Document 1gOayebJo3zQrEZ9pGggx9w5m

St. Louis - General Offices June 24, 1964 SPE/JMC/SJA J. M. Campbell MCL - London * File Destroy 1 ' JTff 1 WHH *" MNJ i ' REtf ^ \ ^ RAM i EPW In Dr. Kelly's absence I am replying to your inquiry concerning[Aroclors. I am sorry for the delay but we had a little trouble finding the reference. Apparently Dr. Parsons made a slight mistake in the name but I think the article we found must be the one he meant and we are enclosing a copy for you. . A paper was presented on the development of chick edema disease-like symptoms with chlorinated biphenyl at a meeting of the Federation of American Societies for Experimental Biology in April 1964. I am enclosing a brief abstract of that paper and also some notes that our Dr. Hunt made after he talked with the authors following their presentation. As you will see from the material we are enclosing, Aroclors apparently can produce some chick edema but are not nearly so potent as the real chick edema factor. KNJsmJb M. N. Johnson, M.D. qS'N STLCOPCB4072423 i'llifr Chick Edema Moot- and Its Relation t<$he it ' l Fatty Acid Industry1 * .- * ^- * THOMAS McGUINE, Wilson-Martin Division of Wilson & Company. Philadelphia P^nna. h - \ : . 7 '' " When the 85th Congress in September, 1958 passed and sent to the President for his signature an _ amendment to the Federal Food, Drug, and Cos* metie Act regulating chemical additives to food, hardly an eyebrow was lifted aiiiong fatty acid producers because of `f. the long historical recognition of these materials as safe. This feeling of security was further enchanced with the..; issuance of the tentative GRAS (Generally Recognized As ` *4- Safe) list in the Federal Register on December 4), 1958.% Oleic and linolcic acids, glyceryl monostearate, magnesium stearate and mono and diglycerides, except lauric, were listed. As stearic acid is a component of glyceryl mono* stearate and magnesium stearate, and is often found in ' 'mono- and diglyceridcs, it was felt that stearic acid was included by implication and the failure to list it separately was simply an oversight. This was found to be the case when a query was made to the Food and Drug Administration, for the reply received March 16, 1959 by Fatty Acid Producers Council said iu port: "We concur in the opinion that stearic acid is gener ally recognized by appropriately qualified-experts as being- safe for food use and that it should not be subject to clear ance provisions of the Food Additive Amendment for those . uses which nrc customary and usual." Here things stood until a reading of the revised GRAS list ` issued November 20, 1959, indicated that instead of correct- ; ing the stearic acid oversight, now oleic and linoleic acids ' were also omitted although, strangely, glyceryl mono- ' stearate remained. A revision of the section dealing with - emulsifying agents listed a group of mono- and diglycerides S requiring their production from edible fats and oils by glyccrolysis. The glyccrolysis limitation was the only proc- . ` S cssing requirement shown by the entire GRAS list and the \ raw material source statement "of edible fats or oils," also was the only such requirement on the list. The Fatty Acid Council speedily appointed a committee ; to meet with the FDA to establish the background for these ' 0 changes. It didn't take long to find out that the FDA was ' t>i now concerned about U.S.P. Oleic Acid because of certain samples they had picked up in a plant manufacturing esters for food use and found them to affect chicks with symptoms - V indicating a similarity to the chick edema disease of 1957 b (1,2,3,4,5,6,9). That outbreak, oad been traced to a fatty acid still residue product high in unsaponifiables and this new finding relative co low u . . ponifiable material was un expected. These .