Document 3Q8nv50y2Zddn4BDLKOaeXB70

APPENDIX 1 II III IV V VI VII VIII IX X XI XII XIII INDEX TITLE EXTRACTS FROM USFDA REGULATIONS PARTS 175-177 EXTRACTION OF BPA FROM FVC COMPOUNDS BY FOOD SIMULATING SOLVENTS LETTER RE EXTRACTION STUDIES ON BPA LETTER FROM UNION CARBIDE ANSWERING QUESTIONS ON THE NHMRC QUESTIONNAIRE EXTRACTS FROM DOCUMENTS OTHER THAN USFDA WHERE BPA IS APPROVED FOR FOOD CONTACT USE UNION CARBIDE LITERATURE ON BISPHENOL A (F40900B) DATA SHEET ON METAL CONTENT OF UNION CARBIDE PRODUCTS COPY OF THE LETTER FROM UNION CARBIDE (AUSTRALIA) RE PURITY OF BPA UNION CARBIDE LITERATURE "UCAR^ BISPHENOL A APPLICATIONSM DEVELOPMENT OF A METHOD TO DETERMINE RESIDUAL BPA IN PVC RESIN COMPUTER PRINT OUT SUPPLIED BY BFGOQDRICH CHEMICAL, USA SHOWING BPA SYNONYMS, USES, TOXICITY TOXICOLOGICAL DATA EXTRACTS FROM LITERATURE RELATING TO THE MANUFACTURE OP BPA Fart 1 * from Manufacture of Plastics, Volume 1 W Mayo Smith Published by Reinhold Publishing Corporation N. York 1964 Part 2 - from Organic Polymer Chemistry K. J. Saunders Published by Chapman & Hall, London 1973 * TWto&fTZ BFG09388 APPENDIX 1 EXTRACTS, FROM USFDA REGULATIONS PARTS 175-177 S'OO&'OTT BFG09389 M $ 175.105 Till* 21--Feed end Drug* wSvc Ap 73 Stu 1785. 1786. a* unended (2) The adhesive Is either separated '^1 u se 348. 371)) from the food by a functional barrier ' :u FR 14534. Mu. 15. 1077) or used subject to the following addi- , tlonal limitations: PART 17J--INDIRECT FOOD ADDI (I) In dry food*. The quantity of ad TIVES} ADHESIVE COATINGS AND hesive that contacts packaged dry COMPONENTS food shall not exceed the limits of lobperi A--[fltierved] good manufacturing practice. (II) In fatty and aqueous foods, (a) lubport I--tuk|lntn lor Uit Only The quantity of adhesive that contacts C**^nuti at Adhoalvoa packaged fatty and aqueous foods 3rt. shall not exceed the trace amount at 175.106- Adhe&Wt*, seams and at the edge exposure be '.75.125 Preuure'ieiutilve adhealve*. tween Packaging laminates that may occur within the limits of good manu Subporl C---lubtlencoa for Uu | C*mp*ionli facturing practice. ; 1 Coollnfk (ft) Under normal conditions of use ns.HO Acrylate Mttr copolymer CUngfc. : 75.23d Hoi-roelt sirippaole food coatings. :?5.250 Paraffin (synthetic). the packaging seams or laminates will remain firmly bonded without visible separation. .75,260 Partial phosphoric acid enters of (b) To assure safe usage of adhe polyester resins. sives. the label of the finished adhe 175 770 Poly(vinyl fluoride) retina. .75.300 Resinous and polymeric coalings. 175.330 Resinous and polymeric coatings for polyolefin him*. 175,350 vtnyl iceute/eroumlc acid copo lymer. 175.340 Vtnylldene chloride Copolymer coating* for nylon film. .75,365 Vinyftdene chloride copolymer sive Container shall bear the statement "food-packaging adhesive*'. (c) Subject to any limitation pre scribed in this section and in any other regulation promulgated under section 409 of the act which prescribes safe conditions of use for substances that may be employed as constituents of coatings for polycarbonate film. adhesives, the optional substances ns.380^X^^^Wi^W^^gwj|ia jKtfj- used In the formulation of adhesives may include the following: 175.300 Zlht-sillcon dioxide matrix coat ings. Autmqitt; Sees. 406. 701. 52 Slat. 1055U5d aa amended. 73 SUL 1785-1784 at 1.ended (31 UAc. 348). unless otherwise /Led. oouact 42 FR 14534, Mu. 15. 1077. unlew TierWU* noLed. Subpart A--(Reierved) (1) Substances generally recognized as safe for use in food or food packag ing. <t) Substances permitted for use in adhesives by prior sanction or approv al and employed under the specific conditions of use prescribed by such sanction or approval, (3) Flavoring substances permitted for use In food by regulations in this part, provided that such flavoring sub Subpart ft--Substances for Uia Only at Components of Adhesives stances are volatilized from the adhe sives during the packaging fabrication process. 175.168 AdWblvaa. (&> Adhesives may he safely used as .mponents of articles intended for ,,c In packaging, transporting, or ulding food in accordance with the ! Mowing prescribed conditions: i 1) The adhesive is prepared from ne or more of the optional substances umed in paragraph (cl of this section, jpject to any prescribed 1imitations. (4) Color additives approved for use in'food. (ft) Substances permitted for use in adhesives by other regulations in this subchapter and substances named in this subparagraph: Provided, however. That any substance named In this sub paragraph and covered by a specific regulation In this subchapter, must meet any specifications in such regula tion. RFG09390 4B0 Chapter I--Food and Drug Administrate AtokUc icM.......................................... -............................ Action*............................................................................... AceuMwuma-fonnaldebydt reln................................... MAceiyl ethuiolunin*.....-............ .................................. Aenyl Ultmiyl .... ,,,,,-- ...... ..... ......... Acetyl UlrWiyl ritrxle................. ..................................... Albumin. blood.................. .......... ............. ..................... -(S-lS-43 tlkoBr ethoxy) tlhoiyl) ethyl] dl tullmwtlfkitc. l AlkyitCrCu) inilno-l-iniino'pnipanc mono*eet*u Alkylated <C> and/or C.) phenol* ................. .. Alkyl tCr-C,,i benxenc................ ....... ............ ................ Alkyl *C-C,.I dtmethyltwfuy! Ammonium chloride...a.AikyHCu, C.* C. or c,,) dimethyl lethyibtnxyl) v tin tyciohtxrkuirunaic. Alkyl kiuu diner* h deunbod la 1171.120 Of thb c Alky] <Cf-C..> uphlhelthe....................... --....... S-AminoftnipaiMdloi..... ,,,,....... .............. . Aluminum...... ........... .......... ................. .. ...................... AlumtPdn ratal*___ _______ -.... ....... ........... . Aluminum dU2-*thylhekbau)................. ............... . Aluminum poMMium alllestc ....................................... k-S-AinlfiOechyl-oomnu-kminoimpyl irimrttwxytll* l-i AmmonuthyUl,5,S-tr1inethyl<yelohtKyUtalne.._. AmironwthylpropvtOl.............................. ....... ............ Ammoaluin benaoat* ................. ... ....................... . AmiBHuua bifluortde.,.,..,,,,,-- ............ ----............. Ammonium bo(Tie......... ....................... Ammonium ciintr.......... .--................. ........ Ammonium penuMate............. ................... ... Ammonium polyaerylal*........--............. -....... Ammonium poiautum hydroen phoaphat*.......... AaiBtmium *Uks>nuorUle ............ Ammonium lulfomata ........... .................. ............ Ammonium thiocyanate.,.,,..,..... ..... .--...................... Amawnltuu IhloeuUeU____ , --.... ...... .... nmyl MeUle-.o..,..---............................................. .... AnhydrOctLMahtpUibi__-............................. . Animal nut a* described In | lllliati tMicn^u 9-AftUmQv)Aone xulfOMc add, nullum tall____ ___ . Antimony oxide.,... ...................................................... *ibutci,,................... ........................... Asphalt. MJtf/lAic and naphthenic... Attlafc add - ASO-Su-UohutynuiUdk.........-- Baiam robber ... Barium tceUt*,,--------------------------.... Barium peroxide---------------------------- Barium aulfat* ........ BenioftlW.---------------------------- ---- Bcnxant (beniol)......------- ----------- BcnxothlatyldlaUUISt..........--..... p-BcAMiyphdnol------------ -------------Bciwayl oerodd* ----------------------Behnri ahoi..,,,------------------ -- Bcmyl bHuoaie..--............... .. Bmiasi bromOaeblaldn......... . ...... ..... b-Wenxylexirpbenol..^.......... ... -- ................ BKA (Satyiated hydroiyanlae)**---- ----------- .... BKT (boiyiaud hydroaytoluena)............. Blcycla(2.>.|lheM-2-ene-b-iiiibyi aerytate......--.. 3'Alphcrtyl diphenyl shotpitaU...... ................ . l.l-BMlbcnjotmawlytmcrtapiOfMthyl) urea....,, d.t-MtOAdlaethytbeiwyUdlplionylaiBtiko..-^.^. l.ABU U-motliylheptadeeyD-eenbol.... .. BklLri e-butyltliil oxide ,.-- *105 Till* 21`--Food ond Drug* Jhteuu<i ' JDLmeihyM.S-propanedlOl dlbanuaU-................................ methyl oxtynedlol....................................,,,,,,,,.......................... l,l-dlmclhyl3-oXOOuLrl) acrylamide-................................ methyl phlhalat*...................................................................... > Uin(vhyl l.l.}.lH-Uin)iylnUUiillulftH'i)ilOht...... viniphitiyl-p-phcnylenediainliia .......................................... ' 4 Dinonyl4-crmO|...................................................................... Ltkiilatiau For uh u pratniilH only. e-ociyldecyt adipate.............................................,,..... .(eiyldiphcnrlamlne,,,.,...... .................. .............. ........,,__ -.uctylph..tl.u.l.a..t.*...^..............r.................................................................................................. pentacrythrltol ptmiiuuila........................................ penumaLhylene-lhltMm.tetmauiridc.............................. fjcnlfnt.................................. ............. .......______________ pentane rmlne............................................... .jhenyM-atnylheAyl phoephata.................................................. phenyl, hyd/cienaied........................................................ V-Diphenylp-phanylenodlimlne,,....-^...,............. .................. phenyl phthxiaie....,...............................................,..................... } Ulphuiyl-Z-ttlMurM.................................................................... propylene ylycdl........................................................................... propylene |lyl dlbemuic...................................................... V'TPrlenr yircgl pionenwlhyi ether., propylene glycol copolymer at adipic ie|d and phthallc 4/- .ydrtde. -mHum cranodlthloimldoearbonatc..... ............................... _ y.Duiearoylaihyienediaaiinc................... ........................... . -tearyl Lhioclipropionate......................................................... .Ditcrt-ouiyM-hydroiyhydroelnnamlc aeld ttfwter with For ue la *Mloxtdxnt only. ..ii.t-trieD'hydrgxyclhylM-lJlaxlM'l.l.POfr. , My riune. Ollhlodlmorphotlnf,,............................................... ..... >odecylmtmpun........ ......... ................................. .......___ < CtoOeoytinerupiAn...... ................. ................... .................... decytph*noxybenune4laulfb&lc add and/or Ite calcium. .lagnoeium. ana Hdium Hila. ,J tone-e r^rntrvtlrfrtniiixtitiim ruM ____ .lehtarohydrln-t.t-aee-buLylldenfdlphcnol reatn............._,, . chiarntiyortn-e.i-laopropyUdenomi^erMOi min..,...... j.rmorotiydnn.piienoltonunMhjde ruin___ ____________ jcamlde (ervoyluMcl_____ ___ _____________ __________ anolamin*..... ............. ....... ..... ,......, ............ ......... . .ukyprcpanol butyl ether............ .............. .................... ...... . *iyl aieohoi (ethanol).... .............. ............ ............................ tylcncthamlne..... .......... ._..... .... ............................... .......... ... ,, ./Icnrdia/DJitLetn-acetlc eel*. rtiTk, p"1***1"- .< tofilum ,*iu, limit or mixed. tiylene dtch. rtd*.___ TM~,,.__..___ r>fkne tflyeol ......._____ ________________ __,... i.yienr glycol rnonobulyl etner............. . ___ __ ________ ylene tlycol monobulyt ether wtitc. .i.ylen* glycol (nonoelhyl ether.......... i.yUn* dyeoi monwdiyl tthtr KttiU__ _________ ______ i.ylene glyesl monoethyl ether ririoat+no,............... --...... nytcnc ll/tol monOmcfchFt ctW.^>.Mn.l.ni.....n..u.,,.i1i.u iiylcne glyOOt monOphenyl ether........... ............. ......... Cd Tl o S LP i tiylene-lultlc uiiiydr.d* copolymer, utmonlum or pOUe- A'.um ult. . Hylcru meUiurylle odd copolymer penial mils Ammon)..m, oklctum. mcfnuluin. >wlum. and/or lino., i.yiene'toefhacryltc uId-vlnyl uetite copolymer partial iK: Alrunonlum. caldum. uipipluia. tMlilW. anl/or .lie. . iiyiene-propyiene^ltcyclepentadltM copolymer tubbrr ...... .ylene. propylene. l.t-heeaiUene enC t t nirr*nrnaiMtm elrapplymer. 1 oyip>hy<lrosybenaoatc nyi hydroLmhytoeUiiioae.... nyl Ipcut*..,.--.......... ............ for uoe aa prutmilu only. .iyl phthalyl ethyl llveolau.. hyl-pHBtueiir euilbnamldc.. Ctaptar 1--Food ond Drug Admlnltf Pale ahd OlU derived from, animal or vefctable I the hydroitnated. euUatcd. Or aultonaud fOi rua ana om Pauy aclOi derived from animal or veieutot* f and aalu of such itld). almlr or nhtd, aa loU< Aluminum.... ......... Ammonium.....-- CMaMiOPuemel--um....------PoUHium .............. Sodium ----- ---------------- . Ferric chiotlda----........ .......... --....... nuoolllele am* (hydrofniadlieic acid).... ( Fonnaldehyde ................................. ..................... FOrmaldthyde O- and pdaluenc sulfonamide...... Fanwmldr......u.-ra.n-- FkiuontoehromliUB (III) nltmtc. Furfural,..--------...................... hirfaryl alcohol........... ......... Fumanc arid....,-----------------------Olutw4dnydc ......................... Oiyccrtdu. di- and monoeauri....... ..................... Olyt ryl tvnie (glycol boriboratk realm........... Glyceryl eater of diw, copal, tleml. and aanda Glyceryl menobulvl minoleato........................... Glyceryl monohydroxy stearaie...... .................... lyocryl oiwiOhydroxy tailovaie..,^..... ,............ Olyceryl polyoxypropylene innl (arerace mole I^OOl. Glyceryl thbencoatc ... .................... Glycol dlacctata-i^^^.....--......................... Gyloxal-------------- .------------------- Heptane--..--_,,,TM------ ........ KeixmathyUneteUamlne...................---.... ....... Mexahe........ .......................... ................................ HtllMUtOU..... ............................. - Hexylene ityOOl-- ------------- --...... -- Hydroabletrl alcohet-----------------.................... Hydrofluoric add................ ------------ Hydrocen peroxide..--......... ............................. . i-UydhMdCda-hydnHypoly'toxytftnmcthylCi ny4roqulnoM..n--,-- Hydrmpilnone unctttiBjrl eiher_,,._..---------- HydrOQUlnone monoethyl ether ,,._TM-----..-- -Hydroxy-J .) dt-im^rnyiphcnyi) bcnxouli Kydroxyacctlc add.-u---mTM-TM,, VBydroxyeoumartn...................... Rydroeyethylccllulecc.-- t-lt-Hydm*y*thyl>-id04hlorotaiilylVl hihyl ( --iiwiiim chloGda. Hydroxy*thyldlethylnetrtamine................... . d-Hydroxyethyl pyrtdlnlja yenercaptobemotl Hydroayetnyl tareh_-................... .-- Hydroiyettiylunt Hydroxytamkne eulfale-.-- HydrOxyprOpyl methyleellulpae........ - 3^Hydreiymthylrt'iDethyi-t>|op*nediel t i-lioldiifllldMM............. i todotorm...................................... .. --`--- laenrortic "*d------------ ------------- botouyti alcohol (hofcuxnoll................. - laobutylene-taeprcnc copelyiDerTM.-.--........ leopharcnt..^--.. ......----.......... ---- tupropanolamina (month, di-. in-> ---- leopnpyl uolate..... ................................. taopropyl alcohol dpopropaholl.^.--------------- `XMlBOl -QUNKI MMIjlf pUf M)M|n tf ---------------------------------------------me* tie iww*m yuui iq Wi jujiiji 9auuuB| tin i* mb m m TO* tppo M*m| 10J ( i* joui c 9U6 j* wpwn "KM) p**R#P mntM ---------------------*tun4JniipHH'4(|jm*)id WPWPMBdu ........... ------- ------------"------------ --.......................................................................................p> W14 .....................................................................................................-- nn atmnrf --* ...................-- .............--......................PR* annim*-* Xjub Hin^Mud n *fn joj --- --------------------------------1-1-----............................ ........ j* ui> MittmtJ(inii*w*-i4u*M (anuoa-uerjvtuatttXjod it xiuc m *04 ...............-............-.....................--------------------------- *opi|HJouij ----------------------f l p*awP ** nT" -- --mpu HHjB).wMwnwHWitf i[|w t*|1*AJmjd n ffn iOj ..................-- --------------------------------'------ miMM inawi niH|UMpiinBini| -innp iDNi aw^|*iA pflwnwwi pm 'WHS IP 'Jni^dlp am l niJ4p pu* mu> jo pui-omoq am 44 pwipoid) tVfftu uoqJwJpXij mtoiiOrf s inP nafWRd pa3i3 |o twmmP mai| ndii mopoi pv `*wn|urtu|A -awixn |o iniua*aipjii| lmitupqm pu* iwuiu>nX|o<i -4 illJI|T|i9 am A| pampMl b*u uoqnmplq mmipd pputl -upAy RiaptiUMlapci) ami ttonmipsa wmw* .....-........................ ........................................................... ---------- a*n|*joj>aj --------------------------------------- -----*uat4mKuaiipj w ..........................................--------`"-`-MMipauvy'nd'*! .......-...........--------------------------------------i<nym***i<ud is-w-Mtt 'on Altman vvai nmnjv4tiuad Xpio a.MitAjaojd n n jc -------------------------------.........................|9i|imAHmi,arf . tpppxqnv jo jap* (eiumAlwtiuj ---------------.......................................................-------- i*uM|daaB(ipnuad "-----------............................ -1-1--""""apXuawTPROpnj ...................---------------------------------------"^-ariOTjma <*>-"3) mm*tf ............ ......................|V|UJ4 p|H JlifBipd) apTUiainwrm ,..--.......-..-..-..-.-..-..-..-....--..................................................-..^..f.f.T.T--TV.W...f.U..i.q.t.u..a..jX..iMn*Q*1*M*M-*0* ...........................................................................................P*nn HP* fc*lO -........................................................."""-<opiwi pp* aifo apfvwio .......------------------"""-nioqjiooipAil umatonad m*n wpgpo tappo MU|Xdojd pv* **M0 |4m* jo riod tit tou*tiiaAxdojiLtiodi`AitO(|i*X|(MUioiMm<cr)0 --------------------------------------------------------------HQu*m*AKHUd, IRO --.............. .......................TM....................................|WHqOp-iao .............----------------------------------------TM" m*mud l^apiARO ......................................................................................................- {(Mioaf* iiiaC .......-......ttttutuujHMpXuXiojpXq-MAtnO-JJJJlPI't (Mpiao *a|oul oC aOxjiAi ltB4*vatAtita<HtA|i m pu* |W|[i |X*|<> onuj pp^ dnait |XuHvmao |f !(f4maXx0) AfoO<xiupAi|->ianuo-(jfuaa*p*tl0f'fR- -------------------vpRpjtMtn oiii(Komaip-trt-*U*UJ04l*N-4l>api<l i*I<nd o IP tat* -jaA tuOiW <aua|Aqi*AiB) (p4 tttl PV* P--I aawRl uapOoiO *| drwul utuou *m ^|*t tunpiotn* 'ai*; in* <*u|Xmxxe Xio44kOJp4t|-D6W0-(|jtB*M4t4<WM-4>-a 'Pt KHtlm* JO B|M pv-l | 1*1 iMO Vi ini* (irann javtm *tui4dwd * ti (tnodl |Amu> Iovvd|Xuou-tf jo *toi \ P mn*M*puoo m 14 panp . -aid Rniittlpjtu) XjodXxBjp4v*0dMi^(jXuoqai4BN^>s teui(n p MtAV |-p niuuf tu*tue9 fawtiqtoiM) xiod up put jaumi Jatuyt u|4dwd * | <moU ixuon am M*ia *iqo -aocftf uaKupxt(OUPUi pu* rj*qdPvd waXojpXqjp j* *n> -inn 4i*d4xoip4v-odaiuo-(|4Baq<M4iiDN-tf)-* ............----------------------------------- aindojMitlN-C --"----------- wumnawinU .......................................... ---ixujqdfQcwiiw* ............... .......... ....... ..................... ........ --pR amiu 00V annaaioia atuax* 'Kmou t-i> iaUa|4d*iiUxo) npijv;iuii7 501IZI 9 U9]|tti|*|U|uipY Bug pup podj--| itdDt(3 jifoa '*! BFG 09392 i4<r '4|Ufl lAJWAjjtud n Mm jqj .... Xpjo ujp*jmid atn p|$i Hi|W paqtiuil am jo wtiai* Xq iun -JSd | RMn Of foU nungi |p uuj PpRP -nu I*10 'axniuMud JO '[|oj nmuiumi* JJ tuat* Wipueq n xn atn jg^ 'Itvo afrtUMJd m atn img t{nipjiwi7 AJQ pUB pOOj--|t OlflX  175,270 Title 21--Food and Drugs (a) For the purpose of this section, partial phosphoric add esters of poly ester reams are prepared by the reac tion of trimellillc anhydride with 2.2dimeihyl-l,3-propaiiediol followed by reaction of the resin thus produced with phosphoric acid anhydride to produce a resin having an acid number of 81 to 88 and a phosphorus content of 4.05 to 4.63 percent by weight. (b> The coating Is chemically bonded to the metal and cured at tempera tures exceeding 450* F. ic) The finished food-contact coat ing, when extracted with the solvent or solvents characterizing the type of food and under the conditions of time and temperature characterizing the conditions of its Intended use, as deter mined from tables 1 and 2 of $ 175.300(d), yields Loial extractives in eacn extracting solvent not to exceed 0.3 milligrams per square Inch of foodcontact surface, as determined by the methods described in | 175.300te>, and the coating yields 2,2-dimethyl-l,3-propancdioi m each extracting solvent not to exceed 0.3 mtcrograms per square inch of food-contact Surface. In tesLing the finished food-contact arti cles. a separate test sample Is to be used for each required extracting sol vent. } 175.270 Polyivinyl fluoride) reilna. polyi vinyl fluoride) resins Identified in this section may be safely used as components of food-contact coatings for containers having a capacity of not less than 5 gallons, Subject to the pro visions of this section. <ai For the purpose of this section, polyi vinyl fluoride) resins consist of basic resins produced by the polymer ization of vinyl fluoride. ibi The polyi vinyl fluoride) basic resins have an intrinsic viscosity of not less than 0.75 deciliter per gram as de termined by ASTM Method D 1243-66, modified as follows: (1) Solvent: W.JV-Dlmeihylacetamlde. technical grade. (2) Solution: Powdered resin and sol vent are heated at 120* C until the resin is dissolved. (3) Temperature: Flow times of the soivciu and solution are determined at 110* C. <4) Viscometer: Cannon-Ubbelohde size 50 semlmlcro dilution viscometer (or equivalent). (S) Calculation: The calculation method used is that described In appendix Al.2.2 (ASTM Method D 124366) with the reduced viscosity determined for three concentration levels. not greater than O.S gram per deciliter, and extrapolated to zero concentration for intrinsic viscosity. The following formula is used for determining reduced viscosity: Reduced viscosity In terms of deciliters per rua-l-lo/toxc Where: (* Solution efflux time. <oaSolvent efflux time. cConcentration of solution In terms of gram* per deciliter. ft7Ui* gfdHui and polymeric com-, jnp, Resinous and polymeric coatings may be safely used as the food-contact surface of articles intended for use in producing, manufacturing, packing. processing, preparing, treating, pack* aging, transporting, or holding food. In accordance with the following pre* scribed conditions: (a) The coating is applied as a contlnuous film or enamel over a metal substrate, or the coating is Intended for repeated food-contact use and is applied to any suitable substrate as a continuous film or enamel that serves as a functional barrier between the food and the substrate. The coating is characterized by one or more of the following descriptions: (1) Coatings cured by oxidation. (2) Coatings cured by polymerisa tion. condensation, and/or cross-llnkLng without oxidation. (3) Coatings prepared from prepoly merized substances. (b) The coatings are formulated from optional substances that may in clude: <1> Substances generally recognized as safe In food. (2) Substances the use of which is permitted by regulations in this part Or which are permitted by prior sanc tion or approval and employed under the specific conditions, if any, of the prior sanction or approval. f I | | i I I | 1 1 ' , 1 j } | ; i | t 1 ! t , | ; I [ ] 1 ` ` * soft Choplev I--Food and Drug Administration (3i Any substance employed In the production of resinous and polymerie coatings that is the subject of a regu lation in Subchapter B of this chapter and conforms with any specification in such regulation. Substances named in this paragraph (b)(3) and further Identified as required: (1) Drying oils, including the trigly cerides or faUy adds derived there from: tt Beechnut. Cindlenut. Cwtor (Including dehydrated). Chlnavwd (tung). Coconut. Corn. Cottonseed. Fish (refined). Hempaeed. Linseed. Oiilclca. Perill*. Poppyseed. Pumphlnseed. Safflower. Sesame. Soybean. Sunflower. Tall oil. Walnut. CO ON m 0\ O PPh CQ The oils may be raw. heat-bodied, or blown. They may be refined by fUtraUon. degumming, acid or alkali washIng, bleaching, distillation, partial de hydration, partial polymerization, or solvent extraction, or modified by combination with maleic anhydride. (ii) Reconstituted oils from trlglycerides or fatty acids derived from the oils listed In paragraph <b)(3MD of this rection to form esters with: i I , , 1 1 Butylene glycol, Elbylene glycol. PetiUcryth/Uol. J'olyetbyien* giycoL Polypropylene glycol. Propylene glycol. Sorbitol. Trlnwthylol *th*n. Trimcthylol ptt>p*ne- (111) Synthetic drying oils, as the basic polymer Butadiene and methylstyrene copolymer. Butadiene and styrene copolymer, blown or unblown. Maleic anhydride adduct of butadiene Sty rene. Polybutadlenc. -- j ** p eto* .ateen o o n o o^ BFG09394 300 fills 21--Food and Drugs j>Nonylphenol. jt-Ociylphenoi. 3-Pvnt.adecyl phenol mixture obtained from cashew nut snel) liquid. Phenol. Trtmethylol ethane. Trtmethyioi propane. * frf) Monohydrfc alcohols: Phenyl o-cresol. p-Phcnylphenol. Xylenol. Ceiyl alcohol. Decyl alcohol. Laury) alcohoL ib> Adjunct (or phenolic resins: Alu* Myrlstyl alcohoL minum buiylate. Octyl alcohol. (v 11 > Polyester resins (including Siearyl alcohol. alkyd-lypei, as the bwlc polymers, formed as esters of acids listed in p&.r&- (vltl) Epoxy rosins, catalysts, and ad graph iQK 3Kvii> (a) and (0) of this sec juncts: tion by reaction with alcohols in para (a) Epoxy mins. BS the basic poly graph (b)(3) (vii) (c) and (rf> of this mer: section. uii Polybasic acids: (Alkoxy Cu-Cnl-S.S-epoxypropane. in which the alkyl groups are. even numbered Adipic. and consist of a maximum vf 1 percent CM Dimerized fatty acid* derived from oil* carbon atoms and a minimum of 42 percent Haled Irt paragraph <b><3)<() Of this teeuou, Diplitnollc told. Puii.^nc. j^pjniialic. Maleic. Orthophthallc. C.i carbon atoms and a minimum of 18 per cent Cm carbon atoms, (or use only in coat ings that are Intended for contact with dry bulk roods at room temperature. 4.4'-see-Butylidenediphenoi-eplchlorohydiin 4,4'Sec-Butylkienedkphenol-epichlorohydrin reacted with one or more of the drying SrtlClC. TcTcphlhalic. oils or felly acids Hated in paragraph {bH3)il) of thb section. Trrpt>ne>tnalelc acid adduct. Trimelliiic. 4,4`-jec-Bety!idenediphenol-epichlorohydrin chemically treated with one or more of it>> Monobasic acids; the following substances: Allyl ether of mono-, fll-, or trlmcihylol BvOiOic icld. phenol. lerj.Butyl bentole acid. 4.4-jfc-Butylldened prro Fluy acids derived frorr oils listed in para graph (>K3Mi) of this section. Koaiha luted in paragraph tbH3)lv)ia> of Melamine-formaldehyde. Phenol-formaldehyde. this section, for use only as reactants in Urea-formaldehyde. on-bued or fatty acid-based slfcyd resins. Epoxldized polybutadiene. (o Polyhydric alcohols; Glyddyt ether* formed by reacting phenolnovotak re&ina with eplchlorohydrln. Butylene glycol. Dicihyiene glycol. 4.4 'fwgngylUnedipftmel'eplebleriF WMMW. '* *i^.*vX****ihV*x,*i'r 2.2 Dimeihyl-l.S-propanedio! for use only In ^g'-UoprOpyWihnedipheivnl idghlnrqhydrtH^ farming polyester resins tor coatings in reacted with one or more of the drying tended (or use In contact with non-alco holic foods. Ethylene glycol. {Jiycrrul. .iMrthyl gjucoiid*. Pvtiu< rythritol. Propylene glycol. siorMul. * oils or fatty acids Hated In paragraph tbHSklloMhis section. ^4-boprM>yUdiiodiiitociMl*evlehlorohy4rtn; chemlcaliy treated with one or more o( the following substances: Aliyl ether of mono-, dk or trlmethylal phenol. aA'-sec-ButyUdenedlphenol-formaidehyde. id *L _____. ha a -.. a.- -- Tnvthyiene slycol. for use as a component in polyester realm for coatings not exceed ing coaling weight of 4 milligrams per uuarc inch and that are Intended for conlari under conditions of use D, C, P or Q Meiamlne-fonnaldehyde. Phenol-formaldehyde. Urea-formaldehyde. described In table 2 of paragraph <d> of this section with iiconoiic beverages con ib) Catalysts and crcts-llnkinc taining less than I percent alcohol. i I i j > 1 ` l 1 4fift Chapter I--Food and Drug Administration o Plbutyl phthsisLe, for use only In coaling* for containers having a capacity or 1.000 gallons or more when such containers are Intended for repeated use in contact with alcoholic beverages containing up to 8 per cent of alcohol by volume. Dietkiylenetrtamlnc. Dtphcny lamina. A B Eihylenediamlne. Isophthalyl dlhydrazlde for use only til coatings subject to the provisions of para- p graph (c) tJ) or (4) of this section. 4,4 -MethyieftedisnUine. for use only in coat ing* for container* having a capacity of 1,000 gallons or mors when such contain- era are Intended for repeated use in con tact with alcoholic beverages containing up to a percent of alcohol by volume. N-Oley)-l.3-propenediamlne with not more than 10 percent by weight of dlethyiemin- oethanol. Poiyamine produced when 1 mole of the chlorohydrin dlether of polyethylene glycol 400 l* made to react under aehydrohtlogenstlng conditions with 2 I moles of N-ociadecyitrimcthyienediarmn? for use only in costings that are subject( the provisions of paragraph <c> (3) or 14) . of ihU section and that contact food at 1 temperatures not to exceed room tempera ture. 1 Salicylic acid, for use only in coating* for I conisihert having a capacity of 1.000 gal- . Ions or more when such container* arc in tended for repeated use In contact with al- 1 cohohe beverages containing up to 8 per- ` cent of alcohol by volume. Stannous 2-ethyihexanoate Tor use only as a , catalyst at level not to exceed l percent by weight of the resin used in coatings that are Intended for contact with food under conditions of use D. E, P, and G de scribed in table 3 of paragraph (d) of this section. Styrene oxide, for use only In coatings for container* having a capacity of 1.000 gal lon* or more when such container* are in tended for repelled use in contact with al coholic beverages containing uo to a per cent of alcohol by volume. Teiraethylenepentamlnc. Teiraethylenepenlamine reacted with equi molar quantities of fatty acids. / Trltdlrncthyiaminomethyl) phenol and its salts prepared from Lhe fatty acid moie ties of the aiu listed In paragraph ibKSHxxUKbi of this section, for use only in coatings subject to the provision* of psragrsph id 131 or m of this section. Trlethyleneietramme. Trimeuitie anhydride lor use only as a cross-linking agent at a level not to exceed 15 percent by weight of the resin intended for use only in contact with food under conditions of use D, E, F, and O described in table > of paragraph <d> of Shi* section. SOS eootwnz 'lanpMdproj jof Xiimhvk* H i tufAfLn uf *[| | mni * 4q ptpMIP *q mm nimw AtAnHilt* **WJ*Hi inujtviu p*ut|'m uo pm aq m mu ivnnjin *HJ JO no -- tftot-4.r..................09 *--* ua v-Afin Mii **i * momftv t 1*1 MO( jq gm |* wt*|niu ....................... ***" "' nym 0C'4-XU .... ...... tt^AI'll`I * W II * *nMiV I ittn jo Mini 1* Jwmooo m 0Oii*ui M) P) p*pu*)if| ^04j pu*d 414-lptDl :tuoi* VRU4 'ip fi/\ usumuo tit) in lurniun ............ ............. .. *"--jm n 'A At 'fl-AI 'in 'll *| mum m jujto " d jy 'A At -------------------- ---- -................................... ........... .... v-lA HA ,fJv|*i --------------------- --------m iva.oj, a-LA 'tt-AI n VI IOHHH1) t*v -mi ou *uini '4 '? 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First as internal diameter metal tube attached certain Lhe type of food product to a hot water line and bent id as to (Table i. paragraph (d) of this section) direct a stream of water upward, may that is being packed commercially In be used. Be sure hot water has the test container and the normal con* reached a temperature Of 1W` F-200* ditions of thermal treatment used In F before starting to rinse the contain packaging the type of food Involved. er. Invert the container over the top Of Using Table 2 (paragraph <d) of this the fountain *nd direct a strong section), select the food-sLlmulatlng stream of hot water against the solvent or solvents (demineralised dis bottom and all sides for I minute, tilled water, heptane, and/or B percent ethyl alcohol) and the time-tempera ture exaggerations of the containeruse conditions. Aqueous products (types I, 11, 1V-B, and VJ-B) require only a water-extraclability test at the temperature and time conditions shown for the most severe "conditions of use.11 Aqueous products with free oil or fat, and water-oil emulsions (types 111. IV-A. and VII) will require deter minations of both water extractabiljty and heptane extractability. Low-mois ture fats and oils (type V with no free water) require only the heptane exiraCLabiiity. Alcoholic beverages (type Vl-A) require only the 8 percent alco hol extractant. Having selected the ap propriate extractant or extractants simulating various types of foods and beverages and the time-temperature exaggerations over normal use, follow the applicable extraction procedure. drain, and allow to dry. (4) Exposure condfffoiu--(1) Wafer 1250' F for 2 hours), ftmufatlnp hightemperature heat iterilieatton. Fill the container within Vt-tnch of the top with a measured volume of deminera lized distilled water. Cover the con-i talner with clean aluminum foil and place the container on a rack In a pres sure cooker. Add a small amount of de mineralized distilled water to the pres sure cooker, but do not allow the water to touch the bottom of the con tainer. Close the cooker securely and start to heat over a suitable burner. When a steady stream of steam emerges from the vent, close the venL and allow the pressure to rise to 15 pounds per square inch <250* F) and continue to maintain this pressure for 2 hours. Slowly release the pressure, open the pressure cooker when the pressure reads zero, and composite the Adapt the procedure, when necessary, lor containers having a capacity of over 1 gallon. water of each replicate Immediately in a clean Pyrex flask or beaker. Proceed with the determination of the amount (2> Selection of coatedeoMainer of extractives by the method described samples. For consumer-sized contain in paragraph <e)<$> of this section. ers up to l gallon, quadruplicate sam (ii) Water ttt? F for 30 minutes), ples of representative containers simulating boiling water sterilisation. (using for each replicate sample the Fill the container within w-lnch of the number of containers nearest to an top with a measured volume of boiling, area of 180 square Inches) should be selected from the lot to be examined. (3) Cleaning procedure preliminary fo determining the amount of extraetabits from coated container*. Quadru plicate samples of representative con demineralized distilled water. Cover the container with clean aluminum foil and place the container on a rack In a pressure cooker In which a small amount of demineralized distilled water Is boiling. Do not close the pres tainers should be selected from the lot sure vent, but operate at atmospheric to be examined and must be carefully pressure so that there Is a continuous rinsed to remove extraneous material escape of a small amount of steam. prior to the actual extraction proct" Continue to heat for 90 minutes, then dure. Soda fountain pressure-type hot remove the test container and compos water rinsing equipment, consisting In ite the contents of each replicate lm* I ' , t BFG09396 Chapter I--Food and Drug AdmlnU mediately in a clean Pyrex flask beaker, Proceed'with the delermV tton of the amount Of extractives the method described In paragrs <eK5) of this section. Oil) Water Uram boiling to 100* simulating hot fill or pastevrieat above isor F. nil the container wit ft-lnch of the top with a measu volume of boiling, demineralized i tilled water. Insert a thermometer the water and allow the uncove container to stand In a room at 70* 85* F. When the temperature re 100* P. composite the water from e replicate Immediately In a clean Py flask or beaker, proceed with the termination of the amount of ext] tives by the method described in pi graph (e)(5) of this section. (Iv) Water (250* F/Or 2 hours), sii Zatinp hot /ill or pasteurization be ISOr F. Preheat demineralized distl: water to 150* F In a clean Pyrex fli Fill the container within V*-lnch of tDp with a measured volume of 150* F water and cover with clean i mlnum foil. Place the test containe an oven maintained at 150* F. Aft< hours, remove the test container fj the oven and immediately compo the water of each replicate in a cl Pyrex flask or beaker. Proceed a the determination of the amount extractives by the method describe* paragraph (e)(5) of this section. (v) Water UOr F for 24 hours), si fating room temperature filling , storage. Preheat demineralized tilled water to 120* F in a clean P> flask. Fill the container within tt-1 of the top with a measured vo)um< the 120* F water and cover with cl aluminum foil. Place the test cont er In an incubator or oven mainlai at 120* F. After 24 hours, remove test container from the incubator Immediately composite the watei each replicate in a clean Pyrex ftas beaker. Proceed with the determ lion of the amount of extractives the method described In paragr (eHfl) of this section. tvt) Water (70* f fores hours), ii lating refrigerated storage. Bring 21104009 j.300 Title 21--Feed and Drugs clean pyrex flask on a water bath or nonsparking hot plate in a well-venti lated hood to l5Q' P. At the same time preheat a pressure cooker or equiva lent to ISO' F In an Incubator. This pressure cooker Is to serve only as a container for the heptane-containing test package inside the Incubator in order to minimize the danger of explo sion. Fill the test container within inch of the top with a measured volume of the ISO' F heptane and cover with clean aluminum foil. Place the test container tn the preheated pressure cooker and then put the as sembly Into a ISO* F incubator. After 3 hours, remove the pressure cooker from the incubator, open the assem* bly, and immediately composite the heptane of each replicate in a clean Pyrex flask or beaker. Proceed with i he determination of the amount of extractives by the method described tn paragraph (e)(5) of this section. ix> Heptane UZ(T F for JO mintifes). simulating boiling water sterilization of fatty foods only- Preheat redistilled reagent-grade heptane (boiling point 208* F) carefully in a clean Pyrex flask on a water bath or nonsparking hot pl&Le in a well-ventilated hood to 120* F. At the same time, preheat a pres sure cooker or equivalent to 120* F in an incubator. This pressure cooker is to serve only as a vented container for Die heptane-containing test package Inside the incubator In order to mini mize the danger of explosion. Fill the test container within V'*-Jnch of the top wiLh a measured vblume of the 120* p heptahe and cover with clean alumi num foil. Place the lest container in the preheated pressure cooker and then but the assembly into a 120* F in cubator. After 30 minutes, remove the pressure cooker from the Incubator, open the assembly, and immediately composite the heptane of each repli cate in a clean Pyrex flask or beaker; Proceed with Lhe determination of the amount of extractives by the method described In paragraph (e>(5> of this* section. txi) Heptane tiztr f/ot n minutes), jrtmulaling hot fill or pasteurisation above JJ0* F for fatty foods only. Pre heat redistilled reagent-grade heptane (boiling point 208* F) carefully in a clean Pyrex flask on a water bath or nonsparking hot plate In a well-venti lated hood to 120* F, At the same time, preheat a pressure cooker or equiva lent to 120* F In an Incubator. This pressure cooker is to serve only as a container for the heptane-containing test package Inside the Incubator in order to minimize the danger of explo sion. Fill the test container within Viinch of the top with a measured volume of the 120* F heptane and cover with clean aluminum foil. Place the test container in the preheated pressure cooker and then put the as sembly Into a 120* F incubator. After 15 minutes, remove the pressure cooker from the incubator, open the assembly, and Immediately composite the heptane of each replicate in a clean Pyrex flask or beaker. Proceed with the determination of the amount of extractives by the method described In paragraph (e)(5) of this section. (xll) Heptane HOST Ffor J0 minutes), simuidffnp hot fill or pasteurization below istr F for fatty foods only. Pre heat redistilled reagent-grade heptane (boiling point 208* F) carefully in a clean Pyrex flask on a water hath or nonsparking hot plate in a well-venti lated hood to 100* F. At the same time, preheat a pressure cooker or equiva lent to 100* F in an incubator. This pressure cooker Is to serve only as a container for the heptane-containing test package inside the incubator in order to minimize the danger of explo sion. Fill the test container within V*- inch of the top with a measured volume of the 100* F heptane and cover with clean aluminum foil. Place the test container in the preheated pressure cooker and then put the as sembly Into a 100* F incubator. After 30 minutes, remove the pressure cooker from the Incubator, open the assembly and immediately composite the heptane of each replicate in a clean Pyrex flask or beaker. Proceed with the determination of the amount of extractives by the method described In paragraph <eX5> of this section. (xill) Heptane iftr Ffor 30 minutes), ihnviadntr room temperature fitting and storage offatty food* only. Fill the test container within *Wneh of the top with a measured volume of the 70* F BFG09397 508 i i n O Q Chapter I--Feed and Drug Adminiiln heptane and confer with clean alumi num foil. Place the test oontainer In i suitable room maintained at 70* F After 90 minutes, composite the hep tane of each replicate in a clean Pyre flask or beaker. Proceed with the d< termination of the amount of extra( tives by the method described in pan graph teX5> of this section. (xiv) Heptane U2(T W for 30 mil vies), iimuiotinp frozen fatty foods r> heated in the container, preheat redt tilled reagent-grade heptane (boilln point 208* F) carefully in a cle* Pyrex flask on a water bath or h( plate in a well-ventilated hood to I2i P. At the same time, preheat a pre sure cooker to 120' F in an tncubato This pressure cooker is to serve on) as a container for the heptane-coi taining test package inside the Incubi tor in order to minimise the danger < explosion. Fill the test contain! within Mnch of the top with a mea ured volume of the 120" F heptane an cover with clean aluminum foil. Pla< the test container in the preheati pressure cooker and then put the a sembly into a 120* F incubator. Aft* 30 minutes, remove the preasui cooker from the Incubator, open t) assembly and immediately compost' the heptane from each replicate into clean Pyrex flask- Proceed with tl determination of the amount of e tractives by the method described paragraph (e)(5) of this section. <xv> Alcohol--8 percent ilStr F for hours), simulating alcoholic beverag hoi filled or pasteurized befoto J50* Preheat 8 percent (by volume) eth alcohol in demineralized distill* water to ISO* F in a clean Pyrex fits Fill the test container with within inch of the top with a measur volume of the 8 percent alcohol. Cov the container with clean aluminu foil and place in an oven maintained 150* F. After 2 hours, remove the cc tainer from the oven and immediate composite the alcohol from each res cate In a clean Pyrex flask. Froce with the determination of the amou of extractives by the method describ in paragraph <eMS) of this section. <XVl) Alcohol--t percent (120* F j 24 hours), simulating alcoholic bev ages room-temperature filled e ,5-300 Title 21--Food end Drugs In parts per million for the particular size of container being tested and for Lhe specific food-simulating solvent used. () Water and 8-percent alcohol. Milligrams extractive* per square inch-*/* Extractives residue f-(*)(al(lQOQ)/(e)(e> () Heptane: Milligrams extractives per square lnch-e/ UK/) Extractive# residue - Ez - < t Max 1000)/ (ehix/l Where; fi-Ekirietlves residue in ppm for any container ilae. e-Milligrams extractives per sample tested. 0-Total coated area, Including closure In square inches. Water capacity of container, in grams. j-Burlsce of coated area tested. In square inches. F- Fne. the ratio of the amount of extrac tives removed from a coaled container by heptane under exaggerated limeleittpefalurc lesL conditions compared to the amount extracted by a fat or oil from a container tested under exagger ated conditions of thermal sterilisa tion and use. e - Chloroform-soluble extractives residue. ee'-Zinc corrected chloroform-soluble ex tractive residue. f or ** is substituted for e in the above equations when necessary. If when calculated by the equations In paragraph (e)(S)(l> (a) and ( of this section, the concentration of extraclives residue <Ei) exceeds 50 parts per million or the extractives in milli grams per square inch exceed the limi tations prescribed In paragraph (c> of this section for the particular contain er size, proceed to par&eraph (CX6XII) of this section (method for determin ing the amount of chloroform-soluble extractives residue). <ii) CViforo/onrwofvble extractive* residue. Add 50 milliliters or chloro form (freshly distilled reagent grade or a grade having an established con sistently low blank) to the dried and weighed residue, (), in the platinum dish, obtained In paragraph (e)(5)(l) of this section Warm carefully, and filter through Whatman No. 41 filter paper in a Pyrex funnel, collecting the fil trate in a clean, tared platinum dish. Repeat the chloroform extraction, washing the filter paper with this second portion of chloroform. Add this filtrate to the original, filtrate and evaporate the total down to>a few mil liliters oh a low-temperature hotplate. The last few milliliters should be evap orated in an oven maintained at 212* P. Cool the platinum dish In a desicca tor for 30 minutes and weigh to the nearest 0.1 milligram to get the chlo roform-soluble extractives residue (e ). This e' is substituted for e In the equa tions in paragraph (a)(5)(l> (a) and (5) of this section. If the concentration of extractives (2) still exceeds 50 parts per million or the extractives In milli grams per square Inch exceed the limi tations prescribed In paragraph (c) of; this section for the particular contain er size, proceed as follows to correct for sine extractives ("Cp1 enamels only): Ash the residue in the platinum dish by heating gently over a Meekertype burner to destroy organic matter and hold at red heat for about l minute. Cool in the air for 3 minutes, and place the platinum dish In the desiccator for 30 minutes and weigh to the nearest 0.1 milligram. Analyze this ash for zinc by standard Association of Official Agricultural Chemists meth ods or equivalent. Calculate the zinc in the ash as zinc oleate, and subtract from the weight of chloroform-soluble extractives residue it) to obtain the zinc-corrected chloroform-soluble ex tractives residue (*). This t? is sub stituted for e in the formulas in para graph <eK5)(i) (a) and lb) of this sec tion. To comply with the limitations in paragraph (C) of this section, the chlo- roform-soluble extractives residue (but after correction for the sine extrac tives in case of "C" enamels) must not exceed 50 parts per million and must not exceed in milligrams per square inch the limitations for the particular article as prescribed In paragraph (c) of this section. (f) Equipment and reagent require ments--(1) Equipment Rinsing equipment, sods fountain pres sure-type hot water, consisting In simplest form of a h-inch-W-Inth inside diameter metal tube attached to a hot water Une deli vering ISO* F-200* P water and bent so as to direct s stream of water upward. Pressure cooker, 21-quart capacity with pressure gage, safety release, and removable rack, 13.5 inches Inside diameter x 11 sio BFG09398 Chapter I--Food and Drug AdmlnWtre inches Inside height. 20 pounds per squari inch safe operating pressure.. Oven, meehanlcal convection, rente to in elude 120* P-212' P e*plosion-proof. lnald dimensions (minimum). 19" x 19" x 19' constant temperature to 2* P (water batl may be substituted). Incubator, Inside dimensions (minimum i9,a x 19'* x 19" for use at 100* P*2' F ) plosion proof (water bath may be subatUui *d). Constant-temperature room or chambe 70' F2* P minimum Inside dimensions II x 19" X 19". Hot plate, nonsperkinf (explosion proof top 12" x 20". 2.900 walu. with temperatui control. Platinum dlsb, 100-mMUiter capacll minimum. All glass, Pyrex or equivalent. (2) Reopen f*. Water, all water used In extraction proc dure should be freshly demineralize (deionized) distilled water. Heptane, reagent grade, freshly redistilh before use, using only material boiling 20*' P. Alcohol. 9 percent (by volume), prepare from undenatured 99 percent ethyl alCOli diluted with demineralized or distllU water. Chlorolorm, reagent grade, freshly red! tilled before use, or a grade having an cit* lished, consistently low blank. Filter paper. Whatman No. 41 or equiv lent. (g) In accordance with good man1 facturing practice, finished coatlm intended for repeated food-contact u: shall be thoroughly cleansed prior 1 their first use in contact with food. (h) Acrylonitrile copolymers idenl fled in this section shall comply wil t*- H O 4b O H* tut ofn&Jfascta (1) Resins and polymers: acrylic MU pblymti and hi ethyl or ncth eaten. AeryUndd* polymerised with etbyl scryLa and/or styrene and/or uwthscrvUe sew. ai the copolymer subsequently reacted with f< maldchyde end butanoL HutAdieM-aenlonltrili Copolymer Buiadicnescrytaniinustynsi ttrpoimsr.... Butyl rubber----------- --------- --- --------- 2-Ethyiheiyl acrylate upoljmcrlMd with w or * of the following: Acrylonitrile lUconle srtd................................................. tleUiacrylonltrlla Methyl wyiu , ------------- Methyl methesrrlsto . Makydfta^ BFG09399 Tri!* 31--FQftd and Drvgi t J.-;il,Dl..... . ................... ......... .......... ..... LimtiatUn* ,, -v '!*!. ir, J-i. -U-.U............................................ i-...... ................... T ,1: , , ................................ .................... . T-. j.i.; .n. Miur.ui'iU'n, or tedium nil Far uae only ss 4 nwl|(kr for unlfla (oltu. A,:-.,'- V j < ii_ .1. ,ti; . !. p;i|ynw-r with For we only o 1 ffuculent. dr*lnM sld or nten- i1 i r.'.yi* -t'K-,-. f,;h! tL\' lie whh not ilon aid employed prior to the sheet formIns r.a.-x 5 ti. r.Mu t-y iH iKM }-ct:Jcrn-2,3-epoiv- operation la the reaiiufuture of paper ud d- l.n-il Win rtot :norf Itiw1 ft pertward pjpJ |tutted W at 4 level pot to by at-rit priy <Li;r>'iic acid) such that a ftO txceed ft: percent by weight of the flmshod [ fkt'iu by wrjftii mifiiui :.ou:ion or the pnduct dry paper pad paperboard fibers. t. J. .. t.iirr.ifrn eu'.irnt u.` 4.7-4.0 percc.H and vi*- 1 ;l# lit 31J isntirOLjia ;i| ;vCb(IriermlRMl by T.V k,`!'.-s liriUfTlj.'a Vi.kkO.-.Hriifj- uilt;tf a No, ft j -i i if (,t oO r.p.sn. tor by Ovtut equivalent k T-'i;."- k-Miuni A-( :,J diLirbfijtyplhyI)-A/,oii.i^<wyljuir6. far use only as an emulsifier In aqueous dltper* alone Of mlf) iti COfltplylrtt wlr.h { ITft.3ft7(Kah4> Of thin chapter and limited to use prler to the iheri.iortnlPf Openttunln the ntnuftetun af faper and paperV.ua at ft level net to eseiuti ft-02 pet by weight or fin> lahed par it apd papertwrwd. 7 --;..-lh. .loSamlne For use crJy to adjust pH during the manufacture of amino ruins permitted fer use m OOmpo- nc.itf of paper and pftperDoard. T'lc yl/cnl aripic w!d rioimefiter produced by for use only as a curl-control afent at a level not in- i..i ryaiiiitilar tu*1 tuie* of tr.elhylcnt glycol i,! m;M. to cxt'ccd Xz* by vrlmi of coated or uncoated paper anil rapertMtu/d. fl .ti I'.) .tliL'Lk'll UmiAf..................................................................... for uss only as a modifier for amino resins. U.ijr >T>ki''0O^!urriksriL'.-n*.'ib^i^:l trier mixture of For ilc only u an oil repellent at a level not to cl.r i nriu&pr.A;.;, ccn'^soiind *11b ft.3' Imlno* J:. '...an* il l); phoip'iate, compound exceed O OftT lb (0,04ft lb of fluorine/ per 1,000 II 1 of mated paper or paperboard, as deter ,,l'h li,! ,t:i..`ioda,I.,rd.i'ii? 41:1 >, tr.d T'.P-d;hydrcgen j)(', i1 . I'l.stc. v.ith : *: iminoJirih- mined by anilysi* ?<-r total fluorlno in the treated papjr or p^.icrboard without correction . , c;-i; w).e?; (be tuner TlV-ire hr* ft fluorine for any fluorine which might be prcecnl In the i't r.i-n 4ft.3 pet to Tfft.I pet u dstenabied oq 4 LlrilS. untreutk.-O paper or paperboard, when sued paper Or paperboard la used In CDAUtl wish food only of the types Identified In paragraph <c) o UtU ieetton, table i. under types iva. V. VlIA, Vilt, and IX and under the ec.idIMons of use B ihKitgh O dturliud Li laolc 2 of para graph tci of this lection. V,! :'jW r-von fiber*.... ............... ...... .. ............. ,.............. ,, V ... pi i.-cicvJM,,,,.......... ....... Complying with f 171.3710 of thla chapter. . .an (turn, confa.-ftiln# to the Identity wd iprilf;- Air iltft only at a maximum level of 0.13ft percent nfiientKJ In ftll2.a!>& el this chapter. by w eight of finished paper os a suspension old eL' up1. Uml ihe (Tridual i^npropyl alcohol shall not or stabiliser for aqueous pigment skirries em el, < ed C.C0O parts par ployed In the manufacture of paper and Paper- board. Xyltar iulfonic tcfdformalaehyds eondenute. sodium For iise only u an adjuvant to control pulp absor s*H, bency and pitch content th the ntnUfKiun of psper and paperboard prior to the sheet-furm- /...u; liji'rr.'iitlfenydi! iL.ifOzylute ,-TTrrTT-TT- l.;,t ocitutp...... ...... ..... ..................... 2l jor.tUAi aside ..................... . Ir.g opcntlon. Fpr use only as pslymerlaatlon catalyst. For use only as a component of waterproof coat ings when Ui glreonltun oitdc U present at level not to exceed 1 pervent by weight uf the dry paper nr paperboard flter and s/he re the urcunluih oxide Is produced by hydroiysli of slrebftit-ia acetate. SiibjUmt^ identified in para;bi <l> and <2> of this section may he j^t'd as components of the fouti-coriiijcl surface Of paper and pa* Pi rhoArd. provided that the food-cont/iCl of the pltpcr or paper* I paard cofnpiies with the extractives lih'.iitiiions iirescf'tbad in pd.r&eniph <c) c.f this aectioi), (2) Substances identified in paragraph (b)(2) follow: this 528 Mk Chapter l~*Fod and Drug Admlniiln r.Hf a/iutifinjeer AcryluUM eopoiynitrlud with ethyl acrylatt er stryene and/or methacryllc acid, subaequ* reacted with formaldehyde and butyl alcohol. AcrylvT'Ide eopolymertzvd with elhy'-cnc end chloride in tueh a manner thst the finished i lymcn have a minimum weight average mole weight of 30.000 and contain not more tha weight percent of total polymer units derived aeryiunide. and In ouch a manner that the ai mid* portion may or stay not be iubawiu*fiU) lially hydrolyrad. Acrylic copolymers produced by copolymerlxlng LWT* of the acrylate monomers butyl *tr: ethyl acrylate, ethyl methacrylate, methyl late, methyl mtlhocrylate, and n-propyl melt' late, or produced by copolymerising one or nt< uch acrylate monomers together with One or of the monomer* acrylic dd, acrylonitrile, bi cne. ft-ethyl-heiyl beTVlate. fumarie add. All methacrylate. n-her.yl-mcthicryUte. Ilaconic methacryttc arid. Uyr/nt, vinyl acetate, vinyl ride, and v|ny|ldene thluld*. The finished lymert than contain t least &0 weight perci polymer unit* derived from one or morr o monomers butyl acrylste. ethyl acrylate, methacrylate, methyl acrylate, methyl melt late, and u-propyl methacrylate: and shall u net more than ft wcighL percent ef total ( units derived from acrylic acid, fumarie acid, dyl methacrylate, n-heayl melhicry1*Le. h arid, and methacrylir acid. The piovlrion Ur the finished scrylic copolymer* to ncL more t unlU derived from acrylic arid, fumarie arid, dyl methacrylate. -hexyl methacrylate, tu arid, and methacrylk arid Is not applicable l lahed acrylic polymen und as coating *4k at S. level net exceeding t weight percent ol watlni solids. t-AlkyUulfpnat* (alkyl group Is In the range l with not leas (Jun ftO percent C-C^i. ].Sromo-4-hydrOiyacetophcnOM.. Butylbeniyl phlhalal*-..^------------..................... Butyl oleate, tuifated. anunooluro. pftUfilUi sodium SiH- Butyralde<hjVyd4ericMQ">Mthylinerao4n-e-cyrinhei ft^learboxlroldcl. Castor OU. polyoxyethyUtcd <43 motes ell oxide). K m)-CMor<ttUyi>').4.7'iriualtnRlud*JtaanUn ride (Chemical Abstracts Sendee Registi *0 Cbpper ft-qutBoUnolsSd .................. 9 `WAAR0E^-0TM4LWE "|A tow SHOW* WQ t|.f..U"lOpWWHl | w* nv*t*hB" H*|nv*1^N '*Xj4 pit* fit) vjqwwfM pin (*td|aw quwaO I pApap ppl ftrfj f u*l 00* *"** icenrMtinw irqttJ jww 3n*inn4* j |vniu pyuxzt|rtj u| *tyo n mi nuwJMl i `iumiu |idn^ j*| hh*W*) mpAU*4 *an|<w4`f|ikl .......... .. .....--nwpttnqKiaJ CO --1 0 0 H CJ iama4 \ 1US9JM3 s o -ftfXUMl x '(4p(xuv4H tOwjnw *IWvW hq4to*.> ------ --'-- --"- 1 tommv iJino t*;aut p| mfwHt <li *M1 pv* iap*onuivft4*inv^4i4u")"<"nI>p^jm*avjp4/!n* -^parf*nof1t-*Vi<tuoawM^PwTUMQ>ma- iuhim f 0 '* (tueiuottifi porn60*0 *r*f *?4*0| J*ru jwjtu^H -jfrt yjnjpo* 'It'ulaauiwaddi o| *'.t.f.t.fHwopuai3m^-(i/?;|kHHCtqA*ip4|MOw|4Jixl|*-Mppi*'lVO)tuaoiqjtfuu*t4n4-nn3nK*-H-Cj1 XVMJKl % `*-- ---------------------.mMiodu au*J4lt-appp4inn 3PPK lunjjd 0 ' ---" jroitndott au4x4m>X|ed-pup4qSWH V.| 01 ll'IVM I ' fU|4|(Iai usf|k >ruTl wajtfoq-Mutfinqoat "toour niai4Yit npjid-nQ ~}UI94 t ' 4(1 p*puslait>4t() aiJ*axxint04p4q-Ci'uoiii t*J*-[!) ... uv4!i4 omu* ixui*iai-na WxPXiltVlUt ox paowwp Pr>ut**u <Kn 4q pMt|aui4p n ;t jo 4-jinatx* 4uoeN smunupd puv '(snPttttl Ult U| paqjjaiop pOM)W] >m 4q pUJUU7]ap rt 000'OM JO mfia* ji|Digm <'.|HHt| mnoi `Iutw v tpip puv '9UMUqjou-|-Mnp;i4in* 4 JC/pm 9uaiuo(p0t)<|>0t)a(4inaui-p unJJ P9aJ1 >9P JJVH aaUl4|Od TV|<n jo s mitt ajoni jou vitiuh ttn|i (h^iwii op uwiomp jsiu/;sdt pavsTvtJ mX `oujujoqjou-z-oottMlXiU* 4 jo/pirt uujwuou-e-9Ut4t|)qui-| mi* pkijjui -4106.73 an awai4daid pm tuai4n> u#n* pnpo<d u^uiomia jau.-A|od09 {uqipoin *U9i4d<u<l>uf4i(t3 ---iu|l(d')jd >ll9t(ip] tUttiM!? -........- '^r-rnm----..................................aplUffl^tfUJ *PVP -4i|m apwoityi) ipfA popponi no inaqXM pazwittO PtJp/q m sntxi*111!^ *xvj* poxjTpom no rt^cnjjt* prooixotfei ............................-------------- iio piPiia `apup 4qm 3pin>Vl qi|A pompom tl (ManiM pa*ipl*c6l ' no powvu p5pJ*o<t3 -l*xna4|0Ui Jid moot uoqno (ft tutPuaAi noq nip4q uijfvnd tn*u>mi|iJii [imuttuiipaia JO *jniit|n (apvil |K)(um3*X> mjw?C2 *awfi(ilnp taqn* nqqfU sfiattttMt co xuntvU pmvTTtn* V} 4|uo atn ioj tvituad o p `iuau>4 ! apiimiwiTxaenjnpixuitXqXOHmuadKi aurtuvipaiuiXuaqd^'iltimtm'f'KI (ouas^ ;a tuaojptf a trniji fjoa oa >inu|ttu neoj 4jiij-uou qxiA xm 1 uw c) pan vucnprtttU* fuxm*`40so( rfl 4JU9 tn )oj mq pm junoun HO uonmum o luauad t *V3ja4t **lV|vitit|<! |Xaapotia `OimpanKjin* umrpM ja wn [Xwifla -- t4Xaqa|4iii1-tO --"Wdim |4xn4qia-I`lCl vcOiiqono Jatu4|0d uo loht}]Wt1 OU f| *J41 `Xtm |(3xa =rUt jo OKt'Otl > au|X|ciuio^ *tja;i1Kv3-iTM laqnll joqqiu siuujuX* ,10 xuniou prurtSil\rt u| 4{U0 *n Mi liua-uMl 1 *Xtl33JM] C i*atpv -ana -pinnqp llOaqd *PlUJmqai<! |p*t|nu pitnap) "-- (npiurt tppw 4VJ no inuosos) ap|iin o3 (iqjinxueo jnqtvj ffurf*a-*vps fo jyoftai 4q iiLKUMl rO pillMdX*) tovowntjo W? pMUpUO^/ wu 0|5IY5 UOl4t>JJ*5Ujuipv Bnjg pup p*d^--J C9S `4(61003 I nenuodi lomid i ................. nmuodl ---*"*iiAUad| ................ iwjtd f *rijadf ""(ttpitii (WtplMHn jvynO fti|HM.nmip J* JlAM *4 * t^anuffUtt ttpnpur Suft^so -amrop jo ainl^inUH^i ax|`j tij po^oid -xna aq 4m ftaweisqns <5) 'paqijasajd suon'oajjja-xl? io Aifiuapt oq) i4i|da fitti20)UiK> jaidvqa nn |0 9>'fiLT pw atl 'Ll! 'flit 'SLI ffj-red uj uonvinsoj e jo jjafqn$ am } suonisodxxioa -04TXsop jo uopotipo-d pqj p7^o{d 'Uia aaurj5C|nE Xuo jcq? papiAOjd j,?qj -Jtij pun tpapjAOXd uqiit}(ui|x Xiix; mi.m aautstuiojuoa uj pun laojja in^jiiqooi ja ivcMsXqd p?pu^|u| om q|{dui03an o pojjnbaj asom paaaxa 01 jou siunoujx: uj pasn -uopaas sjm jo (gxq) qUnjfl 'Tjnd uj p|j|iuup| t>) 'paqij3$?4d suoxi -fpuoa am mi4A aounpjoaM u; poEn pun jaidaqa qm jo 5 pun ?lt *9iT `Sil `Vlt iix suoj^niuaaj jo loarons am wn ittfJ sayjvjrans (ej ja* am J* tsjtoff won -aas jo sujuvaut am tnAojdda jo UOftOUtiS JO|xd n jo uo}SMojd ai;x aounpjooon uj pasn saouaisqng (g> ; 'pooj uj ajc$ sn pazyuSoDai ^uajausa rosucisqng (t> . :3U]Aioi -loj am Suipnpuf saoun^&qns taaujido jamo uiojj pup 'uojjms jo (jixxx) pun *<jxxx) *(A) (CKq) qduaajnd jo uopdaoxa am m!^ '-lo^dnqo sjq^ jo (( -qns -J9A0 ft o\] `Pioq -inaj: 'fl'.nji 40J p aq |M| mi/tt -1*11191 pooj uj pa oq DQ (CnytfgnO njiltyssf W*VA iiffrm 4o (m4 rv jMiula ^OWrPPB/b tjjwft O1** nir;jn;wr; Sajo puo pooj--15 *1^^ nti jo o -OfiC3 ?(p4| tXdojd 'ax 3||4j%-T4U; MPT. `ar I4xnq *a;i JO ftJOUl Jl 3. .r'-J mitt i roet. ...J urbyt pricr Ic ilrilrt use in con tact villi food. (c> xirfe,1.i,*c;& limitation* are appll* cr.olr to tr-: W\lc 'esins in tin* form of l>elkta Li. i" litivc bt`L-n ground or cut f^/.o fT/ii; (.that tvtll pass liirtiii h r. U.. Siandnrd *Sievj Na. 4 urvs Li::-.. ;ii Iti held oh ft U-3- Standaid ir,c Nj. 10. (1> a ltfwiram sample of the resin pctlciA. whrn extracted with 100 milll"`itg of lii.itiilr.d water at reflux lentp^rai^rr f-jr Hours, shall yield total e.x'.ru^.-L : r.ot to exceed 0.CC3 percent iy weight the resins. (*) A Ift?-gram sample of the resin peJlcw, when extracted with 100 milll* liters of V; percent tby volume) ethyl u duililed water at re/lux t+uVfr-`rrik-,;ro for fl hoars, ahall yield total extractives not to exceed 0.003 percent ty v.v.iiht of the resins. iS) a U'O-v'Ttm sample of the resin pdieu. \hc:i extracted with 100 milll' liters of n*h?p;*nt' at reflux tempers* lure :r,r l hours, shall yield total ex* ir^ctiv:.; not to exceed 0.01 percent by of the resins. tlTIJtOO Hjtoxyetftfl cdbakow Um> Wat/ .ir.roluble hydroxyethyl cellu lose tihn rny be safely used /or packliiiTiu' l.^c in accordance with the fol low u.* p.-tctribea conditions: iL> \7ki cr-i.isoluhle hydrocyet hyl ceUuic.'ic fil-n consist* of a base *ret:L manufact7iri*d by the ethcxylaticn of cclliUcEt under controlled conditions, to which may te added certain option al t/uburatfft- of a griie of purity suit* sWo lor use in food packaging as const:iu?nts of the base sheet or as coat ings :.;>p!!ed to .mpart desired techrtolutiCbj properties. M Subject to any limitations pre scribed in Parts 170 through 180 of this chapter, the optional substances UAd in the base sheet and mating r.'y include: (1) Substance* generally recognized or. safe in food. <2) Substances permitted to be used in w-alcrinaolublc hydroxycthyt cellu lose film by Prior sanction or approval i:*4 under conditions specified in such sanction* jr approval, and substances listed in 1181.82 of this chapter. (3) Substances that by any regula tion promulgated under section 409 of the act may be safely used as compo nents or water-insoluble hydroxyethyl cellulose film. <4j Substance* identified in and used In compliance with f177.1200(c). to Any substance employed In the production of the watrr-lnsoluble hy droxyethyl cellulose film described in this section that b the subject of a regulation In ffvtil74, OMI7V.8L77. 