MANUFACTURERS ASSOCIATION July 2, 1984 Mr. William V. Loscutoff Chief, Toxic Pollutants Branch California Air Resources Board P.0. Box 2815 Sacramento, CA 95812 Re: Ethylene Dichloride Dear Mr. Loscutoff: By notice dated May 31, 1984, you requested information as to the health effects of ethylene dichloride. The bibliography attached to your notice lists the draft health assessment document on ethylene dichloride prepared by the U.S. Environmental Protection Agency. CMA's Ethylene Dichloride Panel recently submitted comments on this document to EPA, along with a suggested revision. These materials are enclosed for your review. Please let me know if we can be of further assistance to you in evaluating the health effects of this important industrial chemical. Sincerely, RECEIVED jUl 0 j 1984 Environmental Attatrs --* Hasmukh C. Shah, Ph.D. Manager EDC Program Panel Enclosure c . c. EDC Pane 1 Formerly Manufacturing Chemists Association--Serving the Chemical Industry Since 1872. 2501 M Street, NW Washington. DC 20037 Telephone 202/887-1100 Telex 89617 (CMA WSH) SL 039096