-loir acids were found to abnormally affect rats and'monkey o:. did a food grade glyceryl monooleate having 0.22% uiisaponifiable. while a glyceryl trioleate was even more active Tiis finding was also reported later by Dr. Ames and h ,, 'i jp nt Distillation Products Industries, \ who had this eiiect called to their attention by F. W. Hill of att Cornell UnivcrMt'- He had observed abnormal effects with a food grade gly. ryl monooleate. The group nt i. stillntion Products Industries found that V conversion ot these oleics to glyceryl esters carried over the C.E.F. (chick edema factor) in proportion to its presence ' in the fatty acids. Hcncc, the attempt of the FDA to prevent this possibility in the production of monoglycerides by spell ing out the "glyccrolysis" limitation. It was felt by the FDA, based on the evidence at the time, that the C.EJF. waa .1 somehow related to fatty acid distillation procedures. Cooperative work between the FDA, some association members and feed manufacturers trying to track down the cause of the 1957 edemn outbreak, indicated that split fatty acid stock was satisfactory hut distillation of the split adds .< showed some C.E.F. in the distillates, with even more in the \ \J So`ciPetryo.rated at lit 15th r>.n Vesting of <h .America! On OhamlakT JonsAt, A.O.O.S^ Dioixan ib#i (Von. ItI)t . ,:V ? still resiu. .. irien.v v.. - v.r.^ :i.. r.-y at cl. vine was that dis;illatiOL jou.chou ,**,. ;n appearnniv the C.E.V. One grouy in the Fiia. iV . gie effet. was tr.<-r i in origin, while oikvrs felt it .,ugt; ce contar>,ina*ion fr.. somethin,' such as boiler treat ag compo. ads us.-J in the oductior. the sparging steam for fati a - d aistillaaon.' It was because ot the assoc! - .if the 1Pj7 t-dema . break with low gn.de inedibh si s Out th. FDA . spelled out the edib.e requirement ? jr mono--? ceridcs e . though section 402 of the act eoverca tmt .,n r. While nt evident hnd appeared that *t.*r r.v a -..d ha C.L.F., it n.9 omitu-d from the GRAS clr.Wi. o. u be of the possibility that it could be produted fv. ... deie b'' low pressure hydrogenation, wh>?h * , -n n> . affect the C.E.F. (4). In other wore-, u-t. rts r>- rilit; . placed on the nu>i>n .cturrrs to define . *aric that was safe for 'ood use, rather than .. . ,. the merical product generally under the OKA'- cm* . This situation caused considerable eouven? ng acid and emuisifier producers because it appc. , c. stn- the root of two of their key proc<*>-a* .iun.or , still - and esterification. The concern n sa-. niuAL.-i the time interval allowed to get L. ... -dt. jk Mm.. 196' forccmont deadline by pctitkkvb.y tjf? .<, e v .aim The fatty acid industry set in motion a. ver mte aee~ch for chick edema posit?-- u.f*riajs. Sc:- ng . utilizing hydrocarbon diene ...nU-nt. ehol .t. u enc and chick "'ceding tests, were '.non. iv-rocra.. . i >rk sainles oi C.E.F. positive ' -J 4A.V . Iv . .* furnished by DP.L rapidly es . . > ectin'e s . a> ssne tl. Aholc- adicne and hydrocaiu ; Ui-ne ing chick fcecirg tests to fall bt-ar. on, which :. . <ntal. where v; stand today. Steps were also taken to set in... r-,.n tin- . f . meni obtaining - time extension of the cnturccm. In the ing of 1960 while the fatty -jtrj searching :i aupplies and processes .. dc * . po mnicrial, the ',-kk1 and Drug inspc.'sc r n.ed - uat, of both ac-iai> .nd derivatives in t-ic . ions ducers, for their own evaluation.- The-upshot of all this activity wi.--- CHAV vvtfjT rcan with negative results. No C.E.F . jpcarcc vhert even in first, second, or third si., pr ` ced oleic or cottonseed acids, much . r, the distillrtcs, steario aciis. This threw cold wait, on the nc*. anc. filiation theories for the C.E.F. formation. At about this time, the Association became ^ujua. - w.'h the concentration and isolation work on .he C.;_ . o.:.og done by a group of workers at Merck & Co. and Proc- tc.- tt Gan,ole. Merck had assigned the men wh<> worked on the isolation of vitamins B< and B,i> x> this task, and, in .junction with a quantitative bioas.-_y projedure devcl- oped by Dr. Ott of their nutrition labs, ver., 'oinwing the isolation step by step from large quantities ' the tallow held over from the 1957 outbreak (12). Dr. Norman Brink and his group at Merck onortly . ported the isolation of what they felt was the purified C.E.F They had obtained 1 mg from approximately 1000 lb starting edema positive tallow ' Help was asked of A.-sociation members in supplyi- ..ore concentrated sou oi gnch edema positive fat for . "her work. Shortly thereafter, Merck der. - y found halogen ir. pure C.E.F., dne to work by Dr. Trenner and his gro Within a few more weeks it was established that the haloj. was chlorine, present to the extent of about 47% in t n- aromatic molecule, having from 10-12 carbon atoms, - showing evidence of a diene structure. It sublimed at e!k . 