178 and f 179.4$ of this chapter con forms with any specification In such regulation. I ITl.HIO Isobutylene polymer*. Isobutylene polymers may be safely used as components of articles intend ed for use in producing, manufactur ing, packing, processing, preparing, treating, packaging, transporting, or holding food, in accordance with the following prescribed conditions: (a) For the purpose of this section, isobutylene polymers are those pro duced as follows (1) Polyisobutylene produced by the homopolymerlaailon of isobutylene such that the finished polymers have a molecular weight of 750.000 (Flory) or higher. <2) laobutylene-isoprene copolymers produced by the copolymerization of Isobutylene with not more than 3 molar percent of isoprene such that the finished polymers have a molecu lar weight of 300,000 (Flory) or higher. (3) Chlorinated isobutylene-teopren* copolymer? produced when isobutylenc-isoprene copolymers (molecular weight 300,000 (Flory) or higher) arc modified by chlorination with not more than 1,3 weight-percent of chlo rine. <b> The polymen Identified in para graph (a) of this section may contain optional adjuvant substances required (n the production of the polymers. The optional adjuvant substances re quired In the production of the polymen may include substances generally recognized as safe In food, substances u*cd in accordance with a prior sanc tion or approval, and aluminum chlo ride. <;> The provision* of this section*are not applicable to poiylsobatylene used BFG09401 4ioplr --rooa wd vntg ' ... food-packaging adhesives complying with 1175.105 of this chapter. cord: cond (a) 1177.143# Iiufaiif]ne4itt<iit npol^Mn ichh Isobutylene-butene copolymers iden tified in this section may be safely used as component* of articles intend- ed for use In contact with food in ac cordance with the following prescribed .. resir Of Isop hyd; whl< opt! conditions: (a) For the purpose of this section, isobutylene-butene copolymers consist inti <b star of bSsic copolymers produced by the Copolymerization of isobutylene with mixtures of u-buienet such that the the crai star finished baste copolymers contain not pri< less than 45 weight percent of polymer low units derived from isobutylene and fPrtft the followingspecifications: u ill Average molecular weight is in But) the range 300-5,000 az determined by ASTM Method D 2503. Rl) (2) Viscosity Is in the range 40- Tom 20.000 seconds Saybolt at 2004 F is de termined by ASTM Method D 445. (3) Maximum bromine value la 40 as determined by ASTM Method O 1492. (b> The isobutylene-butene basic co polymen are limited to use: (1) As a release agent in petroleum wax complying with 1176 3710 of this chapter. (2) As z plasticiser in polyethylene complying with S177.1520 and In poly styrene complying with 1177.1640. <3> As a component of nonfood arti cles complying with ff 175.300.176.170, 176.210, 177.2260(dM2). 177.2800. 176.3570 (provided that addition to food docs not exceed 10 parts per mil (< Jcfc foil t&l < tile wh 70* sur Inc ( till wh C fat ln< lion). or f 176.180 of this chapter. < (c? The provisions of Lhis section are tit not applicable to Isobutylene-butene w) Copolymers used as provided under vo f ITS.ICS of this chapter. ijr-lsepnpylMgncdipheDol-opfchtfe rohydrfn 1 retina having a minimum molecular weight of 10,000 may be safely used as articles or component* of articles Intended for use In produc ing. manufacturing, packing, process* lot, preparing, treating, packaging, transporting, or holding food In ag* b 573 A nv*'.:':;, pii-ictf.*. _, inir^porimg. or li'.iidii'.i.f :ri nceordarf'V with the ; f'.'fiou :r.r> i.-r-: p.-ifjfd ^orniin-'inv TKiLic,; 'iitjon resin* are pioi:-yv<: :>y r.h<: iiDiiiO;:: lyi^priiir.ticn Ari.j.j.r i>[ hGEaliuor- . i'i 1 r.e iuvl tf'l.'&fiucrc-.-r.J.ylene. *:> wi.ir.'h :my have been added certain Optional substances to impart desired ttchnclcnical properties to the resim. ShbjivL, ta any limitations prescribed Im .:' if -yy.'!irr., tr.e optional suostcnces i:\ .-i-uy;-: tl> usrerxSly recognized its m food and food packaging, (*) ^'jJ.'Fic.rees the use of which is re.iritf>l c-der applicable regulations r. this p j.l, >,ur,M}oP5. or appro- ibi Pti fluorocarbon c^iint &h*H cor,r'criji to the :,pf-;:;fi<iL[ions prescribed in taragfaph (bun of this section and m.rei the extraetability limits ! prv?-.'tlDi-d :ri paraeraph lb)'2) oi this i ii-.*!'*,;;. * }.< h; ec:.:::a,:Or,,;--ii) infrared idp.n- on. Pirrsluorocarbon resms can hi* i'J::nLi;i^cl by their characteristic in* frurca -ectri, <i.) -f.\J viscosity. Perfluorocarbon resins htvc a melt viscosity of not less thtn 1C4 pcizss at 3P0' C as determined by American Society for Testing Mate rials Method D-1238-5TT. Molt viscos* ity of the copolymers shall not vary more than SO percent within Vi-hour at 380' Cr (iii) Thirtnal instability index. The ihvrmA] iriitnoillLy Index of the tetra> f! -ioii/i.thylcne hcmopolymer ehall not f. kL<'Cd 5*j as determined by American Sct-i-jiy fer Testing Materials Method <2i L'TnifattOTis, Perfluorocarbon resins when extracted at reflux tern* "mtu.vs for 2 hours separately w/th disLiiled water, 50 percent ethanol in v.at.r, n-hrptanc, and ethyl acetate shall meet the following extractabiliiy filTittS'. f,l) Total extractives not to exceed 0.2 milligram per square inch. <il) Fluoride extractives calculated*as ; fluorine not to exceed 0.03 milligram | per square inch. 3177.1170 roly-l'buunt refill* and l*utene/elhylne ropolywe*'*. The pcly*l-burcne resins and biitr-ne/ethylene copolymers Identified in this section may be safely U3ed as articles or components of articles in tended for use in contact with food subject to the provisions of this sec tion. (a) fderttUy. Poly-l-butene resins are produced by the catalytic polymeriza tion of butene-i liquid monomer. Butene/ethylene copolymers are pro duced by the catalytic polymerization of l-bntene liquid monomer in the presence ol small amounts of ethylene monomer so as to yield no higher than a 5 weight percept concentration of polymer units derived from ethylene In the ccpolymer. : (b) Specifications and Kvnifafions. Poty-L-butene resins and butene/eth- yjene copolymers shall conform to the specifications prescribed in paragraph <bKtj of this Jf;C.L'n, t;,d vhal! rnvet the t'Xira'itabihty ii/ruts p/f?.vjrib';d in paragraph (bj(2of this section. <11 Specifications--<1> Infrared, /den* ti/icQiion. PoiyJ-butene resins and butene/ethyiene copolymers can be identified by their characteristic in frared spectra. iii) Viscosity. Poly-lbutene resins and the butene/ethylene copolymers have an intrinsic viscosity 1.0 to 3.2 as determined by A5TM Method D-1601. (iii) Density. Poly-l-butene resins have a density of 0.904 to 0.920 gms/ cm and butene/ethylene copolymers have a density of 0 690 to 0.S16 gms/ cm a. as determined by ASTM Method D1505-33T. tiv> Melt index, Poly*l-butene resins have a melt index of 0.1 to 24 and the huLcnc/cthylcne copolymers have a melt index of 0.1 to 20 as determined by ASTM Method D-123&, Condition E, (2> Limitations. Poly-l-butene resins and butene/ethylene copolymers for use in articles that contact food, and for articles used for packing or holding food during cooking shall yield no more than the following extractables: fl) Poly-l-butene resins and butene/ ethylrne copolymers may be used as articles or components of articles .In tended for use In contact with food. ' Chapter *--rood ana Vrvg provided that the maximum extracts I blcs do not exceed 2.5 percent b] wr:j-KL of the polymer 4vhn film ci I molded samples are tested for tw< I hoors at 50* C in n-heptane; and pro . vided further that the butene/ethyl ! ene copolymer contains no more thai 1.5 percent by weight of polymer unit ] derived from ethylene, i (ii) Butene/ethylene copolymer { comainlng no more than S percent b | weight of polymer units derived fron I . ethylene may be used in food-contac I films of no more than 1 mil thicknes where such films are manufacture from this copolymer blended with tx t lypropylene. complying wit1 1 5177,1520, provided that the finishe 1 film contain no more than 60 part | butene/ethylene copolymer and th maximum extractables of the tinishc ' film do not exceed 9.3 percent b I weight of the film when extracted fc two hours at 50' C. In n-heptane. '1:ij ) f Wl> btiifriie/ethylMf: eopfiiyn.'rr; im-.y iused as articles or components of art cles intended for packaging or holdin food during cooking, provided that th thickness of such polymers in th form in which they contact, food sha not exceed 4 mils and yield maximut extractables of not more than 2.5 pe cent by weight of the polymer whe films are extracted for two hours t 50' C in n-fieptane; and provided fu ther that the butene/ethylene cop< lymers contains no more than 1.5 pe cent by weight of polymer units d rived from ethylene. 4I77.1SM fitrewteuu tnlmi Polycarbonate resins may be safe! used os articles or components of art cles intended for use in produdn manufacturing, packing, proeexsin preparing, treating, packaging. Iran I porting, or holding food. In accordant with the following prescribed COOC lions: (a) Polycarbonate resins are poly* ters produced by: U> The condensation or<&4'dMr-pi *'-*"'* mnA ^arbonyl' chl Tide to which may have been addt certain optional adjuvant substanc required in the production of 11 resins; or by BFG09402 Till 2V-FooJ end Drugs I277.22M 4l4a-Uopriiifyli4A4tph*nel- # holding food, in accordance with the ' p*le2MortihyiJrt tH*TmkH^tlnrtp<nq| following prescribed conditions: mint.' (a) The basic thermosetting epoxy resin Is made by reacting [' M'*# Isopropylldeoediphenol with eptctUor* t4,4''l5cprcpy)iclcnedlphenol`fpichlo ohydrln. rbfcydrin thermosetting epoxy resins? (fe> The resin may contain one or T:u>y Ur :.-Jcb u^ed so Articles or com- more cl the following optional sub jjoner.ts of article intended lor rc- stances provided the Quantity used 10 1.5 vf j.n producing, manufacture docs not exceed that reasonably re mg', proccesing. preparing, quired to accomplish the Intended sar'incinc. Irtmciorting. or effect: f- Y. i./'-'.ij'I ................ .............. -................. ............ Ai flirfns *yiUm additive. Bi- d u-i i.ii'l/i nitf ir.ti.tare rctUiint rm m# Ai jnwti.'lrr At teveli not Xn exceed eautl pxrtx by i - uUh mUed -Sljr.err */n wnulu of tile 4,t,-bwn0ylld*riWphnot.eBLcti' I rj ,::tarawtf Cm t.-.uy uridi lora^/drtn buio reiw end limited to IM4 lit wa- --t-'d.ul kind (iij 4i 6 cUa. l&ct with iicQhollc bvven^tv dnlunlAf .,, . tort thin S penult of tleohoL ,2. ..p'j.y., ?i:i,,z`sl p.-cpuiS........ -- A CLrUlCViUBb estciv*. Oq'or.**............................ ............ .............Pa, jn*oipeiliilmi ttrniiwr.^________________________ rvj. -MflL: ................................... . ................................... Do t)o. T.'irc'.ljill* iJ5ny;ir!i!e_ ............................ Do. j i f.c' !r a.-rdrcla^e with <';;od jnanu. liyl> propylamine (Chemical Ab fscturir.g piacticc. finished articles stracts Service Registry 'So. ,tin*.ai):ing the resins sh-i^l be thor- 000919302) b&ttd on the weight of the i oughiy cleansed prior to their first use calcium silicate. i in cor.v-ct with food. (b> The mineral reinforced nylon i id) The provisions of this section lot applicable U> M'4fOPfppyUdehe< resins may contain up to 3.2 percent by weight of titanium dioxide as an optional adjuvant substance. ..er section* ot^Farta 17. |*T6; 17 (c) The mineral reinforced nylon 177,175 and 179 of this chapter. resins with or without the optional substance described in paragraph (b) `77.i'}5'> f rin,*ral reinforced nylon of this section, and in the form of inch molded test bars, when extracted Mineral reinforced nylon resins iden- tifii.d ir paragraph (a) of this section may he safely used as articles or comPChcnts cf articles intended for re peated use in contact with nonacidic food t r/ri `ibove 5,0) and at use ternpenuu.-es rot exceeding Its* F. In *ecard^fiCfe with the following prescribed conditions: (a) Fcr the purpose of this section the mineral reinforced nylon resins consist of nylon 66. as identified in and complying \ylth (he specifications or 1177.1500. reinforced with up to 40 weight percent of calcium silicate and up to 0,9 weight percent 3-driethoxy* with the solvents, l.e.. distilled water and 50 pci-cent (by volume) ethyl alco hol in distilled water, at reflux tem perature for 24 hours using g volumeto-surface ratio of 2 miHJlUers of solvent per square Inch of surface tested, shall meet the following extractives limitations: * (1) Total extractives not to exceed 5-0 milligrams per square inch of food- contact surface tested for each sol vent. (2) The ash after Ignition of the ex tractives described in paragraph (c)(1) of this section, not to exceed 0.5 mllll* gram per squire inch of food-contact surface tested. 610 BFG09403 1 1 1 V $ Chapter I--Food and Drug Adminittn (dJ In accordance with good mami facturine practice, finished article containing the mineral reinforce nylon resins shall be thorough! cleansed prior to their first use In cor tact with food. 142 PR 94533, Oct 7. 1977. is amended at A FR 61594. Dec. fl. 1977] i 1T7.241C Phenolic mini in molded art ctee. Phenolic resins Identified in this so tlon may be safely used as the foot contact surface of molded articles h tended for repeated use in contat with nonacid food (pH above 5,0), i accordance with the following pp scribed conditions: (a) For the purpose of this sectloi the phenolic resins are those produce when one or more of the pheno listed in paragraph (aXl) of this s* tion are made to react with one c j>utMatat Tibet__ -__ ^ Bulum hydroxide ..................... CUeluu ilfrtAL*....................... Cbrton Mack (channc) pmeoa) Dlitmincui nrth ... .............. Olui fUnr-^------HexitaetbyteteiAn>iQ*-w~..~ Ufa _ __ Oxalic add to>gxt;afate-^...... __h__-- (OThe finished food-contact articl when extracted with distilled water 1 reflux temperature for 2 hours, usir a volume-to-eurface ratio of 2 rr.illi] ters of distilled water per square inc of surface tested, shall meet the fc lowing extractives limitations: (1) Tola) extractives not to excel 0.15 milligram per square inch of foo contact surface. (2) Extracted phenol not to excel 0.005 milligram per square Inch t food^contact surface. <3) No extracted aniline when tesU by a spectrophotometric meihod seru live to 0.006 milligram of aniline pe square inch of food-contact surface. (d> In accordance with good main factoring practice, finished molded a tides containing the phenolic resii shall be thoroughly cleansed prior \ their first use In contact with food. 4 Till* Fofii and Drug* 5! ... v;,, L' Xo. G and t,h."l are re- :.n l iJ.S.a, Steve No, Kr, i.- .U j ivlci total extractives as fol ic V. J. U> Hat to voiced 0.20 percent toy V'cvfi.. o.' ilte copolymer when extract- ad / >r r. siC'!TM with dlstl'.Jtd water at rvii-s; . :,r.^jr;:iure. 'il; V,* to exceed 0.15 percent by weisht oi '.ci, copolymer when extract ed /c.-r d heurs with n-heptane at rcllv; ic.r.j-y.TLturk'. if-) ConTiiwis fif use. tl) The poiio.\vm*'>y]?ne copolymer is for use ?-s a.'ik-l-.-j or component* of Articles intcr-::j :cr repeated us*. (D'&aMteen dotal amount of sta bilisers not to exceed 1.9 percent and amount of any one stabilizer not to exceed 0.5 percent, except that Nylon 66/510/6 terpolymer may be used up to 1.5 percent of homopolymer by weight). (t j 2,2 -M<2thylenebl(4-methyl-6-tert butyiphenol). cm Nylon 66/610/6 terpolymer (set ft 177.1600 for Identification). (Hi) Tetrafcls lmethylene(3,5-dl-tert buiyl-^-hydroxyhydrodonamateil methane- (2J lubricant tyA^Distearoylethyl* enedltmlne. (t'i V ;.i Leii'pcrtture shall not exceed 1250-P. (3) Mcldintr assistant Polyethylene^ glycol 6,000. (i) la a-tiOrdb-nce with good roanufCwturir^ practice. finished articles enntainirg polvoxymethylene ccpoym-i-r sh.:i be thoroujnly cleansed :; thidr firm use in contact with ?C ulJ. (c) Specifications. Cl) Pqlyoxymethylene homopolymer can be identified by its characteristic infrared spectrum. (2) Minimum number average molec ular weight of the homopoiytner is 25.00U, (3) Density of the homopolymer is ii'tV'iiMi PolX'Xynsethyicne lvumopoly- between 1.39 ttid 1.44 as determined rur, by ASTM Method D150S,# P:!:^)vyir..'i.-:yief:e homopolymer M) Melting point is between 172* C iiirrt'Jhed ir tnis section may he safely and 164* C as determined by ASTM ;ir;*cX'S or ecnjpor.ents of arti* Method D2133.* cu-i in;i!^;;td Tor food-contact use in <d) Extractive limitations. (1) Po- acoorJ.-.r.CL* v/uh the following pre* lyoxymethylene homopolymer, in the acvibti ca.'itiUle.ii;: finished form which is to contact food, <a> lc.tv.ray. Fcr the purpose of this seetjen, patyoxymothylcnc homopo* iymer is polymerised formaldehyde iCnchir.\i Abstracts Service Registry No. C?-tS-Si-l). Certain opMcnr.l adjuvnr.t .- il.,' ..'ices, described in pare- srryh <n wi this* section, may be ahe'v.l ;& i.r.part desired technological properties to the homopolymer. <h) Optional adjuvant substances. The pclyoxymcthylene homopolymer Silcr.tl*t;d ir. paragraph la) of this sec* hen r.-.yy eentuln optional adjuvant gucidsccrtf m its production. The uhdidiLy of any optional adjuvant sub stance employed in the production of the hcmo^oiimer does rot exceed the amount reasonably required to accom when extracted with the solvent or solvents characterizing the type of food and under conditions of time and, temperature characterizing the condi tions of intended use under para graphs <c;i3> and <d) of ft 179,300 of this chapter and as limited by para graph (e) of this section, shall yield net chloroform-soluble extractives not to exceed 0.5 milligram per square inch of food-contact surface, <2i Polyoxymethylene homopolytuer, with or without the optional adjuvant substances described in para graph (b> of this section, when ground or cut Into particles that pass through a tl.S.A. Standard Sieve No. 6 and that are retained on a ll.&A. Standard plish the intended effect, Such adju vants may Include tiuostancea general- `Capita may be obtained from; Division of i i v recognized &s sate In food, sub* Nutrition (HFP-2SQ). Bureau of Poods, Pood 6tpr.r,es used in accordance with prior and Drug Administration, 100 C Strati SW- action. substance* permuted under Wa&hlniton. D.C. 301C4, applicable regulation* In tht* part* and the fallowing: *Ccpit may t* obtained from; American Society for Testing and Material 19U Race Street, PhUadeiphla, PA lOUfe, b. BFG09404 010 l Chapter I--Food and Drug AdminUtrat Sieve No. 10. shall Yield extractives as follows: <l> Formaldehyde not to exceed 6.0050 percent by weight Of homopo lymer as determined by a method available upon request from the Food and Drug Administration. Bureau of Foods, Division of Food and Color Ad ditives (HFF-330). 200 C St. SW.. I Washington, DC 20204. I di> Total extractives not to exceed | 0 20 percent by weight Of homopo. lyroer when extracted for 6 hour* with ! distilled water at reflux temperature t and 0.15 percent by weight of homopo* lymer when extracted for 6 hours with n-heptane at reflux temperature. . <e) Conditions of use. (1) Polyoxyi methylene homopolymer Is for use | , articles or components of articles Inj tended for repeated use. I (2) Use temperatures shall nol t exceed 160* F and pH of aqueous food* In contact with the homopolymei shall be between 4 and 9. , (3) In accordance with good manu facturing practice, finished article; < containing polyoxymethylene homo , polymer shall be thoroughly cleansec prior to first use in contact with food 1 ' f0 ^ ^ jv r* VA ft 1T7.24W Polyphenylene culHde reitins. Polyphenylene sulfide resin, <poly(1.4*phenylene sulfide) resins may be safely used as coatings or com portents of coatings of articles Intend ed for repeated use in contact will food, in accordance with the followim prescribed conditions. (a) Polyphenylene sulfide resins con iist of basic resins produced by the r< action of equimolar parts of p-dichloi obenzene and sodium sulfide, sue! tn&t Lhe finished resins meet the fo lowing specifications as determined b methods available upon request froi the Commissioner of Ftood and Drug; (1) Sulfur content; 26.2-29.1 percer by weight of finished resin, (2) Minimum Inherent viscosity: 0.1 deciliters per gram. <3) Maximum residual p-dichiori benzene: 0.6 ppm. (b) Subject to any limitations pr scribed in Part* 170 through 189 < this* chapter, the following optiom substances may be added to the pot; phenylene sulfide basic resins In a */ Titlo 21--Food and Dru|t ::. n,1 ^'L>;.-,/!;uc,nt-p pht'nylcn^> : ;.i.r: r.w.-w bj-.sic iviiins prou.jc;d '.`'i diaodium salt of AA'.t ,a`^dVrtru'iinly to rrv i.i uicnJjio^Ujiv-'i'ij'. sul* a/cr. Ui*it tlic :inlsht'ti resins ,*.v' u'^rir.'.uir. numoer BVjr.'iyn mo- . ,i;Ar ol iis.,000, as determined ;. ,'r.!T;otic pleasure in morxochloro- (b) The basic polysulfone resins identified in paragraph (a) of this sec* iton may coritain optional adjuvant substances required In the production of such basic resins. The optional ad juvant substances required in the proAuction of the basic polysulfone resins may include substances described In 5 174.5(d) of this chapter and the fol lowing: i I Liit of mbjtc-.ptt rr4i.il`,i uili.x.e^......... ;nC'.r,li-f55trjfne....................................... LimiCmttMkl Mot Ut tund 54 p-D-M, m residual solvent ilk ftn- isiid bt*le min. Not to exceed 404 p.pjL at rtefdus} aobeat tat no* lihedkiilcniliL ,c; The fihiihcd food contact article, iim crtrucicd ut reflux temperatures >e b hours '.vun tt.o solvents distilled -der, flb p"rr-r,t (by volume) ethyl al- !iol in water, 3 percent acid m distilled water, and n- .Mer.e, yi.nds total extractives in : h L-xiyacl-iS SvivcnL not to exceed ;;> ::::uir:run r-nr square inch of food* :v.act J.u'ace, (Mote: In tesLlnz the i.:.hrd fv<i<1-conirfi article, useasvp- :.tc tail .' .T'.ple for each required ex* L.-dnc solvent.) d) In accordiirce with food manu.jturinsr practice. finished fcod-con- CC articles containing the cclysul,.:e resir.s shall be thoroughly !.' inred prior to their first use in conr:t with food. tact surface tested: and if the flplsbed food-conmct article Is Itself the sub ject of a regulation In Pans 174. 173, 176, 177, 178 and ) 179-4$ of this chap ter, it shall also comply with any specifications and limitations pre scribed for it by that regulation. (Note; In. testing the finished foodcontact article, use a separate test sample for each required extracting solvent.) <c) In accordance with good manu* factoring practice, finished food-con tact articles containing the polyvinylidv;te fluoride resins shall be thorough* b` cleansed prior to their first use in contact with food. I ardilLi HI I ;7.?510 i'olyvinylidtne fluoride rcblns. f'clyvinyliilfne fluoride resina may : siileiv Ui?d as articles or compo* / nit of articles Intended for repeated re in contact with food, in accordance i'A.h the fol'.QWine prescribed condi- ihiu-.: ai Tor the purpose of this section, he polyvmyli^enc flucrida rc-ins con: X cf bJtiii resins produced by the i-lyniL'riv.aiiun of vinylidone fluoride. ,o) The finished Coed-contact article, hen extracted at re Mux temperatures or ti hours wiLh the solvents distilled ?iLer, 50 percent (by volume) ethyl al- ho) in distilled water, and n-hepne. yields total extractives in each vtracthig solvent not to exceed 0.01 miigraiti. per square inch of food-con Rubber articles Intended for repeat ed use may be safely used In produc ing, manufacturing, packing, process ing. preparing, treating, packaging, transporting, or holding food, subject to the provisions of this section. (a) The rubber articles are prepared from natural and/or synthetic poly* mers and adjuvant substances as de scribed in paragraph <c> of this sec tion. <b) The quantity of any substance employed in the production of rubber articles intended for repeated use shall not exceed the amount reasonably re quired to accomplish the intended effect in the rubber article and shall not be intended to accomplish any effect in food. BFG09405 618 i t l ftopfor I--Food and DrUfl AdmlrtlltrotldB (c) Substances employed in the prep aration of rubber articles Include the following, subject to any limitations prescribed: <l) Substances generally recognised as safe for use In food or food packag Sill n Sil P Styn Vlny po! ing. <2> Substances used In accordance lec m< with the provisions of a prior sanction Vlny or approval. (3) Substances that by regulation in Parts 170 through 169 of this chapter may be safely used in rubber articles, subject to the provisions of such regu lation. tri nu as nu (i Vvl (4) Substances identified in this paragraph (CK4), provided that any substance that is the subject of a regu lation in Parts 174, 175. 176. 177. 178 and {179.45 of this chapter conforms with any specification in such regula tion, (i) Elastomer*. AeryloniUlle-buUdicne copolymer. BuUdiene-acrylonUrlte-elhylenc glycol dl- meihscrylatc copolymen containing not more than 3 weight percent of polymer units derived from ethylene glycol di- 4.4m th lb ar lei to (C at W( Hex or h. Pi methacrylate. Buiuliene-acrylonitrlle-methacryllc add co polymer. Buixrtiene-styrene-methacryltC add copo lymer. Chloroprene polymers. Chtoroirifluoroethylenc-vlnylidene fluoride Ol te Id v n b Sul copolymer. Ethylene-propylene copolymer elastomers urpich may contain noi more than 6 eifihi-percent of total polymer units de rived from fc-methylene-3-norbomene and/or S-ethylldlne-J-norbomene. Ethylene-propylene-dlcydopentadlene copo lymer. Ethylene-propylem-t,4>hexadiene copo lymers containing no mom than 8 weight percent of total polymer units derived from M-h**adiene. hobutylene-lsoprene copolymer. Fotytouttdleim. Potylsoprene. Polyurethane resins derived from reactions of dlplienylmelhajie diisocyanate With sdipie acid and 1,4-butancdiol. Rubber, natural. Blllrone* basic polymen as described In (i 1.5 uct 3-D El Bci 1.3 U N-l Bu ( Cfl r Co NA Dll Dll Dl Pil ASTM CM41I-61T; Silicone (81) elastomers containing methyl groups. Silicone (P*l> elastomer* containing methyl and phenyl groups. 9Uleone iVel) elastomers containing methyl and vinyl groups. 3.4 t)b N,. i a.fl Di Dl 610 TiSlo 2)--Food and Drug* in r,! din* p`n> hll&te. i,3 niiii.1-3 i .'i `L>iUiiifjJ!!r.oMJlio'i:ie. A..V Ui-c-tcjli lc-"L:;idlno, ?ult 0/ pyvoc&techolbar.'ll*:, Zlhyh'iM-'Jia-nlm farbv.itu-i, yit'pfiii-Vhy^e-finiknr resin (iodine number tsn-uo. "e; hl.uwlc 7 M-'K:'.i,u')'.;,!rc.,o'.-ne nv<-i':i''iyur.e-bvn3othla3ole-2. iuiicridiiiiilo. Tipchdinmm p<nt&rncthylcr.edlthlocarb*> r.-.tlf, J!`ji,-TMi;tr. pi-nri.M-. lhyfeiifu'it/llOCftrbamate, C:.<11::. ?-:iS!tiJis JiioiMi'L-umule. r.iiti:;;. (,'i.iM.; hykli; hir.r nrhMnate. la.Mi'i f:i.- ust. only da tin accelera te!1 lor ti'n'rnv r.-iuLon:cre. Tclri'.biiiy'Thi'ircM mohOsuliidc. Tc;rL(-i!-i.vU!ii:iMr*> eHih.ifide. f 1,j Mtriram.'LnylenaJOlo i tr.'-iji*!. "i-M:,.r,,:r/'rhyJ:y.iiJr&f(l diiU.Ildei. Tn;.l'.y ri.-./i.r,`ii- l,3.0'T!ieUiy; li-'-rnhydro-jt-triaMU* (iru l`iyllrm>fU;/ii.-uttnamliie). TfIph* n.ir'i.-y--.-.'. Znc btdyl JiL.-aiSui^. Zinc iV-hk-oarbEmate. 2'uc dibi'tylciihiOk^rhamale. Zitv; V.^ih^UVih/x-itrlnimatr:. Z.lnv ir nitroiiptolj'.ii/.iil.'udfile. ZJrtJj) tzincci!mpinyicUthiOt:arbAJ7JR;<,> Ttt'.tG.rdtrr* {tofnl not to exacd 10 percent oJ \ocPjhl cf rubber product), I'kihiJic {..-.hydride, ith Activators Hotel not to exceed S percent by xocigat of rubber product except magnesium oxide may be tiled hi&hcr levels). Dicthylnmine. Fatty acid amines, mixed, Party acid*. Mi.^nns'um carbonate. W.vi'O'.Jum oxici-e. iicht and heavy, Ol:;;-* lii'id. dibulyiamine *sftlt (dibutylam- morr.Lin, oloiff). Jilanruus chloride. ' TtM nil /airy adds. TV l rath leu o-p-bvnzQQUtnonc lYicthmolr.mine Zinc sails of fatty acids. Aldol-a-nzphthylamlnC. Alkylalca (C*. and/or C> phenols. BllT (buiyi^ed liydroxyloluene). BuiylnteJ. siyrrimted crcsol* Identified in 5 l7ti,2l)JO(l*> o! LV>U chapter. 4.4'-But.ylldlnebis;(6-lef.,'buiyl-r;-cresol). W-CydohRxyl^-phettjilphenyUrvetUaitiine. p,p-Diamlnoiitphenylmithane. 2,^-Di-leri-flm jlhyr'r^q.ilnonc, Oiaryi-p-nht.'iiylctiL-dfair.Inc. where the aryl group may be phenyl, tolyl, or iylyl. a,6-C)|'ffrt'DiU.yl-p-plieny!phenoJ. 1.2- DHiydro-S.2.4-trimethyl'$' dadeevkiumolinc. 1.2- Dihydro-Z,z.4-trirr.ethyl-6- ethoxycpiinc/llne, 1liiydro-2,2,-itrimethyl-6- * phenj'lQuihuinc. a.e'-Dimethcxydiphenylamiru*. 4,G Diiiopyl-O-Cresol. A'.jV'-Dlo^tyl-p-phcnylenedi&mlne. Diphimylnmine-acetone resin, DiphenyUimino &c*u>ri':-tafmr-Mehyde resin. bi.b"Diphtnylethylentidiiimintt, A' /V'-Dlialley 1.'iJpror'>iL"'!.diamine. //.A'-Dl-G-'Olyicthylejicdiamlne. HydroQuimi'iL* monDbenzyi ether. Isnpjopiv'tydiphL'DyJajniiw. A'-lRojtfdpyiArpricnyl-ji-ph enyienediamine. 2.2'-4Sti:thyle5iebisl3-terl-bulyi*4* eth) iphi-nol). 2.2- -Methyloncbl!>(4methyl'(3-f*r(* butylphenol J, 2.2- r.t'thylerietiisl4'niethyl'6-nonylphenol). 2.2- Meihy]eiiebls(4'-methy)-6'(erf* octyl* phenol). Monooctyl- and dioctyldjphenylp.mi/Wr A^-DL-^-naphthyi-p-pbenyleiidiamine. Phenyl -a-naph inylumine, ^henyl-d-naphiLylcminc. Plunyl/J-niipl.thyla.Tiir.e-acetone aromatic Ar.-.tne resin (average molecular weight 60ft. niirosih content 6.S percent). o and p-rh*:; . Iphenol. noolUtri pcr.lacnlorophcnKtc. Slyrer.aied cresnls produced when 2 moles of styrene are made to react with l mole of a mixture of phenol and 0 , m-, and p- .crcsh)!? so thst the flnkl product hu t Brookfield viscosity it 25' C of 1400 to 1700 euntipoisps. Styrenated phenol. M -ThloUls (B-lcr/ buiyi-m-creaol). Toluene-2,4-dlimine. M-o-Tolyj-Ar-phenyl-P-phenylenedliimin*. Fip-Tolylsufanlltmldei dlphenyumine. Trifmixed mono- and dlnonylphenyll phos phite. TTttnonylphciiyl) phosphlte-fomialdehyde resins produced when 1 mule of 620 BFG0940* 1f 1 1 I 1 1 f-t. H s O CD Cliopkr t--Food end Drug Adminiitral irKnonyiphenyl) phosphite is made 10 react with 1.4 moles of formaldehyde or produced when l mole of nonylphennl 1$ made to react with 0,3ff mole of formalde hyde and (he reaction product Ik then fur ther reacted with 0-33 mole of phosphorus trichloride. The rinlshcd resins have 1 minimum vlsconity of 20,000 centipoises at 25' C, as determined by t-V-scrlcs Brook field viscometer (or equivalent) using a No. 4 spindle at 12 r.p.m.. and have an or ganic phosphorus content of 4.05 to 4.15 percent by weight. (ft Plasticisers {total not lo exceed 30 percent by weight of rubber prod uct). n-Amyl n-decyl pluhalatfc. Butylacctyi rictnoleate. <-Butyl ester of tall oil fatty acids, hutyl laurate. Butyl ole&tc. Butyl stearate. Calcium stearate, Castor oil. Ccumarone-indcnc resins. 2,2 -DibaitvamlOodiphcnyl disulfide. Diben/yl adipate. Dlbuloxypthoxyethyl adipate. Dlbutyl phthalaie. Dibutyl xcbACAte, DidcCyl fidipAtC. Didecyl phthalaie, Diisoderyl adipate. Dilsodccyl phthaiate. Diisooctyl adipate. Diisooctyi sehapate. Pioclyl adipate. DiocLyl phthaiate. Diocty l sebacaie. D.pcnLene resin. Diphenyl ketone. Fatty acids. Fatty acids, hydrogenated. Isooctyl eater of tall oil fatty adds, lanolin. a-Methyistyrene-vinyltolucne copolyme; resins fmolar ratio 1 s-methyiatyrene to ! vtnyitoiucnc). Mineral oil. MonLan wax. n-Octyl n-decyl adipate. n-Octyl n-decyl phthaiate. Petrolatum. Petroleum hydrocarbon resin (cyclopcnti diene type), hydrogenated. Petroleum hydrocarbon resin (produced to the homo- and eopolymerlaatlon of diene and olefins of the aliphatic, allcydlc. ani monobenacnoid arylalkene types from dh tlllales of cracked petroleum stocks.) Petroleum hydrocarbon resin (produced b; the catalytic polymerization and aub&e quent hydrogenation of styrene, vinylto APPENDIX II 4 \x EXTRACTION OF BFA FROM FVC COMPOUNDS BY FOOD SIMULATING SOLVENTS BFG09407 020-&OTT2 bfgqodrich chemical limited ALTONA TECHNICAL SERVICE LABORATORY REPORT FOR ^PRODUCT DEVELOPMENT DEPARTMENT extraction OF BISPHENOL A FROM FINISHED PVC PRODUCTS Project No* 6980-2 By: Greg Brown Date: 20th October* 1980 BFG09408 21104021 ..<:*MSMICW. l.lMITUn PROJECT NO; 6980-2 M.TONA DATE: 20th October, 1980 EXTRACTION OF BISPHBNQL A FROM FINISHED PVC PRODUCTS INTRODUCTION This work was initiated aa an extension of Project No* 6980-1 In order . to gain approval for the uae of Blsphenol A (BPA) as a shortstop in the production of Poly (vinyl chloride) (PVC)* Having determined the level of residual BFA in PVC resin, it was necessary to determine its extractability from food contact products* CONCLUSION The work showed that aqueous solvents did not extract a detectable amount of the BFA from the finished product* Fatty type solvent, heptane, extracted 17>ig/square inch. Results are shown in Appendix II, EXPERIMENTAL 1* Introduction Aa there la no Australian Standard covering the presences of BFA In plastics used for food contact applications, ths development of the extraction procedures was based on the American FDA method No 175-300, pages 505-510. Two formulations were tested, one representing rigid food packaging (8) such as bottles end ths other (G) representing flexible food wrapping such as film* They were prepared using the realn which had been shortstopped in a plant trial, and were known to contain 62 ppm of residual BPA. These formulations are shown In Appendix I. Each formulation was fluxed on a steam heated laboratory two roll mill. Plaques 15cm x 15cm x 0.125cm ware prepared on a steam heated press. Small samples, 4cm x 4cm x 0.125cm, were then cut for the extraction testa. ^ **% to mmm *** tobiN* ../2 zzow nz BFG09409 2* Extraction FDA Method 175-300 specifies the following extraction media and conditions: Condition of use Extractant and conditions E. Room temperature filled and stored (no thermal treatment in the container) Rigid package 1) Water, 120F, 24 hour (Simulating room temperature filling and storage) 2) n-Heptane, 70FP 30 min (Simulating room temperature filling and storage of fatty foods only) Type of food (See table below) I, II, III, IV-A IV-B, VI-B Ill, IV-A, V, VII G. Frozen storage (no thermal Water, 70F, 24 hour treatment in the (Simulating frozen storage) Flexible package I, II, III, IV-B, VII Types of food I. Nonacid (pH above 5*0) aqueous products may contain salt or sugar or both and including oil-in-water emulsions of low or high-fat content* II. Acidic (pH 5.0 or below), aqueous products may contain salt or sugar or both, and including oil-in-water emulsions of low or high-fat content* III. Aqueous, acid or nonacid products containing free oil or fat; may contain salt and including water-in-oil emulsions of low or high fat content* ' IV. Dairy products and modifications: * , 'tvV . A. Water-in-oil emulsion, high or low fat* B Oil-in-water emulsion, high or low fat* V* Low moisture fats and oils. VI. Beverages: A. Containing alcohol B. Nonalcoholic VII. Bakery products. VIII.Dry solids (no end test required). **/3 h-* S % w BFG09410 -3- 2. Extraction (cont) Four pieces of the prepared sample- totalling 36 sq*in.in surface area, were placed In a jar to which had been added approximately 300ml of extracting solution. The Jars were sealed with a screw lid, and placed in a water bath of the appropriate temperature. After the specified time, the jars were removed from the bath. The samples were then removed from the Jars, and the solutions analysed for BPA as discussed later. 3. Analytical Method a) Equipment Used The analysis was carried out on a Hewlett Packard Gas Chromatograph fitted with an automatic sampler, and a flame ionization detector. Conditions used were as follows: Column* 6' x 1/8" stainless steel packed with 1Z QV-1 on Chromoeorb G Column Temperature: 200C Carrier Gas: Nitrogen Carrier Gas flowrate: 10 cc/mln Injection temperature; 300C Detection temperature; 3QGC Sample size: 3.2^il b) Detection Limit The detection limit for the analysis was determined by analysing solutions of known*BPA concentration. The concentrations used were; 0, 0.5, 1, 2, 5 ppm BFA. Chromatographs are shown in Figure 1* From these it can be seen that the limit of detection on the equipment available Is lppm derivatlsed BPA# Conversion of this value to a limit of detection per area is shown below: 1 ppm 1 ^ig/ml 100 ^g/100 ml (final solution volume) * 100 yig/36 sq in (area of sample) * 2.7^ig/sq in BFG094U . ,/4 J104024 .4.-1 3. Analytical Method (cone) c) Recovery Data Recovery dace for the analyses was determined by spiking each extracting solvent with a known amount of BPA. A The spiked aqueous solutions were extracted three times with 50ml benzene. The combined benzene extractants were then evaporated to dryness using a rotary evaporator. The residue was taken up in acetone, and then made up to 100ml In a volumetric flask using acetone. The spiked heptane was evaporated to dryness on a rotary evaporator and the residue taken up in acetone* This was then transferred to a volumetric flask and made up to 100ml using acetone. One millilitre aliquots of the acetone solutions was Chen derivstised with n,n bis (trimethyl silyl) acetamide and analysed by gas chromatography* Data for the aqueous solvents were obtained using a level of 4ppm and lOppm BPA In the extracting solvent. Data for the heptane solvent were obtained by adding an amount of BPA which would give a final solution of 5ppm BPA. The recovery data obtained were: Water: 4ppm - 98% lOppm - 93% Heptane; 5 ppm - 75% typical chromatograms are shown In Figure Z for aqueous extraction and Figure 3 for heptane. Earlier work (Project 6980-1) showed that below 25ppm SPA, response of the gas chromatographic detector v- > to the derivatized BPA la linear (Fig 2, project 6980*1). As a result of this, our analyses on recovery (and extractant) solutions were compared to a lOppm standard only. d) Analysis of extractant solutions After the specified extraction procedures had been carried out, the samples were removed from the solvent and these solvents were analysed as discussed above* Chromatograms obtained for analysis of extracting solutions are * shown in figures 4 (water) and 5 (heptane). Results are given in Appendix II. K 1104025 GB:ac BFGQ9412 rr> ) PP/i"v 3 R P p} OPPlvj FW*Odk- X. ' ^t.TC.^.MipjATlCrJ it^r&cr kj rvi i t OF S' R P) BFG09413 920^01 N Zl)fcOTI T 'S )* < \ ' V ., r* A iv. .v ` V. K 7 m kHv -^'-v of J^^-X FV^n^ BFG09414 fifcone. s senwea ft HefTry^ BFG09415 SoOfc'OIT 21104029 FlGiOfcfc 4p TYPICAL, ftrjftwwS^ THE. a6'm<tJA Csi BFG094J6 t "TV^ic^t- ^i^oMyvrcCkA^v **At*iAi*& Pm. *th* #WJftv_^s arf= nefrvHC ^-rAAc^m^t- BFG09417 21104030 APPENDIX I Formulations used to test extractability of BPA from PVC compounds Geon 103EP Kureha BTA III N Paraloid K.120N Mark 465T Advastab CZlll DIOP Paraplex G62 Wax OP G.M.S. Stearic Acid Rigid Compound (E) phr Flexible Compound (G) phr 100 100 10 - 1* 1.5 - - 1.5 - 25 - 10 0.2 - 0.1 _ - 0.4 Formulation E represents a rigid food packaging product Formulation G represents a flexible food packaging product. 21104031 BFG09418 A P P END XX II Test conditions and results for extraction studies of BPA from food contact PVC formulations Formulations used E G E Extraction conditions Water, 50C for 24 hours Water, 25C for 24 hours n-heptane, 25C for 30 minutes Level of BPA extracted ^ 2.7^ig/sq : <2.7 ^Jg/sq I 17 /lg/sq in The formulations given in this report do not in any way constitute an individual endorsement of Che additives suggested for use with our PVC resins or other products. Equivalent additives from other manufacturers may be used with similar effect. 1104032 BFG094J9 bfcoodrich chemical limited ALTONA TECHNICAL SERVICE LABORATORY REPORT FOR DEPARTMENT 40 EXTRACTION STUDIES ON BPA STATUS I - ACETIC ACID Project NO: 6981-1 By: G. Brown Date: 29th January, 1981 BFG09420 21104033 PROJECT NO: 6981-1 bfgoodrich chemical limited ALTONA DATE: 29th January, 1981 EXTRACTION STUDIES ON BPA - ACETIC ACID INTRODUCTION Further work on the extractability of Bisphenol A (BPA) was found to be necessary for approval of our submission to the NHMRC. This project investigates the extraction of BPA from a 5% (v/v) Acetic Acid solution. CONCLUSION No detectable amount of BPA was found to be extracted when exposed to acetic acid at 5QC for 24 hours. EXPERIMENTAL a) Introduction This method is similar to that described in previous work (Project No 6980-2). The BPA was extracted from the solution with benzene. The final working solution was derivatlsed with N,N-bis(trlmethyl eilyl) acetamide (BSA) and analysed by gas chromatography. b) Recoveries Recovery rate was determined by adding a known amount of BPA to a solution of acetic acid and carrying out the extraction. The amount added was determined so as to give final solutions of 5ppm and lQppm BPA. Initial work involved extracting the BPA with benzene* drying on a rotary evaporator, and making up to volume in acetone. This method, however gave low results, usually less than 802, It was then decided to delete the drying step, and carry out the analysis in the benzene. The solution was extracted three times with 25 ml benzene and once with 20ml benzene. The benzene fractions were collected directly in a 100ml volumetric, and the solution made up to volume with benzene. An aliquot (approximately 1 ml) was then derivatlsed with BSA and analysed by gas chromatography. Recoveries by this method for both 5 ppm and ZOpptn were 100%, Typical traces are shown in Figure 1. W 1104034 ,wnw tc ../2 T) T"f\/'\ < , -z- EXPERIMENTAL (coot) c) Sample Extraction A compound was prepared according to the following formulation; phr Geon 104 Kureha BTAIIIN Paralold K120N Mark 465T Wax OP G.M.5* 100 10 1 1.5 0.3 0.2 The formulation was fused In a Brabender fusion head and then pressed into a sheet 150x150x0.125mm on a steam heated press* Samples approximately 50x50mm were then cut from the sheet* Three samples, with a total surface area of twelve square inches, were then suspended in a 5% (v/v) solution of acetic acid. This solution was maintained at 50C for 24 hours in a water bath. After this time, the samples were removed and the solution was analysed for BPA. No detectable amount was found. Typical traces are shown in Figure 2. G. Brown 21104035 GBrsc BFG09422 BFG09423 21104037 BFG09424 BFGQODRICH CHEMICAL LIMITED ALTONA TECHNICAL SERVICE LABORATORY REPORT FOR DEPARTMENT 40 Extractability of Bisphenol A from Finished Products Status,II - 8% Aqueous Ethanol scofcoi Project No: By: Date: 6981-1 BFG09425 BFGOODftICH CHEMICAL LIMITED ALTONA Project No: 6981-1 Date: February 18, 1981* Extractability of Bisphenol A from finished products* Status II - Q% aqueous Ethanol* Introduction Further extraction work was found to be necessary for our submission to the NHMRC for approval of Bisphenol A (BPA) to be used as a shortstop in the production of PVC to be used in food contact applications. This section covers the extraction of BPA by an &% aqueous Ethanol mixture, simulating use in alcoholic beverage containers. Conclusion No BPA was detected after extraction for 2U hrs at 70C. 1104039 t: BFG09426 Experimental a) Introduction As in previous work the BPA was converted to a silyl ether with N,N Bis (trimethyl silyl) acetamide (BSA) and analysed by gas chromatography. For details refer to report No. 6960*1. b) Recoveries The rate of recovery of BPA from the alcoholic solution was determined by adding a known amount of BPA to an 8% ethanol solution. The amount added was that amount calculated to give a final solution of 5 ppm and 10 ppm BPA. The ethanol was allowed to evaporate from the solution. This solution was then extracted six times with 25 ml portions of benzene. The benzene was then removed by rotary evaporation and the residue made up to 100 ml with acetone. An approximately 1 ml aliquot was then derivatised with BSA and analysed on a Hewlett Packard gas chromatograph. Recovery by this method at both 5 ppm and 10 ppm was 82%. Typical chromatograms are shown in Fig, 1. 4 c) Extraction. The sample for extraction containing 69 mg BFA/g of PVC was prepared according to the formulation in the Appendix. The sample, having a surface area of 32 sq. in., was then immersed in 300 ml of an 6% ethanol solution, and maintained at a temperature of 70C for 2k hours. At the end of this period, the samples were removed and the solution analysed for BPA, as described in (b) No BPA was detected after the extraction. A typical chromatogram is shown in Fig. 2. t: H- G.Brown. BFCj0942'7 APPENDIX Formulation Geon 10JEP Kurcha BTA IIIN Paraloid K120N Mark 465T Wax OP G*M*S* 100 10 1 1.5 0,2 0.1 1104041 BFG09428 ,v oew APPENDIX III LETTER RE EXTRACTION STUDIES ON BFA BFG09431 21104044 ft?Or.5 D, E. Bartrum__ M.B,Butterfield t . , lJ i ; * j Cleveland Chemical c.v ui\ `V ^ Akron.- D/0Q2P, ,5-H a;-s \ DA'S this , new 8-10-78 BISPHENOL A i .'i.l-N t , r t/ <\V Concerning your request*for information re BFG Australia's Bisphenol A in PVC resin inquiry, X regret that we are unable to provide much assistance in this matter, I can find no record of.any migration studies done on Bisphenol A, nor are we aware pf any ocher country where it has been approved or rej acted 'W^lfer'tfse^ Possibly Paul Zakriskl at the Brecksville Lab would be able to advise you in the area of analytical methods. I have requested a literature search to be run on Bisphenol A through the various computerized data bases available to us and will forward this to you when it comes in on Monday or Tuesday of next week. Mr. Bachtel requested that I mention to you the fact thAt * hort-stopa, catalysts, i.e., those Ingredients necessary for polymerisation, do not need FDA acceptance as they are assumed used up in the reaction, etc. If we can be of any further assistance, feel free to contact us. v cc: Paul Zakriskl M*B,Butterfield/W,C.Bachtel I - ii-4 ; r.l /II - : BFG09432 N h* O LETTER FROM UNION CARBIDE ANSWERING QUESTIONS ON THE NHMRC QUESTIONNAIRE BFG09433 ICALE L\:i> E-LAS1IC5 Mr. C. F. Comolll UC Inter America New York, N. Y. Dr. W. F. Gorham - BB Dr. T. R. Jones - BB Dr. G. T. Kwiatkowski - BB * Qatf RIVER ROAD, BOUND BROOK, NEW JERSEY C'veD RApril 11. 1979 OnginMin9 Dept. Aniwrfioc, idler Qjie c f, COWIOUU Bisphenol-A Australian Food Clearance At your request I have gathered the following information from my files which might be helpful In gaining Australian clearance for bis-A as an additive in PVC resins for food contact uses. We understand that B. F. Goodrich Chemical Ltd. will petition the Australian Health & Medical Research Council for clearance. They have requested answers to a series of questions which are dealt with as follows: Question 7 - State the maximum amounts that may be absorbed by foods from plastic packaging containing this additive. Me have no data. Question 8 * Give evidence of approval in other countries. Attached are copies of ,the following U.S. Food and Drug Administration Regulations which refer to bisphenof-A (4,4' Isopropylidene diphenol). 21 CFR 175.105 for adhesives 21 CFR 175.300 ' for resinous and polymeric coatings {as reactive monomer In phenolic and epoxy resins) 7s 21 CFR 176.170 for paper and paperboard by reference to 175.300 21 CFR 177,1210`for closures by reference to 175.300 -21 CFR 177.1440 for 4,4' isopropylidene diphenol-epichlorohydrin resins ^21 CFR 177.1580 for polycarbonate resins as a reacted component 21 CFR 177.2280 for 4,4' isopropylidene diphenol-epichlorohydrin epoxy resins ^ 21 CFR 177,2500 for polysulfone resins as a reactive monomer 21 CFR 177.2600 for rubber articles as an antioxidant - a polybutylated mixture with bis-A To our knowledge bisphenol-A has never been rejected for a food contact application. o o BFG09434 y Mr* C. F. Comoll i "2- April 11. 1979 Question 10 - State the nature and amounts of impurities present. Are there heavy metals? We have no data on bisphenol-A as such but theattached data sheet on metals content of some of our products shows data for epoxy resin ERL-2774 which Is a reaction product of bisphenol-A, These data would indicate maximum levels. Question 11 - State a recognized standard of purity for the additive. We are aware of none. Question 12 - Show information regarding the stability and persistence of the additive in the plastic. We have no data. Question 14 - State the analytical method to determine the amount of additive In the raw material, processed and/or finished plastic, in food due to migration and any substance formed in or on foods packaged in plastic. Attached are analytical procedures based upon high performance liquid chroma tography for the determination of blsphenol-A In aqueous 3* acetic acid and either n-nonane or n-heptane which we developed for use with polysulfone resins. Question 15 - Supply a summary of pharmacological and toxicological information Including a summary and bibliography of pertinent literature. Attached are copies of a toxicity study entitled "Metabolism of Bisphenol-A in the Rat" by Knaak and Sullivan, Tox. and Appl. Pharm, 8, 175 (1966), and Acute and Subacute Toxicity of Bis-A (dlphenylol propane), Mellon Institute Report 11-13, dated 1-20-48. Questionsl6 and 17 deal with manufacturing procedures, analytical controls, etc., and I have no information. Question 18 - Reports are required of adequate tests which show that the additive wiTl~"be_safe when used as proposed. We have no data beyond that presented above. We realize that these data may be inadequate but we have nothing more to offer. S frO S O T X WBA;GP Att* W. B. Ackart BFG09435 APPENDU V EXTRACTS FROM DOCUMENTS OTHER THAN USFBA WHERE BFA IS APPROVED FOR POOD CONTACT USE 1. JAPAN HYGIENIC SOCIETY 2. "SURVEY OF HEALTH AND TOXICITY REGULATIONS AND PRACTICES IN THE PACKAGING OF FOOD AND BEVERAGES IN PLASTICS MATERIALS'1 BY INTERNATIONAL TECHNICAL SURVEYS, INC., GENEVA (BELIEVED TO BE 1968) 3. BPF 4. CORRESPONDENCE BETWEEN PIA AND BPF BFG09436 21104049 At. i ached Tab 11: Pod i live* L. a i con feinig PVC Food Cohwiineis and Fuchng'ngs (PL Recommend*tion ) (Revised ha of April, l1!?-) Second Ed i L i uii A PVC Type Ptilyrflei'8 and PoJvh/w Add j i j v/.-s B PJ asticizi>i s C Stabilizers, Antioxidants and UV-absu i be i * D Surface Ac Live Agents t E Lu h 1 ic an t a V Pigments, Colorants and Fillets C Chemical Blowing Agents Note; Materials with asterisk * in the "substance"^column me also described in the section shuwn in the [inieii theses of the "no le'`-col umn, and muik ii n> described as to the revision on Fob, J, 1V7*1 -- tt - BFG09437 OSOi'O h* M Recommendation on the Use <if PVC Products for Food Contact Application Introduction This Recommendation iheresfler called List) is the voluntary regulation prepared by the .Japan Hygienic PVC Association unitor the leadership of the Ministry of Welfare, hi order to promote healthy development of the industry, It is recommended that only PVC products which meet the List he supplied or used. Purpose The purpose of the List is the safety in the use uf 1WC packaging nuucnuls in contact with fmulsmtr in accordance with the intent of the Food Hygienic Law, and to secure hygienic safety of packaged loud*. Preparation Procedure In preparing ihe present List, a study w:is mad. uf ihe standards in the I'nited States, West Germany. France. England and Italy, and then adCLiing Um:,e especially applicable to l'VC packaging materials and related products and determining acceptable standards (nr each constiiueni with respect id its quality, ipiuniity used, application and migration. The follow, big items have Iwen derided on in conformity with the Vnited Slates regulation, Food aqd Drug Adminis tration, Ilfitin In Putil'oruiii}1 with PDA Kmulttilunii ^Mitpurt J| * 121 Mil Substances the safety of which is generally acknowledged, Suhpai I K Suimtaiii'eM for which prior pjiclion have been Krunlrdi ft 121 2uni Substances employed in tht` tnamifiu Hirers of food packaging materials VliUusitlanls \ III unu ot it s I 'l li l s hiving oils I 'last d'i^er.s Kclcasc agents* Si,iliih/.eis Sidj^Uiiices used in the mamd.n iiire of paper- ami paperboard priKlucts list'd in food packaging Suhpuii F FtHwi additives mtultliiK from contact with 1`onliiiiim ol equipment and fond additives otherwise affecting food ft rjl jr.07 t'eiiLiphane $ 121 -fiUM i t l ydrnxy met by 1-2. li teri hotylphcnn) 121 xm Release agents fi i21.2.rill Plasticizers in polymeric substances S I2l.2'ill Resinous and |mlymeru- coatings ft 12I.2IVJ! Vinyl chloride-propylene copolymers ft 121-.r)-d < 'imipinu'iits of paper and poperbuurd in contact wilh aqueous and tally foods ft 121 MH Fmidfiiliers and/or -nil luvo-aemv agents ft 121 L'-Wl ('losim-s with scaling ua .kcts fur fiMHl containers ft 121 2.ViN Isopaiatlinic petroleum hydrocarbons, synthetic ft I21.2fti2 UutilM'r ariirloH intended for repeated use ft 121.2TM I'hruiitarhiP blue | l2L2.r)titl Antioxidants and/or slahiliKcrs fur ft 121 #"! ft \2llW> ft 12L2fiHti ft l2l.2fiKh ft 121 2rk<| polymers Components of paper and papcrlxudd in contact wilh dry tuod I'uroHln, synthetic Petroleum wax * I'etrolalum .Mineral oil S2i-2;.t.2 l<o.-ihs and losin dorivauves < ft 121 ur}` i Odotless light petroleum hydrocarbons ft I2f 2.rid7 Polymer modifiers in semirigid add rigid polyvinyl chloride plastics ft 121 20(12 Ociyllin staliili/i'rs in vinyl chloi iiie plasprs ft I'jl Jddr. I'olyhwlrie alcohol dicsicrs of o\ul:i- i ivcly i-etiiU'd i (;ei`stluH'en process l oiont.'ii wax acids ft 121 L'MlS Vui> I chloride lain yl vinyl ether vnpnl yiMefs ft 121201111 Vinyl rhloildcelhyJene iiipulymcrj? 21104051 BFG09438 --4 Definition In ihi>i I.im, ' I'ootlAiutf" refers to .ill foods and drinks, und `oniuirteis and packaging materials" m those containing and/or wrapping foods in direct cwiducr. I,,uit!v`ii', includes vinyl chloride homo polymers and copolymers of vinyl chloride with other monomer* (when vinyl chloride ac-ounts for a major weight per cvnid and "Additives" include at) those subi-tanee,> such as polymerized additives, suihiii^ers, pliisLii iziTs. surface active agent*, lubricants, colorants, fillers, foaming agents, etr. which are added lo said JHV polymers for the purpose of Improving the pro. cessing and characteristic pru|>ertlos. Content I) Substances other than those in the attach.'d i.ist should not be used for raw materials for I1 VC products used for containers and packaging purpose. In addition, the use ui substances presented in the hist should he within the limitation given with rc^teri hi their nuality, puantity, application, etc. 1`oodstulf additives approved by the Foodsunr Hygienic I .aw may also lie used w ithin the range of the regulation us additives for 4 d) PVC containers and packaging materials should have less extraction than defined according to the toui-uctioii lest determined depending on kinds and conditions of applications. The purpose of this defini tion is to set a certain limitation on the foodstuff coiiliuhinuiioti caused by additives. I) Additions Ui and elimination from the List may be curried out depending on examination other wise defined standards. S) The dehnitiun on sealing PVC gaskets will he issued in due course. 2110405: -- & BFG09439 Extraction Testing Method Migration Regulation A. Containers and packaging myiurials made of polyvinyl chloride should he tesud according to the procedures descried in C. and J>. depending on the kinds of food ami application conditions, and should maintain a migration <iuuniiiy less than UitHingA'm per unit of iiiea of containers md packaging materials. H. b'uutis ate clutcsified into 7 kinds as follows; I. Nortuddio aqueous foods and non-acidic oil-in- water type emulsion foods (with pH value more than '>A) II. Acidic aqueous and acidic aqueous oil-ln-watcr emulslutt type foods (With pH value less than 0.5) III. Aqueous und water-in-oi) emulsion type foods, both containing oils and fats IV. Oily und fatly foods V. Alcoholic food.stuir (with alcoholic conccmni- tiOn lets than H%) VI. Alcohulii- foodsiufT (with alcoholic cont-emry. ttan more than 8% I VII. Dried solid foods t\ Extraction tests should be conducted dc|*cndlng on the kinds of foods und application conditions, and according to the condition* in combination with the following table. * .\s for i'i.uhI cliissidvaiinii Vll. however. the litigra iimi test is uiinecossury. At the extraction tpianlily l>> n heptane, (he rcguluiitm value l.-j to he at the iii i.'i iuined value divide! by ft. h. The extraction test procedure anil the method of obtaining the determined value are to be in lonioimiiv with the extraction lesitng method. Extraction Tasting Method l. EltriCtanti il) Distilled water: Water prepared hy inn ex change method is to lie further dislillaied. (Ill Arctic aeid aqueous solution with rohcrncra- tioh of It',';: Water debited in (1) should he used, Cij h'>; i*thyl alcohol (hy volume) in water; Water defined in < 11 should in* used, III .MiM eliiyl alcohol (hy vulitinei in water: W.itel driihcd lh (I I should In* Used. <-') n heptane; Should t>e used only after distil lation. Nines: )) deagems iM*d should ) of ^opener qyahty, VI K'KtrueUiius hould is- used a) V nil as per I I enP of HfwImUtn. ill The *|H'i'iiueti Niirfyee urea is to lie the sum of txKli surfaces. with die miss-sea ion area ignored. Extractant Application condition* eiiidflcatlsfl la) Thermal filling, sterilization at e temper ature exceeding 60 C, or short term heat ing before application |b| Thermal filling or sterilization at less than 60C (cl Filling or storage at room temperature Id) Cold storage Water 1, III For 2 hours at 60 C For 1 hour at 60 C For 24 hours at 40 C For ?4 hours at 25 C 3s acetic acid II, III Same as left. Same as lolt Same as left Same as left % ethanol V Same as left Same as left Same as lelt Same a$ left 0% PthPnal VI n-heptane III. IV Same as For 30 minutes left at 40 C Same as left Same as left Same as left For IS minutes at 40"C For 30 minutes at 25 C For 30 minutes at 25 C 21104053 -- 6 BFG09440 Cylindrical SWing cover Shape of toot piece StpwaM* iu*K Dimension and number of test piece 45x85 mm*2 Surface Extractant area quantity 152cm1 304 mf Out* wU *1 VMiat Dimension and number of teat piece 73x50 mm*4 Surface Extractant area quantity 208 cm1 596ml ,------ 0#2 ' jO^V 5J5j ^ Tfii 2. Extraction Condition* The extrai'iion conditions should be in conformity Widi the romhjnuiiun of foods kind* and application comJitioiis a.-j described in C\ of Migration f.'Miditionri, Flu. Hdi|prr lirvlrc II 3. Extraction Veaaal* and Stoppers ui) With romped to extractant* (n ull, ll".' cylindrical vos-sel and stopper A shown lit ihi' acI'uiiipan.wntf tliani-ain *hnuld be used- M 7 BFG09441 t^eaVoT \ (iii As fur exiiuriants ( iM.'ii, the separable flask and stopper H Li]so shown in the ui companyinu **iaTraill should In1 used. VmU'. Til*' cessid .iJid a|i|i.jr,i|us hmOimI should (h> n>;id 4, Extraction Prtcadur* '['hr specimen is m lie washed in water, kept free u dust h,y d*iim ^auze and washed in distilled water i .1 ivmpei-uiurt1 i>1 lid .VC by immersing and pulling uia the specimen ft umis in lo seconds (if usinu n hvptanv. the .specimen is to be dried after cleaning). Killing the extractant renUii'ed Inin the extr:iction \ e-.se l ia 1 or (In i in uw ol ii-atiM tin vO's"I, water t-. to Itf supplied through the cooling apparatus), and when the pre-tlelerminvd temperature of dir exMuc. laid is reiiched, the specimen niiaehed pi Dir stopper s unmetsed in the* extractant, and. with the cover attached, is left as is m iho vessel kept at a detinue tcnipemture, No siiiTing it) t onduett-d. However, when u number uf bubbles appear on the surface ol specimen, the shipper is to be moved up and down to ehtniiuhe (he hubbies as fur us pus.-abU'.i The temperature during Immersion is to he determined by (he use of a water haih. After a pr detcrminikl time is pd.sxed, the sperJmrn is to be taken nut, then u whole (juantity uf the extractant and dlH) mi of (he extractant should be rx.Mily colliiinl hi case of the \c'-ol i(i) and (In, respectivclv, as the cxtrui'taid tumidity fur tetitmg, The lasting solution is uj be taken on a quart* < \ apt.i viUnw dish previously dried at lo>V, and ihc dt iinib' weight is irtiched (according to J IS K (Milk)). (Hid rv apor.'iPed into a ihy solid. iluwvver, when nheptane is iiM'd as an exirocianb the icsulputl testing sobdion >li<<old >>e evaporated to several ml to feed into die ipiariy m .derating dish for Cut I itai tn^ e\apoi at i>m .nut solidifying on a water hath. Then, after drymp for 2 fiolirs a| lo.r,*(.\ tin*' evapoi at mg dish is to be cooled foi lid minutes in a de'Ueaim' tt'dizing .'ilnagel as a dryer. Alter cooling, the evaporating dish weight is ilclmimii ii lr .il,( .tin (be u cU.dil dilfi'l *me ul rv ,ijm u al inti dish ImIiii- iinii alter (In' experiment. and (lie weight uf tlif li'suluiiii solid us ealeulalvd aecnnhn^ to iht* followinK oi|umiun: (*l)i`ri<>ii|iij|UKy uf tfMinw Miliiiinnunt tliTf, b; Apparent lest value uhlilined with H^pecl lu an t-Miaiiam the same in volume a* that oi the Testing solution. As for n heptane, a tilth of (fie value ohrumcd to* I hr above t-i|Uailnn is to he taken as an r\apoi at ton residue llmvcti'i, taking it -1!. die appatrni h>t should lie i'oiidnrnd on ouch occasion. -- H -* BFG09442 (A) 36. Starch 37. Dextrin 38. Tragaconth gum 39. Paraffin *40, Chlorinated paraffin 41. Polyethylene adipate 42, Polyvinylethyl ether .............. ... .0,5~0,8ci>^ in viscosity of \% benzene solulion at 20"C (Fluaticizers) 43, Condensation products of gorlitol (or) ethylene oxide ,,, Ethylene glycol is not allowed to be extracted from end-products. 44. Copal 45. Damer 46. Elemi 47. Gilsonite Sandarac Glycol enters of darner, copal, elemt, sandarac 48. Shellac 49. Utah coal resin 50. Epoxy rosin * 51* Coumarone-indent* ream 52* Petroleum hydrocarbon resin 53. Torpene resin 54, Polyvinyl formal 55. Polyvinyl butyral 56, Polye t hy1ene *57. Polypropylene U) M.W. min 10,OOP of 4,4'iso propylidine phenol epichlorohydrir. resin (ii) Non-volatile contents should be satisfied with the following limitations: Dist. H^Os lea* than 2 ppm n-hepton: less than 3 ppm lUvol# ethanol: less than 6 pjxn Quality subject to E-l-(6) (Lubricants) # 58. Modified polyethylene with maleic anhydride Reacted products with intthjc anhydride, less than 6 of saponification value after extraction with absolute alcohol for 24 hrs. using the Soxhiet's extractor 59. Polyvinyl alcohol 60. Polyvinyl stearate -I S" BFG09443 --(C) (19) 2,6-Di-tert-butyl-pphenylphenol (20) 4,6-Dinonyl-o-creaoi Less than 2# Less than 2# (21) Butyiuted hydroxyanisole Less than (J. 5^ with O.OU5# of the extraction amount * , *(22) 4,4'-Di-hydroxydiphenylpropane- Less than 0.3# 22 4(23) Polybuty iated (mixtures) 4,4'-ieopropylidendiphenol ^ (24) 2I2'-Methylene bis(4-meti\yl- 6-lort-butylphenol) Lie s s than 2.0# (25) 2,2'-Methylene bis(4-ethyl6-tort-butylphenol) (26) 2,2''Methylene bis(4-raethyl6-tert-octylphenol) (27) 2,2'-Methylene bia(4-methyl6-nonyIpbenol) (28) 2f 2'-Methylene bis 6-(lmethy1--cyclohexyl)--p--creso 1 (29) Mixture of 2,2''Methylene bis (4-raethyl-6-nonylphenol) and 2,6-bis(2-hydroxy-3-nony1-5methyl-benzyl)-p-creaol /Leas than 0.6# Less than 2# Leas than 2# Leas than 1# Less than 2# for non-ulcoholic foods only (30) 4,4'-Butylidene bis (6-tert butyl-m^cresol) (31) (32) Tris(2-methyl-4-hydroxy-5tsrt-butylphenyl) butane Less than 2# Less than 0,1# in fatty foods and alcoholic beverages, and less than 0.25# in other foods (33) Tetrakis roethylene-3-(3`,5'diter t-bu ty1--4 *--hydroxy phenyl) propionate methane Less than 0.5# (34) 1,3,5-Trimetbyl-2,4,6-tris (3,5-di-tert-buty1-4hydroxy ben2y l ) benzene (35) n-Octadecyl- -(4'-bydroxy-3', 5 1 -d.i-tort-butylphenyl) propionate Less than 0.5# -22- BFG09444 o cn si U`> (13) Pentaerythritol of maleic anhydride-modified wood rosin, further modified by reaction with 4,4'isopropylidenediphenol* formaldehyde condensato (14) Mixed methyl- and pentaerythritol estor of maleic anhydride--modi f l ?d wi th rosin (15) Tnethyiene glycol ester of partially hydrogenated wood rosin (d) Reaction product? of rosins or modified rosins with the following materi&1s: (1) Ammonium, Na, K, Ca, Zn2 (2) Formaldehyde, fumaric acid, maleic anhydride, saligenin Acid value, 10-22; drop-softening point, 162-172^0; colour tone, less than K; supunification value, less than 2b0 UV absorption 29&inu max, 0. 