225*C out it was felt that this figure might be as high a .. b'-v'--" ' V 13- DSW 312438 (I 1- ' V' i-; .- .r' /. k ..* r*. i':': STLCOPCB4072424 2G6*C. A moWfSf weight of approximately 380 was in* T. dieated. This ogLji aril with the figure prcvionsly reported #by Dr. Ames ImSed on molecular distillation work (7). . The high biological activity of 1.6 million times Hint found in the erude fnt, which rendiiy killed chickens, rated this \ 7. -* M- \ J as a potent toxin. In the chick diet, a level of 16 parts per billion showed a positive response. With the first finding of chlorine, and before the molrr- /- " i; ulnr level was established, the possibility that chlorine ,, dioxide bleaching of fnts might be the cause of the C.E.F. was checked by submitting some tnllow, trented in this * f .. manner, and also after prolonged henting subsequent to bjcaching to Dr. Ott, who found these to be negative hy his bionssny procedure. The positive finding of a highly chlorin 4. ated molecule, in the pure C.E.F., was also confirmed by . workers at Procter & Gamble and the FDA, who separately < ' isolated this factor about this time. A comparison of the ` infrared curves obtained by Merck and the FDA showed structural differences, and among these was the indication of f r* aromaticity -n the FDA sample. Dr. Artman reported the isolation work of the C.E.F. done by Procter and Gamble at the 1961 A.O.A.C. convention. C As a result of these findings, the Merck w. convinced that they . re dealing with nn urr, ; were ma- w " terinl resulting from contamination and decide. . ;.on- 1 tinue nny further work. Before doin;.- ..o, th~ . ^ ( . number of chlorinated eyelodienc pesticides, ns ' . .. ... . ber of the members of our Association, a. FDj. ... - i; , ter & Gamble. Also cheeked were chiorinntcd n. ..it. . -* notice.: . which had-been implicated in toxic effect*- on . rtlt - -. . years before. The workers at the FDA Vaned .v : chlorinated naphthalene theory for the C.E.F.. n:l . to Wm their data. The pesticide theory for the C.E.F. e-' .... . most plausible interpretation of the McreW results To ciiecfc these possibilities, severnl pesticides a .d lubri. nts were ; tested and, although found toxic to irying degrees to chicks, in no case did they show positive edema re'jli. They dkemka! we.-e: Aldrin, Dieldrin, "F.udrin, DDT, Cn.ordni.t Hepihn! ' clilur, Hexachlorophcne, rrtrnrhlorotetr?'qydror. hth:i<enct I1 |- hcxachlorocyclohcxane, jientnehlorophen.-l tetr. irotolu- i . cne and hexachloronaphthnlene ' The Association also sponsore-i smnli .` .e ren sts | ai ihe American Meat Institute i.-in: t- hat - .. I Dit-iarin, Endrin and Hcptnchlor nanco .. . let - a to give 10 p.p.ra. of contnmir.m.t in ttie icrcd c ' wei-e nil found to be nrgatii.. to the .h<c. .'edit.. . 'A tests on the rendered fats showed 100% ortn. . .. case, indicating the presence of the ose ci -idcs : . tesri. by the same company on known OK. pos... -... - As pari of our expansion prografn, . : , . we are pleased to announce ' ; and oleic acids had shown no insecticidal a<- ivity I Another company ran the gamut of avn.,ablc ' /. I in testing for thermal breakdown products, oyhe... . f v- : * at a 1% level in fatty acids to over 200' G for ex. i the change in our corporate name ' 1 from . E, F. DREW & CO., INC. * periods of time. In no case did a positive edema .cst r.. : on feeding the acids to chicks. While this work was t>ucceding, the FDA issued a tinn extension covering food grade stearic, oleic, and related straight chain acids, and also the mono- and diglyceridcs t V--.1 .i* *,* to ' ' DREW CHEMICAL CORPORATION ! from them, free of the chick -idema factor .md from edible | fats and oils. The glycerolysis limitation had been .iroppcd. The ice cream standards issuing a few months v hud this limitation, which the commissioner Inter rcr. fi. in his own initiative, after we pointed out the disc .n . V.