14 Acad value, 73-d3; drop-softening point, 113-123 C; colour tone, less than M; saponification value* less than 2H0 Acid value, 2-10, colour tone, less than K; viscosity, 350-425 aye* (10OC) Ext[action amount of Zn-H'Binato, less than 50 ppm (Zn) 1104058 -- 37 -- BFG09445 SURVEY OF HEALTH & TOXICITY REGULATIONS & PRACTICES IN THE PACKAGING OF FOOD & BEVERAGES IN PLASTICS MATERIALS ## t prepared by INTERNATIONAL TECHNICAL SURVEYS, INC. 8, rue de 1* Madeleine Geneva (Switzerland) ISb% ? This private report, subscribed to by a limited number of clients, is strictly for use within their own organization or companies wholly controlled by them, and must not be made available to third parties. BFG09446 6S 0W )TT3 L5U - l T A !. i (Ministerial Decree of the Uth <.-i April Imo) Gaiseta Official* do. Ill of the vt.h. r May, ; >ni'. REGU1.ATlUNLi ON THE HYulEjit uF HAGhA. IIU.} IN CONTACT WITH FOOD AND BEVERAGE.;, Official Gazette No, lit of the ?th. of May 1 >6<b published the ministerial decree pf the 15th of April Wot> concerning the new regulations ,,/i the hygiene of packaging, containers* utensils in contact with food products or product'; or personal use* j7>ii is the text of tin decree 5 Article : The decree sets Out the rules governing the pioducts concei .n?J# Annex A concern* the ;iit of resins and additives for plastics materials* and re.no* B concerns the extrac tion tests; they bath form an integral part or this deui.sr. Article 2- : for the purpose of the decree, the terms used are define., % ; llows ; "objects" are sheets, films, containers, varnishes, utensils and vciUus other manufactured products; "foods" ere foodstuffs a,J beverages, as wail as off,.;, edibles, such as the Chewitig gum* etc.., * Article : The resins add additives ter plastics materials, mentioned in the first jn i second part of Annex A, can be ubed for the preparation of plastic;, materials intended to be In contact with ;ood under the coi.dit.ioi,5, limitation* ..nd tolerances defined in the following articles* Article.jj_ ; fleiir.s to be used In the k anufacture of plastics objects ror contact with food must ppt allow the extraction of substar,ces Known to h<? dai.gej nits to health, such uS Cer tain . r;noi: =rt, catalysts, .u.d .emulsir Urs. 11,r- ?:<rrection tests are-described in Annt-:-. ii# Article b. ; Packaging materials am- recognized as consistent with it,.* r**guldtir:t wt, ?n the roslJne of the extraction tests does not exceed, the lln.lt oi t,..n Artie 1 r . : Sub&tir.cet must far? submitted to *A.-,:nir.5t Ion ny of extinction tests described in Annex ts iftu to n qualitative snu quantitative Analysis oj the t tract ion residues. In audition to the appropriate document at Ion, manufacturers, must provli* the Minis try of Health, at Us demand, with precise information concerning the quality and quantit/ composUiG.. of tpe material ?,nu Us constituents including, for sample, pUs- BFG09447 2 1 1 0 4 OSO - 1M - ITALY ; ticizers, stabilizers, antloxidents, colourants, lubricants, and catalysts as wall as the degree of purity of any other component used, which would be useful In verity ing the conformity of the article in question, Article 7, : Anyone using plastics products covered by the present decree must assure himself of : their suitability for the intended use and must also assist the Health Authorities , to identify the producer or supplier of the articles concerned* Plastics articles sold retail must carry the producer's identification made and rust be marked "for ! foodstuffs" and, in cases where there is a restriction of the use, this must be indicated. The mark and Inscription may be indelibly and clearly marked on a label firmly attach ed to the package. Companies producing packages made of melamine, acrylic or polyester, before allowing; them to come into contact with foodstuffs, must submit them to 6 water wash under the conditions of temperature and duration specified In Appendix A* Article 9. : Colouring matter for plastics may be used on condition that it does not affect the food and does not contain metals in quantities greater than the following percen tages : 1 ead arsenic mercury 0,01% 0,00 i/% 0,005* soluble in HC1 N./lO cadmium 0,20% soluble In HCl N/lO zinc selenium barium 0,20* soluble in HCl N/lO 0,01* soluble In HCl N/lQ 0,01* soluble In HCl N/lO The amount of aromatic amines must not be greater than 0,0^*. The solvent used in the extraction tests must not show any visible colouring. Article 9. : For the preparation of plastics materials which come In contact with food, it is for bidden to use scrap and regenerated plastics materials* Article 10. i The rules contained in the present decree do not apply to rubber products coming in contact with food or beverages or to plastics pipes for drinking or mineral water# Article LI. : After the date of issue of this decree, articles which do not conform to the decree itself, may be produced on condition that they conform to previous regulations; stocks on the other hand must be sold within a period of twelve months. A delay of six months is accorded for irports of foreign manufacture which do not conform to this decree hut which conform to previous regulations. Stocks must be disposed of within a period or' twelve months beginning from the issue date of the decree. Article 12. : , The ministerial decrees of the 19th January 1963 and of the 3rd December 1963, are ami'll led. The present, decree comes into forte 15 days after its publication in the 'Vr r Lc idl 'da/et, t e" ( HH1 O O & BFG09448 152 - APPENDIX A List ot Hiisina and Additives tor r L a s t i o b W.i; urie 1 First ; jrt r TAT V RESJNS : (conditions* limitations* and tolerances,) Polyvinyl alcohol ) ter ....; jl i Cellulose acetate, Cellulose acetobutyrat*i, Regenerated cellulose* Rubber hydrochloride. Vinyl acetate copolymer* with f - crotonic aciu, - allyLalcohol, - maleic anhydride* - vinyl Chloride, - vinyl laurate. Butadiene copolymers with styrene ui.J divinyl benzene. Vinyl chloride copolymers with vinyl ) if rr-1*3 polyvinyl alcohoJ 1 ^ acetate modified with maleic ai.hy- ) drlde chloride* ) pres-nt in Hi-1 i `Sin, it cannot be u.ji'd fur i|U-.iiis fo'Ods. Vinyl chloride copolymers with acrylo- nitrile, Vinyl chloride copolymers with vinyii- dene chloride* Vinylidene copolymers with acrylonitrile, Copolymers of two or more of the following components ; - vinyl acetate, * - acrylic acid, maleic acid, crotonic acid, - acrylamide ) - allyl alcohol and polyvinyl ) alcohol ) ^ there Is ir*M polyvinyl alcohol In resin* it cannot he used tor ^u?ouS foo>is - phthalic anhydride end maleic an hydride, - butadiene* - chlorobutadiene, - vinyl and vinylidene chloride, - acrylic esters, rum&i-ic* maleic and mathscrylic esters, - Lsoprene, - acrylonitrile, - -ulerines, - styrene and/or elpha.v.t-thyl styrene, - butene and ethylene, - propylene and ethylene, - acrylonitrile and divinyl ber.rene, - styrene and/or alphamothyl-styrene with acrylonitrile, - styrene ana/or a Iphe.nethyl-styrene with styrene-butadiene, - styrene anj/or s 1 phair.ethy 1 -styrene with butadiene end acryloni l.rile, - styrene wit:. JivjnyL benzene, BFG09449 Z90&0TTZ - 1>J ITALf styrene and/or alphamethyl-styrene .with methyl methacrylate, tetrafluor-ethylene with hevafluorpropylene, ethylcellulose, lacquer gum, nitrocellulose, poly-beta-pinene, polybutadiene, pol^chlorotri r'luorethyl high,medium and low density poly- ethyl ene, chlorinated polyethylene, polyethyleneglycol tarephthalate, poly-i$o-butylene, butyl, ethyl, and not.hyl acrylates ) and methacrylates polyners ) ) The finished product must be washed with water at room temperature for two hours the polymers deriving from t.he ester ification of one or more organic acids (11000 or polycarboMyl ic) In dicated below with one or several polyaLcohols Indicated below, Cross link od with styrene and/or alphamethyl styrene and vinyl monomers* ) ) ) ) ) ) ) The finished product must be weshed with water at 80C fox three hours. Klims and coatings of less than 0-2 mm thickness are exempt from this treatment. AC l to i Acetic acid, Acrylic acidj Adipic acid, Cdprylie acid, Crolonic acid, 1'ht.hdU add and Its isomers Kumarlc acid Coconut r 11.1y acid, Tall oil tatty acid, {taconlc add, Maleic add, ralmitlc acid, debacle acid, hfearic .,cid* AIjCOHQI.S t 1td-butylglyco1, n-decyl-alcohol, Glycerol, Mono and dl-ethyler.e glycols Mono and di-propylene glycols, Triethylene glycol, Tsodecyl alcohol, Neopentylglycol, i',-octyl alcohol, Pentfliirythrllol, Sorbitol, 1 l :|;tJ; by Lolpi OprtliP, ri spfi'Uio l ^ On condition that, the finished product does not yield monc or diethyler.e glyCoLs. 1104063 BFG09450 L54 - ITALY (olypropylene, i oly6tyi Siie, i-a 1 y t et rar 1 uoro ethy 1 ei u1, > alyuretnanes i products Obtained i ) reaction ot the following com ponents J ) Lii. condi l Luii ilul rln' rii.isliL'd ) product j "* not yield uve ibo) C'/aildtCS -..J ..`Tt.ylOUf - r olyrfst. of adipic acid a..d ethyl glycol, - 1 /o-naphthalei'.edi i socyaiia t n, or 4,-1' diphenyl- ureihanodiLsocyanate or toluene di 1 socyana te, - 1,4-butanediol tri;m?thy 1 olpi opdiiti* 2, i butyiene- ylycoi, dihydroxy-di-ethyl -cUicr of' nydvo.juinuiitif and their condensation pmducts with propylene oxide. Polyvinyl acetai, Polyvinyl butyral, t-olyviiiyl chloride, *-oly vinyl ider.e chloride, Polyvinyl -methyl -ether, Polyvinyl tertiary-tAJtyl-elhei, Ester condensation products L 1*1 CO lophony, maleic jcid and citric acid with polyalCcuols containing i to i C atOrr.4, Condensation products of : 4tAt di-hydroxy-phenyl -2,2' propane, - 4,4' di -oxydiphenyl -1, l * -cycloho,*;>e, - diphenyl-carbonate with phosgene (carbonyL chlorld--), Polyamides condeUSa Lion products 5 - omega-amino-undecanoie acid, - caprolactam, - hexamethyleoe diamine with .idipic acid and/or debacle acid, - ethylene-diamine with tatty acids, - soya polymers, - copolymers of the above. ) For tublowaie i.hn traction limit if. ) 1 gamma of formaldehyde per ml of solut- ) ion and per cn.'Y.f surface. The finished firmaljohyd-? ji.j melamine conJensat- ) articles must n<* washed for two hours in icui products, ) water at room temperature* This provision ) does not appl. i. films and coatings ) below 0,2 mu I iiii.i.hcSS r.ir'ii i Jehydc and urea cond'.-n&utiuil predicts, Epuxidr resins, Phenol io resins, jnue or modifi:-! with glycerG- ) plithal ic resins, epoxides Or polyvinyl butyral ) ini' lr)>_.}Uers and enamels or Lutyl alcohol, ^ tii ycertiplilhsl ic resin*, modified by oil and styi-;W ai'ni/or a I phd::;ethy 1 styrene, Maleic resins moditi-d with colophony nr.j chiellc acid, Weis., i.-.e it-Sxi.s i.-m.ilricd with butyl alcchcl ) for lacquers and enamel* roly&cetal I'eSil'.s, Urea resins .nUttai with hulyllc alcohoL ) for lac juers and end:.$ls 21104064 # ** BFG09451 ANNEX TO CHAPTU TWO GERMANY OFFICIAL I.IST OF RECOMMENDED MATERIALS for packaging BFG09452 S90K H T 2 - 93 GERMANY When during the transformation into finished products stabilizer* and lubricants are added, only the following compounds can be used i a) calcium and magnesium salts of straijnt chain Cj<j^'20 <'.w i boxy I.} y, aliphatic saturated acids, b) calcium octoate, maximum 3ft c) zinc stearate and/or octoate, d) diphenyl thiourea, maximum 1# maximum 1ft e) manganese exyhydrafci?, O 2'phenyl indol >'? maximum lft g) esters of montan acid with ethanedlol and/or 1,3 butanediol, h) trls(nohylphenyl) phosphate (mixture of isomers of tris(mono-nonylphenyl) phosphite) and trls (di-nonylphenyl) phosphate (sic), maximum lft i) polyvinyl ether (viscosity of the solution at lft in benzene at 20C at least 0,5 cP), k) pentaerythritol and dl-pentaerythritol, l) 2,6-di-t-butyl-4-methylphenol and/or t-butyl- hydroxyanisole, m) 4,4,f<<ihydroxy-diphenyl-propane 2,2', generally at a max* 0,5ft maximum 0,$ n) hls-st.earoyl -nthylene-dlamlne and/or blspalmi* toyl ethylene diamine, generally at a max* of lft o) polyethylene in conformity with the prescrip tion* III (1) and III A (2) concerning poly ethyl ene, p) uruanopolysl Ioxjim'S with methyl and/or phenyl groups (silicone oil) (viscosity at at least 1GU qentistokes - 97,3 Cps), (j) Liquid paraffins (.)), r) higher fatty alcohols (C^ and more) maximum 3ft s) stearic acid, t) dirilnocrotoiidtes of dliph.itlc alcohols (mono valent end polyvalent), maximum 3ft u) esters resulting from the combination of glycerol with saturated or unsaturated fatty acids, maximum v) esters of saturated aliphatic acid* (012*034) with aliphatic monovalent alcohol# *1* hydrogenated sperm oil* maximum 3ft (1) 1st communication Bundesgesundhbl 1 (1958) No* 15 - p* 235. (2) 3rd communication Bundesgesundhbl. 3 (i960) No. 15 - p* 23b* (3) purity specifications for liquid paraffins * see Bundesgesundhbl* 1*' (1959) p* 754. Bundesgesundhbl. 1* (1964) p. 703, Bundesgesundhbl* 7* (1964) No 21* - p. 320- Test for carcinogenic hydrocarbons 2 see Bundesgesnndhbl. 7, (l%4) No 9 - p* 137. BFG09453 M 2 O * * 5 Plastics for food contact applications A code of practice for safely in use Revised Edition 1973 BFG09454 j The British Plastics Federation ' 47 Piccadilly London W1V QDN Copyright publication number 45/4 December 1973 Price C3Q Published with the co-operation of 1 he British Industrial 3 Biological Research Association .9 i)W > rrc J --^ -- ' ' " T" Principles used in assessing safety in use Insofar as there is any cause for concern in the use of plastics in intimate contact with food, it arises from the migration of the constituents of the plastics composition into the food at a significant level. Hence, it is necessary to consider the intrinsic toxicity of each of the ingre dients of the composition, their ability to migrate into the food in their original or an altered form, and the amounts which could be consumed as a result Toxic effects can be cither 'acute', i e. more or loss immediate, as in most forms of accidental poisoning, or chronic1, i.e. as a result of the repeated administra tion of a number of small doses each in themselves insufficient to cause an immediate 'acute' reaction, but in the long term havmg a cumulative effect. The former effect can be ignored since the materials employed are of a low order of toxicity and only trace quantifies ate likely to migrate. The possibility of chronic effects must, however, be given close consideration and the results allied to the other two factors. U is convenient to divide plastics compositions into their two mam components, polymers and additives. Polymers It is generally accepted that the high molecular weight polymers which are of commercial importance in food contact applications cannot give rise to toxic hazard because they are essentially insoluble in food and inert. They do not migrate into foodstuffs in significant amounts, nor if they are accidentally swallowed do they react with the body fluids in Jheir passage through the digestive system. * The recommendations made in this code are based on this assumption, but the manufacture of polymers generally involves the use of other materials, such as catalysts, traces of which may remain in the finished polymer, and the polymerization may not be complete, leading to the presence of monomer or low molecular weight polymers ft is thus necessary to specify the purity of the polymer to be used as the basis of a plastics composition for a food contact application Additives These include all those substances such as plasticisers, stabilisers, lubricants, antioxidants and colourants which are deliberately added to the polymer to alter its processing, mechanical or other properties, it is appropriate here to realise that the concentration of additives m a plastics composition is generally, although not always (eg, plasticisers and fillers), small. Further moie, any additive will have had to be handled m bulk by its manufacturer and user with the result that any acute hazard will usually have already become apparent. It is believed that the implications of these facts are not fully appreciated. Were it so, the dangers of using an additive at about the 0 2% level in a food contact application would be seen to be practically negligible. That this is so. however, is not yet universally accepted and the recommendation? m this code do not rely on the assumption that there is no significant hazard from the use of the maionty of additives at such low concentrations, Additives may be considered tnlwo classes: 1 Those materials whose safety has never beenquestioned under the circumstances in which they are used. These are materials which occur naturally in food or which have been added directly to food for many years in quantities vastly greater than they could appear as adventitious migrants from a plastics composition. 2. All other materials not falling into the above category, which must, therefore, be subjected to appropriate toxicological study. BFG09455 Wi pfc* o o GO I PlMtiLi lot FouU Gorrlei I *1 IlHf |lit|tJt Plastics | m|'ri/H>n IlMlItt rtiMl Itmnd Nelttn UM A A > 1 Ric Thule of UK supplier No. UihihI name > Prmciiidl v.tmslituuul nr chemical type Folyuier i.iii** f twin tii r ond nindui t iypg Maximum Limita* Itivul yi iimi non* (% w/w oi final compound) Bast* of return* mendebon T,J7 ArbeMex 600 Robinson t Brothers Lid Modified poly (propylene adipate) PVC All All 36 T.2# Arbeitab DtTP Robinson Brothers Ltd Dileufyl thiodipropionaie All T.29 Arbestsb Robinson Bros. Distesryi Ail 9 DSTP Ltd thiodipropionate All AJ| All All 1 1 T.M Armid HT Armour Heu Chemicals Ltd Slaaramida Polyolefins Ail Ail 02 - T.J1 Armid 0 Armour Hsss Chomicats Ltd Oleamide All All All 02 T.32 Armogel Armour Hots Chemicals Lid Hydrogenated castor oil PVC. All cross-linked polyesters All 3 T.M Armostlt 300 Armour Hess Chemicals Lid Cationic surfactant All All All 01 All Ail Normally 0 IS i T.M AtmosUi 400 Armour Hast Cationic Chamicals Ltd surfactant n T.M ArmoslM 600 Armour Hass Chemical* Lid Cationic surfactant Polystyrene All ABS All Polyolefin* All Polyolefins All All Ail Polyolefins AH All 2 Not 2 alcoholic All 0-1 Non^fatty 0 16 All 0 1 Non-fatty 0*16 % TJ* l AtifoHK ^ HoneywH-'Adee fiifphonol A fumareta Polyesters -if ON- AH |* 70 polyester min T.S7 AtUc 362-06 Honaywtil-AUa* BUphenoi A Polyesters M` , All,. 70 ) Ltd himaret* tpo*y**lM r*in T.M Ad*c 362-2 Honeywill-Atlsi GUphenol A Polyesters AH Ail Ltd furoSrate * T.M At|c 392-13 Honaywill-Atlaa polyester resin Ri*phenol A Polyesters All All Ltd fumarete polyester raain 70 70 T.40 AtUc 367 Honeywill'Atlaa Ltd BiSphenol A lumerate polyester resin Polyesters AH All 70 T.41 Atmos1 60 Honaywill-AUaa v' Ltd All Ail All 3 T.43 Atmos 300 HoneywilhAtles Ltd All Ail All 3 7 BPF BPF None BPF BPF BPF BPF BIBRA" BPF 01BRA BiBRA BIBRA BPF BIBRA BPF BPF BPF BPF BPF BPF BIBRA BIBRA te S u fo rrs 3 BFG09456 Pt*t*hV >0' I-W*l ConlilLl I till H'MUlt I'l.lUlCk I oiltlKlIUm l'ulyH*o< :>(tw i|ir,tMoit PVC 2 Hiwi*n| I! /;! 2.10b Methyl ethyl ketone penixule 2.107 Persulphdtes uf ammonium and potassium 2 108 Porraihonates il Hu' `i111m mm (1,iICOOOOCOH., when* R, and R, are alkyl, tiryI. .ilky'laiyl. ulknv/ ii)r<i'y .ilf-vl 1 *l h'il<>i>on :.ut:dihlhid alkyl, aiyl, .ilkykiiyl, nlknxy in .ilk> -V ulkyl (<', l ,,,) 2.|i)U Cycloalkyl (C4 Gg) i'i.'iuxv<li.,uluiii<iti` 2.110 i>/s'4'^.-Buryl cydohoxyl peroxydtcaibonate 2 111 Acetyl cyclohexyl sulphonyl peroxide 2.112 Poiestois of Urn Mmoiuie R.COOOR, wheie H, and R, are alkyl, aryl, alkylaryl, alkoxy up ImUhium .athsiilnieif alkyl, aryl, alkylaryl of alkoxy (C,-Cl0) 2.113 Mixed peroxide pen aihnnatns of smifluro fi,()COOUOCR, where H, and R, are alkyl, aiyl, jlkylaiyl. ui nlkoxy. oi lujIogtNt substituted alkyl, aiyl. alkylaryl, or dlkoxy (C2-Cl(f) 2.114 Hydrogen peroxide 2.2 Polymerization inhibitors Ttjo total residues of polymerisation inhibitors and^hftir decomposition products shall constitute less than 0 6l*ft by weight oFthia finished polymer 2 3 Emulsifying agents The total residues of Ihe emulsifying agents listed m this section shall constitute less than 3 0% tiy weight of the finished polymer. The residues Of the following emulsifying agents may be present: 2.301 Alkyl and alkylary! sulphates of sodium, potassium and ammonium, the alkyl group containing C1fl-CM 2.302 2.303 2.304 2.305 Alkyl and alkylaryl sulphnnutos of sodium, potassium and ammonium, the alkyl group containing CI0 r.,, I Alpha hydroxy octadecane sodium sulphonate Sodium, potassium and ammonium salts of sulpho-succinic acid and its monoand di-esters with saturated monohydne aliphatic alcohols C,-Cw Sodium, potassium and ammonium salts of saturated aliphatic acids above C, Esters of sorbitol or of soilman with sanitated or unsamraled aliphatic acids above C, Calcium, sodium, potassium and ammcinium salts of hydroxyltc fatty acids C,,-C,, end their sulphonyl or acetyl derivatives Products of cnnduniiuhOM of ethylene oxide with monobasic aliphatic acids C,,'C,, and their sodium and ammonium sulphates Products of condensation uf ethylene oxide with monohydric aliphatic ate i.hnls C,-C#u .iiul itiuii sodium and ammonium sulphates Rmducls uf uiniloiisainin n| ciliyk tic ixuile wilh ulkylphenoli. having alkyl .iroufi!, C, ,imi ahovi, ,ml ihen kIniiii ,nul ammonium sulphates I '< ifyi ixyrtiryk'fK? ,nihil.ii t uuum I'liiiliu I:. m| i iintiiMis.iliMh ill rihylcMr omiIu with alkyl and Uuilkyl omunni C, t`M Pally alcohols C1Q Suspension agents * BFG09457 CSOfrOTTZ The Plastics Institute of Australia Inc. Otficu 1i/ f-H/rfty Sirutit St Kiida Vic 3162 Phone 534 8041 Address correspondence; PO Boh 131 St Krlda West 31B2 February 13, 19Q1 Hr G Warner BFGoodrich Chemical Ltd PO Box 107 ALTONA, 3010 Dear Graeme, It is a long time since you asked the question about BISPHENOL. However, The British Plastics Federation just responded to my question. I have attached a copy of their letter and trust the Information contained therein is in time to be of assistance to you. Yours sincerely, 0 LA FONTAINE National Divisions Manager BFG09458 h" K* O O cd The British Plastics Federation Rvguired Office 5 Bnlflrave Square London SW1 X 8PH A con>p*rty hnnd by BUr*ntM RifliiUrcd in Engltrut No 2fi2tiSJ 4ch December 1980 1 2 FEB 1981 Totophone 01-23&9483 Tltigr*(m Platted London SW1 Tolax 8961628 Pl*fdG &. La Fontaine Esq., National Divisions Manager, The Plastics Institute of Australia Inc., 157 Fitzroy Street, St * Kilda, Vic* 31B2, Australia. Dear Barry, Dr. Holnes-Walker has passed your letter of 21st November to me for attention. According to our Code of Practice for Plastics in Food Contact Applications, which we publish in cooperation with the British Industrial Biological Reaearch Association, BISPHENOL A is considered a safe additive for use in such applications* It is actually identified as an additive for polyesters (with a maximum level of 7QZ W/W of final compound) suitable for use in contact with all food products* I trust this information may be of help to you. Yours sincerely. C.C, Parkhouse Assistant Director Head of Technical Division BFG09459 g O APPENDIX UNION CARBIDE LITERATURE ON BISPHENOL A (F409Q0B) 60>0TT 13 Contents t Page Introduction......................................................................................... ... , 1 Typical Physical Properties..........................................................................2 Specifications and Typical Analyses, 3 Applications........................................................................................... 3 Toxicological Properties...................................... ,.................................. 5 FDA Status . . . , ................... ...................................... ............... .. . , . 5 Storage and Handling................................................................................. 5 Precautionary Labeling .............................. 6 Shipping Data 6 Test Methods for Blsphenol A.....................................................................7 1104095 TUI* information la not to t> taken * a warranty or rapraaantation for which w* amm* legal raappmibilitv nor aa parmiulon or rfcommandatiOn to practice any ptfht*e Invantlgn without a ifcenM. It i* offarad folaly for your egnsidaration, Invattieatlon and Ifleation, UCAH, UDEL.and UNION CARBIDEV* ragintarad tr#o marK of Union Carole Corooratlon, U.S.A, 1973 by Union Carbid* Corporation, UNION CARBIDE CORPORATION * CHEMICALS AND PLASTICS 270 PARK AVENUE, NEW YORK. N.Y. 1007 BFG09461 Bisphenol A 4,4'-lsopropyli<ione diphencjl Chemical Abstracts Registry No. 80-05-7 UCAR Bisphenol A UCAR Bisphenol A-UHP Introduction UCAR Bisphenol A is used as an inter mediate for the production of a wide variety of re$ins and plastics. Two UCAR Bisphenol A products are offered by UNION CARBIDE, in order to assure the requisite quality for any particular application. Both products possess Bisphenol A (4,4'-isopropylidene diphenol) contents of greater than 99 per cent and 2,4'isomer content of less than 0.5 per cent. These high quality products can provide eco nomic benefits to the consumer that are not obtainable from lower quality Bisphenol A. UCAR Bisphenol A-UHP, the higher qual ity product, was developed especially for use in the production of polycarbonate resins. Bisphenol A possessing very low color is re quired for this application. It can also be used to advantage in other applications, especially those involving exposure to the most de manding processing and operating conditions. SGOfcOTTZ BFG09462 t Typical Physical Properties Structural Formula Empirical Formula ...................................... .. . ,............. Molecular Weight ............. ................................................ Appearance . ..................................................................... Odor......................................................................................... Specific Gravity ................................................................... Bulk Density, Flake ......................................... .. .................. Boiling Point ......................................................................... Vapor Pressure at 170C.............................................................................. at 230C.............................................................................. Solubility, approximate (g./100 y. solvent at 25C.) Acetone .............................................................................. Benzene............. ................................................................ Carbon Tetrachloride ................................................... Ethyl Ether.................................... .................................. Heptane...................................... ....................... ............... Methanol ................................................. .. ................... Toluene.............................................. ,,............................. Water .............................................................................. Flash Point, Cleveland open cup (ASTM Method D 92) CiSH1602 228.28 White flakes or prills Mild phenolic 1.195 at 25/25 C. 36-41 Ib./cu. ft. 220*0. at 4 mm. Hg 0.20 mm. Hg 7.00 mm. Hg >120 Qr 0.2 g. <0.1 g. >110 g. <0.1 g. >120 g. 0.2 g. <0.1 g. 405 F, N BpG09463 .1.10409 Specifications and Typical Analyses Specifications*11* for the two grades of UCAR Bisphenol A are given below. Typical analytical results, using the methods described later in this booklet, are also shown for comparison purposes, Specification Requirement Freezing Point, C., (dry basis) APHA Color (35.5g./S0 ml. methanol) Phenol Content, % by wt. Water Content, % by wt. IrOn. ppm. Ash, % by wt. (a) Subject to change without notice. UCAR BISPHENOL A Specification Limit Typical Analysis 155.0, minimum 100, maximum 0.20, maximum 0.15, maximum 1.5, maximum 0,02, maximum 156.0 60 0.15 0.12 <0.5 <0.01 UCAR BISPHENOL A-UHP Specification Limit Typical Analysis 186.5, minimum 25, maximum 0.10, maximum 0.15, maximum 1.0, maximum 0.02, maximum 156.5 15 0.05 0.10 <0.5 <0.01 Applications A. Polymer Applications can be built into epoxy resins and other 1, Epoxy resins Production economies materials by the use of chlorinated or may be possible in making liquid epoxy brominated UCAR Bisphenol A. resins using UCAR Bisphenol A with its 2. Polycarbonates UCAR Bisphenol A-UHP low impurity (including trisphenols) was developed especially for use in the content. Under some circumstances, this manufacture of polycarbonate plastics. permits use of a lower excess of epi- Although the other grade is also useful chlorhydrin to obtain a resin of given viscosity; or, conversely, a lower viscos ity, more easily handled product is ob for the production of this resin class, ultimate performance requirements are most readily achievable with the UHP tained at a given epichlorhydrin/UCAR product. Bisphenol A ratio. UCAR Bisphenol A 3. Polyester resins As an intermediate in also provides solid epoxies which are the production of alkoxylated and sharper melting and have lower melt vis hydrogenated derivatives, useful diols r cosities, permitting the use of more filler for a given consistency, Flame-resistance for specialty polyester resins are ob tained. 1104098 4 bFG09464 1 APPLICATIONS (Continued) 4. Phenolic resins UCAR Bisphenol A-inodfied phenolic resins and UCAR Bisphenol A-formaidehyde resins possess advan tageous properties for certain applica tions, They are used in paints for exterior use, brush enamels, transport finishes. Household enamels, and high quality printing inks, Non-esterified Bisphenol A-formaldehyde resins are used in auto primers and surface finishes, abrasive binders, office furniture finishes, under coats. and wrinkle finishes. It is also used as a modifier for heat reactive, oilsoluble phenolic resins, and epoxy-modi fied Bisphenol A-formaldehyde resins. 5, Polysulfone UDEL Polysulfones are a family of tough, rigid, high strength thermoplastics which arc derived from UCAR Bisphenol A. They are high per formance injection molding and extru sion materials. (>. Phcnoxy resins The condensation of UCAR Bisphenol A with epichiorhydrin yields a family of linear polymers that find extensive use in coatings appli cations. 13. Additive Applications UCAR Bisphenol A, in addition to pos sessing utility as a building block for many polymeric systems, also finds successful ap plication. as an additive for many diverse purposes. Some of these are listed below. 1. Antioxidant and Color Stabilizer Per formance of the following systems has been reported to be enhanced by Bis phenol A1. Butyl rubber, Brake fluids. Hydraulic fluids. Hydrocarbon oils, Oxo alcohols and their esters. Plasticizers. Polyethylene. Resins and rubbers. Soaps. Vinyl chloride resins. UCAR Bisphe nol A inhibits peroxide formation and color development. In combination with a metal salt or hydrogen chloride acceptor type stabilizer, it retards color development, loss of transpar ency, and degradation of strength characteristics. 2. Bactericide 3. Dycabilify enhancer Especially for poly esters and polyolefins. 4. Electrotinning of Iron 5 Flame resistance Chlorinated and brominated UCAR Bisphenol A are used in polycarbonates, polyesters, and epoxy resins. Chlorinated Bisphenol A deriva tives are also used in vinyl resins and cellulosies. 6, Fungicide For textiles and asphalttreated cable coverings. 7, Hydrogenated Bisphenol A Diol for polyester resins. s. Leather tanning agent Sulfonation of Bisphenol A-formaldehyde condensation products. 0. Plasticizer Diethers and polyphosphates are good in cellulosics, synthetic rubber compositions, vinyl polymers, and poly styrene. In vinyl wire insulation, UCAR Bisphenol A imparts superior retention of elongation after aging at high temper atures. 10. UCAR Bisphenol A propylene oxide adduct Used for polyesters with excel lent chemical resistance and high soft ening temperatures. I 1. Ultraviolet absorber 6&sfrttTT BFG09465 Toxicological Properties The toxicity of UCAR Bisphenol A is cstimated to be quite low when swallowed by humans, and should present no problems in regular industrial use. However, if large quan tities are ingested either wilfully or acciden tally, harmful effects can occur. When fed to rats, UCAR Bisphenol A was a little more tox ic than an equal quantity of isopropanol. The oral LD50 for male albino rats is 4.04 grams per kilogram of body weight. The oral LD5 0 for rabbits is 2,23 grams per kilogram of body weight. Skin contact Is only mildly irritating, and is not expected to result in harmful absorp tion. However, direct contact with it should be avoided. Accidental exposure should be re moved immediately by washing with soap and water. Eyes can be injured by the solid and by solutions in as low a concentration as 5 per cent. A one-per cent solution causes only irri tation. Accidental eye contact should be re moved immediately by flushing the eye with plenty of clean running water for at least 15 minutes. After emergency washing is com pleted, medical attention should he obtained immediately. FDA Status Bisphenol A FDA Food Addi tive Regulation iSrf^b for adhesives used in articles that contact food. Storage and Handling UCAR Bisphenol A products are sold in fluke or prill forms and are shipped in paper hags holding 50 pounds (net) and in hopper trucks or rail hopper cars. Trucks hold 40,000 pounds of product per Shipment, and hopper cars hold 180,000 pounds. Bulk shipments can be unloaded in var ious ways, but pneumatic conveying is gen erally used to transport the material from the truck or car to a storage bin. Ambient tem perature storage is suggested; a dry atmos phere (air or nitrogen) should be maintained in the storage bin. Pneumatic conveying sys tems should be designed to preclude the pos sibility of a dust explosion. Aluminum or stainless steel adequately grounded are suit able materials of construction for handling this product. BFG09466 1104100 s Precautionary Labeling Shipping bags containing UCAR Bisphenol A have the following warning and pre cautionary labeling that reflects the reason ably foreseeable hazards of the storage and handling for this product: UCAR BISPHENOLA WARNING! CAUSES EYE INJURY AND SKIN IRRITATION Do not get in eyes. Avoid prolonged or repeated contact with skin. In case of contact with eyes, immedi ately flush with plenty of water for at least 15 minutes; get medical attention. FOR INDUSTRY USE ONLY Shipping Data D#tctrmine0 on typical commercial material Containers and net contents subject to change without notice Bulk * Hopper trucks of 40,000 pounds net weight Hopper cars of 180,000 pounds net weight Begs GO pounds each; polyethylene lined pallets, contain 45 bags each (2,250 pounds per pallet) truckload (bags), contains 18 pallets, or 40,500 pounds. Flash Point, Cleveland open cup (ASTM Method D 92) ................ Freight Description.................................... .......................................... Dangerous Article Description............................................................. DOT Label required................................................................................ 40B*F. isopropylidene Bisphenol None None BFG09467 T o lfc O T 't Test Methods for Bisphenol A l, FREEZING POINT A. Principle Freezing point is that tem perature at which the liquid and solid phases of a compound have the same vapor pressure, and, therefore, exist in equilibrium. The freezing point of a pure liquid is lowered by impurities, and this lowering is directly propor tional to the concentration of impuri ties present. Therefore, the tempera ture at which a compound solidifies is an indication of its purity. The freezing point of a solid is obtained by heating it above its melting point and measuring time vs. temperature as it cools down until solidification. B. Apparatus 1. Test lube, Pyrex, 25 mm. x 150 mm. 2. Dewar flask, Pyrex, 35 mm. (i.d.) x 50 mm. (o.d.) x 200 mm. (height), fitted with a #& rubber stopper with the center drilled out (#14 cork borer) SO that a ^5-mm. x 150mm. test tube can be suspended in the flask. 3. Thermometer, 14Q-16Q*C. in 0.1C. divisions, 76-mm. immersion. 4. Silicone bath fluid. 5. Stirrer, made by spot-welding a brass rod (1/16 inch or 1/8 inch diameter) to a 3/4 inch x 3/8 inch iron washer. 6. Beaker, 600 mi. C. Procedure 1. Dry the sample to a moisture con tent of 0.02 per cent, or less, by heating in an oven at 100UC. prior to determining its freezing point. 2. Add sufficient Bisphenol A to fill a 25-mm. x 150-mm. test tube to a depth of approximately 3 inches when the sample is molten. Insert the stirrer and thermometer into the tube, and place the whole assem bly into a silicone bath (600-ml. beaker) heated and maintained at a temperature of approximately 165C, 3. After the Bisphenol A sample has melted, quickly remove the test tube from the [65C. bath, and assemble in the Dewar flask. 4. Stir the sample in the test tube con tinuously (try not to splash or bring the washer above the liquid level) as it cools, and start recording the temperature at convenient intervals when the melt drops to 160C. 5. Continue recording the temperature until it drops below 15GPC. (the temperature will fall to a minimum li.e. supercool 1; rise to a maxi mum; remain reasonably constant as solidification takes place [socalled "plateau"]; or fall slowly, then fall again rapidly). 6. NOTE: If the amount of super cooling exceeds 0.5C., repeat the determination, and "seed" the mol ten sample at approximately 0.5C. above the expected freezing point by adding a few crystals of the solid sample. D, Calculation l. Plot a time-temperature Curve and extrapolate the freezing portion of the graph back over the region of supercooling until it intersects the liquid cooling curve. Report the in tersection point as the freezing point. f$ BFG09468 1104102 II. COLOR-APHA (Pt-Co) A Principle This method determines the apparent APHA (Pt-Co) color of a methanolic solution of Bisphenol A. This method does not determine the true APHA color, but measures the extent to which the sample absorbs light which passes through a blue filter. The absorbance of the methanolic solution is determined with a colori meter using the standard 23-ml. ab sorption cells and a blue niter. The apparent APHA color is read from a calibration curve prepared by measur ing the absorbance of APHA (Pt-Co) standard solutions under identical conditions as those used to measure the sample. This method is limited in applicability to clear solutions which have a hue similar to the APHA standards. B. Apparatus 1. Fisher Electrophotometer, or equiv alent colorimeter. 2. Blue Filter, Fisher No. 425-B or equivalent. 3. A matched pair of 23-ml, cylindri cal absorption cells (23-mm. optical path length). 4. Balance, 250-gram capacity, 0.1 g. sensitivity. 5. Erlenmeyer flask, glass stoppered, 125 ml. 6. Graduated cylinder, 50 ml. 7. Pipettes, 1, 2, 4, 6, 8, 10, 15, and 20 ml. C, Reagents 1. Methanol, anhydrous, Reagent A.C.S. The methanol must have a 1 color no greater than the distilled water used in the preparation of the calibration solutions. Use methanol from the same bottle throughout a series of determinations. The pho tometer must always be zeroed with the same methanol used to prepare the sample. 2. 500 APHA Platinum-Cobalt Color Standard Solution. This solution can be purchased commercially or prepared by dissolving 1.245 g. of potassium chloroplatinate (K2PtCl6) and 1.00 g. of cobaltous chloride hexahydrate (CoCh 6H2O) in a one-liter volumetric flask containing distilled water and 100 ml. of concentrated hydrochlo ric acid (HCl). Dilute the contents to volume with distilled water. I), Preparation of Calibration Curve 1. Prepare a series of APHA standards having colors of 5, 10, 20, 30, 40, 50, 75, and 100 hy pipetting I, 2, 4, 6, 8, 10, 15, and 20 ml. of the 500 APHA standard solution into 100-ml. volumetric flasks and dilu ting to volume with distilled water. 2. Measure the absorbance of each standard, using the Fisher Electro photometer, 23 ml. cylindrical cells and the blue filter. 3. Prepare a calibration curve by plot ting the absorbance of each solu tion versus its corresponding APHA color. Fv. Procedure I, Weigh 35.5 + 0.5 g. of sample into a 125-ml. glass stoppered Erlenmeyer flask. BFG09469 21104103 3 2. Using a 50-mi. graduated cylinder, add 50 ml. of methanol- 3. Swirl the methanol until the sample is dissolved, 4. Determine the absorbance of the sample solution, using the blue fil ter and 23-mi. cylindrical cells. 5. Read the apparent APHA color of the Bisphenol A sample from the calibration curve, and report this value. 111. FREE PHENOL A. Principle This is a method specifically for the determination of free phenol, and is not applicable for determina tion of the other "classical'* impurities in Bisphenol A. A separate gas chro matographic method is available for the analysis of Bisphenol A for "classicaf* impurities. This gas chromato graphic method involves the use of an internal standard. The use of an in ternal standard is necessary for quan titative determinations when the en tire sample does not elute from the chromatograph or gives no detector response. 8. Apparatus 1. Analytical balance, sensitive to 0.0001 g. 2. Gas chromatograph equipped with a flame ionization detector and a 0-1 mV recorder. 3. Syringe, 10 pi. 4. Chromatographic column, stainless steel, 6 ft, x 0,25 inch, "Siliclad" treated, and packed with 80/100 mesh "Chromosorb" 101 (JohnsManville, Celite Div ), 5. Pipette, 10 ml. 0. Reagents 1. Acetone, reagent grade. 2. Cumene, reagent grade. 3. Phenol, reagent grade. 1). Instrument Parameters 1. Column temperature ........... * 230C- 2. Injection port isothcrmal temperature ............. 180DC. 3. Detector temperature , 310C, 4. Helium flow ............. 50 cc. per minute 5. Air flow . . . ................ 425 cc, per minute 6. Hydrogen flow ........... 55 cc. per minute 7. Sample volume ........... lOpl 8. Chart speed.................. 1 inch per minute F. Determination of Calibration Factor for Phenol Relative to Cumene (In ternal Standard) 1. Determine the response of the de tector to phenol relative to cumene (relative calibration factor) by pre paring and chromatographing mix tures of known composition which approximate the concentration range of interest, 1 Preparation of Internal Standard Sol ution 1. Add some cumene to a 4-dram vial, and cap with a screw top containing an eye dropper. Weigh the vial con taining the cumene to 0.0001 g, on an analytical balance. IAj T frO T T Z BFG09470 9 2. Accurately weigh, by difference from the vial, approximately 0 05 g. of cumene into a 500-ml volu metric flask. Record the weight of cumene added to the flask (Wg). 3. Dilute the contents of the volumet ric flask to volume with acetone, G. Determination of Phenol Content in UCAR Risphennl A 1. Weigh an 8-dram vial. 2. Add 1.00 0.01 g. of Bisphcnol A sample to the vial. 3. Pipette 10 ml. of internal standard solution (see P) into the vial which contains the Bisplienol A, cap the vial, and shake to dissolve the sample. 4. Inject 10 jri of the solution into the gas chromatograph using the chro matographic parameters listed in D. 5. Measure the areas of the cumene and phenol peaks using the same technique employed in F. H. Calculation 1. Calculate the per cent by weight of free phenol in the sample, using the formula: ATFp/cSxlOO % phenol = MTs A = area, in arbitrary units, of phenol peak T = recorder attenuation for phenol peak Fp/c ~ calibration factor for phe nol relative to cumene (sec E) S = grams of cumene in 10 ml. of internal standard solu tion (i.e, grams of cumene added to the sample) (Ws/50). As = area, in arbitrary units, of cumene peak Ts = recorder attenuation for cumene peak IV, water A, Principle The water content of Bisphenol A is determined by direct titration with Karl Fischer reagent to an electrometric endpoint. Karl Fis cher reagent is a standard solution of iodine and excess sulfur dioxide dis solved in a solvent mixture of pyridine and methanol. In the presence of wa ter, iodine is reduced by sulfur di* oxide according to the following sim plified equation: I2 + S02 + H20 + CH30H + 3C5H5N--2C5H5NII+I + Cs Hs NH0S020CH3 R. Apparatus 1, Any commercial or laboratory as sembled Karl Fischer apparatusThis equipment should consist of an automatic burette with reservoir for the titrant, a titration cell equipped with a pair of platinum electrodes and magnetic stirrer, and a microamrtieter connected so as to measure the current between the electrodes. Contents of the burette and titration cell must be protected from the atmosphere with drying tubes. 2* Analytical balance, sensitive to 0.0001 g. 3. Balance, top-loading. 2110$lO 5 BFG09471 10 ) C. Reagents F = water factor, grams of water 1. Karl Fischer Reagent - Commercial consumed by 100 ml of Karl single solution, stabilized, minimum Fischer reagent. 5.0 mg. HjO/ml. diluted with anhy- (1W ~ grams of water added to the drous pyridine to give a solution titration cell in paragraph 4. with a factor of approximately 2.0 V = milliliters of Karl Fischer re mg, H^O/ml. Store the diluted re* agent required to titrate the agent in the automatic burette res* water added (paragraph 6). ervoir, 2. Methanol, anhydrous. 3. Pyridine, reagent grade. F, Procedure 1. Add a sufficient amount of a 1;1 mixture of anhydrous methanol; pyridine to the titration cel! to D, Determination of Water Factor cover the electrodes. 1. Add sufficient 1:1 mixture of anhy 2. Replace the drying tube, turn on drous methanol and pyridine to the the magnetic stirrer, and titrate the J titration cell to cover the elec trodes. contents of the titration cell with Karl Fischer reagent from the auto 2. Close the cell, start the stirrer, and zero the microammeter. matic burette until the microam meter reads the same value rej 3. Titrate the contents of the cell to the visual endpoint with Karl Fis corded for the standardization (D3). cher reagent and record the reading obtained on the microammeter. At the endpoint, the mieroammeter 3. Weigh out on a top-loading balance at least 10 g. of Bisphenol A sample. Record the sample weight (Ws). reading should be stable for at least 10-15 seconds. 4. Introduce the weighed sample into the titration cell, replace the drying 4. Accurately weigh into the titration tube, and titrate the contents of the vessel approximately 0,05 g. of dis flask with Karl Fischer reagent until tilled water. the endpoint (as indicated by the 5. Titrate the water with the reagent mieroammeter). until the mieroammeter reads the 5. Record the volume of Karl Fischer same value recorded for the stan reagent required to reach'the end dardization (paragraph 3). The point (V). reading should remain constant for at least 10-15 seconds. F. Calculation 6. Record the volume of titrant con sumed (V), and calculate the water factor using Vx F % water = Gw 100 F=-- V= milliliters of Karl Fischer re agent required to titrate the 1104106 BFG09472 11 water content of the sample (E5). F = water factor (D6). W, ^ sample weight in grams (3). V. IRON A. Principle The Bisphenol A sample is ashed. Iron present in the original sample remains as iron oxides, which are dissolved, then reacted with thioglycolic acid to form a colored complex. The intensity of color pro duced is measured with a spectropho tometer, and related to concentration with a calibration chart. B. Apparatus 1. Analytical balance, sensitive to 0,0001 g, 2. Crucibles, porcelain, glazed, size 2. 3. Muffle furnace. 4. Crucible tongs. 5. Hot plate. 6. Bunsen burner, adjustable. 7. Tripod, cast-iron, single ring. 8. Triangles. 9. Desiccator charged with an active desiccant such as anhydrous CaClj. 10. Spectrophotometer capable of mea suring absorbance at 535 nm.. Cary Model 14, or equivalent. 11. 10.0-cm. matched optical cells. 12. Pipettes, 0.5, 1, 2, 3, and 5 ml. 13. Graduated cylinders, 5 and 10 ml. 14. Volumetric flasks, glass stoppered. 50 ml. C. Reagents 1. Dilute hydrochloric acid - con centrated hydrochloric acid diluted 1:1 with distilled water. 42 2. 3% Thioglycolic acid solution - 30 ml. of thioglycolic acid dissolved in one liter of distilled water. 3. Ammonium hydroxide, concentra ted. 4. Standard iron solutions for prepara tion of calibration chart'. A. 0.875 g. ferrous ammonium sul fate [FeSO4*(NH4)2SO4-6H20] dissolved in a 250-ml. aqueous solution containing 10 ml. con centrated hydrochloric acid. (1 ml. Solution A contains 500 Mg Fe+ *,) B. Pipette 10 ml. Solution A into a 500-ml, volumetric flask, and di lute to volume with distilled water. (1 ml. Solution B contains 10 Mg Fc++ and is equivalent to 1 ppm. Fe fora 10-g. sample.) D. Preparation of Calibration Curve 1. Pipette 0, 0.5. 1, 2, 3, and 5 ml. of Standard iron solution B into a series of 50-ml. volumetric flasks. 2. Add 5 ml. of 1:1 hydrochloric acid. 10 ml. of 3% thioglycolic acid solu tion, and 5 ml, of concentrated am monium hydroxide to each flask. Dilute the contents of each flask to volume with distilled water. 3. Measure the absorbance of each solution at 535 nm. using the spec trophotometer and 10.0-cm. cells, 4. Subtract the absorbance of the blank (0 ml.) from the absorbance for each standard and prepare a cal ibration curve by plotting net absorbance vereus micrograms of iron in each standard. BFG09473 u m n tz E. Procedure 1. Weigh 10 g. of sample into a dean, dry, #2 porcelain crucible, 2. Place the crucible on an electric hot plate and gently boil off the Bisphenol A. 3. Transfer the crucible to a tripod equipped with a triangle. Slowly heat the contents of the crucibles with gas burners until the sample has charred completely and most of the free carbon has been burned, 4. Place the crucible and residue in an electric muffle furnace at 50(TC. for several hours. 5. Remove the crucible from the oven and cool. 6. Add 5 ml. of 1; 1 hydrochloric acid to the crucible, warm on a hot plate, cool, and filter into a 50-ml. volumetric flask. Wash the crucible and filter paper well with distilled water, and also collect the washings in the volumetric flask. 7. Add 10 ml. of a 3 % aqueous solu tion of thioglycolic acid to the flask. 8. Add 5 ml. of concentrated ammo nium hydroxide to the flask and di lute to volume with distilled water. Shake the contents of the flask thoroughly, 9. Using 10.0cm, cells, measure the absorbance of the solution at 535 nm, with a spectrophotometer against water in the reference beam. Also run a blank vs. water at 535 nm. and correct subsequent calcula tions for any cell imbalance. 10. From the calibration curve, read the mierogrums of iron corresponding to the absorbance of the sample. F. Calculation 1. Calculate the iron in the original sample by: ppm. iron = micrograms iron from calibration curve sample weight in grams VI. ASH A. Principle The residue remaining after heating the Bisphenol A sample in a muffle furnace at 500C, is the ash (i.e., nonvolatile) content of the sam ple. The low ash content of Bisphenol A requires that a large amount of sam ple be burned. B. Apparatus 1. Analytical balance, sensitive to O.O001 g. 2. Crucibles, porcelain, glazed, size 2. 3. Muffle furnace. 4. Crucible tongs, 5. Bunsen burner, adjustable. 6. Hot plate. 7. Tripod, cast-iron, single ring. 8. Triangles, 9. Desiccator - charged with an active desiccant such as anhydrous CuClj. C\ Procedure 1. Condition two, size 2 porcelain cru cibles in a muffle furnace at 500Cfor l hr. 2. Remove the crucibles from the muffle furnace, and place in a desic cator to cool. 3. When cool, weigh the crucibles to 0,0001 g, on an analytical balance <w,). BFG09474 8 0 TfeO TT2 13 r 4-. Introduce approximately 25 g. of sample into each crucible, and re weigh them on the analytical bal ance (W3), 5. Heat the crucibles and contents on a hot plate adjusted to provide slow volatilization. The temperature of the hot plate should not exceed 250C. so as to avoid splattering of the sample. (Use a well-ventilated hood for this operation.) Continue to heat the sample on the hot plate until the crucibles arc free of liquid. 6. Carefully transfer each crucible to a tripod equipped with a triangle. Slowly heat the contents of the cru cibles with gas burners (avoid splat tering) until the sample has charred completely, and most of the free carbon has been burned. 7. Place the crucible and residue in the electric muffle furnace, adjusted to SOO^C. Locate the crucibles at least 2.5 inches from the door. 8. Continue heating in the muffle fur nace overnight (or until an appar ently carbon-free residue is ob tained). 9. Remove the crucibles from the muffle furnace, place in the desicca tor, and allow to cool. 10. When cool, weigh crucible plus res idues on the analytical balance to 0.0001 g.(W3). L). Calculation 1. Calculate the per cent ash for each ^determination as Follows; (W3 - Wi)100 %ash= (Wi-Wi) w, =g. weight of empty, condi- tioned crucible W2 = g. weight of conditioned cru cible plus sample W3 =g. weight crucible plus residue VII. DETERMINATION OF BlSPHENOL A AND IMPURITIES A. Principle This method involves the preparation of trimethylsilyl (TMS) ether derivatives of the sample com* pondhts prior to gas chromatographic analysis. Preparation and chromatog raphy of stable, volatile derivatives is a commonly used procedure for the determination of relatively nonvolatile (c.g, trisphenol) or heat sensitive com pounds (c.g, Bisphenol A). Bis( trimethyIsilyl)acetamide (BSA) reacts with the active hydrogens of a variety of compounds to form the cor responding TMS ether derivatives. The phenolic hydroxyl groups of Bisphe nol A and of the major, high boiling impurities in Bisphenol A are quanti tatively converted to TMS ethers under the conditions of this method. Reaction Of the phenolic hydroxyl groups with BSA is illustrated by the following general equation: ^.OSi(CH3)3 ROH + CH3C --- ^NSi(CH3)3 (BSA) o ROSi(CH3)3 + CH3C VNMSi(CH3)3 Low boiling contaminants (e.g. wa ter and phenol) frequently present in BFG09475 14 601 tnyi i low concentration in Bisphenol A cannot be determined by this method. The water content of Bisphenol A can be determined by Karl Fischer titra tion (See IV), and the phenol can be determined by the separate gas chro matographic procedure (See HI). B. Apparatus 1. Analytical balance. 2. Gas chromatograph, equipped with a dual flame ionization detector and a 0-1 mV recorder. 3. Syringe, 5 Mi4. Chromatographic column, stainless steel, 6 feet x 0.25 inch, "Siliclad'* treated, and packed with \% GV-1 on 80-100 mesh "Chromosorb" G (HP), 5. Two-ml. serum bottles with rubber septum caps. 6. One-ml. and 10 ml. hypodermic syringes. C. Reagent 1. N,0-Bis(trimethyl$ilyl) acetamide. Only use reagent packed in glass sealed ampoules, D. Instrument Parameters 1. Column temperature ,. 200*C- for 18 minutes (or until two minutes after the 4,4*-Bisphenol A derivative elutes from the column), then programmed to 275C at a rate of 2QC./minute and hold. 2. Injection port temperature .. 300C. 3. Detector temperature . . 4. Helium flow . . . 5. Air flow ......... 6. Hydrogen flow. 7. Sample volume. 8. Chart speed . . . 9. Recorder 300*0. 65 ec./minute 530 cc./minute 65 cc./minUte 0.5 m1 of deriva tive preparation lA inch per minute 0-1 mV R. Calibration Factors 1. Determine calibration factors for 2,4'-Bisphenof A, Dianin's Com pound, 4,4'-Bisphenol A, Trisphenol, and other compounds of inter est by preparing and chromato graphing mixtures of known com position which approximate the concentration range present in the samples to be analyzed. F. Procedure 1.Add 0.10 g, of sample to a 2-cc. serum bottle, and stopper the bot tle with a rubber septum cap. 2. Partially evacuate the serum bottle with a 10-cc. syringe. 3. Add 0.5-cc of N,G-bis(trimethyR silyl) acetamide to the serum bottle using a 1-ml. hypodermic syringe. (NOTE: Only use reagent from a sealed glass ampoule.) 4. Occasionally swirl the contents of the serum bottle until the sample is completely dissolved (usually 10-15 minutes). 5. Withdraw 0.5 pi of the prepared de rivative, and inject into the gas BFG09476 o iffro n s 15 chromatograph using the irtstru. ment parameters listed in D. 6. Measure the areas of sample-related peaks using an acceptable tech nique. (NOTE: Do not measure the reagent-related peaks that elute during the first several minutes of the chromatogram.) G. Calculation l. Calculate the per cent by weight of each sample component using the formula: AjTjFj C* (Ac1TClFc1) + (AC2Tr3Fc2) + r - - + (ACnTCnFCn) Q = per cent by weight of component i A| = area, in arbitrary units, under the peak of component i Ti = recorder attenuation for peak of component i Fi = calibration factor for component i, relative to 4,4!-BisphenoJ A Ac i iAcj *Acn " area under the peaks of components 1,2, and n Tc i ,Tc 2 >TCn 86 recorder attenuations for peaks of components 1, 2, and n im o rts BFG09477  Discover, also, how [ can best serve you with its - High quality ^ -- Cumene - Phenol - Acetophenone - alpha-Methyl Styrene Convenient, Fast and Dependable Delivery, Dollar Savings Through Bulk Shipments. Efficient Customer Service, Technical Representatives -- technically edu cated men with industrial "know-how1* ready to serve you and assist you with any particular need you may have. Well-versed Marketing -- Sales Technology Teams. Committed Programs in Product and Process Research and Development - to produce new products that may help you improve your present applications and develop new ones. sn iK irr BFG09478 i: THE DISCOVERY COMPANY Safes Offices UNION CARBIDE CORPORATION CHEMICALS AND PLASTICS 270 PARK AVENUE, NEW YORK, N.Y. 1001 7 United ATLANTA, GEORGIA 30329 ...................................... 17 Executive Park Or.....................................404-633-6161 BALTIMORE (MOORESTOWN, N.J. 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SALES OFFICE).............. *.............................................415-766-1000 FROM IDAHO, NEVADA, OREGON, UTAH. OR WASHINGTON.................................................800-227-0&01 SOUTHFIELD. MICHIGAN 48076 .............................26500 Northwestern Hway..........................313-354-0800 Affiliates Pan America Eamimrn Europe Africa ARGENTINA .........................Union Carbide inter-America, Inc., Buenos AJns BRAZIL .................................. Union Carbide do Brasil S. A., seo Paulo, Rio da Janeiro CANADA.......................... . Union Carbide Canada Ltd., Amherst, Calgary, Fort Garry, Lechlne, Lindsay, Surrey, Toronto, Vancouver CARIBBEAN ...... . Union Carbide Inter-America, Inc., San Juan, Rterto Rico CENTRAL AMERICA .......... Union Carbide inter-America, Inc., Panama City, Panama CHILE .........................Union Carbide Comerciel Chile Ltd., Santiago COLOMBIA .......................... .Union Carbide Colombia, 5. A., Bogota ECUADOR............................. Union Carbide Ecuador. (LA.. Quayaquii MEXICO ............................... Unlcarb Comanbal, $. A. da C. V., Mexico, D. P., Guadalajara, Monterrey PERU ................................... Union Carbide Inter-America, Ine., Lima VENEZUELA .........................Union Carbide de Venezuela, C. A, Caracas WESTERN HEMISPHERE ....Union Carblda Inter-America, Inc., New York, N.Y, AUSTRALIA ................... Union carbid* Australia Ltd., Sydney, N. S. W. HONG KONG ...................... Union Carbide Asia Ltd.. Hong Kong INDIA ........................... Union Carbide India Ltd., Calcutta, Bombay, Madras, New Delhi INDONESIA........................... P.T. Union Carbide Indonesia JAPAN .............................. Union Carbide Services Eastern Ltd., Tokyo NEW 2EALAN0................... Union Carbide New Zealand Ltd., Auckland PAKISTAN ........................... National Carbon Co. (Pakistan) Ltd., Karachi PHILIPPINES ........ ............. Union Carbida Philippines Inc., Manila SINGAPORE ,,,,...... ............. Union Carbide Asia Ltd- TAIWAN ................................Union Carbide Chin* (Taiwan) Ltd., Taipei THAILAND ........................Union Carbide Thailand Limited, Bangkok, Thailand AUSTRIA ..................... ......Union Carbide Austria Qes. mbH,, Vienna BELGIUM ....................... . Union Carblda Belgium N.V., Brussels FRANCE ........................ . Union Carbide Europe s.a., Succursale Freneaisa, Puteeux-Paris GERMANY............................. Union Carbide Deutschland, GmbH, Dusseldorf GREECE ................................Union Carbide Hellas S.A.. Athens. Greece ITALY .................................... Union Carbide Italia S.pA. Milan NETHERLANDS .................. Union Carbide Belgium N.V., Amsterdam SCANDINAVIA ....................Union Carbide Norden A.B.. Stockholm, Sweden SPAIN........... Union Carbide Iberica S.A., Madrid SWITZERLAND ..... Union Carbide Europe s.a.. Geneva UNITED KINGDOM............. Union Carbide U. K. Limited, London. Manchester. Rlekmansworth: England ........ AFRICA (EAST)................... Union Carbide Able* Ltd.. Nairobi, Kenya AFRICA (SOUTH) ............... Union Carbide South Afriea (Pty) Ltd.. Johannesburg. Capetown. Durban; Republic of South Africa AFRICA (WEST)....................Union Carbide Africa Ltd., Abidjan, Ivory Coeat MIDDLE EAST...................... Union Cerbide Middle East Ltd., Athens, Greeco Cw t'--' C? ^ p* F-40900B 6/73--BM BFG09479 Printed in U.3.A. DATA SHEET ON METAL CONTENT OF UNLUN CARBIDE PRODUCTS BFG09480 gj routir.eiv i.'tvt our huik uU' si!1'v'or-irs^ and 1 ixr^ > iof iTi'-Cii:- .:> rw'.5|,pf.-r. lent ,iJ|d iiiiYt'UO. . I >iii > !..'] 1 ,i r 11 : n, ,.i jI iJ,:.. Or;' N);llll] 1 j Cl 11 JY:j Ll'njof con: 1 (ViL.) I'l-ndi [ioi'iS deriuicd ro ii'.i :'i!. I'ii/. t.: =; i, 'ihlis, An* arc cot'1 idem d'..r i i 11 - * .I. ;i:J n.n Jemirif/ i:.:in.iui .'invoiMr.v rY :in-M irrnr . !:;. 'i'!1 s belie! is su[jj:ot ii'il :,iv c r : mki 'i . iiuii',li i mi j . ,'|iic:-i -:.i , 'u.1 .! p:m- nic n. V nc i a love). in ri'.'.. i -.him Lvltm.. !<> in . n.h ,i ci.,nct.,mi'at it1.; i hjwrr die minimum the met tod used wil dvicimmc. The methods used in obtaining the umdyiieal data arc: 1T, Mercury' \m:. dc.-j-.-: mi:^ 1 using "!l iik'k-s.s" atmum absorption Using it badmi n U:: 1 COMljiC ll.-nror wlf. I'n UU'W..-!'V ho-i'i C:. r -J 1 li). 2. Zinc and cadmium ;\cll dewnium-i! nr atomic absorption. 3. Arsenic was dt u nmn^tl nsinjj the Codex colorimetric procedure -- (silver aielhvldi iIiiociLrbLimjtc). 4. Al! other clemtmrs were determined by emission spectroscopy. METALS CONTENT --PPM 1 Ae&tor.v Butyl Phenol 4T Acetate Butyl Cr.lLO^OLVE CELLCSOlVi; Acetate Isopropyl Acetate Isopropanol Methyl Ethyl Keiono Methyl lsobutyl Ketone M oncoi hanolfl mine SYNASGl Solvent PM-3224 TERG1TOL NTX BAKELITE Phenolic Resin CKM 2400 QAKtUTt EpoV Reem EJtl-2774 RAKI-ITE Vinyl Resin VMCC CAKBOWAX H'G-600 CFLIO&ZE HEC Q? 30CH CELI.CSI2.E HEC OP 4400 UCAR Latex i?0 CCAR Litp.y. 350 t'CAR L-itex 2 30 end u {3 13 c Uui e Vi Q <U o.i <1.0 <0, o. f3r! Ci X1 U <0,1 <0. 1 1 j Capper eoL. "O UF3MI CeaT<l. I"UdD1 ad> ci3 t3r uh4_jl 5 'JL 5 c 0.1 <0,1 <0.) <0.1 <0.05 <n.l <0.1 <'J: ta O.-'j 0.5 <1,0 <0, OS <0.1 o.a O.b <0.1 <0,1 <0.1 <0.05 0, i <3.1 j,7: ^0.1 <1.0 <0,05 <0,1 0.4 <0.1 <0.1 <0.1 <0.1 <0.05 <0.1 <0.1 0.17 <0.1 < 1.0 <0,05 <0.1 <0,1 < 0.1 <0.1 <0.1 < 0. r. 5 <0.1 <0.1 <o.or <0.1 <1.0 <J .05 <0.1 0.1 0.1 <0.1 <0,1 <0,1 <0.05 <0,1 <0.1 0,4 <0.1 < 1.0 <0.05 <0.1 <0.1 0.1 <0.1 <0.1 <0.1 <0.05 <0.1 <0,1 <0.00 0.1 <1,0 <0.1 <0,1 0.1 <0.1 <0.1 <0.1 <0.05 0.1 <0.1 <0.1 <1.0 <0,35 <0,1 <0.1 <0.1 <0.1 <0.1 <0,1 <0.05 <0.1 <0.1 0 .0 3 <0.1 <1.0 <0.05 <0.1 0.1 <0.1 <0.1 <0.1 <0,1 <0.05 <e.l <0.1 0.05 <0.1 <1,0 <0,05 <0.1 <0.1 Q.l <0.1 <0.1 <0,1 <0.05 <0.1 <0,1 1.25 <0.1 <1.0 <0.05 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <o.os <0,1 <0.1 0,1 <1.0 <1.0 <0.05 0.6 < .0 <0.0S <1.0 <1,0 <1.0 0.5 0.1 <0.1 <1.0 <1.C <0.05 2.0 0.1 0.6 <0.1 <0.05 <0.1 <0.1 <0, 02 0,4 0.1 n.s 0.2 <1.0 <0,05 <0.1 0.7 0.3 0.2 <0,1 <0,1 <o.os 2.0 <0.1 0.24 3.G <1.0 <0.05 1.9 0.4 2.6 3.0 0.2 <0.1 <0.05 0.8' 0.1 ' 0.7 1.7 <1.0 <0,05 <0.1 <0.1 G.O <1.0 <0.05 <1 2 fi.Q <1.0 <0.05 <1 2 0.5 <1.0 <0.05 <0.1 <0,1 0.5 <1.0 <n.cs <0,1 0.1 0, o <..0 $.05 r.j 0.2 0.6 <0.1 <0.1 0.1 <0.03 1.0 <0.1 <3.Cil 0 1 <1 <1 <0,05 1 0.25 4 l <1 <1 <0.05 <1 0.25 0.3 1.5 <0.1 <0.1 <0.05 <0,1 <G.i '). ? 0.4 <0.1 0.1 <0.1 <0.05 -,0.1 <0.1 i. 5 G./ <0.1 <0.1 io.l <a.Q3 0.1 <r,.l i.i BFG09481 ( i < INDICATE a COMCENTJJATiOJ'f LOWER THAN THE MINIMUM v.rntCH YIJE METHOD USXIJ 21104115 COPY OF THE LETTER FROM UNION CARBIDE (AUSTRALIA) RE PURITY OF BPA BFG09482 UNION CARBIDE AUSTRALIA LIMITED imcmkmatu in ncw south walks S05 ST. KILOA ROAD. MELBOURNE. VICTORIA, 3000. AUSTRALIA G.P.Q, BOX 1227L, VIC. 3001 TELEGRAMS; "UNICARBIDE" MELBOURNE * TELEPHONES! 26-1241, 26-2332 1st March, 1978 Mr. Vincent J* Scully Technical Service Manager B*F. Goodrich Chemical Limited ALTONA VIC. Dear Mr, Scully, Re: PRODUCTS FOR USE AS ANTIOXIDANTS IN PVC UNDER AUSTRALIAN STANDARD 20?C '.Ye advise that chemicals supplied by UCAL are manufactured to Internationally Accepted Standards of quality and are free from impurities likely to have an injurious effect on health. Applies to: - Ethyl Acrylate - Potassium Persulfate - Bis Phenol A. To assist in preparation of a case for the laat named chemical we enclose a Union Carbide brochure on the product. Yours faithfully WLR/eb End brochure IV.L. ROUTLEY Commercial Development Manager U r t H 1 3n BFG09483 APPENDIX IX UNION CARBIDE LITERATURE ,TUCAR^ BISPHENOL A APPLICATIONS" BFG09484 8 T T tO T 'f IMPORTANT This information 4 not to b* taken as a warranty or representation for which wa atturm legal responsibility nor at permlijiqn or recommendation to practica any patented Indention without a license, it ii offered solely for your consideration. Investigation and verification. UCAR, UDEL, and UNION CARBIDE ar* registered trad* merkj of Union Car bide Corporation, U.S.A. 1974, 1976 by Union Carbide Corporation. UNION CARBIDE CORPORATION CHEMICALS AND PLASTICS 270 PARK AVENUE, NEW YORK, N.Y. 10017 BFG09486 0 3 T H )T 7 2 Contents INTRODUCTION POLYMER SYNTHESIS ANL) MANUFACTURE .................. Epoxy Resins ......................................................................... Resin Manufacturing Process ......................................... Critical Product Specifications .................. *............... Bisphenol A Purity and its Effect on Epoxy Resin Manufacturing Processes ................................ Advantages of UCAR Bisphenol A in Epoxy Resin Manufacture .................................................................. General References........................................................... Polycarbonates ............................................................. , .. . Polycarbonate Manufacturing Processes ...................... Phosgenation . ,...................................................... * Ester Exchange ........................................................... Effects of Bisphenol A Impurities on Polycarbonate Manufacture......................................... UCAR Bisphenol A - UHP............................................. UCAR Bisphenol A Impurities .................................. General References........................................................... Polyester Resins .................................... Chemistry ............................................................. . , . . , Applications .................................................................... General References........................................................... Phenolic Resins...................................................................... Resin Manufacturing Process ......................................., Applications V.................................................................... UDEL Polysulfone ................................*............. .. Manufacturing Process................................................ , , UDEL Polysulfone PropertyHighlights ........................ General Reference ........................................................... Phenoxy Resins............................................................. Manufacturing Process ............................................... Applications .................................................................... General Reference ...................................................... Halogenated and HydrogenatedBisphenol A .................... ADDITIVE APPLICATIONS ...................................................... Thermoplastics .................................................................... 1. Poiy(vinyl chloride) .................................................. 2. Polyethylene ....................................................- . - , , 3. Polypropylene............................................................... Page 2 2 2 3 3-4 5 5 6 6 6 6 7 8 9 9 9 9-10 10-11 11 It 11-12 12 12 13 13 13 14 14 14 14 15 16 16 16 17 17 n T2TC 0TI BFG09487 CONTENTS (Continued) Page 4. Polystyrene....................................................................... 5. Poly(methyl methacrylate)........................................... 6. PoIy(vinyl butyral)........................................................... 7. FluoriniiJfd Polymers ..................................................... 8. Polypropylene oxide)..................................................... 9. Polyethylene terephthalate)......................................... 10. Nylon ............................................................................... IK Cellulosics ...................................................................... 18 18 18 18 18 18 18*19 19 Thermosets .................................. 1. Rubbers ............................................................................ 2. PhenolicR........................................................................... 3. Silicones.............................................................................. 19 19 19 19-20 Fluids and Lubricants........................................... 1. Esters ................................................ '............................. 2. Alcohols ........................................................................... 3. Ethers .............................................................................. 4. Hydrocarbons............................................................ .. . 20 20 20 20 20 Bibliography (Additive Applications) ..................................... 21-22-23 APPLICATION AREAS .................................................................. 1. Textiles.................................................... *...................... 2. Adhesives ......................................................................... 3. Thermographic Recording Materials ......................... 4. Photographic Antifoggant .............................................. 5. Electroplating ................................................................... 6. Battery Electrolyte................ 7. Leather Tanning.............................................................. 8. Sand Mold Binder........................................................... 9. Lacquer Peptization ....................................................... 10. Drilling Muds ................................................................. 24 24-25 25 25 25 26 26 26 26 26 26 Bibliography (Application Areas) .................................................. 27 BIO-RELATED APPLICATIONS ................................................ 1. Bactericide ........... 2. Fungicide...................... 3. Herbicide.................................................................. ... 4. Insecticide...................................................................... 5. Physiological Effects -- Miscellaneous .......................... Bibliography (Bio-Related Applications) ....................................... Toxicological Properties........................... FDA Status ............................................... 28 28 28 28 28 28 29 30 30 c BFG09488 i U - d i ii M I M & J UCAR' Bisphenol A Applications 4,4-lsopropylidene diphenol Chemical Abstracts Registry No, 80-05-7 Introduction UCAR Bisphenol A finds utility in a myriad of applications, especially as an intermediate for the production of a wide variety of resins and plastics. An introduction to the function that UCAR Bisphenol A fulfills in many of these areas is presented in this booklet together with appropriate references. Emphasis is placed on the uses that have been reported for Bisphenol A itself, and not on the innumerable derivatives that have been prepared from it. For more definitive product data and information on UCAR Bisphenol A, please refer to our booklet, F-40900B. CHEMICALS AND PLASTICS i: BFG09489 EZTH)TT Polymer Synthesis and Manufacture Epoxy Resins The largest application lor Bisphenol A is in the manufacture of epoxy resins, Ahoul 210 million pounds of Bisphenol A - containing epoxy resins were produced in 1973, Epoxy resins are derived from UCAR Bisphenol A by reaction with epichlorohydrin to form (lie glycidyl ether derivatives of the phenolic hydroxyl groups. Their structure is depicted in the following formula I: CHo-CHCH \/ 0 0-<s >-o ch2chch2^o- \ OH li Bisphenol A Unit I. //T\ OCH3CH-CH2 \/ Qj Glycidyl Ether Unit When n ~ 0 in l, the `'resin" Is simply the.pure diglyddyl ether of Bisphenol A, As n increases, one progresses through the liquid epoxy resin family to solid resins. Commercial liquid resins have an average n value of about 0,1, Semisolid resins have an average n value of about l ,0, and solid resins have n values ranging from about 2 to 19, UNION CARBIDE'S plienoxy resin (see below), which has the above structure (I) with n equal to about 100, can be considered to be an ultra-high molecular weight epoxy resin. Resin Manufacturing Process Processes for the manufacture of epoxy resins involve the elements outlined in the schematic diagram below. Reaction of excess epichlorohydrin with UCAR Bisphenol A (l[) is first conducted to yield a ehlorohydrin v z im tz intermediate via the so-called "coupling" reaction, using catalytic amounts of sodium hydroxide. 50 -60C, HO OH + CH3-CHCH2CI "NaOH CICH2CHCH20 I och2chch2ci OH OH II. Epichlorohydrin Chlorohydrin BFG09490 2 * | j I,I,jjainji riiafnimrniifliMin Sodium hydroxide is used to effect the dehydrochlorination of the intermediate chiorohydrin to yield the epoxy resin. Salt is removed by decantation, and the resin isolated as a residue product by removal of the ClCH2CHCH20 OH ch2~chch; o cpichlorohydrin excess and other volatiles at temperatures as high as 1 50C. Critical Product Specifications The two most critical specifications used to characterize epoxy resins are their epoxy equivalent weight and viscosity. The epoxy equivalent weight of a resin is the weight in grams which contains one equivalent of epoxy groups. It is a measure of the reactivity of a resin, and is used to calculate the optimum amount of curing agent for the resin. Since each resin molecule contains two epoxy groups, the molecular weight of a resin is approximately equal to twice the epoxy equivalent weight. Stated another way, increasing epoxy equivalent weights means increased resin molecular weight. Viscosity, of course, is a measure of the handling characteristics of a resin and increases with increasing molecular weight. Branching in a resin also increases resin viscosity. These two resin properties, epoxy equivalent weight and viscosity, are the key product specifications that must be met when they are manufactured/' Bisplienol A Purity and Its Effect on Epoxy Resin Manufacturing Processes Although the term "Bisphenoi A" is used to describe the commercial products, in a technical sense it refers specifically to.the 4,4,-bisphenol A isomer (HI). S Z T K lT fS 4,4 -Bisphenol A Impurities in commercial Bisphenol A products That are of concern in epoxy resin manufacture are the isomeric 2,4'-bisphenol A (I V) and a trisphenol(V). BFG09491 3 Although isomeric with 4,4'-bisphcnol A, the 2,4'-isomer possesses one of its phenolic-OH groups in a crowded or hindered location. Hindered hydroxyl groups such ns this one react at markedly lower rates Lhan unhindered hydroxyls. Hence, the amount of this isomer present in a Bisphenol A sample will affect the overall reactivity when used to make epoxy resins. The trisphenol V also contains a hindered hydroxyl group and, hence, its concentration can also affect the suitability of Bisphenol A products for epoxy resin manufacture. Because of the need to drive the coupling reaction to completion under mild conditions (^SO'C. and catalytic amounts of base), an excess of epichlorohydrin must be used. Bisphenol A that contains substantial amounts of the unreactive 2,4'-isomer makes it necessary to use larger excesses of epichlorohydrin. Handling losses and distillation loads are increased under these conditions because the excess epichlorohydrin must be recovered and recycled. If essentially all of the phenolic groups are not reacted at the coupling stage, they are present at the later stages of the process where I50C. temperatures are encountered. If unreacted, hindered hydroxyl groups are present at these high temperatures, they can react with some of the newly-formed epoxide groups and adversely affect the critical product specifications. For example, reaction of the monoglycidyl ether of 2,4f-bisphenol A with epoxy groups is shown in the equation below. The hindered phenolic group in the trisphenol (V) can also react now to produce CHgCHCHgO--HCy + C^CHCH2-^^--aaa^ 92TV0T7 OCH2CHCH2OH^^)---- 'VWV OH a branched resin structure. Free phenolic groups can also react with some of the other more volatile, recyclable, epoxide-containing compounds that are present at this stage of the process. The net result if these reactions occur at higher temperatures is an increase in the epoxy equivalent weight and the viscosity of the products. 4 ,w. BFG09492  -. >'. Tiv.v'f J Advantages of UCAR Bisphenol A In Epoxy Resin Manufacture The data in the accompanying table compare typical analytical data for UCAR Bisphenol A with competitive products. UCAR BISPHENOL A - EPOXY GRADE Supplier UCAR Bisphenol A Company A Company B Company C Typical Analyse* (%)* 4,4'-Bisphenol A (III! 2,4rBiiphenol A (IV) 99.5 96.2 94.6 94.8 0.2 2.4 3.7 3,6 Trisphenol (V) 0.1 0.8 1.2 1.1 The above imporitiw do not sum to 100% became other ia*> critical one* ere alio preaant. It shows that all competitive products contain mote than ten times the level of those impurities (IV and V) that directly affect the efficiency and control of epoxy manufacture. Employing UCAR Bisphenol A for epoxy manufacture can provide the followingadvantages: Use of a smaller excess of epichlorohydrin, which will improve epichiorohydrin efficiency decrease distillation loads increase productivity, by increasing effective reactor capacity. Better, `more uniform reactivity of the UCAR Bisphenol A, which will decrease concern for meeting product specifications at the tail end of the process allow stripping and product isolation at higher throughputs, thereby increasing effective capacity minimize side reactions with low molecular weight recyclable, epoxy-containing compounds. General References Lee, II. and K. Neville. "Handbook of Epoxy Resina", McGraw-Hill Book Company, 1967, Epoxy Resin Handbook, 1972. Noyes Data Corpo ration, Park Ridge, New Jersey. Bruins, P. F. "Epoxy Resin Technology", Inter science Publishers, 1968. BFG09493 s L Z J fty n n s Polycarbonates Commercial polycarbonates are based on the linear, thermoplastic polyester of Blsphenol A with carbonic acid, viz., polyfBisphenol A carbonate). Many related polycarbonates have been prepared from other bisphcnols and even aliphatic diols. Polycarbonates have been commercially 0" II OCO' --1 7? available in the United States since 1960 with consumption estimated at 105 million pounds in 1973* Capacity expansions already announced by producers indicate anticipation of a dramatic upswing in their growth rate. Very probably, polycarbonate manufacture will be the largest single application for Bisphenol A within a few years. Polycarbonate Manufacturing Processes Polycarbonate resins are produced by either a phosgenation or an ester exchange process. Phosgenation The reaction by which polymerization occurs is shown in the equation below. Reaction is rapid at mild temperatures (25-504C.), and the polymer is HO /TV/ Bisphanol A H20 H + COClj + 2NaOH Organic Solvent Phosgene /T\ 0 OCO-I--+ 2NaCI + 2HaO / 21104123 Jr V?,*-' obtained in solution in the organic solvent, washed in solution, and then recovered. Theoretically, 0.90 pounds of Bisphenol A are required per pound of polycarbonate. Ester Exchange Polymerization occurs by the reaction shown in the following equation: BFG09494 mi * *. - i **-, Name Phenol EFFECTS OF BISPHENOL A IMPURITIES ON POLYCARBONATE MANUFACTURE Structure OH 6 Effect on Polycarbonate Process Product Acts as terminator to lower molecular weight. No effect. Olenin's Compound 2r4'-Bisphenol A rr0B ^ch3 OH hoh0+^ Acts as terminator to lower molecular weight. Can impart thermal instability if incorpo rated into product. Acts as terminator to lower weight, because reactivity of one phenolic group is de* creased due to hindrance. Imparts instability if incorporated as mono phenol, because of oxidizability of re maining phenol group., Trisphenols Easily oxidiiable phenolic species. hohQ+^-hQhoh ^"OH Reacts like a bisphenol because one phenolic group is hindered. 1 \ ch3 ch3 "`'Qt5 - CHf? -0-OH ' /1 ch3 Affects stoichiometry because of trifunc tionality. Imparts instability if incorporated, because of oxidizability of unreacted phenol group. Introduces branching with effects on flow properties. IsOpropenylphenol and Oligomers ch3 ch3 HO-^^--1-----CH=C-^jrOH ch3 and others Affects stoichiometry according to func tionality of each species. Adverse effect on initial color and color stability if incorpo rated, because of ease of oxidation. S Z J b Q T fz BFG09495 7 Bisphenol A OH + \ / \ Basic__ // -oco ^/Catalyst' Diphenyl Carbonate 1 -OCO--L- Phenol This process is conducted in hulk at high temperatures (300*0 under vacuum, with phenol being removed as it forms. Phenol is then reconverted to diphenyl carbonate by reaction with phosgene. The polycarbonate is isolated as a residue product low in electrolyte content, and is limited in molecular weights attainable because of the high melt viscosities that are encountered. UCAR Bisphenol A - UHP Ultra-higlvpurity or UCAR Bisphenol A -- UHP was developed by UNION CARBIDE expressly tor polycarbonate manufacture and introduced commercially during 1971, Although it is the preferred grade for polycarbonates* UCAR Bisphenol A is useful for the production of the less optically demanding grades of polycarbonate. Specifications for the UHP product are shown along with typical analyses in the accompanying table. UCAR BISPHENOL A - UHP Property Specification Freezing Point, C, (dry) APHA Color |47.5% w/w in methanol) Water Content, % by weight Iron, ppm. Sulfur, ppm. Ash, % by weight Phenol Content, % by weight Dianin's Compound, % by weight 2,4*`Bisphenol A, % by weight Trisphenols, % by weight 156.5, minimum 25 , maximum 0.15, maximum 1.0, maximum 5.0, maximum 0.02, maximum 0.10, maximum 0.10, maximum 0,25, maximum 0.10, maximum Typical Analysis 156.5 15 0,10 <0.5 5.Q <0,01 0.05 <0.02 0.16-0.18 0.10-0.14 Brief inspection of the data in the table readily reveals the extraordinarily high, unsurpassed purity levels that this product meets. One can view the first 6 properties in the table as those that are used routinely for assessing the purity of almost any solid chemical. The latter 4, however, define tolerable levels of certain chemical species that are inherent to Bisphenol A synthesis. The need for rigid control of these impurities stems from (I) their effect on the polycarbonate manufacturing process itself and (2) the effects .that their incorporation into the polycarbonate molecule can have on the product's performance. The initial color of the polycarbonate resin and its color stability on repeated processing at high temperatures is affected by O E T tO T 'fZ BFG09496 s the impurity level in Bisphenol A. Additionally, several tests that measure tiny amounts (ppm. or less) of other impurities that can have an adverse effect on the inherent, water-white color of polycarbonate resins are employed. UCAR Bisphenol A Impurities The roles that Bisphenol A impurities can play in polycarbonate . manufacture are outlined in the accompanying tabulation (page 7). General References Christopher, W. F. and D. W. Fox. "Polycarbonates", Reinhold Publishing Corporation, New York, 1962. Schnell, H, "Chemistry and Physics of Polycar bonates1', Interscience Publishers, New York, 1964. Johnson, K,, "Polycarbonates: Recent Develop ments", Noyes Data Corporation, 1970. Polyester Resins Polyester resins based on Bisphenol A were first introduced in the early 1950's. It has been estimated that as much as 6 million pounds of Bisphenol A will be used in this application during 1973. The outstanding characteristic of this type of polyester is its resistance to corrosive attack by acids and alkalis. Because of this property, they find extensive use in the fabrication of chemical processing plants. Chemistry The first step in the preparation of Bisphenol A polyesters is the reaction of Bisphenol A with an alkylene oxide, such as propylene oxide. The intermediate glycol (VI) that is produced is then esterified with fumaric ch3 ch3 -OH + 2CH2CH-CH3--p-H0HCCH20--och2choh Bisphenol A Propylene Oxide VT. acid (or maleic anhydride) to produce the polyester shown as structure VII, CH3 CH3 h HQCHCH20-^*^~|--^^OChhCHOH + HOGC-C=9-COQH---------*' r- CH' ----- CHCH2Q-^ H CH- 0 QCH jCHQC-C^tp-CQ----------+ 2H20f VII. BFG09497 TCT&OTT IZ Heat is applied to effect the polycondensation in a resin kettle, which is controlled by viscosity and acid number measurements. An inhibitor is normally added before the completion of the reaction, The characteristics of the product vary with the value of n in VII. Normally, the product possesses low n values, and is a crystalline solid, melting at about 10QC. It is cooled, crushed, and milled to yield a fine powder that is used as discussed below. At high n values, the polyester is a very viscous, liquid polymer. The largest application for the powdered polyester described above is as a solution in a crosslinking monomer, especially styrene. This solution crosslinks via a free radical mechanism, when initiated by organic peroxides used in conjunction with amines and/or metallic salts of organic acids. This crosslinking reaction is shown schematically in the following equation: 'WVQ CH3 oh 0 I ;l I ll OCH2CHQ -CC=9CO'^v^ H + ch3 ll + CH--C5H5 ch3 oh 0 ch3 I II I II I ch2cho-cc=ccochch2'w^ H R* 'W\o ch3 0 ^o -CcH --CHCO 'wv CH2 CH--C6H5 ch3 0 0 ch3 ch2cho-c-ch -CH -COCHCH5 /WV In commercial use, these polyesters are generally laminated with fiberglass. Applications The accompanying table contains data that illustrate the superior chemical stability of Bisphenol A derived polyesters. Medio* * (Immersion for 12 months at 99C.) Flexural Strength Retention. % Bisphenol A General Purpose Bisphenol A- Fumarate Polyester Polyester Cpichlorohydrln Epoxy H2S04, 26% NaOH, 6% Distilled Water 73 Deteriorated Deteriorated 80 Deteriorated 50 85 0 to 2CTW m s BFG09498 Several examples of specific applications that capitalize on the corrosion resistance of this family of polyesters follow: 1. Pipework lor handling wet chlorine gas and chlorinated brine. 2. C.as stripping towers that handle wet sulphur dioxide up to 11QC.' 3. Tanks anti pipes that handle sulfuric and hydrochloric acids to 1Q5SC. and caustic soda to40C. in a fatty acid production plant. General References Loader, T. Polymers, Paint and Colour Journal, April 15, 1973. Anderson, E. V. Chemical Eng. News, July 16, 1973, page 6. Phenolic Resins UCAR Bisphenol A possesses typical phenolic reactivity in condensa tion reactions with formaldehyde to produce phenolic resins. It can also be used as a coreuctant with p-alkylphenols to produce substituted phenolic resins. Resins containing Bisphenol A are desirable in a variety of areas, but are especially useful in coatings applications, Resin Manufacturing Process UCAR Bisphenol A reacts with formaldehyde at the four positions ortho to its two hydroxyl groups. It resemblesp-substituted phenols, such as p-t-butylphenoi (2), in its reactivity and can be used as a coreactant in the manufacture of p-substituted phenolic resins. The reactive positions in phenol itself are shown by the arrows in structure (3) for comparative purposes. i: BFG09499 eeTW)T.T Phenolic resins are usually made at 40-I00C, Higher reaction temper atures (120-125"(_\) under pressure arc effective at increasing the rate and also the solubility of substituted phenols in the medium. Kettles or vessels of 1000- to 4000-gallon capacity are the most economical. The larger sizes are preferred because of economy of operation and resin uniformity, whereas the smaller sizes permit greater flexibility. Production of phenolic resins for coatings are made in stainless steel vessels with inert gas blanketing, if very light colored resins are desired. The reaction vessels are equipped with a heating jacket, cooling facilities, and a means of agitating the reaction mixture to insure homogeneity, thereby preventing localized overheating* Reflux condensers and a good vacuum source must be provided to permit dehydration of the resin at low temperatures and to control any reaction exotherms. These reactions can be highly exothermic. Applications Substituted phenolic resins incorporating UCAR Bisphenol A are manufactured commercially for conversion to coatings and varnishes. Non-heat reactive resins are prepared by acid catalysts, and can be blended or worked directly with drying oils to produce coating formulations. They possess outstanding oil solubility which facilitates this step. Modified, substituted phenolic resins are best prepared lTom heat-reactive phenolic resins. The latter, of course, are prepared by alkaline-catalyzed condensation of formaldehyde with the mixture of phenols. Alkaline-catalyzed, Bisphenol A-formaldehyde resins are used for the modifications of rosin or ester gums to give superior varnishes. Varnishes containing this type of phenolic resin dry much faster than the unmodified rosin or ester gum varnishes. Additionally, their initial color and color retention properties are superior. Alcohol-soluble, baking coatings for metals that arc based on BisphenolA-formaldehyde resins possess very good color. Generally, amine-catalyzed resins are employed. UCAR Bisphenol A in mixtures with /7-alkyl phenols to maintain oil solubility can be condensed with formaldehyde to produce both heat reactive and non-heat reactive resins. Varnishes prepared from these resins possess superior drying speeds and durability properties. UDEL Polysulfone UDEL Polysulfone was introduced commercially by UNION CARBIDE in 1965. It is a rigid, strong thermoplastic that can be molded, extruded and thermoformed into a wide variety of shapes. UDEL Polysulfone is stable, and possesses properties that are maintained to a high degree over a temperature range from - 150'F. to over 300F. for long periods of time. BFG09500 1104134 Manufacturing Process The commercial aromatic polysulfones are produced from UCAR Bisphenol A and 4T4'-dichlorodiphenyl sulfone. UCAR Bisphenol A is converted to its disodium salt which is then condensed with the activated haloaromatic compound, as shown in the accompanying equation. Dimethyl NaO Disodium Salt tjf Bisphenol A l\la + Cl 4,4'Dichlorodiphenvl Sulfone sulfoxide and chlorobenzene are employed as reaction solvents. The commercial polysulfones have n numbers from 60-120 that correspond to molecular weights from 30,000 to 60,000. The purity Of the Bisphenol A employed in this manufacturing process is critical, as it would be in any polycondensation reaction leading to a highmolecular weight, linear polymer. The factors that need to be considered are exactly analogous to those that were discussed in the preceding section on Polycarbonates. UDEL Pofysulfone Property Highlights The property highlights of UDEL Polysulfone are presented in the accompanying table. Of special significance is the heat deflection tempera ture of 345F, at 264 psi. It also exhibits excellent resistance to mineral acids, alkalies, salt solutions, oils, and detergents. UDEL Polysulfone Property Highlights Density, g./cm,^................................................................................. Flammability................................................................................ .. . NOTE: These numerical flame spread ratings are not intended to reflect hazards presented by this or any other material under actual fire conditions. Heat Deflection Temperature, 264 psi............................................. Tensile Strength at Yield ................................................... Tensile Modulus . ........................................................ 360,000 psi. Tensile Creep (after 2 years, 3000 psi., 72F).............................. Dielectric Strength, ST...................................................................... Dissipation Factor, 60 cps................................................................. 1.24 AT0, 5 seconds AEB, 0.4 inch.(10 mm,) 345eF, 10,200 psi. 1.06% 425 volts/mil 0.0008 General Reference Lee, H., D. Stoffey, and K. Neville. "New Linear Polymers", McGraw-Hill Book Company, 1967, Chapter 5, BFG09501 S E T K IT T Phenoxy Resins Phenoxy resins are high-molecular weight, thermoplastic resins that combine the application and handling characteristics of a thermoplastic with many of the outstanding physical and chemical properties of a thermosetting resin. They find their major applications in the coatings and adhesives areas; molding compounds are also commercially available. Manufacturing Process PherlOxy resins are high-molecular weight, linear epoxy resins, viz.. They arc manufactured by reacting UCAR Bisphenoi A with epichlorohydrin. The overall reaction is shown in the following equation, although several intermediate products are postulated to be formed in the process. As with other polycondensation reactions, the purity of the Bisphenoi A that is HO OH + CH5CHCH2CI + NeOH OCHgCHCHjO-f-- + NaCl + HaO OH -n employed is critical to the success and reproducibility of the process. These purity considerations are analogous to those described above in the section on Polycarbonates. Applications Although phenoxy resins are available for molding and extrusion applications, solution coating applications consume the largest amount of these products. They make outstanding metal coatings because they have excellent adhesion, chemical and salt spray resistance, impact and abrasion resistance, and flexibility. These properties, plus good overbake resistance, make them especially suitable for metal priming applications. They are also usefut as lacquer coatings for wood and polar substrates. Applied in solution form, they dry into a tough flexible coating without the use of plasticizers, driers, or curing agents. General Reference Lee, H., D. Stoffcy, and K.. Neville. "New Linear Polymers", McGraw-Hill Book Company, 1967, Chapter 2. ^, .vV* Ifk W BFG09502 Halogenated and Hydrogenated Bisphenol A UCAR Bisphenol A is readily halogenated by chlorine or bromine to yield tetrachloro- and tetrabromobisphenol A, respectively. The structures of these increasingly important Bisphenol A derivatives are shown below. Both > 3 of these compounds are finding increasing usage as flame retardants with polymers. For certain applications, the purity of these derivatives is critical and is related to the grade of Bisphenol A that is employed in their preparation. For this reason, UCAR Bisphenol A -- UHP is unexcelled for conversion to extremely pure grades of these derivatives. The halogenated Bisphenol A can be used by directly substituting it for part of the Bisphenol A in a typical polymerization recipe. They react at slightly different rates than unsubstituted Bisphenol A, but suitable adjustments of the reaction conditions can be made to counter any adverse effects. Tetrachloro and/or tetrabromobisphenol A are used commercially as components of epoxy resins, polycarbonates, and polyester resins. Hydrogenated Bisphenol A results by hydrogenation of the aromatic rings of Bisphenol A. This step completely changes the nature of the hydroxyl groups from aromatic phenolic groups to cycloaliphatic hydroxyl groups. Hydrogenated Bisphenol A is commercially available and is used to HO impart improved light stability to a variety of resins, especially polyesters. ^E TH m Z BFG09503 t Additive Applications Thermoplastics l. Polyfvinylchloride) Bisphenol A has been widely studied as an additive for improving the end use properties of poly(vinyl chloride). Although one might think that it functions only as an antioxidant, other roles are possible. For example, it has been reported that it is alkylated by the double bonds that are formed by loss of hydrogen chloride'1 >. This reaction stabilizes the PVC polymer structure against further breakdown. This postulate could explain why Bisphenol A frequently is more effective for PVC stabilization than many commercially available, heavily o-substituted, phenolic antioxidants. The accompanying table lists the properties that have been reported to be favorably affected by incorporation of Bisphenol A into PVC formu lations/ Typical references follow in parentheses. Although some of these Po!y(vinyf chloride) Properties Thermal Stability*21 *31 (4) (5) Oxidation Resistance*21 131 l6> Light Resistance*7* *81 *91 *101 Color Stability*111'*12* <131 (l01 Exudation after Oven Aging*141 Volatiles Generation (plasticizer content)*161 tl8t Odor Development*171 Tensile Strength*161 *181 Tensile Modulus*151 Elongation*161 *161 *181 Low Temperature Flexibility*151 Transparency*161 *191 Water Absorption *201 Volume Resistivity*11 property improvements are obviously interrelated, the overall result is quite beneficial. The amount of UCAR Bisphenol A that is used can range from 0.02 up to 1%. Although the exact amount will vary depending on the specific formulation, 0.25-0.50% appears to be the most common. Addition via masterbatch techniques has also been used. Phosphites <t42l> and glycidyl ethers *331 function as synergists with Bisphenol A, Apparently, Bisphenol A is useful with most of the various metal stabilizing systems that ate used in PVC. Work with tin*12* M* Z3), lead*3- z3> l4>, barium-cad mium*9* 3 4,t <)} and zinc*14 4 Stabilizing systems has been reported. UCAR Bisphenol A is used as a stabilizer/antioxidant for many of the plasticizers that are used in substantial concentrations in polyvinyl chloride resins. One might be tempted to conclude that the beneficial effects that are obtained from UCAR Bisphenol A in PVC systems is due solely to the fact that it is stabilizing the plasticizer therein. Thus, by retarding plasticizer degradation, the performance of the total formulation is improved. Although this undoubtedly occurs to some extent, enough evidence has been presented to rule this out as the sole explanation of improved performance. Some studies have focused on the structure of the plasticizer* i7 *23 *21>? |fS effect on PVC stability. Generally, phthaiates are more stable than adipates, and linear alcohol moieties are more stable than branched chain types. All types are stabilized by Bisphenol A, 21104138 BFG09504 II A synergistic effect on the light resistance of vinyls has been found when Bisphenoi A is used with phenyl salicylate <2 5 > and Tinuvin 6 7). Bisphenol A inhibits the radiation induced crosslinking of polyvinyl chloride resins13 H >. Poly(vinyl chloride) in contact with amine-catalyzed polyurethane foams is stabilized against color and thermal degradation by Bisphenoi At11). Bisphenol A in PVC can be determined by anodic voltammetry, Its half Wave potential is 0.53 V!1**3). The f-octyl derivative of Bisphenol A is a terminator in PVC suspension processes. Fibers of PVC with flame retardants and other vinyl chloride copolymers have been described that are based on antimony oxide-Bisphenol A formulations!31). 2. Polyethylene Bisphenol A effectively stabilizes polyethylene against oxidative degra dation! 3 2.33), As with other polyolefins, a marked synergism is found when it is used in conjunction with sulfur compounds. Thiourea!34-3S), esters of (i>,(j'-thiodialkanoic acids!36 and aliphatic sulfur compounds (distearyl disulfide)!37 \ are several types that have been used, A three component mixture of Bisphenol A, oxygen or sulfur compounds of antimony, arsenic or bismuth, and halophenyl esters of diacids was effective for polyethylene and copolymers with l-butene!3*>. Fibers with good dyeability by basic or cationic dyes were obtained by extruding polyethylene containing 5 per cent of Bisphenol A!i 9). Bisphenol A has been reported to possess utility as a catalyst modifier in Ziegler type polymerizations of ethylene. Improved yieldsofpolyethylene are obtained when Bisphenoi A is added to a TiCl4/(C4H9)3SnH catalyst system<40). 3. Polypropylene Many reports about the effectiveness of Bisphenol A in stabilizing polypropylene toward oxidation are available. Some studies have even found it to be more effective than many of its o-alkylated derivatives!41 *4a43), Generally, mixtures with sulfur-containing compounds are much more effective than the phenol alone. Some examples are 0-25 per cent Bisphenol A plus 0.25 percent of an ester of w.w'-thiodialkanoic acid(44>; 1 per cent of a 1:1 mixture of Bisphenol A and thiourea!45); mixture of 0.001-5 per cent of Bisphenol A monostearate with 0.001-5 per cent of an aliphatic sulfur derivative (distearyl disulfide)!46>; and a mixture of Bisphenol A (0.2-0.25%) with an oxygen or sulfur compound of antimony, arsenic or bismuth and a halophenyl ester of a diacid<47>. BFG09505 6ST&0TT2 Stabilization of polypropylene in the melt at temperatures of 2503QQ*C. is important because fibers arc spun under these conditions. Here again, mixtures (0 05*0*5%) with sulfur compounds (ex., thiourea) not only stabilize the melt but also increase the heat resistance of the fiber*4 8 f4 9 \ The dyeability of polypropylene fibers is reported to be enhanced when they contain Bisphenol A in their stabilizer systems*50 51K 4. Polystyrene Bisphenol A (0.2*0.25%) is a component of an effective stabilization system for polystyrene. Haiophenyl esters of diacids and oxygen or sulfur compounds of antimony, arsenic, or hismuth were the other components of the stabilizer package* 52 >. 5. Polyimethyl methacrylate) Although no reports have been found describing the utility of Bisphenol A in poly(methyl methacrylate), it is a polymerization inhibitor for methacrylic type monomers*5 3 >. Methyl methacrylate, methacrylic acid, and methacrylic anhydride were mentioned specifically. It is especially useful for the stabilization of MMA to be used for the production of latexes*54). 6. Poly(vinyl butyral) Thermal stability of printing inks based on poly(viny) butyral) is improved by incorporation of up to 5 per cent of Bisphenol A*5 s >. 7. Fluorinated Polymers Bisphenol A is used in elastomeric molding compounds based on vlnylidene fluoride copolymers. Copolymer* with hexafluoropropene and trifluorochloroethylene were described*5 6). Bisphenol A and its potassium salt are effective vulcanizing agents for terpolymers of vinylidene fluoride, tetrafluoroethylene, and hexafluoropropene**7). 8. Polypropylene oxide) Propylene oxide polymers are stabilized against decomposition by . incorporation of 0.5-2 per cent of Bisphenol A*5*). 9. Polyethylene terephthalate) Fibere and films of polyethylene terephthalate) are effectively stabilized toward thermal and light degradation by Bisphenol A*59). It was also effective at the 0.1-5% concentration range in some related poly ester-ether) fibers**0). 10. Nylon Bisphenol A is an effective light stabilizer for nylon. Treatment with an emulsion containing 0,25-0.50 per cent Bisphenol A followed by drying at 225PF. (30 seconds) and curing at 325flF, (2.5 minutes) greatly aided BFG09506 O M frO T T . M retention of tensile strength*61 *. It was even more effective than some commercially available, benzophenone type light stabilizers, Additive uses for Bisphenol A with nylons are described in a later section on textile applications, 11. Cdlulosics Bisphenol A improves the resistance of textiles made from cellulose esters to bleaching by chlorine. From 1-10 per cent by weight of the ceilutosjc is used*63). Stabilization of cellulose ethers against discoloration and degradation has also been reported**3*. Additional uses for Bisphenol A with cellulosics are described in a later section on textile applications. Thermosets 1. Rubbers Ethylene-propylene-diene and butyl rubbers are very effectively Stabi lized by Bisphenol A. It was found to be the most effective oxidation inhibitor of those studied for rubbers possessing low levels of unsaturation. Concentrations of 0.25 per cent of Bisphenol A were used in this study*64 *. Chlorinated Bisphenol A was reported to promote the cure of EPDM rubbers with sulfur*65*. Natural rubber recipes are stabilized by 1-2 per cent of Bisphenol A*66'67*- Inhibition of oxidation in synthetic poly(isopiene) is also effected by Bisphenol A addition*69*. An evaluation of butadiene-acrylonitrile rubbers found that Bisphenol A was one of the three most effective stabilizers*69*, Procedures for making dispersions 6f Bisphenol A for use in stabilizing BD-AN latices have been reported*70*. Crosslinking of styrene-butadiene rubbers by a-poly(oxymethylene) is accelerated by Bisphenol A (0.05 mole Bisphenol A per 100 pts. rubber)*71 *. 2, Phenolics The preparation of phenolic resins from Bisphenol A-containing residues and formaldehyde is the subject of a Russian patent*72*. This appears to be an efficient way to utilize the by-products that accumulate from recrystallizing Bisphenol A. Addition of Bisphenol A was effective in preventing formation of paraformaldehyde during long storage of formalin*73*. 3, Silicones Bisphenol A (0.5 % by wt.) was studied as an inhibitor for the oxidation of poly(dimethylsiloxanes) at 250-350C. Synergistic effects were noted*74*. A mixture of Bisphenol A, an aromatic amine, and a copolymer BFG09507 W H IT T S of dodecyl methacrylate and dielhylaminocthyl methacrylate was effective in increasing the induction period for oxidation of hexakis (2-ethylhexyloxy f disiloxane*7 5>. Fluids and Lubricants 1. Esters Esters that are used as plasticizers, lubricants, and hydraulic fluids are effectively stabilized by UCAR Bisphenol A. This is particularly true for esters derived from branched chain alcohols of the type obtained from the oxo process. The stability of both phthalates and esters derived from aliphatic diacids is improved. As was noted in the earlier discussion on the stabilization of poly(vinyl chloride), the stability of the plasticizer directly affects the performance of the PVC formulation, Bis(2-ethyIhcxy 1> sebacate is stabilized against oxidation in the presence of rust by a synergistic mixture of Bisphenol A (0.01#%) and phosphorous (0.001-0,2 % by wt.) as dialkyl hydrogen phosphite*78). Other synergists that work for this ester with Bisphenol A include ascorbicacid (0.02%)<77) and phenothiazine (0.2-3.5 %by wt,)<78-79 >. The presence of Bisphenol A during the esterification of phthalic acid with branched chain alcohols improves the thermal and light stability of the ester*80'8'), Further improvement is obtained by post addition of 0,02-0.25% of Bisphenol A. 2. Alcohols Color development and peroxide formation are inhibited by 0.25 % by wt. of Bisphenol A in branched chain alcohols obtained from the oxo process*82 >* 3- Ethers Hydraulic fluids based on poly(oxyethylenc -- poly(oxypropylene) glycols and their monobutyl and monoethyl ethers are rendered noncor rosive to metals and stabilized against precipitates by a mixture of Bisphenol A (0.5%), sodium tetraborate (0.5%), and 0,002 parts tetraethylsilicate(8 3). 4. Hydrocarbons Bisphenol A inhibits the oxidation of paraffin wax*84> and cumene*85). Motor oils produce decreased amounts of oxidation products when inhibited with a synergistic mixture of succinimide (3%) and Bisphenol A (10%)<8*'87). Hydrocarbon oils are also effectively inhibited against oxidation by mixtures of 0.1-2.0% Bisphenol A with 0.1-1,0% nonacidlc thiocarbonjc acid derivatives such as tetramethyithiuram disulfide or zinc dibutyl dithiocarbamate*8 8). Bisphenol A is a fairly effective oxidation inhibitor for carotene in mineral oil and on alfalfa hay(lt9'90). BFG09508 M H* K O < to 39 j Bibliography (Additive Applications) 1. Young, D. W. and W. F. Fischer. U.S.2,88U5I (1959). Esso Res. and Eng. Co;C.A. S3, l273Kf (1959). 2. Wolkober, Z. and I, Varga, Plasticas, 1970, 18(104), 78-87; C.A. 74, 4l34x(l971). 3. Wolkober, Z, and |. Varga, Kumtpffe, 57 (II), 895-901 (I967);C.A, 68, 50491k (1968). 4. Fischer, W, F. and B. M. Vanderbilt. Mod. Plast., 33, No. 9, 164, 166, 168, 170, 172 (1956);C,A, 52, 788a (1958). 5. Murfitt, H. C. Brit. Plastics, 33, 578-81 (I960); C.A. 55, 10947a (1961). 6. Minsker, K. S,, G, T, Fedoseeva, and I. K. Pakhomova, Vysokomolekul, Soedin,, Ser. A, 10 (2), 395 (1968); C.A, 68,96473 (1968), 7. Rondo, N. and N. Ando, Japan 68/19,633 (1968). Kanegaluchi Chem. Ind, Co., Ltd,; C,A, 71,31319f (1969). 8. Wolkober, Z. and L. Miskolczy. Haste Kaut., 1968, 15(8), 560-4; C.A, 69, 52703a * 1968), 9. Scullin, J. P. and A. 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Monsanto Co.; CA. 67, Pi 1824k (1967), 56. Patel, K, U. and J. E. Maier. Ger. Offen, 1,941,915 (1970). 3M Co,; C.A. 72, Pl01637e (1970). 57. Barney, A. L, and W. Honsherg, French l ,578,405 (1969). DuPont Co.; CA. 72, P91334n(l97Q). 58. Pruitt, M. E. and J. M, Baggett. US. 2,706.189 (1955). Dow Chemical Co.; CA, 49t 9326a (1955). 59. Mitamura, A. and T. Yasui. Japanese Patent 70(03,1 13 (1970); C.A, 72, 112732h (1970). 60. Netherlands Pat. Appl. 6,609.911 (1967). ICI, Ltd, 61. Roth. P. B,, U.S. 3,207,620 (1965). American Cyanamid Co,; C.A. 63, 15042b (1965). 62. Carmichael, D. G,, U S- 3,201,190 (1965), Eastman Kodak Co.; C.A. 63,Pi 1769a (1965). 63. Lincoln, D. C., U.S. 2,849,325 (1958). Hercules Powder Co.; CA, 53, P714g (1959), 64. Bevilacqua. E, M., $. Afr. 68/07423 (1969); C A. 71,82407r(I969). 65. Morita, E., French 1,463,139 (1966), Monsanto Co.;C.A. 67,P33642x(1967), ^ 66. Grinberg, A. A., A. L. Shapiro, T. A. Frishman, and Ya, A. Gurvich, Kauch Regina, 26 (3), 22 (1967). 1104144 BFG0951G i W 1 j j j j j j j j Bibliography (Additive Applications) (Continued) 67. Belorossova, A.G.,N, K. Lorogova, S. K. Kramar ova, K. A.Machtina, Yu. S. Mussbekov, and V. G. Fpshtein. Nauch. Kouf. Yaroslav. TekhnoL Inst.A 1st 1969,208-9; C.A. 75, 77890w (1971). 68. Voijjht, H. U., A. Stelkova, and B. Zoellner. Kaut, Gumtni, Kunstst., 1971,54(4), 150-6; C.A. 75, 22083e(1971). 69. Novikov, A. S., K. F. Kaluzhcnina, N. 5. Gilinskaya, and A. V. Kazakov. Trudy Nauch. Issledovitiei Inst. Resin, Prom., 1960, No. 7, 25-33; C.A. 5$, 10939c 70. Gilcrcase, J. R. and M. C. Fuqua. U.S. 2,662,061 (1953). Standard Oil Devel. Co.; C.A. 48, P4247a, P9096g (1954). 71. Tsukasa, M., Y. Miyazaki, and Y, Minoura, Nippon Gomu Kyokoishi, 1969, 42(5), 359-64; C.A. 71,62113p (1969). 72. Bogatyrev, P. M., et.aL, USSR 241,000 (1969); Chem. Abstr., 71,71407q (1969). 73. Hailon, K, and S. Yamatofuji, Japan. 69/14326, KaoSoapCo.,Ltd.;CA-71,90822n(1969). 74. Kabzova, R. 1., G. S. Tubyanskaya, C. M. Oparina, and N. K. Levkina. Khim, i TekhnoL Topliv iMosel, 9(9), 53 (1964);C.A. 61,16246c (1964). 75. British Patent 807,735 (1959). California Re search Corp.; C.A. 53, 14499h (1959). 76. Orlorf, H, D. ahd G. G. Knapp. U. S. 3,115,463 (1963), Ethyl Corp,; C.A, 60, 6685 (1964). 77. Leach, J, M,, U.S. 2,894,979 (1959). Pfizer & Co,; C.A, 53, P2Q905f (1459). 78. French Addn. 80,928 (1963). Esso Research and Engineering Co.; C.A. 59, J 2579 (1963). 79. Cohen G,, C. M. Murphy, J. G. O'Rear, H. Ravner, and W, A. Zisman, Ind. Eng. Chem., 45, 1766-75 (1953);C.A. 48, 11318(1954). 80. Fischer, W. F.t K. Knoth, Jr., and R. G. Newberg. U.S. 2,593,428 (1952), Standard Oil Devel. Co.; see also Brit. 690,847 (1953); C.A, 46, P6864g (1952); C.A. 47, 8413a (1953). 81. Cer, 922,165 (1955). Esso Research and Engi neering Co.; C.A. 52, 3401 (1958). 82. Fischer, W. F., U.S. 2,658,923 (1953). Standard Oil Development Co,;C-A. 49, l?72d (1955). 83. Shifner, R. W., U.S. 3,324,036 (1967). Union Carbide Corp.; C.A, 67, P66373p (1967), 84. Morawetz, H. A. Ind. Eng. Chem.. 41, 1442-7 (1949); C.A, 44,2212b (1950). 85. Hammond, G. S., C. E. Boozer, C. E, Hamilton, and J. N. Sen. J. Am. Chem. Soc.. 77, 3233-7 (1955); ibid, pp. 3238-44; C.A. 50, 4090, 4091 (1956). 86. Vipper, A. B. and V. A. Tarosov, Vestn. Lenin grad UniP. Fiz.t Khim.. 1970(2), 147-54; C.A. 73, I22l26y (1970). 87. Elliott, J. S., G. J, J. Jayne, and R, L Barber, J, Inst. Petrol., London, 1969, 55(544), 219-26; C.A. 71,83237X (1969). 88. Harle, O. L., U.S. 2,681,316 (1954), California Research Corp.; C.A. 48, PH776e (1954), 89. Bickoff, E.M, J, Am. Oil Chemists Soc., 28, 65 (1951). C.A. 45, 3439d(195l). 90. Bickoff, E. M., A. L. Livingston, and C. R. Thompson, J. Am. Oil Chemists Soc., 32, 64-8 (1955);C.A. 50,894(1956). 1104145 i: 1 i BFG09451 Application Areas 1. Textiles Acrylics Application of the mixture that results from heating Bisphenol A and furfuryl alcohol to polyacrylonitrile fibers speeds dyeing and development of deeper shades from direct or acid dyes*1). Celluloses Studies- on the sorption nnd affinity of Bisphenol A on cellulosics*2*, especially cotton*3*, led to the conclusion that it can be used as the coupling component in cold dyeing. A report that Bisphenol A is useful for improving the crease recovery properties and dimensional stability of cotton and viscose rayon fabrics has appeared*4 *, Polyesters , Bisphenol A is useful for the solvent bonding of polyester'derived nonwoven fabrics*5*. High temperature dyeing of "Dacron*' fabric with disperse azo dyes based on Bisphenol A coupled with diazonium compounds is possible*6*. Nylon Metal complexes (copper, nickel, chromium) of the product obtained from coupling Bisphenol A with diazotized anthranllic acid are useful dyes for nylon*7*. Aqueous emulsions of Bisphenol A are useful for the solvent bonding of Nylon 66 fibers to produce nonwoven fabrics*3*. Impregnation of twisted, nylon multifilament yams with 4-12 per cent methanolic Bisphenol A solutions, followed by heating at 150C, for 10-20 seconds produces threads that are suitable for high speed sewing machines*8*. Bisphenol A-containing adhesives for nylons are described in the next section. Polyurethane Elastomeric Fibers (Spandex) A stabilizer package containing Bisphenol A imparted excellent heat, light, and chlorine bleach stability to polyurethane type elastomeric fibers*9*. Bisphenol A (0.3%) combined with piperidino sulfides (e.g., 2,2,6,6'tetramethylpiperidmo disulfide -- 0.3%) is one such combination. Wool Metal complexes (copper, nickel, chromium) of the product obtained from coupling Bisphenol A with diazotized anthranilic acid are useful dyes for wool*7*. General EmuJsSions containing Bisphenol A in addition to other ingredients BFG09512 34 1104146 facilitated the shaping of textiles made from either natural or synthetic fibers*101, Cold dyeing with Bisphenol A-coupled diazo compounds yields products with good wet fastness*111, Use of Bisphenol A in conjunction with C,6-Cia fatty acids and monoethanolamine stearate facilitated the granulation of finely divided pigments, dyes, and filler materials*12 >, 2. Adhesives UCAR Bisphenol A complies with FDA regulations for use as a component of adhesives used in food packaging*13 >. Adhesives for prctreated steel based on polyvinyl chloride formulations that incorporate 1.5 parts of Bisphenol A and 4.5 parts of hexamethylene tetramine have been described*14 >. Fusible adhesives for plasticized poly(vinyl chloride) contain 10-30 parts of Bisphenol A and 70-90 parts of polyamides derived from fatty acids*1 s Several reports describe the utility of Bisphenol A for bonding textile fibers and fabrics, especially nylons. Acetone solutions of Bisphenol A are useful for bonding Nylon 6 and other polyamides*16 >. Blends of polyamides (Nylon 6 and 66) with Bisphenol A and octyl p-hydroxybenzoate are effective adhesives for nylons, polyesters, and cotton fibers*17>, They excel in their laundering and dry-cleaning resistance. Feel strengths of nylon laminates with polyester/cotton mixed fabrics were markedly enhanced when up to 20 per cent of Bisphenol A was incorporated into the nylon filament*18 >. K 3. Thermographic Recording Materials Bisphenol A finds utility as an ingredient in thermographic or heat developable recording and reproducing materials. One report uses the adduct of Bisphenol A with isopropylamine in a heat sensitive recording layer material*19 >. It undergoes a color change at 154-7C. Several other reports describe the use of a color-forming reaction L between crystal violet and Bisphenol A*30-21'33). Paper is coated with poly(vinyl alcohol) containing particles of crystal violet lactone and Bisphenol A. On heating, color forms where the Bisphenol A melts. 4. Photographic Antifoggant Photographic silver halide emulsions are stabilized by the addition of Bisphenol A against fog*4 3 >. When part of the gelatin has been replaced b\ a poly(N-vinyllactam), 5-50 millimoles Bisphenol A/mole of silver halide is recommended*141. Similarly, 4.7-30 millimoles Bisphenol A/mole of silver halide are used to prevent fogging by non-optical Sensitizers Containing polyoxyalkylene groups*2 5 *. BFG09513 5. Electroplating The addition of Bisphenol A to i chromium electroplating bath at a concentration of >0.000 g./l. suppresses the atmospheric entrainment of liquid particles of inorganic salt solution*26). This entrainment, which is due to Ha and Oj bubbles liberated at the cathode can be reduced by up to 95-100 per cent. Tin plating bath solutions containing 2 g,/liter of Bisphenol A are much improved with respect to loss of tin by oxidation of stannous to stannic sulfates. The latter is deleterious because it hydrolyzes to stannic oxide which precipitates, thereby causing a deterioration in the quality of the tin plate*27>. 6. Battery Electrolyte The addition of 0.05 per cent of Bisphenol A to a battery electrolyte is reported to improve the storage life of the batteries prepared therefrom*2**. Capacity and discharge voltage were not impaired. 7. Leather Tanning Tanning and dispersing agents containing Bisphenol A are reported to yield leathers possessing good light fastness*29*. Bisphenol A can also be used for chrome post-tanning, and it can act as a fixative for pigments in textiles. 8. Sand Mold Binder Binders for sand molds based on Bisphenol A possessed improved properties*30*. A typical recipe mixed 100 parts of Bisphenol A and 15 parts of hexamethylenetetramine with the sand followed by a heat cure. 9. Lacquer Peptization A procedure for the peptization of gelled lacquer or resin solutions employs 20 per cent Bisphenol A solutions in butanol or toluene*31 L This can be effected by heating and stirring the gelled lacquer at 60*C. with 5-10 per cent of Bisphenol A solution. 10. Drilling Muds Bisphenol A effectively preserves the emulsion stabilizing effect of lecithin when it is used in dry concentrates for invert emulsion well fluids. It was one of the 5 best compounds of the 31 that were tested. It was used at a concentration of 0.1-20 per cent by weight based on the lecithin weight*32*. BFG09514 a 21104148 Bibliography (Application Areas) 1. Evans, C. G., U.S. 2,812,230 (1957). Deermg Milliken Research Corp. Chem. Abstr., 52, P4)96h (1958). 2. Klynev, V. N. and T. J. Meshkova, Izvest. Vysskekh Ucheb. Zavedenii, Tektxol. Tekstil. Prom, I960, No. 3, 113-17; Chem. Abstr., 54, 25839h (i960). 3. Lamparsky, D. and E. Rack, KolloidZ, 160,7-16 (1958). Chem. Abstr., 53,1704i (1959). 4. Francis, T., Can, 867,255 (1971). Ontario Re search Foundation. Chem. Abstr., 75, 37854F (1971). 5. Hudsun, R. E,, Jr., and W. C. Monk, Jr., U S. 3,574,523 (1971). West Point - Pepperell, Inc.; Chem Abstr75, 7367g (1971). 6. Klynev, V, N., L. A. Dogadkina, and L. N. Kwngurjna. Izv., Vyssh. Ucheb. Zaved., Tekhnol. Tekst. Prom., 1966(6), 87-90. Chem. Abstr., 66, 116674q (1967). 7. Kraus, W., Jr,, French Pat, 1,471,639 (1967); Chem. Abstr., 67,91674v(1967). 8. Masuki, T., T. Tomida, M, Kitinaka, and li. Mizumo, Japan, Pat, 70/36,872, Toray In* dustrles, Inc,, Chem Abstr,, 75, 99215g (1971), 9. Suzuki, 1., K. Ichikawa, K. Murayama, and S. Murimura. Ger. Often. 1,928,916- (1969). Asahi. Chem. Ind. Co., Chem. Abstr.. 72, 44815k (1970). 10. Boka, Bm L. Fuzi, and F. Peter, Hung. Pat. 156,654 (1969). Chem. Abstr., 72, 44977q (1970). 11. Klynev, V. N. and L. A. Dogadkina. Izv. Vyssh. Ucheb. Zaved., TekhnoL Tekstil. Prom., 1961, No. 5, 113*16;CA#m Abstr., 56, 10325h (1962), 12. British Put. 1,238,118 (1971). ChemUche Werke Muenchen Otto Daerlocher G.m.b.H; Chem. Abstr., 75, 130878b (1971). 13. Fed, Register 30, 16067*8 (l965);C/rcm, Abstr., 64,8S45e(]9fifi). 14. Whittaker, B.f and P. J. Corish. Ger. Olfen. 2,033,078 (1971) Dunlop Co.; Chem. Abstr. 74, 126828X (1971). 15. Shering, A-C.,, French 1,475,376 (1967). Chetri. Abstr., 68, P30684x (1968). 16. Komarov, G. V., Trostyanskaya, E. B., and Pavlova, A. P, Plast. Massy. 1968 (9), 52-5; Chem Abstr., 70, 12336x (1969). 17. Matsunuira, S,, S. Qgawa, m, Shinohara, H. Matsusaka, and I. Matsumoto. Japan. Pat. 70/05,400 (1970); Chem. Abstr., 73, P36447* (1970). 18. llosokawa, M.( M. Katsube, and Y. Kolayashi. Japan, Pat. 69/21,661 (1969). Toyo Rayon Co., Ltd.-Chem Abstr.. 72,68144s (1970). 19. Lawton, W, R. and E. F. Lopez. Ger. 1,301,955 (1969); Nashua Corp,; Chem. Abstr., 72, 37754m (1970). 20. British Patent 1,135,540 (1968). National Cash Register Co.; Chem. Abstr., 70, 487l9p (1969). 21. Neth. Appl. 6,505,970 (1965). National Cash Register Co.; Chem./46s/,, 64* 15234a (1966), 22. Futaki, K. and M. Motoki, Ger OFfen. 2,110,859 (1971). Mitsubishi Paper Mills, Ltd., Chem. Abstr. 75, 157047s (1971). 23. Smith, T,, U.S. 2,955,038 (1960). E. I. DuPont de Nemours Co.; Chem. Abstr., 55, 23138c (1961). 24. British Patent 867,900 (1959). E. I. DuPont de Nemours Co.'.Chem Abstr., 56, I34(|962). 25. British Patent 842,062 (I960). E. 1. DuPont de Nemours Co.; Chem Abstr.. 55, P42l6i (1961). 26. Van der Horst, J. M. A., U.S. Pal. 3,423,297 (1969). Surface Research, Inc.;Chem. Abstr., 70, 83696a (1969). 27. Golikov, N. S. and M. E, Simonova. Zaschtta Metal., 1 (4). 447 (1965); Chem Abstr., 64, 3028h(l966). 28. Mendelsohn, M, and C, Horowitz. U.S, 2,872,362 (1959), Ions Exchange and Chem. Corp., Chem Abstr., 53, 6840h (1959). 29. Hertel, O., H. Nebel, and F. W. Guthke, Ger. Patent 1,164,424 (1964). BASF; Chem. Abstr., 60, 16116c (1964). 30. Yatnada, M-, Jap. Patent 608/60. Matsushita Electric Works, Ltd.;Chem. Abstr., 54, P24302c (I960). 31. Eberbuch, A. F. and C. Niehaus, Ger. Patent 969,972 (1958); Chem. Abstr., 54,9321 (I960), 32. Reddle, W. A.. U.S. 2,986,516 (1961). Magnet Cove Barium Corp.; Chem. Abstr., 55, P19219i (1961). BFG09515 21104149 37 Bio-Related Applications 1. Bactericide Bisphenol A possesses bactericidal activity and has been examined in several studies. Activity was found, though it was usually not the highest of the compounds studied*1 i* >. In a search for Ihroat disinfectants, it was found to have low activity against mycobacterium tuberculosis*^), 2. Fungicide Bisphenol A was cited as one of the ten compounds from among the 506 that were tested, with the highest toxicity to fungi*4). Other studies of its fungicidal activity are available*1's>. [j ajso exhibited fungicidal activity in cured neoprene rubber formulations*6) and on alfalfa hay*7). 3. Herbicide Bisphenol A has been tested for herbicidal activity and found to be practically inactive against the many different kinds of vegetables that were examined*8). 4. Insecticide Bisphenol A was not particularly effective as a moth-proofing agent*9 >, Jts insecticidal activity parallels its low bactericidal activity*1). Incorporation of Bisphenol A (0.1-10% by Weight) into solid insecticide formulations based on vinyl phosphates, -phosphonates, or -phosphinates markedly reduces their decomposition*'0). 5. Physiological Effects -- Miscellaneous The maximum allowable concentration of Bisphenol A in water is reported to be 0.01 mg./l. based on its organoleptic properties. Its presence is more noticeable if the water is chlorinated*1' >. Amounts up to 0.5 mg./l. will not affect self-purification of a stream, however. Quantitative feeding and inhalation data for rats are available and confirm its low order of toxicity*' The estrogenic activity of Bisphenol A has been noted,*13>,4>. Evaluation of Bisphenol A as a purgative has been studied*1 s >. &2SS&I Q STUm ?. Bibliography (Bio-Related Applications) Wen ften, W, and L. Richter. Phantiazie, 1970, 25(8). 4804; C.A, 73, I 28140v (1470). 2. Oka7.jki, K., K. Mjisui, anil H. Kaion.y. Pharm, Hoc. Japan, 71, 122740 (1051); C.A. 46, 4608a (1052), 2. Wahlig, H., H, M. Herming, L. liepding, and II. J. Bertram. Arzneimittcl-Forsch, 12, i 122-7(1962); C.A.58, I0630e(|963). 4. Goldsworthy, M. C- and S, J, Gertler, U.S. Dept. Agr., Plant Disease Reptr. Suppl., 182, HO-109 (1949);C.A, 4.3, 635 tg (|949), 5. Marsh, P. B,, M. L, Butler, and B. S. Clark, hui. Eng.Chem., 41, 2176-84 (1949); C.A. 44, 2 I 571 (1950). 6. Rilzinger, G. B. Ruhher 41 Plastics Age, 40, 1067-9 (1959); C\A. 54, 15984c (i960). 7. Schenk, R, U. and W. K. Kennedy. Agron. J., 47, 64-9 (1955); C. A. 49, U937c (1955). 8. Lobov, V, P., G. 0. Efimov, and M. V, Corda. Dupovidi Akad. A(auk Ukr. RHR, 1964 (5), 682*6; C.A., 6J,897Jg(|965). 9. Matsui, K., J. Hoc, Org. Synthetic Chem., 9,92-6 (195LJ-.C.A. 47,815c (1953)! 10. Sprinkle, C. R., L. F. Sekula, M. R, Johnson, and B. I. Sparr. Belgian Pat. 612,272 (7/4/62), (Shell Ini.) C-A,, 57, 14237b (1962), 1L Fedyanina, V, N. Gig. Sanli-1968,33(7), 25-30; C.A. 69,695602(1968). 12. Gage, J. C. Brit. J. hid. Med., 1970, 27(1), 148; C.A. 73, 12650b (1970). 13. Bitman, J. and 11. C, Cecil. J, Agr. Food Chem.. 1970, 18(6), 1108-12, C,A,, 74, 22133a (1971). 14. Miqnel, J, F., E. H. Barany, and W, Miiller. Arch, intern, pfiarntacodynnmie, M7, 262-76 (1958); C.A., 53, ] 3388a (1959). 