* v This change attests to the new and more In September of 1960 another outbreak idem number of independent laboratories os "Chick El . . . prominent role of industrial chemicals . in our total production and research. I sense" occurred in some brooder houses in Geor - ' I C.E.F. positive feed concentrate was traced to th. ..r_ - tio.. of a single day. Unfortunately, neither the fnt , >.icr : nor the feed manufacturer retained fat samples, . .. <ns ! not oeen possible unequivocally to prove that corn . .. fat, which in this case was Nc. 1 tallow, was the < e . various other feed components were cheeked by fee. . - .id DREW CHEMICAL CORPORATION is EAST 2BTH STREET NEW. YORK 10. NEW YORK ' FORMERLY E. F. DREW A CO.. INC. ` ' ` : n Cmnmaa, DREW CHEMICAL LIMITED found not at fault. Our laboratory received samples of tht C.E.F. positive feed and extracted the fat. This was tested for chlorinated material by a member laboratory using a Dohrman instru ment and also using the Mills pesticide procedure. A find ing of approximately 60 p.p.m. of Chiordane was noted. That this fat contained the C.E.F. was established by feed ./ f . ing tests indieating a moderate level of toxicity. Other * ** 14 I ---------- ' Jovmvii, A.O.O.B., Dicsnra lSSl (Vol. 8) DSW 312439 STLCOPCB4072425 --j, j^loxie feeds taken from pn>dueti| [trout the aatne time \ * 1 J_timeA a few p..p..m.. oDCblordnne,. _ and Lindane and I* fnonund nonnnt(onx(tfct no>n rchhnerekkininixg the extracted fat. The 1 ;tt supplier was positive that the. particular shipment of Vo. 1 tallow contained no fatty acid residues of any kind. Approximately 12,000,000 chickens were fed this toxie 4nplemcnt utilizing 4000 gal. of No. 1 tallow. CondemnsHons ran about 20% of the flocks with 80-90% condcmna- EpX havmv ** top- ** -* the r~ Itive finding enhsteat.-...^ . -.osed ne An'jntTrerf* C * Vr An interesting dn*c,-.s-,.vn hiw -rmalljr "sen- Ir -aft in the diet. i.odjwn ..'a*- 'eveb -:r relation to chicv hy i-opene.- _ ,-iven by uc of t^is yeiie(18)Ultr> ^ ^ held - tions at times. The affected chickens showed laTge aecumu- itions of pericardial fluid with associated liver damage, separate tests absolved crotolnria seed and pathogenic or* ' nnisma as alternate, possibilities. The nature or Utto tihUireril, arid other infnrmaUno to jite makes1 it aeem probable that fata entering fatty acid pUnts at times contain the-C.E-F. in marginal quantities, kich become concentrated by various processing steps. Since the finding of a chlorinated pesticide in C.E.F. post lira fat, further work showed Chlordane to be present in . t apooinlly concentrated edema toxic fatty acid prepared /tom some toxic residue material. Recent industry evidencesubstantiates the earlier findings ( the FDA that vegetable fatty acids also contained the C.E.F. at times. This eliminates the nccr>*itj of postulating Ike animnl body as a metabolic intermediate in the produc tion of the C.fc.F. from some chlorinated precursor. ' In an article .to appear shortly in the Journal of Poultry ' Science, Dr. O'Dell, et al., of the University of Missouri, till report on an occurrence of chick edema indistinguish able from thnt of edema positive fats, which he traced to a iklorinated biphenyl compound incorporated into an epoxy paint and mixed with sand (15). He had coated the bottom of his galvanized chick batteries with this composi a"?ther collaborative survey during 1961 o> Ural tnlie the FDA -reposed a ste.t. Tbii r, Lnlf^-dCC,d,n=' V*? consituteb . live response. Tins is now being reviewed by our indue * Pr?dnccrs Council cur..... before the FDA a petition for a rcgnmtiou cove.-,;.*- acids and derivatives thereform. It is expeeted that the don will not issue until problems eoncerr.ed with the r. . ; c!earod P- Th petition include a fbTthe C.E.F tb req0,rement for running any type of tes It would seem from the evidence available tr the presence of the C.E.F. in food o^adi rV unusual. and rare occurrence and our V < be required to test for this factor as a . j. date that V-, i it -Id more than we should be required to test i .. other toxicants which might accidentally get ir.. . . te n jnntterfnr carefnl production and is alrca.. sibMity spelled out in section 402 of the act ap adn.lrri.fed foods. The problem should be looked i' a nio.ider frame of reference than only the fatty tion, and the chicks pecking on the sand picked up the toxic : * factor. The chlorinated biphenyl material responsible for. reference* this edema toxicity was found to be Aroclor 1242. Ur. O'Dell reports his belief that the active ingredient is a minor ronstituent in the Aroclor 1242. This product is substantially biphenyl, with 