15. Schmidt, L. and E. Seeger. Arzneimiitct-Fonch., 6, 22-6 (1956); C.A., 50, 12308e (1956). H04151 BFG09517 Toxicological Properties The toxicity of UCAR Bisphenol A is estimated to be quite low when swallowed by humans, and should present no problems in regular industrial use. However, if large quantities are ingested either wilfully or accidentally, harmful effects can occur. When fed to rats, UCAR Bisphenol A was a little more toxic than an equal quanlily of isopropanul. The oral LD^0 for male albino rats is 4.04 grams per kilogram of body weight. The oral LDS0 lor rabbits is 2.23 grams per kilogram of body weight. Skin contact is only mildly irritating, and is not expected to result in harmful absorption. However, direct contact with it should be avoided. Accidental exposure should be removed immediately by washing with soap and water, byes can be injured by the solid and by solutions in as low a concentration as 5 per cent. A one-per cent solution causes only irritation. Accidental eye contact should be removed immediately by flushing the eye with plenty of clean running water for at least 15 minutes. After emergency washing is completed, medical attention should be obtained immediately. FDA Status /7SWflS" Bisphenol A is cited in FDA Food Additive Regulation L21,2T20 for adhesives used in articles that contact food. f BFG09518 30 2STK)T72i Discover, also, how can best serve you with its- High quality - Cumene - Phenol, Synthetic -- Acetophenone - o/p/w-Metliyl Styrene Convenient, Fast and Dependable Delivery, Dollar Savings Through Bulk Shipments, Efficient Customer Service. Technical Representatives -- technically edu cated men with industrial "know-how" ready to serve you and assist you with any particular need you may have. Well-versed Marketing -- Sales Technology Teams. Committed Programs in Product and Process Research and Deveidpment -- to produce new products that may help you improve your present applications and develop new ones. BFGQ9519 e s i Farrs: UNION CARBIDE CORPORATION CHEMICALS AND PLASTICS 270 PARK AVENUE, NEW YORK, N-Y. 10017 Safes Offices NIEEP other union carbide* 1 ^ PRODUCTS--8ERVICES7 CALL The Nearest Corporate Infarrrwtlon Gemer York ..... 12121 561-37B3 Chicago , , , Homto" . . . (3121 464-2072 (7l3l 6il todd Long Beach (2131 435-3771 United State* Affiliates ATLANTA. GEORGIA 30329................................17 Executive Perk Or........................ ,,..404 $33 6161 BALTIMORE (MOORESTOWN, NJ. SALES OFFICE!.................................................. ,,,,301 -944-8211 BOSTON, MASSACHUSETTS 02194 ................... 300 First Ave,, Needham Hgti....... CHARLOTTE (ATLANTA, GA. 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SALES OFFICE)....................................................800-352-3789 FROM ARIZONA, IDAHO, MONTANA, NEVADA, OREGON, UTAH, WASHINGTON, OR WYOMING...........................................................................................800421-3724 SOUTHFIELD, MICHIGAN 48076........................ 26500 Northwestern Hw*y......................... . 313-354-08Q0 Pm Jkfnarica ARGENTINA ,,,...... ..............Union Carbide Argentina, S.A.I.C., Buenos Aires BRAZIL..,........................ ...... Union Carbide do Brasil S. A., Sao Paulo, Hid de Janeiro CANADA ........................ Union Carbide Canada Ltd,, Calgary, Lindsay, Montreal (Lachine), Toronto, Vancouver CARIBBEAN ................ Union Carbide fnier Amerlra, Ine., San Juan, Puerto Rico COLOMBIA ................Union Carbide Colombia, S. A,, Bogota ECUADOR..............................Union Cacbtde Ecuador, C.A., Guayaquil MEXICO.................................. Union Carbide Mexican#, . A., Mexico, D. 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UnionCarbide Ana, Ltd., Peialing Jsya, Selangor NEW ZEALAND......................Union Carbide New Zealand Ltd., Auckland PAKISTAN........... ...............National Carbon Co, (Pakistani Ltd,, Karachi PHILIPPINES...,......................Union Carbide Philippine* Inc., Manila SINGAPORE..........................Union Carbide Asia Ltd. TAIWAN................................... Union Carbide Formosa Co,, Ltd., Taipei THAILAND............................ UnionCarbide Thailand Limited. Bangkok Evrop* Africa F-44716A 10/75--4M AUSTRIA............................... Union Carbide Austria G.m.b.H., Vienna BELGIUM..... ......................... Union Carbide Belgium, NV, 8-2730 Zwi}ndrecht. Antwerp FRANCE.................................. Union Carbide France, F-94533 Rijngis (Paris) GERMANY.............................. Union Cerbide Deutschland, G.m.b.H., DiisseldOrf GREECE................................. Union Carbide Hellas Industrial and Commercial S.A., Athens ITALY...................................... Union Carbide Italia 5.p.A,, Milan NETHERLANDS....................Union Carbide Belgium, Amsterdam SCANDINAVIA..... ...............Union Carbide Norden AR, Stockholm, Sweden SPAIN.......... Union Carbide Ibsrica, 5,A,, Madrid SWITZERLAND.................. ..Union Carbide Europe, S.A,, Geneva UNITED KINGDOM..... ........ Bakeiite Xylonite Ltd., London; England Union Carbide U. K. Limited, London, Manchester, Rlckmanywcirth; England AFRICA (FASTI.................... Union Carbide Alrica Ltd., Nairobi, Kenya AFRICA (SOUTH).................Union Carbide South Africa iPty.l Ltd., Johannesburg, Capetown, Durban; Republic of South Africa 'AFRICA (WEST)....................Union Carbide Africa Ltd., Abidjan, Ivory Coast MIDDIEEAST AFRICA INOrTH)............. UlUun Carbide Middle Ban Ltd., Athens, Greece nr^AncoA I$r'\_jUyD-ZU K M* h* O htn* 4 Printed In APPENDIX X DEVELOPMENT OF A METHOD TO DETERMINE RESIDUAL BPA IN PVC RESIN % m BFG0952I SST&OTT BFGOODRICH CHEMICAL LIMITED ALTONA TECHNICAL SERVICE LABORATORY REPORT FOR DEPARTMENT 40 ANALYSIS OF PVC RESINS FOR RESIDUAL BISPHENOL A Project No; 6980-1 Byi Greg Brown Date; 18th July* 1980 BFG09522 9STbOT T2 BFCU0DR1CH CHEMICAL LIMITED PROJECT NO: b98G-l ALTQNA DATE: 18th JuLy, 1980 ANALYSIS OF PVC RESINS FOR RESIDUAL DlSPHENOL A INTRODUCTION Sodium Nitrite, the shortstop currently being used by the Production Department, is corroding the metal plumbing. Production would like to use Blsphenol A (BPA) as a shortstop, but it Is not presently approved In the Standard for food contact applications. As a part of a submission to the National Health and Medical Research Council, we were requested to develop a method for the quantitative detection of BPA in PVC resins intended for food contact use. CONCLUSION A method was developed using an extraction technique, followed by gas chromatographic analysis of a derivative of BPA. This method Is given in the Appendix. EXPERIMENTAL & DISCUSSION All work In developing the method Involved spiking PVC resin known not to contain BPA* Two spiked samples of PVC resin were prepared by suspending a known weight of resin In ethanol and adding an appropriate amount of a standard BPA solution. The solvent w*a removed by drying In an oven* Samples containing 50 ppm BPA and 100 ppm BPA were prepared In this manner. When we had developed the method, the Production Department shortstqpped a charge with BPA and `supplied a sample for analysis. The BPA was determined by converting It to a volatile silylether with N,N bis(trimethyl silyl) acetamide - BSA. This derivative, in acetone, was then analysed on a Hewlett Packard 5706A Gas Chromatograph with flame ionisation detector. A Hewlett Packard 7671A Auto-Sampler injected a 3.2 jiL. sample onto a 6ft x 1/8" SS column packed with IZ 0V-1 on BQ/1000 Chromosorb G, The response was determined by measuring the height of the peak on a chart recorder. An automatic integrator unit (Autolab System 1VB, from Spectra Physics) was available but results were not reproducible by this method* This was due to poor resolution of the derivative which eluted on the tailing side of the solvent peak, la an attempt to improve the resolution, several other solvents including ether and benzene, were tried, but none was successful. A number of other columns were tried, but these too were unable to improve resolution. M ../2 JL104157 BFG09523 2 (coni ) The linear response range for the analysis was determined by derivscieing solutions containing known amounts of BPA. Figure 1 shows examples of traces obtained for the standards. Figure 2 shows the plot of peak height vs ppm BPA. As can be seen, the graph is linear within experimental error up to 100 ppm BPA. Initial development work InvoLvod mechanical stirring of a resin suspension to extract the BPA. Both acetone and ethanol were tried in this technique. Acetone proved to be unsuitable, as it dissolved the PVC* Ethanol was mote suitable, although it was necessary to remove all of it, as it reacts with the BSA. Separation of the solvent from the resin was achieved by vacuum filtration. Recovery of BPA by this technique was low - 50%. A method whereby the solvent was removed by decanting the supernatant liquid also gave low results. Continuous extraction in a Soxhlet apparatus was then employed. Aa before, acetone was unsuitable. Ethanol was therefore used to extract the BPA from the resin. After extracting a 20g sample for three hours, the solvent was removed by rotary evaporation* It was found that the addition of bengene (10% v/v) to the ethanol aided in the removal of any moisture present. The residue was then dissolved In a minimum volume of acetone (dried With anhydrous sodium sulphate) and quantitatively transferred to a 50ml volumetric flask. This was made up to volume with dry acetone. (Earlier work, where only 25ml of solution were prepared, gave greeter sensitivity, but was not used due to greater handling problems). Approximately 1ml of this solution was then placed in a vial which was sealed with a rubber septum* Through the septum was added 100 jil BSA by a syringe* A blank was also run using resin known not to contain BPA. These solutions were then analysed by GC* Figure 3 shows examples of the traces obtained for the recoveries. Table 1A presents data showing the recovery level. At 100 ppm BPA, average recovery was 90%. However, at 50 ppm BPA, the approximate working range of the analysis, recovery was 99%* The plant then produced a batch of resin which was shortstopped with BPA. The amount of BPA calculated to have been added was 89 ppm. Table IB shows the results of the analysis, in which the detected level of residual BPA was 62 ppm. Figure 4 shows a typical trace of the analysis. This method has been written up as Method No T-3021, and Is given as the Appendix. GB iSC G. Brown BFG09524 ?: a 4> !r+ w r a a i is i A. Recovery Oac<t Sample ppm BPA* Actual BPA X Recovery Blank n.d. Blank N.D. 50 ppm 19 ,, 6 '.9 9HX 50 ppm 20. 1 50 1002 100 ppm 33.7 85 852 100 ppm 32.6 B2 822 100 ppm 36,7 92 922 100 ppm 37.0 93 932 100 ppm 36.7 92 922 100 ppm 36.7 92 922 N.D. - not detected * multiply by dilution factor 2.5 to give Actual BPA Average recoveries 50 ppm - 992 100 ppm - 902 Over 0-100 ppm - 94.52 Plant Trial Sample 1A 24.7 IB , 25 2A 24,7 2b 25 Average 62.25 ppm BPA 62 62.5 62 62.5 BFGG9525 w O cn U) * . 11 I !' "U. ; LZS 60Dd9 I T 'ec 1I r* _ s <S s' ............................ sa -- - -- ------------------------------------- ) ') iV 1 i i i i y i i i i i &KCOOUKICH CUBICAL LIMITED APPENDIX mm METHOD NOi T-J021 TITLE; ANALYSIS OF PVC RESINS FOR RESIDUAL BISPHENOL A PRODUCTSl PVC KLSINS TYPE OF ANALYSIS: EXTRACTION AND C.C. SCOPE The method is designed to determine Che amount of residual Blsphenol A (SPA) shortstop in PVC resins. PRINCIPLE The resin is first extracted in a continuous extraction process. After preparation of the final solution, the fiPA is converted to a volatile silyl ether derivative and determined by gas chromatography# SAFETY Observe normal safe laboratory practice. Carry out the extractions in a fume hood. The detector and inlet of the chromatograph are very hot, around 300C. INTERFERENCE 4 If using an automatic integrator, a small peak before the one of interest causes interference. Use peak heights as a measure of quantity of product present# REASON FOR ISSUE; NEU METHOD Date Issued: 18th July, 1980 Distribution: Issued from; Written by: Checked by: Technical Service Lab G. Brown H# Deahl Analytical Services Laboratory Supervisor (DP) Customer Service Officer (GJU) Technical Service Laboratory (RJ) Customer Service Laboratory Supervisor (2) (HZ Quality Assurance Laboratory (AR) Supercedes Method No: BFG09530 21104164 2- - PUKClBLON Precision has not been determined. Recovery rates are greater than 90%. APPARATUS a) Normal laboratory equipment b) Soxhlul extraction appurnlno. c) i) Gas chromatograph equipped with flame ionisation detector, A Hewlett Packard 5706A chromatograph was used, and the analysis refers to this machine, ii) Column; 6ft x 1/8" SS, packed with 1% OV-1 an 80/100* Chromasorb G. REAGENTS a) BPA solution - L000 pg/ml Dissolve l.OOOg BPA in 1 litre dry acetone in s volumetric flask. Store in a refrigerator b) N,N bia(trimethyl silyl) acetamide - BSA. Store in a refrigerator. c) Dry acetone - store over anhydrous sodium sulphate d) 102 v/v Benzene in Ethanol - store over anhydrous sodium sulphate PROCEDURE In duplicate, plus a blank* Weight out 20g of resin Into a Soxhlet extraction thimble. Extract the BPA with 10% Benzene/Ethanol In a Soxhlet apparatus for 3 hours. After allowing the solution to cool, che solvent is removed by rotary evaporation under vacuum over a water bath. When the solvent has been removed, the residue is quantitatively transferred to a 50ml volumetric flask and made to volume with dry acetone. Using a teat pipette, transfer approximately 1ml of this solution to one of the vials for the Hewlett Packard automatic injector and seal with a rubber septum. With the aid of a syringe, Inject 100 ^il BSA through the rubber septum, and shake for a few seconds. s Analyse the solutions on the Hewlett Packard gas chromatograph using the automatic sampler. Also run a sample containing a known amount of BPA (about 25 ppm) as a standard for calibration. ../3 BFG09531 i 104165 - 3- UmIhh the Hewlett Packard Chromatograph The column used lor EDC analysis will have to be removed, as ic win not withstand the high temperatures to be used. Place the OV-1 column in the chromatograph oven on the "Column a" connections and block off the "Column A" inlet with an appropriate fitting. Ensure all Joints arc tight. Set the oven temperature to ZOQC, and the Injection port and detector to 3Q0C. Allow about 2 hours for the system to stabilise, then zero the chart recorder. Load the samples Into the turntable, with the last sample in position "35". This will ensure that the machine stops after analysing Che last sample* Set the analysis time on the auto-sampler to 30 minutes, and the integrate time to 20 minutes. Also, sat the sensitivity of the chromatograph to "Range 10", and set the channel module beside the chromatograph to an attenuation of Mx2M, A 'syringe stroke* setting on "Stop 2" Increases the sensitivity of the analysis. Normally only one injection per temple is required, although two or more may be used If desired. Rotate the turntable to the position of the first sample. Start the analyses by pressing "Run", "Reset" on the auto sampler control panel, and set the chart recorder In motion at a speed of 0*25 In/mln at a sensitivity of 0.001 Sample traces are shown in the Appendix. Programming the Autolab System 1VB Ttiis can be done while waiting for the chromatograph to stabilise. Turn off the "Data Protect" switch and the computing function ewitch behind the fold-down panel on the Channel Module beside the chromatograph. Select "Channel 3" on the thumbwheel on the Integrator unit and programme the following functions Into the Autolabt T1 * 0 Peak Width 10 Slope Sensitivity - 100 T2 - 200 Min Area * 0 Run I.D. appropriate number Aux Reg 60 " 1 Aux Reg 61 * 200 Turn on the "Data Protect" at the channel module. ../4 BFG09532 99T&OTT 4 CALCULATION Although the Autolab gives an Integrated area of the peak, it does not give very reproducible results. This is due to the BPA/BSA eluting on the tall of the solvent peak. Peak heights on the chart recorder are a better indicator of concentration. by drawing a tangential baseline on the chart recording, measure the height of the peak. ppra BPA " height of peak x ppm in Std x 2.5__________ peak height of Std % recovery* *%rccovery in the O-lQOppm range 94.5% Report the results to the nearest whole ppm. SPECIAL INSTRUCTIONS The preparative work, up to the derivatlsation step, should be carried out within the one day to give reproducible results between duplicates. ^9T>O TT i: BFG09533 1 ________________ i f\ s )- 100 i Ur+.6>+ K4$****C ****+/- ) BFG09537 Calibration Graph and Range. The calibration graph is linear over the range 2 to 16 #g of tantalum in 10 ml of ben zene. The optimum range for absorbance measurements on the spectrophotometer is 0.2 to 0.7 absorbance unit. With the recommended procedure these values correspond to 4,4 to 16 ag of tantalum in 10 ml of benzene. The effective molar ab sorptivity for the tantalum complex in ben2en is 83,000 at 635 m,u. Precision and Accuracy, (n order to obtain a measure of the reproducibility of the determination of tantalum in pure tantalum solutions, the same amount of tantalum (4 Mg) was determined 21 limes over a period of several days, The aver age absorbance was 0.184 and the standard deviation 0.005 ab sorbance unit or 2.8%. Table 1 shows tbc results of analysis for tantalum of some simulated tantalum sample solutions which contained other ions. The table also includes the re sults for the determination of tantalum tn several ferromolybdenum alloys. Effect of Foreign loos oe Determination of Tantalum. Solutions were prepared containing 4 m8 of tantalum and a 100-fold weight excess of each iOQ to be tested. The tantalum was then determined by the recommended procedure. An ion was considered to interfere when an error in the net absorbance for 4 fi$ of tantalum of greater than 5% was produced. The presence of a 100-fokl excess of the following ions caused no interference: Al, Ag, As(V), Ba, Bi, Ca, Cd, Co, CKTO), CiKH), FedH^MofVI), Na, Ni, Pb,'SWlll), SnUY), 5n(H), Sr. Ti(IV), U(VE), W(V1), Zn, Zr, acetate, chloride, bromide, citrate, nitrate, silicate, and tartrate. The presence of a 100* fold excess of Ce(IV) and V(V) caused interference by oxida tion of the Victoria Blue B reagent. The presence of the fol lowing ions at 100-fold excess gave rise to the error in absorb ance given in parentheses: NH/ (+19%), Hgfll) (+22%) Th(IV) (100%), and BA1" (100%), The presence of a 100 fold ca.'css of niobium(V) caused a positive interferes (+66%). The available niobium metal, however, containa ca, Q-Q2% of tantalum. After allowance for the cpniributia of the tantalum impurity to the absorbance, this error is r< duced considerably. A 10-fold excess of niobium (tantalus free) cab be tolerated without interference. Nature of Complex, Victoria Blue B is blue (absorption maximum 635 rim) in aqueous solution between ca. pH l an pH 12, and exhibits a yellow color (absorption maximum 47 mu) in acid solution at pH lower than 1. In the recommend* procedure for the determination of tantalum, therefore, tfa aqueous blank solution is yellow. The maximum absorbs^: of both the reagent blank and tantalum complex occurs at 63 n*M after extraction into benzene. The slope ratio metta (7, 0) indicates a reagent: tantalum combining ratio of I ;| The reagent-tanLilum-6ut>ride ion association complex wtoxd is formed and extracted into benzene thus appears to rend from the interaction of the protonated reagent cation with (hi UtUaium-fluoro complex, TjjFt*-, $o that the empirical ft* mule is represented by RH" TaF, The mole ratio m*ta (0) failed to give deer indication of the reagent : tantalus molar ratio, presumably owing to the low stability of the satiation complex. Rjceivsd tor review June 7,1968. Accepted July 26,1961 (7) A. E, Hrvy and D. L. Manning, J. Amt*, Chem, Sorn 19 4488(1950). (8) A. E. Haryey and D. L. Manning, ibid., 74, 4744 (1952), (9) i. H. Yoe and A. L. Jones, Imo, Eno. ChM,, Anal. En.t tt 111 (]?44). Determination of Bisphenol A and Impurities by Gas Chromatography of TheirTrimethylsilyl Ether Derivatives L. E. BrydU Chemical* ood P/attic*, Union Carbide Corp,, Bound Brook, N. /. 08005 Bisphenol. A (4,4'-iiopropylideoediphenol) ir an' important chemical which ii used in tbc production of polymers such as epoxy and phenoxy resins, polycarbonates, and polysuifonea. Commercial bisphenol A generally exceeds 99% in parity and a product having a purity greater than 99.8% is normally con sidered a requirement for the synthesis ofhigh polymers. The major, high boiling impurities in high purity bisphenol A, orig inally identified by Anderson, Carter, and Landua (/), are 2,4'-bi$phenol A (2,4/-isopropylideoediphenoi); Duukin's compound (4.4'-hydroxyphenyl-2.2,4-trifne(hylchronisri), also called monophcnol or codimer; and triiphenol [2,4-bis(,dimeihyt-4-hydroxybenzyl)phezu>]), also referred to as BPX. Despite the widespread use of bisphenol A as> a raw material for the production of polymers, no quantitative method suit able for rapid analysis of this product was found in tbc litera ture. Chromatographic procedures have most frequently been used for the analysis of bisphenol A. Paper chromatography was employed by Anderson, Carter, and Landua (/), Chalia < I) W. M Anderson, G B. Carter, and A. J. Landua, Anal,, CHsm., 31,1214(1959). 2212 * ANALYTICAL CHEMISTRY and Hermans (2). and Reinking and Baniabeo UY Aureus Degeorges, and Normand (4), and Zowall and Lewandowali (5) used thin-layer chromatography for this analysis. Hoi ever, quantitative results are difficult to obtain with these td cliques. Gas chromatography has also been used for the aoa yris of bisphenol A. Direct methods have been reported 1 Tonunaga (6) and Davis and Golden (7), but GUI was unab to determine bisphenol A directly because of serious pei tailing (fl) and Anderson, Garter, and Landua (/) and Freud wald (9) observed decomposition when a direct procedure w< employed. (2) G. Challa and P. H. Hermans, ibid., 32,778 (I960). (3) N. H. Reiokitig and A. E. Bamatao, ibid.t 37, 395 (1965). (4) J. Aurcoge, M, Degeorgd, and J. Normand, Bull. Soc, Chi Ft., 1963. 1732. (5) H. Zowall and T. Lewandowska, Chem. Altai, (Warsaw), l 947(1965). (6) S. Tominage, Bunxki Kagaku, 12, 137 (1963). (7) A. Davis and J. H. Golden, /. Chromatogr., 26,255 (1967), (8) H. H. Gill, Anal. Gum., 36,1201 (1964), (9) J, E. Fftudewald, unpublished work, Union Carbide Corj Bound Brook, N. L, 1964. 21105172 BFG09538 I Table I. Analysis of BispbeooJ A Synthetio by Gu Chromatopapfcy of TMS Ether Derivative* 2,4'-BPA> 0.20 0.10 0.48 0.09 0.05 Wt, % added______________________ Diamtv* 4,4'-BPA Trisphenot 0.10 0, II 0.19 0,05 0.01 W.3Q 99.79 98,85 99,77 99.89 0,,24 0t 0.48 0,09 0.05 ________________ Wt % found* 2,4'-BPA Diaain'i 4.4'*BPA 0.20 0.10 0,48 0.09 0-06 0.11 0.10 0.18 0.05 0.01 99.49 99.80 98.91 99.76 99,88 All results ait averages of two or more determinations. * BPA -- bisptiertOl A. Trisphenol 0.20 0.43 0,10 0,05 J The direct method of Tominaga is tiot desirable for the -apid determination of trace impurities in bisphenoi A because he procedure requires an extraction with boiling xylene prior !.o chromatographic analysis. Furthermore, a different chro matographic procedure is required for the determination of li- and trinuclear phenolic impurities. Davis and Golden late that bisphenoi A can be quantitatively determined by I direct analysts providing an all glass inlet and column system is used (7), but these authors provide no quantitative data to upport this claim nor do they indicate whether their chroma- . ographic procedure is capable of determining separately the { individual impurities in bisphenoi A. Gill determined bis* nhenol A and associated impurities by gas chromatography iftcr converting them to acetates by reaction with acetic aithy- !Jride. However, the Gill procedure has the disadvantage of being extremely time consuming. An analysts which deter mines each impurity individually takes over 2.3 hours. This uper describes a method for the analysis of bisphenoi A and { die determination of the major* high boiling impurities in bisphenoi A by gas chromatography of their trimethylsilyl ither derivatives. | experimental ' Append*. An P and M Model 810 dual column gas ! hromaiograph equipped with a hydrogen dame ionization ietcctor was used. The chromatographic columns were stainless steel* 6 feet X 0.25 inch, SflicZad (rested* and packed with 1 % OV-1 on 80 to 100 mesh Chromosorb G (HP)* Supeko* Inc.). The injection port and detector were main* aiiud at 300 *C. Gas Hows were: helium, 65 ml pa1 min* jie; hydrogen, 65 ml per minute; and air, 530 ml per minute. The column temperature wi* held isothwmelly at 200 4C mtil the bisphenoi A derivative eluted, then programmed to 175 4C at a rate of 20 C per minute. All peek areas were iileasured with a planimcta and the weight ptf cents were calculated by using the appropriate response factors and formalizing. Chemicals* Bi$(trifnetbylsilyl)scetamide was obtained either /rom Supelco, Inc- or Applied Science Laboratories, Inc* and was used as received. Only reagent packed in glass 'eated ampoules was used. The 4,4/'bispheno( A was the tigh purity product of Union Carbide Corp. and was rejrystalliad twice from benzene before use. The Dianin's compound, 2,4'-bisphenol A, and traphenol were isolated | from commercial bisphenoi A by fractional crystallization j md distillation, i Procediae. Approximately 100 mg of sample were) weighed into a two-ml serum bottle* and the bottle was stoppered with a rubber septum cap. To aid the reaction i partial vacuum was pulled by evacuating air from the xntle with a 10-mi hypodermic syringe. One-half milliliter of bis(trimethylsilyl)&cetamjde reagent was then added to 'he serum bottle with a hypodermic syringe. The derivative I ipararion was shaken continually until the sample was ] completely dissolved (15 minutes). A 0,5-nl aliquot was then withdrawn and injected into the gas chromatograph. Table II. Relative Retentions and Relative Responses for TMS" Ether Derivatives of Comi>iients of High Purity Bispbenot A Samples Component Structure Of derivative Relative Relative retention response 2.4'-BiaphenoI A eras 0.655 1.12 Dtanin'* compound 4l4'-BUplMQOl A 0.807 1.42 .00 1.00 TriapbeflOl 1,22 CH, TMS - Si--CH, CH* RESULTS AND DISCUSSION In the determination of relatively nonvolatile (* g , trigphenol) or heat sensitive compounds (e.g., bisphenoi A) gas chromatographic analysis is frequently preceded by the prep aration of stable, volatile derivatives. Trimethylsilyl (TMS) ether derivatives have been widely used for this purpose, Bis(trimethylrilyltaceUmide (BSA) is a relatively new silyjating reagent which reacts with a variety of active hydrogen-contabling compounds to form TMS derivatives (JO). The phenolic hydroxyl groups of bisphenoi A and of the major, high boiling impurities in bisphenoi A are quantitatively con verted to the corresponding TMS ethers within 15 minutes (10) J, P. Klebe, H. Finkbeiner, and D. M, White, J. Amer, Chem. Sot., M, 3300 (1966). vou 40, NO. 14, DECEMBER 1968 2213 < Z L l POTTS ! k t \ t 1 Figire l. Chromatogram of ifce TMS etbfit derivative* of bisphenol A and of the major, high boiling impivitiea Id MaphcnolA after (he BSA reagent is added to the bisphenol A sample, pro viding the sample is completely dissolved in this time. The products of these reactions were verified by mass *pectrt> metric analysis of traps of the individual gas chromatographic peaks. Each of the compounds gave parent 1<m,of,4hn proper size for all QH's being replaced byOSi(CHt)'i. The emphasis in this work was on the analysis of high purity (>99%) bisphenol A. The method was developed with a hydrogen flame ionization detector because the conceit* iration of impurities in high purity materiel is frequently below the detection limit of the thermal conductivity detector. The present procedure can readily determine impurities at the 30 ppm level without a concentration step. The separation of the Di&nin's compound derivative from the 414/*hlptbnol A derivative is critical to this analysis. The beat results were ob tained by operating the oven Isothenrnlly until the 4,4'-isomer derivative eluted, then rapidly programming the temperature to dote the trisphenol derivative. Chromatographing time for a complete analysis--le., separate determination of each component--by this method is approximately 90 minutes end this time can be cut in half if it is not necessary to determine the low concentration of Dianin's compound which is nor mally present in high purity bisphenol A. To miAlmim anal ysis time, the excess BSA reagent is not removed from the derivative preparation prior to chromatographic analysis. The excess reagent and the derivatives bum at the detector to form silica, some of which is deposited on the collector elec trode. These deposits adversely affect the response of the hydrogen flame ionization detector. Daily cleaning of the collector electrode mitigates this problem. This preventive maintenance takes less than 5 minutes a day. Table I shows data which were obtained by analyzing syn thetic mixtures of the major, high-boiling impurities to hisphenol A and illustrates the reliability of the method for the analysis of high purity material The synthetics wen pre pared by accurately adding acetone solutions of the impurities to weighed amounts of twice recrystallizcd bisphenol A and evaporating the acetone with a stream of nitrogen. The de rivatives were theo prepared in the usual way. The relative intentions nod the relative responses of the TMS ether deriv atives ofthe compounds of ituereu are listed in Table II. ... jTba results .of a study on the precision of the method are summarized in Table 111. These data were obtained from 5 surowwive analyses ofa synthetic mixture- figure l shows a chromatogram of the TMS derivatives of* ofhigh purity bisphenol A. r In.addition to the high boiling impurities, low concentra tions 0.1,%) of water nod phenol may also be present in high purity bisphenol A. BSA rapidly hydrolyzes in the pres* mCe of Water aitd the TMS ether derivative of phenol elutes with the BSA reaction products under the conditions of the method. Therefore, these impurities can not be determined bythe promt procedure. If their detenninatiQn is necessary, they can bo measured by alternate procedures. The water Content of bisphenol A can be determined by a Karl Fischer titration and the phenol can be determined by a separate gas chrqcnetographk method (4, 11). Preliminary work in this laboratory indicate* the feasibility of determining both watw and phenol in bisphenol A by a single gM chromatographic iDtthod using a column packed with Porapak Q (Water* Aug. atafsirlnc,). t A troubkaome problem encountered during the early part of this investigation was the sporadic appearance of extra neous peaks in the chromatograms. The source of then peaks was traced to BSA reagent which was purchased in sili cone rubber stoppered serum bottles. BSA apparently reacts with impurities in the septum to form volatile compounds which elute under the flondMu*** of the method. Similar ob- (11) F. KanM and K. Slang*, 2. A*U. Chem,., l*, 261 (1962). Table QL Precision Study on the Gae Owen*toyphlr Method far Analysis of High Parity Bisphenol A Component wt. % added Wt. % found (Average 5 analyses) % *14. dev. Absolute Relative 2,4'-Bi*phcDoJ A Dianin's compound 4.4'-Bupbenol A Trisphenol 0.09 0.05 99.77 0.09 0.09 0.03 99.81 0.08 0.0044 0.0017 0.0031 5.6 5.1 6.2 JVh 2214 * ANALYTICAL CHEMISTRY BFG09540 stations were recently reported by others (Chromatography Lipids, August J967, Supelco, Inc., Beliefonle, Pa.). This in terference was eliminated by using ftSA reagent purchased in glass sealed ampoules. Glass vials stoppered with septum, as recommended in the present method, can be safely used &$ saction vessels for preparation of derivatives; however, pro longed exposure ui the derivative preparation to the septa should be avoided. acknowledgment The author thanks W. F, Beach, O, M. Garty, and J. W. Lewis for helpful discussions. The provision of pure samples of the impurities by A. G. Faftiham and of twice feCrysldllizIed bisphenol A by F. Schnur is gratefully acknowledged. Received for review July 22, 1968. Accepted September 9, 1968. Indirect Spectrophotometric and Atomic Absorption Spectrometric Methods for Determination of Thiocyanate Richard S, Danchik and D, F. Boltz Deportment of Chemistry, Wayne State University, Detroit, Mich. 48202 Absorption spectrometric methods for tt>c determination Reagent*. CorPERfU) Solution. Dissolve 0.252 gram of nonmetals are being investigated in this laboratory. This paper reports a study of indirect spectrophotometric end atomic Absorption spectrometric methods for the determina tion of thiocyanate. These methods are based on the forma tion or a dithiocyanatodipyriditie p6pper(H) complex which is extractable with chloroform. Specu (J-J) ha* studied the precipitation of coppet<II) aS/CufpyJifSChOt on both the micro and macro scales, The' colorimetric determination of copper using this comptot has been investigated (4-7). of pure copper shot in dilute nitric acid and dilute to a liter with distilled water. One milliliter of (his solution contains 0.252 mg of copper. Standaiuj/Thiocyanat* Solution. Weigh out 0.194 gram of pptassium thiocyanate and dissolve in 1 liter of dis tilled wgfer, Use standard silver nitrate as thrum and ironflUf indicator to standardize (he thiocyanate. One miUjJiur of the thiocyanate solution contains 0.116 mg of thipcyanatc. /All chemicals were reagent grade and all aqueous solutions Colorimetric methods asjAg the copper-pyridine reagent for /went stored in polyethylene bottle*. the determination of thiocyanate have also been studied / Procedure. Weigh or measure by volume an amount of (8-11). / , / sample containing no more than 800 ofl of thiocyanate in a In utilizing the qualitative formation and selective solveqr extraction of the/tomplex, thiocyanate can be determined indirectly by tljif determination of copper in the complex. total volume not exceeding 16 ml, The sample should con tain no more than 360 when the atomic absorption spec- trometric method is used. Transfer the sample solution U) a 125-ml separatory funnel, add 20 ml of the copper(II) The determination of copper by atomic absorption j^pectro- nitrate solution and mix thoroughly. Add 1 ml of pyridine mciru method is very sensitive (12). The indircot atomic and 20 ml of chloroform to the aqueous solution and shake ubsorption/spectrometHc determination of thiocyanate has for 6 minute* With an automatic shaker. After allowing 3 to S a sensitivity of 6.05 ppm and has the advance of speed, minutes for the layer* to Separate, collect the green organic high precision, and simplicity. EXPERIMENTAL /, / Apparatus. Absorbance measurements were made in 1 .00em matched ceils with a Cary Model 44 spectrophotometer. A reagent blank was used in the reference cell. The atomic absorption measurements were made with a Beckman Model 1301 Atomic Absorption Accessory, a Beckman Model DB prism spectrophotometer equipped with a Beckman potentiometric recorder, and a Techtron burner assembly. The hollow cathode tube was neon filled and supplied by Beckman. A Thomas shaking apparatus was used for solvent extractions. layer in a polyethylene bdttle. Spectrofhotometr)^ Method. Measure the absorbance of the organic extract at 407 m^ in a I.UOO-cm cell using chloroform in the matched reference cell. Refer absorbance reading to a calil^uon graph. Atomic Absorption Spectrometri? Method. Adjust the current applipa to the hollow cathode tube at 10 mA. Adjust acetylene-ail* flume until a luminous flume is just observed. Use a slitXvidth of 0.20 mm and adjust the monochromator setting until a maximum absorbance reading is obtained at the wavelength. Aspirate a standard solution corrafpoflding to 232 or thiocyanate in the chloroform lay^r and, < iust the restrictor to obtain maximum absoi bance. Aspirate standard and unknown solutions using the ab- J>orbnnce readout of the recorder. Prepare a calibration (1) G. Spacu, Bull. Sot. Stlinte Chtf,, 1,284 (1922). (2) /bid., p 314, (3) (i. Spacu and J. Dick, Z. Anal. Chem., 71, 183(1927). (4) R. Bimo, Ann. Chim. AppUcaio,, 16,96 (1926). (5) J, B. Hester. ; hemist+Ahalyst, 25, 78 (1936). f graph. In order to improve the sensitivity of the atomic absorption spectromefric method, evaporate the chloroform layer f almost to dryness and then dilute to 25 ml with ethyl acetate. , Aspirate the unknown solution and standard solutions using (6) L. Chalk. Analyst, 55, 187 (1930), (7) C. Bennoit, Ann. Chim. Anal. Chim. Appt,, 12,66 (1930). (8) /. Kruse and M. G. Mellon, Anal, Chbm,, 25, 446 (1933). the absorbance scale of the recorder. Prepare a calibration graph. (9) K. C. Bailey and D. F. Bailey. Frpe, Roy. Irish Acad., 37B, 1(1924). RESULTS AND DISCUSSION (ID) I . Moeller and R. Zogg, Anal. Chem., 22, 612(1950). (11) Y. Y. Lur'c. Zaafdskaya Lab., II, 273 (1945). (12) Beckman Instruments, Inc., Flame Notes, 1, 88 (1966). liminary Information Shaft. Pre Spectrophotometric Method. Thiocyanatf Cunce^tkation. Figure 1 shows the visible absorption spectrum of the organic solution containing (he Jithiocyanatndipyridine VOL 40, NO. M, DECEMM* 17*8 2215 ti i-- 'r* 5 u\ n rv r a APPENDIX XI COMPUTER PRINT-OUT SUPPLIED BY BFGOODRICH CHEMICAL, USA SHOWING BPA SYNONYMS, USES, TOXICITY BFG09542 S llV O T H f 1l o- r Hiit- r* i K !' PF'UF-: tif1 'ii*- . T (n [ItJt (7*. l.H of' *" i~ rl' i! r r*' R i *- i *i.i' TO.: CHI F, r H, '> ! -i 11 11 i- r* MULPrU-Hi- I,ir i-'ir, | 11 J * -1" DPR U1' YL I l ,LM" n'* I. IM-Mle -LK- 't - m`.i -- 7 i.'I Hi tJUl Ml 7 MLl 711* L ! He 1 *i "1 ril 1 0i , f*;mvn'. MUM , M'. I (' [i. > " :vIT\". -i -i-MT'c IV. YHhRi-,L' -KGPHMF r. I . 1-HtYU : H) 1 'i'i Ili'm *;)'! h '* F * '1 7 T t- Ur1 'i'l. "] lit Hr. I'l ^;,ht r,:LlL `I VI iC:> lil'.' TVMDM'.M" `.VHL'iMVrf; ~ 'i f iLi* * M'' 7 VMIJMYM7 71 mi.]m', iv: 1 YM'Jh'i ir. 7 YULiM'i l\r, 7 YM7i;r. H'; *: '.`i.lViym'- 7 `i`f iLIMYH'. 7 I'HDi i Yl'Y. 7YMOMYK7 CYMOHYU'. i'MOh i M'! 7-yhgm iY'*: F'NEHML 4,4 -- ( 7 I ir> LI?'Y LL I Irh Hf. Ei 1 -* H r; rrTC H ? 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SOLUBILITY .............................. SUL 1H RCET1C HC-I I* SOLUBlLlTl...............................................SLIGHTLY SQL 1N CAP POM' TETPACHLUP 7 DE SOLUBILITY ' ''VERY SOL' IN' Aij AlIhF.' SDLN* ALCOHOL' ETHER* ' BENE'EHE spectral' s' othEF props' mepc i-' hide gth ei,-- 590 mild phenol is - odor SF'ECTRhL DTHeP PPOR1 t.it'ftST. HDlP (. HEM RHYS'- S*?TH ED'-1 t-44 0 mrv ..................................... ........................... RtiSOFFTlDM' ' RLCDhL'L J .?'' HM' (LOO p:-4,4>* ........................................................75 MM >LOO P-- S. *' SPEC TRFiL *! OTHER PROPS' ' MERST.' HL'EP T HEM J' RHYS'- 557 H ED'- ' ' C-E-74 SF'ECTRRL S OTHEF PROF S SRDTLER' REF - MIJf-iRER; 04*- `IF:* -PR1SM.M' 10S4? IP* I7-.RRT1 Ml? * MERCK INDEX Pl H Rf ' ' 5Ri'.i'- DECOMPOSES RtOVE R ....................................................MM' PRESS UR E-UHEM HfeTiTED'- RELIVE'- S&u DE5C TOXKITV- VRLUES TUXK1TY VALUES .................. fUO'.H. 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HRUSER't ` i.il TH OR Wl THOUt' VOMITING* SEVERE ' RDDOt'UNRL` PRIN*'&' CORROSION OF'* HPS>' MOUTH* thrort* esofhrgus a stomrch.there mrv be ' PERFOPFUION. >PHEMOLSX RCUTEIS SHDSOPRL5 DIGESTIVE' SYSTEMSNftUSER esophrguststomrchi burns* chemkrltpeptic ' ULCER PERFORHTTON ` RCUTE1 S ? NDS OPhL i MOUTH'' RND 1 TFETHMlOUTHl PHRRYNX ' L1PI BURNT* ' CHEHIC'RL ' RCUTET T!ND1DPRLSHD*RBDQMEH*PRlN ' SRX.' DRN15ER'-PROPS-INDUS - MHTER-4TH ED- ' 458 SEE' PHENOLS. UN SPIN'* '* THE'1 RPFECTED RPER* 1S ' WHITE*' liiPlMh LED RND ![OFTEflED PHD THERE ' 15 ' USURLLY HO IMME.DIRTE'-CONPLRINT'-OF'-PR1N3 ' LRTER* 1NTEM'; E BURN 1 MG'- IS FELT* FOLLOWED-BY LOCRL RHE5 THE'; 1ft RND" TILL LHTEF BY-GANGRENE'. - PHEMUl-S: Rr.UTFSMriD!FEPpUTRHb'au;s:- INS tiiRN*-; CHLMTCRL ' PRINTGRhGPEHE SCUTESsSHD*Pfc'RCUIRNEOUS;HEPVGu: SYSTEM ' NFRVOLfV YSTFl'i M " `-f-' F ^ L ft:' [tMM'j i:P FL; , j: . i,r. .. .ild'Lli ' 45!:; SEE PHtML'lLY. ' I'Jlil C PQ1 5 OH i NL-. FOLLOWING ppptUf t'.'ti d Exi- rr t.ij* h." i low i onrH of vrpoR qp IIKl Ft'.UL.l". Ill nlGtSTlVE DlSTUPthh! El `VCIMIIIMRi DlrF ICUlTV, . .SWhLLOwlHU* -EXCESSIVE " til 1 \.'M I 1 fill , (VI t-i. C'UI-'Li. . i nc e ni: c.ct-1.- t t tc - . cdmnrsue prihnngt HbPvO',i. DT.DFDtiPS* PRINT!HGi -DIJriHbSS* ML Ml RL I'l " T i.iPBftnC 11 *' jk Hi EPUPTHirr-. ''PHLHOLZ vi:xnu C3TM)TT2 BFG09546 MtUbl HUNAN' TOWTCITV |.VUOF(**i-'` ''CHKDHlClt UlL'tfU.l HIM*': I1 VS V* UN* VIIH IT llih .............................................................. D1 AMi*HfeflUKG*l.un r 1 an l.i ItlK LIki H ........................................... ..................... CHRONIC I t H0I MOUTH WiLi TEETH ..................................... .............. ..............:J*LDf*frHR .................................................................... CHROMIC* * v 11- MS Hh> VUU' Z Vi TH .....................;........................ iiisEftie'.^.vrn fii-1 * vtpttgu ....................................................................... CHfrUHK* 1 <<|Hiii.U*.'KhL rmke'-'vec - :.................................................WEHTAL OUUkDbfC .................................................................. chroiuc?sino*Nil?mm: irror.Efties ..................... CHRQMl Cl i 5 HD? ML** HO* hntiRfcMft S$ & SC7 USEftl "FILS' RTEC PMJ61 YOU ARE' NOW CONNECTED TQ Th'- RTECS' FTLE. 5S 1 ^CT USER) i 80-05-7 1104181 BFG09547 r: u u i I i i 4 i WI"' '.rjufr.'j/ in n, n ]' 111 inn F F | hr. 11 .!( h` f p i 11 J >> , * jt if`i 11 fi tLH *, lil ' U'D lMi.u SYmUuyh: SYliCMi. rt: SVJtfMhV syhuh. h\ tvtiOhf i-r. VihUMYM': TYhOifYM XYHtlMiTI1- SYNGhVMV SYHGhYMy SYNONYM* rvriOhVhV- SYMfltlYM* SYHOMYMT WtUViYtt': VrhLHvnr jymohym: SYHOKTflV s'.'uahvh' SYHOMVM'. ' ranrihMt. ppimtimp-'. ye': mu *< i l Ml IM 1 H' t- IH-Ilhi-I I, [> M-1| H. . II '. 11 1 I . Ili I II ll' * 111- i 11.( M .r 11 | `I V LV f fit 11 'i-tf11 M I ll" H| I ' l I I i I* I'll h' l ih fh. fcViFFFUL t-* M- iS.'-- t- (: "M v 11*' * i. i ! h i i l i:,f* r irvHfi > r. i: c h fj| 1 *4 'Hi L'l- n:I-Hh f * YL -III HI; \ H , 1. Ml: I HHIrt. ' > 4 --H i i."' ( 1 i h W IIYL. 1 (- V* l Jf V~H?T < t-fc: I 7 * h -- H i L'f* T I.;'hi- hr I r.'i, ' (-> Q*- nt 'F * - L 1 '4-HiLiKir ihHl.M'iL F f* l'!; Hi Y fcUPHFHtlL .1-F'HlrhL'JL' H 4 *4 ' -LI IFht I lul. M D1 Til < F'.P -MH i I'Kn, .YblFHfHYLMMh TMYL NETHHilt' 4*4 -DIN i DPli; YFM I-hi-H'i (. L]cIl 1 h . LMr f HnhL; P* P` _l*l MYC'PU' i L l F cn: HYL PM-lNNHE * " ` 4 * 4 -- D f M i L'F |.V' i til F`Hi; I YL ' F'F'CJFRHh 4.4' -DT H YDF 0-'. Y D 1 F Hr'/ IYL b F'DPHME 4*4 '-tHHYDKl 'I.'-*F'Hr'HHF 4* 4 ' --Dl HY DF [!' ' i -j * --l` 1 F He HYL.F FTlh HflF DIME Thymic TM .LcMt-P.P- -H PHFHL'll f:ETH-D'I-P-H ,-u^rY '.'PHHV.LPC-Of di<!" r I ' 4"H i D'* |j. i h Hr: tl i L ' t-'b Pf *t ho . - UtER* V i PfrOS* v i if.if'. Y j i, 4 ".jM ' ^YhUhYM'i SYNDHYrt'. SYHOHYMY DIMETH'i'L Li: -F-HYl.^O; :VFHhM i U Dl PHt H'i'l. Ml F F I iF *'. -- DI ' 4 -i-'Hb M i I. LiL 1 HF OFftf it p.p^-riOPFrjF-.LlDuHEMlFHrnUL 4*4 -l^OPFOPil 1 DEMFLlTPhtflDL SVMOMVM^ P. P' -1 F; OfPUPVt I I'E 1 D J PHfcI UL SYrtomw jyhohvm': Svi40Hi>r; MUCECUtftfr KOPK'Lfi HGLECULhP htKihl ttUWE^:Efr UHtMuTRTlLiH ttiTfry kqmh TOXIC I'HTP ';QUFCE PHEfiOL 7 4.4 -MI METH'YLNfeTHYL EhEn - PPOPRME * ^ c-t ] : * P-rtYI.PQ;-;YFHfchTL,' - Cl^-Mlo-QS ES3.3I rp <: i;.s is*'- e<h 79 03- SSZPFtF DOPM l VY'J LEriFH TDM XOl 0151 CL PHD V7S6TPEM Lh ! M h FPIPPPvm.i*j.V.' hhPhOLD* i ir n i u r pro m i: muvu veoouc i cm ppRr. uvhu u CHEMICLfcHO FHIMVIIUJ PPPhh* C^ECHUCLUVHl IB* 19? 7S' TOXDRTCl * E VMuc l't ' ESF'HPMTSrWfcHTMTPF` 17ftT1 DM30 W5' S4H TO:-:it. effect:severe TOW"C DftTR -OF'ft- FL. Ph- v]; iV* 1-^ '1f F*u h', : CiL 'i til i 111 i nP`. n l Vt OF' IHIUJ'TPIRI. HYMlEHt fh UCCUFMILjHK rTTi^TFi i MEDTCIMC. 4* I 1 '? Ci 1 r-U-Hl F P1 * F'Cr |i-. 11 | 1 I J:' fUl .i*- I'H 1 " r - L HI hHnF -Wit K 11. Ml' 1 Mi FTiCUUHT lOh JiH.iKMMl i r * i. nil. S * SOI *67 COMTIh'.'e PFlhlTh'5" ' MU BFG09548 M H* H* O K pVjl'lT L>L l.UNfMl I MU! MILL* U-EF* Y P-G.OSs TpKDHTfi'-^YMOFI'; to;; it r*R i f* ;Gi.*hCe to;;i'Htr i eymufi*: TO`,;U WilB U':MH.e' TQtfflHTR -eYI.*L>[*: IOa'IC r*MP `LH.tKfJt TD/DhTft \ 'M>KiC' (C raac iri*;> TaYDRTft 'i`j.iUK l*" FPL J MCltj-.ET F'U ritHl"; 5 L I<T-u 5^00 hm LG Ml r:** MhTIQMHL TECHMKhL IHFQFnnI 1 DM 1EFVKE. Rt"r'- I --Mfui T r^TFHF t f1 7 TCl/t<- *-ti *1 l^gs mlYI G PiIHhMF hht h-1 f. hm lCff*i_*" IFlRl* MY'/ltflL RIYOC lhTiQM .iLn.VMhi., m:h r. r FPL l FhSf I TUIJUt-Ml*. i L Iif.nisc *" f \i hntRia'iM ME bit hi R*: : I'M. 1 H I'l Offh- I! H'l VL UF IMUU'.TPlhl. Hi'M 1 c ME ?. OCCUrRl 10MML llgDKTfie. 4-tl,vLi| LHhiFPKM t^'U,eur: s l . oou -u- \ g 34 zi Fife* 'TD;:irni.iir?Y' of r^<u-T* rh' ru*Mii;rl'v m, ?!. i!'" I r (* y r ' * f i, 11 `i. \' ] V*f -- L i o'-' OFhk, MRHMPLMi!':'M<5 I G 7 i i \ BFG09549 9 1ta n : n APPENDIX XII TOXICOLOGICAL DATA fi BFG09550 - MIC = cci !ime* la*= atyl- vi-` . )- -III" set .,i-o -Mi* HIV=* Wi* -4 j[a H.- j.i C IrJL^thyl-1 -eyelahntft- ] -vj|tci SCI i Larzliivt-tf-ldnott Ci^iTjiuaci thyl-3-(2,2JhtriiQithyttycJute|? yllpiapyll-, dichlorido SCI Acint-iitim. Ii..*a=wtJivlcr.. W*|di* - tii'A-ydalieayi^opyl]-. dwbla* i;t2e SCI RoS-Cdlft/i TiJburtitt `1'iiLjiucUloride ( Tkicl&Vtzi .lima cht&ridt t*-:-1-1 Crihtfh j ll- `uri ncr/bosylic weld, tvifuhy* , :.,u 901. 3-, rrid, U'ndiydfo,'.t2_<]lB _;t yl-6^i;0' SCI 7_y-L!:^:w-thylitOrtie ucid Y.v^ii--l!.53ylpiii-mfAdd ; tj,J.4v ;-.id 1C-EI.i1i-/Jcu fr'iliaH.mlp.v-tine, i,2;dun*^ * tliy'. I'.weii- '^fie- 9CI C._.-, -`.ti UU- '. J .- .i sj. 'l~ r *4 thltHTjuii*! i*i|) J-msihyi- SCI J iT.Nliei. i'lp-vlilmojihif* uyil-j-fiwtbyF- ^cl AcaltiL* It; Aetlo Fsliayn i `` f j . ' Phint'^Ja-gdol SU;fwil ; ' Suiil UltftM 79^; N7 CitHiDriO Phased, `i.-i'-U'-niuiliyli'iJiyiMeiiei* tbii.^-dibio.ao- CCl PlK.r., *i4,-Ji1>;osy|idsndiiiU-* dlfcn^nv- SCI &1rdEiL-- iip4A 1, TcU^bfS'Jiibb^^ncl A 24',&9'-Turab7<Hiwbfspiiiin4ii A S^A-T^mbromobiipheDul A T5-C,vC CuiluCbOj PcsrcJ, 4,4^{I-iL:tby1jthylI<)dno)B "diebicru- vL'I Phr-.'.l, 4,4'-UttCi`:rIopyuU5RebbHA-* 2,2'A3,'-Tii^liioiobipheJKil A 7J-L7-0 CitHlj02 Pi:.::, si, ]-rz:;thvloiKyl:JBe|" b',;!2-fii.Miiyl- SCI CTi l.L ,:.::JC ;t-yUJi-:i Jrii.il LCP 7-j-j.J-i CisthiCbCJj Sri.w.ti, 4,4'-(l -.r, :,>\yiciLyliiitiit)1=l CCI F 'l,`4,-v.6j.4v5jUdaBibi5i2-1* cci in S--:` - y-c. i. 1.2 1M A- 'SI Prct;Uyl Snilhl Uilfttt* 2- {a -tiuUnAilyluiliiwitiltixwl 2- N-&iU,enUylaniIi|Ki)*tb4eK>l CiHitNaOft Glyciaa, JV-J4-114 MBinaphenyl|a utfonyt)bhtiylJ- &CI Giy^nj, /tf-ip-autfeAilytpkeQyi)- AoMi^ulfoM - Cilcprio Cyvlv^nBiuk), 4^*-(l-meihylevhy> l[jin*lbb- 9C1 CycbnaxAnob e^'-ieopropylkieuev SCI 1, DHSitaVr-. iK3ntnbiaebe:A*l A U'v' rcmtBd hiapheitnrA________ Phenol, M'-d-mMliytethvlidaA#)* bit- 9CI ' Phtnoi, 4.4ViaQpropyUdaitdi- BipIiMalA i !' Bt^hnnoiA , { 3 1 DiphifiyMpnnan* pj'-leepwipyUdimblipfemi Mr-tupropjrUdenb4Mplieneil p.p1-UopeopylidiitoBdiplHfiQt, M-Iaopfofvwe^tdtrMncI' fipi*!*A,,Tnrr-A4^UWpyUdMM4l9)wpi mm . cbicr&pbiiyl)-ti-pHKhylu 0CI B^^t^,ydrt^4(4,^iieWorlJHl*-nw' BL/pr^;dorapbayt)0>chy| carbi* ;rei Bl-^4-<bk>pltMyl)U4Utyi eubiito) BPii CiJetr^actluil DCPC DDWitvC.j*y ; : ENT 0.424 S0-C7-S C2MC1iOi$ l.l'-Milfti&ylbiitS-chlaro- Sul.'o^l.', tii^p-chlorophinyi) tCI Bi3<p-t;,]oft>phoyJ| tulfocit Bia|-l-ruaniptanyii tul/ona 4-CMi4'C|)henyi eulfon* p.p'-Diciilaroaiphtnyl aulfop* 4.4'--ri-*blriiplMiiyl fui/ono 4.4'-0ij:ilorodiphi;n>1 ALd^hon* &9-K^ CiiHisNsOaS- C1 Aijiii:;^. 4,4' huifonyWi- SC] Avl..1.-! .hoi nii'-one &i^(4-i..'.]nopheny|} suirou CrojT.ii.u.ia Cr:_,-?iion# D-*... J C; ,,. ! E ' ,. o L.-J DUd <: ptfl'-h:. :,'.J.ntiiphinyl *u!fon* -M'-: .JiiH dipLv.'.yl Buiidtic 4,.,-n;^j-,,cdiplieit>'l saipbont C;ip-c`. t'jbov.j LM4 .'.hinyiiiulTtl/rf uifan W-. J):. .. .rrrrjj r/,-:-. :- k V i 1 r* r F ! t ? } w . a h 05 VT BFG09551 t&rt 1 SO no-7 31 ** $1* THIS IS AN OFF-LINE BIBLIOGRAPHIC CITATION LIST GENERATED BY * l* * ' MEDLARS II t> . ' K.L.M.'S NATIONAL INTERACTIVE RETRIEVAL SERVICE * t * -* * ** fc******************* *+.*********:**:*# *:*:tt*.'*:*****#********;:*:*l:***:; ###*.*:***** *0-05*7 UMBER OF CITATIONS PRINTED * 95 THIS SEARCH UAS PERFORMED ON THE TOXLINE REQUESTED BY _ .BARTRUM KATHLEEN FULLER JUNE 20 * 1979 FILE. LEASE SEND THIS LISTING TO - FGOODRICH KATHLEEN FULLER M>0 OAKTREE BIVD, CLEVELAND* OHIO 44131 98TKJTT2 BFG09552 irfi SI au AA TJ SO JC AB - CA/003/005239F (jJ - KHAAK JB i SULLIVAN LJ - MELLON INST, , PITTSBURGH PA. - METABOLISM Of BISPHENOL_ A IN THE RAT - TOXICOL. APPL.^PHARrfXcOLt l VOL St IS3 2, 1966.175-84 - txapa - CBAC COPYRIGHT* CHEI1 ABS THE METABOLIC TATE OF AN ORALLY ADMINISTERED DOSE Of 14C-LABF' " 188-0S-71 : R' ,t0 THE HAT WAS STUDIED OVER AM PERIOD. DURING THIS PERIOD# 28 Of THE LABEL WAS EXCRETED ' <&? URIHE 56 IN THE FECES. NONE IN RESPIRATORY t 11U-38-9 I C J" .OXIDE. TM TME CARCASS AT THE END OF TF A* JD* CHROMATOGRAPHIC ANALYSIS OF THE URINARY METABOLIC r SS .S SHOWED THAT HISPHRNOL A WAS PRIMARILY EXCRETED AB *3 2002-48-4J GLUCUROHIDE. WITH LESS THAN 1 AS TREE BI5PHEMOL V .HROMATOGRAPHIC ANALYSIS Of THE TECAL METABOLIC PRODUCTS SNOw j THAT 35 OF THIS MATERIAL WAS FREE BlSPHENOL A# 35 WAS THg HYDROXYLATED PRODUCT OF SlfffHCKQl AMD THE REMAINING 3* WA* PROBABLY A GLUCURONIC ACID CONJUGATE. * 184-38-t; 8002-46-4 1 SI AU AA TI SO LA JC AB RH ? Si - AU AA TI SO LA JC AB RN CA/013/001 1419C Bitman J i Cecil HC Anim. Hush* Re*. Div.i Baltsville. Md. Estrogenic activity of DDT analogs and polychlorinated biphenyls J. Agi Food Cham.# VOL 13# ISS 6# Eng JAFCA 1970,1108-12 CBAC COPYRIGHT * CHEM ABS oiphenylmethanes# diphenylethana* , and txiphanylnethanas had estrogenic activity, as avaluatad using tha IB ha glycogen rasponaa of immature rat utaxus. whan a p or p* position was unoccupied ox oeoupiad bp a hydroxy ox methoxy gxoup. Halida or alHpl gro in tha p ox p* positions rendered tha coapds. inactive* Pol' ^ginatad biphenyl* and polychlorinatad triphanyl pollutants of industrial ^ d*. which axa environmental , u*i *troganically activa. Phanolphthalol (I) and ,> nthalain. compds* usad as laxatives in drug prepn*.# war* A trogenioally activa since they containad tha ippcepA" p'-dihydroxy structures* (81-92-5 PhanolphthalolH77-^ Aq nolphthalain) Staxao nodal* indioatad that ptp'-dihydtoMf . of tha activa nuclai hava intarnuolaar distance^ tha hydroxyl groups which would approx, those of tha natuxei steroidal estrogen* and the synthetic stilbena astrogans. 81-92-5; 77-09-8* 3424-82-6; 789-02-6; 2971-22-4; 72-43-5; 30667-99-3; 14835-94-0^ 50-29-3; 3563-45-9; 620-92-8; 80-OB-li.' 30666-06-5; 2 1388-77-2; 101-53-1; 611-99-4; 1 137-42-4; 90-76-0; CA/077/15BIMB ' , ------------------------------ Auvenshina RC i Emsff ub Sch. Dent* Emory Univ,. Atlanta, Ga Pul pal response 0| monkeys to modifications of a bisphonol A composite resin and cement J* Dent* Has.; VOL 51, iss 4, 1972. Eng -6 JDREA CBAC COPYRIGHT; CHEM ABS Th' J*9 Jp* pupal response of monkey taath with Axptl, cavities u 4.1ax following topical treatment uith bisphanol A th. `Ajd with methyl methacrylate or with dinothaccylate. (80-62- -6- Methyl methacrylate) Ho Significant differences in restorative action were obad* between thin*::, Iu,'h*Bo1 * * .* Hith th. 80-62-6; 7446- 14-2; 60-15-7 BFG09553 2 a T frn iY - n HEEP/77/ 10654 ';'& , Atf LARSON or f MAYALI^B 1 W* VMNt til fi HEMOLYSIS DUE TO CHEFt^J^ LAMINATION OF CLINICAL PERFUSION APPARATUS so ANN THORAC SUROi J* <*77 374-375 c ATH5 A '' m* B HEEP COPYRIGHT * A, BBS, NOTE CHILD OPEN HEART SURGERY HEMATURIA H - HkSkm SI CAv'OBfi / 1B4 10 5T A ^ *, AU Thozgeizsson A ; FtegeztjS AA Dap. Dermatol. Univ. Lund, Lund, Sued. TI Allergenicity of epoxy zesins in the guinea pig ^>A fly* SO Acte Darm.-Venereol.j VOL 57, ISS 3, 1977,253-6 LA Eng OC ADVEA AB CBAC COPYRIGHT* CHEH ABS The sensitizing cepeoity of epoxy zesins of diglyoidyl bisphenol A type ether was investigated using the guinea pig maximisation test. One isolated resin had eel. bit. (MU) of 340* which is the lowest among this type of epoxy resin. The othez zesins were mixta, with different MUs. Theiz distribution is not known, but only their iv. nu. The low mol. wt. resin sensitised ell of the animals end can be classified as an extrane allergen. The sensitizing capacity decreased In inverse proportion to the increase in the av. MU of the xesih stints. The orosetesting also indicated that the resin mints, with higher av, rlW contained enough of the low MW resin (MU 340) to render this resin a sensitizer. Elepha^ol A (I) did not sensitise the eninals at all but epiehlornydritiTxi) eeneitized 6OK. (00-06-7 Blsphanol A)(10fi-9-0 Epiohlorhydrin) Thus, in order to formulate hypoallergenic epoxy zesins it will be necessary to aehieva sensitisation of animals uith isolated resins of varying tool. ut. U- l67-4*-li 3B06B-2I-6 n n so dc i i# KM >KM KM W! iWiilil# (0,*v*isepzoyll<aMdiphenoli 3#2*bis<4-hydtexypahnyl>pz' \ene>. Aft 2nd Hyg Assoc ant VOV ' fl 3. 1*67. P301-4 SCI 600J-AI94 TOXBXi i Anitoal i . " vnmental Exposure j HUMAN OCCUPATIONAL OltEASl PREVENTION G CONTROL PHENOLS ASTERSt RfFECTS/^ANALYSlS/TOXlCITY I Ventilation n 1104188 BFG09554 r 6 SI CA/005/00490OU &- AU HICULESCU-DUVAZ I I NEACSU C * DOBRE V s FEYH5 V A A ONCOLOGICAL INST.* BUCHAREST* ROMANIA. TI HYPOTHESIS CONCERNING THE MECHAHXStl Of ACTION OF SOME NEW ALKYLATING AGENTS FROM SYNTHETIC ESTROGENS Vtjsl JL&~- V SO NEOPLASMAi VOL U, ISS 6* 1966*503-9 JC NEQZ.A AS - CBAC COPYRIGHT' CHEM ABS THE ANTITUMOR ACTIVITY OF 21 NEW URETHAK-TYPE NITROGEN MUSTARDS AGAINST WALKER 256 CARCINOSARCOMA* AND THE ESTROGENIC ACTIVITY Of SOME OF THESE COMPOUNDS AND OF THE DJHYDROXYPHENYL DERIVATIVES USED AS PRECURSORS IN THE SYNTHESIS* t MERE STUDIED IN ORDER TO ESTABLISH A RELATION BETWEEN THE ESTROGENIC ACTIVITY OF THE PRECURSORS AND THE ANTITUMOR ACTIVITY OF THE CARBAMATES. COMPOUNDS HAVING THE HIGHEST ANTITUMOR ACTIVITY WERE 1991-23-11 ALPHA * ALPHA 4-DIETHYLSTXLBENEDIOL BIS1BIS 2-CHLOROETHYL CARBAMATE). (1064-27-3) 4*4*- 12-DIETHYLETKYLENE DIPHENOL BIS(BIS 2-CHLOROETHYL CARBAMATE)* AND 12096-11-9} 4,41"AZODIPHEHOL BISCBIS 2-CHLOROETHYL CARBAMATE). NO RELATION EXISTED BETWEEN THE ESTROGENIC ACTIVITY AND THE ANTICANCER ACTIVITY OF THE DERIVATIVES. A HYPOTHESIS IS PRESENTED CONCERNING THE POSSIBLE METABOLIC PATHWAYS Of THE ALKYLATING AGENTS. RN 991-23-1* 1064- 27-3; 2096-11-9; 620-92-6; 2971-36-0; 2095-99-0; 2096-04-02 1965 -09-9) 2050-16-0; 2266-76-6; 2095-96-9) 3246-65-9; 6526-07-0] 5635 -50-71 14666-03-2) 15056-36-3* 2266-68-2; 6546- 19-2 ; (| jr-7j 60-0 9- 1 i 6526-69-2) 2096-03-9* 2268-90-6* 1774-34-1; 2096 -02-8) 2664-63-3) 5397-34-2; 6526-84-7; 788-57-8; 6526-62-5) 843- 55-0* 6548-20-5 * 150 15-57-3.; 6526-8114; 3600-64-4; 6052-64-2) 6526 -63-6; 6526-68-1* 5466-23-9] 2288-89-3; 611-99-4; 6696-97-1) 3600 -61-1; 6526-66-9i 2096-00*6] 92-68-6 i9 SI AU AA II SO uc AB CA/005/002864T PALA G ) COPPI G ; CRtSCENZI E RES. LABS. INST, ANGELI S.P.A.* MILAN- h THE LAXATIVE PROPERTIES OF SULFURIC ESTERS OF PHENOLS* WITH PARTICULAR REFERENCE TO 4*4*- 2-PlCOLYLXDEME-BIS-PHEHYLSULFURIC ACID DISQDIUtl SALT PICOSULFOL ARCH. INT. PHARMACOOYN. THER.; VOL 164* ISS 2* 1966*356-69 AXPTA CBAC COPYRIGHT * CHEM ABS THE LAXATIVE PROPERTIES OF ORALLY ADMINISTERED 177-09-81 PHENOLPHTHALEIN. 180-05-7} 4.4f-DIHYDR0XYDlPHENYL DIMETHYLMETHANE* AND (603-41-61 M.4,-DEHYDROXYDIPHENYL- 2-PYRIDYL METHANE WERE COMPARED WITH THE SULFATED COMPOUNDS* (10089-29-9} DISODIUM 4.41- 3-PHTHALIDYLIDENE BIS-PHENYL SULFATE* (10040-44-5) DISODIUM 4.4l-ISOPROPYLIDENE-BIS-PHENYL SULFATE. AND 110040-45-6} DISODIUM 4*4*- 2-PICOLYLIDENE-BIS-PHENYL SULFATE PICOSULFOL. DISODIUM 4*4*- 3-PHTHALIDYLIDENE BIS-PHENYL SULFATE* AND DISODIUM M.M'-ISOPROPYLIDENE-BIS-PHENYL SULTATE were TWICE AS EFFECTIVE AS THEIR CORRESPONDING PARENT PHENOLS* WHEREAS PICOSULFOL WAS AS POTENT AS THE PARENT PHENOL AND WAS THE MOST ACTIVE OF THE SULFURIC ESTERS CONSIDERED. PICOSULFOL AND 1603-50-9) BISACODYL GIVEN ORALLY TO RATS EQUALLY AFFECTED THE INTESTINAL TRANSIT OF* CHARCOAL AND INDIA INK, PICOSULFOL WAS HOT TOXIC TO RATS AT 5 fl./KG.* ORALLY, 3 <5./KG. SUBCUTAKEOULSY, OR 700 MG./KG. INTRAVENOUSLY. ORAL ADMINISTRATION OF 10 AND 30 MG- OF PICOSULFOL PER KG. TO RATS FOR 3 WEEKS SLIGHTLY REDUCED THE WEIGHT INCREASE AND FOOD INTAKE OF MALES. WHEREAS FEMALES WERE NOT AFFECTED. BISACODYL AT 10 MG./KG. SIGNIFICANTLY INHIBITED WEIGHT INCREASE AND FOOD INTAKE IN BOTH MALES AND FEMALES. NEITHER BISACODYL NOR PISOSULFOL MODIFIED THE NEHOCHROMOCYTQMETRIC PATTERN* WEIGHT OF THE PRINCIPAL ORGANS, SERUM PROTEINS. GLUTAMIC-OXALACETIC TRANSAMINASE. GLUTAMIC PYRUVIC TRANSAMINASE. OR KIDNEY FUNCTION * IN VITRO. GLUTAMIC-OXALACETIC TRANSAMINASE. GLUTAMIC-PYRUVIC TRANSAMINASE. ALKALINE PHOSPHATASE. CHOLINESTERASE. PEPSIN, TRYPSIN. PANCREATIC LIPASE. AND AMYLASE ACTIVITIES MERE NOT MODIFIED BY PICOSULFOL. NEITHER PICOSULFOL NOR ANY OF ITS METABOLITES MERE FOUND IN THE SERUM OR URINE AFTER ORAL ADMINISTRATION OF 100 MG./KG. OF THE DRUG TO RATS. PICOSULFOL. BUT NO CORRESPONDING FREE PHENOL OR ACETYLATED PRODUCT. MAS FOUND IN THE TECES. PICOSULFOL HAD HO INFLUENCE ON THE CENTRAL NERVOUS SYSTEM. HEART. ARTERIAL BLOOD PRESSURE, DIURESIS, OR GLYCEMIA, AND IT DID NOT DISPLAY ANY IN VITRO AKtIBACTERIAI OR ANTIFUNGAL ACTIVITIES. RK 77-09-6; ll|*2iEB 10*69-29-9* 1*040-44-5; 100*0-145-6; IOS-SO-I V 81 C1/0I1/901776N XU Pazpalei XX XX USSR TI Dynamics of tissue autoantibodies and activity of soma enzymes l0f guinea pi?*) aftersensitisation to *4mv*epoxy rosins end their hardening agents 80 Xmmunologiye. Resp. memhved. slf. ; ISS^Vyp. 7. , 1974 66-70 LA JC A* Russ D6JOU tVr .C* CBAC COPYRIGHTi CMEM JLBjB^Titifc r.tiiy translated- Antibody enrnyme epoxy resin ^ ,,' SI CA/084/055335Cn AU Kurata M ; Yoko^&Mj *\Yoshid*^5 ; Sakina B AX Japan ^^ TI Suppression of the toxicity Of O.O-dipropyl 0-4-nethylthiophenyl phosphate to animals SO Japan. KOkai PATENT NO. 75135633 10/27/75 (Nippon Kayaku Co., Ltd.) AB CBAC COPYRIGHT; CHEM ABS The toxicity of 0,0-di-Pr O-4-methylthiophanyl phosphate (I), an insaotieida. to domestic animals is decreased when used with II (R1 " alkyl or alkylthio; R2 and R3 H lower alkyl, or halogen), novolaks. or blsphanol (7292-16-2 O.O-Dipropyl O-4-mathylthiophanyl phosphate)(60-05-7 bisphenol A) Thus. I 2. 3-nathyl-4-(inethylthio)phenol 2. silicic acid 1. and clay 95 parts bier* mixed and pulverised. ( 3 120-74-9 3-Methyl-4-(methylthio)phenol) Four mice exposed to this prepn. (1.5 g) spread in a cage (330 cm2), survived for .gtoreq.24 hr. However, without II. X was 67.5X lethal. EH 7292- 16-2* 3120-74-9* 57993-15-4* 25154-52-3* 104-43-6 0 6 T ^ ()T i: SI TOXBIB/'69/2G0347 AU Fotlianina VN TI lExperimental sanitary-toxicologic studies of djphenylolpz o p ane in connection with standards for its presence in reservoirs I SO Gig Sanit* VOL 33. 155 7, 1966, P25-30 LA Rus JC FPZ IS 00 16-9900 KU TOXSIB ; Animal ; ENGLISH ABSTRACT ; RABBITS RATS KU Water Pollution * Mater Supply * BFG09556 - riAt'A*<r7 1/OXJ lb v^ A U - Teisingar d JR TI - (Biological exposure tests.) SO - PiQcovni Lekan 21(9)* 387-95 LA - Czech 1969; (REF>96) AB - HAPAB This report surveys* from the literature* the present knowledge of and possibilities for evaluating the extent of exposure bp means of biological tests. The compounds covered are lead, mercury* carbon monoxide, carbon disulfide* benzene, toluene* ethylbenzene* styrene* nitrobenzene, p-diehlorobensene* Hpfi-dinitro-ortho-cresol, Alan*, trichloroethylene* tetraohloroethylene, methyl chloride, metathion. BHC* DDT and parathion. (Author abstract edited* 1969 RH - 50-29-3. 56-30-2# 71-93-2* 79-87-3* 75-15-0. 79-01-6* J0-05-7,i 91*95-1. 100-41-9. 100-92-5* 106-96-7. 108-88-3# 122-14-57 127-18-4, 534-52-1, 630-08-0, 7439-97-6 IX SI AU ti so jc AB . BN *L' SI AU AA TI SO LA JC AB RN HEEP/73/04310 KARUSZ N t HAGY L i tRAUH H-S j TTE5S D The clinical use of the Hungarian alcohol prohe Plyracol. < DTSCH GESUHDHEITSWESt 24 (43). 1969 2047-2049 ------------ *sa '*-< ' HEEF COPYRIGHT* BIOL ABS. The range of application of the Hungarian alcohol-probe Flurelcol in the clinical fields is reported* The 1st results of its application at the medical examination of 63 unconscious or slightly conscious patients is reported* Of these patients 43 showed an increased blood alcohol level* The rtudie* were done by means of valve-supplementary appliance. Such tests are of great importance for differential-diagnostic purposes in medical practice. 64-17-5 __________________________ . CA/085774T3STK Rudski E > Kzajewska D Klin. Dermatol.# Akad* Med. Uatscauie Warsaw* Pol Antigenic determinants of epoxy resins Immunol. Pel.2 VOL 2# ISS 4# 1977*333-8 Pol ihpod > WQ--V CBAC COPYRIGHT! CHEft ABS Sensitization studies were conducted with epidians. dlan, phenyl glycidyl ether* butyl glycidyl ether* pelidcl* epichlorhydrin* and eiterifiad epoxy resin in human subjeots oooupetionally exposed to epoxy resins* human controls* and guinaa pigs. (80-05-7 Dlan)(122-60-1 phenyl glycidyl ether >(0426-08-6 butyl glycidyl tlier H 4 17 1-1 1 -3 PelidolM106-89-8 Epichlorhydrin) The sensitizing action of' epidians decreased with increasing mol. ut. Sixteen percent of occupationally exposed subjects showed a pos. reaction to dian* whereas almost none of the controls reacted to it. Allergic reactions to epichlorhydrin in resin-sensitized guinea-pigs* deorease in sensitivity With epoxy group blockade or esterification* and orcss-reactivity with monoglycidyl others were also obsd. 122*60-1 * 24 26-08-fii 4 171-11-3; 106-89-8i 25068-38-6 21104191 BFG09557 SI AU AA TI SO LA JC AB ftN 35 SI AU AA TI SO LA JC AB AM CA/07 9/07 45 19 0 Stssenkova KP t Shumskaya NX ; Grinbetg AE Moscow* USSR Regularities governing the biological action of bisphenol A derivatives as a function of their chemical structure Gig. Tr. Prof. Sabol. # ISS 6, 1973*30-3 .. RUSS GTPZA CBAC COPYRIGHT: CHEM ABs .. :,,r-i Rj^ifphenol A (I) and its derive, thiobisphenol* ionox 220 . and AO 21 were only slightly toHic toward mice upon oral administration. (80*05*7 Bisphenol AX 24742-39-0 Th io bi s phenol X It 8-82- 1 ionox 220)09394-07-5 AO 21) I end thiobiuphenol showed the greatest cumulative toxicity upon chionic ndnimstration. All these compds. somewhat irritated the skin, and penetrated it only slightly. Tnu presence of s hr-tween the phenol sings and of a methylene group in the para position with respect to the OH groups renderd me compds. less toxic. Inhalation studies show that the toxicity of vapors fromcheated AO 21 was due to their styrene content. (100-42-5 Styrene) Under industrial conditions the max. cone, of thiobisphenol in the air should be 5 mg/ml. and for ionox 220 it should be 10 mg/m3. 10-05-7: 247U2-39-0. M8-6&-1' 35394-07-5* 100-42-5 CA/087/02 AJ'4Uft * ....... ' 1------ L" Bokov AH USSR ^ Effect of meteorological conditions on the kinetics of the emission of chemical substances from polymer structural materials Gig. Toksikol. Poll*. Stroit. Mater.; VOL 2.V 1973*5-37 RUSS l\^ '-T" GTPMD " CBAC COPYRIGHT: CHEM ABS The emission of harmful low-mol^.-wt. substances from plastic.building materials is studied with respect to temp.* relative humidity* air movement rate, and intensity o air exchange. The harmful emissions measured' Included tsidual>onotntf* catalyst*, plasticisers. etc., contained in thenplastics compir. 50-00-0; 67-64-1; 0-05-7; 80-15-9;^00-62-6; 84-74-2 98-01-1; 100-42-5* 106-89-8; 108-88*3; 108*95-2; 7664-41-7* 8064-03-7; 900 3-35-4; 11114-33-3* 2S068-38-6; 25085-74-9* 27637-75-8; 28436-99-5; 39347-10-9; 42424-30-6; 60267-46-1 d SI AU AA TI . SO LA JC AB RN CA/083/001506V Zavadskii VN ; Khovnnova EM Dip. Dermatol. Pharmacol.. Med. Inst.. Yaroslavl. USSR Morphogenetic properties of certain phenols inducing vitiligo phenocopy Genetikai VOL 11. ISS 2. 1975.132-9 Russ GHKAA CBAC copyright: chem ABS Artif ^ial vitiligo induced by pyrocatechol or p^tert-butylph#* 'I) irv guinea pigs showed all the primary and secondary pig* (120-80-9 Pyrocatechol)(96-5 v ritoms of the clin. disease. ?} -f t"Butylphenol) pyrocatechol i 104192 and I exerted morphogenetic in Drosophila melanogaster (changes in the color of and wings of the imago* disruption of wing forint a in the case of pyrocatechol changes in the color of i arium). Pyrocatechol. I. diphenylolpropane, or 2*4*b .i-tert-butylphenol had no mutagfcnic effect-onthesomatic cells of D. melanogaster. thereby decreasing the likelihood of a mutational origin for leukodermic patches. (80-05-7 Diphenylolpxopane)(732-26-3 2*4* f. Tri-tert-butylphenol) 120-60-9; 98-54-4; 80-05-7; 732-26-3 BFG0955J SI HEEP/78^03481 AU 5HEFTE1 VO J TSAM ZS ; KALINICHENKO LT ri Hygienic evaluation of ryoxy compositions intended for use in water supply. so GIG SAKITi U2). 1974 (RECD 1975) 81-82 JC GISAA AB HEEP COPYRIGHT* BIOL AB5. The effects on Hfltec quality of water-main filters made of epony resin were studied. The migration of epichlorohydr: polyethylene polyamine (PEPA), diphenylolpropanei dibutyl phthnlate and acetone into the water was determined. The maximum tolerance and absolute lethal dose of an aqueous solution and pure PEPA for rats and mice were determined. The recommended maximum allowable concentration of PEPA is 0.15 mg/1. RK 26913-06'4; 106-89-8; 80-05-7; 84-74-2; 67-64-1 SI - HEEP/75/01853 AU - GUL'KO 5N ; PIKUL'SKAYA AF --- TI - PROFESSIONAL H E P ATO P AT 111A S AND ALLERGY -- SO - VRACH DELOi 10. 1973 30-32 JC - VRDEA AB - KEEP COPYRIGHT: BIOL ABS. HUMAN DIAN EPOXY RESINS w cq to BFGG9559 ............1 U,... Im. i > . . |..i^ln 1 l'<ui* I-- * I-.. I'.-....-. .... ....... . ' ... ir .- > i i .1 i , i, r<*i r,*?.:! , t a. J. J.lVI' t'J l V AM. St'f; f| |l I'll <!lM MMKK.v ft 1 7 ' l S I ll^'H Mefaboiism of Bisphenol a in the Rot /, >ri /< .ii J,V:iIHh J* Kn.aAK AM) Li.OVU J. Sl`LLlVr\N i;r |;t llv* l hif. Mrliflu ImtHutt, FiU 1-r g/t, /VHH yltQrtiti HH,* R'i'tnfd January !r>. /Jrt* In recent years the chemtcMt imlU'My ti.is introduced several resins oS food pazkag- ins materials for jiid<i>t:ijl ptuceiHny mul tuiooir.yr use- liiiphfnol A |4(4''iso* propylidene biphtnol, 2.2'l>;up-hydro\Ypht:iivl)piopane; Ij as a copolymer is 4l> important monomer in several resins (or uvse application*. Since some unreacted monomer does migrate to food, federal iatv specilieb that studies must he carried out in determine the biological safety of the umipounri. Results ij> the literature from metabolic tale studies of other diphviiuli could not be extrapolated with sufficient FlG. J, Structural formula o( biqilionol certainty to this compound. `1 hen fore, the present work was undertaken to investigate the metabolic fate oi bisphenoi A in rats. METHODS Radioactive bisphenol A ^A'-isopropylidciu'-J-C14 diphenol) with a specific activity of 1.3 pc mg was purchased cummer J'llty.' It contained less than 1.0% phenol as determined by gas ohraiiaiaL*rphic analysis id the acetates. Male rats (t'aruonh farms--F.lias MuJ:j weighing approximately 150 g were dosed orally with a mixture of 120 me o: labeled and nonlabek`d'; bisphcnol A dissolved in 900 me of propylene glycol by the weighed syringe technique, Approximately 10 pc of radioactivity was administered to earh anii;ul. The rats after being dosed were maintained in rnelabolir>m cases m order tu laciUt?'!*. the separate collection of u.uie and fecti, Or, in the case of the r^jpiraiorv studies, they were placed immediately in a metabolic chamber OVeinhouse .nd Fritu. ,itin, 1951) lor collcclion of exhaled CO*. The daily urine and iei_al camples from four animals were pooled, frozen and stored to await analysis for C14 and metabolites, '{'nny and fecal samples were collected loi a period of 8 day* whereupon Ui* animals weu- vicriftfud and their eaitroimesui.il tracts removed. The uj'jt'Gintestiiii] tract* and the carcasses were frozen and stored to await C44 aiwlycis. * New EnpUnd Nutli-.ir Correlation iUMur, M.-i'.'.acli'jtms. - PLoiti Hitiiiiiu. I iiu-t LlitmK* C*-'rjjorz.tii>n. U -unn JiruuL. Xnt Jrrir> r.i to BFG09560 freifrOT'f ' ,;; ' * V 1 * t m- * .1 * f ii , k \ A'/V-' s . "ts* % 176 james a. knaak and iloyd j. 5vu.ivan Sr Misay of radioactivity in fftol, urine, (Crbon dwxidf, end tissue sen pin. AH ing was done in glass vials of the low-potassium, tinfoil, screw-cap variety. The merit used was a liquid scintillation spectrometer* operated at 32 lF, Count* ^ corrected to I00fi efficiency value? by adding a weighed amount of standard nn^ cirbonate-C1* to the counted sample, calculating the percentage efficiency based ag^ additional count obtained from the addition of known activity, and dividing activity of the sample by the calculated efficiency, t or the urine samples, the assay of CH was accomplished by diluting the urine Lj with water (to reduce quench and increase sampling accuracy) and adding 1.0s|f the diluted urine to 16,6ml of the scintillation mixture (Bruno and Christian, The fecal samples were dried and ground, and 1.0-g quantities were weighed^ email cellulose bags made from dialysis tubing (Kelly el ol.t 1961), Of a sucrose solution 0.5 ml wa added, the sample wa? thoroughly wetted, and the bag^a closed and dried. The sucrose served to act as a binder for the fecal material. Tht>|| ^ waa then burned in a Parr oxygen bomb (Sheppard and Rodegker, 19*2). Affect bustion. the gases in the bomb were evacuated into a series of two traps (Kamphafij^ 1962) each containing IS O ml of 20r* ethanolamine in monomethyl ether of ftitfjfc ; glycol (Jeftay and Alvaret, 1961). Two milliliters of the trapping reagent was : counting purposes along with 18,0 ml of the scintillation mixture. Each trMjjp assayed separately for radioactivity. .. ; For assayihg the C** remaining in the animal body after S days, thr gastrointMQa t*' tract1 and carcasses were frozen in dry' ice, chopped into small pieces, and ground *i . ' dry fee in a Wiley mill precooled to the temperature of dry ice. Cooling wasacfiit r pliihed by constructing cardboard boa around the body of U*e miff and filling ffa# _v:f dry ice. The ground tissue was dried in a vacuum oven for 24 hours at 40LG>1jj||b being dried, the tissue? were reground in the Wiley mill at room temperanidFpi ' 4 prepared for combustion and scintillation counting in the same manner u fecal samples- ^ i$j For the collection of respiratory* CJ#Oj, the animals were placed for 4 hour*,%* apparatus similar to that described by Wtinhouse and Friedmann (1951). In uitrJt gas absorber (K&mph^usen. 1962) containing 15.0ml of 1.0 ,,Y KaOH ffK <4iHj ijj remove atmospheric CO$ from the incoming air. A second gas absorber conttMt 15.0 ml of 20ry eihanolamine in monomethyl ether of ethylene glycol was used tojfc the expired C140.. from the rat. Slight negative pressure was employ ed to bring wi ij| the animal. At the end of the 4-hour period. 2-0 ml of the trapping reagent wtj JBP ^ to 18.0 ml of the scintillation mixture for counting. Recovery of bisphenol .4 from urine. Free btfphenol A was recovered from ifcE g urine samples (pH SO) by 24-bour%contimi0ug extraction using diethyl ether-l*.1 H extracting solvent. Tor glucuronic acid conjugates, pooled urine sample? frtnojl^ SS day s collection were adjusted to pH 4.7 using acetic acid, incubated with a maiWBli* Cffi P-gtucuronidase preparation at 37'C for 48 hours (Block and Forter, i960), andGfgg extracted with three successive volume? of diethyl ether. Hydrolysis of the the K& ronidase*treated and extracted urine samples with 2.0 .V HC! for 4 hours yielded ^ H| * Packard Tritrb ?cir.tillation fpacirt mtttr. mc*d*t Packard Instrument Co,, Eg 21104195 B --ammm--> mm i .......... BFG09561 fl } MLTAAoLtSU of BISPHTN'Ol. A IN THE 177 pi^nol A, derived finm sulfate conjugates, upon continuous extraction with diethyl , For analysis, these extracts were filtered separately through anh\rfrou sodium to remove water dissolved in the ether. Tht ether was then evaporated, and ^ dry ttUicta were acetylated with 5 0 ml of aettk anhydride and four drops of tftbantftulfonk add. To ensure complete reaction the mixture was brought 10 its foiling point. Acetylated bisphtnoi A was extracted with chloroform after neutralize' non of the reaction mixture with 10 A' NaOH. The chloroform extract.? were dried with anhydrous sodium sulfate, concentrated to 1.0 ml: and transferred to a tared via) i*. weighed and analyzed by gas chromatography. fifitii'ery of biifkirtot A from fetgl samples. Five-gram amounts of the dried fecal ample* were extracted with diethyl ether in a Soxhlet apparatus for 4? hours To 1 rmure complete extraction, the samples were reextracted for an additional 4g hours i acetone. These extracts were combined, dried, and acetylaied by procedure similar (i those used for extract? from the urines and were analyzed for bisphenol A diacetate h gas chromatography. (Tor i kromaiography o} biipheno! A dim date. The analyses of acetylaied urine extract* containing bispbeool A diacetate were made on a gas chromatograph4 using 0?5'intb diameter, J.S-meter aluminum column containing 0 5by weight of Cirhowax*1 JQ-M on acid wished 50' 60 mesh Chromosorb* W, The maximum number p' theoretical plates for the system was obtained at a flow rate of 80 ml minute. How* ever, optimum results (due to background) for urine sample analyses were obtained *.th helium at a flow rate of 150m| and I temperature of 210 C, The detector used a flame ionization unit. Optimum flow rates of hydrogen and air were fixed by fcrsi setting the column conditions and varying the hydrugen and air flows to give tiaxirmim response for l.Ctyl samples of 0.5^ by weight of bfsphenol A diacetate uandards in chloroform. Calibration standards were prepared using the same tech niques employed in the preparation of samples for analysis. Jn addition, comparisons were made with material recrystallized from metbanol-waier. The results were tdemical. Infrared spectra of acetylated samples did not show the presence of free bydroxyl bands, Hisphenol A diacetate in acetylated fecal extracts was chromatographed under the urn* conditions as the dfacetite present in the acetylated urine extracts except for an rkvated temperature of 726'C. The retention time of hisphenol A diaceialr ai J10JC a* x minutes while at 278CC It was 5.5 minutes. The retention time varied from 9.5 "mutes on a fresh column to 8 minutes on a column operated continuously for 1 ffrituh. /<? exchange chtomatography oj bisphettpl ,f-CM [Ivcuriyuidt. Sixty milliliters of * first .day urine sample from pooled studies was adjusted to pH 2.0 with 1.0 .V HC1 evaporated to an oily residue in a rotary spray evaporator/ Acetone then *iJrd to (he residue along with a small quantity of methanol to facilitate solution. ^ excess of acetone was then added to precipitate urea and other acetone insolubles. * h* precipitate was filtered off and washed with small quantities of acetone, The 1 birLmin GC2A. Beckman Infirumtntt. Fullftion. California. "( fbowa*" jy a irtdtmark of l`nk<n Carbide Corporation. N> York, N'en- York. `'Chrrtnosorb" is a trademark of Johiu-Marn'iDe, Celiir Diusion. New York. New York, Vsnf faun, Newark. DfUww. * i ' ,`*l w3*V7 ' 178 JAMF.S B KXAAK AXr 1U'\ U J. jvn.n l\ '4'?**1 acetone fihrair was evaporated to dryness at above, and the residue dcatn treated in the manner previously described. The r-ea-nd preLi|M;oiun Mrr'.uvni g additional quantity of insoluble material, The washed precipitates u(H ^liiie ^ contained very* little radioactivity, The acetone tWai? was r\ ^.orated t<< dry** nd the oily residue was dissolved in 5.0ml of 0.01 At trig < hydroxymethyl methartf-HCI buffer (Tris*HCl), pH 7,5. If the pH of the solution fill below fi I.O.Y NaOH was added to establish the pH at 7,5, One milliliter of the mlvtfc containing approximately If mg of bisphtnol A-C14 equivalents w.` applied to ^ top of a J.5 X 2^-0-cm column of diethylairiinoethyk-etKilose (LJEAE-ceJluloj*) ^ pared for chromatography in the Inflowing manner. The column was packed byca tinuously pouring a slurry of 6.0 g of DEAE-celluh'se in 300 ml of 0.0! hi TrisA buffer. pH 7,5. into the column while allowing the buffer to drain freely from thet^ tip. As the column filled and the flow decreased, air pressure up to 10 pounds* applied to the top of tbe column to ensure a tightly packed column. The ceHfc column w* t^en washed with 0 01 M Tris-HCl buffer, pH 7,5, until the pH effluent was 7.5. Jtjjf. The bisphenol A-C14 metabolites were eluted from the column using a linear Sil ent consisting of" 300 ml of O.OJ M Tris*HCI buffer. pH 7.5, in the mixing chaon|i and 300 ml of 0.05 33 Tri$.HO buffer. pH 7,5, in the reservoir, The flow rrie^t adjusted to 4.0 ml minute using a microbellows pump.4 The gradient device co&dfe uf two 500-ml graduated polyethylene cylinders connected at (he bottom witbikq of 5-mm i d. polyethylene tubing, The gradient solution was taken off Utrod^ka second Nxp of similar tubing connected through the bottom of tbe mining vtidbi continuous flow mocnmi iloring system utilizing ft 4,0-ml flow chamber* was used todtflE and record tbe presseennce of C14 in the column effluent. ^ Bitiiyrttkesis o\ bitphenol glururonidc, Guinea pis liver microsomal prepared according to the method of Smith aod Bteuer \ 19ft,`If for rabbit liver gilt*! Homes. The micro$omal fraction was suspended in ),S0ml of o.i54 3/ KCI *>4*r 1.0 ml of th'g suspension corresponded to l.Og of fresh liver. For synthesis 1.0 <* bisphenol A-C14 was disrobed in 0,7 ml of a poly oxyethylene glycol *03 and inalafcj for 1 hour at 3B C in a water J^th with I 0 mg of uridine dipborphate glucuronic |& 1.0 ml of 0.1 M phosphate buffer, pH 8 0. and I 0 ml of the microsomal suspaw* After incubation. 3 ml of buffer were added and the incubation mixture was exUlrt* with ether (3X5 ml) to remove uwonjugaied bisphenol A*C14. Protein was rew**| from the reaction mixture by the addition of 70 ml of ethanol followed by cenwiftP; lion. One milliliter of the solution was analyzed for C'\ The deprateinized j was then concentrated to a volume ol 7,0 ml in a rotary evaporator and chr^sf* `graphed on DEAE.feMuluse a* described above. , yy RE5VJLT5 The averaee cl>^tih'Ution and rate of excretion of t14 metabolites in urine andh^ &ye given in Fin 2 for ilvee typical studies Each sludy represented the pooled*1 and urine collection? from four animals. In studies 2 and 3. the majority oi f administered dost ^..i* excreted in 24 hour?. In study ( however. .llmot equaling k fteM'jTth Appliance Ci'ropany, Allbi-n Park. Pt-nh*> Ivainii e Chr<ma cell dti*cicr asscnitit.'. N'utlt&C'C'fcicaso. fie* p?aiis#. Iflimis ,v ,, t'7">1 fv 1104197 BFG09563 METABOLISM 0* SISFHl.KOL A IS THE HAT 119 vrrf excreted Ip the first and second 24-hour periods In all case? thereafter. the daily ani(<imls excreted were approximately the same for all three studies. The intal am"unt cure ted oh the eighth day w-** 0.01 mg. Simple phenols are es-eMialh i-lhomaied from the body in 4S hours, A summary of the total recovery from urine and feces is f-\^n in Table 1 for the three studies. Radioactive residues could not be detected in Sjf ; t'rinary and fecit ctrrftjon Of bhj'heftel .VC1* meuhclile; by tljf Ml. = Ft: rent ir HfiiJt und fern; Q = per cent in teccr^ 0 = per cent in urine The cendil'Onj. urp pi'tn in th* ic5 TABLE J EifHT-D'V CtMVLATrvi Exoution or BisPHf'tm A-C]4 EgrnLtNtf v Rts Muri\ Dcse (mp) Recovery from urine iTTi?) (*> Recovers from ft(CI 'roe* Fto*ver\ trim ewet i! hinpr (mpl i*i )a 4*6f 147 0 .10 1 ; ei.4 54.0 15 ! 1% : 476,5 12? 1 26.5 J86.0 60.0 IJJ 4 7 4 79.9 J4T.J sot :to.9 55.0 f.4 1 l 4 SI .0 155.0 2P0 269.0 56 0 14 0 5 0 * A- iNfi't nlapt- nf the dwe, f Ur 150-p male rati wtre used pr study <tl in lv tract dose of eoO Wf kp Total recovery mo <f># 4;,i 455.6 4)40 4r*5 0 90 95 $6 S? th ground carcasses or gastrointestinal tract? of six animal? 6 days afftr bisphenol administration. ^`rury of Bisfktnol A from Urine I ret bhphenol A. extracted from pH .0 urine could not fie found in concentrations 1 *'ve r, by gas chromatography, while acid hydrolysis of the urine after glucuronj* 'u'- treatment produced less than an additional \r/<- 1U<- 2 gives the best result? obtained upon treatment of urine sample? with M 86IK 1TT f,*r |, to kr. wi=*>v-f .l Ot \ A' 'I'%V-' 'x J80 J*ME5 S, K.VA.4K AST 11>V!> J. StLl)\AS P-g)ufUH<nMh<if, The value* obtained by ga? chromatography are compared ivi-h ho* obtained fium count data and ate reported by day of evcretion. Control values mi under the ``awe condition* gave a rand'.-m variation in l-.m.kjp'Hinii f-oin 0 05 to 24 mg. Since the total recovery after the third day was Its* than f '< of the e.\cretaj urinary count, no further attempt was made to completely resolve the bi?;henol A from the background. To verify the gas chromatographic data, 330 ml of urine containing a mum equh> lent of fTCmg of bUphrnol A was treated with a jS-glucuroniciase friparettmjj ugg in the study reported in Table 2. The litated urine was e\tra`-\rd with diethyl etfe and dried at room temperature under vacuum. The dried sample was rccrystafliof by diisohing it in hoi toluene and then cooling. The precipitate was recnstallin( a second time from hoi toluene, A yield of 595 mg was obtained, The infrared sp* trum of the precipitate was compared to that of the material fed. and found tola TAPLE l iJcrmMnMtjox of Bismksol A a??d Metavoutls i> t.Vvc. Ci\>jfaju>o* or Rnvire Oitainw bv Gas CHSOilATrtcHrifV AXt> RaDIOaCTTVTTY *,$[ V-?' B Rrtoverv by n> Recovers by cbrnmaio^ra^hy* radioactivity Day (m*l 'mg) A B y IOO a* 1 2 .t 4 J 6 > a Total 64.0 tifi.O 5-6 10 061 0.2? 026 0.15 1 }1.S 72,4 69,6 44 0 68 0.24 0.0& Otti 001 147.4 69 95 l?0 140 ?oo i* #: * Alter trntrotni 0/ the urine with P-pluturonidase and wFijlaiion of lh* liWriitd ptaod# described in the text. /ft; identical. No change in the spectra resulted from recry#tal)i*atjon. The materia)-U on recrystaMUation was 0,0fi25 g It was recovered, and the infrared spectrum oirtaarf from it was that of bisphenol A. Corrections for recryjtallitation indicated a yield of bisphenol A from the original 770 mg by radioactivity to be in excess of 0 mg. or SR/J1. which is good agreement with the values shown in Table 2. / Rreovery 0j Bitphenol A from Ffcvt $Qnflcs Recovery' results for the fecal samples as determined by gas chromatogriphjf ffc reported in Tablr 5 at a percentage of the CM present. During chromatograph1 second peak appeared which varied significantly from the controls. The size ol peak varied regularly from day 10 day and reiurned to nearly normal values ^ on the eighth day after dosing. It was apparent that ibi> component was a meiat** of bisphenol A and one of importance. No evidence for this metabolite was toupd* urine, It is presumed to be a metabolite resulting from bacterial activity, and I** duced solely in the intestine. 21104199 /1 - X BFG09565 **' * I MtABULl*M Of fil&>HLSOL A JN THE k *T ]fl (v ]n an attempt to give tentative identification of this material and since hsdrnxy- jjtjon iecmed to be t likely possibility, a sample of pure Msphrnol A was nested according 10 the method of Vdenfriend ef cl. 11954). The reaction products uere txtracted with diethyl ether, evaporated to dryness under vacuum, and acety'ated. The mixture was analysed in chloroform on the same column and under the same rendition? a? bisphenol A diacetate, A product of the reaction was found to ha\* the same retention time a? the metabolite of bisphenol A. The area response of this iwrabotite was assumed to be the same as that of bisphenol A di-urtate. The fas chromatographic values while low are compatible with the radioattive studies. In order to determine the reason behind the low yields, samples of eMractrd feces were burned and the trapped C1,4Os was counted. Less than of the bisphenol equivalents were found uneXLracted. Thus, considerable material extracted Day 1 w s 4 Total TABLE i DimMDiATiois or Bikpulnoi A *.*! Mliaboute* in Ficcs COKfAfitH'S gf Rtsnfs OffAiNCd #i QaS CnfeOVtAtOTKAFPV AJfB RAIMOACTTVJTY Feenvery by (hromaiocraphy Free ' bitphinnl A (ma) Hvdrorvbisphertgj A (me) A Total (mf) Rccnvtry tv radi<wllfiiiy i U E 1 20 6 17.0 63.6 56.2 4J KVO 1.2 4 0 69.7 90,2 57.6 119.6 17J fJ 179,9 *.f.o t:s.o 21.4 53 339 6 A U X tOO 69 AS SO 100 69 4 > . t V. from the feres could rot be accounted for by gas chromatography. If bisphenol A was rnexcreJed back into the intestinal tract as a conjugate; this compound would wt lie determined by gas chromatography. Ich Exfhangt CfrrOmdttigr&phy oj Bispkcnpt A-Cu Glucutcnidt Fipure J Is a chromatogram of the urirrafy metabolites of bisphenol A-CH obtained dug t>AE-cellulose. Metabolite UA'' eluted as a wash fraction and was identified by fa* chromatography as free bisphenol A. Metabolite "B" *if found to he present m U urines examined, but because it represented less than )r`< of the radioactivity eluted from the column, no attempt was made lo characterize it. Metabolite ``C" con stituted more than 957r of the radioactivity applied to the resin column, This metabniitr wag, eluted as an asymmetrical peak from DEAE-cellulose. The metabolite produced bj: guinea pig liver microsome? chromaTographed as indieatfd by the dashed line in Fig 3. This material wa# e.Tpecied to be the glucuronide 1,1 bisphenol A, while metabolite "C" has been identified by enzyme hydrolysis and **Sht-nol A analysis to be the glucuronide. The front and rear portions of metabolite were* concentrated separately and rechromatographed. The results are show'n in 1 e 6 The shift in retention of the metabolite is probably due to interactions with Serial normally found in urine. The peaks are more symmetrical on rechromaloaUph\ bm are definitely not pure. The sum of the two peak? compared with the peak to K 2 O o BFG09566 Jev" ;A 182 JAM HR 6. KS VAK ANP U.OVn ,f. f i.' l.L1\ AS obtained from mkrosomal treatment of bilpl'Min! \ is both *-hfi* d viyhtly tjjf broadened, although it is now more symmetrica) The agreement vOth `.Hr mbrosun^ glucufonid* wa? considered to bo satisfactory. h.v . S' % .*i,' FtO 5. Gradient elution of the urinn and mkreiwmil metabolite* Of bispheTU'l A-C" va UPth lamlnonhylMlluJose, The cupiinuou* line represent* the urinr\ meUbolhe* and the ouM line *ipreenU the micrnsr-nMil mtuhclitr thirphetiol A glucur>>nitie) P*ak ,4 j$ Fee bjfphfntf i Kak 8 is an unidtOtifird mrUHolite, and peak C is Uifphvnnl A glvcuronide, Tb* condition* i* pn*n in the tent. Fjf 4. RechTomU>prphy of urinary hisphcnol A*CM pluturmiidt <<r. dielhyliinjfiotthd3^ lose The continuous line represents \kr front portion of peak C, Fie. *nd the smili dMWI* rept-srtus the rear portion of peak C, Fif. 3 Thu larpe dgrhed line r*p'es*nls Wiphenfll plucuronifie trained from njicroscmaf activity The o.inditiorr aft given in the test. . *. UISCVSSIOX The major excrriory path for an orally administered dose of bi*phenol A **T` the feces The finding of a fret hydroxy laitti product was interesting since hyiTM* ^ Jalitm of other diphenols probably incurs in the rat e\tn though their product?^ noi been reported in the literature. The remaining bisphenol A appears in the ** almost solely as a glucuronic acid conjugate, . 21104201 BFG09567 i UETinOLl\! OF BlSFHtSOL A IS' 1 Hi KAT lyn cxchangf chromatography on DEAE-cellub?* pavt quantitative kfpai3ti"n of thf urinary mpiaboHfes. Williams (1959) has reported urir.ary ru fr-tinn ficu'V*' for diphenols varying from A to 71^ of thu den*. Thtie i? ^u-i-mviM that tht rta}t>r metabolite of the diphenol is the gUjcurn:,i(U. a* rcpiried in ihi? work The variation in the percentage reported is due in part to the route of administration and the experimental animal. We bfliw*. however, that the major variation is due to the analytical procedure. The gluturonide of bisphcnol A was found to be eMtvmely n-joant to acid hydrolysis, finre re:ovfTv of free hisphenol A from u'lnc by ihi> mute not possible. The tnamwaliari P-eJururomda^ preprt'ativnf jested in Jhj.-; study v.rod in their ability to liberate bisphenol A frcirri its corjuuste. UrJ\ one enzyme preparation out of five examined wa* capable of hybohzinp hMy:\ of the idncu* n.titdr present. The other preparation? hydrolysed from 40 to SC,f f of the tlucuronide. pr.nuse enayoie preparations were found to vary 5n their ability to 'ibt-rate this diphenol from its conjugate, analytical procedures based solely on freed bfsphenul \ or gfucuromY actd art entirely inadequate. Then fore. c recommend that the ion ruhangt* procedure or a variation of it bt used to ime'ti^ate the yii.arv metabolites of vumpounds of this type. STMMARV A stud' ha? been made of the metabolic fate of an orally administered dost of ti'pheno) VC1 it tht ml. Ovir ae fl-day period of ttic C'1 mo e^'Hed In the v'im and Sf". in iM fecrv \ti C'*0.. crutrj fit d*leted in respiratory CO:.. and at tht ind of 5 dk> s no C,J '<'Sdue> muld U i\u . led in tin ciicass Cm-llary informaticn was obtained to par chiom?iiet:rii'h} and jt.fra- rr<` '|i< r'.'i'stopy, Tin mrulioli- products ipj*nring In the urine were examined by ion e.uhjncf and car chro. matofiraphy, TM mult; show that bhphtnol A b primarily excreted a* tin g/jnjrontdr Lr*> than l*; <>r ilit. mau'ial present in urine war fret hisphtnol A No evidence was found fur Iht fxi-ttnee nl rlhcrenl sulfate*. Tin metabolites appt-arJnff in the feces were txlracled and rxatt.incd l?\ va* chiomsli-triphy. S>nu w'J} of this materia! Was identified as fret bi< phenol A. while jn additional .jJ'.'i mj- idenu- a* a'hvdroxvlated product of bisphenn) A, The remaining iC?i could not bt chromanw.ij'hed rit as probabh- prewnt nr conjugate. <'ni>lHrir?in of the** rcylte with literalun studies on father diphennb are in apreemmi that thru compounds are reied is jpucuronidfi, not is elhetial sulfur*. ACK.NOWLrtGMF.NTS Wi wish to thank Mirs Marilyn J. TallaM for ber Skilled technical assistance and Dr. A E. Aivfi'i'f /nr Me imerrsl and advice. REFERENCES lt;><ik G E.. and PoUttH, C- W. (Ih0l, A comparison of urinary estrogen determinations rmplt Niny varjnus methods of h? <Jro|ysis Atirh At*d. Bull SB. BJ-W, *t k`>, G A . and CHIUSTIV?. J E. 119M), tJelermination of c*rbon-1- in aquroys bicarbc-nate wdutinne b> liquid scintillation counting trehniqur-: application to tiiotockal'fluids ,ria/ CArtn. l.'16-t'lF br*v, H. and ^Lt-airu. J. MP6I), Ldwid 'fintilJatinr counting of car|-/>n.}J, jy of fjfcanol* *niiin .uh\ f< i., jrfvcol nsortrm* th>) ethej-tolurne Anti Chtnt SS. k vi ii '1 si v. H A. (J9bl. An abn^ption li'jhblet for thi mi<rc**d ttrmiraili'n of ttascs GArm. f*.: . ) M6. 111 v k U . Pi.lts. E A O 'Vnns ? . and D A HM). Dterminations oi and Ki + 4 t0 t' ' -t* *1 184 JAM 15 B. K.NAAK AND 1.1 OVD J. M LlIVaN `z V$` H., and PoDLT.kW, W, Dtn iviLna tj on o i H,J and V*ine o*>>tn botnb fombuntor AnaI Pi<uhtm 4 ? m ?111 ir ! * li'CiCLl SfcflTR. E R., ard BulVLi, H Eu." r.;f ffrs.stinr, <! liver Ptn<-/krn J 80. U>>.]7?. . j.t .-l!. i-an-M-!, \.y r^.y. UDtvnuEKTj, S.. Cu**t, C T Vouw J , krw; Bf-oi'U. H B. Vo-Nr u: arcimi^ bydroiylatJoD,' I- -4 mede! FyMttn for ^r^inatK b) dmvlitii. ii / Firf ('km 208 T ' l-Jjj; WEEmot'M, S,, and B. (I9M). Mri*buli>rn 61 lal.flfd .-carbon sodF in th* ia^ rat J Pft>1 Ckrm 1*1, 707-?l7. IVilluvs. R T- (1959). DtlPTit otivn Mrrkomtnis. 2nd ed (`bipUr 0 j, c^c V.'ibv VP IT In* ^\ Xt-> .-r t .s .HLx Mv 3` >j>\ ?0 h* K CO ! ' S$| BFG09569 rHp, ffl(r /8*'4* Estrogenic Activity of DDT Analogs and Polychlorinated BiplicnylsCv/'^i v.A'V '"'O JtVl UiUltUlC .Hid JIck'IK'C. Cecil ' y *'<*c *4Qe Ofi 3y ^Ooy_ because of the geometric similarity of DDT 10 tile sy nthei ic esi i oi'cit. -u ilhesi ml. Dm and -i.1 ivlan-d soiilpouuJs u'i`i e 11 sled m ;i `i'mmIiu: csiioucn assay m i.iis, Ikirogeni.' activity was o.limited using the 1 8-hr gly\ ogeii response ofi lu imuu. lure mi m 1.1 uv DiphenyImethaiii1, Jipheny lei bane. and i nphcnv imcthanc tumpouuds woe active when a j> *.m h' tion w;b unoccupied Oi occupied hy an lisdrow or melhovy group. Halide or alkyl groups in the />.//positions rendered ihe compounds inactive I'oUehlorm.ilcd hipheny Is and polychlorinated tn- plU'ns Is, v. oulpOiiikls uhull :iio environmental pol- i.il.UUs n| uiOiislii.il vsiii'iri. uei, . I me!.-ii i. a j k ;o_lisi`. I'luaiolphlhalol aiul phen-s, luh.nein. eonipoiiiuis which aiv used a a la sal i\vs in drug prepaldiions. `AiTi; also i. siroj.'riiii. alI v a e 11.. mii> a [Ih.\ ..oh1 am I ho appi opi i.ile />,/j '-diliy di ii\\ a 11a |m ,-s. Stereo models indicated lhai /\/0-i!ib\diovy <.omi'lHiiuts til ilia ,ua i\v nuclei would hav i- ink nun U-.i r Ji-4.mces of the liydrosyl groups which uoehl ap11uii;i(i* those ol ilk- natural styioidal estrogens aikl lilt' synthetic slilhene esi i ngens. In 144."' Solimseii published an cvcilent and compivhen- sivc 117-payu review of the synthetic estrogens and the relation between their structure and activity, In the 25 years suite Solmsscn's review, DDT, a chlorinated hvdrocarbon with a jjeometne simiiarity to ihe synthetic tsiroyens, has Iven widely used throughout the world lor pest control, flic recent demonstration hy Welch ci /, (dO^) of the evtro- nie aetivity of u.//-DDT and our own investigations (l)d,ii-.;n cl a!., 1%8) hast prompted lis to investigate a series of DDT analogs, homologs, and structurally related compounds m an attempt to determine relationships of structure to estro genic aetiv ny, miinous Wc used the sensitive IN-hr glycogen response ol thi' rat uterus as a measure of e-Otogcnic activity ((Inman cf /,, I%5), /he potency of active compounds is icporicd in terms ot" the minimal Milvuianeous dose which will increase t'lytOyen to a level siynilieamly tlill'erent from tonlml. The IS-hr lilycoiienit response is illustrated in l-'ifciurc I. in which the dnse-rtspoitse curve for n,/>'-LM)T is ivpIVsenied. Ihe sleeper response line lor tlyeoLcii, as aintpaieil to uterine wtitihi, is readily apparent. lest SLihslanCts Were dissolved in olive oil or an aqueous ethanol solution and injected subcutaneously at a suvenint dost rate of S mg per rat. Immature female Wistur rats (21 23 liny sold: 3(i 4S y) were killed I S hr nfier the in.iection ; uteri were quitklv e.\tiv d, weighed, anil /ed lot glycogen by the aiuhronv procedure (hcillcr cr ul.. I'JsOi. Mibsi.me.k showing tit-lmlv Were tested luilller at dosage f vels tt> Ikici nig. Sitnisueal eomparisons were made using ,V.Mult's t test wall correction for unequal group si^c. i miKi'viA rin?ss I a bit I ; DDI . 1. 1.1 - i i u hloi o 3.2 I'i't /'>. Iilot o plany I lel I nine: I el/oJdoj o- DID. 1,1,1,2-ieli ;> \ Idol o-2.2-hk- (/i-cliliiioplleiiy Delhane; /i./d-DI l) 1', 1,1, i -li'k hloi'o-2.3 his- i /j-tliiorophenyDcihiinc; /'.//IVriiume. 1.1 .ldncliioro-2.2- his( ^-eihv I phenyl )ethane; /i./d-Kelilume, 1.1.1 inchluro-3,2- hid/kchloropheny Dediane; /j./j'-niyiT, 1,1,1-triiluon >-2.2- bis(/j-chlnrophi'ny l)eihanc; /j,/)'-iyi">ry, 1.1 -iliehk>r\>-2.2-bis- (/M'hlnmphi'nyIjethane; /\/*'-l')l)t , 1,1-tljililoio-2.2-his- Anunal llushaiulfv Research I5ivisi.ai. Hellsville 2'i7il5 ' I'o whom correspondence should he addressed. Mil, t/i-chloropheny llelliy lene, I . lilorn-2.2-bis- (/i-chloi'iiphenv Del hy lene: and /cp'-DDA. 2,2-hivt /i-Llllpro- pheily 1 l.ieelie acid- Table 11: o./d-DDl, I. I. I 1 noh U>ik'2 i />-ch lorop h*.-n> h-2- (o-ehlorophcny l)elh;uU:; n.p'-lM3lI. I -diehloro-2-t />-s hloro- phcity D.2-b'-chk>rophcn> Dcihy lene; >*./'-1 XJMU. 1 -i hloro- 2-(/i-e hlofophcny l), 2-(o-ehioropln,iiy l let tty lene; n./T-DDD. I, I -diehloro- 2 - <;i-ehlon>phenyD, 2 - to - l lilorophi-ny Delhane; wi.fi'-DDD, I,I-dieliloi'o-2-(p-ehloropheily I l.2-(n/-ehlorO- pheny l let ha lie aiu.1 fKl>' Methovy i1'hlor, I .1.1 -t m'h loro. 2.2-bis. (/MUcthoNy phetiy / letliane. Table 111; C'oinpounil 20, I, l-Diplk ay liiieih.me; 21, 1,1- I )ic hloro-l ,1 -dipheiiy Ititeih.mik 23. I. I -his(/i-bfoniopheiiy 11- me ilia ne; 23. I -(pin nyh -1 -(/i-li> ilrit.sy plieuy I Iiiki haiu'; 24. I, I - hist yi-hy iliosyplidiy I line I liane; 2.">. I -| />-h> ill osy plieuy 1 )- I -l/>-mclho.\y pheuy Dniethanc, -(>. I -(pli. m I ] I -t / -met hosy - a-hyili'o\y plieuy l)metllaiie ; 27, I,I hi-.b< hy di osy pheuy 11 nielhaile: 2-S. I .l-histo-ludi ow m-t hioroplidiy Dinelhane; 2d, | -(phenyD-1-(/)-eliloropheny 11-1-methanol; 3d, I. I-bi'(/>- Jilorophem ll -1 - methanol: 31. 2.2'-dihy drosy hen/oplunone; 12, 2,1-dihydi osy hen/opltenoiu'; 33, 4,4 '-dills dl osy tvn/o> pheniue; and 34, 2,2'-dihydro.sy-4,4'-dmietfiosy heii^iophe- none. Sources of the compounds used in u... study weie; Nos. 4, 5, lf- Rohm and llau-.. I'hiladelphia; 13 Dr. G. I-. I lies, U.S. Dept. Agr,, fleksedle: 17 }. K, IX. Rom tie Nemours iN; Co., |tie., Wilmingum ; 18 Siuma C'b> lineal (."o.. ,S| I Miis; 21, 27, 35, 12 K iS K I aboi alone-'. Iik.. Hain- view, N.5.: 38 | astman K.otlak Co.. Roehe'kr, 43 53- Monsunio Co., S|. l.oms. All oilier compounds were pur chased Irom the Aldrich Chcrniml ko., tne., Milwaukee. Purity, .is given by the maiHil'aeHirers, w.is Ivti.T than W*,]. HI.SI l.T'S AMI DISCUSSION I he itatni a I evliogcus air s|> i'ohI-. wtiu h inm.iiii a pin nolle i iiie A and an o sy gen I Mini ion ;n I lie l . p. >sil.oii. wink- the sviiliktk esllogi.ns. wfueli are slilhene ilei i\at iv k si'inui't two phenolic rings (l-iguie 2). It is apparent thaL active estioeeincilv h dependent upon the presence of at least one phenolic hydirivy i ine sfi uUuie. In most i-sp og. n n sis these lumpoiiiuls arc adn ui die mkrogram or snl!imt.Migrain ra nge. I u . out t a s| In lb is. | In . h lot ala U d li\ > ii o.. 111 ant | >iv l a aU s lelated f>' DD| aie onl\ .i.me as esliondis >n milluuain aiuiiunls, a IllUll-lold dlflereiiee. Ihe DID analogs are not phenolic, bin thus mav give rise to aiomalic phenolic suhsptniion dur ing niL'I.iholie conversions in the animal. I lie I tOH J. ACK. FOOD CUFM., \ !M . IS, \0. D70 BFG09570 tV Z W T tZ \ i 1 1 iuri.' I. Uoii>rc>|ioi!si' rclaiimisliip: uIlthil1 tuiuM, idM'uucii, and n./i'-j)l>T DI3T analogs are compounds of die diphepx lelhaile Is pc (I'lyut'c 2). Ollier analogs tested wcl'c Compounds of dk' diphenslmcdmnc or tripheii) liiiethanc senes. We hme also examined |>e>Ks.IlirtHi11 ll! biphenyls and poly i Idotinak d nipheliyls. Compounds which have become lucic.isinidy im plicated as emwoniinnial pollutions of industrial on.mn. We luxe 11OI included in this studs any Steroids, symhelic Lsiro^ns, or ami-esirotjens of die stilhenv sirwuure, and haw excluded almost all compounds of the auininrin, isuibwuio. anthracene, and phenumhrene type. DIPHfcM Lf.THAM: COMi'OCNDS /it/j'-l'ii!iitKins Occupied hy Halide or Alkyl. Ihe mmpounds evaluated in lahle 1 are diphunyleilvint' dcriiuhvvs m Ial)le I. DipheiislL'Uiiine Gunipowiids with y>./i'-Positions Occupied hs Halide nr Alkyl (irniijis R x<0Mr^0>x R' Crmijis \ K li' Name Cl H CCI, /c/P-nm' Cl Cl - CC1. Teiradiluro-DDl' 1' H .1 cu.cn. II < Cl, CCI. r.r'-l>l l)T /f./.'-Perihane (1 fl Cl fill CCI, p./P-Kellhanc 11 Cl , Jl) I'K Cl H cun. s Cl cn. Cl CllCI pp'-DDMlJ III Cl It coim />,/)`-nn.A ' M. .1) miiHDum el u'lik ill SC, '' 1 lll.li'l 1 l c. \Oidu M.t'.n. m 4 4 r p1 i'1 ]' i" i'- r which ihe /'.p'-posilioux arc' occupied I is lialule or alkyl groups. Alniiisi ,dl were devoid of esiroyenic activity ; ji,p'ni)l' Iciupd li and k tmchloro-nO l (unpd 2i cxlnhned a slijjlu piscOycnie response. It appears that halide or :cILy I substitutions in tin.' >',/''-|iosmoiis were sialde. and duniin mela holism in tin.' animal body, little if ails />,//' phenolic hydroxy compounds me produced. /j-nr/e/>'I'nsition Occupied liy 11 nr ()( U . When one of the pout positions ol the aiomuik rmy is substituted hy a hy drogen iSr i1ied)0\y croup, llie eompotunl exhibits eslroitenie aetiviiy ( ladle II), Potency of a low order of mUfciuiUidc, hciily approximately IdiMi limes less active than compounds of the Milhene series, hut is sinlilai' in potency lo eounlarin and isotlaume estroyens (Hickoll rr n!.. l%th. Ihe minimum eil'etlive dose (Ml l>) of diethylstilhesirol which elicited it plscopctl iespouse was d.l jiy, as eomp.mil lo ihe most active compound of I'ilhle II. n./P-[ )l) I'. cnipd II. whose Ml-'D wasO.2? illy. The phenolic ehnnieler of the natural and 'iihvtie i.-slroyens has deinoiisutiled ihe dependency o| estroyefiieity upon the presenee ol a phenolic strut Lure. Ihe aromatic fulys ot the active compounds of ruble li are open, />., they have a /> or /I'-poMimn oecupieti by II and may fc'ice rise to phenolic suhsliUilum during nielahohsin. Theiu also appears to he n H'lpiiieinent for the ethane chain to he inert, he, either Ihe triehloroeihane ( Cll CCI,) or the vinyl halide proup OfC'C'I ) nuisi also lie piesent (empds II, 12, l 31. Thus, einpds 14, 15, and 14, eomaminy more reactive 2-carhon chain tontlyurapons. are inactive, evert thouyh one of ihe aromaue rinp.s could he hydroxylatcd io the phenolic siiuchirc. We have eonLluileil dial rapid in nn> melaholisii) ol these compounds is responsible for their lack of activity. In the siilhesin.il series(.Sulmssen, l`kb}anil m thecomuaim series (ihckoll i7 nL. 1 W>| of esiriiyeiis, />,/>'-ilimcihnx\ com pounds arc less aeloe than vninparaMv />,p'-dili)dtoxx e'liipounds. In die ehloriiiaied diphenyleihiuie scries t I'ahle II), the /i./t'-melho.xy c.imptuind, medlosx v hlor (.mpd 17) was BFG09571 J. AGU, t OOl) UIE-M., VOL. O. N<) <. M09 Table II. Dipheily icliiune Compounds with m n '`Position Occupied by R p'43)"C -^)p II or No. 11 i' 13 14 15 m 17 IS 19 M.L.n. /' 11 it It M >i H OCH, octr.i n {roups P' n <i ci Cl C| H OCH, OCH, H a VI Cl V. 1 Cl m-C \ H H H ,.`-CI n-CI mwiimiim ellse 1 w: il.isc, 1 1 lll.k ( IS . If II ll 11 It 11 It it R' 1C V(1 < V 1. l MCI (. MCI CM I; Ski, t'CI, - COl, CHO ,>./i-nni .DIP )PM u . u'-noti j./c-Mnn 1 . |. | - | ll, ll 1. H O- ' 1- In si | ilii-ns 1 )elh:iiic '- Mi 1 hov ) ehloi leeli. Melllovy ehlur i 2.2 Mis(</.s.l||i)ui|'in'n\ It,), s'i:ikUi_s ,k Vetiviu fill! ll JS .1 s r 1' 1 4 1 l" approximately as active as other compounds which miylit pivc rise to phenolic hydroxy substitution ot\ metabolism, Tech nical melhovychlor (empd IS), which may contain an o./i'mcLhovydilor, was tour times more active than pure {>,(>'mcthoxychlor, MICH I NVI Mt rilANI- COMI'OUNDS: ill.;s/a>r*U;nom: (/dmpounds A series of diphcnylmelhune compounds was examined to determine structural correlates of esirottenic activity t'lahle ill). Active compounds conn'iineil eillicr one or two /'-hy droxy or /nuethoxy groups (empd* 23, 24, 25. 32, 33, 34). ruble (ll. Dipluny imcduine Compounds', lleii/uplienime ( aimpmmds R I C I R (I'rmips Activity .No. If H' IBM DiphenyImelhaiie tlerivatives 20 H 21 H 22 Hr 23 ll 24 OH 25 OCIG 2(> OC'Mj 27' It 2K1 H 2!) H 30 Cl } 1 II H H Ilf OH OH Oil II H ll n Cl n 11 li Cl Cl HH HM II II II il II II HH HH H OH tl OH p p 1'' 2 1 I1' p p r rr- Ilem'-nplienone ileriv.ilives I' H OH 33 OH OH 34 OCHi OCH 3 s J 4 1 M.El.D, - minimum cll'cctivc dose. ''l - iiiiielivo. Umio-liyJ hisltf-hydroxy, Mi-eldorophenyb methane. Ihe most active compound was /'./'`-slihysltnvvdiphenylmelhane which elicited a plycoLienie response at the I mi) dose level. Solmssen {1945) repot ted uelivilv lor this compound at the Ion mt; level, Inn the tljll'ei'viHes in hioassay procedures eonld esplaiti pail of this difference in result. In the diphciiylellianc senes, compounds w ith a p-hydrotten a ltd a stable ethane chain wore ineinholiA'd lo active csiropens. probably comaiinnij a // hvlrox\ Miueluiv. In eonuasi, dipheny 11ne11une compounds with u p-hy si rope n were mil act ive, probably heilifA ineltlholi/ed rapidly at the methane linkage and excreted from the body . denzophenoiie dorivaiivcs, which contain the more Mahlc keioiu- strueltire at the methane carbon, were active if a /'hydroxy was present ( I'aMe 111). ntrin nvi. i*i)i'ANi: t uMrousns: J |<i I'J It NX I Ml 1 11 AN!-. C< >M I'l M .N|1S I'wo dipln.'uy I pi opailc compounds wcl'e active (ellipsis 35 and 3h), the (>,//-hydroxy compound oshihiuntt much greater activity than a />.p '-diuielhovy eompoimd. Dihydi'OJty di phenyl propane fcnipil 35) was as active us n.p'-DD r. Sol mssen (1945) found that this compouinl was acLive at a Mm mu dose level, .Since the/>,/Adiby<lrn\> sii'iieairc appeared to he the struc ture couftTriily activity, phenolphthalol, a phenyl suhsuiiiJed cltphenytmcthaile compound commmnp p,/<'-dihy dross groups was tested. Phcnolphihnlo! was ns potent as any compound of the types studied. Rinp closure, as ill phuliolphlhtdein. roMilied in a 20-fold loss in potency'. These compounds are not known to have cMropcnie activity and are extensively used as laxatives m a number of dr tut piv pat at ions. In Table IV two miscellaneous derivatives which hcai iiinic relation to closed riny diphenyImcihaiic structures arc in cluded : lluorene ami l*.M)-dinieil\s lanthracvne. Moth oi tliesc c i nil pounds were inac Inc vs lien lesled at dose levels up to tt inp. Per rat, III J'l 11 N Y! AND Till P IU:N VI C( >M I'OL1 MIX I'wo hydroxy biphenyl compounds were active Inn only ot the I arid # mi: dose levels ( fable V). In a series of poly chlorinated biphenyls, the compounds containing up to 4Sn(i chlorine were aetivi-. Asjudyed from glc chromaluprnlns. HID j. acr. food chem., vol, ts, no. g, 1970 BFG09572 I * " f .Cj (: i tHANf : IOpX ; 11.62 <Ohc,c^. intN u lX l2.dX c. C n(6ltNY\.PROf>AM c DIPMeNVLtrHANe : ra : io ?X .JifHfMVlMfTnANE P'hjX 9aX TRlPJtLNYl weiMANE BIPHENYL ATOB 99X 106 X TfilPMEHYt. a r 0 B 14 v X 15. oX tp) B IfllPUl NY l 6A 10 /.2 % 9.\X AroC 62X 7.0 X AtoC 10 3X 111 X I l iftin' 2. Mnu.mr.il bimiulae of I'Mmgeiik' Limi>oinnb ihese products arc crude mixtures containing a number of imnpouiuls. A polychlorinated iriphcny 1 lonia mmg 42 chlorine was found to In: more uctiw, m a 1 mg dose lev Table IV, l)i|)l)L'i)\||M't>punc and ITi|tlieiiylriielli:iiiL` Onti pound* t'OKKLl.A IIONS ULl'WI I N ( IIPMU'AI S I K LC I I'lll: I\ AND ACIIVII'V . Sehuclcr (!'J46) and his coworkcis dishcr cr <//, tv^2; Kuaslmtj and Ncluiclcr. 1950) have theorized ihut a rather Iftrye. rigid, lipoid soluble molecular structure with two tit live 35 hydrogen-born! forming groups U rented at an optimum dis tance of 14.5 A units from cadi other would he estrogenic. i They further staled that potency is decreased as the disumee 36 between group* i* decreased or increased. While DDT possesses a relatively large, rigid, lipoid soluble molecular constitution, i[ does dol present active hydrogen atoms at the hypothesized optinium distance of 14.5 A, how ever. The presence of the elccironcgttlive chlorine atom* in I nriitiiiii cb H0<g)-C-<g)0N CH, CH.CI l Ch.ci OH 'v'linic Wthitv M.i:.!lO mg 2.2-Iljs(/j-liy* JnjxyphuU yl)proptnic 0 25 I, UlbL'Iilorn. 2.2-l>is(/i- niethoxy, mmielhy Iphcity li- pmpanu 4 j the ^./j'-orietumions would prohibit the existence of active j hydrogen, If these />./>' chlorine atoms wore metabolized to j groups possessing active hydrogen, the possibility ol estrogen 6'"' OH Phenolpluliiilui 0. Z t action would c\ist. The general lock ol estrogenic activity of I /),/j'-DDT analogs suggests that such metabolism does not I occur readily in the biological siuiniirms studied thus far. I Conversely, the activity ol o./i'-DDI raises interesting i\ ; theoretienl relationships between ilu-nmal constitution and j eslnttvnii- miiviiy. t lie ,<,/<' thimine ;iU>ms aie not ill the H0a ;fH i'a c3risu PIuimInhllulcm I hypothesized optimum disumee. I he exact nature ol (he \- active estrogen structure arising from u./>'-l)l>r. if it is not y) e./i'-DDl" itself, might provide important iuformaium relating I Iuorene to ihe spatial configuration of an in live estrogen, j Dreiding Stereomndels were constructed of many of the j active structures m determine wlielher consistent stcrendiemii ul factors were pfexem. him nuclear distance* were rni.u| tailed and were given m 1'iguic 2 for both O to U atoms of 411 >1^ CH , `J.UMtimctli- \ l.iniluu- ceiie I' j assumed dihydroxy compounds, and for the II 1o M distance the hydroxy I groups. Interatomic distances for the Drvid- M.E-.D. i w in mi in n eikviiv l uu-e. I m.ikU" "c models of' esiratie and stiihcnc were fotnid to be much BTG09513 I, AtiU. IU1ID L 111; M\ I.U.. I*. NO. f\ 0>7f) lilt U2W m Table V. Diphenyl i`il l ril Compounds CiK>' <hh> \n. Name H <i.(/-Riphonol 42 /'./.''-Pil'hcnot 2.3'- Pii>v'drosyaliphian l l.4'-tiiUy drnxy diphenyl I'olsehtoruvated Hif'lieriyl (PCD) 47 PCD Aroclnr I22t 21 "Chlorine 44 l'( U Arocior 12.1,? 45 PCD Arocior 1242 42",; Cl 46 PCD Arocior ! 24S aft",; ci 17 PCD Arocior 1254 M`i; ci 4ft PCD Arocior 1260 60",; ci 49 PCD Arocior 1262 62",; Cl 50 PCD Aioelor 126ft 6S";, ci 51 PCD Arocior 44&5 60",, PCD, -10",; potvctiliiii- ilaletl tnpheny 1 i PCT). 65 Cl 5> PCT Arodor 5442 42"; Cl 53 PC7 Arocior 5-160 60!': Cl '* M I'M), - minimum eM'cctiw: dose. 'I inactive. W'lmh M.IM).' mg 4 ft ft ft ft ft P P r !' r i P sninllur than the 14.5 A quoted by Kcusliity: and Neluieler ('[950). The in.9 A we found agree closely wuh ihe X-ray crysiallngraphie data of Norton vi <<!, < 1%?, 1W), who found 10.95 A Tor 17p-c>trndiol. This disercparley in interatomic dif ferences may he related to tin: improved .'Ketir.K'y of the cur rent .ionite models, when compared to those used in 1950. The diphenylolhano, dipheitylmellviue. diphenylpropnne, triphenyImetiiane. biphenyl, and tripheny! compounds all have interatomic distances '*.4 to 10.!t A for the most likely o to o substitutions. The H to H inter nuclear distances of the hydroxyl groups range' from 9.1 to 1 U A in these compounds. Roth the O--O and H --H imenutclcar distances, therefore, are only slightly smaller than corresponding; bond distances in natural and synthetic estrogens. The structural observations regarding estrogenic activity in lhe compounds slushed indicated that activity is conferred vc In:n a //- or //'-position is limit copied ( 11), pr is substituted by - OH or-- OOl a, l Inlide, or alkyl groups, t>ccupy iiig the ('"-positions render the compounds usirogonically inactive. A stable ethane chain tens I'oniid to he necessary for activity, c.g., the triehloroctluinc or the inert vinyl halide group: if either C of the ethane chain bears an oxygen function (alco hol, aldehyde, or acid), the comptuind is iiivluholi/ed and no islrogcnie activity IS observed, Some poly chlorinated bipheny I and tnpheuy 1 compounds exhibited estrogenic activity. Metisurenients of uNciinidcar tliMances of iVciding Meric models mdieati'd that active silt's would be 4 11 A apart, a ranee similar i. those lomnl m natural ami synthetic estro gens ^oaminuivcly similar estrogenic aciivity was obtained with a senes of diphcMyimethanc or triphenyiineihane deriva tives w hivh continued p-Ol I functions, Correlations ol structore wuh activity suggest that the active estrogens derived from u./j'-niKiloys of DDT ale //-phenolic metabolites. 11 run a runt it i t.u |!ii;kol|, \ , M., Livingston, A, l... Rook. A, N.. tpr/r, ISiiKhi'M. 88, 262 t i960). Hitman. J., Cecil, It. C.. Harris, S. J , lues, (i. I ., Sch'iwv 162, 371 I l*)6S). Hainan J (Veil. M Mcnoh. M. ].., WiemL T. R., J.'/u/i>rn'n- o/njf.f 7(i. n.M 1'islicr, A- l Kciislme, It, t|., Seltticici. I . XV.. f'rm-. Sui. L\p. Itio. A/i'i/. ftt. 4 ty (l`/52). K.casting. 11. 11., ScUiie'Ivi , b, \Y. Im> / I'lh/r. } \ v 39. 87 i 19 507. Norton, I). A.. Karllia. (i.. I u. ( . I'.. Jfiu ( /y.\i. 16, ft9 ( 196 7). Norton, I >. A., knitlia. (l., I n, t . T,, lorn (Vr.o 17, 7 M 1964). Schuelcr. I U\, .S;-/c/v HU, 22) 11941.1, Sc'Uut X., Diij toil, S., Novie, II . Mmaws lei , -hvfi, /.h'uWft'w, 25, 191 | 1950). .Sivlnisccii- bl. V., CV/iv/i, Ri i. 37, 4ft I (1945). Welch. K. M , I ci ut, NX"., C omiev, A. II., t <r\hnl. ,-l/yi/. J'/hirtiuicn/. (4, 358(1909). Ri-ceiictf for rericiv Jmir 25, 1970. . I< fe/wn/ /l/vn.w /.I, 1970. U12 J Atilt, t oon CULM,. VOL. l, NO. ft. H70 BFG09574 kav w CO Pulpal Response of Monkeys to Modifications of a Bisphcnol A Composite Resin and Cement K(f\'ALl) C. At \ i:\SHI\f. nnd lULStift II /.AMI <* School nJ Dcttii.sirw L.mi>r\ L niwrw/v. Atlanta, Get>f,-n. ( \1 7 hr* irtYi'Uiiftiliifn clc ou>n\irnlt it tin nnnitihil pnlp/rl rc*ptm\c nl ifn tath nt on>nke\s to bixpltctutl A restorative nintctutl^ in the Uimi tn a cement atut u.\ a cotnpoait t\`\tn. l.tuii auneriul wax thinned with tt motuaiui 01 methyl mcthacrykitc or of iliou tlnit ryfate. Bowen1 ha* supplied that certain dimethcicrvlalc monomers can he prepared instead ot methyl methaerx late monomer* that arc suit able lor tormulaiinn as a binder for compo'tie mater iftfs This experiment ,(% th'sipned to determine the pulpa) response produced hy two commercial!1* available product*, a hisphenol A resin cementing! material^ nnd a gkutonxJ-fillcd resin material.+ These ma terial* with mcthxl methaerx late monotnet as a thinner were icxtcd and compared w ith the same materials with a *JmK'lhaer*l.ilc substituted .IS thinnet. Material^: and Method* Five 12 to 20 pound adult rhou* monkey* were used in the experiment. Class V cavity preparation* were made on the I acini sur face* in the gingixul region of 130 intact teeth, The cavity preparations were made with straight fissure no. 5b carbide burs at speed* of 250.OOC) to 400.000 rpm. Attempts were made 10 place the floor of the cavity preparation 0 5 to 2 0 mm from the pulp. Air-water spray coolant was used in each preparation. No hand cutting instruments were used in an effort in decrease the possi bility of variables in the procedure. The preparations were dried with cotton pellets Th wind* anjyw.n*d. ip pan. Pi fhp Dlviiirai r>< [Vnii lltthh. NiihwiI Insuiuin >i Mnim. Brthfhli. MU: (he Anerlen Dental AuKimum Rr**arc-h and EUwtimiil Foundanon. and tfw American Cnmulidairij MinilacuiiU|i Co,. Inc KetftvrU lor publication July 1. I97l. * Army Dcmtl Corps, audretx t o W. | tamn. 4 LAMCO. PbiliAHfihii- Pa, f Poufr, AMCO, Pbiliidrlpliia, Pa. J062 u* avoid desiccation of the fre-hly cut dcmin The Cement with nicthxl meih.icrvlalq xx.ie inserted in 25 c.ivhx preparations, and the cement with dimcthacrvNile xxa* inserted into IS pi , ,uioii'. The composite resin ihul contained niethW methaerx late was placed m : 2 cavitx prepar:iiions. and the composhe rt'xin milh dimethiicTS laic xxas pi..ceil mi*' l> prep. iratiotix . Ht'thi ihc *c* moot jiirul tlic resin w ere placed direclh i'n Ircshh cm dentin..! mbuic x. No ha*e or fax iu liner- xx ere i :*i. FoM x -s* x teeth of ihe t**i .,; sain.pte xx ere tilled X* nH Itlll.llLMIU LIS C0'llrol* X* Ilhout a base *i1 C.'Mii\ Im.'i . nuv of a 1.1 mcrctirv -to-; ill.'X ratio: am: *l`4.im w a* in- scried \\ iih inlodeiate later. 1 thrust* to I* ord stie-so', iix.ii XX..UIJ tv 1 Tall !** .oj ti> ih* i* nip (. are xx ... I.;ii.en t.1 ad: ipt the , iU.iij!ami !* the X\.||k C'1 the prep,.!..'; <n f, L'l H`d m.iry inal .lJilpt,llliv'd. 1 he :e*l oralH" . xx-cr* carved liuh'ly itiKb Xsilh The e;o :!*. siir 1 a*.: margin ansi tell unpoli-h.-i*. Specimen* well. lake;. a* the end of 4* hour* am/ 45 das*, flint'*. OMlx'ly :,!ter ex tractions lho root tip* wore tcmo*cd with a straight lissure bur to ucilit.no fixation. The iL-oth woic placed in 10r' Formalin solution fot live to ten days. When fixation was com plete. the specimen* were decalcified with the use ol a st.mdatdi7od laboratory method, embedded in paraffin. sectioned, and stained wuh homaiowlin and eosiri. The sections xitvu about b micrometer* innii thick. Microscopic comparisons were made be tween ertch modification of both materials and the control. The rent.lining denim be tween the cavity wall and pulp chamber was measured h\ a micrometer along the length of the dentinal tubule. 5 Nrt Tiut rwntaiw. S S. PWUUelrhia. Pj . trim Lent, Wtular. Orr. DmUt Wlp. Co., * m BFG09575 L I of M \n. 4 PULP RESPONSE TO PLUS < CEMENT The pathologic condition of the pulp >*as evaluated according to the criteria of S*crd- lc*w und Stanley.2 Recording* were made of the intensity and incidence of cellular div. placement into dentinal tubules. the inflam matory response in the superficial layers (odontoblastic layer, zone ol Wfi|, and cellrich zone i, end in the deeper las'crs. The degree of intensity ol pulp change brought about by the \arying conditions of ihe ex periment was recorded according to an arbitrary numerical scale of ft to .V2 The remaining dentin thickness ranged from 0.5 to l.H mm. with an average thick ness of I I mm in the specimens included for histological study. Of the l JO teeth in the total sample. 43 were not included tor evaluation because of losses in technical procedures, or because the remaining denim thickness w;\s found to be less than 0 5 mm. The remaining speci mens evaluated ranged from 5 to 1 I teeth for each experimental condition. Results The t\picul 4ft hour response of the ce ment wnh methyl methacrylate as a thinner is shown m f igure 1, The remaining dentin thickness u\is 1.2 mm. Notable aspiration ol odontoblastic nuclei was present with asso ciated mild acute inflammatory changes in superflciul and deep layers Figure 2 repre sents the as v rage 4H hour response in (be cement with dimcthacry late us the thinner. Essentially the response was ihc same us (hat in the cement with methyl meihacryluie as the thinner. Fir. --Cement with dimethacrylaie after ahours, Rem.nmne denim. <1.9 mni Slight henvrhupc. with aspiration of odontoblastic nuc1; and polymorphonuclear leukocytic infiltijik'fv A 45 dav specimen <>r the cement is shi>w in Figure .v Dmi.-thycrylau- or methyl nu'b acrylate demonstrated essentially the s..i>i. range of response. There was a well-derine. huryd of reparau'e denrin <u the hasc ol I1', cavity preparation with underlying norm,! pulp tissue. The composite resin with dimethaciy; or methyl methacrylate as thinner, cm;:\, essentially the same range of response I' . 4# hour specimens *Frjj 4i showed u-r (ton of odontoblastic nuclei with ussckk- .. mild inflammatory changes in the Mipcme: and deep layers, Conversely, the 4* 2 specimens fFie 5i showed a weM-defir,;. hand of reparative dentin formation at ih. 2 V104210 Fig 1.--Cement with meihucrylaie after 48 hour*. Remaining demin, 1.2 mm. Slight hemor rhage, with aspiration of odontoblastic nuclei and polymorphonuclear leukocytic infiltration. Fkj 3,--Cement with dimethacrylate after 45 days. Remaining dentin, 1.3 mm. Normal pulp constituents, with thickening of predentin User and reparative dentin formation. BFG09576 1064 AUVENSHISE A,\D EAMES 1 Dent Res Jith-Auftu<> 1972 Fio 4.---Composite resin with dimeihacrylate after 48 hours. Remaining dcunn. 0 ?? mm Aspiration of odontoblastic nuclei. with mild inflammatory changes in superficial and deep Inters. base of the cavity preparation with normal untlcrlvine pulp tissue. The histopathologic response in the con trol group showed mean intensity \jlues m the 48 hour specimens. us seen in Figure tv 1 he pulp essential^ was normal With an absence of itiflumuiiiiory chances. The 45 Uav specimens showed significant reparative demin formation fFic 71 with norniol umlerlyina pulp tissue. t srtnoaV J. ceMrvT.^lhc moan inten sity values of pulp reaction to the cement were higher initially, as illustrated in the 48 hour specimens (Fie 8i. which indicated minimal response However, a distinct drop was observed in the intensity values elicited in the 45 day specimens t Ftp 9). The mean remaining dentin values remained constant Fir. fi,--C ontrol after 48 hours. Remaining dentin. 1,2 mm No;ni.t| pulp absence oi in- llammiiior) ctomgr tr SBT.5g^*. ' JbrW. I n- "--t opitol tiMvr 4f i:*\t on'idcrablr rcpartilnr dj'rwin h'T'litirn. ' >!l> normal underJtilJi' Tdlp V", Fig f. 4.'onjpi>silc re.sio with dimethacrylaie after 45 days. Remaining denua, 1.2 mm. Btutd of reparative demin formation with oormaJ pulp constituents. Fin 8--Forty-eight hour rulnaj response, in relative degrees of imens-.: of the cement. Comparison of use of thtn:i."s composed of monomers of methyl methacrtlate /AIWA) in ten teeth, with dtmerhaerviate motjoirw fPMA) in' five teeth Nine amalgam-filled teeth were used as. controls. ''fft'Wf" w 4* ,-*1w*."^y-7*Am,t v**,' \ .I* 'T w : r BFG09577 Vol 5/ No. 4 PULP RESPONSE TO RESIN 4 CEMENT 3. Or cellula* Sup-eaf;:ial <<'-- DISFLACf'EST RESPONSE P:r:ML CEMENT MTH *1MA m CEMENT *! \ TH LMA tm COMPEL PlO 9--Forry-five day pulpal response, in relative degree* of intensity, of the cement. Comparison of use of thinners composed of methyl methacrylate fMMA) in six teeth, with dimelhocrylate monomer (DMA) in eijiht teeth. Six amalgam-filled teeth were used a>- controls. throughout this category. The cement with dimethacnlale had higher initial mean inten sity ratings than did the material with methyl methacrylate and the control group. How ever, the range of response appeared the same, which did not indicate significant dif ferences between each material and the con trol group. Category 2. comimmte hems--The mean intensity values of the composite resin were similar to those in the cement category', which were only slightly higher- The 48 hour intensity values (Fig 10) were higher than the 45 day values (Fig II), which indicated minimal inflammatory response in the shorter postoperative period. The mean remaining dentin thickness remained constant. The composite min with dimethacrylate elicited a greater mean response than did the resin with the methyl methacrvhte: however, the range of response was similar in each group, and the control category indicated no sig nificant difference between the groups. The most significant factor in the 48 hour specimens of the cement the composite, and the control groups was the movement of the odontoblastic nuclei into the predentin*! tubules. In tome instances there was con siderable nitration of nuclei into the tu bules, but more commonly, there was only a break in the integrity of the odontoblastic layer. The roost significant factor in tin 45 day tpsciacM in the cement, composite, and F1 LIE- SeCIN WITH K-'.A FILLS* fi ES I H WITH Dr,A aw ccr.Tt;, n Fig 10.---Fortx-eipht hour pulpal response, in relative degree* of intensity, of the conipr*np resin. Compan>on of use of thinner* compos.! of methyl methacrylate (MMA in 11 teeth with djmcthaerylate monomer (DMAi in fuc teeth. Eight amaieam-filled iceth vert u*ed controls. control group was the appearance of repar..(ive demin beneath the cavity preparation. In most instances this formation spanned the length of the floor of the preparation, and in a few instances in each group. Jonnaiuvn was accompanied by chronic inflammalorcells, but this wav not true consistentlx. On the basts of un analysis of varumci. there was no significant difference ;ii i'v 95 ft. level of confidence between the exjw mental groups and the control group*. LCif CELLUkAS SUf-EfiFICIA^ DlSPtACCMENT RESPONSE J.f r~ FILLED RESIN WITH H>'A FILLEh RESIN WITH DMA CONTROL = H Fn 11.--Forty-five day pulpal response, in relative dtgreet of intensity, of the composite iwia Comparison of use of thinners composed of methyl methacrylate <MMA| in six teeth, with dimetluaybie monomer (DMA) in six teeth. Six teeth were used us controls. 2 J.M H Z J2 IM6 AUl LS'SfftM. AM) I.AStLH J !)riil Res )u\'-.-tuf/i'i lfJ Dlscmsion 1 he Iwo materials tested produced pulpal reactions lhai were considered to be within the limits ol tolerance Eacn material demon strated a hither imiial response than the lone-term 145 day i response, which showed well-defined repair and rnnifii'fatum ol the underlying pulpal tissue. Amalgam was used in this experiment as a control because wc believed that if it is uses! properly, it is innocuous and will not in itself produce an adverse response in the pulp. Previous studies have suggested that the most adverse pulpal effects ol amalgam wen- produced bv the lorce ol condensation and by thermal conduct" ny 1 ` Jn this study, the amalgam was condensed under modefjtir lateral forces. The materia) was well-adapted to the walls ol the cavity preparation to ob tain a good marginal seal. Thermal conduc tivity was ieduced to a minimum because ui the consistence and nature ol the monkey ilie:. Operative techniques in themselves may cause adverse pulpal responses * Although proper steps were taken to minimize the trunlua ut C;o|iv prepai.ition histologic signs were present that suggested operative iruum.i and uifiammalory response io the maiviuiK icMcd. It has been suggested b> Savegh and Rccvl' that monkey teeth mav he mote sensi tive tv* certain techniques than human teeth' Iherelore. xhirhl variations may be evidenced when this material is tested in human teeth Conclusions A commercially jvjj|ithi? cementing sub stance and a composite resin were used in this studs ol pulpal responses Modifications i>! each material, with substitution ol do methacrylate tor methyl merhacrvluic as a thinner, were evaluated bi-lolot-icallv . Class \ e.jvilv pn`p. i.0ioiv, '.vere "lade :il monkev loclh. >" Ol which were acceptable within the criteria ol the experiment Amal gam was used ,is the contio,. i Ml uvth were extracted at the etid oi - - hour- an. ' day s 7 he minimal pulpal respun'V of the con trol group suggested that dir operative tech niques used for the experiment were airaunuiic doth the cement .mil the composite resin hat) higher tniti.d values of intensity than chrome values Significant repair vvtlhmil m;lam/n*iJ*on was jJn- m<"0 commonly observed biologic response )*' the 45 d.o specimens. Although the mean values ol intensity ol tespouse were greater in both materials Willi dmieth.iCrv l-itv. there was >.* significant dif ference between this muddle alum ami the Common tali' available piinliiet PrVprvilvi's 1 11< IW 1 s K 1 1 iv-:. iMiitv It , ntf thacn i.iu Morti.nii11 / /. A. i 4:> ' t.'. flo>. Svvj fi l ! ov. H . an,' Si -M. 11 HR: Rt- `rv'tis* v' Ihf Hum.:: .Ih 'if. 1- lr i' Anv.iiCan K*'ie. =-. < .- > - U: r, , , g, - Mvssu i. M . i.ib,o or 1 "e M.iieiiu1- oi, d e Malp. V . s 1 />< - );I(; 'S V |`tS/, Sw i ui >i . . 1 ..nd s.* \M 1 UK Rva- l i. 'i' . 11 e. i .. r I'rep.a. a t, t. i I1 v. r- i" c . . . l> 1V;;; i j: ]so Saiui t > ,.a.l ki i n. X i h"i*e Kcae- tu-n- i. .i \o. tv.