42 weight percent of chlorine. Among uses for this, material suggested .I by the manufacturer is one as a vapor suppressant for inecticidcs, with from 5 to 25 weight per cent of the chlorin ated biphenyl increasing the eiTect.vc kill life of Lindane by a factor of 10. I quote the following from the manu facturer's bulletin on Aroclors. "The most pronounced effect for increasing the kill-life of the insecticide is obtained with . f Lindane, Chlordane and BHC" (16). I Is this recommendation a coincidence, or is it related to I tor finding chlorinated pesticides associated with edema i toxic fat I The chlorine content is of the order of magnitude * f the purified C.E.F. P*2<*K0n' R: ^XXn^l'd, &S - Rurn,,t- K- 1VnOl-w14o8, Fpe'l'bll!m!"a! Yr 1959. ,n of the Amm a oar Afrle. Choa^ Dor*-J- B- r H., Pott* 8. sad *. Friedman. L, Pir**ton, D,, Borand Bhn*. G, Ibid. . W.. Ban**, D j-tMd. If, *' J- S- *n<* Alexander, J /tut. - OilVC.hrromt,.'srt-*,C8soeB..nSwS-, w21-4-B21- 7Pattern R L and Bipoa, E. , 7' Swannon, W. LudAm. Oil Chfmwt*' B<w . 37. 10-11 (106C S.. and Brokaw . "Sit 6'. Pederallon Proe., 19. )2.'i ,in0` Am. Oil Chemiafa' 8oe_ 37. 10-11 (I860). lb^Tr^?^l?, A. Oil Chemiata' mm.. 416-422 (18dl i soiei U9>: A- J. Am Or C nomtut*' Boc., 33. 11. Harman, R. E,, Daxl*, G. E.. OtL w R Jr. r. A., Ibid. St, 2078-9 (I960). ^ d `r * I*' Klrk'j' ?- j `f'' ~ItTr, 8el*n. <0 . *S-U- J: jA!b.A.o^-/4,AiT7-07,,(?h9T]:t*'Boe',7 ,<- a PiipaWIranon* 4.0.J' E- "4 -u~ ( Our Association is currently trying to track down these ' I leads. 0.lniTM]?Z Compoond*--Monsanto Chemical L mpanr BsDetin "l7:`5.I:o1I.o^;,^od^c,(o,r96^^>:Uc,"" '* ' V!( In addition to these problems concerned with the nature" l of the C.E.F., the industry has been confronted with the ''If onerous task if feeding chickens for three wepk intervals )' u a quality control check on /hushed food grade acids. You tan imagine the scheduling and storage problems entailed. AnfritAmi.d"' J` - 60th Annu"I Htin,,. Pooltrr Bcianeo A*. (Received November 1, 19811 We are try.ng to work out an acceptable diet and cri- lerion for deciding what constitutes a positive finding of . U.CL.A. Announces Gas Chromatography -a. I"edema*' hj collaborative work with the FDA. Originally, Aick feeding tests were run using a laboratory procedure A Gas Chromatography Course will be he provided by the FDA. It was known as the "Friedman" . versify of California, Los Angeles, January < lest- This test used visual scoring to determine an edema 2,1962. This intensive three day course is tr.- v positive chicken. A modification requiring the presence of lnrs? presented in response to requests fr,n. } a definite fluid level was an improvement. The first course was held in February 1959, the ,econd * Numerous workers were not satisfied with this test for j June 1959, and the.third in August I960. This fourth* : course has been redesigned and brought up to date with rations reasons, so a collaborative study was made using a emphasis on recent developments and applications. V having higher salt levels designed to increase the aenai( irity. The diet also was nutritionally better. It was issued The course is basic rather than advanced. It is aimed primarily to instruct personnel from industry, although ^ early in 1961 as a tentative A.O.A.C. procedure (17). This it may be equally valuable to person^ .n academic and 3 lest again called for visual scoring, but in work with our government laboratories. Enrollment will be limited, with association, the FDA picked a level of 0.2 ml of heart fluid a bachelor's degree jn science or engineering, or juivalent, 00 a single chick in 10 as a positive response. required as prerequisite. The course will consist principally '' . Using this procedure a number of laboratories began find ing what appeared to be false positives on control fate. This would be indicated by a single chick showing a level f heart fluid of over 0.2 ml while the balance of the test of lectures, augmented by .adequate laboratory demonstra tions. The fee for the course will be $100; additional infor mation and application blanks may be obtained by writin to H. L. Tollman, Room 6532, Engineering Building, Of ; veraty of California, Loa Angeles 24, Calif. I : i ' JtnurAi JL0.0.8, Dinun nil (VouSS) ' 3^2.44 1 O I. STLCOPCB4072426