- mi an ' L /*! . < . /i i /, t,. - ; " Sk l < Ir.W VMWtRvr --ywwiiJWlii wi WWffi H" BFG09579 NOTE < Hemolysis due to Chemical Contamination of Clinical Perfubion Apparatus Douglas F. Larson, M S,, Bruce Mayall, M S , and Robert M. Ander&on, M.D, ABSTRACT A chemii^/ contaminant found on the inftrlcu surface of the extracorporeal appafaiu* man ufactured b) the William Km rj Corporation wa* believed to have caused *>e\ en, hematuria in 2 chil dren. The biological artt\ it% of the contaminant Has tested b} mixing 50 ml ot whole* hloud in Contami nated caidiotomies; after 5 nunutes of exposure lysis of one-sixth of the red blood cells -Has found. This hemolytic agent was concluded to be bfsphenol A dU*ol\ ed in an organic soh eni, but the mechanism of ic-nlamination Has never found- Two children who underwent operi-heart opera tions developed severe hematuria ai the onset of cardiopulmor.r> bv pute and continued to have hematuria into the postoperative period. The hematuria could be explained by chemical con tamination of the interior pofycarbonaie sur faces of the disposable William Hajvey cardiotom) reservoirs, A )4 2 Xg 3-year-old girl underwent openheart operation for the removal of a pulmonary artery band and closure of a ventricular septal defect. The b^ pcsf system vtsed was a William Hare ey H-bOO, Serial Number 10445. oxygenator and a William Harvey Model H-500, Lot Number 0tfl45, cardiolomv reservoir. This bypass Ft stem was primed with 50Q ml of pachvd red blood vi-llts avid toO ml of Ringer's Irfi-idie The priming fluid w as put n through live cardiotom) reservoir and recirculated through it prior to the initiation of cardiopulmonary bvp,?ss. Marked hematuria appeared aj the onset of Ctudiopi.hviorop, bvpats, continued during the - hours cj bvpass, arid lasted for 24 hours postoperativ eJv. A second child, wfie weighed 11 1Xg and was also ?v cars old, undt,rw ent closure of a v entricuJar sepial defect. A William Harvey Model t r. n- L'i T*. Jj. `w: c Lnivenn oi Aru C ol- 7,,. `.T, AZ r* i"I l.it111!1' aus ii i<t \:l -t'l"", rc;:: o** e^.it*'.! lo Mr Lrfr>-^r H*. fi.r'fponi of S.,\i rs i.\-')!< o: k.t-.J,u ,: -t !.< soft, AZ' f'r~:4 H-S00, beriui Vumber ld442, o\\ge-nctor end a Model H-5P0, Lot Number t>l34, cardiotomy res- ervoir were primed and recirculated in the same manner a? foi the first patient Againgvoss hematuria was noted at the onset of cardiopul'noi.a-y bvpajf, during the 29 minutes of bvpass, and foi 9 hours postoperarively. The source of the hemolysis was m\ e&tigated by looking at blood incompatibilities and cold agglutinins, but no cause was found. Examina tion of the bypass apperafus disclosed a faint vs Lite, palchv crystalline pattern on the interior surfaces of some of the William Harvey car- diotonf.^ reservoirs (Fig 1). The biological activ ity of the residue was tested by injecting 50 ml of 12'day'dld blood with a hematocrit of 38% uito three v isually contaminated Model H-500 cardiotonvj reservoirs and into two other reservoirs from diffeitnl lots that were visually clean The plasma of each sample as well as a blood control visual)) demonstrated the dc-gree of hemolysis produced by a 5-minute exposure of 50 ml of blood to the residue-containing and the- clean cardiotomy reservoirs (Fig 2), Plasma hemo globin values from the contaminated units were 1.5 gm, 2 4 gm, and 2.0 gm per 100 ml, respec tively i from the Control cardiotomy reserves. 22.2 mg and 23.6 mg per 100 ml, rej-pevtwvJy, ar.d fiom the- blood control, 35.9 rig pu Ktf ml Appjoxitr.ately one-sixth of the red bhu'd cell* were lysed in 5 minutes of exposure to the residue-containing i^djotomy re>vr\ oir& An attempt was made to find out the *. he mica, nature of the residue found in the reservoir* W'uh the use of mass spectrometry, the ivm i.-.minan! was found to be 4,4'-isopropyl' idtncdiphenol (bNpherto) A), Bisphenol A a component of tpoxv resin, but no epovt rosins were known to be used in the (abn* cation of the \\;lhvm Haney pc-lycarbonatf apparatus. The puu bisphenol A crystal wouL not hcrnolv z* blood, ihert fc-re, other vhemicafv in cunibir.ation with bisphenol A were irvesK* gated, Some products from the ration d viiiylene oxidv arid bi^phcno) A were ^ I i 374 BFG09580 tr'tzmvf -- N'oJ* LirMTi MjvjII. and Hrfnolvfu frum r^rf-swr Afpn.'AfU!- Ci'nrarTiiriJtiC'n l yl. 7lji ,.7:if ifusM/fM/rffitfrni mi f/ijs 'iVW/.n; Hr; rr :ii* J;: jowy irsrr; ;V ^ <i*- hnni Jhy f'-fyUrno! A ir/MdJ* .i/nm c>'ay'('rat<.'i\ of flff .); . iif mas?. spectrometry, bui the- product of these two chemical* also was found !o be nonhemolytic. It was concluded fhat the herpolytic agent was bisphenol A dissolved in an organic solvent. Gas chr n:,ilOgraphic 3r,ak?'> was done* io ar.ajy/r for res/dua! f-r-k i-n I \ i j\->r hi: I rn; ne *\ as found d.;r- to the l*itk ui ir>t^t CL'!ilfjiViin4.ted rardiotorr.v k-^tvou units. The in v itjo observation of hem ok &ic due to the bifphtrm! A-contaminaied ur.its u j. dose related. This relationship may explain why adults undergoing open-heart operation did not develop marked hematuria, foi ihe adult blood volutn'es. had a dilution*! effect In small children with their small blood volumes, however, the contamination was toxic. The source of contamination was nevi*r found. The William Harvey Corporation products in* volved were Model H-200 oxygenators, Serial Numbers 27089-26^21, and M.idel H-500 cardiotomy reservoirs, Serial Numbers 2014526344 All the units vsith these serial numbers that hrtd not been used were recalled with, the assistance of the federal Food and [>ug Admin* istration. Tig 2 Vi,- 0;i dt Jii'wrkso dui tr i\ 5-,on*ft` nj'i'mri r,1JJ in/ of 12`d?y-p/.fN, < fit J;cirtii//y i`C,;Mir:i.;rdiiffJ Harvey. rtnfiWewu reservoirs, t A. B) Plasma from tv'i/^ani Hilary CiirJiOfi'fHi/ rt sen Oirs wluoh liO.I HO iVi;.,,;>i;:/..ifkrn; 'CJ fliiMoodcoufiof tD F .J.vif.i, Jk .OHMr.-'iijfi.rccidiOfi.''';'., f- p/r*;. A B C D EF I I TZM) T fZ BFG09581 ' v": .' -:1;rrMLt:ZTiri-y1 -'-',.< ^v>;Vv^D^-vX, t vy 'l. . V--; . fiisphenol A; r,; 1 '' *t - j^^'-I^opropylidtnfdipbeiio]; 2,2-bis(4-Hydroxypbenyl]propane) ** 'V-T V . \. . ' 177' _ - Significant Physic*! Properties V 7;J '.;Bf4pHew>l> i* * crystalline material, white to tan in color. It has many aynonyritr v'and',ti`ad* wune*? A topical commercial sample has the following properties:* . weight; ;**!> ' ; F|i`h: pointy A'Spi'Cifc gravity: .^.s"ohitibisiUiy: Greeting point: -Vapor- pressure; 328.28 175CF (Tag orten cup) *A'v 1.IW (25/25*0) <0,3tf at %C\ 0,34# ai 83C in water; very highly soluble in acetone and methanol 457CC mm Hg 0 20 0.66 2.25 4 7.60 PC 170 190 210 220 250. 1 50 I, Hygiene-Standards A ktC- WMEND> MAXJUAL .AlWOifWUUC , c/'NCfcNTJunoKa (eight hours); In v , 5 uig/ni* was recommended as ir^xhjpum allowable concentration ^ wir fnr manufacturing installation* by Russian sources.* In 1964 it was a^ain- recommended after a five-year ds one of the standard levels of industrial chemicals in the air of w^A pjemises-4 Only- these Russian < kfandards were found in die literature. below 13 lug/m*. Unacclinuited per sonnel ran withstand conccmjauon* ap* proaebing IS mg/m* before coenpUiis* ing of ocular or nasal irritation,* Aft\ &$*..) other inanufaeturer lilewii* Constdov '^ the ntatarsa) to be a nuhancc du and,. - .; operates satisfactorily if the duit cocs* '^ cviiiraiior jj erporiad bel^w.SS ] No symptoms, (omplaiau or of philological effect, hivy cccwwd;7^; vnider the fcregoing_cc^ittojsi.*( B. Short exposv**tom*ah^' No data on industrial experience in tin United States has been published: Im u t ver, the following heretofore un* . |4<blithcd experience during monufac* luir and handling of Bisphcnol A sug gests dun the 5 mg/nV limit is extreme* 4y runservative. Environmental $.ir. ey? <4 one operating plant show air con* t-jitjitions of a few jjjg/jji8 and no (>in|<iaiTiis. Bisphenol A lias ion* dcred a mihoncf dusi and attempts Vstre made lo keep the i-ojn>mr;ition Ttw ( lUUl.lllet k-.st.Cl t` ##" t If ift til* ijMUkllCt l>| lmta.tr ,,| |-(i ficlj*- fetid Clinufei Ttt ifctlcn^ CV*lWjinr( tit "I , ^ 11 ftrfcb-i'MLjOB t>l iK* airdiCfeJ ti.funiD.iitiii rnn>|i ' l/i at able in/ormatidfl 4M -''Y'Vv-V- atclv haZaroou$ to Wg'+Sat Z`\ , Toiit Properties **: m'* *.1 k.. h il A. Inhalation: In young' 130 to ].*n, iats the re]i<ated inhalatioAn* oa(f diiw ai i.uruei.tiai>ons bets^een 15-86 i..i;/iiit caused retardation of weight L-in viftei 45i days Jrriuuior. of central n.r'ko.is ivuem wa*. noted oi. tiiC 22nd and H'htl davs. HeiiK>fil<:rbin les el and riMiiiocyie counit were belnx\ noniia)., No change in urine protein found. If.. . 301 BFG09582 ft ^ S>J'/ . i!'- ` ^ * 'r%t \ *- 302 In nearly all "barrier organs" the mnount of ascorbic acid was dtcita^d,1 B. Skin contact: A dewage of 6.4 cm/kg (as a 40 Cy solution in dimethyl sulf* oxidej killed only one nf four rabbits following a single 24-hour covered skin application. In pi opt lent t^ly cot. Bis* plieno] A was sli-rhtiv wcti* iovii becauy- 2.0 gni Tc : as a K:l"i soh.tio/j killed three f'f i U rabbits, 1'iH.v\ end applications of a 5t"fD >hi non :n atetone oi of M,rr in dirnrthvl ,uhr "\'de caused onlv slight reddening of the flipped skm of the rabbit bclh. Two of 12 mail, albino guinea pig1- \-t-rr ^takh scnsmed in a ii'iodifii**d L^nds'.ciuer test.7 Three of m \ cn patients hypersrniiiivt to diri?>yl<tilhe$tro) rca< u*d to Bispbenol A.4 Only slight urit-xtlng ac tion t>n jiiutdus membrane and 'Tin is lepi'iird Ijy blitunskiiya.'" hi a/ifitkei ];ilani usiny Bisphenol A i.li- only derma! troubles hem been mild primary ivriuition of the forearms front Contact with dlist or ponder during hot weather, The physician leporthw the above has not encountered case* of der matitis or sensitization as a result of evtenfhc In-plant handlin'; of tin- com pound.10 C- Eye contact: Instillation of 0 5 ml quantities of elutions of Bispbcnol A in dutteihyl sulfoxide or propylene gly col produced irate tie ir.jury at 1^'c concentrations and severe injury at ton* rentrations of 5^e.T D, Ingestion: By stomach intubation, as a lO'f >uspen#ion in semisolid agar, die LD.-,,. is 3.25 for rati and 2.23 gut.'kg for rabbits. A> a l0r< solution in di methyl `Ufcxirit the LD.-, it- 3 66 gm.'kg fot rau.r This tange emnu,passes the LDm of 4.24 em/kg reported by Bormann and Loeser.1' Tot mice Shurnskaya found tlte peroral LD-.r to be 2.5 Pohmn: made bom F-.s-pln-mv A aie ph'>ioJoji'a)lv inert at bO ccnicentrations in food.11 Bitpltenol A fed for 50 days to rats at a concentration of C b'< in their diet .(i.i2 gin.'kgi caused no delti^X' "Ui effrd Higher !: vt ft. were not Ml. Industrial Hygiana Pracfic* cC-iV 'A&-. A. Industrial t -1 s: Bhph-mo! A ]*^ Important monomer "Kick 6nd? usrj* a cc'polyiuei in ;liLr:!ir.Neti|:,jT "csin,L n.adt " tl; ei. i- :On;:. Cii^ '.v-i are in coating 1 , 'I "r nrervmk^' .tSc-s arc in fioonng. 1 epavy fc&a*. rh.-.nEi'.';;la>'.it' poh- a: rrafc Oy rein Uug Bit-phenol A nd pho^j^ They ha\e high impact strenyrh r*>tc vpitc >Tjai !i t i`:.iiu e and a.;* V-W primarily [oi mjrftio.'t noidtrjff.1*' ' B. t aLI ATION or uxt .'SORES : 1, Ait iotripling and analysis: :.;-r i ;S: a. Direct held methods: lOminerCiiilh' available, .. . b. X-ib6ji*iDr) methods: Rwraibwuh NaNCh or diLzotizcd njj* fonilic acid was ust-d by Ffcna. ova. The method has a sentliviiy of- 0 (H_l2 mg but pheoafc interfere.14 PhjK`1 c hroniateja. J phy,;"5',->T and gas-liquid chrrK> ] at"gi apliy 3 `'!t or diffet eritUM thtrriia! analysis by die dvntiinir gas it?<.hnique1* at v^ell red specrrorieiry2'' and clLluiic-nVJ i:ia\ be used for 4^ aj,alysh afu-r appropriate fii-stion. ,v' 2. /Jji-r/,i v,iin' finding!' In the rat lowing peroral administration gm/kg of Bisphenol A (jjrofiilf labelled in the 2 pohiir.n : 2&5r t*H found iij the mini-, .`lb*"? iu Uieftrt* t | and norn,- in the CO_, Eig):l jjost-do1''-. hmiH-d ^mjdps <*/ 4 | tine .tnd (;-.!i.-ist gave on'.y btfr \ ground count. Ei-pht-nol A pW* j iorude is tlie majot evinu'rt pft^ j duct in .iT-.nt' -ncJ frev unchain1 j Hi--;dn.'"'i V <u i pfobat'ii' -=**' j I'odr OV'1,'iU'd 1. Uiiio'llr. "i'* ' in it .>(. eionc ivnaciew tc-1 san.pk'S.-'- ya (j ilZ b O T j BFG09583 :?*v^. i'' ,'>?{! jst* * &'Vj IKwJ'T '*}<'-J !.; I y.,4:, ` J l iI ':, ;^'' E ifc' '*>' f li*. i>fp .,'.Y M 4rtT>V# Industrial Hygiant Aisotwtion Journal 303 HaZ^IDI and THEI* RtCOMMESUED CiSTtOL`, ). Juhalation: An adequate ventilation system should be tniphwrd id main* tain airborne dust below nuisatue levrsH, if tucuniiiaiicos arise which do not permit adequate rontro) then l.\ S, Bureau of Mine* apprvned is evident adii.ntisiei coovrrn if possible. In all Cisvs of over dost* tall * physician nnmrdiait-Iv so that ho r,0rt irtai the jijlir.ni sytiiptomaCK alb l ire u<jal 15ttitnutc irrigation of t*)es ^-icr encouju* er with impinged du.M and ihornujfh cleansing of comarninaitd sk,in are ra tional procedures io follow, respiratory ptc.icriise do ires iln>uid be tisfd to present inhalation of the V. References B'Vplunol A dust. A hjlf-nusk type rrspiiatot designed /or protection against dusts* having a maximal atmosphnic concentration above 0 1 ms'/ru' of air and oiga/m \ jpor be- 1. Synthetic Oiyaitit C'.lu*mif.jl M^nufac* hirers Association. SOC WfA Handbook: Covin-., h ial Qigauic Cfo mica! Samct. Amer ican Chemical Sot iety. 11 hS Six* tetrith Scfet-f. U'.ld.hjgfon. D- C. |i i'V 0.) b) i .`JiL'Liitj I'll n-iil, 11 Wo . Tin- lull Lcepicn syjn n-hpi! moi or 2. k i*ii*n C ail idi t'<n )i.u iii- !: Phw^nl pii* mask designed for use against Piufri tIu s, BcHkklei f-b j .thL' organic vajor> and fiut-1 v divided Admin, <1 Tt cbubal Jn4,;<jnnaliffn* Book airborne particulate* should he emplovt'd wherever Bisphenol A is ! tea led to teui|.K`ntMU^ tausmy de* composition. 2. Sf.iti fontort' Clothing imisi l*.- fjrquently laundered io present con tinuous skin contact and pMTK'ua) cleanliness is essential to avoid skin difficulties, let F-40fi00 \ \%62! h'nion Carbide Cor* pmaiion, 270 Park Avenue, New York* N, Y. 3. Sliumd.jya. N. 1.: Pl*vmV-1< Chrnnie In U'\ic:>tici by Diphen) loipropane Dust. 7 ol.iJ.ol, Xciylih Pfor/i AV.mi, fYM* if,i st; 4: 43 , 1 %2 i. Cited from C, A58. ltJ6.?2/ (1963i, 4 Korbakova, A. 1: Standard Let ell of St\- Industrial Cl'ifehiitalf. in the Air of !h Eye umlact- Stt/ets yliise^ l?i>Hild Wnrk Premises. Vt \jrt. t4had. Aft //. Kayk . jiioside adequate proieciicm fui the MIR 19; 17 (1 %4 \. Cited from C. A, etes when die dust is liundlr-d hoi 61: lh6&4c )f64l. " glasses with bide shields or their equivalent must be worn when snony solutions ait handled, 4. Fiu and \ plosion; Two dust t*v j.|o*,innb occurred within one week m a plant iliar aii-comevi granu lar Bisplicnol A because of higher il.Afi nomul content of fines. When ever possible avoid dutoaii mixtures rt.'id follow an r.pptovfd dowi. f.it nil u.l -t *uA rv ihu svvteuiv lui L.iud- hug core Ijusubli's."' 5. Torktlson. T K.: Periona) Co/nmtmifiation, Dow Chemical Conipaav^^lidhu^. Micliigan 48^40, ' 6, White, \ G ; Personal Communic^tioii.i ^ Shell 0)enm:aJ Company, 50 W, S8th Street New York, N, Y. 10020, L'ppublished dau; Cbrmic*} Hyj5e Fellowship. Union Carbide Corporation, 44CK!) Fifth Av enue, Pimhurgh* Pe^a^l* , vania 15213. H. Fu-LtTi. S. and H Knisman'. H^*p*r*'x'li-itiv ity to Dlythv Istilbevirol wih Cross- . Si.:'.du/aiiou to Ileuresl'nl Ada Drr- 1 i M itol. 4J 29U i 1^82 Cited tV Med.cal Information 1 ).i I r- !,,\r hi-- ii im d> " M 0M cd 0...K*! u( licit :,ls .ifu'iv hiliut 0 <. .: I '' .e'lil f.',.n C A 57: l5??Ub ih62,r. H. Siciiuikaya, N'. I : Tevii olocicaJ and Sji.Itarv Ch..vu(tfi,!'istifv. n! ]jo\v Reiins .n.d H/t.i Ciintixi'icnis. Pr-rn. TokHKob 1.:s hi-fj, ]i'.-i;t`ss,ii-y. It vw'.ild `..i:,,i logi- Sb.; 132 tl^nO . Cited from vA.1 to vacate- the ti<iiLjuunMrti environ* C A 5:. broh f)f*62 . ' ;nal area ami if iespirjion dioies-s 10 Nh'Kinlt'v. C. S.; Per^n.al Comaimtica* i'i K f P M ?f! 1 ; - -<i| ii f.-! Ul 14 ttfiir *>1S.rHii 4 :\-t\ I Uo<\ A BFG09584 - r -v j.n, 'irJ .t i : * 1 \: 12. Shumshaya. N 1.; The Toxicology of Diphenylolpropane, Tah fit. nl S'oi yhh Khim 1' , 2: 30 JM)1 . Ciicd from C. A. 57: 14}13c 1962 i. 13. Faith, \V, L,, D. B. Keyes. and R. L, Clark' Industrial CLunualt. 3rd Ed.. 6 132. John Wiley and Son. NV York. . Y. J965). M- Pimenova. Z, M.. and S O. Khartiua: DeierJiihijiion'in Air ul .Yoxiojj Sub stances Found in tbs Prftduc-tinn and L'sr of Epoxy Resins, .Vcn Oi i Sam/- Rhiin .4><a/i,n. 113 ,\9h2>. C-Urd from C. A 59.- 2(KHf 0963.-. )5. Fijcdka. P. W. Radfmii/. and F. Rouge; P^per Cl.:ti:ii4H*graphy Anahsis of Diiarbt'Nj]tc Acid*- and GKcoU oi Polvrsier Resins Platt4 Jfaul'fhvi 10: 521 (1963). Cited from C. A. 60: 3492h t. 1964 i. 16- Mlejnek. C>.. and H. Serkarova: Iden tification and Deiennination of Phenol, p-Ciooh Dun ^fiispht-nol A), and pHydirxyberooic Acid with Paper Chro matography. CfittH. Zitsli 15: 885 Gill, H. H,: Quantitative Analvifc Hipphvnol A by Gas-Liquid Chiom raphv. Anal, Cfum. 36: 1201 (if Curd from C. A. 6): 4967c il96fj^ 19. Slone. R, L.: Diffetentjal Anah'&if b\ the Dvrusnik Ga* T< Anal Chrtn. 32': 1582 (I960!, frame, A. 55: 4234g (196h. . ;f 20- H&cskaylo,' M.: Pieparanon of'v pounds for Infrared SpectroiaeHv. Ch.fn. 76: 1410 (1934). Ciirf C, A 49: I431g (1953). .21 Griftn. L. H : Analysis of 4,4' pvlkiuicdipheiioi by Isotope Anal Res. 34: 364 (1962). 22. Knaak. J B., and L- J Snllivant oltim .*1 ftifriilitnoj A in the Rat:^ rol Apfil PuaTiuatol. 8; 175 ( 23. Manufacturing Chemists Aaid<nt Cast Hisioritt. Case No. 1250. Dust Explosions--! A. Manufacturing Cjiemutt 1825 Connecticut Avenue, YV D. C. 20009 (1966)-, Pressure Transducer! The National Bureau of Standards has announced * publication eni^Jed' Afvthodi for Pt rfottnana -Tt sling of EUctTQmf(l\tinical RttuHrr 7*r##idnf#W hy P.S. Ledcrn. This report describes methods used in par particular pregwd: at the National Bureau of Standards for the prriomianre testing of elinvmechanic jJ pre-cme- nansdiktrs A thorough and accurate know*4le*dge of ihe^l perform,mfr t |j,ir,*. iri :mii> of ltlemeiwring trailed.i t-rs is nei*iAr) to obt^ioT, jufjs.ins'ful i..i'.i'UiieiiH-ni> of physical quanmie? such as pressure, acceleraiioo, ` ;-.xd lrr.ipfianju- h> uu- u! i!k-w tiansdiKer*. The n.:.in objective of this report . w;- U ti> pit-'dii ft wvoup ot u'^i pifKedurt's which been developed during the several vars. pix^^dures permit the eflrttivr detennination ttf the i ii-r fi'i'M.arn C'f a Jji ei-Ni.i t- li aiiuduV ej', J'),< j,. Mu .'iiK-rt <i;i11e and d'r<imu caliV.i jtion prctcedures in detail. t.l, I i.i a`.t*v envii ciiiia-ritftl and other tests, and dewribe* the test ecjutpiiient ' . ust'd. This 32-pa^i1 puMk.ition n.a> (h* jtuichaaed h<i 25 terns a copy from thr ,'^^v.fr- Supi-rirujidt-m of Dik ameriis. L'. S. Goveinit.em priming Offtre, Washington, DC, 2(402, ' -`.vi. nr:' 1 :/Jjuffi: BFG09585 EXPERIMENTAL investigation of the morphogenetic properties or certain phenols inducing a vitiligo phenocopy V. N. Zavadflkli and E, M, KhovsnQVh UDC 575.24 :599.32 i 595.773.4 IN TRODLCTION Ordinary (idiopathic) vitiligo has been known since remote antiquity, ft Is found In persona of all races, of both sexes, and at any age. It affect* nut less than 0,2-0.35% of the population in various coun tries of the world. Including the USSR, but among certain groups that have been studied it is observed with i frequency of up to 1% (In the USA, Egypt. .Japan) or even higher (in India) |1-3|, The disease is charac terised by a permanent patchy loss of cutaneous pigment, which arises without any preceding eruption (primarily) and, unlike partial albinism, U develops after birth and Is at times progressive. On the baBis of the data so far collected Idiopathic vitiligo can be regarded as a genodermatoals (autosomal dominant type of inheritance with Incomplete penetrance) (2-10], Since 1939 in some other countries |ll] and since the end of the 1950s in the USSR, a disease known is "occupational leukoderma," "YltlUgolddermatosis,* or "occupational vitiligo" has been reported among chemical workers (LI, 12). The writers previously [13] presented material which shows that the so-called occupational vitiligo is a phenocopy of idiopathic hereditary vitiligo. The two diseases to fact are identical la clinical picture and course and the only difference between them is that "occupational vitiligo" la formed under the influence of certain chemicals and is not inherited (a detailed examination of this problem will be given In a separate communication). In the same publication (13) the first account was given of an experi mental biological modal of occupational vitiligo (in guinea pigs). The objects of the present Investigation were, first, to continue the analysis of occupational (artifi cial) vitiligo as produced in guinea pigs and, secood, to test certain hypotheses on the possible mechanisms of origin of the depigmonted arena. In organisms heterozygous for one or more recessive genes, mosaic spots ere known to appear either spontaneously (14) or under the influence of various types of inducing agents (ionizing radiation (15-17), exposure to a raised Or lowered temperature (IS), certain chemical compounds [19, 201); these spots are localized areas of tissue In which the action of these genes is manifested, whereas the areas surrounding the spot have the normal (wild-type) phenotype. The chief mechanisms of formation of the spots are somatic crossing-over, elimination of chromosomes, point mutations, chromosomal aberrations, and also morphoaea [21). Since the phenomenon of idiopathic vitiligo and also occupational vitiligo in man and experi mental vitiligo in animals all present a clinically typical picture of somatio mosaicism (as regards color of the skin and hair), it was necessary to verify whether certain substances causing occupational and ex perimental vltlUgo (13) possess mutagenic and racomblnagsnlo activity in somatic tissue, l.e.. to examine whether artificial vitiligo (in man and animals) is the result of somatic mutagenesis Ibdoced by the sub stances tested. The quickest and most effective method of testing for the presence or absence of mutagenic (and recomblnagenic) properties in these substances during their action on somatic tissues is by testing Department of Skin Diseases and Department of Pharmacology, Yaroslavl' Medical Institute. Detriment of Skin Diseases, N.I. Pirogov Second Moscow Medical Institute. Research institute of Medical Radiology, Academy of Medical Sciences of the USSR. Obninsk. Translated from Genetlka, Vol. Ut No, 2, pp, 132-139* February, 1975, Original article submitted July 4, 1974. r------------------------------------------------------------------------- ------ -- --" " &IV7S Plenum Publishing Corporation, 221 hta/ tlfh Street, New York, A' Y. lOO'l. Au pert of this pubUnttbM may be reproduced, uoml in a retrieval xvf/tmi, or transmitted, in ittiy ft>rtn or by any meant, electronic, mechanical, photocopying, micn*fUtnin&, recording or otherwise, without written permission of the publisher. A copy of this article is gvaibblt from the puhhshrr for SI5.00. 233 BFG09586 TABLE 1. Chemical Compound* Studied and Their Effect on Pigment For mation In the Skin of Black Guinea Pigs a Chemical formula l u Application of rutlva prep* No. of 3 a ration to ikln * anlnuli ?! 9 5 0 a !I" .3 qn 5B"5J SS'_S Is g a z% 1 j I S. 0 b 18 HIU gu 11 s s 3 S fi. n * i 3 * PT&P PC DDP TTBP Oil 1 /*\ u i /I s h.c ru. cm, OK tr OH 6 i /-CV H,C | CH, ,? \ u. 1 OH OH l 'j -Ctciltii Ftacilcjlly - 4-ftdayt Negli Not insoluble (flank) gible marked keadllyiol- 2-G min uble <3U* (eat) by wt.) COhiId * erablt Practically inaolubln (0.000tffr by wt.) 4-Adjiyi (flank) NegU* glble Not marked The ume The lame The fame The ume tl) (4 U li l /n\ 13 V 111 [(gold depig* mentation to The fame IS Vltlligoid hypopiginentatlan 4 PlgmennilwJiilurbancei flight `All chemical! axe cryiialllne powdert. their ability to induce somatic mosaicism In Drosophila. On the other hand, since occupational vltlll a typical phenocopy of Idiopathic vitiligo, it seemed an Interesting task to study whether these substa: (or some of them) can Induce morphoees, l.e., permanent phenotypical changes resembling the resu the action of genetic factors but not the result of a mutation in the somatic tissues and gonads and, c< quently, not transmitted to the progeny. MATERIALS AND METHODS Four chemically pure substances were chosen for investigation: pyrocatechol (PC), p-tcrt-but phenol (PTBP), dlhydroxydlphenylpropane (DDL), and 2,4,G-tri-tert-butylphenol (TTBP) (Table 1). effect on pigment formation In vivo was studied by the method described previously ji3) on a speclnll reared breed of black guinea pigs. The essence of this method le that the test substance is applied t< animal's skin in the natlvB form on a gauze compress slightly moistened with water. The compress covered with polyethylene and fixed with Cleol gum and a bandage so as to completely prevent d la peri removal of the compound by licking. Only one substance, applied to one pctrt of the body, was tested each animal. The exposure was chosen so as to avoid side effects In thv form of dermatitis or potso The exposure for PC was 2-6 min (on the ear) and for substances in powder form, Insoluble In water not Irritating the skin, It was several days (on the skin of the flank). The substances were tested for their mutagenic activity In somatic tissues on Drosophila melai ter. For this purpose, virgin females of the y + /y genotype (y - yellow, the recessive gene in the ` chromosome, responsible for the appearance of a yellow color of the body and bristles) were crosuei masse with tsn/Y males (sn = singed, a recessive gene In the same chromosome, responsible for tv of the bristles) In tubes 20 mm in diameter containing 10 ml of standard nutrient medium. On the 3r 234 BFG0958"? 21104221 Fig, L. Artificial vitiligo obtained on a black guinea pig. Foci on limb and at margin ofear appeared aa a result of spontaneous dlssemtnatlon and persisted throughout a year of observa tion (the original focus of leukoderma Induced by the direct action of PTBP was on the animal's right flank), ^ rente were removed and 5 mg of the test substances was added to each tube. The temperature was Upt at 24 i 0,5C throughout the experiment. On the occasion of their first flight the F| individuals were tlfmined under the MBS-2 binocular stereoscopic microscope In incident Light. The macrochaetae of the ^dand thorax of heteroxygous y+Z+su females were examined for the presence of mutant macrochaetae tmang them (yellow or singed). To test the morphogenetic properties of the preparations, as well ae gttteat macrochactae, disturbances of the following features also were recorded in the heterozygous y+/^sn (males from Ft and in their y+/Y brothers; the color and shape of the facets of the eye, the color of the body and bristles, the presence and regularity of arrangement of the macrochaetae, the shape and color of ms wings, the character of venation of the wing (In the last case, only gross disturbances such as thickenjajor rupture of the veins ware recorded; no.measurements of distances were undertaken), and die color the pupae. EXPERIMENTAL PTBP and PC, when applied to the skin of guinea pigs, caused the appearance of sharply delineated foci of lose of pigment varying from transient hypopigmentatlon to snow-white and irreversible depigmentadoa, DOPandTTBP caused.Only temporary hypoplgmentnUon; the last compound was the least active (Table l), It is important to note that the loss of pigment developed primarily in all cases (without pro* ctdlflg dermatitis) and it was manifested about a week after the end of application -- during physiological renewal of the epidermis. In this sense the experiments in which an exposure to PC for only 1.5-2 min *ii required to produoe subsequent development of permanent leukoderma are demonstrative. White hairs grew on the deplgmented skin. At the periphery of the focus a zone of hyperpigmentation of the skin and hair was formed. The general condition of the experimental animals was virtually Indistinguishable from that of the controls. The prindpal property of the leukoderma described above, and one chamctertnttc of vitiligo only, wis its ability to undergo spontaneous focal dleeemlnation*. One or more months after removal of ail the compounds from the ekln. foci of deplgmentatlon appeared In regions remote from the original Bite, on f*rfectly healthy skin which had never been In contact with the compound; the clinical manifestations In ibeae new foot were no less clearly defined than in the original site of the lesion (Fig. 1). In the present case the leukoderma differed significantly from that previously induced in animals |22-24). The latter wee confined to the region of action of the substance and was not permanent; in addl(jm, it could not always bs confidently regarded us primary (often there was a superadded dermatitis). The leukoderma that Is the subject of this communication can justifiably he called vitlltgold, for it bia tit the essential features Of idiopathic vitiligo: the primary character of the deplgmented spots (without preceding inflammation), the tendency toward epontaneous focal dissemination, Its persistence (irreversi bility in some cases), but the state of health of the animals remained generally satisfactory. Other less important features alio corresponded: the typical localisation, the sharpness of the boundaries, the hypgrpigmentiUoft at the periphery of the foci. Consequently artificial vitiligo obtained In animals (as the 235 BFG09588 TABLE 2. Teat* of Mutagenic Effect of PTBI\ PC, TTBP . and DDP la Somatic Tlssuas of D. raelnnognster subtunce No-offe- No, o/ mosaic mcteiofy Individuals /ty\tp>e inveit. ftoul for y and itt) Catm-al PTflP PC POP TTBP 19 ft 229 5 3fl6 i 245 6 MB 8 result of the compound tested), like occupational vitiligo in man. la A phfcnocopy of common vitiiigo (which ia also known In animal* as well as In man). Ag was stated In the introduction, it was easiest to verify the hypothesis that the deplgmented spots might possibly be the result of induced somatic mosaicism in experiments on D. malanoflEster. The grounds for this approach were, first, the facts of the knows mutagenic activity of phenols |25| and, second, Individual variation in the severity of the leukoderma; although the guinea plga were black In color, they could be sufficiently heterozygous for many of the genes of skin and hair color. The results of the study of the mutagenic activity of thB compounds in somatic tissues of D. melanogaster are given in Table 2. Comparison of these five variants with one another by the method {%* = 4.477; 0.25 < P < 0.50) showed that variations in the frequencies of somatic mosaicism lay entirely within the bounds of random fluctuation, I.e., differences between all the variants taken together were not atattstl* caJly significant. All the substances tested, in the concentration of 0.5 mg/mt medium used (which la **4* ficlently high), evidently had no mutagenic effect in the somatic tissues of Drosophila, The results of the investigation of the authogenlc properties of theae compounds were more Interesting Since the effects of each of the four compounds were sufficiently distinctive, the best plan will be to con sider each of them separately. PTBP. Practically 100% of the Fj females and males receiving PTBP in the specified concentration at the larval stage had characteristic and uniform disturbances of wing development: The winga of most i individuals did not straighten out properly but remained twisted and crumpled, and their surface was rouftu . the wings were dull and opaque In appearance and they were darker in color, Even if the wings were prop* l arly straightened out (as in a fsw Individuate) their surface was always curved, Disturbances of this sort made it almost completely impossible for the Insects to fly, and soon after emerging from the pupa, they stuck to the surface of the food or to the walls of the tube and died. It therefore seems proper to conclude that PTBP can be classed as a morphogenetic agent: The specific action of this compound (or of its meta bolic products in the Larval organism) on the cells of the alar imagtnul disk led to absolutely uniform dis turbances of wing structure and function In practically 100% of Individuals exposed to its acLlon. PC. In the writers' opinion, pc must also be classed as a morphogen. First, under the influence of PC the puparium developed a deep reddish-brown color similar to the color of the puparlum in red- puj* J species of Drosophila. Changes In color of the pupa also were observed in the series of experiments wllfc 1 PC at a temperature of 18*C; the result was the same (the main experiment, as stated above, was carfls* M out at 24*C). Second, the following changes in the imago were observed. Nearly all males had much mor* a darkly colored wings with a distinct brownish hue (the mates belonged to the y+/Y genotype, and the wlaft J in "yellow" files are known to be golden yellow or pale In color). The wings of the females were a little j lighter, but still darker than in the untreated Individuals. Of 3B6 females examined, 9 had additional pher notypicaldlsturbances. On the back of one fly, between the eupra-alar and anterior dorsocentral bristles, symmetrically on both sides there were areas completely devoid of mtcrochaetae. Three Individuals #*rt distinguished by particularly dark coloring not only of the wings, but also of the body, similar to their color in Individuals homozygous for the recessive autosomal black mutation; one of the females had twisted, very dark wingB. In five individuals the body color was normal but the wings appeared much darker and brownish-lilac In cotor; in one the shape of the wings was modified, their surface appeared uneven, and the wings gave the impression of being crumpled. PC must also thus be classed as a morph*gen (a change in color of the pupa and wings in practically 100% of individuals treated). TTBP. Of the 363 females receiving TTBP at the larval stage only five had relatively severe dis turbances. In one female the right wing remained fused, in another the left wing was completely absent and the thorax was curved and under-developed. A third female had coarsely fashioned, small eyes and ti* irregular arrangement of raacrochaetae on the head and thorax; the wings were narrower than normal, to* Left wing was notched, and the radius did not reach the edge of the wing. Two other individuals had crumpled, wrinkled wingB, The color of the body and wingB was normal in all Individuals tested. Chang** in morphology during the action of this compound, as this description shows, were much less specific thsl. those produced by the action of the first two substances and they were present In only a few (1.4%) of th* individuals treated. This compound can thus hardly be classed as a morphogen (a very small proportion^ i23fi BFG09589 had disturbances and these could be explained simply by the nonspecific harmful action of com`pounds on the differentiating cells)) or it could be said to have a weak morphogenlc action (nevertheless) i I (a all of the five individuals there was some degree of disturbance of wing structure). m PDP. In three (of 245) females receiving DDP, the wings resembled miniature mutants In their deflgn (the cells were smalt, the wing appeared dark and covered with hairs), but they were shorter and ir regular in shape. One of the males had wlngB of the same sort. The small proportion (1,2^) of flisa with hd | disturbance of wing structure suggests that the remarks made above about TTBP also apply to DDF. The results of the experiments on D. melanogaster thus provide no grounds for asserting that artifij L'tal vitiligo in animals following exposure to the compound tested Is the result of Induced mutagenesis in tbs culls of the epidermis* The following objections can be put forward against this view. Certain chemical compounds are known to be mutagenic for some species but not for others. Considering that a phanocopy of vitiligo was Induced *-- by these very substances in guinea pigs and that the mutagenic activity of these compounds was tested on Drosophila, and also that the mode of administration was different In the two cases (applied to the skin in . ooeand given with the food in the other), it must therefore be concluded that there la still some chance j tbit the substances could have mutagenic activity in the somatic cells of guinea pigs although the chance youId seem to be very slight. Epigenetic mechanisms of development of the depigmentation are ail the pore likely. The phenomenon of spontaneous dissemination, l,e., the appearapee of leukoderma in re-* flops never in contact with the compound (and also its appearance a long time after the end of the experi' - meat), is also added evidence against the hypothesis of the mutation origin of the deplgmented spots. The spontaneous progression of the process in the late periods after removal of the irritant (1-7 J niontha In the experimental aeries) end the persistence of the leukoderma suggest that endogenous factors -- ilmilar in their chemical nature to the exogenous are concerned in the formation of the vitiligo pheoocopy. These factors probably act as a "trigger mechanism," after which a closed circle Is formed with constant . ^production of the metabolite that is the inhibitor of melanogeneeis. Very probably the endogenous me( _ tabolite incorporated Into the closed circle and Inhibiting melanogenesls is PC or a homolog of phenol or PC (p-crssol, p-ethylphenol, p-methylpyrocatechol, and so on). A high depigmentlng and vltlilgogenlc poten tial has been demonstrated for these substances experimentally (13|, They can ap|>esr in the body in the process of vital activity of the intestinal microflora [2a, 27}, following the consumption of various food l - pfodiots, such as tea [28. 20], or of products to which antioxidants of the phenol class have been added, apd so on. Certain synthetic materials [30], cosmetics (31}, and eo on may have a similar action. The possibility cannot,therefore be ruled out that only some of the cases diagnosed as Idiopathic vitiligo are in (net a genodermatoela; the others are a phsnocopy, The proportion of phenocopies of different origin is possibly fairly high and vitiligo, as a nosological form, is a composite concept. Tble probably explains ioma of the difficulties that have arisen in the clinical-genetic analysis of idiopathic vitiligo. I The phenomenon of artificial vitiligo in guinea pigs, in the writers' opinion, is a convenient biological model of idiopathic vitiligo and can be used both for the investigation of the pathogenesis and also for the experimental analysis of the treatment of occupational and idiopathic vitiligo. t- CONCLUSIONS Artificial vitiligo Induced In guinea pigs by p-tert-butylphenol (PTEP) and pyrocatschol (PC) is b ^eoooopy of Idiopathic vitiligo, for It coincides in alt its principal and secondary features with the clinical - picture of the latter and can be used as an experimental model of it. The morphogenetic effect of PTBP and PC In D. melanogaster is manifested as changes in pigmenta tion of the pupariumf PC), the body, and the wlnga of the imago and disturbances of wing structure. ] PTbP. Pc, 2,4,6-trl-tert-butylpheool, and dihydroxydiphenylpropane have no mutagenic effect In toe somatic tissues of D. melanoguatcr; in the light of this fact the hypothesis of the mutation origin of , tb* leukodermic spots Induced by these compounds seemed improbable. J t. j- 2. LITERATURE C IT E D . M. KaralitskU, "A first attempt at dermatological examination of a rural population," In* Current Problems in Dertnnto-Veosrealogy. Trudy Tsent. Inst. Usov. V.uchal, 150, 93(1970). A* B, Lemer, "Vitiligo," J. Invest, Dermatol., 32, No. 2, 286 (1969). 237 b Z Z K Y il BFG09590 f f If,/, /rvtufir. 1970, 27, MS The subacute inhalation toxicity of 109 industrial chemicals J, C. GAGE i Imperil Chemical Industries Limited. Industrial Hygiene Research Laboratories, Ald&rley Park. Macclesfield. Cheshire :: C Cage, J. C. (1970). Brit J, indunr. Mi d, 27, Mft. Tli< subacute inhalation toxicity of 709 Industrial chemicals. The inhalation toxic it) of 109 substances hat been studied by exposing experimental animals to known concentrations in air for periods of about three weeks. The toxic properties of these substance* are reviewed in relation to the effects of similar cornpounds on animals and on man. Provisional operational limits are suggested to as.hisi in the design of new plant and in the establishment of codes for safe manufacturing practice. Most serious occupational diseases arising from real's have |cd to a decision on whether the com exposure to chemicals art caused by an attack on, or pound may be handled without special precautions absorption through, the respiralorx tract. On ocs.on such effects can he predicted from oral or P^enteral administration of the chemical to experi mental animals, but, in'general, if a substance presents inhalation risk, it is preferable 10 under take a direct instigation by exposing animals to other than those demanded ty sound manufacturing pr&ctice, whether exhaust ventilation should be in stalled or u briber other feature* in plant design are requited to prevent excessive exposure. The results have also enabled a prediction of the effects likely lo be encountered in man from brief Or repealed known concentrations in air. This survey coven the work on inhalation toxicity which has been under taken over a period of 20 yean in a laboratory enfagad itt the study of the toxic properties of ihc-i'cals ud in industry1. ovcr-expOSure, and have provided guidance on treatmertkio a works medical officer confronted with an accident or with a failure to apply the recom mended safety precaution*. The compound* investigated are indexed below in A!'. Of the samples investigated for inhalation alphabetical order. U'v;iiy over this period were submitted by the manu- rji.unng dh isionx of 1C1 Ltd.; the> a'.caged about ?0 e year. Sot all of (hex* have been included in this survey. Sum* were of loo indeterminate a com position. such jj sr/JJ residues; some er/ proprietary products whose formulation wax uncertain; for some |.,ftaetyl >'butyro!actone, JO Acrylic d, 6 Aerylyl chloride, 14 Adipic ac<d, 6 2 Arin^bvjtiti'l-ol, )0 hr investigation was never completed for a variety of reason*; for a few. publication ha* been restricted for commercial or other conMiderarions. The aim of ihest investigations has been tc> pro' ide nformation to aid m plant design and in the estabMmeot of safety precautions to prevent i*ccupational disease when the materials arc produced or used in manufacturing operations, The experimental 2 ftminomc'hyl-?. Adih>dropvran, II BiM^Moro'l'nwthylfihj! ether, 6 Bix---<thCT>cthy! ether, 6 2,j-B!vp-hydro*yphen>lpropane, 1* Bi*-r-methc3xyeih>) ether, 6 Bis'3-meth>lhut>l peroxydicarhonate II Bivpemafluorosulphur oxide, 13 <2-Bromoeiho.x>) benzene, 7 5-Bromopentan-~-one, 6 1 BFG09591 ** .as'dfc'x? 2 J C Gage 2-i-Buiov>e'htnnl. 5 1- Buivlanimf. 9 ( Bui> I pcractitte. )) 1`Buiyl pero\>piva[iiic, 11 ti-Buiyral<Vi,.dt:, fi Cetovteit)! iiwthcr;< late. 8 CWortMutiunitrik, IQ t-Chlorod(>Jfiafluoic'h.\j Isulphui pcmafluorid*, H 2- Ch*oroeth:'hulphur pcniefluonde, 13 l-Chlc'rc,'if?r'hihMkpt (tt\^ni*ah. 8 4'OiliTri`*0. `i.ny^u'tiyi-jx^lphni pemafuof ide. 13 Chlor-opcru'fiOOrpben/ene. 7 :-ol. i 2*Ch)nr'pM-pafK, A r*Cfiln'OiLi'aflyo'f<ihji Isulp^uT peniafluopde, 13 Cumene c-\ .droperovide, 11 >-r-Cr'.i;t :th;lfcniline. 10 rvecab.-d'ni-uphthatene. J .'Sivanc. 9 DicMc f.>*' 'entj ini'ed `tomeryt. 7 M-Dicb'.m'i'f'thne, 7 D>r> Jorvmetjicnc. 4 I-Dietbi li Trmr'pi-nian '-ont, tO Dif lh> U VTifemtne. 10 0C-Deih>' phocphorothlofidoihionate, ]2 Di''ieih.'v> methane. 5 ' '< -nin.x ;h>! meibacr? In it, 8 ?.b-Dinn-;l.) l-l .r.h-.f1z>0'.AJrl*. 11 Piiueth;1 ,j'K.'iftiie. 9 Dimoh>t J <ulph'de, |3 *,f Dinti:1'. Inv'phpltne. It Omen) lar.ine. 9 Piphemici-nethotj silane. 12 Dipfppii'r>l pern\u1e. II Di-i'k.1'; '.urine, 9 Qiciri)' dui I, h`de. 1? r>ix> 1> - iW JfiiMjc. 13 F;h>i ci;)i'*ofv*rrrait. 9 Eth)! ?*tViOfOphn>irt.iTmirnidatei M r-J-lX'.'sIhfv' 4v'r>)ait. 8 J-Ethslhevl methacrylate. 8 J*t'ih>l-M:>drc\>ne!hjJpzopiPf'l. Ethjl perey cxiiate. l| i A-Forrmlj-vperidiM. IQ 01> to* *4i;-.iC haciiflK. 8 He\acblciobutad>ene. 7 H<xf uorobrniene. 7 A A-MfNa,,'f!h<.;E'nfddjpaw)`de- J4 Z-H>dTt-">chvl methpCr> late, 8 1- H>d,f'VFr<.ir>' mfthacr; late. 8 4-H}dnv>>ir(*al ; drops fan. 11 Jor. ptI'Ui,'j:bon>I, ]4 lsobc!CV"-'h*p*. J [>oh-t>T.j Idehj de. 6 ]k,o*iXianol. 5 Jnnprupjl Lhlorofc-imaie. 9 Laur>? r^uipian. JJ Laur?) mc;hc.,,> late, 8 Meihiitn !>c acid. 6 2-Me they dr ops ran. 11 Methoy ethen*. J l-MethsISenjocteole, 30 *} & j? 1- Met1', tbu'i PC- 4 Mtlh>' LMom^irrnalc. 8 2'MoiJv I-1 ./`OitAuiin 10 ^-Tvihy I ooilnoo- ina'e 8 Mcih: l tvirite. 9 Meihs! xln;>late. 6 2- Meihj itI'ndzvlc. 10 Ne-O) lam me. 9 Oerjl meihac.^late. 8 PePtachhYx'p1 [ixhne. 10 Ph\"o! . "i-ir-oo ans>e. prpptonaidiSde. 6 n 'Prop) ' C; a!:'dt. 10 VP'or>ic*h>hdcn*4'v.ini\ 14 Sil'ton ifr.'bfluonde. 12 Silicon icTfcii^vjaralc. 12 Sulphur thlo^'dt pentifljoride. M Sulphur ck'No-ide J2 I. 4A,7il.7trrab>drc,i 4.?-mc:hanoimJrne1 4 Tr.ranitfiK,- l2 Tnhuila'iimi. 9 Tribu:>l pl'to^piie, 12 1,2,4-Tflch'oTobcnzene. 7 i: V 1 Tr>i:hl^ipmeih\l-ulphen\l fiMOnde. 13 [,?,? Trhhk'r-.,*:ri*lui1vi^'t,n7cne1 7 Tn,',.<-il*<.'v> Svnvin*. 14 I, 2. 4 T?ii^,i!*)lbenzcne, 5 Triooni 'amine, 9 'r | Ti `if'vlhanol. 5 i; I, l, l-Tr!fc(iiiirox>nitLhjlp'i'f-ani bicyclff phosph-k. t* Vin) i ncrak. R Vipj [sulphm ptniaflijorlde* 13 Method* amf ]f Samplf*. J The )oxubTi:*1*'*! I'S <CI DMsicn* p'tp&rti if, either i.'it he*<ar*'h CkpArtmeni Or an experiment^ plini. or vn,-re ibi.ep from fulhi-ZAlt p-pduenon Tht pf the wimplf axii'-abic determi6ed to J.'nr tvefil itt Sv*le of iht t vperimemal Vkprl. ?;eu of ;hf cot^ be de*.ui ibt'd tis pure uK4H>*Mls they ueie not fracliOiuM^ before use a* the icvlcoloBica! pfof'e.'tiei of ihc maieriifc *. suppled *erc elr*ant to ibew in\eMiganoni ^'bsl8 the 5.r\pl< a$ >0 cnntuti conid<rabie id' miMute of other conponent* th:#- information h includd in (lie Results vection. Dexi^n ofev^tcurt clwmbi'es In ali of 'be** experii'erv* the antnliU been CVpO to dynamic atrrit*spberes, that is, to atniospheref Cuu- tinuoush ^neraied And passed throufh'tbe exposA than lxT. Tbe design of exposure chamber has ''arid v uh the number of animals ir.vphed and utih :he ra:utt of the substance urdei tTuevtigatjon For groLfi O'' feat or fc^er rats a glas* desiv'cator, containing wire . panmorw to separate iht ariimals. iaf> vfed nun.Hers, up if- eight rats, were cvp^t-d in lhr chAiit# de^itbcd eht"ltere 'Gage. u*iisl!> the intibr ^ PeT*[-ses of t.'td' de>igr v.-as replied b> a glff c> imder. 30 Li.. Jttmfiei and 2S cm high. For aimoe phenes tontu" s parnculait matter a chamber with*- i r 'n.'t'jf^ir ;< .vici'/t o' f'1'- m' t he /Mi Ji\ J (,tf>fri'ft of Ihe It-*I itnvosph.frs TIk a U&ed foi \he alnu'spk-'v wa* filtered. dried to a rC|anvt humidity of less thtm iOnt.. supplied si s line r^*-ure * atm 11 C13 HJ{ Nm-!j In the Re?ali!- sedl'On, ihe hvelbodt lived to p-epire ihe atmos phere* are ind-.aJed h> lefleis ir p?11wbkh refer io the following list. The Inter i* followed b> anv mformat'Oti relating to Ihe panvuldi evpci invent. A A nearly wlurated vapour obinint i by passing air through A liquid contained in a bubble* wnh a <>nlered glfis* ai'-d*tritui<nr doc Tht volume of the ) quid was lisuall;. lO.JO in' a,r.ej. jf ihe i/f of the ..-pie a'-adab'i pe'i'Miitd. u was replaced dA'iy !. hie*? oihe-wist s'ated. the bubbler w*s maintained ,j a wnipi.b.itb at roof!, ictnpc-at'i-e about 21' C B A neatly 'atuiaifd vapour %):Jim ; by paving air [hrougb b column o'a tpa'iulur solid Jf the s*mple Lupp'ier1 was * fine powder, it was dispersed on tlie of g'ani'lar ktesclguhr, C Afl Btncspbfrr prtparrd by n*ti*-.`ds A or B and d:ii;ted 'r. n k ester' wi'h Jp air, A sap'Siii con-. aiion by in.ii-cung a liquid at s kno>*n ra*e info a meirped Mo.'iim of air by mean* of a controlled fluid-feed ilomizer tCaw, |4S?) foi toficemratinns much less thim lt*1 ppm a solution of the liquid in A lOMsOlojnjns men solvent was u-ed For very volatile l.quut- i!t sy nt'gf w*.. cooled ir. an iee-aicr baih f *> meie'ed firman, of a gas m .aj'ou' f'Otr a blinder 0 diluted wnb a mficed t a mi of ft it Tin diluted ..l was passed through a jsi to produce e^hoe/u vin by turbulence. f 4 gas or vapour cuntoined jr . ' j|ir po'velhylent bag ?: Ainiospherk p-esv,".: a` *ru .cd imps nveired air si ream at a ktiowr rate by i..v*nv or a permalnc pump tWatson Marlow h C A poviJetrd solid indeed mi(' a melered Air st-varTi at a known -ate by the'apparatus descntxrd by B-en and Gage ilGM |. M 4 condensed fume prepared b> passing Ar f.e0'Ol obtaitird b> meihods D O' ft ilirou^l, a wef.in*t,Sated cvhndrida' eleciri; furpaoe l.xhued ir> lh< vempa! i.:be of ihi expocure chambei The furnace was heated to a lemperature suffiuienih lugh to volAldi/e the s.:hnin;*. which on cooling condensed to a fume. I 4 ineihod was deosed for I hr lonhnuous gmeraiion ; ' ivethvl nitrile, which is loo urstabie to be isolated w-.dstored 4 toluiion of h>drochloric ac'id ir ^tfihanof 1 v it; wcvd a; a I cicnv r rait on in e misiuri of t-0 ual or K.diufT nttnle And an* vdrou* snd'um sul- rh'i'e In the presenve of eve" netharo1 :hv ra'v of Addition of bj'j-<'<Mork *'f defined the t-.n- of ' N-tiMion of uinuc P' sfep^nir di!f-u-ed "rvugj-, a Ainesesf glai-s plate into a i iiir ''1i;vsi,rfnieni of c(nienrrBliivft TI'i. `i.r'v sj'jraieL1 conif'*;,: <( prepared mr'luitls ' f h`. P eslirrH'ed b; wngb nc savnpk Vkue :>nd -''.r tf.e dav's run. and iclaimg the weigh! loss to 'Ol.-nio of ai' pitting Thb coritvnrraiion. opre: >ed " i'v!he.rammes per litre, was converted io parv per t on ihe ^sumption thai the sample was puio b;>|!- nf Mi-sf csi -V?I"` an or !;. i p pro' 'iv.aii' 1 sqpUev paT.'uijrlv uwid'e'iah of fov ..-!.i..! i^ m pi;t saniples when the r-..-<rL void; U f'.j.-i >n T.tiv f.i.'o Aie firsi For ih'.--i: rcivn* j-*,c:1 '^1 p v,.-:-. usujiiv p oh -eq fn` s. i s f ,sia l l "ial?. Nki;h '.hr oihif infthods th< t -t-ni-m.. ,r'v h;..j iisualls Keen thour c-ilc ,!uiiH Iron: ihi- kio`wn Mir of ir>""d j?`ior v'f (he suhrinc.t inloih' air sneam !r `.me < pe* r-irni4 the i'onv<'fi'.ruhon w.as L'ht^ked K> due^t anahs" of ihr atfnosp.h<-u- ^-id a` h-und u S. withm J(l ` t of '.he t'vpe.'ied v a 'jf \ .1 r t-t- deifnv nab'm v as a'wfo. vads iht nt'ih'V *.vi id w g'vt j ''tliible indi j*;'of c'nferi-aii in as u.::)- arrosr.ls f ovmic C . t rl; u. >' u ' u-r1 hv rna''*'1 are imlioitied b> b `-jpersefrp: leiin whch tefcv i,-> ihe fnll.'Vv : t'Sl a Cm- htjuid ihroiTAU'peapbv A P>e l(U inMru'nent w uh A hltne tonirJiior deiecior vsas used The li t.uivn wjs < p bs J m b[leJ Will fy,; SO flesh C'fhu wvifd vpir s,i-ifi jbk itmpfftfTufv or iiu- eolwn-.p uh> n',e'n- tainrd aihoi.i dOrt btl.-".' i'.( KtIuic poipt of ihe liqiod A smuple of l.`*< o'-p'iere was ir iw'td rtireci)v inio the N\ v'i"irt gas b' rnrans of a gas samplmc valvelO' IOmlj b Ptv'ideS bv Kvd>rTvefrv A mts-ired volume of the Ai> was pjissed 1 h rough A I",, w \ HCliieOu' potto stum u'O-dt sokmun. and the I'^f'iUes' u`d;nt was niravured uK-n-fAt 4'5 mh ( Prv-s'.lcs b_v o'pdauon of fi-,',<vtis thiivvA tO-rvl sample rsf ihe air wa` ito'U-.ud in a L u< gliivs spring* coniainihg ffl ml fwou* ibuvdnjre 'tagenl (U.gl 0 5'`t u s irnn-ionuinv thi.n.\anate. I ml f s ilr ^v-is Bed. 0 I g Terrous thu'iomum s-j!p]is'e. UK) m1 w-ier. prep^rfd f>esM> ea*1, da> r The sjrmgt was shaken Tor * mmules and ihi ft-r*L ihi--;'v tr-.aie cop. ~c r; * - i ,or was mease fed kh-orplKint Itica IK a; inO nm. d ti'fv'-on 4 r'ieu`."ed volt"'**, of ibt ttu i< p.o-ed 1 hrublk'i (su)phui d*s*hliUidt i >i 10' v ii'-i.ii i'U* ethsmv' (3Jip>v a;>di and llu jhsLv fitd a^ul w; > i ."."ed w>!f `(.``UF- Sv'Liii'Vn. i MiMo.'I h'triie 4 nteas-.,r(d voku'tc of lh( A:r uge pevsr-d th'.'iigh 10 ml tetigem uM g shi.''"rtt,l;ne. 10 ml s MCI jure, and to 1 liifei. r ml I;tgl'.ir-'u4 .N-i U-r*p!uhvlte:l;; Ifr.ediat-ine d ! .-,s1,'s.,il'"ide was Asktffil Afid After I? llnn,;'0 I'h abvi*fbii"sq was mcv', rd al .`.40 nm. Ocsiqr (d (hi1 tVpfnmrtvM Mdi-'c* Fail v'-*;ifk.pathogenTret rsv uri|, ar`s v*-Ll'- of r'YI J wt'-< used in mi"*i "f 'hev {Vpe`1 I'Ctk Tb>c> v*cv frHmiAined m Ihe t\p-.'*.urr ehjftbsr fs>r pe'"vj> or up io P hours knd b^'weefi reptfsiod daily pyp '<v ihfv ant rei..~neil ir the'* cate* where food fend ' wcf l'r?ch available In the imt.al csptn* "vi'p'i ;L,t (ovtniration were Mk\(cd io produce, if pj"'-hk. j" " edicts ark>i ilmr: e'pi'4!'*?? Thcu'ifier Thr csP'Vi.irf r 11 "f"1 e' k'il.lr'd l:"s' I.hf L'O'V f hi '.'It., 'ft 1 ,'IV i ..nil1 till jPu`'a's S( HI Id S,u * Ut h hvsir t ' p 'V-TrS. fuc (5.-V a verk. fiT up 10 four uirl s 1'- .i1- !u;"i.1s ihe Vflpo.ii p`ei`urc hr1-led the :u"uc of loncvnirationy wlvch sv.jij be levied in tV" ,;;;( end suhacuie fiperjmertii Thf rats weri* wf-g'u-kt s'.n'h morning. and their s i''n(jinons ^nd b^hav tour wt-i rov-rdt'd throughout she cspi'sirt ivu'd l.'nne w;is <'"vioc/ ovem'Bhi s t i: JI04227 BFG09593 4' C. Gag* 4 '< *Ittr the lair t\pc.utTt day for biochemical icsts. The animals were IrJi o^-emight wuh food and dr. Ori the foKowini day the rat* were anaesthetized with hilothane and parti*)!) exsanguinated by heart puncture for hacmatoltifH;*} tests, After a grew examination of the organ*, the lungs weie indited with furmolsahne and kuaertad in the uni* f,wi. The following Organs were gh6 lakes for microscopical examination after fixation fo fonnol-corTOive: lungs, liver, kidneys, *p)D. and adrenals; a"d occuionally heart. jejunum, ileum, and (hymua, jr ai any stage effects were observed which could be amibuied 10 the exposure, the experiment was repeated with progressist!) lower concentrations tmnl a concert* tntion was reached which a* without effects on the animals. At imerval* of about two months, batches of control rats <*ttf mainlined in a chamber for the expo sure period, is ordei to check the characteristics of the colony, Result! Presentation of ev-pertraenta] multi Where practicable, (he chemical name used is that recomiviended b)' the International Union of Pure and Applied Chemistry (TUPAC) classification. This is followed in brackets bv any oihej name in common usage. Where the ll PAC nine is little used, sts with meihacryltc aod, the wiJely used name appears first, followed by the svMem.uic name. An) information on purity is included. A structural formula is given The physical state and the melting or boiling points (where known) are stated. Details of the experiments undertaken and the results obtained arc prevented atvording io the following scheme; Atmospheric conrcPtration and method of generation, number, sex, and spec let of animal*; number and duration of exposures; clinical observations; autopsy. The following annotations explain the conventions used in this presentation. Atmosphere The measured or calculated concen tration followed in pareniheses by a )euer indicating the method of generating the atmosphere and any special deuil*. A supe^crlpt letter indicates, the method used for deierTming the concentration. These Jetiers refer to procedures detailed id the Methods section. Unless otherwise staied, the ccftcentrauoDS were dilutions of a vapour or a gas. With `saturated' atmospheres, the concentration in brackets is that estimated frem the weight los*. unless otherwise indicated. Clinical observations The following descriptive terms have been used; nc>)t irritation, sneezing progressing wnh iricreusing seventy 1o a nas*) discharge 4nd a bloody tvud.J^ .> irritation, ey^ closed, progressing to lach.'vmation; mpirctorj difficulty, r.'^pid shallow bathing progressing to laboured and slow breathing; Ict^ti'py, less than normal activity and a fewer rrvp. ttsc to noise; ftypersmsitiic or urm ipnnsivc, an increased or dimin ished reaction, respectively, to noise and handling; incw>rdincition, unsteady movements, staggering gait; no texit implies that the- inimak remained )D good condition. In most expe: iments bkiod and urine tests were made at the lo^er concur trations. and any abnormal results are indicated.' The urine <e*ti included specific gravity, pH* reducing sugars, bilirubin, and piotein. The bloog tests included haemoglobin (Hb) concern ration, packed cell volume, mean corpuscular Hb content, a while and differential cell count, a platelet cfuiftt, clotting function, and the concentration of umlj odium, and potassium Control tests fo> the hacmaj tological examination were made oo the group d animals hefore exposure, Autopsy--no comment the gross pathology indicates that the orgug appeared rormal. Comment after (Ai.uo/.) Indicataj effect* *wn on mictcfscop'cal examinafion of lipsues Or^mml indicates fhal these examm* lions reveultd no changes which could be at'.ributj to the iritrperu. Hydnxarbufit 2. Meihylbuts-1,3-diene CHt:CH 'CMi [isoprenel )iq. h.p. ?4 C nttflri ppm (D, cooled): 2M 27- ra?>; 6 > NJh expo yurts: no toxic signs: auiopsy, lungs slight corigesied. (bind,) organ* norma) j' left) ppm (D, cooled): IM IF rats: IS > 6-hr expt fures. no toxic signs autopsy, organs norma) 3a,417,l*-Tetnh>dto-4,?.fiwihaoointJere [i-Dicyclopcntadienc) solid m.p. I>?C*'C, b p. PO* (decomp.) IJOOppmtCl.pet ether):IM HC S \ "s. CH. I fl I IF rats: 1 * J-hi expo* ""'v> I----- -x. z' j sure; eye and r<`sc irri* * tation. d;spnoea, narcosis. 1 d>e4 later autopt (hiMOt 1 lungs,livei and kidney? congeJted jooo ppm XD. pet. ether): IM IF rats: 1 > 44 evposure. eye and nose irrnafiort. d'tpfroeil muscul.if incoo'dinauotl. ti-cnxor*. h``pe,sensiin-oi ni* difd laier, amopsy, lungs congested, (hi<A lang>, |ier. and kidneys congesird v I?0 ppm tD, pet ether)' IM IF rats: 10 > Si exposures.' J d*ed afier 2nd exposure, suniw tost weight, nose irritation, dyspnoea. lelharpt tremors, hypersensitive, blood tests normal: auiopfl organs normal ^ 100 ppm tD, pet ether): 4M 4p f*tl! 15 X W exposures: no toxic sign*, autopsy, organs no1r 21104228 I BFG09594 9 ''"XT*, J. J' t 7^f iniKj/offOAi'c/M of 109 industrial C^Crriicelh 5 i.^.Trimethylbenier* Ipscudocumcnt) ],;,4-<CH1>,C4Hf i^. b p. m*c Saturated (A) (10 mf.4Jtre, Jooo ppm]: am 4F rata: J} * Mu expose. note and eye irnialion, reapiralory difficulty, lethargy, tremors, low, weigh kfrCTMw, blood testa normal: iutopay. organs normal jtflO ppm (D), 4M 4F rat*: |J :> frhr exposures: millet alight tyt Afld nOie irritation, blood teats nPrfnAl; AUtOPiV, OffAM fiOfrftAl {Vuihydroupblhaltnc C,*H,. IJua'-nl It, bp UfrlM'C lOCO ppm I'D): 4M 4F ttn: l / 4.hr expoiure; tremor*, convulsions, 3 deaths: autopsy, lung* cnnge*ted 20C ppm (D): 4M 4F ms: 20 y Mr exposure*: do toxic signs: autopsy, organs normal Alcohols Isw^tanot (mixture of branched chain alcohols, approx. C,HJrOH) Ik], b p JSS-9fcC Saturated (A) |1 mg litre. 180 ppm]' ?F ralr, 13 y 6-tif exposures: no toxic signs' autopsy, organs normal : Hop'opoxyethanctl [or: * .ipv| glvcoi elhei) Me,CM-(YCHi'CH,OH i ; s r I40144 C (90*) jilC- ppnt (D): 4M 4F rats; 1? v 6-fu exposure*: ir-uial nasal irritation, lethargy. haemogi^binuria, porphyrinuria, Hb lots, (4th day) MCHC low, reticulocytosis, |ait blood and urine normal: autopsy, organs appeared normal, (histol.) luDgs congested ?n0 rrm (I: 4M 4F ret$; is Mr exposures; slight transient (at) ip Kb and MCHC (3rd day); autopsy (histol) lungs congested JOO ppm (D): 4M 4F nttf: 13 >' 6-hf exposures; no toxic signs, autopsy, organs normal r i Butoxyethanol Me.C O |i-hut> 1 glycol ether] hq bp. I52*C ht-t-jraied (A) [13 mg litre, 2400 ppmj: 4M 4F rats: I > 5-lu exposure: comatose, haemaH* Hb :f-507'i normal, ill dud 1-2 days later 35Q ppm (D): 4M 4F rus: 4 > 6-hr exposures: mttial haemaglobinum and lethargy, low Hb and MCHC, weight Joss tO(t ppm fD). 4M 4F rats: 15 * 6-hr exposures: no toxic signs, urine and blood tests normal apart from increased red cell osmOtK fragility; auiopty, Organ; normal 50 ppm (D): 4M 4F rats: 15 * 6-hr exposures; as 1OC ppn* experiment 20 ppm (Dl: 4M 4F rats: 15 v 6-hr exposures: no toxic sign*, blood normal autopsy, organs normal 1 r'stprntafluoroethyDmethafldl |nvfluoretrieihxlrbinol] l-c bp, 105-C (CF,)sC-OH JOO ppm fD.i. 4M 4F rai$: I t hr expo* jrp pax ping respiration, nfesal d scharge, 7 rats d.ed, rapid rigor 25 prm (D, pet ethei): 4M 4F ralv 2 Mr Cipo* sures; gapping, nay&i discharge, l died autop*y, Ijngs haemorrhagic Id ppm <D, r*( ether. 4M 4F rats: 4 6-hr expo sures: increased water consumption, rectal temp. 39 4 C, nasal discharge rapid breathing, prcstrai*, blond tests normal, 2 died' autopsy. Ilp?1 haemor rhagic 3 5 ppm <D. pet ether): 4M F4 rare' 15 - f-hi exposures: increased uaicr corxi_T,pnon. proytrelf. btoed and unixt ism-. hyima'. aeth' ini'ease nnrmir. autopsy, orpins normal J'O ppm tD. pet ether); 4M 4F rats 15 > Mir exposures do toxic aigns, autopsy, org-m normal l-Chloreipropaft-2-ol MeCH'OH) C HjCl [piopxlene chlorohtdrin] hq h p. 133 C 1000 ppm (D>: 2M *F rats' 2 > f^hr exposures; lethargy after 1st exposure. 3 days later g-'en 2nd exposure. I died: autopsy, lung: ocdemilnut and congested, livtr pale, (histol.) lungs interstitial mflammaiory txuda'e, fixer cell*swollen ?nd vacuo lated win, nuclear dr-general ion 250 ppm1 (P>: 2M JF rats: 15 . expo sures* lethargy, irreeular weigh: cain, ptCKid and u.'ine iestx normal aulcps)' (hislnl * lungs conyeSled with pcrixascular oedema JOO ppm ID): *M rais: 1? v t>-hr exposures: no tovk autopsy (histol.) lungs congested with perivascular c*edema 30 ppm4 (D, ethanoh, 4M 4F rals: 14 > -hr expo sures: no toxic yigtu organs normal r-E!hyl M,>dTc*ymcih>lp'cpane-l, 3-diol fTTishydrcxynieit-.yipropane] C|HtC<CH.OHr solid m p 5(rC. b.p cii 150 C (0 243 4 mm) Saturated (A, 70'C| [20 Mg Jure, 3 5 ppm): 2M 3F rats- 15 - 6-!it exposures: no toxic signs: auiopxy, organs normal Fibers Dimethoxy methane <MeOj:CH, [meih' lalj |>q h.p 41-3 C 4000 ppm ID): 4F rats. 8 v 6-hf 4vpoj,ur^s no toxic signs autopsy, organs normal Meihoxxethrne MeOCH'CHi [methyl vinyl ether) # vapour b p 5 5`C `'supplied in cylinder) 2P00 ppm |F) 4F rare: 15 > 6-hr expr-`.;re: no tnyic signs, blood and urine test; normal: autopsy, o'gans normal Isoburo'yeihent Me:CH'CH,`0-CH CH [isobxml tint I r'.her) liq. b p ?3 C Saiurered (Ay 2M 2F rats: 1 > 15*mirt exposure: rapid anaesthesia, all died 1000 ppm (CM: 4M F rati: 15 > Mr exposures: It 1104229 v 4 J. C, Cagr i h)(ti*I lachrymaiion, low weight g*in. bkx>d tests r**mxl: auiopsy (histol > slight lung mfliiiTiTaiioft 30(1 ppm (D>; 4M 4F rats. 15 N 6*hf exposures low weight gain if), blood and unne tests normal: autopsy, orgxn? normal 250 ppm <I3). 4M 4F rats. 13 r g-hr exposures no lOltc Signs, blood and urine tests ootiTill1 autopsy, organs normal Bi>-2-meiho\>f!`s t ihr (diethyJeneglytx)! sJimoth\I ether. digh me) MeOCH CHlO CH.CH.OMt )iq bp t?9 C 6f*D ppmk (O). 4M 4F mis- )5 - 6-hr exposure*: irregular weigh' gam blood and aunt less normal: autopsy. thymus mi.sphied, fa.irenals tongesied 200 ppm* ID) 4\f 4f rn 15 ' 6-h exposures no toxic signs, blood and urine iett< normal autopsy, organs normal Bis ^tbouynhyl ether EiO CH, CH. O CH; CH, OEl Idieihytene gl'col d'Cth) I ether, d*ethw oarhnot] hq/b p I8f C Saturaied i4i |2A mg litre *00 ppm): 4M raij: 17 > 7-hr exposures. rjtutopsy. Organ* normal Bi-2'%h1orf>-1 -r-cihyltihi tether (CtCH^CHMet.O lq b r H7 c "00 ppm tl>t: 2M 2F rats: ) " 5-bt etptsuH nose and eyt irritation, respiratory difficult, ,7 died later: autopsy rh'Mol ) cringes(ion of live' and Sidney s wi tu'25V0 p^rpglmlJt (t,DU)f:. 4i <M | 4F ran; 8v 5'-'hur ei xprx'Myiics: ileth_argy., --re.s-pii--rato--ry diffic--u.lirty, 'r-e*t-a?rdded wetight giip' autopsy (histol i congestion of luer and kid ney* ^0 ppm (Pi. 4M 4F rat*: 20 f-ht evposuT*: letha'gy. weighl gain retarded- auiopy. o-ganj normal 20rpiMDnhandli.4M4Frais.20 > 6-hr e^C^res: no tov>c signs autopsy, organs normal Aldehydes and helunet Propionaidehyde CHr-fH.-CHO Iprcipanall )*q b.p 46-50 C Saturated <M; 2M 2F rats; ! ` 30-min esposyre: nr.aeMhi'cd. at! died 3500 ppm <r>) AM 4F rBts' 6 6-hr exposures no weight gain autopsy thisiol ) li\r cell ia^/-'iron 90 ppm <Di 4M 4F rats. 2Q ^ 6-hr cvporures no lo\ic S'^nS auit'psy. o'guns normal Ju'buiy-iijtb; dt i^2',v) M(,,CM CHO (rsobutinal) Itq b.p 64 C 1000 ppm (Dt; 4M 4f rats 12 b-hr exposves:' slight noSi1 imidiion- aji<,?M' o'^an* nuTtal 3-Bronirvpen(an-2-one BrCH.CH.-LH, CO CM, fiq b p 80 111.' in i n) Sauniled (At, ?M rats- 9 - T-hr exposures: cyt irritation, sa!;vatinn. shghf nar;ovs. rr^pi-aiory drflkully. slight imp * '* C: u<op>. o-fcinr corgtvtfd, lur.^s hatrr."--^^ (htxtol.) ihiitcring of shec^: xx}!s MiM (*/ J9 ppm |0j- 'Vf rat- ' 15 6-b' cijxV.'-pi; flight l<riha:g>. no o`gid Jtimage Acids Acry lic acid Cll: CH CCtf [prnpet'ok ac<d} liq b.p, 14? C Saturated (At |t9 mg litre, 6f>00 ppmj: 2M 2F ran* 1 > 5-hr exposure: nose and eye jiT<ation resprru Tory difficulty. unrespinjixe. 1 died: autopsy (histol ,1 lung haemorrhage, iner and ludney tubulesdegcncraiivt- changes 3 500 ppm <D) <M 4F rats 4 6-hr e.xposurex nasal discharge, lethargy, weight lost: autopsy (two!.) kidneys congested ?00 ppm (Dt- <M 4F rats' 20 ' f-hr exposures: sojw po*c irntariitn. lethargy, reta'ded weight saiai Bpiop`y. O'gan* n(<rmal 80 ppm (D>. AM 4F rats- 20 A-hr expb!Ure. io\ii-signs autopsy. organs normal 4j, Methec'xfrr arid i CH; CMe CO^ IT-niethy Ipropeno'C acid) ^ liq b p. IM `C 1 Saturated 14 3 mg litre, 1200 ppm l 2M 2F ra j J-hr vxpt'sufes. no and eye irritation, weififf loss, bks.id and urine tests normal: autopsy, orgaafc norma) ^ 200 ppm (D) 4M 4F rats: 20 {Whi exposures, nt toxic signs autopsy, organ? norml (slight rertf congestion') * Adipic acid HO;C |CH>.h-CO|H [hcVanedioic acid) yol'd. ni p 151 Dust )2h tig litre *C) 7V 2T rart: 1? 6-lu rurof. no 10"i fifin5- bi>.',,d tests norma! au'.'pfl organ* nonnal t n-Buiyraidchyde CHj C H. CH, CHO (butanal) [iq b p, 75 C )f>00 ppm lD>; 2M 4F Tali- 12 6-hr exposures no toxic yignv autopsy, o'6an normal Chlorinated bydntarbotw 2-Chl(rOpropar>e CH.CHCl (isopropyl cltloride) liq bp 36 5'C 3000 ppm (Dl. 4M 4F rats: 20 > 6-hr exposur J2X104230 BFG09596 * Tic fu'tacuit i>:ha!c.`ion tr.\u!t} oj K" ijf i>" uls ? nc toxic sign*; aqicipsy (hi*ws] ) liver -extensive vaCuOlltiOh and necrosis *50 ppffl (D); 4M 4F rats: -Cl 6*hr exposure*- no toxic sign* autopsy, organ? normal J.l-Dichloroeihtn* CH* CCl, [oins |iden chlorideJ liq. h.p 31-J'C ?00 ppm tO); 4m 4F r*is- 70 < f>-hr exposures: now irritation. retarded weigh! gain: auic-p^; (hi*tol liver cell degeneration ;oo ppm iD); 4M 4F rats 20 6-h cxposures slight now im;*:ion autopsy. O'tiins normal p ,} Iprobuienex (mixed isomers) 1 c'UpCH CHfl CH.CI 2 and ? r/i and nu/o-t H;Cl CH CM CH.CI [I. 37 3,4JichWirnbui-U'ne 2, 17",, r/>-l,4* diiVorohui-7-ene 2. 4y-7*t /r<iw.t-l,4Hjichlorohui-2<ne} |iq h.p IlMSh-C I ft ppm <D. pci ether): 4M 4F rats: -* 6-hr expo sures: inriial laehryrr.ation, leihargy, respiratory dtflicul'y, low rectal temp.. pn-gressixe wei^hi loss, blnod and urine test* normal: autopsy, emuciaied. lungs haemorrhagic, ihymtix ui'fph'rd. thiMol.) lung? emphysematous '`Mh areas or fi&env'n hage jirn? oedema ( ppm (D pel ether): 4M 4F r,i?*. 15 * f*-hr expo* ' arcs: itiitia1 weigh' loss and lethargy, later normal; : '.nopsv. thymus 'light atrophy ` ppm <D, pet ether) aM <JF rat?' IS > f-hr exposures: no toxic signs autopsy. organs normal ] ,2.4-Trtchilotfbei'.icne tup to 20', 1,3.3-i> p,,1 !;>r I'b.-n- arnel CrHjCl, liq b p 206-225 C f^ti_:a:cd t A i |2 5 :ig liire. 2<V; ppn-,]. IS* .T rsis; 15 (-hr expo'w'es te'k;.:y\. u'la'ii^d u,-uhl j;,. n u 1 'ip; y r-n- r , u| 7C ppm iDt 2M ZF ran |5 f> h <'vpoi,.'*t j; ' iaI Uchry malion. lelhargy, f.':ar.1ed x*o,cthi ujin: autopsy, organ' normal 70 ppm fD. eihiinoh: 4M 41" i,u. 20 *>-h: expo sures no rovic i;gns aui''*p'x normal Hrxa^yvoSe-rene C 1-q hr P0 C H/n ppm rD) 4M 4F rait 6 5-hr evn iurrx no fight gam iFl autopsy th-sli*! i lurcy --matre- phages. spxen --rtactixf hjperpla-ia 500 ppm iDi 4M 4F rats )? M,r e'pnx.irps no porphyrinuria, birxid end urine le'ts no'nial. weight gam maided fFc cutop'y. organ- no-mal 250 ppm 'D|. 4M 4F rats: )? f-hr exposure* no irvit signs, autopsy orgsrss normal Chloropentafluors.ibtrizene CtF4Cl solid, m p )M C. bp. ))6 C 1000 ppm iPr *Jhi 4F rats: 4 6-hr exposures: lethargy incoordination, no porphyrinuria autopsy, organ*, normal 500 ppm -D) JS1 4F rats: 15 6-hr cvp*'Mi'-es: unresiXTsixe. no porpbyr.nuria: auiopsy. o'gan* no'mal 50 ppn- iDj. 4M 4f rais IS 6-hr exposure* no loxte signs, autopsy, organ' normal Hexachlorobutadienc ClcC COCCI CCl, hq. 250 ppm IID): aM 4F rats- 2 4-hr-expp*u*e*: eye and po*e irritation. respiratory difficulty, females aPecled more than mkles. apparent recovery after exposure: autopsy (histol l degeneration of middle renal proximal tubules and of adrenal cone* 100 ppm 1D). 4M 4F rais; 12 6-hr exposures eye and nose irritation, respiratory difficulty, poor condition, weight If"*. slight anaemia in females, urine tests normal. 2 females died ' autopsy, kidneys pale and enlarged, adrenals enlarged, degeneration of renal cortical tubules wiih epithelial /c-generaiion ppm fD. pel ether). 4M 4F rats 15 6-hr expo'j_es' poor rood11 ion. diminished weight gain in fxr-.'.sle*. respiratory difficulty. blood and urine tests rn *"mal: autopsy, kidneys pale and enlarged, i,|ivjp) i damage io renal provttia! tubule* 10 ppm iD. pel ether): iM 4F rat*,: |? v 6-hr expo- - ;res- retarded xxei^hi gam in females autopsy, organs normal 3 ppm iD. pet. eiher). 4N4 4F rais: 1? 6-hr expo sures no toxic signs autopsy. organs norma) :yBion--oetho'>iben?ene PhO CH: CH:Br ' nVnoxyethy! bromide] `ltd. m.p. 30 C, bp ru 145 C <50 mm) ''Unrated <A. 37 C) (0-4 mg liire. SO ppm]- ?F rats: 13 5 5-hr exposures: discomfort, lethargy, inirnl ? hj loss autopsy. organs normal 1.3-Dichioroieiraflon*obfn2ene fcont6ns about 5*,, 1,2-isomet) C'4F4-|,3-CI| hu b p 156 C Squuraied i4) pO mg litre. 3000 ppm]- 2M 7F rail' 1 * 30-mir exposure eye irrimion. nasal d'S^htoge, rexp'ratory difficulty, light narcosis I00T ppm tO) 4S1 4F r*li; 4 - 6*hr exposures lighl narccsi* with reco\er> O'emight. inccased urnary coproporph>Tin (M|. porphobilinogen (M and Ft: autopsy (hisiol.) damage to kidney tubules 500 ppm ID): 4M 4F rais: 15 > 6*hr exposure*; light narcosis with recovery overnight weight gain retarded, blood and urine tests normal autopsy (hi*lol.| slight kidney tubular lesions )00 ppm i Of - 4M 4F rat*: 15 > 6*hr exposures no ioxic sign* autopsy, organ* normal I 3,y-TrieMoTOinfluoioberiene C*F,-I.3,?-Cli solid, m p. 50*nO C Saturated <Bl [3 6 mg litre 3SO ppm]: 2M 2F rats: 2 - 6-hr exposures: nose imtaiion, respiratory difficulty, narcosis, male* died, increased urinary protein and porphobilinogen, high blood upea: autopsy 'M'tol.l li'er--focal nextosi* and cemh- lobular xacuolaiion with fatty changes, kidney -- tnbiitar necrosis F3 ppm <C>. 4M 4F rats; J5 - 6-hr exposures no toxc sign*, blood and urine tests normal: autopsy, I'xcrs enlarged BFG09597  J. C. Gage t-Ch!oronAphil,jknt (technical) liq. b p 250-2300 Saturated (A) JO 2? mg'litre. 37 ppm): IS x 6*hr exposures: DO toVC sight: orgatli notmk] r,,H.ci ir rsK: autopsy, Octy' meihjo"> laic !<*cr> I ?*pi :l\` Ipriv^noau} liq bp. i 12 'iflinmi SjiLrcitd I A) IM 2F; 'ills t".x.i,, s.jins ,.p<>. ,y> C H. CM- CO O <\H, :n ex,>. 4,1'l`v ijo nil Ejtert Vinyl acetate rH: CO O CH CHt liq, b p. 7; C Saturated lAl. 4M 4F rats 5 min. rapid anaesthesia, H died 2000 ppm if?r 4M 4F rats 13 f-hr exposures eye and nose irritation. respiratory difficulty. poor condition, lo* "eight gain: autopsy (histol.) excess macrophage?' in lung* b?0 ppm if);, 4M 4F rt*? 15 - ft-br exposure* lo*` "ejght gair. (T)- autopsy, cx'c.in? normal 2?0 ppm (O); <4M 4F rals: 15 (-hr e-posures low "tight gain (7 I, Pl'.n*' and urine li st; noimal: autopxy. 0'gi.fis nOtmal' 100 ppm (D): 4M 4F rets: 15 v fr-Ju exposure?: no toxic sign? autopsy. organ? noma! Methyl salicylate C,H, ' [methyl 2-h'drovbsncoate) liq. h r 2:? C Saturated 1A | COO mg`rpj. J20 ppm]. 4F rats: 20 > 7* hr exposure?: no toxic sign?: autopsy, organs normal Methyl ivoihioryanaie CH,>CO liq. 10 ppm (D. pci. ether). 4M 4F rais: 13 : b-hr expo sure*; Inha'gv, Jou, "fifbi gain iF), blood and urine tests normal: autopsy, thymus small, (hiitol.) organs norma! 23 rpm (D, pci, eiherj; 4M aF ran: 15 ' fr-hf exposures: no toxic signs- abH'psy. organs normal 2.Eihjlhcxyl acrylate [2-ethylhe\' I propcnoate) CHt CM CO 0 CHt CHt ICH ]4 CH* liq h p. C Saturated (M |l mg litre. 1?0 prm): 2M 2F rats; 13 b-hr exposures: initial "eighi loss, lethargy, slight respiratory difficult?,, blood and urine icsis norma! autopsy, organs normal 30 ppm (D, ethanol): 2M 2F rats, no love sign?: autopsy, organs normal :-Eih}!hex}l methacrylate 12-oihx ihex' I 2-neth? ipropenoate) CH,-CM* CO OCH CHtt !CHJ3CHa liq h.p. 224 C Saturated 1 A) 10 15 mg lice. bO ppm}. 4M 4F rats; 15 b-hj exposures no toxic signs, blood and urme lefts normal: autopsy (h;sioU irweascd cellulariiy in lungs 25 ppm <D, ethanol): 4M 4F rats: t5 f^hr expo sures: no toxic signs: autopsy, organs normal Lauryl infi-rttfslaie CH. t Me CO C`C1TH,, [dodeoy 1 2-niL`ih> Ipropc-n xaie] icoptainx 23 "4, C,4 e.`ier) )q. b.p. J^O C (10 rort-.i. 2>.*3 C (SC -hoi) S(jturaied <4' 2M 2F 20 f-h1 exposures no iox'i. .'igO' autopsy, o.'tcnj r.-riwl Cciosieftfx I mfthaxTylaie [lit' ic ! Z- me;h' if" ope"1 pate 1 CH, CM? CO OR ;R - to C,,H,, solid, m p. 20 C Saij'ved ;r r's I? '-`if exp^'-.irei. at tovc signs autopsy, vx-gan: normal r ni "tby Iamr-''cihy ' rneihocry !aie [2-du*'Cib-y lairiin- tiby l 2-rtcihy !pi t'fn n.'-atc] CH^CMeVOt'iCH.-OIjNM*, liq. b.p. 167 C Mist (?) 250 ppm (D> 4M 4F ruts. 1? 6-b.r expo sure? nos* and eye irritation, rapid brea^im, "eight gain lou. and irregular, blood and Urio test? normal, autopsy, organs normal JO0 ppm (Dl 4VS 4F rai?1 1? ' mbr exposures: no icxic Signs: autopsy, organ? normal 'Hydr ovyeihyl methacrylate ir-hxdro"ethx I Z-meihx )p*-openoaie| CH^CMe-COnCH.-CH.Op !iq. Saturated (A) |0 f mg litre. W ppm]: 4M 4F ra< 15 6-hr exposures: trrat'c xieighi giin (F) autopsy, organs normal u 2-Hydroxy propyl methacry late 4 IJ.h'droxxpropxl 2-meth'Ip1 npenoatt 80') CH, CMt CO O CH, CHtOHi-Cfl |2-h\drox)'I'fT>eihjlcthvl 2-meib' Ipropmoate 20"*} CH^CMeCOOCHMeCH.^ liq. b.p. 79 C (5 mm) < Saturated (At 10 3 mg litre, ?0 ppm); 4M 4F nft 15 6-hr exposurw. no texte sign?, auiopt organs normal -5. GJy*l dimethaciy late <CH C M1 CO O CHi fethy lent bt?-t2-methy Ip*'^perpo^tc>] liq. b.p. 120 C t20 mm) i Saturated (A* |1 mg 1'lre. 120 ppm] 3F rats 13 x H exposure?. ?hphl Ifihfti g> : autopsy thiStol. 1 slxeofc uallx thickened, peribipnchiolar lyt!'.phoji-tic tt tion x^eihyi chkiroformate C CO OJ [methyl tMoromemarxciate) liq b.p. 7; c 20 ppm tD- pet ether): 4M 4F rats: 15 x f-hi et Sum: neje iirualion, respiratory difficuJiy. lethl poor condition, "eight lo autopsy, lungs distet Bnd hatmorrhagu.. thistol.) areas of consohdai, 21104222 BFG09598 jfi. 7~hf 'i'.'ufi/'i i'tha/ij'ii-n rr.xicin .>/ /' <' /d,' ..-A, 9 4 and collapse and tome nedtma and haemonhBgc in lungs, kidneys congested $ prro CD. P*1 ether): 4M 4T rati: )5 V 6*hr evpoluret: nn$* tmlition, leihaigy: autopsy, organs normal J ppm (D, pet. ether)- 4M 4F rate: 15 v fr.ht expo* ur; no ionic signs: eu:-'piy, organs normal Saturaied iM l:0 mf l ire. )001 % *) * M ruts; 1 f-hi exposure: inierix; eye ind nos* irritation reSpiiaiury difficulty, corv> uhionv all died autopsy, cnrneji opaque and whne. (hinc'l > orpin pnmal 233 ppm (D), 7M ran J? ( <-hf (ip-vuT' r!ixComforl, !' '.urgy, relaultd \t,chl gain aulopsy, organs norma) f,hy| chldrofoi-mile Cl CO OFt [eih> I chloromethanoale) |iti bp 9J;C 20 ppm (D. pet. ether); 4M 4F ran: i0 > fr.hr expo sures; now Irritation. rep;-3tor> difficult), pcvor condition. weight loss: autopsy. lungs distended, Ihistol ) lung haemorrhage / ppm (D, pet ether): 4M 4F nls. 20 > 6-hr expo* surer retarded weight increase: autopsy, organs normal ! ppm (D. pet. ether): 4M 4F rats: 20 > khr expo* suiei no toxie *rgn$: autopsy, Organs nOnnBl hopropyi chtorofoTmete Cl CO QPri j^oprop)1 chlotomethanoate) |iq. 103- IQS^C (detomp ) 200 ppm (D): 4M 4F rats: t > S*hj exposure' 3M rats dyspnoea both died later * ?0 ppm (D): 4M 4F rst- ll ,x fr-hr exposures: rrspiiatory difficulty, weight loss, J died: autopsy flvstol) lung haemorrhage 2C ppm (D, isopropatml): 4M 4F rats: 20 > ft-hr exposures: nasal irritation amop*y. organs normal * f pm (D, isopropanol): 4M 4F rats: no lo*c signs: autopsy, organs norma) Mcihj l nitrite ' CH. O NO vapour (b p, --12 'O 250 ppm* M). 4M 4F rats: 1 >' 4-hr exposure rats gasping and pale, 7 died HO ppm* (I): 4M af rets; 12 > fr-hr exposures: good condition though pale, melhaemoglohin tow to 30*40*4 of toul Hb by end of each exposure w ith recovery overnight: autopsy, organs normal fca ppm* (I): 4M 4F rats: 15 v 6*hr exposures: good condition, melhaemoglohin JO": autopsy, organs normal 2* ppm* (I): 4M 4F rats: 15 v 6-hr exposures: no toxic signs: autopsy, organs normal .V ppm* (I): IF cat (3'4 kg): 1 > 6-hr exposure: behaviour norma), methaemoglobin 6% Hirvchsl carbonate Mt.CO bq bp W2C Saturated (A) {5000 ppm. 2ft mg lit re) 2M 2F rats; 1 6*hr exposure eye irrif?:ion. Mbvatiori. re'-pira* tory difficulty, ioeoo'dination. rapid recovery after exposure: autopsy, organs normal 1000 ppm (D): 2M 2F rates' 15 >. 6-hr exposures; no toxic signs - autopsy, organs normal 4imino compounds '"Putylamint !: ampf)0buiane| ho t p 62X CH* CH, CHMe NH, P'-s-bufy famine <CH, C'H, CKMei.VH [lvt*(2-melhy )pop\ I limine] l.q l p 1 ty C Saturated (Ai 1*0 mg'hire. lr' - r] 4M 4F rats: 19 x fr ?-h' r\pc*urex re<-,lfsness. mitia' tremors, incoordination, no veight guin iutop'x. o'gans normal Tributylamirte Su4V I'd, 120 ppm (D): 4M 4F rats: |9 ' fr-hr exposures: Pose irritation, restlessness, incoordination and tremors, no weight gain: eulnpsy. organs normal 62 ppm CD. pet, ether): 4f rjis 19 ^ 6*V expo sures: lethargy, no weight gain- autopsy c^garu normal 29 ppm <D, pet. ether): 4M 4F rats: 19 > 6-hr expo* sures: slight lethargy . autopxy, o-ganv normal Non? lamine CMts CII: CHMe lCHttt \H, ||.amipc*3,5.?-trin'ie<hv!hexanel Ii4. bp 1 7fr C Saiuraied (A) |2 mg litre. 340 ppm) ?F ran. I > 35- min exposure nose and eye irritation, salivation, tremors autopsy, organs normal 66 ppm fD>: 6F ms, 6 >. 6*hi exposuics pose and eye irritation, tremors autopsy, p'gjinx normal I6'5 ppm >n. pel ethcri' 6F rats 10 . fr-hr exposures' no tex'c Signs' ai iopjy, organs normal Dinotiy lamine |CMe4 CH4 CHMe(CH.i.ltVH [bim3.5.5'lrimethavlhexyMamine) liq b p. I"2'C (20 mm) Saturned (A) [Olfi mg'hire, l? ppm): ?F rats: 14 v ^hr exposures: slight resilessness: autopsy, or4g/ans rtoimal Tilnonvlamine [CMe, CHj CHMe (CH.hj.N [im43.J,J'tiimethylhexyl)wnine) liq b p 2lfr'C 120 mm) Saturated (OOF mg litre, 7 ppm): 3F rats: 8 ` 6-hr exposures; no toxic signs: autopsy, no organ damage ] ,fr-Diaminohtxane NHjtCHiijVHi [hsxameihylenediaminej , liq, b p :0O C (supplied as 90*, aqueous solution) Fume (H) 10 mg litre; 4M 4F rats 2 ' f^hr expo sures nose initaiion. Tespiraiory difficulty, feihargy, 1M IF died: autopsy, lungs congested, (hisiol.) pK-ribronehiolar mflammaiictn, arras or hsemon'hage and oedema in lungs, vacuolaticr of kidney tubules Fume tHl 5mg litre. 4M4Frars; 11 k 6-hrexpoxu^s: nose and lung iihubon. lirtle weighi gam. Inhs'gy, poor condition, J died, urine and blood tests normal: autopsy, petechial haemorrhage in lungs, thisiol ) lung inftammition 10 J. C. C7oj' Fume <H) 1 *-i l|,re : 4M 4F rats 15 > f*-hr exposures1 no ionic signs. (histol.) organs normal expo-ures no toxic vgns- a:.n.'pe>. slight kidnpyij congestion Dielhyknotnij'-iint NHitCHjA'HfCH.l.NH, liq. tip. IW C Saturated <*; JO 55 mg'Jiire, l.W ppm): IM IP rats: 15 fi-hi exposures; no ionic signs (ha' coarsened): autopsy, organs normal I'4tnincibuiBPl-ol CH. CH. CH'NH,) CHtOH |tq b.p I "f> C Saturate (4> (0.1 mglitre. ft? ppm]: IM IF rats: 15 b*hi exposures; increased while cell count, high blood urea, urine tests normal: autopsy, organs normal 50 ppm ID). 4M 4F rat*: 1? . Mu evpm-tire*: no toxic signs. Mood and urine ie<normal. auinpsv. organs nurmit 1'DieihylaminopentanO'CJne CH, lCM*k C(> CHc'NEt, liq. bp. 100 <2.1 mm) Sirufaicd (A).` 3M riti: 10 > h-hj1 exposure*! eye irritation, salivation, tie weight gain: autopsy Jhistol I s'n;hl thickening or alveolar walls 78 ppm iPi; 7M ran; 14 fi-hr exposure*' slight nasal iiri nfion: autopsy (hiMol ) slight thickening of alvtclai w alls Nitriles A'-I-Cy anocthy laniline Solid. i`t p 50-51 C Pr VH (TH.i. CN Saiur-uied <Ct (l'0` mg lilrf. II pp'n]. 4M 4F ~a|^ 15 h-hr exposures ho lo'ic signs ^uioopj-, organ1- normal Hctwrocvclirs ] 4>cet> I-; -bury [ -Ixri lone AcCH. ro O-C. H. CH, liq bp co 115 C 11.1 mini Saturmed iM: 3M rats: 10 7-hr exposure?' qgj tovtc tiigrts autopsy, organ* i mal I- Me)h> l-J, 3-d i,xv n)an MfCH OCH CH.O liq. b p "Ml C 500 ppm iE>): 4m if rats; 1? 1 f-hr expoxureit| retarded weigh* gain in females, blood and tests normal autopsy, organs normal 250 ppm (D) 4M 4F rats: |J b-hr exposure*: ggl toxic signs autopsy organs normal -*1 A'-Fotmylpiperidine dH(hv CbG| liq h p 210 C Saturated (A) )l> j'4 mg'litre. I 50 ppm): 2M IT ntj. 12 0-hr exposures: no toxic sign?; autopsy,) organs normal 31 n-Propyl cyanide C.H,-CN (J'CyBnpprcfvincl liq h.p 1 IP-" C Saturated tl (tu 2e,, > t]- 4M rats: 1 . l-hr t\po* sure <>t and nose irritation, respiratory difficulty, coma. ><i' died IiXlO ppm (D|; 4M 4F rats; 1 * 4.hr exposure; respiratory difficulty, weight loss, lethargy, convul sions. rectal temp. ?2 C autopsy, lung? congested 400 ppm <C>); 4*4 4F rati; 2 > 5 5-hr-exposures; lethargy, weight loss, |Ow b<?d> temperature, gasping, I died ?iiiop?y organs normal 100 ppm tOl: 4M 4F rat?: 20 6-hr exposure*: no toxic ;<gns, daily urinary' thiocyanate 6 ^ig rat (normal 0 07 ^g)- autopsy. organ; normal ChloroBceU'oi'rik [Chlorome'h;. 1 cyanide) )>q bp \M.i C ClCH.-CN Saturain! tM |)4 mg'litre, vv); IM IF 1 ' .:P*--iin exposure acute laihry mation. all d>ed 500 ppm <D) IM IF rats: 3 \ 5-hr exposures: respiratory difficulty, lachrynation. incoordination, low b<i<*v temperature, uerght loss autopsy, organs congvjied 80 ppn' jDi. 4^1 4f rats 6 f-h* exposures sl-ght respi'aiory difficulty, leihAtgy, low we-ghi gdio; autopsy, lungs congested, thisiol.) congestion of kidney. liver and spleen 10 ppm tD, isopropandl: 4M 4F rBts' 20 > ^-hr I-Methvfthiaeole MrC V CH'Ctffl liq b p i:'C ]0 pprr, (Dl. 4M 4F rats' 13 > 0-1.r expprjres: and nose irritaiion. retarded w-etght gatit leihaip blood and urine lests normal, autopsy, prg*at| bn mat 3? PpmtD. pet. ethei): 4M 4F rats 15 Mir expb| >urei lethargy: autopsy. organs nOrm*l 25 ppm (D,psi ether): 4M 4F rats: 15 >. t-hr e sure*: no (otic signs' autopsy, organs normal 51..^ Pentachloropyridine c2 solid, m p H? 125 C Saturated (B> {OOI mg lure. I ppm): IM IF r*{ 15 6*hr exposures; no lovtie signs, urine te normal autopsy, organs normal 2-Methy!b-`n7o^ii?ole liq bp 2W'C $gtura>ed (4,> [i 9 m? Jure. 140 ppm): IM IF raty. 13 6-hr e\posu>es eyt uritanon. narcosis, weight loss autopsy organs normal 18R ppm" (D) 4M 4F tats. 15 v 6*hr exposures: texts Signs, blood and urine test* normal: autc (hiVK'l ) slight lung irlflammatron SO ppm* (Df- 4M 4F rats: 15 > fr-hr exposures: toxic signs: autopsy, mgans normal BFG09600 The xuhocutc ir.ho!^t,o>, <f ir\ r.f 1i'trf,/' is! II sDiocthyl-1.2-bcnziicxaioic frq b p 70C (0 5 mm) Saturated (A) [0 35 m|-* litre, 60 ppm]: no toxic signs, bipod and urine 164IS hOrtnil; auiop^.GiE*10* norma) r ^iTiinPmelhv).3.4-dihvdrop'Tar " j.q bp 74-C :rr rrm (Dr 4M 4F rats: I 5-hr exposure eye t :ir) ncxe irritation. res* 1 NHj ; -story difficulty I.M more i'V^rcd). jvsor condition- autopsy (hind) excess -,iiophaees ^ lung* :fto ppm rD); 4M 4t rats ( f-Iir exposures: nose imitation. lethargy, u-nfii loss. blood and urine k\i< normal, )M dted. autopsy (histol.) excess macrophages ip lungs }0 ppm iD. pet ether): 4M 4F rats: 15 6-ht expo sures. retarded weight gain, blood and urine tests normal; autopsy, organs normal f ppm (D. pet ether). 4M 4T mv 15 > 6-hr expo sores; no toxic signs. autopsy, organs normal Ali!hc,v\-?,4-dihvdfopvran t.q Y p' I3VC Itvy ppm iD) 2M 2F ms: ' 6-hr exposures leih- :. 't>. weight loss, blood and urine tests normal: OMs autopsy ..ojgirS normal `50 ppm (D). 4M 4F rats: 15 v 6-hr exposures: unresponsive autopsy. organs normal VO ppm (D); 4M 4F rat*: U 6-hr e*posuies: no Itm< signv autopsy, organs normal H'si'v\'tetr*hvdropvT4n l.q hp. 196 Q SatL riled (A): 6F raij: 6 6-hr exposures: slight 1 ext lessnes$: autopsy, .-pins normal Pcroxy compounds Ethyl i-butyl petoxyoxDaii !'0fio; u. in while spirit) ) u i (fit o D O fMij Sarurau-d t'4 i [I ppm1 ]. 4f rais 15 > r' i nc. trvic signs autopsy. o:g<inj hot ,<tl Curnenc -!> droperoxide (4) J fc w 'w in cumeneJ [isopropy Ibertfene hydroperoxide) Saturated (A) |50 ppm1 J 2F CM*-.O.OH rats ? v 4-hr exposures: ini.(".ordination. tremor, narcosis ] died, autopsy (hisiol I lungs coni'rsird. kidney- songt-xicd 31 5 ppm'lD, ethanol) 6F rats: 7 > 5-hr exp.^ures: sah-alion, rexpi-oipry difficulty. nen'o's. hx {-t.-hcrnia of ears and lail, weight loss autopsy (htviol I Jungs--emphysema and ib'cheping Or i^eclkr wa'ls If ppm' (D ethanol): 6p ral- )2 4 c.hr exposures: saltation, nose i.-nioiinrr autnp4>. ortiri normal Pipiopiopyt peroxide c;; 7% w u in wJiiu spirit) 'C,Ht (.0-0), Saturated (A): 3M rats: I l 5-Jn exposure nose and eye irritation. respira'ory diflficuljy. all drad 3 hr laler autopsy lungs Haemorrhagic 300 rpTi*' tD) TM 2F rals: 2 5-.hr expofu'ev nose and eye irritation, rfipiratory dif^rulty, Jcthargy, weigln loss, 1 died 2 days laler autopsy, organs normal 30 ppm1 iD) 2V1 2F rats: 4 5-hr exposures, nose irritation autopsy, organ4 normal 10 rrm1, 'D. pet etheiy: aM 4T rais: 39 - *-hr exposures: lelh2Tg>, rcta'ded wtiyhi gain auiopxy, organ* normal " ppm' pet ether): Jf 14 *-1.' expo- * ..re* no toxic signs: autop-.'. * o r j; _ 7,; ;-,o,inal t-Buty I pe>oxv poalaie 133 3f,u w vs ir w hitt spirit) Meft l'O O (U`Me, 200 ppm (Dr 2M 2F rais: 1 5-hr exposure nose irtiianon, respiratory difficulty, leiha'gy. weighi loss; tuepsy. organs normal 50 ppm iD) 2^4 26 rats 20 :> 6-hr exposures' no ICmc signs: autopsy, organs normal M' -e'hvlmorpholine I'u 1 p 143-5'C `50 ppm <Di. 4M 4F jam )5 6-hr exposures -nose irritation. respiratory (iiffculty lethargy weight loss, urine tests normal. Mood-'reduced leucocyte count with increased polymorphs in females, anaemia and renculocyipos: autopsy (histol I h'nerplasia of reticuloendothelial cells in spleen and of lymphoid litsue in lungs VO ppm <D) 4M 4F rats: )5 6-hr exposures: diminished weight increase (F): autopsy. organs normal ppm (D, water): 4M 4F rats: )f > 6-ht exposures: r irsic signs autopsy, organs normal Bjs-3-nirlhy I hut) | peroxydicarhonate (20 * w;w in w hite spirit) 0 CO O), Saturated (A) [1 7 ppm^'J 2 6-hr exposures no toxic xlgns apart from slight nov iniiaiion atm- hutfchle to white spirit auiopy o'ceni normal Mist ]An rrt mTh ID, white fpirii): 4F tats; ? 4-hr exposure*' nofe and eye irrili>on. Tfsp.rfliory difficulty, weight lors: autc'psy (histoi 1 pneumonia Mist 44 mg m5t (D, while spirit). 4M rats' 8 5-hf exposure* eye and nose irritation, 'cxpiraiory difficulty, lethargy' autopsy rhiMnl I lung*--ihick- ened ahec-lat wails, penb'omhiolar lejxtvytic reaClion t-Bun I pcracetatr (50*6 w w in dimeihvl phthtlate) CH--CO 0 O CMti fi BFG09601 f. ** *r. 12 J, C 0\jne Saturate'! IA) [30 ppmr); 2VI 2F jls, ] j <Mu exposure: pou irritation, jespuatory difficult): autopsy. long oedema 16 ppm' (Pv eihjl aoeiatf!: ZM 2F ratv; P - 6-hr exposyes,, nose irmaiion, rtspuator) difficult), lethargy ungbt lenr 07 ppm1 ID. eihyl acetate) 2M 2F rats: 20 - 6-hr exposure?' lethargy, diminished weight incr<>e, nose ir*tation 0 IS ppm1 |D, ethyl acetic) ZM rat* jq >' 6-hr expi'sj'C:. no toxic Mgm autopsy, organs normal au'or?). l-iMf; Mu-Hen. fu1 d^'t-nOrd >"h tai, (histo!) LTii c'.nph,'M-ma 20 ppm iD). 4M rats: Id > 5-hr fxpoM'ifv "-cverr nose irri;*iii'n. respirator) difficulty t..5i; suVpsy 'I'ljif'l ( lurjcf. - :hct- -'i 're and '.< of 1'oIJfcpf.f. JcSCWdOi'n L'r Wlncy lihjiai Co-tex f ppiV ( P, chloroform!. 4 M raty. 14 ! h' < vp--" ut*: flight no* irrilai mn. antorsy (hiMol ) lungs- shtln thut-cmne or aheo'41 walls <1 OrginU ph'-sphonis compound* Silicon cnmpotindi Silicon teir-aflut'?*de SiF* TfihuijJ phrphite P(OBu), liq. b p fZMZ'C (15 mm) Satutfeicd (At (2? mg litres. 220 ppm) 2M 2F ran; )5 > f^hr exposure* no toxi* signs. blond and urine comp-efs-J gas fh r -^'Cl JO00 ppm IF): 4F rats: 1 ' ZO-nxin exposure 'Oftl nose and eve irritation. n-pTjior; d-^rulfy, lethi'g; jiu;,.ips;. orgar,' lesti normal iuiopsy organs normal m rpinlf) 4Prat;.J - 4 5-ht exposures: nose ifsl eye iiriibiion, rtspiraior; riiffiodl;; rt- toeoixe J,J ,1 -Tt i'b>dro*> m*ih) Ipropant bie*chc phosphite solid 'i r Sb C Saturated (C): 4F /Hi\ rats: I > J-hr expdiure: tTcmrrv, cotyulxions, all died d-iring or soon after t< CM; - C --"P \ / exposure: uiopsy, fixer, adtenals and Kidneys CHj-O concealed, lungs pale wuh petechial haemorrhage JO ppm ID, pet etheri. <M 4F rats; I :< 4-fir expo sure rn.-mt.trs, convulsions aM died-, autopsy. organs normal 5ppmfD,pei ether): 4M 4F ml*-2 - f-hr exposures: rap'd breathing, tremor* end convulsion*, all d*d 3 * ppm iD. pel. ethen: 4M 4F ms: 5 fr-hr expo* . sure*- tremor? on 3rd day. weight loss, l died: dete'Mxrd''0),' of condition. 1 died cuvpti. ijncj distended. (Ivisiol \ lung congestion arid er.iphyxcmt Iner congested, dcfe-ener.oiort of Kidno* evnic*) tubules tO ppm (F) 4F isli: 14 x f-hr exposures: lohlifli nose irritation, wejgfit rtii*rdcd aui.ipsl, organ? normal > 15 ppm O') 3M 4F r*is- 20 * 6-hr e.xpofu'ts. na toxic sign*, autopsx. organ* normal `t. TetramethyKilane liq b p 2h 5 C ^ MOO ppm <D. eooledi: 4M rats: 1 > b hr exposunt nxs toxic signs. aun.>ps>. o'^ans normal "** 100T ppvn ID, cooled): 4.M rats J5 b-h' c*pos,ir*%: letharg;: autopsy otgant congested >' autopsy, organs norma) 1 ppm D. pn ether): 4M 4F rats )5 > fr-hr expo sures slight transient head tremors on 4th day, rew'drd eghi gain, blood and utim lesu normal' autopsy, organs normal 0 5 ppm (D, pet. ether), 4M 4F rati: 15 >: ^hf exposures: reduced weight gam (F>: autopsy, organs noimal 0 25 ppm <D, pet. etherl: 4M 4F rats' 15 6-hr exposures: no toxic signs, autopsy organs normal 3iphen> Uiniethoxxcilane t.C^M.IiSi'.OM^ liq non-xolatik 140 C tZ min) Saturated (A). 4M 4F rai< 20 > 6-f/ exposures. icxi< signs: autopsy, organs normal V silicon (eliaifOCxanBle SitN'CO), solid-liq (tip 2b C, b p, IJlfc'C ' Saturated (A. ?0 Cl [J A nig hire, 200 ppm): 4F 6 J-hr exp-osUTes: eye and nose irritation. !* pirator; difficult;, nu* weight gain autopsy, Iuni Phosphot us tfj-isoc'anate P(NCO), ]>q t p. IPS C Supplied a* solid polymer and depolyme/ired by * a*d K'dr'c;* congested j 50 ppm <0. *ifi;l acetate) 4M 4F rats 2C e\pixt>,Tf-x tio io\ic signs' autopsy, organ? norm ha;ing a: SO C and 2s* mm pressure. Saturated (Al (6 mg line, W)0 ppm) ZM 2F rats: ) l-hr exposure nose and e>e tvi'ranon, respira tor; (Jiffiruli). autops;. organ* normal lUlphui ftifipourds sulphur dichlOride s^dj 500 ppm <D, etb>) a^etaie) bF rat*: 2 > 5-hf expojyres: esc and nose irritation, rct-piratur; difficulty, weight loss, au'opj;, organ) nvrmil liq. b p fd C [approx. "5* / pure, contained 20*t :*4tJ mg m' d tD. Cooled): 4\1 F rats; 8 ' 64 exposures Jimp. e;v and nO*o irnfabpn. respr'auij OO *D`eth; I phospliorochlondothionate ttlOljPS-Cl liq bp RO-fO C U? trmil 104 ppm iD): 4M rats: 2 ' 4-hr exposures nose and eye irritation, saJisauon. respiratory difTiculry, difficult), weight loss- autopsy, organs normal i- 100 mg m* 4 tD, cooled): 4M 4F rats: 15 .* 64 exposures: eve and nose irritation, respirata difficulty, lethargy. autopsy organs normal % 33 mg. m'* 4 (D, pet. ether, cooled): )5 > 6-hr exp 1 j t ) 21.104236 * # The subiicnU Jliomc/ij oj c>\l nt.-ais 13 sure*: 4M 4F m&: no toxic Mgns autopsy, organs i normal Trichforomethyljulphenyl chloride C)C SCI i<q b.p I4-91C J(W ppm fl5): 4M ft?*.' I ` 1 -hr erp^tute severe respiratory difficulty, all died: autopsy (hisiol.) lung oedema 1(1 ppm ID, acetone): 4M nts: 1 > 6-hr exposure: lethargy. respiratory difficulty, } died later: autopsy thisiol ) lung oedema : ppm (D, acetone): 4M tars. 30 > 6-hr exposures1 initial respiratory difficult): autopsy, lungs ton- . *>ied (! ppm (D, acetone): 4W 4T'rais; 20 * 6-hr expo jwres; do toxic signs: auti >p\. orn`i` normal JlVtf pp.m tD. cctoltdj. 4F -a'.1 1 I-hr s\p;'ture: repiraitiFy difficulty, ri*'v L-y^: ,'vi, frmh at post, all died sutrp`y. Kin 1 ,iig tn-Jcma 100 ppm t'D, coolfiJi if pjiy ) .> 2 5 hi exposure: Texp^aiory difficulty. nt-c.-fv oanosis. all died: xutopsy. *eveu- In^ r*:-d,--a 20 ppm <6. pet. ether). 41" rats 1 6-hr evpo*-ijre: nr it" >i. 'igpc during expo-ure, I cU-i Ilk: autopsy (histol ) marked pe*jvawjlit &rd peribtonchioiar lung oedema, kruit bronchitis 10 ppm (Q, pei ether). 4M 4F raiy :0 '* 6-hr expo*ures lethargy. rejpra'orx d'ffi.-ulty. weigh! gain retarded: j.vtrpcy (hlsiol i lung ly-ihtma. liver, kidney* and spltei, toogssied 5 pprr iD. pet lihcr), 4M 4F 'ut*- 10 e-L exposurrj- no ioviv sign* auk'p,y. o'gbr* normal Dimeth'I disulphide MeS $Me hq bp 11Z C 2)0 ppm (D); 2M 2F rats: 13 ? 6-hr exposures: lethargy, respiratory difficulty, Jo* ^ciphit gain: aulorsy, oryari? congested 100 ppm (D)- ;,M 2F rats; 2Q v 6-hr exposure*; no toxic Sign*: autopsy, prf^ disulphide (solution in mineral oil contained aht'Ul *0*/^ w ith other sulphides) (MsC,Hf S), Sj'urated |3 5 ug litre): 4F rats- I 5 x 7-hi exposures: Pi.- toxic signs, autopsy, u-^ns normal D disulphide U b.p. M> C |CH,`CH S) 4SP ppnt (D): 2M 2F rats: 1 ' 4 5-hr exposure: eye and doh irritation, respiratory difficulty, weight loss, I rat died later: autopsy th-nol.) livers con gested with necrosis and fibrosis 130 ppm (D, acetone)' 2M IF teis: 4 v 5-hr expo sures intense lachtp'malio;). nose irritation, lethargy, weight loss: autopsy, organs normal IF ppm (D, acetone): 2M 2F rats: 15 * 6-hr expo sures: initial nose and eye irritation. lethargy, poor condition, retarded weight gain, blood and urine tests normal autopsy, organs normal 6 ppm (D, aceionc): 2M 2F rats: 15 x 6-hr exposures: no toxic signs: autopsy, organs normal Su p'-j-chloride pentafluoride SCIF* *onur bp, - 20 C IW ppm (F): 2M ran: 1 x ]-hr exposure: severe respiratory difficulty, both died: autopsy, lungs pollen and dark, (histol 1 lungs---i^edfma and haemorrhage, liver and kidneys--congestion 20 ppm (F): 2M IF rats: 1 r 5-hr exposure: re*- r7ifor> difficulty. auiorr> 'histol.) lungs--oedema and congestion. Fver and k doeys--vongefiion 5 rrm tF). 4M 4F rats: 3 5-hr exposures: respira* lory difficulty, weight loss: autopsy (histo.1 ) lungs-- congestion and oedema 1 ppm (F); 4V 4F rats: 20 6-hr exposures no toxic signs: agEr-psy, organs normal H,-,ptniaftuorosulphur oxide I'm b p. 29C 5F|40 Lauryl trtervaptan (dodecancthtol] C..H,*SH hq b.p )44-i a*' C {?5 mm) Stljriird (A < 2M IF rats 20 6-h: txpnsu'e*.: nO ti>xie pa'u'opty o'gtr.x <-,-i'rr,al Viny(`ulphui pintafiuof'de CH, CH SF* hq t. p 41' C B0T ppm (D, cooled,': 2M If rats: 1 ' 5-h' exposure; fF-piratory difficulty, lcthi'gy, in--:ord;natt.m, 1 died: auiopsy (hisiol.i i-.fTS-'-ir-^immisfion and ferry infiltration, kidney s - lubules dil=;ed w ith degreeration 20b ppm CD, tooled)1 2M 2F ,-ais 5 fi-hr exposures: respiraterx difficulty, lethargy weight loss. 1 died: autopsy (hiMol) lungs--c*ineetion and inflamma tion, livers Congestion and fatty m^V-ation, kidneys--tubules dilaied ur.b some degeneration 50 ppm lD, cooledj 4M 4F ta:* 19 6-h? i\p:'SUt-es: no toxic signs: auiop'y '>r*'f'v fiurmal 2-Chlorocihvlsulphur pcritat'iiK'-'ide C'i CH L M, 5,F4 liq bp 92 C 200 ppm (Q): 4M rats: l > 2-hf exposure: tremor* and convulsion*. 1 died: autopsy organs normal 50 ppm (Oj: 4.M 4F rat: 20 . b-hr etptHjres, no toxic signs- autopfy, cug-rn; normal 4 a 2-Oilxnotetr*fluOToeihxlxijlpliu? peniADuoride ci-uvcr.sp, Itq, b p *6 5 C 5000 ppm (D. cooled): 2M 2F tais: 1 > ?-hi expo sure respiraioo difficult) leading ic* gasping and convulsions, all died during or soon arte exposure: utopsx (histol) lungs congested and ivdemauius, liver congested KWrpm<D,cooled):2M 2Fr^s 1 6-hr exposure: respiratory difficulty, 3 died af'er exposure autopsy (hi<tq} ) lungy oedemarous Z00 ppm (D, ctvoled) 2M 2F rais: 15 - 6-hr exp<y suies. no io\ic signs auiopsy. organs not ma| 4-ChlorO-ociaf*LjorPbut)! sulphur pcnlafluoride CI'CF,h SF, hq bp 99 C *000 ppm (,D): 4\f rats: 1 .- ?-hr exposure no lOXic si^ns: aumpsy, organs normal tt > iA y BFG09603 '*ItfttllBltflriTgttBit'ar~*iTf-Ti*wTJ'i 14 J, C. Oug* ,5U 900 ppm (D); 3F rat*: 15 > f-hr exposures no toxic s<*ni` autopsy, organs normal (slight lung congestion?) S^rblorodudeciftuorohexyljulphui r<ft,Aflunnde liq br UJ'C CKCF.i. SF. 2900 ppm <D): 4F flit: 2 > 5-h> expesum no weight fiin' autopsy, organs normal 500 ppm (D)' 4F ran: 13 .* 6-hr exposure*. no iomc sign* autopsy, ogam normal Mltrtlteutoui AT,V'Hc><imrlhy Irncadiparrudc oltd. rr p 250 C Fun* l? mg litre Of): 4M 4F rats: 15 v f-hr rpo- ures: no toxic signs: blood and urine tests normal: autopsy (hisiel) Ihei cell vacuplaiion and JVb / 'CD-r#t necrosis Fume 15 mg litre (H): 4M 4F rats: 13 > 6-hi expo sure*, no toxic sigjn: autopsy, o'gam normal Acryly! tMnride CHj CH CO Cl tpiopf no- ' chloiide] liq. r p. 73 C )00 rrm (Dj: 4M rats: 1 > 3-lv evpotut*1 lethargy, respuaimy difficulty, autopsy, lung oedema 25 pp.v- tD. utrnel: 4F rats: 1 4-Ki exposure: eye iitUMion, respiratory difficulty, incoordination. 1 died: autopsy, lung; distended and oedematous, tl' Mo! ) lung empty *ent and oedema . 5 ppir <0. acetone): 4r nuv 3 - 5-hr exposure*, eye i-'iaiinn, jespiritorv difficulty, lethargy, low recta? temperature, weight loys. ? rat died on 3rd day autopsy thistol.) pneumonia 2 5 ppm tD, acetone): 4M 4F ais: 3 fi'hr espo- tsires- weight loss, ic recta* remperature. 1 died: autopsy, lungs distended. (hi*loi.)4uftg nrderna and jnfiarnptation 1 ppmtD,acetone) 4M4r rats: i? 6*h exposures: no toxic signs: autopsy. organs normal 2,**Bls*/*h) drcxypfteny Iprcpane MejCtCiHiOH'/t), solid, nvp |?2'J5n C Saturated (8); 4.M rais: ? N 6*hr exposures- no irvic signs autopsy, organs normal Ethyl '-chWophepyIfftnim'date ?-C*CHtN CH OEt liq Kp. 120 C tIJ mml Saturaird <A) |0 26 mg life. ?? ppm): 3M ran: 9 6 hrerpf>ure* nos* sort *%, irtiianon, lethargy, respiratory dirficufry. uf;gbi Joss: aulppsy. lungs di>volouied- (h'siol 1 lungs --area* of ccnsoMation and cotlapxE uh peribronchiolar fy mphocytie reaction 2- ppm iD. ethanol). hM rais: 1] ' f*-hr exposures: slight lethargy- and respiratory difficulty : autopsy, organs normal Tnmeihny horovine liq de.unip. SaiLiT^'r.-d <A> |.l mp hue, tftO T';i,nl: 3 M<F rsis: 9 - f-l.r fvp-'^.u'x y slight Ifihh^y ti-u'pS. organ1 normal :>U .F'OHt .V-Prop' let hv (idencai-mne liq b.p. "4 C 250 ppm iD): 4M 4F rat*: I CH(C'H:NC,H, 4 *'ht eipv^Ti- and r.o.-i' ir-italion. rtxpi*aiory d:ff.\!;> tM more alfiff,ie,Ji. pot" tondition autopsy thMui > irvTised psaw*' ogi'f ir lungs 100 ppir (O) M 4F raif 6 A--h' exp.-sure* no* trriiation. icspiram-y diffic.tiy. >L:ha'L'y, v.tiphi Jnsg I died bl'M*d and utinc tec:? r;i': iul c,:.'.ip^i (hiMOl 1 ittc'eexed riactophaces n. lungs JO ppm <D, prl. elhcrj: 4hi 4F rais; If ^ 6*!.r sxpflj sures: no xign* p4i f-.'m fsta'-ded '*ri|d< gt-'p, N-*od and urine tesu normul ainopx. organ normal 3 ppm tO, p<t ether): 4M 4F rats: J5 f-hr expg- f-UffS no loxic signs, autopsy, c'rgans normal Iron pentaca'-fion' I Fc'COjj liq. b.p. t0? C 33 ppm <D. pet. etlifr'; 4M 4F rats: I - 5-5-lu r.ppxu'C Ictha-gy, i-e'-pi-aiory difficulty, 4'',, cat-' boxy hjfmoflofiin * ih-od n<yi d2y amor^y (himl.l lung Ot'd-.'-'T-a and `.ongeslnm 15 ppm tE>. pet ether): 4M 4p rats, 2 5 3-1^ exposures leihargj, re-pi-atory ddficulty. 0 24'4^ carbc-v\haemi'glohir.4 dead 3-4 day* Jaier aulop (hisioi.) |ut-g nedf-na and congestion 7 ppm tD. pet. ether): 4X1 -F rats: If ' 5 5*1# e\poS-irex ro toxic sign1- auiop'x. organs fu'orf Dt^rusx'Oti Rexiesx of to-xUul'tglcaf propcrlies Hydrfwrhtm* None of the compounds examined showed any effects on the Mood cell*; the result with irimethylbcnzcne did not confirm the ratiar J; doublFu] e'depee that tbi* compound has such L effect ip man (Biitlig. Grandjean. Ro*?i, and Rick bacher, 1958). Sovtel u,ork tKorbfcl>ova, 1%^' claims fhal lo^ concentration* of c>clopeniadieii| ; and dicyx'iopcniadicnr can affect the Wood as wsi . as the li'P? **nd the functioning of the nervim f, fvciem. Other Soxict work cusis doubt on ihe k tovicMy *of i>< prent, indicating marginal Ofp durr.ayc afu-r pw-dnnged exposure io h7-200 pj^ (Kx*rhakoxa and Fedoroxa. l^M). Alcohols The alcohol* examined show jnicrewrKg features. i-Buiovxethanol had the characleri haemolytic action of -buio\>ethafiC'l desetibedh Werner, S'awrocki, Mitchell Miller, and via! Oettingcn i )94?1, andCarpcntei, Smylh, and Pc (194$), The results strongly niggesi that the ale 2lX(M238 BFG09604 I Tht xuhacurt' inhoJa'itif, ftwicii 0} !0L i'> Jm 'r\u! r/, nut u/.' IS fit ilS metabolite (Carpen'cr, PoiZAni, Weil, K'ajr, fifck, and Smyth* |956i increases ihe fragility af aged r*d cell*, and that the effect disappears when ihc average age h t educed by haemopoiesis, reluming pnlv wbm ihe normal age distribution is restored, lsopropo*>tihaDOl shews the same effect but to a le'-ser event. Perfluoro*triethy)c*rbinOl is a power* fu| gneoupter of oxidative phosphorylation, an effect which hat been confirmed by in vitro studies 0n mitochondria in which a dissociation between pxsticn uplaVe and the phosphorylation of ADP :'h-er>ed which was quantitatively and quail;j: s-'> similar to that f'o'v. dmiirophenol (Cape, j- -. i'ched work). Thi* compound must be One of i*k simplest to show this e^ecl, it conforms to The fc^wiirements of an uncoupler (Hemker, )9#0) in ihat ji is acidic due to tht influence of the fluorine jjomy on the hydroxyl group, and it is lipidvoluM* in its non*ioni:ed form Chloropropanal is irr i4ini but it does not `how ihr central erects of i-!.ioroeiltauol (Goldblitt and Chiesman, 1944). Fillers AH the ethers had the central depiessam j'.-.-sir of diethyl ether, with the exception of di- 'i.kdii^opropyl ether. which showed irritant r',`per:ie^, like its ethyl bomologue l,American Pc Institute. )94?). damage, but wuh d.ch'oiobuienc lung irrtation pTedomnates and tht renal cf'wt has bL-vr obsc^ed o.ily after percutaneous ab'.orpiion (Ferguson. unpublished work). Smyih, f",i'penler, and 'Aeil (IVP1T found that expo'-urc of i.t* for 4 hours Ip 62 ppm tl'ChlOM'buiciie fooim wr>pciiritdi kilted 2/6. The chlorinated cthylenes. on the other hand, are of relatively low toxicity. The results with !,! dichloroeihene are extended by the observations of Prendergast. Jones, Jenkins, and 5iegel (1967). who found no dear toxic m.-jrirrVjI'OhS apart from & retarded weight increase in a *arieri of -preies exposed to l00 ppm f hour* day Few six weeks, while some liver damage wa* found afiet conrinoous expcvsiJTes 34 hours day io 4^ ppm fpr 90 days. Rylova (*9??) stales that 3? ppm is irri'.ani io man. Pentafluorobcn/ene is a na-coiic, Ctarmer and Ligh (1967) have shown ihai live anesihetc concentration for cals is l -5-2 *a(J ' v As tbe fluorme moms are replaced by dili'il'v;. the br.dtfr* ihetic action remains but a cytotoxic atiitu. appears, together with an effect or. px^rp^ynn n'ctr-hpbvm. T>ie results with chloronaphthdlene arc in con tradiction to Soviet claim1*- (Kapkaev, 19fTi that concentraliOhs ift tht region of I ppm C-jU^C h'CT d*mage with a variety of blood changes and a hyperacidic gastritis. Mm ; les and berimes Tl, aldthydes- ha'e anaes* ilif... popertie>, with nc marked irritant action, According to Skog <19?P>. the LCW (30 minutes) of buiyraltfehyde to rats is 6% y\ Sim and Panto iiyS^j state that groups of men exposed to con centrations of butyraldehyde and isnbutyraldehyde (.''eater than 200 pppi for 30 minuiev experienced no r'riiation. but some nausea with iscihutyraldehyde. S.'.iet investigation* on man (I'lnysn, J965) claim that a variety of effect* are produced at 3 ppm. Acids A comparison of the results with acrylic and methacrylk acids demonstrates the reduction in nrium action by the introduction of a methyl group, ur. i Vc observed with the methyl esters which show l- '?'d difference in American Conference of Ciov, . mema) Industrial Hygienists (ACCIH, 1968) 'h-e'.old limit values, The low toxicity of met ha* .`nIic acid in animals is in conflict with Soviet Jjirns (Stulova, Rumyantseva. and Ivanova, J962) ;hut concentrations down to 6 ppm produce rosrgj. changes in the function of the nervous system man. Esters The uns-aiuraied es'erx of vfciura'ed curb* oxylic acids are iypicallv of low toxicity, high con* tvntranons producing irritatior- and narcosis. With the exception of vinyl acetate, none Of the esters of ihh type which hast been examined wav sufficiently volatile to xhow these effects Dimeih>| carbonate rapidly hydrolyses so its toxicity may be taken to be tba! of meihanoV The high toxicity of the chlorofornutes is due to their grcji chemical reactivity; presumably like phosgene ihey modify cell mem branes to produce permeaNlity changes. Methyl nitrile produced meihaemoglobinaemia in vivo 4 raVsimilar to that of sodium nitrite, tf its aciton is due to inorganic nitrite then its hydtolys/s ;Vr vivo must be very rapid. Amines The amines examined showed irritant and central stimulant effects; these increased with the degree of substitution, bui the higher members have too low s volatility to present a cgnifl^ant vapour hariird The result!,with diatwnohevane are in contradiction to Soviet claim* Kulakov. }9t>"i that changes in the blood cells and in motor responvey are seen in rats at 0 04 nig mJ. f htorinaled hydrocarbons The aliphatic chlorinated ' i'^arbons demonviraied ihe liter and kidney J.image charactciistic of some members of this | wne-s The twq unsatyrgied ^-carbon compounds, 'tshhxrobuiene and hexachlorobutad'ene. are highly ' m-. both are capable of producing severe kidney Nririles The compounds levied were primarily irritant, and ihere is no clear indication that any of the effects observed were due to liberated cy anide. Heterocyclic* There are no notable common features in this group. i * i 6S^&O TT2 BfG09605 (1 /+ * hW'-' n. -: ' 4 -'tl i t C r 1 1*11 16 /. C. cT^f TT*^m ` IJ .w 1 OrpL&k peroxides These compounds were irritant give, in general. p qudhaFve indication of tl to the eyes and respiratory tract, presumably be* iysifm'C effect'. obtained b> inhalation -m die%, bu cause of (hctr high rcti'ity, but it is not possible because of the differenves in raio of absorption an ' to relate their toxicity to their reactivity wnh iodide metabolic transformations, there is little uvefi solution. The results obtained with cumene hydro* quantitative information, ; peroxide may be compared with those of Floyd Inhalation experiments are of 'peciai value for :{ end Slokinger (1958). who found the LC (.4 hours) study of those compounds which have an immi lobe 220 ppm in rats. Soviet claims (Solomin, 19M, diate or delayed irritant action on the lungs, for U 1966) suggest that the concentration of this com* intensity Of these effects cannot be predicted v >th or pound mus: be reduced tc> 'v00l ppm to avoid effects certainty by Other routes of administration. A survi on animals and on man. of ihe results g'ves a jirong iiidicslion that lha Organk phokphorn* compounds Trishydroxymethylpropane phosphite has shown an unexpectedly high toxicity: it b one of the most toxic compounds handled in this laboratory. It b fairly readily hydrolysed to yVd dihydroxybutvlphosphonic acid, which t< of low ipxicrty by oral or parenteral administration. Jts marked action on the central nervous system is probably due to its having suffi cient stability to penetrate cell membranes as a nofl-ionijed molecule, and its ultimate action may be due to its hydrolysis product or a reaction m irVu, Diethyl phosphorchloridothicnsle is primarily an irritant, presumably due to the reacthe chlorine tom, but it b also a weak in iYve inhibitor of cholinesterase, effects on the lung urc associated with the chthiic reactivity of the molecule, particularly if iht ersett severe symptoms is delayed ft seems probable iti tbtie is an initial modification of cell membrane as postulated for the action of phosgene fend keieu followed by permeability change* leading to oederi and haemorrhage- ; After short exposure* to high concentrations i lung irtitanis. the effects seen at histological evai inaiiort of lung tissue indicate that death can 3 attributed to an interference with gas exchang After more prolonged exposure to lower coocn (rations, the cause of death is less certain, fi although lung changes may be apparent, they a sometimes insufficient to at count for the Jeih action. Moreover, at soil lower concem^itiits the animals may be in poor condition with a dim* SQJcoa compounds The toxicity of silicon tetrifluoride is probably due to hydrogen fluoride re leased by hydrolysis. Similarly, the irritant action of silicon tctrabocyanale may be due to isocyanit acid- The stable silane derivatives are of low, toxicity. shed weight increase, w ithout any trace of dam* being deiacubJe in the lungs ft seem? likely lb exposure to irritant gases and vapour* gives nsaj stress which is responsible for the marginal tol effects, and U is possible that the occasional obsei* lion of a diminution in the si*e of the thymus os Sulphur compounds ThiJ- group contains members which, presumably because of iheir high reactivity, are powerful lung irritants, Sulphur chloride pentafluoride, bispenufluorosulphur monoxide, and trichlnromeihylsulphenyl chloride ra-at loast as toxic as phosgene. The toxicity of sulphur dichJor* ide is ptobably due to hydrolysis to hydrogen chloride. Vinylsulphur peniafluortde and divinvl disulphide have, in addition to their irritant action, a toxic effect on the lixer Or kidneys. be in some way connected with such sires* effed 1 Provisional operational limits Subacute inhalation experiments lasting apprtu mately three weeks cannot be regarded as an a^ quate basis for the establishment of threshold Itfl values which will define safe working eoncentratig under all conditions, although a study of the ortf of the list puulished by the ACGIH (19661 sho that Some of their value* have been derived frt more tenuous evidence. Nevertheless, the resu Miscellaneous Iron pentaearbonyl i? a lung irri obtained in the-* investigations permit an tant, it affects the centra! nervous system and causes ,.rnent of the toxic hazard which is of value to l liver and kidney damage. A measurement Of Mood chemical engineer in the design of plant, or wW carboy haemoglobin would preside no guide to can form the basis of a code cf safety precsutioi intoxication. provided that those exposed are under edequi medical supervision. The limning conccmratifl The value of inhalation experiments derived from iheve experiments may be term Most of the substances which base been tested in these inhalation experiment* have also been siud-ed in these laboratories for oral and parenteral toxicity and for their effects on the skin and eyes. The provisional operational limits to distinguish fl> from threshold limit values, which should prf ably be based on more exieoded experiments 1 a variety of species, supported by evidence frt systemic effects elicited after oral or intrapcritoneal human exposure. o administration, or by percutaneous absorption, The limits in Table 1 have been derived froflil 1104240 BFG09606 77if Uihflculf inhoiJiirn u.iifit) tt) //'n.V.., ats 17 highest concentration prodding no toxic effects ,n animats b) the application of a 'safety factor', which has varied according to tlit effect *tn at the next highest concentration. Jn some cases the limit has been influence*! by the established threshold I,mil values of analogous substances, and any information on human exposure has been taken into consideration. With materials with a strong odour, the limit has been set at the expected tolerable level, Sot all of the substances studied have proved to t* of commercial interest. Those which have been produced into manufacturing processes hfcve been ha: J>d undet proper supeni- tm tnd there is no inJ'-ahon 'bat the provisional operational limit ht- been set too high. CuiTprI*ftn with Soviet limit* Vone of the substances studied has yet been con* tiJered by the At'GlH Committee on Threshold Limit Value* (]9Mt>, but several have been the subject of investigations on animals and on man ih \hc Soviet Union, w hich have led to the recom mended maximal allowable concentrations in Table 2 The difference* between the limits in Tables 1 and 2 are too large to be igno^d. The Soviet animal f\pe*imenls ore usually of several months' dura tion but it is unlikely that ihi* p)a>-s an important pa- as there is often a vuk divergence bivn the aCGIH threshold limit values and Soviet mavmal allowable concentrations. even when the exposure period* are similar The Soviet result* cannot be passed over by doubting the toxicological significance of studio* oft ne^ous system function by technique* such a* the condtiibned reflex, negative induction op electK*encephalo^raphy. It i` iruc that these methods arc extensively used and that there is little information in the Engliih Ian* dealing with the experimental details and the interpretation of the result*; the review by Medved aid Kagan (I9bd) indicates that many of the original publications are in journals inaccessible outside the Soviet Union, It it more disturbing that the Soviet ,r\r-'igators appear to have far more sensitive md.es of early haemaiological changes and of or^-.r damage. In the few Russian papers available to t!.< author in translation, there !< hlilc indication how ihe statistical significance of differences between 'he test animals and a control group under identical ^iiiition* has been established. There is no doubt of the need for closer collaboration between toxi*;'Nicistj> inside and outside the Soviet Union. ' v-wh if acknowledge the skilled assistance which I avt received over the year*, particularly from Mr. Z. v Hf^czy, Mr. C. A, Manley, and Mr R A. Riley. Pathological reports have been prepared by Dr J G. S. (rahhe. Dr E Weston Hurst. Dr. I, F. McElligott, and Dr D, M. Conning. TABLE I Ppommoxal Opir*-ii Limit* ('Figures arc ppm unle**, nth<-n so stated! tvcffne , . D*f 1 .'h-p*nudicr ISeralm t ;.1-Trinrin'thfnifM T-Ivopropov^f ihiinol 2-1-RufC." fiV-nn) Chff'ft'P*rijvi^pl TriMpeMSf* i inf;hifip| tv<ih!t'lOdi.lK<.pr.`'p 1 tlfitr Djfiht itrif^KrO' dimeth)! ether .. Mfih-' irrv! eit>er Kohn'i 1 v ini1 fiber D'lT'ft'voV' r^thijne Pri*f'K,r,attli h, de ti-BiM''dtf-i dc fsohotj'rjldehydr y-B'err,r'ptntan.r-xVne . . ;*Chlf'i4ipop<ine t ,1 'biehWooifitiK Dichlvrohulrne* Hexichlornbvi#d*ene l,2.4-Trichlornbrn7fnc HrvBflui'ff brnirne Chlc'icpr'MaftufTt'txT'iene t 1 J-TricMorolrifLmwhenien* icTVll. S.ld Mnhufxliv nod xu ii-|^t piiriie Dimciro* ctrhonat* Vmv l hcctaie Mrth-! ivoihiocvanaie 2.Fth'lhe*v! act'late.......................... 2 htr.'ihexv! methacrvltie Mrthvt ctiU'iol'orrnat* ., Ethvl vMdforcrrrate Jiiip>op; fMerv'CcTiiitiU S-BuivUftnn* . , Ttit'ut',lumine \m Umine A'TnrtohulariOl .> 1 .fi-PuitlllVC'HBXfcM Dietbylairiinopenian-r-one Prcipvl e.anide .. (PMftri'aieicmitnl* J-Mfthoxv^.^-dihjdropyfan 2-Anxinorreihvl-.V4-dihv(tropyran J Meth'lbenrrvfeiole............................ A Fv'rm'-ir'pv*? 2 MfU ' ulwi/ote ............................ ............................ ?. v. Dirvwih' imrrphpline J-Mci hv 1-1 ,'t'dio.C`liine 1-Buijt perfxypi'aUte Ethv) i-huivt pero'voxalitc nipror'onx'peroxide Dir^e-amvi perc-v'ditarbonaie Cutt'ere h'drope'x*vd 1-But'l pttiCelilr T r imr'.V" If.) proflirt phosphite Phofphoruv turtaie .. Silifor 5iii.o` .eir<!,!"i.vcvanate . TetrirneihvHiline Solphur drchlonde 20 25 100 20 10 10 <' 2 J5 iOO 41HJ no nm ?no 200 ,00 10 SO 23 01 1 25 too 100 25 2ft 20 10 jno so 1 50 23 1 1 2 ?i 3$ 10 10 ;s 25 :j 50 i too s 50 50 10 25 50 20 :5 2 lo mi m1 10 003 dl 2 20 250 5 (a; HC1> M f* K 2 a M i< i BFG09607 W8ME8W 'Ejj'rTT' iWMifaMIfHri^iTiiJaiiailjigtiiii I 'it'i. . a. IS J.c. Oogi t j" r P< 1u * 1-- f TABLE ] (contbutd) Tf*ch1ornrr>fihyjtglpheftj I chloride Sulphur cl,1 T.dc ptmaOuond* Bis{'frUPi/`,-f,"*ilpSui evde , , Drmethv I diMiiptMde Oivjn)l diMilphide .. Yin} I Fulphui pcntifluoridc l"Chlonrih.'l vulphut pcnwHuunde J-Chli-'foirrrafluOfiwjh}] nylphyf pentiduoi'idc . , d-CWoroocu- flu^'chu'? t *ulphur Pffiliiflu Tii} . , f*-CTrK*f4>t1 'dr:aflurrf>het!il iulphur pe^mffi....r>e .. Ar\UI chl'-'f'd* Elh> I J'ChloTt'rhcnjlfofnumidsje Fihj luieni prcp> limine Iron proLicarbonyl 01 0i 05 1 2 :q 20 20 100 250 01 5 2 2 Soviet TABLE 2 RtCOMMfsTH.D Mavimm. Concent* aTiqvs All(iv>ahle Isoprtn* C'aMptni Jnnr Mfthutr. Dl apid Rulj nt irtt N, J* CuiTfOC h'drof^rOvd* ppm,, 17 2 0 w? oy (*<*(40? KorSkkota and Fedorpva <1SM> L'li" an t lr>4) Siijlpta, Aurhian{ao>d, apd| (!9M) kofhak.Pt* (l^M| Kulakov (1967) 0 001 Sotrmih (!9hf) Rtfereoctt America' Ci" ferencf <if Gd*-niNmt1 IndvMfial H> jfemm (laMi). 1><h c<f threshold Tm.: *lo*i. 1 T^'n^oM limii Vkluti for AJ .tw'ru comuriniim. ABrerrcj" p4tvl*kiifi lnfi<>L'i (19aPj API Tr>>oi(i|<4l' *.**, tj .DttMo'Nihyl ih*r. tain*. K-, Crndj**n. L.. Rtmi. L,. and Rukenbachcr, J. Il95f), 14T(sii<*lf|iilw L'nlfTMJthoniin iibei Triftiffiyfhfiwol. A'tk. faf-Vpd(A. Gt*trbrh>% . fA 4*6, P D, and Ga*t, J i ilUfcl) The thi,icil 0< pripnird ulica *-n J f,ird, It 29J.W1. Carpenter. C P-, Pi't4api, L 0 . C . S. Naif, J M . Vl C *> and Sirylfi. H. F Ir (IvVfj Thf of t>uil crHSitiKa tnlteni iHduH'. HitA, (4. lla l.'l. C*ipnte C V Wt-F jJ F J-. r iijn l_ < -4 | p; rcu : c : ri'>o. l p . rrfli'V. I'c* #"< V'? ~t ' - r: " - ,V . " . >J'. "f.r- . f'-i M -f V -i iTpr, V! L i u'*i Tr vcn> ^ ........ ,< Jc ,.nd h'd1. per.o.dev .i'*./- in/i.'f Hu A 19 2<'f .'li Gape J l t!*'? A i'-'jii- >' tc J!.J .Ml, 2i. ------- (1MPU, Tht ,, ym., >4, n-u ------ (1IKK 1 tr s |.'|. > pr p. "igaa- '.s' d ,W.. i-jiifti*. *rf*ei 25. >(kI >14. Qarnwi, N L and Lci|h. J V| :vt~, S tt.< htiF. ,v i> n*1' B't: J ,r'iw'i i. 71 CtOHJ'*lan. M 'A i-.d C * -,> , . U T :V> L t"f: f|M W A-ii J tifljm M/c1 1. T'2,` i Hir-I.r 11 r I. ,..' , . ! 11- a. k f,. it\ o' ur.k.'L.rln> r-.eTi.MT t !<,/, .4. . *>.' fcfpLan. A <`h-at;cN.o' <!<**' - ,n.-.i. p<'Hir Oui'ird Witt Chf* . 5Z. aOl'f*. KorPAioia, A. I i l^J) S-nd't' it'rl- o' nr* .r ,- in lh< *rf <'I prfmi,ev Quoi(<i fi.-n O.'n. 4*'" c'-- ------- and Feiljrpj, V. J |!9f>4| Tr^KOlrj' o' :* -i-i;r-c Q IrOTi. C^-ip 19ft.* 4J. PCH7*. Kolkk," * t. (I<*A7j. PcrTf'l hlt t,*r.e*nif'kihnr of I'' '*d' i rr.iht (K l>lr 4l> i- p^-f"Lilj.4d k'clk OucC frf."T { Ai"i< . f i::r fh>r m-. > L I . ift* ;S 7i-\rfO>op ^<1*. *fv, mAi o/.. 6, XBi. Irtnd#*cani, y A-- * A . VnAift*. L. J . and tH E(T4li on Lperimcmat animaK Cf I/np.itr.T :riliimiia lnchl.*riiii^jWm. e*fh(n irrrcKI(nd, J. I.' !< Mi.'ia: dtfblo'.*tlihunro*meihari and I,I'duhll'il'cibjlent Tii`tfH fihu'fifti-o'. in Ritfn* M L Touat> of t.l^iliftw dichki'id* Oj 'ed C*i- da<r.. iv', 47. irfdi. Sim, V. M . and P#nk, * F |.fiec;Orri'HP .'4 r lift borriar *i>P/4Cl.a J- A**-'- hid di; . JM. !W*n I ** I .*. Sko*. E ()9Wp A inirf 'k.jKi1 of k>*fr i ; aid^tisde* I `ff.jitily tW fi.*Oiid*l->de. .flj fit dch;d and PuiryraidfKd<: ar '*P ' or acMUei; a"d d(h;c(c .4r/t (VIiA). 4- Sinyil H I . Cnr*nnr, L. P i-iC CS Ranj-f-A tCSKi: tfll Ml >V 4r<A indmlt H-f 4. llt,122 Snlor-in, Ci. I iI9Ad| Mfluinum pt'r.iaF'til* coMdririiis". O pn-ifvllvr.^Tftc and nv p. d*Ot>a*o'da in ih< fr!.FiYn-.: 4'iri*., |6A4. *, '7*2f. O' ___ , 4*kWriAI Hytiatiif (jbilanlMliOP f>( |He dti'y n>un. r^rm'liahlf cpncepirt->t'`. of jai-propylbcr.irnr an F'iJioperr*idt ir IN aiiriwrhari Qumad fr.'rr Cke* A ji*6f *f. Sltdoi*. f A . RuirianiW'*. P.. and I'anOv# A O T InPtiOWf (>I m',F,acr>In acd or\ i(h health Of ar'ft". Q fnim fhi n. iMn., |944. FI. Ccltintr SfifWfc. Ulrvar. S M. IJO*1! Prrm*tihJ* conrtiumion of hutjuideh.' i he an of ihdvfir'a- ticaa. Quoitd fidin Oijitt. Ah.'i'i f, 4`?4h. Vk'etftai. H. 4V., Na^iAekii, C l., Mnth*l>, ) L-, Mill*'. ) W \PH C*` I nifrlj, w F t **4 ' I Lffwi* or r*p*alrd ftp."*.1 r*> It '4ps'" of mcprtaityI #ihi|*p* iljftof *'h*f J PfCfi'td for pi.Miwi.iipr July w'1. lVh9. ZT/ZVQTT APPENDIX XIII EXTRACTS FROM LITERATURE RELATING TO THE MANUFACTURE OF BPA Part 1 - from Manufacture of Plastics,Volume 1 W, Mayo Smith Published by Reinhold Publishing Corporation N. York 1964 Part 2 - from Organic Polymer Chemistry K. J Saunders Published by Chapman & Hall, London, 1973 N u-. K 4^ t-J BFG09609 Epoxy Resins 501 Up to now, both of these intermediates have found only minor use outside of the epoxy field, although the use of bisphenol in polycarbonate resins and in specialty polyester resinB is growing. There are some four major procedures of bisphenol in this country: Monsanto, Dow, Shell, and Union Carbide, and there are four epichlorhydrin producers; Shell, Dow, Ciba, and Union Carbide. Bisphenol is perhaps the most easily prepared of the dihydric phenols and, as mentioned earlier, remains the principle component in most epoxy resins. It is prepared by the reaction of acetone with an excess of phenol at moderately elevated temperature in the presence of a strong acid catalyst. Phenols react readily with moat aldehydes and ketones and the phenol formaldehyde reaction forms the basis of all phenolic resins. The initial reaction product of phenol with formaldehyde using an acid catalyst is termed a novolak. Depending largely on the mole ratios employed more or less phenol groups are joined together with methylene (--CHr--) bridges. Since there can be up to three methylene bridges per phenol group, many bridges are possible. These novolaks form useful intermediates for reaction with epichlorhydrin to epoxy resins. They are, however, variable in structure and somewhat difficult to purify. When condensing acetone with phenol essentially one product, bisphenol, is obtained, and this can easily be purified to a white crystalline solid melting at 156*0. Depending on reaction conditions, 2 to 6 per cent ortho-para and other isomers are obtained. These isomers depress the melting point. They can be removed by crystallization. Their presence in minor qualities does not seem to be deleterious to the usual epoxy resin properties, but they must be eliminated from all bisphenol utilized for polycarbonate resin synthesis. According to their recent patent11 Union Carbide, with the most recent bisphenol plant, is believed to operate a continuous reaction possibly utilizing an acid ion exchange resin bed. The more usual processes involve batch operations in glass-lined kettles. Phenol, in considerable excess, and acetone are charged to the kettle and a mercaptan catalyst is fre quently added to speed the reaction. Agitation is begun, the temperature is raised to 50 to 60*C, and at the same time hydrochloric acid gas is added to slight overpressure. After several hours the HC1 is released and the water formed in the reaction removed by distillation. The excess phenol is then removed by vacuum stripping and the residual bisphenol crystal lized from & solvent. All of the producers have special techniques, details of which are proprietary information. LT , o Ci BFG09610 Part 500 Manufacture of Plastic* All the early patent* react bisphenol with epichlorhydrin in aqueous medium. The effect of varying the molar ratio of epichlorhydrin to biephenol was already shown by Caatan, but was more fully described by Greenlee*, Greenlee first mentioned the principle of gradual addition of an alkali to reduce polymerization and lessen hydrolysis of the epichlorhydrin prior to condensation. The reaction of bisphenol with medium molecular weight bisphenol diglycidyl ethers to higher molecular weight resins was also mentioned. This latter technique is more fully described in USP 12,615,007*. It has the great advantage of simplifying the salt separation and purification steps. The direct condensation to high molecular weight resins via the taffy process is difficult because of the high viscosity of the reaction, mass. Werner and Farenhoret* carried out the reaction in a really large excess of epichlorhydrin which also served as a reaction medium in place of water. The large molar proportion uf epichlorhydrin resulted in a very low molecular weight liquid epoxy resin. A modification of this procedure*, operates under azeotropic conditions whereby the greater part of the water of reaction is removed as it is formed. Preferably the concentration of water in the reaction mixture is maintained at 0.5 to 1 per cent by weight. Recently it was suggested that the stepwise addition of caustic in a series of reactors, achieves a continuous reaction14. A somewhat different condensation technique forms liquid resins11. Here the reaction is carried out in two distinct Bteps. First epichlorhydrin is condensed with bisphenol in the presence of catalytic quantities of lithium salts in the absence of caustic soda. Bisphenol diglycidyl chlorhydrin is formed which is then dehydrohaiogenated with caustic soda to the diglyoidyl ether in a completely separate operation. Ciba has shown that liquid resins can readily be converted to moat any higher molecular weight solid resin by condensation with biaphenol and a lithium catalyst1*. Many other interesting patents relate to epoxy resin manufacture, but these would go beyond the scope of this discussion. PRODUCTION PROCEDURES FOR EISPHMOL AND IFICHLOROHYDRIN Before discussing the procedures for preparing epoxy realm, a short summary will be given on the commercial processes for preparing blaphenol and epichlorhydrin. These two building blocks alone make up the resin molecule and the only other chemical used of any consequence is caustic soda. *' M -h* H At ro BFG09611 N S2 372 ORGANIC POLYMER CHEMISTRY The Ion-nation of bisphenoi A is thought to proceed as follows fl j: oh CH> 16,3.12. Epichlorhydrin r\ The preparation ol epichlorhydrin (CHj-CH-CHjCI) is outlined in Section 10.5.2.1. Epichlorhydrin is a colourless liquid with an irritating odour, b.p. I l5ftC. 16-3.2. Resin preparation In a lypical process for the preparation of a liquid epoxy resin, a mixture of bisphenoi A and epichlorhydrin (about l : 4 molar) c, heated to about 6U9C with stirring. Solid sodium hydroxide (2 mole per mole bisphenoi A) is added slowly at such a rate that the reaction mixture remains neutral. The reaction is exothermic and cooling is applied to keep the temperature at 60C. Excess of epichlorhydrin is then removed by distillation under reduced pressure. The residue consists of epoxy resin mixed with sodium chloride. The latter is filtered off, toluene having been added to the mixture in order to facilitate filtration. The toluene is removed by distillation under reduced pressure and then the resin is heated at 15Q*C/S mm Hg to remove traces of volatile matter. This last step is important since the presence of volatiles may lead to bubble formation when the resin is subsequently used. Finally, the resin is Clarified by passage through a fine filter. In the preparation of solid epoxy resins the above process is slightly modified 12|. A mixture of bi&phenoi A and epichlorhydrin (the molar ratio of